Topical compositions and methods for treating pain

专利摘要:
The present invention provides methods and topical compositions for treating or preventing pain. The compositions of the present invention can be administered topically to natural skin to provide a local anesthetic effect, thereby treating or preventing pain such as, for example, neuropathic pain. In one embodiment, the present invention provides a stable, topical local anesthetic composition comprising a mixture of one antidepressant and one NMDA-receptor antagonist. In a second embodiment the invention provides an antidepressant or a pharmacologically acceptable salt thereof; (b) an NMDA-receptor antagonist or a pharmacologically acceptable salt thereof; (c) fat-soluble components; (d) water; And (e) an emulsion comprising a surfactant wherein the emulsion is an oil-in-water emulsion. Preferably the average oil drop size is in the range of about 0.01 to 100 microns, more preferably in the range of about 0.1 to 10 microns. In another embodiment the invention provides an antidepressant or a pharmacologically acceptable salt thereof; (b) an NMDA-receptor antagonist or a pharmacologically acceptable salt thereof; (c) fat-soluble components; (d) water; And (e) a surfactant, wherein the emulsion is an oil-in-water emulsion. In another embodiment, the present invention provides a pharmaceutical composition comprising (a) a therapeutically effective amount of an antidepressant or a pharmacologically acceptable salt thereof; (b) a therapeutically effective amount of an NMDA-receptor antagonist or a pharmacologically acceptable salt thereof; (c) fat-soluble components; (d) water; And (e) topically administering an emulsion comprising a surfactant, wherein the emulsion is an oil-in-water emulsion to the skin of the mammal in need thereof. In another embodiment, the present invention provides a pharmaceutical composition comprising (a) a therapeutically effective amount of an antidepressant or a pharmacologically acceptable salt thereof; (b) a therapeutically effective amount of an NMDA-receptor antagonist or a pharmacologically acceptable salt thereof; (c) fat-soluble components; (d) water; And (e) an emulsion comprising a surfactant, wherein the emulsion is an oil-in-water emulsion topically administered to the skin of the mammal in need thereof.
公开号:KR20040053112A
申请号:KR10-2004-7002327
申请日:2002-08-14
公开日:2004-06-23
发明作者:로버트 오 윌리암；펭 장
申请人:에피셉트 코포레이션；
IPC主号:

专利说明:

Topical compositions and methods for treating pain {TOPICAL COMPOSITIONS AND METHODS FOR TREATING PAIN}
[2] Pain is due to harmful stimulation of the nerve endings. Nociceptive pain is caused by noxious stimulation of the trauma receptors (eg, needle stings or skin pinching) and transmits the stimulus to spinal cord neurons and to the brain via neural pathways. Neuropathic pain is due to damage to nerve structures, such as peripheral nerve endings or vortices, and is very sensitive to stimulation and can produce irritation without stimulation (eg, herpes zoster pain after the rash has been treated). Peripheral nerve injury can lead to a decrease in pain threshold (ie, allodynia), and a pathology of increased or sustained response (persistence) to noxious stimuli (pain sensitivity). GOODMAN and GILMAN'S THE PHARMACOLOGICAL BASIS OF THERAPEUTICS 529 (Joel G. Hardman et al., Eds., 9th edition, 1996); HARRISON'S PRINCIPLES OF INTERNAL MEDICINE 53-58 (Anthony S. Fauci et al., 14th edition 1998).
[3] In contrast to pain treatment with systemic medications, pain can be treated locally by topical treatment of local anesthetics directly to the pain area to block the painful mechanical pathway. Local anesthetics prevent the generation and conduction of painful nerve stimuli. Thus, for example, local anesthetics can be applied intradermally (non-systemic intradermal injection) or applied locally to the pain area. Advantages of topical local anesthetic administration over systemic administration of pain relievers include reduced or prevented side effects and improved patient compliance and reversible action (ie, removal of the anesthetic from the site of application may reverse the action). AND TOPICAL DRUG DELIVERY SYSTEMS 33-112 (Tapash K. Ghosh et al. Eds., 1997).
