Ascorbic acid and quinone compounds in combination with an antiparasitic agent for treating a parasi

专利摘要:
Provided herein is a method of treating, preventing, or alleviating one or more symptoms of Chagas disease in a subject, comprising administering to the subject: (i) ascorbic acid, or a single enantiomer, a mixture of enantiomers, or a mixture of diastereomers thereof; or a pharmaceutically acceptable salt, solvate, or hydrate thereof; (ii) a quinone compound, or a single enantiomer, a mixture of enantiomers, or a mixture of diastereomers thereof, or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; and (iii) an antiparasitic agent.
公开号:ES2811674A2
申请号:ES202090057
申请日:2019-06-05
公开日:2021-03-12
发明作者:Sueli De Oliveira Silva Lautenschlager；Vania Cristina Desoti；Celso Vataru Nakamura；Valdecir Farias Ximenes
申请人:Ic Medtech Corp；
IPC主号:

专利说明:

[0004] CROSS REFERENCE TO RELATED REQUESTS
[0006] The present application claims the priority benefit of US Provisional Patent Application No. 62 / 681,500, filed June 6, 2018, the disclosure of which is incorporated herein in its entirety by reference.
[0008] FIELD
[0010] Provided herein is a method of treating, preventing, or alleviating one or more symptoms of Chagas disease in a subject, comprising administering to the subject: (i) ascorbic acid, or a single enantiomer, a mixture of enantiomers, or a mixture of diastereomers thereof; or a pharmaceutically acceptable salt, solvate or hydrate thereof; (ii) a quinone compound, or a single enantiomer, a mixture of enantiomers, or a mixture of diastereomers thereof, or a pharmaceutically acceptable salt, solvate, hydrate or prodrug thereof; and (iii) an antiparasitic agent.
[0012] BACKGROUND
[0014] Chagas disease, also called American trypanosomiasis, is a tropical parasitic disease caused by the protozoan Trypanosoma cruzi, which affects millions of people worldwide. World Health Organizer !. Chagas disease (American trypanosomiasis), WHO, Geneva, 2015. It is spread mainly by insects known as triatomines or reduvids. Id. Chagas disease is considered a silent pathology, since the first symptoms can appear several years after infection. Maguire, N. Engl. J. Med. 2006, 355, 760-761. The symptoms of Chagas disease change over the course of infection. In the early phase, symptoms are commonly absent or mild, and may include fever, swollen lymph nodes, headaches, or local swelling at the site of the bite. After 8 to 12 weeks, individuals enter the chronic phase of the disease and in 60 to 70% it never produces additional symptoms. The other 30 to 40% of people develop additional symptoms 10 to 30 years after the initial infection, including enlargement of the ventricles of the heart in 20 to 30%, leading to heart failure. Enlargement of the esophagus or enlargement of the colon can also occur in 10% of people.
[0016] Currently, benznidazole and nifurtimox are the only drugs available for the treatment of Chagas disease, and both were developed more than four decades ago. Coura et al., Mem. Inst. Oswaldo Cruz. 2002, 97, 3-24. Benznidazole and nifurtimox are also known to have variable efficacy and high toxicity. Id. For example, benznidazole and nifurtimox cause temporary side effects in up to 40% of people, including skin disorders, brain toxicity, and digestive system irritation. Chagas disease (American trypanosomiasis) Fact Sheet # 340. Therefore, there is a need for effective therapy for the treatment of Chagas disease.
[0018] DISCLOSURE SUMMARY
[0020] Provided herein is a method of treating, preventing, or alleviating one or more symptoms of a parasitic disease in a subject, comprising administering to the subject (a) a therapeutically effective amount of: (i) ascorbic acid, or a single enantiomer , a mixture of enantiomers, or a mixture of diastereomers thereof; or a pharmaceutically acceptable salt, solvate or hydrate thereof; and (ii) a quinone compound, or a single enantiomer, a mixture of enantiomers, or a mixture of diastereomers thereof, or a pharmaceutically acceptable salt, solvate, hydrate or prodrug thereof; and (b) a subtherapeutically effective amount of an antiparasitic agent.
[0022] Also provided herein is a method of inhibiting parasite growth in a subject infected with a parasite, comprising administering to the subject (a) a therapeutically effective amount of: (i) ascorbic acid, or a single enantiomer, a mixture of enantiomers, or a mixture of diastereomers thereof; or a pharmaceutically acceptable salt, solvate or hydrate thereof; and (ii) a quinone compound, or a single enantiomer, a mixture of enantiomers, or a mixture of diastereomers thereof, or a pharmaceutically acceptable salt, solvate, hydrate or prodrug thereof; and (b) a subtherapeutically effective amount of an antiparasitic agent.
[0023] Additionally provided herein is a method of eliminating a parasite from a subject, which comprises administering to the subject: (a) a therapeutically effective amount of: (i) ascorbic acid, or a single enantiomer, a mixture of enantiomers, or a mixture of diastereomers thereof; or a pharmaceutically acceptable salt, solvate or hydrate thereof; and (ii) a quinone compound, or a single enantiomer, a mixture of enantiomers, or a mixture of diastereomers thereof, or a pharmaceutically acceptable salt, solvate, hydrate or prodrug thereof; and (b) a subtherapeutically effective amount of an antiparasitic agent.
[0025] Also provided herein is a method for enhancing the quality of life of a subject infected with a parasite, comprising administering to the subject (a) a therapeutically effective amount of: (i) ascorbic acid, or a single enantiomer, a mixture of enantiomers, or a mixture of diastereomers thereof; or a pharmaceutically acceptable salt, solvate or hydrate thereof; and (ii) a quinone compound, or a single enantiomer, a mixture of enantiomers, or a mixture of diastereomers thereof, or a pharmaceutically acceptable salt, solvate, hydrate or prodrug thereof; and (b) a subtherapeutically effective amount of an antiparasitic agent.
[0027] Provided herein is a method of increasing the efficacy of an antiparasitic agent in a subject infected with a parasite, comprising administering to the subject a therapeutically effective amount of: (i) ascorbic acid, or a single enantiomer, a mixture of enantiomers , or a mixture of diastereomers thereof; or a pharmaceutically acceptable salt, solvate or hydrate thereof; and (ii) a quinone compound, or a single enantiomer, a mixture of enantiomers, or a mixture of diastereomers thereof, or a pharmaceutically acceptable salt, solvate, hydrate or prodrug thereof.
[0029] Provided herein is a method of increasing tolerance to an antiparasitic agent in a subject infected with a parasite, comprising administering to the subject a therapeutically effective amount of: (i) vitamin C, or a pharmaceutically acceptable salt, solvate, or hydrate. Of the same; and (ii) a vitamin K compound, or a single enantiomer, a mixture of enantiomers, or a mixture of diastereomers thereof, or a pharmaceutically acceptable salt, solvate, hydrate or prodrug thereof.
[0031] Provided herein is a method of reducing a side effect of an antiparasitic agent in a subject infected with a parasite, comprising administering to the subject a therapeutically effective amount of: (i) ascorbic acid, or a single enantiomer, a mixture of enantiomers, or a mixture of diastereomers thereof; or a pharmaceutically acceptable salt, solvate or hydrate thereof; and (ii) a quinone compound, or a single enantiomer, a mixture of enantiomers, or a mixture of diastereomers thereof, or a pharmaceutically acceptable salt, solvate, hydrate or prodrug thereof.
[0033] Provided herein is a method of reducing the toxicity of an antiparasitic agent in a subject infected with a parasite, comprising administering to the subject a therapeutically effective amount of: (i) ascorbic acid, or a single enantiomer, a mixture of enantiomers , or a mixture of diastereomers thereof; or a pharmaceutically acceptable salt, solvate or hydrate thereof; and (ii) a quinone compound, or a single enantiomer, a mixture of enantiomers, or a mixture of diastereomers thereof, or a pharmaceutically acceptable salt, solvate, hydrate or prodrug thereof.
[0035] Provided herein is a method of inhibiting parasite growth, which comprises contacting a parasite with: (a) a therapeutically effective amount of: (i) ascorbic acid, or a single enantiomer, a mixture of enantiomers, or a mixture of diastereomers thereof; or a pharmaceutically acceptable salt, solvate or hydrate thereof; and (ii) a quinone compound, or a single enantiomer, a mixture of enantiomers, or a mixture of diastereomers thereof, or a pharmaceutically acceptable salt, solvate, hydrate or prodrug thereof; and (b) a subtherapeutically effective amount of an antiparasitic agent.
[0037] Provided herein is a method of killing a parasite, which comprises contacting the parasite with: (a) a therapeutically effective amount of: (i) ascorbic acid, or a single enantiomer, a mixture of enantiomers, or a mixture of diastereomers thereof; or a pharmaceutically acceptable salt, solvate or hydrate thereof; and (ii) a quinone compound, or a single enantiomer, a mixture of enantiomers, or a mixture of diastereomers thereof, or a pharmaceutically acceptable salt, solvate, hydrate or prodrug thereof; and (b) a subtherapeutically effective amount of an antiparasitic agent.
[0039] Provided herein is a method of increasing the cytotoxicity of an antiparasitic agent to a parasite, comprising contacting the parasite with: a therapeutically effective amount of: (i) ascorbic acid, or a single enantiomer, a mixture of enantiomers, or a mixture of diastereomers thereof; or a pharmaceutically acceptable salt, solvate or hydrate thereof; and (ii) a quinone compound, or a single enantiomer, a mixture of enantiomers, or a mixture of diastereomers thereof, or a pharmaceutically acceptable salt, solvate, hydrate or prodrug thereof.
[0041] BRIEF DESCRIPTION OF THE FIGURES
[0043] FIG. 1 shows the effects of vitamin C, vitamin K3, APATONE® and benznidazole on parasitaemia in a murine model of Chagas disease, where the symbol * indicates a significant difference compared to the control group (p <0, 05).
[0045] FIG. 2 shows the effects of vitamin C, vitamin K3, APATONE® and benznidazole on the survival rates of mice with acute Chagas disease infection in a murine model.
[0047] FIG. 3 shows the effects of vitamin C, vitamin K3, APATONE® and benznidazole on cytokine levels in the heart in a murine model of Chagas disease, where the symbol * indicates a significant difference compared to the control group (p <0.05).
[0049] FIG. 4 shows the effects of vitamin C, vitamin K3, APATONE® and benznidazole on blood cytokine levels in a murine model of Chagas disease, where the symbol * indicates a significant difference compared to the control group ( p <0.05).
[0051] FIG. 5 shows the effects of vitamin C, vitamin K3, APATONE® and benznidazole on the parasite load in cardiac tissues in a murine model of Chagas disease, where the symbol * indicates a significant difference compared to the control group ( p <0.05).
[0053] FIG. 6 shows the effects of vitamin C, vitamin K ³ , APATONE® and benznidazole on the parasite load in blood in a murine model of Chagas disease, where the symbol * indicates a significant difference compared to the group of control (p <0.05).
[0055] DETAILED DESCRIPTION
[0057] To facilitate understanding of the disclosure set forth herein, a number of terms and expressions are defined below.
[0059] In general, the nomenclature used herein and the organic chemistry, medicinal chemistry, biochemistry, biology, pharmacology, and other laboratory procedures described herein are those well known and commonly employed in the art. Unless defined otherwise, all technical and scientific terms used herein generally have the same meaning commonly understood by one of ordinary skill in the art to which this disclosure belongs.
[0061] The term "subject" refers to an animal, including, but not limited to, a primate (eg, a human), cattle, a domestic pet, cow, pig, sheep, goat, horse, dog, cat, rabbit. , rat or mouse. The terms "subject" and "patient" are used interchangeably herein to refer to, for example, a mammalian subject, such as a human subject, in one embodiment, a human.
[0063] The terms "treat", "treating" and "treatment" are intended to include alleviating or stopping a disorder, disease or condition, or one or more of the symptoms associated with the disorder, disease or condition; or alleviate or eradicate the cause or causes of the disorder, disease or condition itself.
[0065] The terms "preventing", "preventing" and "prevention" are intended to include a method of delaying and / or preventing the onset of a disorder, disease or condition, and / or one or more of its concomitant symptoms; preventing a subject from acquiring a disorder, disease or condition; or reduce a subject's risk of acquiring a disorder, disease, or condition.
[0067] The terms "alleviating" and "alleviating" refer to facilitating or reducing one or more symptoms (eg, pain) of a disorder, disease, or condition. The terms can also refer to reducing the adverse effects associated with an active ingredient. Sometimes the beneficial effects that a subject obtains from a prophylactic or therapeutic agent do not cure the disorder, disease or condition.
[0068] The term "contacting" or "contacting" refers to bringing a therapeutic agent and a cell or tissue together in such a way as to produce a physiological and / or chemical effect as a result of such contact. Contact can take place in vitro, ex vivo or in vivo. In one embodiment, a therapeutic agent is contacted with a cell in cell culture (in vitro) to determine the effect of the therapeutic agent on the cell. In another embodiment, contacting a therapeutic agent with a cell or tissue includes administering a therapeutic agent to a subject who has the cell or tissue with which it will come into contact.
[0070] The terms "therapeutically effective amount" and "effective amount" are intended to include the amount of a compound or combination of compounds that, when administered, is sufficient to prevent the development of, or alleviate to some extent, one or more of the symptoms. of the disorder, disease or condition being treated. The term "therapeutically effective amount" or "effective amount" also refers to the amount of a compound or a combination of compounds that is sufficient to elicit the biological or medical response of a biological molecule (eg, a protein, enzyme, RNA or DNA), cell, tissue, system, animal or human being, which is sought by a researcher, veterinarian, medical doctor or medical professional.
[0072] The terms "subtherapeutic amount" and "subtherapeutically effective amount" of a therapeutic agent are used interchangeably herein and refer to a dose less than the amount that is effective when the therapeutic agent is administered alone.
[0074] The terms "pharmaceutically acceptable carrier", "pharmaceutically acceptable carrier", "physiologically acceptable carrier" or "physiologically acceptable carrier" refer to a pharmaceutically acceptable material, composition or carrier, such as a liquid filler, diluent, solvent or encapsulating material or solid. In one embodiment, each component is "pharmaceutically acceptable" in the sense that it is compatible with the other ingredients of a pharmaceutical formulation, and suitable for use in contact with the tissue or organ of humans and animals without toxicity, irrigation, allergic response, excessive immunogenicity, or other problems or complications, consistent with a reasonable benefit / risk ratio. See Remington: The Science and Practice of Pharmacy, 22nd ed .; Allenet al., Eds .; The Pharmaceutical Press, 2012; Handbook of Pharmaceutical Excipients, 7th ed .; Rowe et al., Eds .; The Pharmaceutical Press, 2012; Handbook of Pharmaceutical Additives, 3rd ed .; Ash and Ash Eds .; Synapse Information Resources, Inc., 2007; Pharmaceutical Preformulation and Formulation, 2nd ed .; Gibson Ed .; CRC Press LLC, 2009.
[0076] The terms and expressions "approximately" or "approximately" mean an acceptable error for a particular value determined by one of ordinary skill in the art, which depends in part on how the value is measured or determined. In certain embodiments, the terms and expressions "approximately" or "approximately" mean within 1, 2, 3, or 4 standard deviations. In certain embodiments, the terms and expressions "approximately" or "approximately" mean within 50%, 20%, 15%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, 0.5%, or 0.05% of a given value or range.
[0078] The terms "active ingredient" and "active substance" refer to a compound that is administered, alone or in combination with one or more pharmaceutically acceptable excipients, to a subject to treat, prevent or ameliorate one or more symptoms of a disorder, disease or condition. As used herein, "active ingredient" and "active ingredient" can be an optically active isomer of a compound described herein.
[0080] The term "quality of life" or "QOL" refers to the maintenance or enhancement of the general physical and mental state of a subject, for example, a subject infected with a parasite, such as the subject's cognitive ability, ability to communicate and interacting with others, decreased dependence on analgesics for pain control, maintenance of walking ability, maintenance of appetite and body weight (lack of cachexia), lack or decreased feeling of "hopelessness"; continued interest in playing a role in treatment and other similar mental and physical states.
[0082] The term "alkyl" refers to a linear or branched saturated monovalent hydrocarbon radical, wherein the alkyl may be optionally substituted with one or more Q substituents as described herein. For example, C1-6 alkyl refers to a linear saturated monovalent hydrocarbon radical of 1 to 6 carbon atoms or a branched saturated monovalent hydrocarbon radical of 3 to 6 carbon atoms. In certain embodiments, the alkyl is a linear saturated monovalent hydrocarbon radical having 1 to 20 (C1-20), 1 to 15 (C1-15), 1 to 10 (C1-10) or 1 to 6 (C1-6) carbon atoms, or branched saturated monovalent hydrocarbon radical from 3 to 20 (C3-20), 3 to 15 (C3-15), 3 to 10 (C3-10 ) or 3 to 6 (C3-6) carbon atoms. As used herein, C1-6 linear and C3-6 branched alkyl groups are also referred to as "lower alkyl." Some examples of alkyl groups include, but are not limited to, methyl, ethyl, propyl (including all isomeric forms, eg, n-propyl and isopropyl), butyl (including all isomeric forms, eg, n-butyl, isobutyl, sec-butyl and f-butyl), pentyl (including all isomeric forms) and hexyl (including all isomeric forms).
[0084] The term "alkenyl" refers to a linear or branched monovalent hydrocarbon radical, containing one or more, in one embodiment, one to five, in another embodiment, one, carbon-carbon double bond or double bonds. The alkenyl can be optionally substituted with one or more Q substituents as described herein. The term "alkenyl" encompasses radicals with a "c / s" or "trans" configuration or a mixture thereof, or alternatively, a "Z" or "E" configuration or a mixture thereof, as recognized by those skilled in the art. in technique. For example, "C 2-6 alkenyl" refers to a linear unsaturated monovalent hydrocarbon radical of 2 to 6 carbon atoms or a branched monovalent unsaturated hydrocarbon radical of 3 to 6 carbon atoms. In certain embodiments, the alkenyl is a linear monovalent hydrocarbon radical of 2 to 20 (C2-20), 2 to 15 (C2-15), 2 to 10 (C2-10), or 2 to 6 (C2-6) atoms of carbon, or a branched monovalent hydrocarbon radical of 3 to 20 (C3-20), 3 to 15 (C3-15), 3 to 10 (C3-10) or 3 to 6 (C3-6) carbon atoms. Some examples of alkenyl groups include, but are not limited to, ethenyl, propen-1-yl, propen-2-yl, allyl, butenyl, and 4-methylbutenyl.
[0086] The term "alkynyl" refers to a linear or branched monovalent hydrocarbon radical, containing one or more, in one embodiment, one to five, in another embodiment, one, triple bond or triple carbon-carbon bonds. The alkynyl can be optionally substituted with one or more Q substituents as described herein. For example, "C 2-6 alkynyl" refers to a linear unsaturated monovalent hydrocarbon radical of 2 to 6 carbon atoms or a branched monovalent unsaturated hydrocarbon radical of 4 to 6 carbon atoms. In certain embodiments, the alkynyl is a linear monovalent hydrocarbon radical of 2 to 20 (C2-20), 2 to 15 (C2-15), 2 to 10 (C2-10), or 2 to 6 (C2-6) atoms. carbon, or branched monovalent hydrocarbon radical of 4 to 20 (C4-20), 4 to 15 (C4-15), 4 to 10 (C4-10) or 4 to 6 (C4-6) carbon atoms. Examples of alkynyl groups include, but are not limited to, ethynyl (-C = CH), propynyl (including all isomeric forms, eg 1-propynyl (-C 2 CCH 3) and propargyl (-CH2CHCH)), butynyl (including all isomeric forms, eg 1-butyn-1 -yl and 2-butyn-1 -yl), pentynyl (including all isomeric forms, eg, 1-pentyne-1-yl and 1-methyl-2-butyn-1 -yl), and hexynyl (including all isomeric forms, eg, 1-hexin -1-yl).
[0088] The term "cycloalkyl" refers to an unsaturated or non-aromatic saturated cyclic monovalent bridged or unbridged hydrocarbon radical, which is optionally substituted with one or more Q substituents as described herein. In certain embodiments, the cycloalkyl is a saturated cyclic saturated monovalent hydrocarbon radical. In certain embodiments, the cycloalkyl has 3 to 20 (C3-20), 3 to 15 (C3-15), 3 to 10 (C3-10), or 3 to 7 (C3-7) carbon atoms. Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, bicyclo [2.1.1] hexyl, bicyclo [2.2.1 jheptyl, decalinyl, and adamantyl.
[0090] The term "aryl" refers to a monocyclic aromatic group and / or multicyclic monovalent hydrocarbon aromatic group containing at least one aromatic hydrocarbon ring. In certain embodiments, the aryl has 6 to 20 (C6-20), 6 to 15 (C6-15), 6 to 10 (C6-10) ring atoms. Examples of aryl groups include, but are not limited to, phenyl, naphthyl, fluorenyl, azulenyl, anthryl, phenanthryl, pyrenyl, biphenyl, and terphenyl. In certain embodiments, the term "aryl" refers to a bicyclic or tricyclic carbon ring of the rings that is aromatic and the others can be saturated, partially unsaturated, or aromatic, eg, dihydronaphthyl, indenyl, indanyl, or tetrahydronaphthyl (tetralinyl). In certain embodiments, aryl is optionally substituted with one or more Q substituents, as described herein.
[0092] The term "aralkyl" or "arylalkyl" refers to a monovalent alkyl group substituted with one or more aryl groups. In certain embodiments, the aralkyl has 7 to 30 (C7-30), 7 to 20 (C7-20), or 7 to 16 (C7-16) carbon atoms. Examples of aralkyl groups include, but are not limited to, benzyl, 1-phenylethyl, 2-phenylethyl, and 3-phenylpropyl. In certain embodiments, the aralkyl is optionally substituted with one or more Q substituents as described herein.
[0094] The term "heteroaryl" refers to a monovalent monocyclic aromatic group or monovalent polycyclic aromatic group containing at least one aromatic ring, wherein at The least one aromatic ring contains one or more heteroatoms, each of which is independently selected from O, S, N, and P on the ring. A heteroaryl group is attached to the rest of a molecule through its aromatic ring. Each ring of a heteroaryl group can contain one or two O atoms, one or two S atoms, one or two N atoms and / or one or two P atoms, provided that the total number of heteroatoms in each ring is four. or less and each ring contains at least one carbon atom. In certain embodiments, the heteroaryl has 5 to 20, 5 to 15, or 5 to 10 ring atoms. Examples of monocyclic heteroaryl groups include, but are not limited to, furanyl, imidazolyl, isothiazolyl, isoxazolyl, oxadiazolyl, oxazolyl, pyrazinyl, pyrazolyl, pyridazinyl, pyridyl, pyrimidinyl, pyrrolyl, thiadiazolyl, thiazolyl, thieniazolyl, and triazolyl, triazolyl, and triazolyl. Examples of bicyclic heteroaryl groups include, but are not limited to, benzofuranyl, benzimidazolyl, benzoisoxazolyl, benzopyranyl, benzothiadiazolyl, benzothiazolyl, benzothienyl, benzotriazolyl, benzoxazolyl, furopyridyl, imidazopyridinyl, imurazinyl, indozolylobiazolyl, inuranyl-dynobotiazolyl, isurazolynobotiazolyl isoquinolinyl, isothiazolyl, naphthyridinyl, oxazolopyridinyl, phthalazinyl, pteridinyl, purinyl, pyridopyridyl, pyrrolopyridyl, quinolinyl, quinoxalinyl, quinazolinyl, thiadiazolopyrimidyl, and thienopyridyl. Examples of tricyclic heteroaryl groups include, but are not limited to, acridinyl, benzindolyl, carbazolyl, dibenzofuranyl, pyrimidinyl, phenanthrolinyl, phenanthridinyl, fenarsazinyl, phenazinyl, phenothiazinyl, phenoxazinyl, and xanthenyl. In certain embodiments, heteroaryl is optionally substituted with one or more Q substituents as described herein.
[0096] The term "heterocyclyl" or "heterocyclic" refers to a monovalent monocyclic non-aromatic ring system or a monovalent polycyclic ring system containing at least one non-aromatic ring, wherein one or more of the non-aromatic ring atoms are hetero atoms. , each of which is independently selected from O, S, N, and P; and the rest of the ring atoms are carbon atoms. In certain embodiments, the heterocyclyl or heterocyclic group has 3 to 20, 3 to 15, 3 to 10, 3 to 8, 4 to 7, or 5 to 6 ring atoms. A heterocyclyl group is attached to the rest of a molecule through its non-aromatic ring. In certain embodiments, the heterocyclyl is a monocyclic, bicyclic, tricyclic, or tetracyclic ring system, which may be spiro, condensed, or bridged, and in which the nitrogen or sulfur atoms may optionally be oxidized, the nitrogen atoms partially or fully present. optionally quaternized and some rings can be partially or fully saturated or aromatic. The heterocyclyl can be attached to the backbone at any heteroatom or carbon atom, resulting in the creation of a stable compound. Examples of heterocyclic groups include, but are not limited to, azepinyl, benzodioxanyl, benzodioxolyl, benzofuranonyl, benzopyranonyl, benzopyranyl, benzotetrahydrofuranyl, benzotetrahydrothienyl, benzothiopyranyl, benzoxazinyl, pcarbolinyl, chromannyl, chromininisohydrolinyl, di-pynyl-isohydroinyl, benzynyl-isohydroinhydrolinyl, benzoinisohydrolinyl, benzoinisohydroline, , dihydroisoindolyl, dihydropyranyl, dihydropyrazolyl, dihydropyrazinyl, dihydropyridinyl, dihydropyrimidinyl, dihydropyrrolyl, dioxolanyl, 1,4-dithianyl, furanonyl, imidazolidinyl, imidazolinyl, indolinyl, isobenzotetrahydrofuranyl, isobenzotetrahydrothienyl, isochromanyl, isocoumarinyl, isoindolinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl, octahydroindolyl, octahydroisoindolyl , oxazolidinonyl, oxazolidinyl, oxiranyl, piperazinyl, piperidinyl, 4-piperidonyl, pyrazolidinyl, pyrazolinyl, pyrrolidinyl, pyrrolinyl, quinuclidinyl, tetrahydrofuryl, tetrahydroisoquinoli nyl, tetrahydropyranyl, tetrahydrothienyl, thiamorpholinyl, thiazolidinyl, tetrahydroquinolinyl, and 1,3,5-trithianyl. In certain embodiments, the heterocyclyl is optionally substituted with one or more Q substituents as described herein.
[0098] The term "halogen", "halide" or "halo" refers to fluorine, chlorine, bromine and / or iodine.
[0100] The term "optionally substituted" is intended to mean that a group or substituent, such as an alkyl, alkenyl, alkynyl, cycloalkyl, aryl, aralkyl, heteroaryl, or heterocyclyl group, can be substituted with one or more substituents Q, each of which is independently selected from, for example, (a) C1-6 alkyl, C2-6 alkenyl, C2-61 alkynyl, C3-7 cycloalkyl, C6-14 aryl, C7-15 aralkyl, heteroaryl, and heterocyclyl, each of which is substituted further optionally with one or more, in one embodiment, one, two, three or four Qa substituents; and (b) oxo (= 0), halo, cyano (-CN), nitro (-NO2), -C (O) Ra, -C (0) 0R a, -C (O) NRbRc,
[0101] -C (NRa) NRbRc, -ORa, -0C (O) R a, -0C (0) 0R a, -0C (O) NRbRc, -OC (= NRa) NRbRc, -0S (O) R a, - 0 S (0) 2Ra, -0S (O) NRbRc, -0 S (0) 2NRbRc, -NRbRc, -NRaC (O) Rd, -NRaC (O) 0Rd, -NRaC (O) NRbRc, -NRaC (= NRd) NRbRc, -NRaS (O) Rd, -NRaS (O) 2Rd, -NRaS (O) NRbRc, -NRaS (O) 2NRbRc, -SRa, -S (O) Ra, -S (0) 2Ra, - S (O) NRbRc and -S (O) 2NRbRc, wherein each Ra, Rb, Rc and Rd is independently (i) hydrogen; (ii) C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-7 cycloalkyl, C or 4 aryl, C7-15 aralkyl, heteroaryl or heterocyclyl, each optionally substituted with one or more, in one embodiment, one, two, three or four Qa substituents; or (iii) Rb and Rc together with the N atom to which they are attached form heteroaryl or heterocyclyl, optionally substituted with one or plus, in one embodiment, one, two, three, or four Qa substituents. As used herein, all substitutable groups are "optionally substituted", unless otherwise specified.
[0103] In one embodiment, each Qa is independently selected from the group consisting of (a) oxo, cano, halo, and nitro; and (b) Ci_6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-7 cycloalkyl, C6-14 aryl, C7-15 aralkyl, heteroaryl and heterocyclyl; and (c) -C (O) Re, -C (O) 0R e, -C (O) NRfRg, -C (NRe) NRfR9, -0 R e, -0C (O) R e, -0C (0 ) 0R e, -0C (O) NRfR9, -OC (= NRe) NRfR9, -0S (O) R e, -0 S (0) 2Re, -0S (O) NRfR9, -0 S (0) 2NRfR9, -NRfR9, -NReC (O) Rh, -NReC (O) 0Rh, -NReC (O) NRfR9, -NReC (= NRh) NRfR9, -NReS (O) Rh, -NReS (O) 2Rh, -NReS (O ) NRfR9, -NReS (O) 2NRfR9, -SRe, -S (O) Re, -S (0) 2Re, -S (O) NRfR9, and -S (O) 2NRfR9; wherein each Re, Rf, R9 and Rh is independently (i) hydrogen; (ii) C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-7 cycloalkyl, C6-14 aryl, C7-15 aralkyl, heteroaryl or heterocyclyl; or (iii) Rf and R9 together with the N atom to which they are attached form heteroaryl or heterocyclyl.
[0105] In certain embodiments, "optically active" and "enantiomerically active" refer to a set of molecules, which have an enantiomeric excess of not less than about 50%, not less than about 70%, not less than about 80%. , not less than about 90%, not less than about 91%, not less than about 92%, not less than about 93%, not less than about 94%, not less than about 95%, no less than about 96%, not less than about 97%, not less than about 98%, not less than about 99%, not less than about 99.5%, or not less than about 99.8% . In certain embodiments, the compound comprises about 95% or more of one enantiomer and about 5% or less of the other enantiomer based on the total weight of the racemate in question.
[0107] When describing an optically active compound, the prefixes R and S are used to indicate the absolute configuration of the molecule on its chiral center or centers. The (+) and (-) are used to indicate the optical rotation of the compound, that is, the direction in which a plane of polarized light rotates through the optically active compound. The prefix (-) indicates that the compound is left-handed, that is, the compound rotates the plane of polarized light to the left or counter-clockwise. The prefix (+) indicates that the compound is dextrorotatory, that is, the compound rotates the plane of polarized light to right or clockwise. However, the sign of optical rotation, (+) and (-), is not related to the absolute configuration of the molecule, R and S.
[0109] The term "solvate" refers to a complex or aggregate made up of one or more molecules of a solute, for example, a compound provided herein, and one or more molecules of a solvent, whether or not they are present in stoichiometric amount. stoichiometric. Suitable solvents include, but are not limited to, water, methanol, ethanol, n-propanol, isopropanol, and acetic acid. In certain embodiments, the solvent is pharmaceutically acceptable. In one embodiment, the complex or aggregate is in crystalline form. In another embodiment, the complex or aggregate is in non-crystalline form. When the solvent is water, the solvate is a hydrate. Examples of hydrates include, but are not limited to, a hemihydrate, monohydrate, dihydrate, trihydrate, tetrahydrate, and pentahydrate.
[0111] The term "chromium-free" refers to a chemical (eg, a compound or composition) that contains no more than 100 ppm, 50 ppm, 20 ppm, 10 ppm, 5 ppm, 2 ppm, 1 ppm, 0.1 ppm, 10 ppb or 1 ppb of chromium. In one embodiment, the term "chromium-free" refers to a chemical that contains no more than 10 ppm of chromium. In another embodiment, the term "chromium-free" refers to a chemical that contains no more than 5 ppm of chromium. In yet another embodiment, the term "chromium-free" refers to a chemical that contains no more than 2 ppm of chromium. In yet another embodiment, the term "chromium-free" refers to a chemical that contains no more than 1 ppm of chromium. Chromium content can be determined using a conventional technique known to one skilled in the art, for example, inductively coupled plasma (ICP) technique.
[0113] Ascorbic acid compounds
[0115] In one embodiment, the ascorbic acid compound is L-ascorbic acid or a pharmaceutically acceptable salt thereof; or a pharmaceutically acceptable solvate or hydrate thereof. L-ascorbic acid is also known as vitamin C, L-xyloascorbic acid, 3-oxo-L-gulofuranlactone (enol form), L-3-ketotreohexuronic acid lactone, antiscorbutic vitamin, cevitamic acid, adenex, allercorb, ascorin, ascorteal , ascorvit, sing, cantaxin, catavin C, cebicure, cebion, cecon, cegiolan, celaskon, celin, cenetone, cereon, cergona, cescorbat, cetamid, cetabe, cetemican, cevalin, cevatine, cevex, cevimin, ce-vi-sol, cevitan, cevitex, cewin, ciamin, cipca, concemin, C-vin, daviamon C, duoscorb, hybrin, laroscorbin, lemascorb, planavit C, proscorbin, redoxon, ribena, scorbacid, scorbu-C, testascorbic, vicelat, vitacee, vitacimin, vitacin, vitascorbol, and xitix.
[0117] In one embodiment, the ascorbic acid compound is L-ascorbic acid. In another embodiment, the ascorbic acid compound is a pharmaceutically acceptable salt of L-ascorbic acid; or a pharmaceutically acceptable solvate or hydrate thereof.
[0119] Suitable bases for forming a pharmaceutically acceptable salt of L-ascorbic acid include, but are not limited to, inorganic bases, such as magnesium hydroxide, calcium hydroxide, potassium hydroxide, zinc hydroxide, and sodium hydroxide; and organic bases, such as primary, secondary, tertiary, and quaternary aliphatic and aromatic amines, including, but not limited to, L-arginine, benetamine, benzathine, choline, deanol, diethanolamine, diethylamine, dimethylamine, dipropylamine, diisopropylamine, 2 - (diethylamino) -ethanol, ethanolamine, ethylamine, ethylenediamine, isopropylamine, A / -methyl-glucamine, hydrabamine, 1H-imidazole, L-lysine, morpholine, 4- (2-hydroxyethyl) -morpholine, methylamine, piperidine, piperazine, propylamine, pyrrolidine, 1- (2-hydroxyethyl) -pyrrolidine, pyridine, quinuclidine, quinoline, isoquinoline, triethanolamine, trimethylamine, triethylamine, A / -methyl-D-glucamine, 2-amino-2- (hydroxymethyl) -1,3-propanediol and tromethamine.
[0121] In one embodiment, the ascorbic acid compound is an alkali or alkaline earth metal salt of L-ascorbic acid; or a pharmaceutically acceptable solvate or hydrate thereof. In another embodiment, the ascorbic acid compound is sodium, potassium, calcium, or magnesium L-ascorbate, or a pharmaceutically acceptable solvate or hydrate thereof. In yet another embodiment, the ascorbic acid compound is sodium L-ascorbate, or a pharmaceutically acceptable solvate or hydrate thereof. In yet another embodiment, the ascorbic acid compound is sodium L-ascorbate, which is also known as vitamin C sodium, ascorbine, sodascorbate, natrascorb, cenolate, ascorbicin, or cebitate. In still another embodiment, the ascorbic acid compound is potassium L-ascorbate, or a pharmaceutically acceptable solvate or hydrate thereof. In still another embodiment, the ascorbic acid compound is calcium L-ascorbate, or a pharmaceutically acceptable solvate or hydrate thereof. In yet another embodiment, the ascorbic acid compound is calcium L-ascorbate. In still another embodiment, the ascorbic acid compound is magnesium L-ascorbate, or a pharmaceutically acceptable solvate or hydrate thereof. In still another embodiment, the acid compound ascorbic is magnesium L-ascorbate.
[0123] In certain embodiments, the ascorbic acid compound is D-ascorbic acid or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate or hydrate thereof.
[0125] In one embodiment, the ascorbic acid compound is D-ascorbic acid. In another embodiment, the ascorbic acid compound is a pharmaceutically acceptable salt of D-ascorbic acid; or a pharmaceutically acceptable solvate or hydrate thereof.
[0127] Suitable bases for forming a pharmaceutically acceptable salt of D-ascorbic acid include, but are not limited to, inorganic bases, such as magnesium hydroxide, calcium hydroxide, potassium hydroxide, zinc hydroxide, and sodium hydroxide; and organic bases, such as primary, secondary, tertiary, and quaternary aliphatic and aromatic amines, including, but not limited to, L-arginine, benetamine, benzathine, choline, deanol, diethanolamine, diethylamine, dimethylamine, dipropylamine, diisopropylamine, 2 - (diethylamino) -ethanol, ethanolamine, ethylamine, ethylenediamine, isopropylamine, / V-methyl-glucamine, hydrabamine, 1 / - / - imidazole, L-lysine, morpholine, 4- (2-hydroxyethyl) -morpholine, methylamine, piperidine , piperazine, propylamine, pyrrolidine, 1- (2-hydroxyethyl) -pyrrolidine, pyridine, quinuclidine, quinoline, isoquinoline, triethanolamine, trimethylamine, triethylamine, / V-methyl-D-glucamine, 2-amino-2- (hydroxymethyl) - 1,3-propanediol and tromethamine.
[0129] In one embodiment, the ascorbic acid compound is an alkali or alkaline earth metal salt of D-ascorbic acid; or a pharmaceutically acceptable solvate or hydrate thereof. In another embodiment, the ascorbic acid compound is potassium, calcium or magnesium D-ascorbate, or a pharmaceutically acceptable solvate or hydrate thereof. In yet another embodiment, the ascorbic acid compound is sodium D-ascorbate, or a pharmaceutically acceptable solvate or hydrate thereof. In still another embodiment, the ascorbic acid compound is sodium D-ascorbate, which is also known as vitamin C sodium, ascorbine, sodascorbate, natrascorb, cenolate, ascorbicin, or cebitate. In yet another embodiment, the ascorbic acid compound is potassium D-ascorbate, or a pharmaceutically acceptable solvate or hydrate thereof. In yet another embodiment, the ascorbic acid compound is calcium D-ascorbate, or a pharmaceutically acceptable solvate or hydrate thereof. In yet another embodiment, the ascorbic acid compound is calcium D-ascorbate. In still another embodiment, the Ascorbic acid compound is magnesium D-ascorbate, or a pharmaceutically acceptable solvate or hydrate thereof. In yet another embodiment, the ascorbic acid compound is magnesium D-ascorbate.
[0131] In certain embodiments, the ascorbic acid compound is free of chromium. In certain embodiments, the chromium-free ascorbic acid compound contains no more than 100 ppm, 50 ppm, 20 ppm, 10 ppm, 5 ppm, 2 ppm, 1 ppm, 0.1 ppm, 10 ppb, or 1 ppb of chromium. In certain embodiments, the chromium-free ascorbic acid compound contains no more than 10 ppm chromium. In certain embodiments, the chromium-free ascorbic acid compound contains no more than 5 ppm chromium. In certain embodiments, the chromium-free ascorbic acid compound contains no more than 2 ppm chromium. In certain embodiments, the chromium-free ascorbic acid compound contains no more than 1 ppm of chromium.
[0133] Quinone compounds
[0135] In one embodiment, the quinone compound is vitamin K. In certain embodiments, the vitamin K is a 2-methyl-1,4-naphthoquinone of Formula I, II, or III:
[0140] or an enantiomer, a mixture of enantiomers, or a mixture of two or more diastereomers thereof; or a pharmaceutically acceptable salt, solvate or hydrate thereof; where R1 is C1-20 alkyl, C2-20 alkenyl, C2-20 alkynyl or -SO3H; and R2 is hydroxyl or amino.
[0142] In certain embodiments, the vitamin K is vitamin K1, vitamin K2, vitamin K3, vitamin K4, vitamin K5, or a mixture of two or more thereof.
[0144] In one embodiment, the vitamin K is vitamin K1, or a pharmaceutically acceptable salt, solvate, or hydrate thereof. Vitamin K1 is also known as phylloquinone, [R- [R *, R * - (E)]] - 2-methyl-3- (3,7,11,15-tetramethyl-2-hexadecenyl) -1,4-naphthalenedione, 2-methyl-3-f¡ til-1,4-naphthoquinone, 3-phytylmenadione, phytomenadione, phytonadione, aqua-merfiton, konakion, mefiton, mono-day, veda-Ki and veta-Ki.
[0146] In another embodiment, the vitamin K is vitamin K2, or a pharmaceutically acceptable salt, solvate, or hydrate thereof. Vitamin K2 is also known as menaquinones and 2-methyl-3-fodo frans-polyprenil-1,4-naphthoquinones. Some non-exhaustive examples of vitamin K2 include menaquinone 4, which is also known as vitamin «2 (20)! menaquinone 6, which is also known as vitamin K200); and menaquinone 7, which is also known as vitamin K205).
[0148] In yet another embodiment, the vitamin K is vitamin K3, or a pharmaceutically acceptable salt, solvate, or hydrate thereof. Vitamin K3 is also known as menadione, 2-methyl-1,4-naphthalenedione, 2-methyl-1,4-naphthoquinone, menaphthone, vitamin K2 (or>, kanone, kappaxin, kayklot, kayquinone, klottone, kolklot, tyloquinone Sodium, 1,2,3,4-tetrahydro-2-methyl-1,4-dioxo-2-naphthalenesulfonic acid and 1,2,3,4-tetrahydro-2-methyl-1,4-dioxo-2-naphthalenesulfonate In certain embodiments, the vitamin K is menadione (ie, 2-methyl-1,4-naphthalenedione).
[0150] In one embodiment, the vitamin K is 1,2,3,4-tetrahydro-2-methyl-1,4-dioxo-2-naphthalenesulfonic acid, or a pharmaceutically acceptable salt, solvate, or hydrate thereof. In another embodiment, the vitamin K is 1,2,3,4-tetrahydro-2-methyl-1,4-dioxo-2-naphthalenesulfonate (also known as menadione bisulfite), or a pharmaceutically acceptable solvate or hydrate thereof. Suitable bases for forming a pharmaceutically acceptable salt include, but are not limited to, inorganic bases, such as magnesium hydroxide, calcium hydroxide, potassium hydroxide, zinc hydroxide, and sodium hydroxide; and organic bases, such as primary, secondary, tertiary, and quaternary aliphatic and aromatic amines, including, but not limited to, L-arginine, benetamine, benzathine, choline, deanol, diethanolamine, diethylamine, dimethylamine, dipropylamine, diisopropylamine, 2 - (diethylamino) -ethanol, ethanolamine, ethylamine, ethylenediamine, isopropylamine, / V-methyl-glucamine, hydrabamine, 1 / - / - imidazole, L-lysine, morpholine, 4- (2-hydroxyethyl) -morpholine, methylamine, piperidine , piperazine, propylamine, pyrrolidine, 1- (2-hydroxyethyl) -pyrrolidine, pyridine, quinuclidine, quinoline, isoquinoline, triethanolamine, trimethylamine, triethylamine, A / -methyl-D-glucamine, 2-amino-2- (hydroxymethyl ) -1,3-propanediol and tromethamine.
[0152] In one embodiment, vitamin K3 is an alkali or alkaline earth metal salt of the acid 1,2,3,4-tetrahydro-2-methyl-1,4-dioxo-2-naphthalenesulfonic acid, or a pharmaceutically acceptable solvate or hydrate thereof. In another embodiment, vitamin K3 is sodium, potassium, calcium, or magnesium 1,2,3,4-tetrahydro-2-methyl-1,4-dioxo-2-naphthalene sulfonate, or a pharmaceutically acceptable solvate or hydrate thereof. In still another embodiment, the vitamin K3 is sodium 1,2,3,4-tetrahydro-2-methyl-1,4-dioxo-2-naphthalenesulfonate, or a pharmaceutically acceptable solvate or hydrate thereof. In yet another embodiment, the vitamin K3 is potassium 1,2,3,4-tetrahydro-2-methyl-1,4-dioxo-2-naphthalenesulfonate, or a pharmaceutically acceptable hydrate or solvate thereof. In yet another embodiment, the vitamin K3 is magnesium 1,2,3,4-tetrahydro-2-methyl-1,4-dioxo-2-naphthalenesulfonate, or a pharmaceutically acceptable hydrate or solvate thereof. In still another embodiment, vitamin K3 is sodium 1,2,3,4-tetrahydro-2-methyl-1,4-dioxo-2-naphthalenesulfonate. In yet another embodiment, vitamin K3 is anhydrous sodium 1,2,3,4-tetrahydro-2-methyl-1,4-dioxo-2-naphthalenesulfonate. In yet another embodiment, vitamin K3 is 1,2,3,4-tetrahydro-2-methyl-1,4-dioxo-2-naphthalenesulfonate sodium hydrate. In still another embodiment, vitamin K3 is 1,2,3,4-tetrahydro-2-methyl-1,4-dioxo-2-naphthalenesulfonate sodium trihydrate.
[0154] In certain embodiments, the vitamin K is vitamin K4, or a pharmaceutically acceptable salt, solvate, or hydrate thereof. Vitamin '4 is also known as menadiol, 2-methyl-1,4-naphthalene diol, 2-methyl-1,4-naphthohydroquinone, 2-methyl-1,4-naphthoquinol, and dihydrovitamin K3. In certain embodiments, the vitamin K is sodium menadiol diphosphate.
[0156] In certain embodiments, vitamin K comprises vitamin K3 and vitamin K4, or pharmaceutically acceptable salts, solvates, or hydrates thereof.
[0158] In certain embodiments, the vitamin K is vitamin K5, or a pharmaceutically acceptable salt, solvate, or hydrate thereof. Vitamin K5 is also known as 4-amino-2-methyl-1-naphthalenol, 4-amino-2-methyl-1-naphthol, 1-hydroxy-2-methyl-4-aminonaphthalene, 2-methyl-4-amino -1-hydroxynaphthalene, 2-methyl-4-amino-1-naphthol, 3-methyl-4-hydroxy-1-naphthylamine and synkamine.
[0160] In certain embodiments, the vitamin K is free of chromium. In certain embodiments, the chromium-free vitamin K contains no more than 100 ppm, 50 ppm, 20 ppm, 10 ppm, 5 ppm, 2 ppm, 1 ppm, 0.1 ppm, 10 ppb, or 1 ppb of chromium. In certain embodiments, the chromium-free vitamin K contains no more than 10 ppm of chromium. In certain embodiments, the chromium-free vitamin K contains no more than 5 ppm of chromium.
[0161] In certain embodiments, the chromium-free vitamin K contains no more than 2 ppm of chromium. In certain embodiments, the chromium-free vitamin K contains no more than 1 ppm of chromium.
[0163] In certain embodiments, the vitamin K is chromium-free vitamin K3. In certain embodiments, the chromium-free vitamin K3 contains no more than 100 ppm, 50 ppm, 20 ppm, 10 ppm, 5 ppm, 2 ppm, 1 ppm, 0.1 ppm, 10 ppb, or 1 ppb of chromium. In certain embodiments, the chromium-free vitamin K3 contains no more than 10 ppm of chromium. In certain embodiments, the chromium-free vitamin K3 contains no more than 5 ppm of chromium. In certain embodiments, the chromium-free vitamin K3 contains no more than 2 ppm of chromium. In certain embodiments, the chromium-free vitamin K3 contains no more than 1 ppm of chromium.
[0165] In certain embodiments, vitamin K is sodium 1,2,3,4-tetrahydro-2-methyl-1,4-dioxo-2-naphthalenesulfonate without chromium. In certain embodiments, sodium 1,2,3,4-tetrahydro-2-methyl-1,4-dioxo-2-naphthalenesulfonate without chromium contains no more than 100 ppm, 50 ppm, 20 ppm, 10 ppm, 5 ppm. , 2 ppm, 1 ppm, 0.1 ppm, 10 ppb or 1 ppb of chromium. In certain embodiments, sodium 1,2,3,4-tetrahydro-2-methyl-1,4-dioxo-2-naphthalenesulfonate without chromium contains no more than 10 ppm of chromium. In certain embodiments, sodium 1,2,3,4-tetrahydro-2-methyl-1,4-dioxo-2-naphthalenesulfonate without chromium contains no more than 5 ppm of chromium. In certain embodiments, sodium 1,2,3,4-tetrahydro-2-methyl-1,4-dioxo-2-naphthalenesulfonate without chromium contains no more than 2 ppm of chromium. In certain embodiments, sodium 1,2,3,4-tetrahydro-2-methyl-1,4-dioxo-2-naphthalene sulfonate without chromium contains no more than 1 ppm of chromium.