[4] Various medications have local anesthetic properties and can be administered as topical agents. Sodium channel blockers, such as conventional local anesthetics or lidocaine, reduce or prevent the temporary large increase in the permeability of the excitable membrane to sodium ions to inhibit the generation and conduction of nerve stimuli. Other agents with local anesthetic properties include nonsteroidal anti-inflammatory agents ("NSAIDs") (TRANSDERMAL AND TOPICAL DRUG DELIVERY SYSTEMS 87-93 (see Tapash K. Ghosh et al. Eds., 1997), opioids such as morphine (US patents). 5,948,389 (issued September 7, 1999); see Christoph Stein & Alexander Yassouridis 71 Pain 119 (1997).
[5] N-methyl D-aspartate ("NMDA") receptor antagonists such as ketamine have local-aesthetic properties, and topical administration is an effective neuropathic pain treatment (US Pat. No. 5,817,699 (Issue 6 October 1998). Reference). In another embodiment, topical administration of antidepressant medications such as amitriptyline has been reported to be effective in treating neuropathic pain (US Pat. No. 6,211,171 (April 3, 2001, Issue); J. Sawynok et al. 82 PAIN) 149 (1999). In addition, mixed topical administration of tricyclic antidepressants and NMDA-receptor antagonists has excellent local anesthetic properties when applied topically and has been reported to be useful for the treatment of neuropathic pain (US Pat. No. 6,197,830 (March 6, 2001, issue).
[6] However, although topical local anesthetics have been commonly used to treat minor signs of natural skin, their use has not been found useful in treating very severe pain and neuropathic pain because it is difficult to obtain effective concentrations through the skin barrier. Less than about 15 percent of the drug is usually bioavailable in topical formulations due to drug penetration resistance in skin as small as about 1 percent (TRANSDERMAL AND TOPICAL DRUG DELIVERY SYSTEMS 7 (see Tapash K. Ghosh et al. Eds., 1997). Another problem associated with topical topical administration is the stability of the composition Local anesthetic emulsion compositions are inherently unstable and phase separation may occur during shipping and storage In addition, many topical topical anesthetic compositions cause oxidative destabilization. The composition is commonly used as a base for topical topical-anesthetic compositions, but is very oxidatively unstable (AM. PHARM.
[7] ASSOC., HANDBOOK OF PHARMACEUTICAL EXCIPIENTS 292-294, 292 (Arthur H. Kibbe ed. 3rd edition 2000). For example, US Pat. No. 6,197,830 (March 6, 2001) describes a lecithin based composition for mixed topical administration of tricyclic antidepressants and NMDA-receptor antagonists, US Pat. No. 5,817,699 (October 1998) 6 day patent) and 6,017,961 (January 25, 2000 patent) describe topical administration of ketamine in pluronic lecithin organogel.
[8] In short, topical local anesthetics have an advantage over systemic administration of analgesics. Unfortunately, local topical anesthetic compositions have instability and less skin-permeability, limiting their use to less severe pain. There is a need for stable topical local anesthetic compositions with good skin-permeability. In particular, there is a need for stable, topical local anesthetic compositions comprising a mixture of one antidepressant and one NMDA-receptor antagonist.
[9] The citation or identification of references in the Background section of the present application is not an admission that such references are used as prior art in the present invention.
[1] The present invention relates to a method for treating or preventing pain through topical preparations that cause a local anesthetic effect when applied to natural skin. The compositions include antidepressants and N-methyl-D-aspartate-receptor antagonists.
[10] The invention may be more fully understood by reference to the following drawings, detailed description and detailed examples, which illustrate non-limiting examples of the invention.