[0167] In certain embodiments, chromium-free vitamin K3 is manufactured through cerium-mediated electrochemical technology (CETECH ™) as described in US Pat. U.S. No. 6,468,414, the disclosure of which is incorporated herein by reference in its entirety. Alternatively, chromium-free vitamin K3 is available from commercial sources, such as PRO-K ™ (Lonza Group Ltd, Switzerland).
[0169] In one embodiment, the quinone compound is one that is capable of increasing the production of a reactive oxygen species (eg, in one embodiment, superoxide anion, in another embodiment, hydrogen peroxide) in a cell.
[0171] In another embodiment, the quinone compound is one that can induce autoschizis.
[0172] Taper et al., J. Histochem. Cytochem. 2001, 49, 109-119; Jamison et al., Biochem. Pharm. 2002, 63, 1773-1783; The disclosure of which is incorporated herein by reference in its entirety.
[0174] In certain embodiments, the quinone compound is a naphthalenedione, which is optionally substituted with one or more Q substituents as defined herein. In certain embodiments, the quinone compound is a naphthalene-1,2-dione, which is optionally substituted with one or more Q substituents as defined herein. In certain embodiments, the quinone compound is a naphthalene-1,4-dione, which is optionally substituted with one or more Q substituents, as defined herein. In certain embodiments, the quinone compound is a naphthalene-1,4-dione, substituted with one, two, three, or four Q substituents, each of which is independently selected from amino, halo, cyano, nitro, C1-alkyl 6, -ORa, -SRa and -CORa, where Ra is (i) hydrogen; or (ii) C1-6 alkyl, C6-15 aryl, or heteroaryl, each optionally substituted with one or more Q substituents. In certain embodiments, the quinone compound is a naphthalene-1,4-dione, substituted with one, two , three or four Q substituents, each of which is independently selected from amino, bromine, chlorine, cyano, nitro, methyl, -ORa, -SRa and -CORa, where Ra is hydrogen, methyl, phenyl, chlorophenyl, fluorophenyl , tert-butylphenyl, methoxyphenyl, trimethoxyphenyl or (methoxy-2-oxo-2 / - / - chromenyl) methyl. In certain embodiments, the quinone compound is a naphthalene-1,4-dione, substituted with one, two, three, or four Q substituents, each of which is independently selected from amino, bromine, chlorine, cyano, nitro, methyl , -ORa, -SRa and -CORa, where Ra is hydrogen, methyl, phenyl, 2-chlorophenyl, 3-chlorophenyl, 4-fluorophenyl, 4-tert-butylphenyl, 4-methoxyphenyl, 3,4,5-trimethoxyphenyl or (7-methoxy-2-oxo-2H-chromen-4-yl) methyl. Additional quinone compounds include, but are not limited to, those described in US Pat. US Public No. 2013/0219528; and Benites et al. Invest. New Drugs 2011, 29, 760-767; the disclosure of which is incorporated herein by reference in its entirety.
[0176] In certain embodiments, the quinone compound is 2-bromo-1,4-naphthoquinone, 2-methoxy-1,4-naphthoquinone, or 2-methyl-1,4-naphthoquinone; or a pharmaceutically acceptable salt, solvate, hydrate or prodrug thereof. In certain embodiments, the quinone compound is 2 - (((7-methoxy-2-oxo-2 / - / - chromen-4-yl) methyl) thio) naphthalene-1,4-dione, or a salt , solvate, hydrate or pharmaceutically acceptable prodrug thereof. Additional quinone compounds include, but are not limited to, those described in Baña et al., Mol. Carcinog. 2015, 54, 242-247, the disclosure of which is incorporated herein by reference in its entirety; or pharmaceutically acceptable salts, solvates, hydrates, and prodrugs thereof.
[0178] In certain embodiments, the quinone compound is 2-amino-3-bromo-1,4-naphthoquinone, 2-amino-3-chloro-1,4-naphthoquinone, or 2-amino-3-methoxy-1,4-naphthoquinone. ; or a pharmaceutically acceptable salt, solvate, hydrate or prodrug thereof. In certain embodiments, the quinone compound is 2,3-dichloro-1,4-naphthoquinone or 2,3-dimethoxy-1,4-naphthoquinone; or a pharmaceutically acceptable salt, solvate, hydrate or prodrug thereof. Additional quinone compounds include, but are not limited to, those described in Graciani and Ximenes, Braz. J. Med. Biol. Res. 2012, 45, 701-710, the disclosure of which is incorporated herein by reference in its entirety; or pharmaceutically acceptable salts, solvates, hydrates, and prodrugs thereof.
[0180] In certain embodiments, the quinone compound is 2-dibenzoylamino-3-chloro-1,4-naphthoquinone, 2-dibenzoylamino-3-bromo-1,4-naphthoquinone, 2-dibenzoylamino-3-methoxy-1,4-naphthoquinone, 2 -bis- (2-chlorobenzoyl) amino-3-chloro-1,4-naphthoquinone, 2-bis- (2-chlorobenzoyl) amino-3-bromo-1,4-naphthoquinone, 2-bis- (2-chlorobenzoyl) amino-3-methoxy-1,4-naphthoquinone, 2-bis- (3-chlorobenzoyl) amino-3-chloro-1,4-naphthoquinone, 2-bis- (3-chlorobenzoyl) amino-3-bromo-1, 4-naphthoquinone, 2-bis- (3-chlorobenzoyl) amino-3-methoxy-1,4-naphthoquinone, 2-bis- (4-chlorobenzoyl) amino-3-chloro-1,4-naphthoquinone, 2-bis- (4-chlorobenzoyl) amino-3-bromo-1,4-naphthoquinone, 2-bis- (4-chlorobenzoyl) amino-3-methoxy-1,4-naphthoquinone, 2-bis- (4-fluorobenzoyl) amino-3 -chloro-1,4-naphthoquinone, 2-bis- (4-fluorobenzoyl) amino-3-bromo-1,4-naphthoquinone, 2-bis- (4-fluorobenzoyl) amino-3-methoxy-1,4 -naphthoquinone, 2-bis- (4-tert-butylbenzoyl) amino-3-chloro-1,4-naphthoquinone, 2-bis- (4-fercbutylbenzoyl) amino-3-bromo-1,4-naphthoquinone, 2-bis - (4-tert-butylbenzoyl) amino-3-metho x¡-1,4- naphthoquinone, 2-bis- (4-methoxybenzoyl) amino-3-chloro-1,4-naphthoquinone, 2-bis- (4-methoxybenzoyl) amino-3-bromo-1,4-naphthoquinone , 2-bis- (3,4,5-trimethoxybenzoyl) -amino-3-chloro-1,4-naphthoquinone, 2-A / - (4-chlorobenzoyl)) - amino-3-chloro-1,4-naphthoquinone , 2 - (/ V-benzoyl- / V- (4-chlorobenzoyl)) - amino-3-chloro-1,4-naphthoquinone, 2- / V-acetylamino-3-chloro-1,4-naphthoquinone or 2 - (/ V-acetyl- / V- (4-chlorobenzoyl)) - amino-3-chloro-1,4-naphthoquinone; or a pharmaceutically acceptable salt, solvate, hydrate or prodrug thereof. Additional quinone compounds include, but are not limited to, those described in Brandy et al., Molecules 2013, 18, 1973-1984, the disclosure of which is incorporated herein by this reference in its entirety; or salts, solvates, hydrates and pharmaceutically acceptable prodrugs thereof.
[0182] In certain embodiments, the quinone compound is plumbagin, also known as 5-hydroxy-2-methyl-naphthalene-1,4-dione. In certain embodiments, the quinone compound plumbazeilanone. In certain embodiments, the quinone compound is lawone, also known as 2-hydroxy-1,4-naphthoquinone. In certain embodiments, the quinone compound is juglone, also known as 5-hydroxy-1,4-naphthalenedione. Additional quinone compounds include, but are not limited to, those described in et al., Med. Res. Rev. 2012, 32, 1131-1158, the disclosure of which is incorporated herein by reference in its entirety; or pharmaceutically acceptable salts, solvates, hydrates, and prodrugs thereof.
[0184] In certain embodiments, the quinone compound is mitomycin C, also known as [6-amino-8a-methoxy-5-methyl-4,7-dioxo-1,1 a, 2,4,7,8,8a, 8-boctahydroaziren. [2 ', 3': 3,4] -pyrrolo [1,2-a] indol-8-yl] methyl carbamate. In certain embodiments, the quinone compound is daunorubicin, also known as (8S, 10S) -8-acetyl-10 - [(2S, 4S, 5S, 6S) -4-amino-5-hydroxy-6-methyl-oxan -2-yl] oxy-6,8,11-trihydroxy-1-methoxy-9,10-dihydro-7H-tetracene-5,12-dione. In certain embodiments, the quinone compound is doxorubicin, also known as (7S, 9S) -7 - [(2R, 4S, 5S, 6S) -4-amino-5-hydroxy-6-methyloxan-2-yl] oxy -6,9,11 -trihydroxy-9- (2-hydroxyacetyl) -4-methoxy-8,10-dihydro-7 / - / - tetracene-5,12-dione. In certain embodiments, the quinone compound is mitoxantrone, also known as 1,4-dihydroxy-5,8-bis [2- (2-hydroxyethylamino) ethylamine] -anthracene-9,10-dione.
[0186] In certain embodiments, the quinone compound is free of chromium. In certain embodiments, the chromium-free quinone compound contains no more than 100 ppm, 50 ppm, 20 ppm, 10 ppm, 5 ppm, 2 ppm, 1 ppm, 0.1 ppm, 10 ppb, or 1 ppb of chromium. In certain embodiments, the non-chromium quinone compound contains no more than 10 ppm of chromium. In certain embodiments, the chromium-free quinone compound contains no more than 5 ppm chromium. In certain embodiments, the non-chromium quinone compound contains no more than 2 ppm chromium. In certain embodiments, the non-chromium quinone compound contains no more than 1 ppm of chromium.
[0188] The quinone compound can also be provided as a prodrug, which is a functional derivative of the quinone compound and can be easily converted to the original quinone compound in vivo. Prodrugs are often helpful because, in In some situations, they may be easier to administer than the parent compound. For example, they may be bioavailable by oral administration while the parent compound does not. The prodrug may also have better solubility in pharmaceutical compositions over the parent compound. A prodrug can be converted to the parent drug by various mechanisms, including enzymatic processes and metabolic hydrolysis. See Harper, Progress in Drug Research 1962, 4, 221-294; Morozowich et al. in "Design of Biopharmaceutical Properties through Prodrugs and Analogs", Roche Ed., APHA Acad. Pharm. Sci. 1977; "Bioreversible Carriers in Drug in Drug Design, Theory and Application", Roche Ed., APHA Acad. Pharm. Sci. 1987; "Design of Prodrugs," Bundgaard, Elsevier, 1985; Wang et al., Curr. Pharm. Design 1999, 5, 265-287; Pauletti et al., Adv. Drug. Delivery Rev. 1997, 27, 235 256; Mizen et al., Pharm. Biotech. 1998, 11, 345-365; Gaignault et al., Pract. Med. Chem.
[0189] 1996, 671-696; Asgharnejad in "Transport Processes in Pharmaceutical Systems," Amidon et al., Ed., Marcell Dekker, 185-218, 2000; Balant et al., Eur. J. Drug Metab. Pharmacokinet. 1990, 15, 143-53; Balimane and Sinko, Adv. Drug Delivery Rev. 1999, 39, 183-209; Browne, Clin. Neuropharmacol. 1997, 20, 1-12; Bundgaard, Arch. Pharm. Chem.
[0190] 1979, 86, 1-39; Bundgaard, Controlled Drug Delivery 1987, 17, 179-96; Bundgaard, Adv. Drug Delivery Rev. 1992, 8, 1-38; Fleisher et al., Adv. Drug Delivery Rev. 1996, 19, 115 130; Fleisher et al., Methods Enzymol. 1985, 112, 360-381; Farquhar et al., J. Pharm. Sci.
[0191] 1983, 72, 324-325; Freeman et al., J. Chem. Soc., Chem. Commun. 1991, 875-877; Friis and Bundgaard, Eur. J. Pharm. Sci. 1996, 4, 49-59; Gangwar et al., Des. Biopharm. Prop. Prodrugs Analogs, 1977, 409-421; Nathwani and Wood, Drugs 1993, 45, 866-94; Sinhababu and Thakker, Adv. Drug Delivery Rev. 1996, 19, 241-273; Stella et al., Drugs 1985, 29, 455-73; Tan et al., Adv. Drug Delivery Rev. 1999, 39, 117-151; Taylor, Adv. Drug Delivery Rev. 1996, 19, 131-148; Valentino and Borchardt, Drug Discovery Today 1997, 2, 148-155; Wiebe and Knaus, Adv. Drug Delivery Rev. 1999, 39, 63-80; and Waller et al., Br. J. Clin. Pharmac. 1989, 28, 497-507.
[0193] Antiparasitic agents
[0195] In one embodiment, the antiparasitic agent is an antiprotozoan, an anthelmintic, an antinematode, an antichode, an antitrematode, an antiamebic, or an antifungal. In other embodiments, the antiparasitic agent is albendazole, amphotericin B, benznidazole, bephenium, diethylcarbamzine, eflornithine, flubendazole, ivermectin, mebendazole, meglumine antimonite, melarsoprol, metronidazole, miltefosine, niclosamide, pyrazolimide, nifurtimovantimonium, antifurtimovalent pirvinium, sodium stibogluconate, thiabendazole or tinidazole. In yet another embodiment, the antiparasitic agent is nifurtimox.
[0197] In one embodiment, the antiparasitic agent is a nitroimidazole. In another embodiment, the antiparasitic agent is a 2-nitroimidazole. In yet another embodiment, the antiparasitic agent is a 5-nitroimidazole. In yet another embodiment, the antiparasitic agent is azanidazole, dimetridazole, megazol, metronidazole, nimorazole, ornidazole, pretomanid, or tinidazole. In yet another embodiment, the antiparasitic agent is benznidazole.
[0199] Pharmaceutical compositions
[0201] In one embodiment, a pharmaceutical composition comprises (i) ascorbic acid, or a single enantiomer, a mixture of enantiomers, or a mixture of diastereomers thereof; or a pharmaceutically acceptable salt, solvate or hydrate thereof; and (ii) a quinone compound, or a single enantiomer, a mixture of enantiomers, or a mixture of diastereomers thereof; or a pharmaceutically acceptable salt, solvate, hydrate or prodrug thereof.
[0203] In certain embodiments, the pharmaceutical composition further comprises a pharmaceutically acceptable vehicle, carrier, diluent, or excipient, or a mixture of two or more thereof.
[0205] In certain embodiments, the ascorbic acid used in each of the pharmaceutical compositions is independently free of chromium. In certain embodiments, the quinone compound used in each of the pharmaceutical compositions is independently free of chromium.
[0207] In certain embodiments, each of the pharmaceutical compositions is independently free of chromium. In certain embodiments, each of the pharmaceutical compositions independently contains no more than 100 ppm, 50 ppm, 20 ppm, 10 ppm, 5 ppm, 2 ppm, 1 ppm, 0.1 ppm, 10 ppb, or 1 ppb of chromium. In certain embodiments, each of the pharmaceutical compositions independently contains no more than 10 ppm of chromium. In certain embodiments, each of the pharmaceutical compositions independently contains no more than 5 ppm of chromium. In certain embodiments, each of the pharmaceutical compositions independently contains no more than 2 ppm chromium. In certain embodiments, each of the pharmaceutical compositions independently contains no more than 1 ppm of chromium.
[0209] In one embodiment, the weight ratio of the ascorbic acid to the quinone compound in each of the pharmaceutical compositions independently ranges from about 4 to about 500, from about 10 to about 500, from about 50 to about 500, from about 25 to about 250, from about 50 to about 200, from about 50 to about 150, or from about 80 to about 120. In another embodiment, the weight ratio of the ascorbic acid to the quinone compound in each of the pharmaceutical compositions is independently about 10 , about 20, about 30, about 40, about 50, about 60, about 70, about 80, about 90, about 100, about 110, about 120, about 130, about 140, about 150, about 160, about 170, about 180, ap About 190, about 200, about 210, about 220, about 230, about 240, or about 250. In yet another embodiment, the weight ratio of ascorbic acid to the quinone compound in each of the pharmaceutical compositions is independently about 100. In yet another embodiment, the weight ratio of the ascorbic acid to the quinone compound in each of the pharmaceutical compositions is independently about 200.
[0211] In one embodiment, the molar ratio of the ascorbic acid to the quinone compound in each of the pharmaceutical compositions independently ranges from about 10 to about 500, from about 25 to about 250, from about 50 to about 200, from about 50 to about 150 or about 80 to about 120. In another embodiment, the molar ratio of the ascorbic acid to the quinone compound in each of the pharmaceutical compositions is independently about 10, about 20, about 30, about 40, about 50, about 60, about 70, about 80, about 90, about 100, about 110, about 120, about 130, about 140, about 150, about 160, about 170, about 180, about 190, about 200, about 210, about 220, about 230, about 240, or about 250. In yet another embodiment, the molar ratio of ascorbic acid to quinone compound in each of the pharmaceutical compositions is independently about 100. In yet another embodiment, the molar ratio of ascorbic acid to the quinone compound in each of the pharmaceutical compositions is independently about 200.
[0213] In certain embodiments, each of the pharmaceutical compositions is independently formulated into various dosage forms for oral, parenteral, and topical administration. In certain embodiments, each of the pharmaceutical compositions is independently formulated as modified release dosage forms, including, but not limited to, delayed, extended, prolonged, sustained, pulsatile, controlled, accelerated, rapid release dosage forms. , directed and programmed; and gastric retention dosage forms. These dosage forms can be prepared according to conventional methods and techniques known to those of skill in the art (see, for example, Remington: The Science and Practice of Pharmacy, supra Modified-Release Drug Delivery Technology, Rathbone et al., Eds ., Drugs and the Pharmaceutical Sciences, CRC Press LLC: 2008; Vol. 183).
[0215] In one embodiment, each of the pharmaceutical compositions is independently formulated into a dosage form for oral administration. In another embodiment, each of the pharmaceutical compositions is independently formulated into a dosage form for parenteral administration. In yet another embodiment, each of the pharmaceutical compositions is independently formulated into a dosage form for intravenous administration. In yet another embodiment, each of the pharmaceutical compositions is independently formulated into a dosage form for topical administration. In yet another embodiment, each of the pharmaceutical compositions is independently formulated in a dosage form for local injection.
[0217] In one embodiment, each of the pharmaceutical compositions is independently formulated as a capsule. In one embodiment, the capsule comprises (i) from about 10 mg to about 1000 mg, from about 25 mg to about 900 mg, from about 50 mg to about 800 mg, of about 100mg to about 700mg, from about 200mg to about 600mg, from about 300mg to about 600mg, or from about 400mg to about 600mg of ascorbic acid, or a single enantiomer, a mixture of enantiomers, or a mixture of diastereomers thereof; or a pharmaceutically acceptable salt, solvate or hydrate thereof; and (ii) from about 0.1 mg to about 10 mg, from about 1 mg to about 9 mg, from about 2 mg to about 8 mg, from about 3 mg to about 7 mg, or from about 4 mg to about 6 mg. of a quinone compound, or a single enantiomer, a mixture of enantiomers, or a mixture of diastereomers thereof, or a pharmaceutically acceptable salt, solvate, hydrate or prodrug thereof.
[0219] In another embodiment, the capsule comprises (i) from about 400 mg to about 600 mg of ascorbic acid, or a single enantiomer, a mixture of enantiomers, or a mixture of diastereomers thereof; or a pharmaceutically acceptable salt, solvate or hydrate thereof; and (ii) from about 4 mg to about 6 mg of a quinone compound, or a single enantiomer, a mixture of enantiomers, or a mixture of diastereomers thereof, or a pharmaceutically acceptable salt, solvate, hydrate or prodrug thereof.
[0221] In yet another embodiment, the capsule comprises (i) about 200 mg, about 300 mg, about 400 mg, about 500 mg, about 600 mg, about 700 mg, about 800 mg, or about 900 mg of ascorbic acid, or a single enantiomer. , a mixture of enantiomers, or a mixture of diastereomers thereof; or a pharmaceutically acceptable salt, solvate or hydrate thereof; and (ii) about 1 mg, about 2 mg, about 3 mg, about 4 mg, about 5 mg, about 6 mg, about 7 mg, about 8 mg, about 9 mg, or about 10 mg of a quinone compound, or a single enantiomer, a mixture of enantiomers, or a mixture of diastereomers thereof, or a pharmaceutically acceptable salt, solvate, hydrate or prodrug thereof.
[0223] In yet another embodiment, the capsule comprises (i) about 500 mg of ascorbic acid, or a single enantiomer, a mixture of enantiomers, or a mixture of diastereomers thereof; or a pharmaceutically acceptable salt, solvate or hydrate thereof; and (ii) about 5 mg of a quinone compound, or a single enantiomer, a mixture of enantiomers, or a mixture of diastereomers thereof, or a pharmaceutically acceptable salt, solvate, hydrate or prodrug thereof.
[0225] In certain embodiments, the capsule consists essentially of (i) ascorbic acid, or a single enantiomer, a mixture of enantiomers, or a mixture of diastereomers thereof; or a pharmaceutically acceptable salt, solvate or hydrate thereof; and (ii) a quinone compound, or a single enantiomer, a mixture of enantiomers, or a mixture of diastereomers thereof, or a pharmaceutically acceptable salt, solvate, hydrate or prodrug thereof.
[0227] In certain embodiments, the capsule contains (i) ascorbic acid, or a single enantiomer, a mixture of enantiomers, or a mixture of diastereomers thereof; or a pharmaceutically acceptable salt, solvate or hydrate thereof; and (ii) a quinone compound, or a single enantiomer, a mixture of enantiomers, or a mixture of diastereomers thereof, or a pharmaceutically acceptable salt, solvate, hydrate or prodrug thereof.
[0229] In one embodiment, the ascorbic acid compound in each of the pharmaceutical compositions is independently L-ascorbic acid or a pharmaceutically acceptable salt thereof; or a pharmaceutically acceptable solvate or hydrate thereof. In another embodiment, the ascorbic acid compound in each of the pharmaceutical compositions is independently an alkali or alkaline earth metal salt of L-ascorbic acid; or a pharmaceutically acceptable solvate or hydrate thereof; or a mixture thereof. In yet another embodiment, the ascorbic acid compound in each of the pharmaceutical compositions is independently a sodium, potassium, calcium or magnesium salt of L-ascorbic acid; or a pharmaceutically acceptable solvate or hydrate thereof; or a mixture thereof. In yet another embodiment, the ascorbic acid compound in each of the pharmaceutical compositions is independently sodium L-ascorbate. In yet another embodiment, the ascorbic acid compound in each of the pharmaceutical compositions is independently calcium L-ascorbate. In yet another embodiment, the ascorbic acid compound in each of the pharmaceutical compositions is independently magnesium L-ascorbate. In yet another embodiment, the ascorbic acid compound in each of the pharmaceutical compositions is independently a mixture of two or three of sodium L-ascorbate, calcium L-ascorbate, and magnesium L-ascorbate.
[0230] In one embodiment, the quinone compound in each of the pharmaceutical compositions is independently vitamin K, or a single enantiomer, a mixture of enantiomers, or a mixture of diastereomers thereof, or a pharmaceutically acceptable salt, solvate, or hydrate of the same. themselves. In another embodiment, the quinone compound in each of the pharmaceutical compositions is independently vitamin K3, or a pharmaceutically acceptable salt, solvate, or hydrate thereof. In still another embodiment, the quinone compound in each of the pharmaceutical compositions is independently 2-methyl-1,4-naphthalenedione, or a pharmaceutically acceptable solvate or hydrate thereof. In yet another embodiment, the quinone compound in each of the pharmaceutical compositions is independently 2-methyl-1,4-naphthalenedione. In yet another embodiment, the quinone compound in each of the pharmaceutical compositions is independently 1,2,3,4-tetrahydro-2-methyl-1,4-dioxo-2-naphthalenesulfonic acid, or a salt, solvate, or hydrate. pharmaceutically acceptable thereof. In yet another embodiment, the quinone compound in each of the pharmaceutical compositions is independently an alkali or alkaline earth metal salt of 1,2,3,4-tetrahydro-2-methyl-1,4-dioxo-2-naphthalenesulfonic acid. ; or a pharmaceutically acceptable solvate or hydrate thereof; or a mixture thereof. In yet another embodiment, the quinone compound in each of the pharmaceutical compositions is independently 1,2,3,4-tetrahydro-2-methyl-1,4-dioxo-2-naphthalene sulfonate, sodium, potassium, calcium, or magnesium; or a pharmaceutically acceptable solvate or hydrate thereof; or a mixture thereof. In yet another embodiment, the quinone compound in each of the pharmaceutical compositions is independently 1,2,3,4-tetrahydro-2-methyl-1,4-dioxo-2-naphthalenesulfonate, or a pharmaceutically solvate or hydrate. acceptable of the same. In yet another embodiment, the quinone compound in each of the pharmaceutical compositions is independently potassium 1,2,3,4-tetrahydro-2-methyl-1,4-dioxo-2-naphthalenesulfonate, or a pharmaceutically solvate or hydrate. acceptable of the same. In yet another embodiment, the quinone compound in each of the pharmaceutical compositions is independently magnesium 1,2,3,4-tetrahydro-2-methyl-1,4-dioxo-2-naphthalenesulfonate, or a pharmaceutically solvate or hydrate. acceptable of the same. In yet another embodiment, the quinone compound in each of the pharmaceutical compositions is independently 1,2,3,4-tetrahydro-2-methyl-1,4-dioxo-2-naphthalene sulfonate. In yet another embodiment, the quinone compound in each of the pharmaceutical compositions is independently anhydrous sodium 1,2,3,4-tetrahydro-2-methyl-1,4-dioxo-2-naphthalene sulfonate. In yet another embodiment, the quinone compound in each of the pharmaceutical compositions is independently Sodium 1,2,3,4-tetrahydro-2-methyl-1,4-dioxo-2-naphthalenesulfonate hydrate. In yet another embodiment, the quinone compound in each of the pharmaceutical compositions is independently 1,2,3,4-tetrahydro-2-methyl-1,4-dioxo-2-naphthalenesulfonate sodium trihydrate.
[0232] In one embodiment, the capsule contains approximately 500 mg of sodium L-ascorbate, and approximately 5 mg of 1,2,3,4-tetrahydro-2-methyl-1,4-dioxo-2-naphthalene sulfonate or a hydrate. of the same. In another embodiment, the capsule contains approximately 500 mg of calcium L-ascorbate, and approximately 5 mg of 1,2,3,4-tetrahydro-2-methyl-1,4-dioxo-2-naphthalene sulfonate or a hydrate. of the same. In yet another embodiment, the capsule contains about 500 mg of magnesium L-ascorbate, and about 5 mg of 1,2,3,4-tetrahydro-2-methyl-1,4-dioxo-2-naphthalene sulfonate or a hydrate thereof. In yet another embodiment, the capsule contains about 500 mg of sodium L-ascorbate, and about 5 mg of anhydrous sodium 1,2,3,4-tetrahydro-2-methyl-1,4-dioxo-2-naphthalenesulfonate. . In yet another embodiment, the capsule contains about 500 mg of sodium L-ascorbate, and about 5 mg of 1,2,3,4-tetrahydro-2-methyl-1,4-dioxo-2-naphthalenesulfonate sodium anhydrous trihydrate. . In yet another embodiment, the capsule contains about 500 mg of calcium L-ascorbate, and about 5 mg of anhydrous sodium 1,2,3,4-tetrahydro-2-methyl-1,4-dioxo-2-naphthalenesulfonate. . In yet another embodiment, the capsule contains about 500 mg of calcium L-ascorbate, and about 5 mg of anhydrous sodium 1,2,3,4-tetrahydro-2-methyl-1,4-dioxo-2-naphthalenesulfonate trihydrate. . In yet another embodiment, the capsule contains about 500 mg of magnesium L-ascorbate, and about 5 mg of anhydrous sodium 1,2,3,4-tetrahydro-2-methyl-1,4-dioxo-2-naphthalenesulfonate. . In yet another embodiment, the capsule contains about 500 mg of magnesium L-ascorbate, and about 5 mg of anhydrous sodium 1,2,3,4-tetrahydro-2-methyl-1,4-dioxo-2-naphthalenesulfonate trihydrate. . In another embodiment, the capsule further comprises a pharmaceutically acceptable vehicle, carrier, diluent, or excipient, or a mixture of two or more thereof.
[0234] In one embodiment, the capsule contains about 500 mg of sodium L-ascorbate, and about 5 mg of 2-methyl-1,4-naphthalenedione. In another embodiment, the capsule contains about 1000 mg of sodium L-ascorbate, and about 10 mg of 2-methyl-1,4-naphthalenedione. In yet another embodiment, the capsule contains approximately 925 mg of sodium L-ascorbate and approximately 9 mg (eg 9.25 mg) of 2-methyl-1,4-naphthalenedione.
[0236] In one embodiment, the capsule contains approximately 500 mg of calcium L-ascorbate, and approximately 5 mg of 2-methyl-1,4-naphthalenedione. In another embodiment, the capsule contains about 1000 mg of calcium L-ascorbate, and about 10 mg of 2-methyl-1,4-naphthalenedione. In yet another embodiment, the capsule contains about 925 mg of calcium L-ascorbate and about 9 mg (eg, 9.25 mg) of 2-methyl-1,4-naphthalenedione.
[0238] In one embodiment, the capsule contains about 500 mg of magnesium L-ascorbate, and about 5 mg of 2-methyl-1,4-naphthalene. In another embodiment, the capsule contains about 1000 mg of magnesium L-ascorbate, and about 10 mg of 2-methyl-1,4-naphthalenedione. In yet another embodiment, the capsule contains about 925 mg of magnesium L-ascorbate and about 9 mg (eg, 9.25 mg) of 2-methyl-1,4-naphthalenedione.
[0240] In one embodiment, the capsule consists essentially of ascorbic acid, or a single enantiomer, a mixture of enantiomers, or a mixture of diastereomers thereof; or a pharmaceutically acceptable salt, solvate or hydrate thereof; and vitamin K, or a single enantiomer, a mixture of enantiomers, or a mixture of diastereomers thereof, or a pharmaceutically acceptable salt, solvate or hydrate thereof. In another embodiment, the capsule consists essentially of ascorbic acid, or a single enantiomer, a mixture of enantiomers, or a mixture of diastereomers thereof; or a pharmaceutically acceptable salt, solvate or hydrate thereof; and vitamin K3, or a pharmaceutically acceptable salt, solvate, or hydrate thereof.
[0242] In one embodiment, the capsule consists essentially of sodium L-ascorbate and 2-methyl-1,4-naphthalenedione. In another embodiment, the capsule consists essentially of calcium L-ascorbate and 2-methyl-1,4-naphthalenedione. In yet another embodiment, the capsule consists essentially of magnesium L-ascorbate and 2-methyl-1,4-naphthalenedione.
[0244] In one embodiment, the capsule consists essentially of sodium L-ascorbate, and sodium 1,2,3,4-tetrahydro-2-methyl-1,4-dioxo-2-naphthalenesulfonate or a hydrate thereof. In another embodiment, the capsule consists essentially of calcium L-ascorbate, and sodium 1,2,3,4 tetrahydro-2-methyl-1,4-dioxo-2-naphthalene sulfonate or a hydrate thereof. In yet another embodiment, the capsule consists essentially of magnesium L-ascorbate, and Sodium 1,2,3,4-tetrahydro-2-methyl-1,4-dioxo-2-naphthalenesulfonate or a hydrate thereof.
[0246] In one embodiment, the capsule consists essentially of sodium L-ascorbate and anhydrous sodium 1,2,3,4-tetrahydro-2-methyl-1,4-dioxo-2-naphthalenesulfonate. In another embodiment, the capsule consists essentially of sodium L-ascorbate and sodium 1,2,3,4-tetrahydro-2-methyl-1,4-dioxo-2-naphthalenesulfonate trihydrate. In still another embodiment, the capsule consists essentially of calcium L-ascorbate and anhydrous sodium 1,2,3,4-tetrahydro-2-methyl-1,4-dioxo-2-naphthalenesulfonate. In yet another embodiment, the capsule consists essentially of calcium L-ascorbate and sodium 1,2,3,4-tetrahydro-2-methyl-1,4-dioxo-2-naphthalenesulfonate trihydrate. In yet another embodiment, the capsule consists essentially of magnesium L-ascorbate and anhydrous sodium 1,2,3,4-tetrahydro-2-methyl-1,4-dioxo-2-naphthalene sulfonate. In yet another embodiment, the capsule consists essentially of magnesium L-ascorbate and sodium 1,2,3,4-tetrahydro-2-methyl-1,4-dioxo-2-naphthalenesulfonate trihydrate.
[0248] The pharmaceutical compositions can also be formulated as is known to those of skill in the art. Some examples of pharmaceutical compositions containing an ascorbic acid compound and a quinone compound are described in US Pat. U.S. Nos. 7,091,241 and 8,507,555; and Sol. of Pat. US No. US 2012/184609, US 2013/178522 and US 2014/0200270; each of which is incorporated herein by reference in its entirety.
[0250] In certain embodiments, each of the pharmaceutical compositions is independently provided in a unit dosage form or multiple dosage form. A unit dosage form, as used herein, refers to a physically discrete unit suitable for administration to a subject, eg, a human and animal subject, and individually packaged as is known in the art. Each unit dose contains a predetermined amount of one or more active ingredient (s) to produce the desired therapeutic effect, optionally associated with one or more pharmaceutical vehicle (s), carrier (s), diluent (s), or excipient (s). Some examples of a unit dosage form include an ampoule, syringe, and an individually packaged tablet and capsule. A unit dosage form can be administered in fractions or multiples thereof. A multiple dosage form is a plurality of identical unit dosage forms packaged in a single container that is administered in separate unit dosage form. Some examples of a way of Multiple dosages include a vial, bottle of tablets or capsules, or bottle of pints or gallons.
[0252] The pharmaceutical compositions can be administered in one go, or multiple times at time intervals. It is understood that the exact dosage and duration of treatment may vary with the age, weight, and condition of the patient being treated, and may be determined empirically by using known test protocols or by extrapolating intra-diagnostic or test data. in vivo or in vitro. It is further understood that, for any particular individual, specific dosage regimens should be adjusted over time according to the individual need and professional judgment of the person administering or supervising the administration of the formulations.
[0254] B. Oral administration
[0256] Pharmaceutical compositions for oral administration can be provided in solid, semi-solid or liquid dosage forms for oral administration. As used herein, oral administration also includes buccal, lingual and sublingual administration. Suitable oral dosage forms include, but are not limited to, tablets, rapid orodispersible tablets, chewable tablets, capsules, pills, strips, troches, lozenges, lozenges, wafers, granules, medicinal chewable gums, bulk powders, powders or effervescent or non-effervescent granules, oral sprays, solutions, emulsions, suspensions, wafers, dispersible formulations, elixirs and syrups. In addition to the one or more active ingredient (s), the pharmaceutical compositions may contain one or more pharmaceutically acceptable carrier (s) or excipient (s), including, but not limited to, binders, fillers, diluents, disintegrants, wetting agents, lubricants, glidants, coloring agents, dye migration inhibitors, sweetening agents, flavoring agents, emulsifying agents, suspending and dispersing agents, preservatives, solvents, nonaqueous liquids, organic acids, and carbon dioxide sources.
[0258] Binders or granulators impart cohesiveness to a tablet to ensure that the tablet remains intact after compression. Suitable binders or granulators include, but are not limited to, starches, such as cornstarch, potato starch, and pregelatinized starch (eg, STARCH 1500); jelly; sugars, such as sucrose, glucose, dextrose, molasses, and lactose; Natural and synthetic gums, such as acacia, alginic acid, alginate, Irish moss extract, panwar gum, ghatti gum, isabgol shell mucilage, carboxymethylcellulose, methylcellulose, polyvinylpyrrolidone (PVP), Veegum, powdered arabogalactan, tragacanthus powder and guar gum; celluloses, such as ethyl cellulose, cellulose acetate, calcium carboxymethyl cellulose, sodium carboxymethyl cellulose, methyl cellulose, hydroxyethyl cellulose (HEC), hydroxypropyl cellulose (HPC) and hydroxypropyl methyl cellulose (HPMC); microcrystalline celluloses, such as AVICEL-PH-101, AVICEL-PH-103, AVICEL RC-581, and AVICEL-PH-105 (FMC Corp., Marcus Hook, PA); pectin; and mixtures of two or more thereof. Suitable fillers include, but are not limited to, talc, calcium carbonate, microcrystalline cellulose, powdered cellulose, dextrates, kaolin, mannitol, silicic acid, sorbitol, starch, pregelatinized starch, and mixtures of two or more thereof. The amount of a binder or filler in pharmaceutical compositions varies depending on the type of formulation and is readily discernible to those skilled in the art. The binder or filler can be present from about 50% to about 99% by weight in the pharmaceutical compositions.
[0260] Suitable diluents include, but are not limited to, dicalcium phosphate, calcium sulfate, lactose, sorbitol, sucrose, inositol, cellulose, kaolin, mannitol, sodium chloride, dry starch, and powdered sugar. Certain diluents, such as mannitol, lactose, sorbitol, sucrose and inositol, when present in sufficient quantity, can give some tablets properties that allow them to disintegrate in the mouth when chewed. Such tablets that are compressed can be used as chewable tablets. The amount of a diluent in pharmaceutical compositions varies depending on the type of formulation and is easily discerned by those skilled in the art.
[0262] Suitable disintegrators include, but are not limited to, agar; bentonite; celluloses, such as methyl cellulose and carboxymethyl cellulose; wood products; natural sponge; cation exchange resins; alginic acid; gums, such as guar gum and Veegum HV; citrus pulp; cross-linked celluloses, such as croscarmellose; cross-linked polymers, such as crospovidone; cross-linked starches; calcium carbonate; microcrystalline cellulose, such as sodium starch glycolate; Polacrylin potassium; starches, such as corn starch, potato starch, tapioca starch, and pregelatinized starch; clays; alginas; pectin; and mixtures of two or more thereof. The amount of a disintegrant in pharmaceutical compositions varies depending on the type formulation and is easily discerned by those skilled in the art. The pharmaceutical compositions may contain from about 0.5% to about 15%, or from about 1% to about 5%, by weight of a disintegrant.
[0264] Suitable lubricants include, but are not limited to, calcium stearate; magnesium stearate; mineral oil; light mineral oil; glycerin; sorbitol; mannitol; glycols, such as glycerol behenate and polyethylene glycol (PEG); stearic acid; sodium lauryl sulfate; talcum powder; hydrogenated vegetable oil, including peanut oil, cottonseed oil, sunflower oil, sesame oil, olive oil, corn oil, and soybean oil; zinc stearate; ethyl oleate; ethyl laureate; agar; starch; club moss; silica or silica gels, such as AEROSIL® 200 (W.R. Grace Co., Baltimore, MD) and CAB-O-SIL® (Cabot Co. of Boston, MA); and mixtures of two or more thereof. The pharmaceutical compositions can contain from about 0.1% to about 5% by weight of a lubricant.
[0266] Suitable glidants include, but are not limited to, colloidal silicon dioxide, CAB O-SIL® (Cabot Co. of Boston, MA), and non-asbestos talc. Suitable coloring agents include, but are not limited to, any of the certified and approved water soluble FD&C dyes, and water insoluble FD&C dyes suspended in alumina hydrate, and color lakes and mixtures of two or more thereof. . A colored lacquer is the combination by adsorption of a water-soluble dye to a hydrated oxide of a heavy metal, which generates an insoluble form of the dye. Suitable flavoring agents include, but are not limited to, natural plant-derived flavors, such as fruits, and synthetic combinations of palatable compounds, such as peppermint and methyl salicylate. Suitable sweetening agents include, but are not limited to, sucrose, lactose, mannitol, syrups, glycerin, and artificial sweeteners, such as saccharin and aspartame. Suitable emulsifying agents include, but are not limited to, gelatin, acacia, tragacanth, bentonite, and surfactants, such as polyoxyethylene sorbitan monooleate (TWEEN® 20), polyoxyethylene sorbitan monooleate 80 (TWEEN® 80), and triethanolamine oleate. . Suitable suspending and dispersing agents include, but are not limited to, sodium carboxymethylcellulose, pectin, tragacanth, Veegum, acacia, sodium carbomethylcellulose, hydroxypropyl methylcellulose, and polyvinylpyrrolidone. Suitable preservatives include, but are not limited to, glycerin, methyl and propyl paraben, benzoic acid, sodium benzoate, and alcohol. Suitable wetting agents include, but are not limited to, propylene glycol monostearate, sorbitan monooleate, diethylene glycol monolaurate and polyoxyethylene lauryl ether. Suitable solvents include, but are not limited to, glycerin, sorbitol, ethyl alcohol, and syrup. Suitable non-aqueous liquids used in emulsions include, but are not limited to, mineral oil and cottonseed oil. Suitable organic acids include, but are not limited to, citric and tartaric acid. Suitable sources of carbon dioxide include, but are not limited to, sodium bicarbonate and sodium carbonate.
[0268] It should be understood that many carriers and excipients can serve various functions, even within the same formulation.
[0270] Pharmaceutical compositions for oral administration may be provided as tablets that are compressed, crushed tablets, lozenges, chewable lozenges, fast dissolving tablets, tablets that are multiple tablets, enteric coated tablets, or sugar or film coated tablets. In one embodiment, enteric-coated tablets are tablets that are coated with substances that resist the action of stomach acid, but dissolve or disintegrate in the intestine, thus protecting the active ingredients from the acidic environment of the stomach. Enteric coatings include, but are not limited to, fatty acids, fats, phenyl salicylate, waxes, shellac, ammonia shellac, and cellulose acetate phthalates. Sugar-coated tablets are tablets that are compressed surrounded by a sugar coating, which can be beneficial in masking unpleasant tastes or odors and in protecting the tablets from oxidation. Film-coated tablets are tablets that are covered with a layer or thin film of, for example, a water-soluble material. Film coatings include, but are not limited to, hydroxyethyl cellulose, sodium carboxymethyl cellulose, polyethylene glycol 4000, and cellulose acetate phthalate. In one embodiment, the film coating provides the same general characteristics as the sugar coating. Multiple tablets are tablets made by more than one compression cycle, including layered tablets and compression coated tablets or dry coated tablets.
[0272] Tablet dosage forms may be prepared from the active ingredient in powder, crystalline, or granular forms, alone or in combination with one or more vehicle (s) or excipient (s) described herein, including binders, disintegrators, controlled release polymers, lubricants, diluents and / or colorants. Flavoring and sweetening agents are useful in the formation of chewable tablets and lozenges.
[0274] Pharmaceutical compositions for oral administration can be provided as hard or soft capsules, which can be made of gelatin, methyl cellulose, starch or calcium alginate. The hard gelatin capsule, also called dry-filled capsule (DFC), consists of two sections, one of which slides over the other, thus completely enveloping the active ingredient. The soft elastic capsule (SEC) is a soft globular shell, such as a gelatin shell, that is plasticized by the addition of glycerin, sorbitol, or a similar polyol. Soft gelatin casings may contain a preservative to prevent the growth of microorganisms. Suitable preservatives are those described herein, including, but not limited to, methyl- and propyl-parabens and sorbic acid. Liquid, semi-solid, and solid dosage forms can be encapsulated in a capsule. Suitable liquid and semisolid dosage forms include solutions and suspensions in propylene carbonate, vegetable oils, or triglycerides. Capsules containing such solutions can be prepared as described in US Pat. U.S. No. 4,328,245; 4,409,239; and 4,410,545; each of which is incorporated by reference herein in its entirety. Capsules can also be coated as is known to those skilled in the art to modify or prolong the dissolution of the active ingredient.
[0276] Pharmaceutical compositions for oral administration can be provided in liquid and semisolid dosage forms, including emulsions, solutions, suspensions, elixirs, and syrups. An emulsion is a two-phase system, in which a liquid is dispersed in the form of small globules through another liquid, which can be oil-in-water or water-in-oil. Emulsions can include a pharmaceutically acceptable liquid or non-aqueous solvent, emulsifying agent, and preservative. Suspensions can include a pharmaceutically acceptable suspending agent and preservative. Aqueous alcoholic solutions may include a pharmaceutically acceptable acetal, such as a di (lower alkyl) acetal of a lower alkyl aldehyde, eg, acetaldehyde diethyl acetal; and a water-miscible solvent with one or more hydroxyl groups, such as propylene glycol and ethanol. Elixirs are clear, sweetened, hydroalcoholic solutions. Syrups are concentrated aqueous solutions of a sugar, for example sucrose, and may also contain a preservative. For a liquid dosage form, eg, a solution in a polyethylene glycol, it can be diluted with a sufficient amount of a pharmaceutically acceptable liquid carrier, eg, water, to be conveniently metered for administration.
[0278] Other useful semi-solid and liquid dosage forms include, but are not limited to, those containing the active ingredient (s) provided herein, and a dialkylated mono- or polyalkylene glycol, including, 1,2-dimethoxymethane, diglyme, triglyme , tetraglyme, polyethylene glycol-350-dimethyl ether, polyethylene glycol-550-dimethyl ether, polyethylene glycol-750-dimethyl ether, where 350, 550 and 750 refer to the approximate average molecular weight of the polyethylene glycol. These formulations may further comprise one or more antioxidants, such as butylated hydroxytoluene (BHT), butylated hydroxyanisole (BHA), propyl gallate, vitamin E, hydroquinone, hydroxycoumarins, ethanolamine, lecithin, cephalin, ascorbic acid, malic acid, acid phosphoric, bisulfite, sodium metabisulfite, thiodipropionic acid and its esters, and dithiocarbamates.
[0280] Pharmaceutical compositions for oral administration can also be provided in the form of liposomes, micelles, microspheres, or nanosystems. Micellar dosage forms can be prepared as described in US Pat. U.S. No. 6,350,458, which is incorporated herein by reference in its entirety.
[0282] Pharmaceutical compositions for oral administration can be provided as non-effervescent or effervescent granules or powders that will be reconstituted into a liquid dosage form. Pharmaceutically acceptable carriers and excipients used in non-effervescent powders and granules can include diluents, sweeteners, and wetting agents. Pharmaceutically acceptable carriers and excipients used in effervescent powders or granules can include organic acids and a source of carbon dioxide.
[0284] Coloring and flavoring agents can be used in all of the above dosage forms.
[0286] Pharmaceutical compositions for oral administration can be formulated as immediate or modified release dosage forms, including delayed, sustained, pulsed, controlled, targeted, and scheduled release forms.
[0287] C. Parenteral administration
[0289] The pharmaceutical compositions can be administered parenterally by injection, infusion or implant, for local or systemic administration. Parenteral administration, as used herein, includes intravenous, intraarterial, intraperitoneal, intrathecal, intraventricular, intraurethral, intrasternal, intracranial, intramuscular, intrasynovial, intravesical, and subcutaneous administration.
[0291] Pharmaceutical compositions for parenteral administration can be formulated in any dosage form that is suitable for parenteral administration, including solutions, suspensions, emulsions, micelles, liposomes, microspheres, nanosystems, and solid forms suitable for solutions or suspensions in liquid prior to injection. Such dosage forms can be prepared according to conventional methods known to those of skill in the art (see, for example, Remington: The Science and Practice of Pharmacy, supra).
[0293] Pharmaceutical compositions intended for parenteral administration may include one or more pharmaceutically acceptable carrier (s) and carrier (s) including, but not limited to, aqueous carriers, water-miscible carriers, non-aqueous carriers, microbial agents, or anti-growth preservatives. microorganisms, stabilizers, solubility enhancers, isotonic agents, buffering agents, antioxidants, local anesthetics, suspending and dispersing agents, wetting or emulsifying agents, complexing agents, scavenging or chelating agents, cryoprotectants, lipoprotectors, thickening agents, agents pH adjustment and inert gases.
[0295] Suitable aqueous vehicles include, but are not limited to, water, saline, physiological saline or phosphate buffered saline (PBS), sodium chloride injection, Ringer's injection, isotonic dextrose injection, sterile water injection, dextrose injection and lactated Ringer's. Suitable non-aqueous vehicles include, but are not limited to, plant-based fixed oils, castor oil, corn oil, cottonseed oil, olive oil, peanut oil, peppermint oil, safflower oil, sesame oil. , soybean oil, hydrogenated vegetable oils, hydrogenated soybean oil, and medium chain triglycerides from coconut oil and palm oil. Suitable water miscible carriers include, but are not limited to, ethanol, 1,3-butanediol, liquid polyethylene glycol (eg, propylene glycol 300 and propylene glycol 400), propylene glycol, glycerin, A / -methyl-2-pyrrolidone, A /, A / -d¡methylacetamide and dimethylsulfoxide.