[11] Justice
[12] As used herein, the "composition of the present invention" refers to (1) a therapeutically effective amount of an antidepressant or a pharmacologically acceptable salt thereof, a complex thereof (e.g. hydrates, sorbates and c1athrates), Mixtures of prodrug or stereoisomeric forms or stereoisomeric forms thereof (eg, geometric isomers, enantiomers, diastereomers, racemates, or mixtures thereof); (2) A therapeutically effective amount of one NMDA-receptor antagonist or a pharmacologically acceptable salt thereof, a complex thereof (e.g. hydrates, sorbates and c1athrates), its prodrug or stereoisomeric form or its conformation Mixtures of isomeric forms (eg, geometric isomers, enantiomers, diastereomers, racemates, or mixtures thereof); (3) fat-soluble components; (4) water; And (5) an oil-in-worker emulsion having an average droplet size in the range of 0.01 microns to 100 microns comprising a surfactant.
[13] As used herein, a "therapeutically effective amount" of one antidepressant or one NMDA-receptor antagonist is one antidepressant or one that is necessary in the compositions of the present invention to induce a sufficient topical anesthetic effect to treat or alleviate pain in a mammal. Mean amount of NMDA-receptor antagonist.
[14] Mammals used in this specification include, for example, humans, pets (eg dogs and cats); Farm mammals (eg horses, cattle, pigs, and sheep); And laboratory animals (eg, monkeys, guinea pigs, rats, and mice). Preferably the "mammal" is a human.
[15] As used herein, "intradermal admistration" refers to the administration of a medicament to the skin of a mammal, preferably a human, to deliver the medicament to local tissues below and around the site of administration. Preferably intradermal administration is performed without absorption of the agent into the mammalian blood stream. The purpose of intradermal administration is to produce a topical effect as opposed to transdermal administration in which the subject delivers the medicament through the skin and through the bloodstream for systemic effects.
[16] As used herein, "topical administration" or "topical delivery" refers to intradermal administration of a medicament by administering the medicament or composition comprising the medicament to natural skin. For example, it means placing the composition of the invention on the area of natural skin or placing an intradermal patch comprising the composition of the invention on the area of natural skin.
[17] As used herein, "topical composition" means a pharmaceutical composition designed for topical topical administration and comprising a medicament.
[18] As used herein, "intradermally-acceptable" refers to a pharmaceutical excipient or other component of a topical formulation that is safe and approved for intradermal or topical administration in a mammal.
[19] As used herein, "pharmacologically acceptable" includes, but is not limited to, acidic or basic salts that may be present in the compounds of the present invention. Compounds of the present invention that are basic in nature are capable of forming various salts with various inorganic or organic acids. Acids that can be used to prepare pharmacologically acceptable salts of such basic compounds are acetic acid, benzenesulfonate, benzoic acid, bicarbonate, bitartrate, bromide, calcium edetate, campylate, carbonic acid, chloride, bromide, iodide Id, citrate, dihydrochloride, edetate, edisylate, estolate, esylate, humarate, gluceptate, gluconate, glutamate (glutamate), glycollylarsanilate, hexylresorcinate, hydrabamine, hydroxynaphthoate, iseionate, lactate , Lactobionate, malate, maleate, mandelate, mesylate, methylsulfate Methylsulfate, muscate, napsylate, nitrate, pantothenate, phosphate / diphosphate, polygalacturonate, Salicylate, stearate, succinate, sulfate, tannate, tartrate, teoclate, triethiodide And pamoate (ie, 1,1'-methylene-bis- (2-hydroxy-3-naphthoate)) to form salts comprising pharmacologically acceptable anions. Compounds of the present invention comprising amino groups can form pharmacologically acceptable salts with various amino acids in addition to the acids mentioned above. Compounds of the present invention that are acidic in nature can form basic salts with various pharmacologically acceptable cations. Examples of such salts include alkali metal or alkaline earth metal salts, and in particular calcium, magnesium, sodium, lithium, zinc, potassium and iron salts.
[20] As used herein, the term "solvate" further comprises a stoichiometric or non-stoichiometric solvent bound by noncovalent intermolecular forces or a salt thereof. Means. Preferred solvents are volatile, non-toxic and / or acceptable for topical administration in humans.
[21] As used herein, the term "hydrate" refers to a compound of the present invention or salt thereof that further comprises stoichiometric or non-stoichiometric water bound by noncovalent intermolecular forces. it means.