[0297] Suitable antimicrobial agents or preservatives include, but are not limited to, phenols, cresols, mercurials, benzyl alcohol, chlorobutanol, methyl and propyl phhydroxybenzoates, thimerosal, benzalkonium chloride (eg, benzethonium chloride), methyl and propyl paraben, and sorbic acid . Suitable isotonic agents include, but are not limited to, sodium chloride, glycerin, and dextrose. Suitable buffering agents include, but are not limited to, phosphate and citrate. Suitable antioxidants are those described herein, including sodium bisulfite and metabisulfite. Suitable local anesthetics include, but are not limited to, procaine hydrochloride. Suitable suspending and dispersing agents are those described herein, including, but not limited to, sodium carboxymethylcellulose, hydroxypropyl methylcellulose, and polyvinylpyrrolidone. Suitable emulsifying agents are those described herein, including, but not limited to, polyoxyethylene sorbitan monolaurate, polyoxyethylene sorbitan 80 monooleate, and triethanolamine oleate. Suitable scavenging or chelating agents include, but are not limited to, EDTA. Suitable pH adjusting agents include, but are not limited to, sodium hydroxide, hydrochloric acid, citric acid, and lactic acid. Suitable complexing agents include, but are not limited to, cyclodextrins, including α-cyclodextrin, p-cyclodextrin, hydroxypropyl-p-cyclodextrin, sulfobutyl ether-p-cyclodextrin, and sulfobutyl ether 7-p-cyclodextrin (CAPTISOL®, CyDex, Lenexa, KS).
[0299] When the pharmaceutical compositions are formulated for multiple dosage administration, the multiple dosage parenteral formulations contain an antimicrobial agent in bacteriostatic or fungistatic concentrations. All parenteral formulations must be sterile, as is known and practiced in the art.
[0301] In one embodiment, pharmaceutical compositions for parenteral administration are provided as sterile ready-to-use solutions. In another embodiment, the pharmaceutical compositions are provided as sterile dry soluble products including, for example, lyophilized powders and hypodermic tablets, which will be reconstituted with a vehicle prior to use. In yet another embodiment, the pharmaceutical compositions are provided as sterile suspensions ready for use. use. In yet another embodiment, the pharmaceutical compositions are provided as sterile dry insoluble products that will be reconstituted with a vehicle prior to use. In yet another embodiment, the pharmaceutical compositions are provided as sterile ready-to-use emulsions.
[0303] Pharmaceutical compositions for parenteral administration can be formulated as immediate or modified release dosage forms, including, for example, delayed, sustained, pulsed, controlled, targeted, and scheduled release forms.
[0305] Pharmaceutical compositions for parenteral administration can be formulated as a suspension, solid, semi-solid, or thixotropic liquid, for administration as an implanted reservoir. In one embodiment, the pharmaceutical compositions are dispersed in a solid internal matrix, which is surrounded by an external polymeric membrane that is insoluble in body fluids, but allows the active ingredient in the pharmaceutical compositions to disperse.
[0307] Suitable internal matrices include, but are not limited to, polymethylmethacrylate, polybutylmethacrylate, plasticized or unplasticized polyvinyl chloride, plasticized nylon, plasticized polyethylene terephthalate, natural rubber, polyisoprene, polyisobutylene, polybutadiene, polyethylene, vinyl copolymers of acetate, silicone gums, polydimethylsiloxanes, silicone carbonate copolymers, hydrophilic polymers, such as acrylic and methacrylic acid ester hydrogels, collagen, cross-linked polyvinyl alcohol, and cross-linked partially hydrolyzed polyvinyl acetate.
[0309] Suitable outer polymeric membranes include, but are not limited to, polyethylene, polypropylene, ethylene / propylene copolymers, ethylene / ethyl acrylate copolymers, ethylene / vinyl acetate copolymers, silicone rubbers, polydimethyl siloxanes, neoprene rubber, chlorinated polyethylene, polyvinyl chloride, copolymers of vinyl chloride with vinyl acetate, vinylidene chloride, ethylene and propylene, ionomeric polyethylene terephthalate, butyl rubbers, epichlorohydrin rubbers, ethylene / vinyl alcohol copolymer, ethylene / vinyl acetate / vinyl alcohol terpolymer and ethylene / vinylxyethanol copolymer.
[0311] D. Topical administration
[0312] The pharmaceutical compositions can be administered topically to the skin, the orifices or mucosa. Topical administration, as used herein, includes (intra) dermal, conjunctival, intracorneal, intraocular, ophthalmic, atrial, transdermal, nasal, vaginal, urethral, respiratory, and rectal administration.
[0314] The pharmaceutical compositions can be formulated in any dosage form that is suitable for topical administration to obtain a local or systemic effect, including, for example, emulsions, solutions, suspensions, creams, gels, hydrogels, ointments, drying powders, dressings, elixirs. , lotions, suspensions, tinctures, pastes, foams, films, sprays, irrigation, sprays, suppositories, bandages and dermal patches. The topical formulation of the pharmaceutical compositions can also comprise liposomes, micelles, microspheres, nanosystems, and mixtures of two or more thereof.
[0316] Suitable pharmaceutically acceptable vehicles and excipients for use in topical formulations include, but are not limited to, aqueous vehicles, water-miscible vehicles, non-aqueous vehicles, antimicrobial agents or preservatives against the growth of microorganisms, stabilizers, solubility enhancers, isotonic agents, buffering agents, antioxidants, local anesthetics, suspending and dispersing agents, wetting or emulsifying agents, complexing agents, scavenging or chelating agents, penetration enhancers, cryoprotectants, lipoprotectants, thickening agents, and inert gases.
[0318] The pharmaceutical compositions can also be administered topically by electroporation, iontophoresis, phonophoresis, sonphoresis, or microneedle or needle-free injection, such as POWDERJECT ™ (Chiron Corp., Emeryville, CA) and BIOJECT ™ (Bioject Medical Technologies Inc., Tualatin, OR).
[0320] The pharmaceutical compositions can be provided in the form of ointments, creams, and gels. Suitable ointment vehicles include, for example, oil or hydrocarbon vehicles, including shortening, benzoin shortening, olive oil, cottonseed oil and other oils, white petroleum jelly, emulsifying or absorbing vehicles, such as hydrophilic petroleum jelly, hydroxystearin sulfate, anhydrous lanolin, water-extractable vehicles, such as hydrophilic ointment, water-soluble ointment vehicles, including, polyethylene glycols of various molecular weight, and emulsion vehicles, water-in-oil (W / O) emulsions or oil-in-water (O / W) emulsions, including cetyl alcohol, glyceryl monostearate, lanolin, and stearic acid (see, for example, Remington: The Science and Practice of Pharmacy, above). These vehicles are emollients, but generally require the addition of antioxidants and preservatives.
[0322] The suitable cream base can be oil-in-water or water-in-oil. Suitable cream vehicles can be washed with water and contain an oil phase, an emulsifier and a water phase. The oil phase is also called the "internal" phase, which is generally composed of petroleum jelly and a fatty alcohol, such as cetyl or stearyl alcohol. Typically, but not necessarily, the aqueous phase exceeds the aqueous phase in volume and generally contains a humectant. The emulsifier in a cream formulation can be a nonionic, anionic, cationic or amphoteric surfactant.
[0324] The gels are semi-solid suspension-type systems. Single phase gels contain organic macromolecules substantially uniformly distributed throughout the liquid vehicle. Suitable gelling agents include, but are not limited to, cross-linked acrylic acid polymers, such as carbomers, carboxypolyalkylenes, and CARBOPOL®; hydrophilic polymers, such as polyethylene oxides, polyoxyethylene-polyoxypropylene copolymers and polyvinyl alcohol, cellulosic polymers such as hydroxypropylcellulose, hydroxyethylcellulose, hydroxypropylmethylcellulose, hydroxypropylmethylcellulose phthalate, and sodium gummeric x-propylmethylcellulose, and sodium gum traginoma xxpropylmethylcellulose. To prepare a uniform gel, dispersing agents such as alcohol or glycerin can be added, or the gelling agent can be dispersed by grinding, mechanical mixing and / or stirring.
[0326] The pharmaceutical compositions can be administered rectally, urethrally, vaginally or pervaginally in the form of suppositories, pesanos, probes, plasters or poultices, pastes, powders, bandages, creams, plasters, contraceptives, ointments, solutions, emulsions, suspensions, buffers, gels , foams, sprays, or enemas. These dosage forms can be manufactured using conventional processes as described in, for example, Remington: The Science and Practice of Pharmacy, above.
[0328] Rectal, urethral and vaginal suppositories are solid bodies for insertion into body orifices, which are solid at common temperatures, but melt or soften at body temperature to release the active ingredient (s) within the orifices. Pharmaceutically acceptable carriers used in rectal suppositories and Vaginals include bases or carriers, such as hardening agents, that produce a melting point near body temperature, when formulated with the pharmaceutical compositions, and antioxidants as described herein, including, for example, bisulfite and metabisulfite. of sodium. Suitable carriers include, but are not limited to, cocoa butter (theobroma oil), glycerin-gelatin, carbowax (polyoxyethylene glycol), sperm whale, paraffin, white and yellow wax, appropriate mixtures of mono, di, and triglycerides of acids. fatty acids and hydrogels, such as polyvinyl alcohol, hydroxyethyl methacrylate, and polyacrylic acid. Combinations of the various vehicles can also be used. Rectal and vaginal suppositories can be prepared by compression or molding. The typical weight of a rectal and vaginal suppository is about 2g to about 3g.
[0330] The pharmaceutical compositions can be administered ophthalmically in the form of solutions, suspensions, ointments, emulsions, gel-forming solutions, powders for solutions, gels, eye inserts, and implants.
[0332] The pharmaceutical compositions can be administered intranasally or by inhalation to the respiratory tract. The pharmaceutical compositions may be provided in the form of an aerosol or solution for administration through the use of a pressurized container, pump, aerosol, atomizer, such as an atomizer through the use of electrohydrodynamics to produce a slight mist, or nebulizer, alone or in combination with a suitable propellant, such as 1,1,1,2-tetrafluoroethane or 1,1,1,2,3,3,3-heptafluoropropane. The pharmaceutical compositions can also be provided as a dry powder for insufflation, alone or in combination with an inert carrier, such as lactose or phospholipids, and nasal drops. For intranasal use, the powder may comprise a bioadhesive agent, for example chitosan or cyclodextrin.
[0334] Solutions or suspensions for use in a pressurized container, pump, aerosol, atomizer, or nebulizer may be formulated to contain ethanol, aqueous ethanol, or an alternative agent suitable to disperse, solubilize, or extend the release of the active ingredient (s) provided herein. document; a propellant as a solvent, and / or a surfactant, such as sorbitan trioleate, oleic acid or an oligolactic acid.
[0336] The pharmaceutical compositions can be micronized to a size suitable for administration by inhalation, such as about 50 microns or less, or about 10 microns or less. Particles of such sizes can be prepared by a grinding method known to those skilled in the art, such as spiral fine grinding, fluidized bed fine grinding, supercritical fluid processing to form nanoparticles, high pressure homogenization, or spray drying. .
[0338] Capsules, blisters and cartridges for use in an inhaler or insufflator can be formulated to contain a powder mixture of the pharmaceutical compositions; a suitable powder base such as lactose or starch, and a performance modifier such as L-leucine, mannitol or magnesium stearate. Lactose can be anhydrous or in the form of a monohydrate. Other suitable excipients or carriers include, but are not limited to, dextran, glucose, maltose, sorbitol, xylitol, fructose, sucrose, and trehalose. Pharmaceutical compositions for inhaled / intranasal administration may further comprise a suitable flavor, such as menthol and / or levomenthol; and / or sweeteners, such as saccharin and / or sodium saccharin.
[0340] Pharmaceutical compositions for topical administration can be formulated to be immediate or modified release, including delayed, sustained, pulsed, controlled, targeted, and timed release.
[0341] E. Modified release
[0343] The pharmaceutical compositions can be formulated in a modified release dosage form. As used herein, the term "modified release" refers to a dosage form in which the rate or site of release of one or more active ingredients is different from that of an immediate release dosage form when used. administered by the same route. Modified release dosage forms include, but are not limited to, delayed, extended, prolonged, sustained, pulsatile, controlled, accelerated, rapid, targeted, and timed release dosage forms; and gastric retention dosage forms. Pharmaceutical compositions in modified release dosage forms can be prepared using a variety of modified release devices and methods known to those skilled in the art, including, but not limited to, matrix controlled release devices, osmotic controlled release, multiparticulate controlled release devices, ion exchange resins, enteric coatings, multilayer coatings, microspheres, liposomes, and combinations thereof. Speed of The release of the active ingredient (s) can also be modified by varying the particle sizes and / or the polymorphism of the active ingredient (s).
[0345] Examples of modified release include, but are not limited to, those described in US Pat. U.S. No. 3,845,770; 3,916,899; 3,536,809; 3,598,123; 4,008,719; 5,674,533; 5,059,595; 5,591,767; 5,120,548; 5,073,543; 5,639,476; 5,354,556; 5,639,480; 5,733,566; 5,739,108; 5,891,474; 5,922,356; 5,972,891; 5,980,945; 5,993,855; 6,045,830; 6,087,324; 6,113,943; 6,197,350; 6,248,363; 6,264,970; 6,267,981; 6,376,461; 6,419,961; 6,589,548; 6,613,358; and 6,699,500; the contents of which are incorporated herein by reference in their entirety.
[0347] 1. Controlled release devices in the matrix
[0349] Pharmaceutical compositions in a modified release dosage form can be made using a matrix controlled release device known to those of skill in the art (see, for example, Takada et al. In "Encyclopedia of Controlled Drug Delivery," "Vol. 2, Mathiowitz Ed., Wiley, 1999).
[0351] In certain embodiments, pharmaceutical compositions in a modified release dosage form are formulated using an erodible matrix device, which is water swellable, erodible, or soluble polymers, including, but not limited to, synthetic polymers, and naturally occurring polymers and derivatives, such as polysaccharides and proteins.
[0353] Materials useful for forming an erodible matrix include, but are not limited to, chitin, chitosan, dextran, and pullulan; agar gum, acacia gum, karaya gum, locust bean gum, tragacanth gum, carrageenans, ghatti gum, guar gum, xanthan gum and scleroglucan; starches, such as dextrin and maltodextrin; hydrophilic colloids, such as pectin; phosphatides, such as lecithin; alginates; Propylene Glycol Alginate; jelly; collagen; cellulosics, such as ethyl cellulose (EC), methyl ethyl cellulose (MEC), carboxymethyl cellulose (CMC), CMEC, hydroxyethyl cellulose (HEC), hydroxypropyl cellulose (HPC), cellulose acetate (CA), cellulose propionate (CP), cellulose butyrate (CB ), cellulose acetate butyrate (CAB), CAP, CAT, hydroxypropylmethylcellulose (HPMC), HPMCP, HPMCAS, hydroxypropylmethylcellulose acetate tinmethylate (HPMCAT) and ethylhydroxyethylcellulose (EHEC); polyvinyl pyrrolidone; polyvinyl alcohol; polyvinyl acetate; glycerol fatty acid esters; polyacrylamide; polyacrylic acid; copolymers of ethacrylic acid or methacrylic acid (EUDRAGIT®, Rohm America, Inc., Piscataway, NJ); poly (2-hydroxyethyl methacrylate) polylactides; copolymers of L-glutamic acid and ethyl-L-glutamate; degradable lactic acid-glycolic acid copolymers; poly-D - (-) - 3-hydroxybutyric acid; and other acrylic acid derivatives, such as homopolymers and copolymers of butylmethacrylate, methyl methacrylate, ethyl methacrylate, ethylacrylate, (2-dimethylaminoethyl) methacrylate and (trimethylamineethyl) methacrylate chloride.
[0355] In certain embodiments, the pharmaceutical compositions are formulated with a non-erodible matrix device. The active ingredient (s) are dissolved or dispersed in an inert matrix and are released primarily by diffusion through the inert matrix once they are administered. Suitable materials for use as a non-erodible matrix device include, but are not limited to, insoluble plastics, such as polyethylene, polypropylene, polyisoprene, polyisobutylene, polybutadiene, polymethylmethacrylate, polybutylmethacrylate, chlorinated polyethylene, polyvinyl chloride, methyl copolymers. acrylate-methyl methacrylate, ethylene-vinyl acetate copolymers, ethylene / propylene copolymers, ethylene / ethyl acrylate copolymers, vinyl chloride-vinyl acetate copolymers, vinylidene chloride, ethylene-propylene, polyethylene terephthalate ionomer, gums butyl, epichlorohydrin rubbers, ethylene / vinyl alcohol copolymer, ethylene / vinyl acetate / vinyl alcohol terpolymer, ethylene / vinylxyethanol copolymer, polyvinyl chloride, plasticized nylon, plasticized polyethylene terephthalate, natural rubber, silicone rubbers, polydimethylsanos and silicone carbonate copolymers, hydrophilic polymers, such as e Tylcellulose, cellulose acetate, crospovidone, and cross-linked partially hydrolyzed polyvinylacetate, and fatty compounds, such as carnauba wax, microcrystalline wax, and triglycerides.
[0357] In a controlled release system in the matrix, the controlled release kinetics can be controlled, for example, through the type of polymer used, the viscosity of the polymer, the particle sizes of the polymer and / or the active ingredient (s), the ratio of the active ingredient (s) to the polymer, and other excipients or carriers in the compositions.
[0359] Pharmaceutical compositions in a modified release dosage form can be prepared by methods known to those skilled in the art, including direct compression, dry or wet granulation followed by compression, and melt granulation followed by compression.
[0360] 2. Osmotic controlled release devices
[0361] Pharmaceutical compositions in a modified release dosage form can be made using an osmotic controlled release device including, but not limited to, single chamber system, two chamber system, asymmetric membrane technology (AMT). and extruder core system (ECS). In general, such devices have at least two components: (a) a core containing an active ingredient; and (b) a semi-permeable membrane with at least one delivery port, which encapsulates the core. The semi-permeable membrane controls the influx of water into the core from an aqueous environment of use to cause drug release by extrusion through the administration port (s).
[0363] In addition to the active ingredient (s), the core of the osmotic device optionally includes an osmotic agent, which generates a driving force to transport water from the environment of use to the core of the device. One class of osmotic agents are the water-swellable hydrophilic polymers, which are also referred to as "osmopolymers" and "hydrogels." Hydrophilic water-swellable polymers suitable as osmotic agents include, but are not limited to, hydrophilic acrylic and vinyl polymers, polysaccharides such as calcium alginate, polyethylene oxide (PEO), polyethylene glycol (PEG), polypropylene glycol (PPG), poly (2-hydroxyethyl methacrylate), poly (acrylic acid), poly (methacrylic acid), polyvinylpyrrolidone (PVP), cross-linked PVP, polyvinyl alcohol (PVA), PVA / PVP copolymers, PVA / PVP copolymers with hydrophobic monomers such as methacrylate methyl and vinyl acetate, hydrophilic polyurethanes containing large PEO blocks, croscarmellose sodium, carrageenan, hydroxyethylcellulose (HEC), hydroxypropylcellulose (HPC), hydroxypropylmethylcellulose (HPMC), carboxymethylcellulose (CMC), and carboxymethylcellulose (CEC), sodium carboxyethylcellulose , polycarbophil, gelatin, xanthan gum and sodium starch glycolate.
[0365] The other class of osmotic agents are osmogens, which are capable of absorbing water to affect an osmotic pressure gradient across the surrounding coating barrier. Suitable osmogens include, but are not limited to, inorganic salts, such as magnesium sulfate, magnesium chloride, calcium chloride, sodium chloride, lithium chloride, potassium sulfate, potassium phosphates, sodium carbonate, sodium sulfite. sodium, lithium sulfate, potassium chloride, and sodium sulfate; sugars, such as dextrose, fructose, glucose, inositol, lactose, maltose, mannitol, raffinose, sorbitol, sucrose, trehalose, and xylitol; organic acids, such as ascorbic acid, benzoic acid, fumaric acid, citric acid, maleic acid, sebacic acid, sorbic acid, adipic acid, edetic acid, glutamic acid, p-toluenesulfonic acid, succinic acid, and tartaric acid; urea; and mixtures of two or more thereof.
[0367] Osmotic agents of different dissolution rates can be used to influence how quickly the active ingredient (s) are initially delivered from the dosage form. For example, amorphous sugars, such as MANNOGEM ™ EZ (SPI Pharma, Lewes, DE) can be used to offer more rapid delivery during the first two hours to rapidly produce the desired therapeutic effect, and gradually and continuously release the remaining amount to maintain the desired level of therapeutic or prophylactic effect over an extended period of time. In this case, one or more active ingredients are released at said rate to replace the amount of the active ingredient that is metabolized and excreted.
[0369] The core can also include a wide variety of excipients and carriers as described herein to enhance dosage form performance or to enhance stability or processing.
[0371] Materials useful for forming the semipermeable membrane include various grades of acrylics, vinyls, ethers, polyamides, polyesters, and cellulosic derivatives that are permeable in water and insoluble in water at physiologically relevant pH, or that are capable of becoming insoluble in water by alteration. chemistry, such as crosslinking. Some examples of suitable polymers useful for forming the coating include plasticized, unplasticized and reinforced cellulose acetate (CA), cellulose diacetate, cellulose triacetate, CA propionate, cellulose nitrate, cellulose acetate butyrate (CAB), ethyl carbamate CA, CAP, CA methyl carbamate, CA succinate, cellulose acetate trimellitate (CAT), CA dimethylaminoacetate, CA ethyl carbonate, CA chloroacetate, CA ethyl oxalate, CA methyl sulfonate, CA butyl sulfonate, CA p-toluene sulfonate, agar acetate, amylose triacetate, beta glucan acetate, beta glucan triacetate, acetaldehyde dimethyl acetate, locust bean gum triacetate, hydroxylated ethylene vinyl acetate, EC, PEG, PPG, PEG copolymers / PPG, PVP, HEC, HPC, CMC, CMEC, HPMC, HPMCP, HPMCAS, HPMCAT, poly (acrylic) acids and esters of poly (methacrylic acids) and esters and copolymers thereof, starch, dextran, dextrin, chitosan , collagen, gelatin, polyalkene s, polyethers, polysulfones, polyethersulfones, polystyrenes, polyvinyl halides, polyvinyl esters and ethers, natural waxes and synthetic waxes.
[0372] The semi-permeable membrane can also be a hydrophobic microporous membrane, wherein the pores are basically filled with a gas and are not dampened by the aqueous medium, but are permeable to water vapor, as described in US Pat. U.S. No. 5,798,119, which is incorporated by reference herein. Said hydrophobic but water vapor permeable membrane is commonly composed of hydrophobic polymers such as polyalkenes, polyethylene, polypropylene, polytetrafluoroethylene, polyacrylic acid derivatives, polyethers, polysulfones, polyethersulfones, polystyrenes, polyvinyl halides, polyvinylidene fluoride and esters. polyvinyl, natural waxes and synthetic waxes.
[0374] The administration port (s) in the semipermeable membrane can be formed after coating by mechanical or laser drilling. The administration port (s) can be formed in situ by erosion of a plug of water soluble material or by breaking a thinner portion of the membrane over a notch in the core. In addition, administration ports can be formed during the coating process, as in the case of asymmetric membrane coatings of the type described in US Pat. U.S. Nos. 5,612,059 and 5,698,220, each of which is incorporated by reference herein.
[0376] The total amount of active ingredient (s) released and the rate of release can be substantially modulated by the thickness and porosity of the semipermeable membrane, the composition of the core, and the amount, size and position of the administration ports.
[0378] Pharmaceutical compositions in an osmotic controlled release dosage form may further comprise additional conventional excipient (s) or carrier (s), as described herein, to enhance the performance or throughput of the formulation.
[0380] Osmotic controlled release dosage forms can be prepared according to conventional methods and techniques known to those of skill in the art (see, for example, Remington: The Science and Practice of Pharmacy, supra; Santus and Baker, J. Controlled Release 1995 , 35, 1-21; Verma et al., Drug Development and Industrial Pharmacy 2000, 26, 695-708; Verma et al., J. Controlled Release 2002, 79, 7 27).
[0382] In certain embodiments, the pharmaceutical compositions are formulated as a AMT controlled release dosage form, comprising an asymmetric osmotic membrane overlying a core comprising the active ingredient (s) and other pharmaceutically acceptable excipient (s) or carrier (s). See, for example, US Pat. U.S. No. 5,612,059 and WO 2002/17918, each of which is incorporated herein by reference. AMT controlled release dosage forms can be prepared according to conventional methods and techniques known to those skilled in the art, including, for example, direct compression, dry granulation, wet granulation, and a dip coating method.
[0384] In certain embodiments, the pharmaceutical compositions are formulated as an ESC controlled release dosage form, comprising an asymmetric osmotic membrane overlying a core comprising the active ingredient (s), a hydroxyethyl cellulose, and other pharmaceutically acceptable excipient (s) or carrier (s). .
[0386] 3. Multi-particle controlled release devices
[0388] Pharmaceutical compositions in a modified release dosage form can be made as a multi-particle controlled release device, comprising a multiplicity of particles, granules or pellets, ranging from about 10 pm to about 3 mm, from about 50 pm to about 2.5mm or from about 100 pm to about 1mm diameter. Such multiple particles can be made by processes known to those skilled in the art including, for example, wet and dry granulation, extrusion / spheronization, roll compaction, and melt solidification and by spray coating of seed cores. See, for example, Multiparticulate Oral Drug Dellvery, Marcel Dekker: 1994; and Pharmaceutical Pelletization Technology, Marcel Dekker: 1989.
[0390] Other excipients or carriers as described herein can be combined with the pharmaceutical compositions to help process and form the multiple particles. The resulting particles themselves may constitute the multiparticulate device or may be coated by various film-forming materials, such as enteric, water-swellable, and water-soluble polymers. The multiple particles can be further processed as one capsule or tablet.
[0392] 4. Directed administration
[0394] The pharmaceutical compositions can also be formulated to target a particular tissue, receptor, or other area of the body of the subject being treated, including, for example, liposome-based delivery systems, resealed erythrocytes, and antibodies. Examples include, but are not limited to, those disclosed in US Pat. U.S. No. 6,316,652; 6,274,552; 6,271,359; 6,253,872; 6,139,865; 6,131,570; 6,120,751; 6,071,495; 6,060,082; 6,048,736; 6,039,975; 6,004,534; 5,985,307; 5,972,366; 5,900,252; 5,840,674; 5,759,542; and 5,709,874; the contents of which are incorporated by reference herein.
[0396] Methods of use
[0398] In one embodiment, provided herein is a method of treating, preventing, or alleviating one or more symptoms of parasitic disease in a subject, comprising administering to the subject (a) a therapeutically effective amount of: (i) ascorbic acid, or a single enantiomer, a mixture of enantiomers, or a mixture of diastereomers thereof; or a pharmaceutically acceptable salt, solvate or hydrate thereof; and (ii) a quinone compound, or a single enantiomer, a mixture of enantiomers, or a mixture of diastereomers thereof, or a pharmaceutically acceptable salt, solvate, hydrate or prodrug thereof; and (b) a subtherapeutically effective amount of an antiparasitic agent.
[0400] In certain embodiments, one or more symptoms of the parasitic disease include, but are not limited to, abdominal pain, body aches, congestive heart failure, constipation due to colon enlargement, diarrhea, difficulty swallowing due to esophagus enlargement, liver or spleen, swollen eyelids, fatigue, fever, headache, irregular heartbeat, loss of appetite, nausea, rash, sudden cardiac arrest, swollen glands, and vomiting.
[0402] In certain embodiments, the parasitic disease is African trypanosomiasis, amebiasis, ascariasis, babesiosis, Chagas disease, cryptosporidiosis, cutaneous larva migrans, heartworm, echinococcosis, fasciolosis, filariasis, lymphatic phylahasis, giardiasis, helminthiasis leishmaniasis, leishmaniasis infection, viscous leishmaniasis, leishmaniasis infection. , malaria, neurocysticercosis, onchocerciasis, protozoan infection, schistosomiasis, taeniasis, tapeworm infection, toxocariasis, toxoplasmosis, trichinosis, or zoonosis.
[0404] In certain embodiments, the parasitic disease is a protozoan infection. In certain embodiments, the parasitic disease is African sleeping sickness, amoebiasis, babesiosis, Chagas disease, giardiasis, leishmaniasis, malaria, or toxoplasmosis. In certain embodiments, the parasitic disease is Chagas disease. In certain embodiments, the parasitic disease is leishmaniasis. In certain embodiments, the parasitic disease is cutaneous leishmaniasis, mucocutaneous leishmaniasis, or visceral leishmaniasis.
[0406] In one embodiment, provided herein is a method of treating, preventing, or alleviating one or more symptoms of Chagas disease in a subject, comprising administering to the subject (a) a therapeutically effective amount of: (i) ascorbic acid, or a single enantiomer, a mixture of enantiomers, or a mixture of diastereomers thereof; or a pharmaceutically acceptable salt, solvate or hydrate thereof; and (ii) a quinone compound, or a single enantiomer, a mixture of enantiomers, or a mixture of diastereomers thereof, or a pharmaceutically acceptable salt, solvate, hydrate or prodrug thereof; and (b) a subtherapeutically effective amount of an antiparasitic agent.
[0408] In another embodiment, provided herein is a method of treating, preventing, or alleviating one or more symptoms of leishmaniasis in a subject, comprising administering to the subject (a) a therapeutically effective amount of: (i) ascorbic acid, or a single enantiomer, a mixture of enantiomers, or a mixture of diastereomers thereof; or a pharmaceutically acceptable salt, solvate or hydrate thereof; and (ii) a quinone compound, or a single enantiomer, a mixture of enantiomers, or a mixture of diastereomers thereof, or a pharmaceutically acceptable salt, solvate, hydrate or prodrug thereof; and (b) a subtherapeutically effective amount of an antiparasitic agent.
[0410] In another embodiment, provided herein is a method of inhibiting parasite growth in a subject infected with a parasite, comprising administering to the subject (a) a therapeutically effective amount of: (i) ascorbic acid, or a single enantiomer, a mixture of enantiomers, or a mixture of diastereomers thereof; or a pharmaceutically acceptable salt, solvate or hydrate thereof; and (ii) a quinone compound, or a single enantiomer, a mixture of enantiomers, or a mixture of dlastereomers thereof, or a pharmaceutically acceptable salt, solvate, hydrate or prodrug thereof; and (b) a subtherapeutically effective amount of an antiparasitic agent.
[0412] In yet another embodiment, provided herein is a method of eliminating a parasite from a subject, comprising administering to the subject (a) a therapeutically effective amount of: (i) ascorbic acid, or a single enantiomer, a mixture of enantiomers , or a mixture of diastereomers thereof; or a pharmaceutically acceptable salt, solvate or hydrate thereof; and (ii) a quinone compound, or a single enantiomer, a mixture of enantiomers, or a mixture of diastereomers thereof, or a pharmaceutically acceptable salt, solvate, hydrate or prodrug thereof; and (b) a subtherapeutically effective amount of an antiparasitic agent.
[0414] In yet another embodiment, provided herein is a method for enhancing the quality of life of a subject infected with a parasite, comprising administering to the subject (a) a therapeutically effective amount of: (i) ascorbic acid, or a single enantiomer, a mixture of enantiomers, or a mixture of diastereomers thereof; or a pharmaceutically acceptable salt, solvate or hydrate thereof; and (ii) a quinone compound, or a single enantiomer, a mixture of enantiomers, or a mixture of diastereomers thereof, or a pharmaceutically acceptable salt, solvate, hydrate or prodrug thereof; and (b) a subtherapeutically effective amount of an antiparasitic agent.
[0416] In yet another embodiment, provided herein is a method of increasing the efficacy of an antiparasitic agent in a subject infected with a parasite, comprising administering to the subject a therapeutically effective amount of: (i) ascorbic acid, or a single enantiomer. , a mixture of enantiomers, or a mixture of diastereomers thereof; or a pharmaceutically acceptable salt, solvate or hydrate thereof; and (ii) a quinone compound, or a single enantiomer, a mixture of enantiomers, or a mixture of diastereomers thereof, or a pharmaceutically acceptable salt, solvate, hydrate or prodrug thereof.
[0418] In yet another embodiment, provided herein is a method of increasing tolerance to an antiparasitic agent in a subject infected with a parasite, comprising administering to the subject a therapeutically effective amount of: (i) vitamin C, or a pharmaceutically acceptable salt, solvate or hydrate thereof; and (ii) a vitamin K compound, or a single enantiomer, a mixture of enantiomers, or a mixture of diastereomers thereof, or a pharmaceutically acceptable salt, solvate, hydrate or prodrug thereof.
[0420] In yet another embodiment, provided herein is a method of reducing, minimizing, or eliminating a side effect of an antiparasitic agent in a subject infected with a parasite, comprising administering to the subject a therapeutically effective amount of: (i) ascorbic acid , or a single enantiomer, a mixture of enantiomers, or a mixture of diastereomers thereof; or a pharmaceutically acceptable salt, solvate or hydrate thereof; and (ii) a quinone compound, or a single enantiomer, a mixture of enantiomers, or a mixture of diastereomers thereof, or a pharmaceutically acceptable salt, solvate, hydrate or prodrug thereof.
[0422] In certain embodiments, the side effect to be reduced, minimized, or eliminated includes, but is not limited to, abdominal pain, allergic dermatitis, amnesia, anemia, anorexia, anxiety, bone marrow suppression, chills, confusion, decreased blood pressure. appetite, depression, dermatitis, dizziness, dysgeusia, eosinophilia, fever, headache, impotence, insomnia, leukopenia, lymphadenopathy, muscle weakness, nausea, neutropenia, numbness of hands or feet, paraesthesia, peripheral neuropathy, pruritus, purpura, rash, seizures , sore throat, thrombocytopenia, tremors, hives, vomiting, and weight loss. In certain embodiments, the side effect to be reduced, minimized, or eliminated includes, but is not limited to, amnesia, anorexia, dizziness, headache, nausea, weight loss, and vomiting. In certain embodiments, the side effect to be reduced, minimized, or eliminated includes, but is not limited to, allergic dermatitis, anorexia, bone marrow suppression, dermatitis, dysgeusia, insomnia, nausea, peripheral neuropathy, weight loss, and vomiting In certain embodiments, the side effect to be reduced, minimized, or eliminated includes, but is not limited to, allergic dermatitis or peripheral neuropathy. In certain embodiments, the side effect to be reduced, minimized, or eliminated includes, but is not limited to, abdominal pain, anemia, decreased appetite, eosinophilia, fever, headache, leukopenia, lymphadenopathy, nausea, neutropenia, paraesthesia, pruritus. , purpura, rash, thrombocytopenia, hives, vomiting and weight loss. In certain embodiments, the side effect to be reduced, minimized, or eliminated includes, but is not limited to, abdominal pain, decreased appetite, eosinophilia, headache, nausea, neutropenia, itching, rash, hives, vomiting, and loss of weight. In certain In embodiments, the side effect to be reduced, minimized or eliminated includes, but is not limited to, skin hypersensitivity reactions.
[0424] In certain embodiments, the side effect to be reduced, minimized, or eliminated includes, but is not limited to, a side effect of benznidazole. In certain embodiments, the side effect to be reduced, minimized, or eliminated includes, but is not limited to, a side effect of nifurtimox.
[0426] In yet another embodiment, provided herein is a method of reducing the toxicity of an antiparasitic agent in a subject infected with a parasite, comprising administering to the subject a therapeutically effective amount of: (i) ascorbic acid, or a single enantiomer , a mixture of enantiomers, or a mixture of diastereomers thereof; or a pharmaceutically acceptable salt, solvate or hydrate thereof; and (ii) a quinone compound, or a single enantiomer, a mixture of enantiomers, or a mixture of diastereomers thereof, or a pharmaceutically acceptable salt, solvate, hydrate or prodrug thereof.
[0428] In certain embodiments, the toxicity is neurotoxicity. In certain embodiments, the toxicity is bone marrow toxicity. In certain embodiments, the toxicity is nephrotoxicity. In certain embodiments, the toxicity is CNS toxicity. In certain embodiments, the toxicity is peripheral toxicity. In certain embodiments, the toxicity is gastrointestinal toxicity. In certain embodiments, the toxicity is pulmonary toxicity. In certain embodiments, the toxicity is cardiotoxicity. In certain embodiments, the toxicity is hepatotoxicity. In certain embodiments, the toxicity is metabolic toxicity. In certain embodiments, the toxicity is renal toxicity. In certain embodiments, the toxicity is dermatological. In certain embodiments, the toxicity is immunological. In certain embodiments, the toxicity is pulmonary toxicity. In certain embodiments, the toxicity is genotoxicity. In certain embodiments, the toxicity is carcinogenicity. In certain embodiments, the toxicity is embryo-fetal toxicity.
[0430] In certain embodiments, the parasite is Plasmodium, Trypanosoma, Entamoeba, Giardia, Leishmania, Toxoplasma, or Schistosoma. In certain embodiments, the parasite is Plasmodium. In certain embodiments, the parasite is Trypanosoma. In certain embodiments, the parasite is Entamoeba. In certain embodiments, the parasite is Giardia. In certain embodiments, the parasite is Leishmania. In certain embodiments, the parasite is Toxoplasma. In certain embodiments, the parasite is Schistosoma. In certain embodiments, the parasite is Entamoeba histolytica, Giardia lamblia, Leishmania aethiopica, Leishmania amazonensis, Leishmania braziliensis, Leishmania donovani, Leishmania mexicana, Leishmania major, Leishmania tropica, Plasmodium berghei, Plasmodium falciparumii, Plasmodium macenosoma bruiseii, Plasmodium macenosoma cruzi or Toxoplasma gondii. In certain embodiments, the parasite is Entamoeba histolytica. In certain embodiments, the parasite is Giardia lamblia. In certain embodiments, the parasite is Leishmania aethiopica. In certain embodiments, the parasite is Leishmania amazonensis. In certain embodiments, the parasite is Leishmania braziliensis. In certain embodiments, the parasite is Leishmania donovani. In certain embodiments, the parasite is Leishmania mexicana. In certain embodiments, the parasite is Leishmania major. In certain embodiments, the parasite is Leishmania tropica. In certain embodiments, the parasite is Plasmodium berghei. In certain embodiments, the parasite is Plasmodium falciparum. In certain embodiments, the parasite is Plasmodium yoelii. In certain embodiments, the parasite is Schistosoma mansonii. In certain embodiments, the parasite is Trypanosoma brucei. In certain embodiments, the parasite is Trypanosoma cruzi. In certain embodiments, the parasite is Toxoplasma gondii.
[0432] In certain embodiments, the ascorbic acid and quinone compounds used in the methods provided herein are administered as a single dose, such as, for example, as a single bolus injection, or as a single tablet or pill. oral. In certain embodiments, the ascorbic acid and quinone compounds used in the methods provided herein are administered over time, such as, for example, continuous infusion over time or bolus doses divided over time.
[0434] In certain embodiments, the weight ratio of the ascorbic acid compound to the quinone compound used in the methods provided herein ranges from about 1 to about 1000, from about 10 to about 500, from about 50 to about 500, from about 100 to about 500 or from about 200 to about 500. In certain embodiments, the weight ratio of the ascorbic acid compound to the quinone compound that is used in the methods provided herein is about 100, about 200, about 300, about 400, about 500, or about 600. In certain embodiments, the weight ratio of the ascorbic acid compound to the quinone compound that is used in the methods provided in the herein ranges from about 200 to about 400. In certain embodiments, the weight ratio of the ascorbic acid compound to the quinone compound used in the methods provided herein is about 200. In certain embodiments, the ratio in The weight of the ascorbic acid compound to the quinone compound used in the methods provided herein is about 400.
[0436] In certain embodiments, the weight ratio of the ascorbic acid compound to the quinone compound used in the methods provided herein ranges from about 25 to about 250, or from about 50 to about 200, from about 50 to about 150 , or from about 80 to about 120. In certain embodiments, the weight ratio of the ascorbic acid compound to the quinone compound used in the methods provided herein is about 1, about 2, about 4, about 10 , about 20, about 30, about 40, about 50, about 60, about 70, about 80, about 90, about 100, about 110, about 120, about 130, about 140, about 150, about 160, about 170, about 180, approximately 190, approximates daly 200, about 210, about 220,
[0437] about 230, about 240, or about 250. In certain embodiments, the weight ratio of the ascorbic acid compound to the quinone compound used in the methods provided herein is about 100. In certain embodiments, the weight ratio The ascorbic acid compound to the quinone compound used in the methods provided herein is about 200.
[0439] In certain embodiments, the ascorbic acid and quinone compounds used in the methods provided herein are administered once daily (QD), or divided into multiple daily doses, such as twice daily (BID), three times a day (TID), four times a day (QID), five times a day, six times a day, seven times a day, eight times a day, nine times a day, or ten times a day. In certain embodiments, the ascorbic acid compound used in the methods provided herein is administered QD, or divided into multiple daily doses, such as BID, TID, QID, five times a day, six times a day, seven times a day, eight times a day, nine times a day, or ten times a day. In certain embodiments, the quinone compound used in the methods provided herein is administered QD, or divided into multiple daily doses such as BID, TID, QID, five times a day, six times a day, seven times. a day, eight times a day, nine times a day, or ten times a day.
[0441] In certain embodiments, the ascorbic acid compound and / or quinone compound used in the methods provided herein are administered from about 1 to about 20 times per day, from about 1 to about 15 times per day, of about 1 to about 10 times a day or about 1 to about 5 times a day. In certain embodiments, the ascorbic acid compound and / or quinone compound used in the methods provided herein are administered every 1 to 10 hours or hours, every 2 to 8 hours, every 3 to 7 hours, every 4 to 6 hours or every 5 to 6 hours. In certain embodiments, the ascorbic acid compound and / or quinone compound used in the methods provided herein are administered every hour, every 2 hours, every 3 hours, every 4 hours, every 5 hours, every 6 hours. hours, every 7 hours, every 8 hours, every 9 hours, or every 10 hours. In certain embodiments, the ascorbic acid compound and / or the quinone compound that is used in the methods provided herein is administered once a day. In certain embodiments, the ascorbic acid compound and / or quinone compound used in the methods provided herein is administered 5 times per day. In certain embodiments, the ascorbic acid compound and / or the quinone compound used in the methods provided herein is administered 10 times per day. In certain embodiments, the ascorbic acid compound and / or quinone compound used in the methods provided herein is administered every 4, 5, or 6 hours. In certain embodiments, the quinone and ascorbic acid compounds used in the methods provided herein are administered daily.
[0443] In certain embodiments, the ascorbic acid compound that is used in Methods provided herein is administered to the subject in an amount ranging from about 1 to about 1000 mg / kg / day, from about 5 to about 500 mg / kg / day, or from about 10 to about 100 mg / kg / day. . In certain embodiments, the ascorbic acid compound used in the methods provided herein is administered to the subject in an amount of about 10 mg / kg / day, about 20 mg / kg / day, about 30 mg / kg / day. day, about 40 mg / kg / day, about 50 mg / kg / day, about 60 mg / kg / day, about 70 mg / kg / day, about 80 mg / kg / day, about 90 mg / kg / day, about 100 mg / kg / day, about 200 mg / kg / day, about 300 mg / kg / day, about 400 mg / kg / day, or about 500 mg / kg / day.
[0445] In certain embodiments, the quinone compound used in the methods provided herein is administered to the subject in an amount ranging from about 0.01 to about 50 mg / kg / day, from about 0.015 to about 50 mg / day. kg / day, about 0.05 to about 40 mg / kg / day, about 0.2 to about 30 mg / kg / day, or about 10 to about 30 mg / kg / day. In certain embodiments, the quinone compound used in the methods provided herein is administered to the subject in an amount of about 0.015 mg / kg / day, about 5 mg / kg / day, about 25 mg / kg / day. or about 30 mg / kg / day.
[0447] The administered doses of the quinone ascorbic acid compounds can also be independently expressed in units other than the unit "mg / kg / day" or "g / kg / day". For example, doses for parenteral administration can be expressed as mg / m2 / day. One skilled in the art would know how to convert doses from mg / kg / day to mg / m2 / day given either the height or weight of a subject or both. For example, a dose of 1 mg / kg / day for a 65 kg human is approximately 38 mg / m2 / day.
[0449] In certain embodiments, the ascorbic acid compound used in the methods provided herein is administered to the subject in an amount ranging from about 0.1 g to about 3 g every four hours. In certain embodiments, the quinone compound used in the methods provided herein is administered to the subject in an amount that ranges from about 0.2mg to about 300mg every four hours.
[0451] In certain embodiments, the ascorbic acid compound used in the methods provided herein is administered to the subject in an amount ranging from about 500 mg to about 3000 mg per day. In certain embodiments, the quinone compound used in the methods provided herein is administered to the subject in an amount ranging from about 3 mg to about 30 mg per day. In certain embodiments, the ascorbic acid compound used in the methods provided herein is administered to the subject in an amount ranging from about 500 mg to about 10,000 mg per day. In certain embodiments, the quinone compound used in the methods provided herein is administered to the subject in an amount ranging from about 3 mg to about 100 mg per day. In certain embodiments, the ascorbic acid compound used in the methods provided herein is administered to the subject in an amount greater than about 500 mg per day. In certain embodiments, the quinone compound used in the methods provided herein is administered to the subject in an amount greater than about 3 mg per day. In certain embodiments, the ascorbic acid compound used in the methods provided herein is administered to the subject in an amount up to about 10,000 mg per day. In certain embodiments, the quinone compound used in the methods provided herein is administered to the subject in an amount up to about 100 mg per day. In certain embodiments, the ascorbic acid compound used in the methods provided herein is administered to the subject in an amount up to about 15,000 mg per day. In certain embodiments, the quinone compound used in the methods provided herein is administered to the subject in an amount up to about 150 mg per day. In certain embodiments, the ascorbic acid compound used in the methods provided herein is administered to the subject in an amount up to about 20,000 mg per day. In certain embodiments, the quinone compound used in the methods provided herein is administered to the subject in an amount up to about 200 mg per day. In certain embodiments, the ascorbic acid compound used in the methods provided herein is administered to the subject in a amount up to about 30,000 mg per day. In certain embodiments, the quinone compound used in the methods provided herein is administered to the subject in an amount up to about 300 mg per day. In certain embodiments, the ascorbic acid compound used in the methods provided herein is administered to the subject in an amount up to about 40,000 mg per day. In certain embodiments, the quinone compound used in the methods provided herein is administered to the subject in an amount up to about 400 mg per day. In certain embodiments, the ascorbic acid compound used in the methods provided herein is administered to the subject in an amount up to about 50,000 mg per day. In certain embodiments, the quinone compound used in the methods provided herein is administered to the subject in an amount up to about 500 mg per day. In certain embodiments, the ascorbic acid compound used in the methods provided herein is administered to the subject in an amount up to about 60,000 mg per day. In certain embodiments, the quinone compound used in the methods provided herein is administered to the subject in an amount up to about 600 mg per day. In certain embodiments, the ascorbic acid compound used in the methods provided herein is administered to the subject in an amount up to about 70,000 mg per day. In certain embodiments, the quinone compound used in the methods provided herein is administered to the subject in an amount up to about 700 mg per day. In certain embodiments, the ascorbic acid compound used in the methods provided herein is administered to the subject in an amount up to about 80,000 mg per day. In certain embodiments, the quinone compound used in the methods provided herein is administered to the subject in an amount up to about 800 mg per day. In certain embodiments, the ascorbic acid compound used in the methods provided herein is administered to the subject in an amount up to about 90,000 mg per day. In certain embodiments, the quinone compound used in the methods provided herein is administered to the subject in an amount up to about 900 mg per day. In certain embodiments, the ascorbic acid compound used in the methods provided herein is administered to the subject in an amount up to about 100,000 mg per day. In certain embodiments, The quinone compound used in the methods provided herein is administered to the subject in an amount up to about 1000 mg per day. In certain embodiments, the ascorbic acid compound used in the methods provided herein is administered to the subject in an amount up to about 200,000 mg per day. In certain embodiments, the quinone compound used in the methods provided herein is administered to the subject in an amount up to about 2000 mg per day.
[0452] In certain embodiments, as used in the methods provided herein, the ascorbic acid compound is administered to the subject in an amount ranging from about 10,000 mg to about 30,000 mg per day; and the quinone compound is administered to the subject in an amount ranging from about 100 mg to about 1500 mg per day. In certain embodiments, as used in the methods provided herein, the ascorbic acid compound is administered to the subject in an amount ranging from about 10,000 mg to about 20,000 mg per day; and the quinone compound is administered to the subject in an amount ranging from about 100 mg to about 1000 mg per day. In certain embodiments, as used in the methods provided herein, the ascorbic acid compound is administered to the subject in an amount of about 15,000 mg per day; and the quinone compound is administered to the subject in an amount ranging from about 150 mg to about 600 mg per day.
[0454] In certain embodiments, as used in the methods provided herein, the ascorbic acid compound is administered to the subject in an amount ranging from about 2000 mg to about 3000 mg per day; and the quinone compound is administered to the subject in an amount ranging from about 12 mg to about 19 mg per day. In certain embodiments, as used in the methods provided herein, the ascorbic acid compound is administered to the subject in an amount ranging from about 2000 mg to about 3000 mg per day; and the quinone compound is administered to the subject in an amount ranging from about 20 mg to about 30 mg per day.