[22] As used herein, the term "clathrate" refers to a compound of the present invention in the form of a crystal lattice comprising a space (e.g. a channel) having a guest molecule (e.g. solvent or water) trapped therein, or a compound thereof Salt.
[23] As used in this specification, "prodrug" refers to a compound that can be converted to an antidepressant or NMDA receptor | antibody via in vivo changes after administration in a mammal. Prodrugs can be synthesized using known methods, such as BURGER'S MEDICINAL CHEMISTRY AND DRUG DISCOVERY, 172-178, 949-982 (Manfred E. Wolff ed., 5th edition 1995).
[24] As used herein, "emulsion" means a dispersion system that includes at least two systems that are not mixed with one another (one fat-soluble system and one hydrophilic or water-soluble system), where one unmixed system is a droplet to another system. Are dispersed in the form of). The emulsion is thermodynamically unstable as a result of the excess free energy associated with the surface of the droplet. Stable emulsions should have at least three components: a dispersion medium, a dispersed system, and an emulsifier.
[25] As used herein, an "oil-in-water type emulsion" is a stable emulsion in which the water-soluble system is a dispersion medium and the fat-soluble component is dispersed. Several tests are possible to determine whether it is an oil-in-water type emulsion or a water-in-oil type emulsion. Dilution tests, conductivity tests and dye solubility tests are possible, for example, as described in 1 REMINGTON: THE SCIENCE AND PRACTICE OF PHARMACY 282-291 (Alfonso R. Gennaro ed., 19th edition 1995).
[26] The composition of the present invention comprises an antidepressant and an NMDA-receptor antagonist in a colloidal dispersion (emulsion). Colloidal dispersions include water-soluble, fat-soluble, and surfactant-based systems, wherein the fat-soluble system is dispersed in the water-soluble system (oil-in-water), and its average droplet size ranges from about 0.01 to 100 microns, preferably Is in the range of about 0.1 to 10 microns. In a preferred embodiment the composition of the invention further comprises a curing agent and a hydrophobic surfactant. When administered topically to a mammal, the compositions of the present invention can be transported through natural skin to a mixture of antidepressants and NMDA-receptor antagonists at high flux rates and induce local anesthesia thereby treating and alleviating neuropathic pain. Or prevent. Moreover, the compositions of the present invention are physical (resistive to coalescence of droplets and deterioration of Oswald deterioration) and chemically stable (e.g., resistant to oxidation reactions) and give a feeling of soothing.
[27] A indication of pain
[28] The compositions and methods of the present invention can be used to treat or prevent signs that cause noxious stimulation of peripheral nociceptors. The compositions and methods of the present invention are effective for inducing local anesthesia and for treating neuropathic pain. As used herein, "neuropathic pain" refers to neuropathic pain syndrome, ie pain due to impairment or dysfunction in the nervous system. The compositions and methods of the present invention can be used to treat or prevent pain associated with or induced with a disease, trauma or condition such as: general neuropathy conditions (eg, peripheral neuropathy, phantom pain, reflex-sympathetic dysfunction). Trophies, burning pain, spinal cord cavities and sore wounds); Specific neuralgia at the local points of the body; Back pain; Diabetic neuropathy; alcohol neuropathy; metabolic neuropathy; inflammatory neuropathy; Chemotherapy induced neuropathy; Herpes neuralgia; Traumatic toothache; Endodontic toothache; Outlet syndrome of the rib cage; nerve root disorder of the cervix, rib cage or lumbar spine with nerve compression; Cancer with neuroinvasion; Traumatic ablation damage; Mastectomy; Thoracic pain; spinal cord injury; stroke; Nerve fragments in the lower abdomen; Tumors of neural tissues; Arachnoiditis; Stump shaker; Fibrosis; local sprains or strains; myofascial pain; Psoriatic arthrosis; Nodular polyarteritis; Osteomyelitis; Includes nerve damage and burns; AIDS related pain syndrome; Connective tissue abnormalities (eg systemic lupus erythema, systemic sclerosis, multiple muscle inflammation, and dermatitis); And inflammatory conditions (eg acute inflammation (eg trauma, surgery and infection) or chronic inflammation (eg arthritis and gout)).