[0456] In certain embodiments, as used in the methods provided herein, the ascorbic acid compound is administered to the subject in a amount of about 2000 mg per day; and the quinone compound is administered to the subject in an amount of about 12 mg per day. In certain embodiments, as used in the methods provided herein, the ascorbic acid compound is administered to the subject in an amount of about 3000 mg per day; and the quinone compound is administered to the subject in an amount of about 19 mg per day.
[0458] In certain embodiments, as used in the methods provided herein, the ascorbic acid compound is administered to the subject in an amount of about 2000 mg per day; and the quinone compound is administered to the subject in an amount of about 20 mg per day. In certain embodiments, as used in the methods provided herein, the ascorbic acid compound is administered to the subject in an amount of about 3000 mg per day; and the quinone compound is administered to the subject in an amount of about 30 mg per day.
[0460] In certain embodiments, as used in the methods provided herein, the quinone and ascorbic acid compounds are administered as one or more capsules, each of which comprises about 500 mg of sodium L-ascorbate and about 3 mg of 1,2,3,4-tetrahydro-2-methyl-1,4-dioxo-2-naphthalene sulfonate. In certain embodiments, as used in the methods provided herein, the quinone and ascorbic acid compounds are administered as one or more capsules, each of which comprises about 500 mg of sodium L-ascorbate and about 5 mg of sodium 1,2,3,4 tetrahydro-2-methyl-1,4-dioxo-2-naphthalenesulfonate.
[0462] In certain embodiments, as used in the methods provided herein, the quinone and ascorbic acid compounds are administered as one or more capsules, each of which comprises about 1000 mg of calcium L-ascorbate and about 10 mg of 2-methyl-1,4-naphthalenedione. In certain embodiments, as used in the methods provided herein, the quinone and ascorbic acid compounds are administered as one or more capsules, each of which comprises approximately 925 mg of calcium L-ascorbate and approximately 9 mg (eg 9.25 mg) of 2-methyl-1,4-naphthalenedione.
[0463] Depending on the condition of the parasitic disease to be treated and the condition of the subject, the ascorbic acid and quinone compounds used in the methods provided herein can be independently administered by oral, parenteral (eg, intramuscular, intraperitoneal, intravenous, IVC, injection or intracisternal infusion, injection subcutaneous or implant), inhalation, nasal, vaginal, rectal, sublingual or topical (eg, transdermal or local). In certain embodiments, the quinone and ascorbic acid compounds used in the methods provided herein are independently administered via an oral, parenteral, intravenous, or topical route of administration. The ascorbic acid and quinone compounds used in the methods provided herein can be formulated, alone or in combination, in suitable dosage unit with one or more pharmaceutically acceptable excipients suitable for each route of administration.
[0465] In one embodiment, the ascorbic acid compound is administered orally. In another embodiment, the ascorbic acid compound is administered parenterally. In yet another embodiment, the ascorbic acid compound is administered intravenously. In yet another embodiment, the ascorbic acid compound is administered topically.
[0467] In one embodiment, the quinone compound is administered orally. In another embodiment, the quinone compound is administered parenterally. In yet another embodiment, the quinone compound is administered intravenously. In yet another embodiment, the quinone compound is administered topically.
[0469] In one embodiment, the ascorbic acid compound is administered simultaneously with the quinone compound. In another embodiment, the ascorbic acid compound is administered separately with the quinone compound. In still another embodiment, the ascorbic acid compound is administered sequentially with the quinone compound. In yet another embodiment, the ascorbic acid compound is administered before the quinone compound. In still another embodiment, the ascorbic acid compound is administered after the quinone compound.
[0471] In certain embodiments, the ascorbic acid and quinone compounds are administered together in a single composition comprising ascorbic acid, or a single enantiomer, a mixture of enantiomers, or a mixture of diastereomers thereof; or a pharmaceutically acceptable salt, solvate or hydrate thereof; and a quinone compound, or a single enantiomer, a mixture of enantiomers, or a mixture of diastereomers thereof, or a pharmaceutically acceptable salt, solvate, hydrate or prodrug thereof.
[0473] In certain embodiments, the quinone and ascorbic acid compounds are administered to the subject after lunchtime. In certain embodiments, the quinone and ascorbic acid compounds are administered to the subject with a meal.
[0475] In one embodiment, the antiparasitic agent is an antiprotozoan, an anthelmintic, an antinematode, an antichode, an antitrematode, an antiamebic, or an antifungal. In other embodiments, the antiparasitic agent is albendazole, amphotericin B, benznidazole, bephenium, diethylcarbamzine, eflornithine, flubendazole, ivermectin, mebendazole, meglumine antimonite, melarsoprol, metronidazole, miltefosine, niclosamide, pyramid, nifurtimoanquantium, antifurtimovanquimide, nifurtimovanquantimony, pirvinium, sodium stibogluconate, thiabendazole, or tinidazole. In yet another embodiment, the antiparasitic agent is nifurtimox.
[0477] In one embodiment, the antiparasitic agent is a nitroimidazole. In another embodiment, the antiparasitic agent is a 2-nitroimidazole. In yet another embodiment, the antiparasitic agent is a 5-nitroimidazole. In yet another embodiment, the antiparasitic agent is azanidazole, dimetridazole, megazol, metronidazole, nimorazole, ornidazole, pretomanid, or tinidazole. In yet another embodiment, the antiparasitic agent is benznidazole.
[0479] In certain embodiments, the subtherapeutically effective amount of the antiparasitic agent is not more than about 1/2, not more than about 1/3, not more than about 1/4, less than about 1/5, not more than about 1/10 , no more than about 1/20, no more than about 1/50, or no more than about 1/100 of the therapeutically effective amount of the antiparasitic agent when used alone.
[0481] In certain embodiments, the subtherapeutically effective amount of the antiparasitic agent is no greater than about 1/2 the therapeutically effective amount of the antiparasitic agent when used alone. In certain embodiments, the subtherapeutically effective amount of the antiparasitic agent is no greater than about 1/3 the therapeutically effective amount of the antiparasitic agent when used alone. In certain embodiments, the amount subtherapeutically The effective amount of the antiparasitic agent is no greater than about 1/4 the therapeutically effective amount of the antiparasitic agent when used alone. In certain embodiments, the subtherapeutically effective amount of the antiparasitic agent is no greater than about 1/5 the therapeutically effective amount of the antiparasitic agent when used alone. In certain embodiments, the subtherapeutically effective amount of the antiparasitic agent is no greater than about 1/10 the therapeutically effective amount of the antiparasitic agent when used alone. In certain embodiments, the subtherapeutically effective amount of the antiparasitic agent is no greater than about 1/20 the therapeutically effective amount of the antiparasitic agent when used alone. In certain embodiments, the subtherapeutically effective amount of the antiparasitic agent is no greater than about 1/50 the therapeutically effective amount of the antiparasitic agent when used alone. In certain embodiments, the subtherapeutically effective amount of the antiparasitic agent is no greater than about 1/100 the therapeutically effective amount of the antiparasitic agent when used alone.
[0483] In certain embodiments, the antiparasitic agent is administered to the subject prior to administration of the ascorbic acid and quinone compounds. In certain embodiments, the antiparasitic agent is administered to the subject at the same time as the ascorbic acid and the quinone compounds. In certain embodiments, the antiparasitic agent is administered to the subject after administration of the ascorbic acid and quinone compounds.
[0485] In certain embodiments, the antiparasitic agent, as used in the methods provided herein, is administered QD or divided into multiple target doses such as BID, TID, or QID. In certain embodiments, the antiparasitic agent as used in the methods provided herein is administered QD. In certain embodiments, the antiparasitic agent as used in the methods provided herein is administered BID. In certain embodiments, the antiparasitic agent as used in the methods provided herein is administered TID. In certain embodiments, the antiparasitic agent as used in the methods provided herein is administered QID.
[0487] In certain embodiments, the antiparasitic agent as used in the methods provided herein is administered to the subject in an amount that ranges from about 10 pg / kg / day to about 10 mg / kg / day, from about 20 pg / kg / day to about 5 mg / kg / day, from about 50 pg / kg / day to about 2 mg / kg / day, or from about 100 pg / kg / day to about 1 mg / kg / day. In certain embodiments, the antiparasitic agent, as used in the methods provided herein, is administered to the subject in an amount ranging from about 10 pg / kg / day to about 10 mg / kg / day. In certain embodiments, the antiparasitic agent, as used in the methods provided herein, is administered to the subject in an amount ranging from about 20 pg / kg / day to about 5 mg / kg / day. In certain embodiments, the antiparasitic agent, as used in the methods provided herein, is administered to the subject in an amount ranging from about 50 pg / kg / day to about 2 mg / kg / day. In certain embodiments, the antiparasitic agent, as used in the methods provided herein, is administered to the subject in an amount ranging from about 100 pg / kg / day to about 1 mg / kg / day.
[0489] In certain embodiments, the antiparasitic agent is benznidazole and is administered to the subject in an amount ranging from about 10 pg / kg / day to about 10 mg / kg / day, from about 20 pg / kg / day to about 5 mg / kg. / day, from about 50 pg / kg / day to about 2 mg / kg / day, or from about 100 pg / kg / day to about 1 mg / kg / day. In certain embodiments, the antiparasitic agent is benznidazole and is administered to the subject in an amount ranging from about 10 pg / kg / day to about 10 mg / kg / day. In certain embodiments, the antiparasitic agent is benznidazole and is administered to the subject in an amount ranging from about 20 pg / kg / day to about 5 mg / kg / day. In certain embodiments, the antiparasitic agent is benznidazole and is administered to the subject in an amount ranging from about 50 pg / kg / day to about 2 mg / kg / day. In certain embodiments, the antiparasitic agent is benznidazole and is administered to the subject in an amount ranging from about 100 pg / kg / day to about 1 mg / kg / day.
[0491] The administered doses of the antiparasitic agent can also be expressed in units other than the unit "mg / kg / day" or "g / kg / day". For example, doses for parenteral administration can be expressed as mg / m2 / day. One skilled in the art would know how to convert doses from mg / kg / day to mg / m2 / day given either the height or weight of a subject or both. For example, a dose of 1 mg / kg / day for a 65-year-old human kg is approximately 38 mg / m2 / day.
[0493] In certain embodiments, the antiparasitic agent as used in the methods provided herein is administered to the subject in an amount ranging from about 0.01 mg to about 200 mg per day, from about 0.02 mg to about 100 mg. per day, from about 0.05 mg to about 50 mg per day, from about 0.1 mg to about 10 mg per day, from about 0.1 mg to about 5 mg per day, from about 0.1 mg to about 2 mg per day, or from about 0.1 mg to about 1 mg per day. In certain embodiments, the antiparasitic agent as used in the methods provided herein is administered to the subject in an amount ranging from about 0.01 mg to about 200 mg per day. In certain embodiments, the antiparasitic agent as used in the methods provided herein is administered to the subject in an amount ranging from about 0.02 mg to about 100 mg per day. In certain embodiments, the antiparasitic agent as used in the methods provided herein is administered to the subject in an amount ranging from about 0.05 mg to about 50 mg per day. In certain embodiments, the antiparasitic agent as used in the methods provided herein is administered to the subject in an amount ranging from about 0.1 mg to about 10 mg per day. In certain embodiments, the antiparasitic agent as used in the methods provided herein is administered to the subject in an amount ranging from about 0.1 mg to about 5 mg per day. In certain embodiments, the antiparasitic agent as used in the methods provided herein is administered to the subject in an amount ranging from about 0.1 mg to about 2 mg per day. In certain embodiments, the antiparasitic agent as used in the methods provided herein is administered to the subject in an amount ranging from about 0.1 mg to about 1 mg per day.
[0495] In certain embodiments, the antiparasitic agent is benznidazole and is administered to the subject in an amount ranging from about 0.01 mg to about 200 mg per day, from about 0.02 mg to about 100 mg per day, from about 0.05 mg to about 50 mg per day, from about 0.1 mg to about 10 mg per day, from about 0.1 mg to about 5 mg per day, from about 0.1 mg to about 2 mg per day, or from about 0.1 mg to about 1 mg per day . In certain embodiments, the antiparasitic agent is benznidazole and is administered to the subject in an amount ranging from about 0.01 mg to about 200 mg per day. In certain embodiments, the antiparasitic agent is benznidazole and is administered to the subject in an amount ranging from about 0.02 mg to about 100 mg per day. In certain embodiments, the antiparasitic agent is benznidazole and is administered to the subject in an amount ranging from about 0.05 mg to about 50 mg per day. In certain embodiments, the antiparasitic agent is benznidazole and is administered to the subject in an amount ranging from about 0.1 mg to about 10 mg per day. In certain embodiments, the antiparasitic agent is benznidazole and is administered to the subject in an amount ranging from about 0.1 mg to about 5 mg per day. In certain embodiments, the antiparasitic agent is benznidazole and is administered to the subject in an amount ranging from about 0.1 mg to about 2 mg per day. In certain embodiments, the antiparasitic agent is benznidazole and is administered to the subject in an amount ranging from about 0.1 mg to about 1 mg per day.
[0497] Depending on the condition of the parasitic disease to be treated and the condition of the subject, the antiparasitic agent used in the methods provided herein can be administered by oral, parenteral (eg, intramuscular, intraperitoneal, intravenous routes of administration). , VSD, intracisternal injection or infusion, subcutaneous injection or implant), inhalation, nasal, vaginal, rectal, sublingual, or topical (eg, transdermal or local). In certain embodiments, the antiparasitic agent used in the methods provided herein is administered by oral, parenteral, intravenous, or topical routes of administration. The antiparasitic agent used in the methods provided herein can be formulated, can be formulated, alone or in combination, in suitable dosage unit with one or more pharmaceutically acceptable excipients suitable for each route of administration.
[0499] In one embodiment, the antiparasitic agent is administered orally. In another embodiment, the antiparasitic agent is administered parenterally. In yet another embodiment, the antiparasitic agent is administered intravenously. In another embodiment Additionally, the antiparasitic agent is administered topically.
[0501] The routes of administration of the ascorbic acid compound, the quinone compound and the antiparasitic agent may be the same or different.
[0503] In certain embodiments, the ascorbic acid compound, the quinone compound, and the antiparasitic agent are administered repeatedly if necessary, for example, until the subject experiences stable disease or regression, or until the subject undergoes disease progression or unacceptable toxicity. Stable disease or the absence thereof is determined by methods known in the art, such as evaluation of the subject's symptoms, physical examination, or diagnostic tests. In certain embodiments, the ascorbic acid compound, the quinone compound, and the antiparasitic agent are administered repeatedly until the subject becomes a negative agonist for immunoglobulin G (IgG) antibodies, a recombinant antigen of the parasite. In certain embodiments, the ascorbic acid compound, the quinone compound, and the antiparasitic agent are administered repeatedly until the subject becomes a negative agonist for immunoglobulin G (IgG) antibodies, a recombinant Trypanosoma antigen. In certain embodiments, the ascorbic acid compound, the quinone compound, and the antiparasitic agent are administered repeatedly until the subject becomes a negative agonist for immunoglobulin G (IgG) antibodies, a recombinant Trypanosoma cruzi antigen.
[0505] In certain embodiments, the ascorbic acid compound, quinone compound, and antiparasitic agent are administered to the subject over an extended period of time, ranging from about 10 days to about 5 years, from about 20 days to about 2 years, from from about 20 days to about 1 year, from about 20 days to about 6 months, from about 20 days to about 90 days, or from about 30 days to about 60 days.
[0507] In certain embodiments, the ascorbic acid compound, the quinone compound, and the antiparasitic agent, as used in the methods provided herein, are administered cyclically. Cyclic therapy involves the administration of an active agent for a period of time, followed by a break for a period of time and the repetition of the same administration. sequential. Cyclic therapy can reduce the development of resistance to one or more therapies, avoid or reduce the side effects of one or more therapies, and / or improve the effectiveness of treatment.
[0509] In certain embodiments, the methods provided herein comprise treating a subject regardless of age. In certain embodiments, the subject is a pediatric patient. In certain embodiments, the subject is a pediatric patient 2 to 12 years of age.
[0511] In certain embodiments, the subject is a mammal. In certain embodiments, the mammal is a human. In certain embodiments, the subject is won. In certain embodiments, the subject is a domesticated animal.
[0513] In certain embodiments, the ascorbic acid compound, the quinone compound, and the antiparasitic agent act synergistically to treat, prevent, or alleviate one or more symptoms of the parasitic disease as compared to administration of the ascorbic acid compound, the quinone compound, or the antiparasitic agent alone.
[0515] Without being limited by any theory, a synergistic effect of the combination of the active ingredients provided herein allows the use of lower doses of at least one of the active ingredients, and / or a less frequent administration of the combination to a subject. to treat parasitic disease. The ability to use lower dosages of certain active ingredients in the combination (for example, a prophylactic or therapeutic agent) and / or to administer the combination less frequently reduces the toxicity associated with administering the combination to a subject without reducing the efficacy of the combination in the prevention or treatment of parasitic disease. Furthermore, a synergistic effect can result in an improved efficacy of the active ingredients in the prevention or treatment of parasitic disease. Additionally, a synergistic effect of the combination can avoid or reduce adverse or unwanted side effects associated with the use of at least one of the active ingredients.
[0517] In one embodiment, provided herein is a method of inhibiting parasite growth, comprising contacting a parasite with: (a) a therapeutically effective amount of: (i) ascorbic acid, or a single enantiomer, a mixture of enantiomers, or a mixture of diastereomers thereof; or a pharmaceutically acceptable salt, solvate or hydrate thereof; and (ii) a quinone compound, or a single enantiomer, a mixture of enantiomers, or a mixture of diastereomers thereof, or a pharmaceutically acceptable salt, solvate, hydrate or prodrug thereof; and (b) a subtherapeutically effective amount of an antiparasitic agent.
[0519] In another embodiment, a method of killing a parasite is provided herein, comprising contacting the parasite with; (a) a therapeutically effective amount of: (i) ascorbic acid, or a single enantiomer, a mixture of enantiomers, or a mixture of diastereomers thereof; or a pharmaceutically acceptable salt, solvate or hydrate thereof; and (ii) a quinone compound, or a single enantiomer, a mixture of enantiomers, or a mixture of diastereomers thereof, or a pharmaceutically acceptable salt, solvate, hydrate or prodrug thereof; and (b) a subtherapeutically effective amount of an antiparasitic agent.
[0521] In yet another embodiment, provided herein is a method of increasing the cytotoxicity of an antiparasitic agent to a parasite, comprising contacting the parasite with: a therapeutically effective amount of: (i) ascorbic acid, or a single enantiomer , a mixture of enantiomers, or a mixture of diastereomers thereof; or a pharmaceutically acceptable salt, solvate or hydrate thereof; and (ii) a quinone compound, or a single enantiomer, a mixture of enantiomers, or a mixture of diastereomers thereof, or a pharmaceutically acceptable salt, solvate, hydrate or prodrug thereof.
[0523] In certain embodiments, the methods provided herein further comprise the administration of an additional therapeutic agent or therapy that is useful for treating, preventing, or ameliorating one or more symptoms of the parasitic disease. Effective dosages of the additional therapeutic agent can be administered in conjunction with, alternatively to, or sequentially with the administration of the active ingredients provided herein. Dosages provided will depend on the rates of absorption, inactivation, and excretion of the therapeutic agents, as well as other factors known to those of skill in the art. It should be noted that dosage values will also vary with the severity of the condition to be alleviated. It should further be understood that, for any particular subject, specific dosing regimens and schedules should be adjusted over time according to the individual need and the professional judgment of the person administering. or supervises the administration of the compositions.
[0525] In certain embodiments, kits are provided herein that, when used by the medical professional, can simplify the administration of appropriate amounts of the active ingredients to a subject. In certain embodiments, the kit provided herein includes containers and dosage forms of the active ingredients provided herein.
[0526] The kits provided herein may further include devices that are used to deliver the active ingredients. Examples of such devices include, but are not limited to, syringes, needleless injector drip bags, patches, and inhalers. The kits provided herein may also include condoms for administration of the active ingredients.
[0528] Kits provided herein may further include pharmaceutically acceptable carriers that can be used to administer one or more active ingredients. For example, if an active ingredient is provided in a solid form that must be reconstituted for parenteral administration, the kit may comprise a hermetically sealed container of a suitable vehicle in which the active ingredient can be dissolved to form a sterile, particulate-free solution. which is suitable for parenteral administration. Examples of pharmaceutically acceptable vehicles include, but are not limited to: aqueous vehicles, including, but not limited to, USP Water for Injection, Sodium Chloride Injection, Ringer's Injection, Dextrose Injection, Dextrose, and Chloride Injection. sodium and lactic injection of Ringer; water miscible vehicles, including, but not limited to, ethyl alcohol, polyethylene glycol, and polypropylene glycol; and nonaqueous vehicles including, but not limited to, corn oil, cottonseed oil, peanut oil, sesame oil, ethyl oleate, isopropyl myristate, and benzyl benzoate.
[0530] The disclosure will be further understood by the following non-limiting examples.
[0532] EXAMPLES
[0534] Example 1
[0535] Evaluation of vitamins C and K3 in combination with an antiparasitic agent in mice infected with Trypanosoma cruzi
[0536] Male BALB / c mice (approximately 7-8 weeks old) were infected intraperitoneally with 104 parasites per mouse. Treatment began 24 hours after infection. Administration of vitamin C (ie, L-ascorbic acid), vitamin K3 (ie, 2-methyl-1,4-naphthoquinone or menadione), APATONE® and benznidazole, alone or in combination, is administered once daily orally in different concentrations.
[0538] The mice were divided into the following groups and each group contained seven mice: i. infected and untreated;
[0539] ii. infected and treated with 200 mg / kg of vitamin C;
[0540] iii. infected and treated with 3.5 mg / kg of vitamin K3;
[0541] iv. infected and treated with APATONE® (200 mg / kg of vitamin C and 3.5 mg / kg of vitamin K3);
[0542] v. infected and treated with APATONE® (200 mg / kg of vitamin C and 3.5 mg / kg of vitamin K3) plus 5 mg / kg of benznidazole;
[0543] saw. infected and treated with benznidazole at 5 mg / kg;
[0544] vii. infected and treated with benznidazole at 100 mg / kg; Y
[0545] viii. uninfected and untreated.
[0547] Parasitaemia levels were individually monitored every day from 3 days after infection (dpi) for a period of 21 days by direct microscopic analysis of 5 µl of blood taken by puncture from the tip of the tail of each mouse. . Parasites present in 50 fields were counted in 40 x objective. Mortality was checked daily up to 21 dpi and expressed as a percentage of survival. All the tests were carried out after the approval of the Ethical Conduct on the use of Animals in Experiments (CEAE) of the UEM, protocol number CEUA 6642060717.
[0549] As shown in FIG. 1, APATONE® decreased parasitaemia levels compared to the infected and untreated group (group I). This reduction in peak parasitaemia (8 dpi) was 77%. At the end of 21 dpi, no trypomastigotes were observed in the bloodstream of mice treated with APATONE®. Mice treated with APATONE® plus benznidazole (5 mg / kg) in combination completely eliminated the parasites from the bloodstream, even from the onset of infection. In view of the superior and unexpected results obtained with this treatment, three mice from group v were kept for another 15 days to verify if the parasitemia would return. after finishing the treatment. During these 15 days, no parasites were observed in the bloodstream and all three mice survived (FIG. 2).
[0551] Mice treated with only vitamin C or vitamin K3 alone died from day 14, showing that vitamins alone are ineffective. The amount of parasites observed in the bloodstream of the same mice was similar to that of the infected and untreated control. Three mice died in the group treated with only benznidazole at 5 mg / kg, a concentration known to be ineffective, only 4 mice remained. The amount of parasites observed in the bloodstream of the same group (group vi) was also similar to that of the infected and untreated control, confirming that benznidazole at 5 mg / kg is not effective in eliminating parasites. No mice died and no parasites were observed in the bloodstream in the group treated with benznidazole at 100 mg / kg, the effective concentration which, however, is known to induce severe toxic effects (FIG. 1).
[0553] At the end of 21 dpi, the infected group treated with APATONE® had a 77% survival rate, while the group treated with APATONE® and benznidazole (5 mg / kg) in combination had 100% survival (FIG. two). The mice infected and treated with APATONE® and treated with the combination of APATONE® plus benznidazole presented a similar appearance to the mice of the uninfected and untreated group.
[0555] Cytokine analysis was performed in mice infected with T. cruzi. A cytokine microsphere kit (CBA) was used to quantify the levels of Th1 (IL-2, TNF-a and INF-y), Th2 (IL-4, IL-5 and IL-10A), and Th17 ( IL-17) by flow cytometry. Seven populations of microspheres with different fluorescence intensities were conjugated to a capture antibody specific for each cytokine, mixed with the CBA, and read without the FL3 channel from a FACSCalibur flow cytometer. The microsphere populations were visualized according to their respective fluorescence intensities: from dimmer to brighter.
[0557] Acquisition tubes were separated with: 50 µl of a sample, 50 µl of microspheres and 50 µl of Th1 / Th2 / Th17 PE (mouse Th1 / Th2 / Th17 PE detection reagent / 1 vial, 4 ml). The same procedure was carried out to obtain a standard curve. The samples in the tubes were homogenized and incubated for three hours at room temperature in the dark. Data acquisition and analysis were performed by using a FACSCalibur flow cytometer equipped with CelIQuest software.
[0559] The levels of pro-inflammatory cytokines (IL-6, TNF-a, INF-y, IL-2 and IL-17) and anti-inflammatory (IL-4 and IL-10) were determined in the heart (FIG. 3) in blood in mice infected with T. cruzi. FIG. 3 shows that untreated T. cruzi-infected mice had significant high levels of IL-6, TNF-α, and IFN-y (up to 15.3, 30.5, and 135.5-fold, respectively) compared with the uninfected and untreated mice. Mice infected with T. cruzi and treated with benznidazole at 5 mg and 100 mg showed a significant decrease in IL-6 and TNF-α levels, compared to the infected and untreated group. However, the levels of IL-6 and TNF-α in this group were still high compared to the uninfected and untreated group. It is important to remember that treatment with benznidazole (5 mg) did not decrease the amount of parasites in the bloodstream as in the infected and untreated group (FIG. 1). Therefore, it is likely that the high levels of IL-6 and TNF-a in mice infected by T. cruzi and treated with benznidazole (5 mg) are related to the inflammatory process induced by the parasite in the bloodstream. On the other hand, in mice treated with benznidazole at 100 mg (the effective concentration), no parasites were detected in the bloodstream (FIG. 1). Therefore, it is likely that the high levels of IL-6 and TNF-α in mice infected with T. cruzi and treated with benznidazole (100 mg) are related to the pro-inflammatory activity of benznidazole (a side effect). However, mice infected with T. cruzi and treated with APATONE® and benznidazole (5 mg / kg / day) in combination showed a marked and significant decrease in the levels of IL-6, TNF-α and IFN-y (up to at 30.8, 30.7, and 65.7 times, respectively), compared to the infected and untreated group. The levels of IL-6, TNF-a and IFN-y in the group treated with APATONE® and benznidazole (5 mg / kg / day) in combination are similar to the levels of IL-6, TNF-a and IFN- and in the uninfected and untreated group. Mice infected with T. cruzi and treated with APATONE® alone also had significantly decreased levels of pro-inflammatory cytokines (IL-6, TNF-a and IFN-y) (up to 29.7, 18.6, and 15.0 times, respectively), compared to the infected and untreated group, however, the decreases in the levels of TNF-a and IFN-y were not as significant as the combination of APATONE® and benznidazole (5 mg). FIG. 4 shows that blood cytokine levels are very similar to heart cytokine levels in mice infected with T. cruzi.
[0561] Real-time quantitative POR (RT-qPCR) was performed to determine the parasite load in the tissue of control mice and mice treated and infected with T. cruzi.
[0562] Cardiac tissues were collected from mice at 21 dpi, weighed, and washed in PBS. The DNAs were purified with the PureLink Genomic kit. Real-time DNA PCR was performed using the QuantiNova SYBR green PCR kit with 100 ng of total genomic DNA (gDNA). The primers used were TCZ-F (5 GCTCTTGCCCACAMGGGTGC-3 ') and TCZ-R (5'-CCAAGCAGCGGATA-GTTCAGG-3'). The samples were amplified with a LIGHTCYCLER® 480 under the following PCR conditions: a denaturation phase at 95 ° C for 2 minutes, then 35 amplification cycles at 95 ° C for 15 seconds, 60 ° C for 10 seconds. At the end of each run, a melting curve from 65 ° C to 97 ° C was obtained to monitor primer dimers or the formation of non-specific products. A standard curve was established using purified T. cruzi DNA; Serial dilutions ranging from 100 to 0.001 ng of parasite DNA in triplicate. The standard curve was generated by the LIGHTCYCLER®96 software and was used to calculate the level of parasites in each sample. Parasite levels were based on DNA per epimastigote cell, where DNA per cell was considered 200 fg / parasite.
[0564] The group treated with APATONE® and benznidazole (5 mg) in combination had a complete elimination of the parasites from the cardiac tissues (FIG. 5) and the bloodstream (FIG. 6). The group treated with APATONE® had a significant reduction in the parasite load in the cardiac tissues (FIG. 5) and a complete elimination of the parasites from the bloodstream (FIG. 6) compared to the infected and untreated group.
[0566] The examples set forth above are provided to give a person skilled in the art a complete description and disclosure of how to make and use the claimed embodiments, and are not intended to limit the scope of what is described herein. Modifications that are apparent to those skilled in the art are intended to be within the scope of the following claims. All publications, patents and patent applications in the present specification are incorporated herein by reference as if each publication, patent or patent application had been specifically indicated and

权利要求:
Claims (85)
[1]
A method of treating, preventing, or alleviating one or more symptoms of parasitic disease in a subject, which comprises administering to the subject: (i) ascorbic acid, or a single enantiomer, a mixture of enantiomers, or a mixture of diastereomers thereof. ; or a pharmaceutically acceptable salt, solvate or hydrate thereof; (ii) a quinone compound, or a single enantiomer, a mixture of enantiomers, or a mixture of diastereomers thereof, or a pharmaceutically acceptable salt, solvate, hydrate or prodrug thereof; and (iii) an antiparasitic agent.
[2]
The method of claim 1, wherein the parasitic disease is African trypanosomiasis, amoebiasis, ascariasis, babesiosis, Chagas disease, cryptosporidiosis, cutaneous larva migrans, heartworm, echinococcosis, fasciolosis, filariasis, lymphatic filariasis, giardiasis, infection, helminth infection. hookworm, leishmaniasis, visceral leishmaniasis, malaria, neurocysticercosis, onchocerciasis, protozoan infection, schistosomiasis, taeniasis, tapeworm infection, toxocariasis, toxoplasmosis, trichinosis or zoonosis.
[3]
3. The method of claim 1 or 2, wherein the parasitic disease is Chagas disease.
[4]
4. The method of claim 1 or 2, wherein the parasitic disease is leishmaniasis.
[5]
The method of any of claims 1, 2 and 4, wherein the parasitic disease is cutaneous leishmaniasis, mucocutaneous leishmaniasis, or visceral leishmaniasis.
[6]
6.
[7]
7. A method of eliminating a parasite from a subject, which comprises administering to the subject: (i) ascorbic acid, or a single enantiomer, a mixture of enantiomers, or a mixture of diastereomers thereof; or a pharmaceutically acceptable salt, solvate or hydrate thereof; (ii) a quinone compound, or a single enantiomer, a mixture of enantiomers, or a mixture of diastereomers thereof, or a pharmaceutically acceptable salt, solvate, hydrate or prodrug thereof; and (iii) an antiparasitic agent.
[8]
8. A method of increasing the quality of life of a subject infected with a parasite, which comprises administering to the subject: (i) ascorbic acid, or a single enantiomer, a mixture of enantiomers, or a mixture of diastereomers thereof; or a pharmaceutically acceptable salt, solvate or hydrate thereof; (ii) a quinone compound, or a single enantiomer, a mixture of enantiomers, or a mixture of diastereomers thereof, or a pharmaceutically acceptable salt, solvate, hydrate or prodrug thereof; and (iii) an antiparasitic agent.
[9]
9. A method of increasing the efficacy of an antiparasitic agent in a subject infected with a parasite, comprising administering to the subject: (i) ascorbic acid, or a single enantiomer, a mixture of enantiomers, or a mixture of diastereomers thereof; or a pharmaceutically acceptable salt, solvate or hydrate thereof; and (ii) a quinone compound, or a single enantiomer, a mixture of enantiomers, or a mixture of diastereomers thereof, or a pharmaceutically acceptable salt, solvate, hydrate or prodrug thereof.
[10]
10. A method of increasing tolerance to an antiparasitic agent in a subject infected with a parasite, comprising administering to the subject: (i) ascorbic acid, or a single enantiomer, a mixture of enantiomers, or a mixture of diastereomers thereof; or a pharmaceutically acceptable salt, solvate or hydrate thereof; and (ii) a quinone compound, or a single enantiomer, a mixture of enantiomers, or a mixture of diastereomers thereof, or a pharmaceutically acceptable salt, solvate, hydrate or prodrug thereof.
[11]
11. A method of reducing a side effect of an antiparasitic agent in a subject infected with a parasite, comprising administering to the subject: (i) ascorbic acid, or a single enantiomer, a mixture of enantiomers, or a mixture of diastereomers thereof ; or a pharmaceutically acceptable salt, solvate or hydrate thereof; and (ii) a quinone compound, or a single enantiomer, a mixture of enantiomers, or a mixture of diastereomers thereof, or a pharmaceutically acceptable salt, solvate, hydrate or prodrug thereof.
[12]
The method of claim 11, wherein the side effect is abdominal pain, allergic dermatitis, amnesia, anemia, anorexia, anxiety, bone marrow suppression, chills, confusion, decreased appetite, depression, dermatitis, dizziness, dysgeusia. , eosinophilia, fever, headache, impotence, insomnia, leukopenia, lymphadenopathy, muscle weakness, nausea, neutropenia, numbness of hands or feet, paraesthesia, peripheral neuropathy, pruritus, purpura, rash, seizures, sore throat, thrombocytopenia, tremors, hives, vomiting, or weight loss.
[13]
The method of claim 11 or 12, wherein the side effect is a side effect of benznidazole.
[14]
The method of any one of claims 11 to 13, wherein the side effect is abdominal pain, anemia, decreased appetite, eosinophilia, fever, headache, leukopenia, lymphadenopathy, nausea, neutropenia, paraesthesia, itching, purpura, rash skin, thrombocytopenia, hives, vomiting, or weight loss.
[15]
The method of any one of claims 11 to 13, wherein the side effect is abdominal pain, decreased appetite, eosinophilia, headache, nausea, neutropenia, itching, rash, hives, vomiting, or weight loss.
[16]
16. The method of claim 11 or 12, wherein the side effect is a side effect of nifurtimox.
[17]
17. A method of reducing a toxicity of an antiparasitic agent in a subject infected with a parasite, comprising administering to the subject: (i) ascorbic acid, or a single enantiomer, a mixture of enantiomers, or a mixture of diastereomers thereof; or a pharmaceutically acceptable salt, solvate or hydrate thereof; and (ii) a quinone compound, or a single enantiomer, a mixture of enantiomers, or a mixture of diastereomers thereof, or a pharmaceutically acceptable salt, solvate, hydrate or prodrug thereof.
[18]
18. The method of claim 17, wherein the toxicity is a benznidazole toxicity.
[19]
19. The method of claim 17, wherein the toxicity is a nifurtimox toxicity.
[20]
20. The method of any one of claims 17 to 19, wherein the toxicity is bone marrow toxicity, carcinogenicity, dermatological toxicity, embryo-fetal toxicity, genotoxicity, or neurotoxicity.
[21]
21. The method of any one of claims 6 to 20, wherein the parasite is Plasmodium, Trypanosoma, Entamoeba, Giardia, Leishmania, Toxoplasma or Schistosoma.
[22]
22. The method of any one of claims 6 to 21, wherein the parasite is Entamoeba histolytica, Giardia lamblia, Leishmania aethiopica, Leishmania amazonensis, Leishmania braziliensis, Leishmania donovani, Leishmania mexicana, Leishmania major, Leishmodium tropica, Plasmodium berghei, Plasmodium berghei, falciparum, Plasmodium yoelii, Schistosoma mansonii, Trypanosoma brucei, Trypanosoma cruzi or Toxoplasma gondii.
[23]
23. The method of any one of claims 6 to 22, wherein the parasite is Leishmania aethiopica, Leishmania amazonensis, Leishmania braziliensis, Leishmania donovani, Leishmania mexicana, Leishmania major or Leishmania tropica.
[24]
24. The method of any one of claims 6 to 22, wherein the parasite is Trypanosoma.
[25]
25. The method of claim 24, wherein the parasite is Trypanosoma brucei, Trypanosoma cruzi, or Toxoplasma gondii.
[26]
26. The method of claim 24 or 25, wherein the parasite is Trypanosoma cruzi.
[27]
27. The method of any one of claims 1 to 26, wherein the ascorbic acid is administered orally.
[28]
28. The method of any one of claims 1 to 26, wherein the ascorbic acid is administered intravenously.
[29]
29. The method of any one of claims 1 to 28, wherein the quinone compound is administered orally.
[30]
30. The method of any one of claims 1 to 28, wherein the quinone compound is administered intravenously.
[31]
31. The method of any one of claims 1 to 30, wherein the ascorbic acid and the quinone compound are administered together in a single composition comprising ascorbic acid, or a single enantiomer, a mixture of enantiomers, or a mixture of diastereomers. of the same; or a pharmaceutically acceptable salt, solvate or hydrate thereof; and a quinone compound, or a single enantiomer, a mixture of enantiomers, or a mixture of diastereomers thereof, or a pharmaceutically acceptable salt, solvate, hydrate or prodrug thereof.
[32]
32. The method of any one of claims 1 to 27, 29 and 31, wherein the ascorbic acid and the quinone compound are formulated together in a single oral dosage form.
[33]
33. The method of claim 32, wherein the single oral dosage form is a tablet.
[34]
34. The method of claim 32, wherein the single oral dosage form is a capsule.
[35]
35. The method of claim 34, wherein the capsule comprises about 500 mg of ascorbic acid, or a single enantiomer, a mixture of enantiomers, or a mixture of diastereomers thereof; or a pharmaceutically acceptable salt, solvate or hydrate thereof; and about 5 mg of a quinone compound, or a single enantiomer, a mixture of enantiomers, or a mixture of diastereomers thereof, or a pharmaceutically acceptable salt, solvate, hydrate or prodrug thereof.
[36]
36. The method of claim 34 or 35, wherein the capsule consists essentially of ascorbic acid, or a single enantiomer, a mixture of enantiomers, or a mixture of diastereomers thereof; or a pharmaceutically acceptable salt, solvate or hydrate thereof; and a quinone compound, or a single enantiomer, a mixture of enantiomers, or a mixture of diastereomers thereof, or a pharmaceutically acceptable salt, solvate, hydrate or prodrug thereof.
[37]
37. The method of any one of claims 1 to 36, wherein the ascorbic acid is L-ascorbic acid or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate or hydrate thereof.
[38]
38. The method of claim 37, wherein the ascorbic acid is an alkali or alkaline earth metal salt of L-ascorbic acid, or a pharmaceutically acceptable solvate or hydrate thereof.
[39]
39. The method of claim 37, wherein the ascorbic acid is sodium L-ascorbate, potassium L-ascorbate, calcium L-ascorbate or magnesium L-ascorbate, or a pharmaceutically acceptable solvate or hydrate thereof; or a mixture thereof.
[40]
40. The method of claim 37, wherein the ascorbic acid is sodium L-ascorbate, or a pharmaceutically acceptable solvate or hydrate thereof.
[41]
41. The method of claim 37, wherein the ascorbic acid is potassium L-ascorbate, or a pharmaceutically acceptable solvate or hydrate thereof.
[42]
42. The method of claim 37, wherein the ascorbic acid is calcium L-ascorbate, or a pharmaceutically acceptable solvate or hydrate thereof.
[43]
43. The method of claim 37, wherein the ascorbic acid is magnesium L-ascorbate, or a pharmaceutically acceptable solvate or hydrate thereof.
[44]
44. The method of any one of claims 1 to 43, wherein the quinone compound is vitamin K.
[45]
45. The method of claim 44, wherein the quinone compound is vitamin K3.
[46]
46. The method of claim 45, wherein the vitamin K3 is 1,2,3,4-tetrahydro-2-methyl-1,4-dioxo-2-naphthalenesulfonic acid or a pharmaceutically acceptable salt. of the same; or a pharmaceutically acceptable solvate or hydrate thereof.
[47]
47. The method of claim 45, wherein the vitamin K3 is an alkali or alkaline earth metal salt of 1,2,3,4-tetrahydro-2-methyl-1,4-dioxo-2-naphthalenesulfonic acid, or a pharmaceutically acceptable solvate or hydrate thereof.
[48]
48. The method of claim 45, wherein the vitamin K3 is sodium or magnesium 1,2,3,4-tetrahydro-2-methyl-1,4-dioxo-2-naphthalenesulfonate, or a pharmaceutically acceptable solvate or hydrate of the same.
[49]
49. The method of claim 45, wherein the vitamin K3 is anhydrous sodium 1,2,3,4-tetrahydro-2-methyl-1,4-dioxo-2-naphthalenesulfonate.
[50]
50. The method of claim 45, wherein the vitamin K3 is 2-methyl-1,4-naphthalenedione; or a pharmaceutically acceptable solvate or hydrate thereof.
[51]
51. The method of any one of claims 1 to 50, wherein the molar ratio of ascorbic acid to quinone compound ranges from about 50 to about 500.
[52]
52. The method of any one of claims 1 to 51, wherein the molar ratio of the ascorbic acid to the quinone compound is about 100, about 200, or about 400.
[53]
53. The method of any one of claims 1 to 52, wherein the ascorbic acid is administered once, twice, three times, four times, five times or six times a day.
[54]
54. The method of any one of claims 1 to 53, wherein the ascorbic acid is administered every 4 to 6 hours per day.
[55]
55. The method of any one of claims 1 to 54, wherein the quinone compound is administered once, twice, three times, four times, five times or six times a day.
[56]
56. The method of any one of claims 1 to 55, wherein the Quinone compound is administered every 4 to 6 hours a day.
[57]
57. The method of any one of claims 1 to 56, wherein the ascorbic acid is administered in an amount ranging from about 500 mg to about 30,000 mg per day, and the quinone compound is administered in an amount ranging from about 3 mg and about 1200 mg daily.
[58]
58. The method of any one of claims 1 to 27, 29, and 31 to 57, wherein the ascorbic acid and the quinone compound are administered as one or more capsules, each of which comprises approximately 500 mg of L -sodium ascorbate and about 3 mg of 1,2,3,4-tetrahydro-2-methyl-1,4-dioxo-2-naphthalene sulfonate.
[59]
59. The method of any one of claims 1 to 27, 29, and 31 to 57, wherein the ascorbic acid and the quinone compound are administered as one or more capsules, each of which comprises about 1000 mg of L -calcium ascorbate and approximately 10 mg of 2-methyl-1,4-naphthalenedione.
[60]
60. The method of any one of claims 1 to 59, wherein the antiparasitic agent is an antiprotozoan, an anthelmintic, an antinematode, an anticetode, an antitrematode, an antiamebic or an antifungal.
[61]
61. The method of any one of claims 1 to 60, wherein the antiparasitic agent is albendazole, amphotericin B, benznidazole, bephenium, diethylcarbamzine, eflornithine, flubendazole, ivermectin, mebendazole, meglumine antimonite, melarsoprol, metronidazole, miltefosine , nifurtimox, nitazoxanide, pentavalent antimony, praziquantel, pyrantel, pirvinium, sodium stibogluconate, thiabendazole or tinidazole.
[62]
62. The method of any one of claims 1 to 60, wherein the antiparasitic agent is a nitroimidazole.
[63]
63. The method of any one of claims 1 to 62, wherein the antiparasitic agent is a benznidazole.
[64]
64. The method of any one of claims 1 to 61, wherein the antiparasitic agent is a nifurtimox.
[65]
65. The method of any one of claims 1 to 64, wherein the antiparasitic agent is administered in a subtherapeutically effective amount.
[66]
66. The method of claim 65, wherein the subtherapeutically effective amount of the antiparasitic agent is less than about 1/2 of the therapeutically effective amount of the antiparasitic agent when used alone.
[67]
67. The method of claim 65 or 66, wherein the subtherapeutically effective amount of the antiparasitic agent is less than about 1/10 of the therapeutically effective amount of the antiparasitic agent when used alone.
[68]
68. The method of any one of claims 1 to 67, wherein the antiparasitic agent is administered in an amount ranging from about 10 pg / kg / day to about 10 mg / kg / day.
[69]
69. The method of any one of claims 1 to 68, wherein the antiparasitic agent is administered in an amount ranging from about 100 pg / kg / day to about 1 mg / kg / day.
[70]
70. The method of any one of claims 1 to 69, wherein the antiparasitic agent is administered in an amount ranging from about 0.01 mg to about 200 mg per day.
[71]
71. The method of any one of claims 1 to 70, wherein the antiparasitic agent is administered in an amount ranging from about 0.1 mg to about 1 mg per day.
[72]
72. The method of any one of claims 1 to 71, wherein the antiparasitic agent is administered orally.
[73]
73. The method of any one of claims 1 to 72, wherein the antiparasitic agent is formulated in a single oral dosage form.
[74]
74. The method of claim 73, wherein the antiparasitic agent in a single oral dosage form is formulated as a tablet.
[75]
75. The method of claim 73, wherein the antiparasitic agent in a single oral dosage form is formulated as a capsule.
[76]
76. The method of any one of claims 1 to 75, wherein the antiparasitic agent is administered twice daily.
[77]
77. A method of inhibiting parasite growth, which comprises contacting a parasite with: (a) a therapeutically effective amount of: (i) ascorbic acid, or a single enantiomer, a mixture of enantiomers, or a mixture of diastereomers of the same; or a pharmaceutically acceptable salt, solvate or hydrate thereof; and (ii) a quinone compound, or a single enantiomer, a mixture of enantiomers, or a mixture of diastereomers thereof, or a pharmaceutically acceptable salt, solvate, hydrate or prodrug thereof; and (b) a subtherapeutically effective amount of an antiparasitic agent.
[78]
78. A method of killing a parasite, comprising contacting the parasite with: (a) a therapeutically effective amount of: (i) ascorbic acid, or a single enantiomer, a mixture of enantiomers, or a mixture of diastereomers thereof ; or a pharmaceutically acceptable salt, solvate or hydrate thereof; and (ii) a quinone compound, or a single enantiomer, a mixture of enantiomers, or a mixture of diastereomers thereof, or a pharmaceutically acceptable salt, solvate, hydrate or prodrug thereof; and (b) a subtherapeutically effective amount of an antiparasitic agent.
[79]
79. A method of increasing the cytotoxicity of an antiparasitic agent to a parasite, comprising contacting the parasite with a therapeutically effective amount of: (i) ascorbic acid, or a single enantiomer, a mixture of enantiomers, or a mixture of diastereomers thereof; or a pharmaceutically acceptable salt, solvate or hydrate thereof; and (ii) a quinone compound, or a single enantiomer, a mixture of enantiomers, or a mixture of diastereomers thereof or a pharmaceutically acceptable salt, solvate, hydrate or prodrug thereof.
[80]
80. The method of any one of claims 77 to 79, wherein the parasite is Plasmodium, Trypanosoma, Entamoeba, Giardia, Leishmania, Toxoplasma or Schistosoma.
[81]
81. The method of any one of claims 77 to 80, wherein the parasite is Entamoeba histolytica, Giardia lamblia, Leishmania aethiopica, Leishmania amazonensis, Leishmania braziliensis, Leishmania donovani, Leishmania mexicana, Leishmania major, Leishmodium tropica, Plasmodium berghei, Plasmodium berghei, falciparum, Plasmodium yoelii, Schistosoma mansonii, Trypanosoma brucei, Trypanosoma cruzi or Toxoplasma gondii.
[82]
82. The method of any one of claims 77 to 81, wherein the parasite is Leishmania aethiopica, Leishmania amazonensis, Leishmania braziliensis, Leishmania donovani, Leishmania mexicana, Leishmania major or Leishmania tropica.
[83]
83. The method of any one of claims 77 to 82, wherein the parasite is Trypanosoma.
[84]
84. The method of claim 83, wherein the parasite is Trypanosoma brucei, Trypanosoma cruzi, or Toxoplasma gondii.
[85]
85. The method of claim 83 or 84, wherein the parasite is Trypanosoma cruzi.

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CA3031979A1|2016-08-01|2018-02-08|IC-MedTech Corp.|Ascorbic acid, quinone compound, and sodium glucose cotransporter inhibitor for treating cancer|

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