[29] B. Antidepressants
[30] Antidepressants are known or found to be clinically effective in treating depression in mammals, including clinically approved antidepressants or compounds and compositions approved to treat depression in humans when tested in standard in vivo or in vitro. By known or developed compound or composition exhibiting receptor binding or other mechanical properties associated with the compound or composition.
[31] Classes of antidepressants include norepinephrine-reuptake inhibitors (NRls), selective serotonin-reuptake inhibitors (SSRIs), monoamine oxidase inhibitors (MAOIs), serotonin and noradrenaline-reuptake inhibitors ("SNRls"); Stimulating hormone releasing factor (CRF) antagonists, alpha-adrenoreceptor antagonists, NKl-receptor antagonists, 5-HT _1A -receptor agonists, antagonists, and partial agonists, atypical antidepressants and other antidepressants.
[32] One antidepressant may have one or more chiral centers and / or double bonds, so that it may exist as stereoisomers (eg, double bond isomers (ie, geometric isomers), enantiomers or diastereomers).
[33] As used herein, the term "antidepressant" refers to all of these types of enantiomers and stereoisomers (ie, stereoisomerically pure forms (e.g., geometrically pure, enantiomerically pure, or diastereomericly pure). And mixtures of enantiomers and stereoisomers, such as, for example, racemates. "Antidepressants" include all pharmacologically acceptable salts, all complexes (eg hydrates, sorbates, clathrates) and all of antidepressants. Contains prodrugs.
[34] In particular, the method of the present invention is suitable for topical administration in combination with an NMDA-receptor antagonist in accordance with the compositions and methods of the present invention in combination with topical administration, which is unsuitable for systemic administration in mammals due to toxicity or other causes. Can lose.
[35] “Antidepressants” suitable for use in the present invention can be identified by testing antidepressant compounds for local-anesthesia and peripheral anticiceptive properties by standard pain models. See, eg, J. Sawynok et al., 82 PAIN 149 (1999); See J. Sawynok et al. 80 PAIN 45 (1999).
[36] Preferably the antidepressant is a norepinephrine-reuptake inhibitor, more preferably tricyclic amitriptyline, most preferably amitriptyline hydrochloride.
[37] Norepinephrine-Reuptake Inhibitors
[38] As used herein, an "antidepressant" inhibits norepinephrine reuptake when administered systemically to a mammal ("norepinephrine-reuptake inhibitor") or receptor binding properties or nore in standard in vivo or in vitro experiments. Compounds that exhibit other mechanical properties associated with epinephrine-reuptake inhibitors. One skilled in the art can readily identify norepinephrine-reuptake inhibitors by in vivo or in vitro experiments.
[39] For example norepinephrine-reuptake inhibitors include Wong et al., 61 J. PHARM. EXP, THERAP. 222 (1982); Skolnick et al. 86 BR.J. The in vitro test methods described in PHARMACOLOGY 637-644 (1985) can be modified and identified.
[40] Examples of norepinephrine-reuptake inhibitors are amitriptyline, desmethylamitriptyline, crimipramine, doxepin, imipramine, imipramine-imipramine -oxide, trimipramine, adinazolam, amitriptylinoxide, amoxapine, desipramine, maprotiline, nortrip Nortriptyline, protriptyline, amineptine, amineptine, buttriptyline, dimesiptiline, dibenzepin, dimethzepine, dimetacrine, dothiepine ), Fluacizine, iprindole, lofepramine, lofepramine, melitracen, metapramine, norclolipramine, noxiptilin, Opipramol, perlapine, pizotyline, fr Blood benzodiazepine (propizepine), kwinu plastic Min (quinupramine), ribonucleic paroxetine (reboxetine), thiazol neptin (tianeptine), and includes a pharmacologically acceptable salt thereof is not limited thereto. Examples of other norepinephrine-reuptake inhibitors include the tricyclic compounds included in the general formula set forth in US Pat. No. 6,211,171 (2001.4.30 patent) column 9, lines 30-65 and acceptable salts thereof. All patents and published patents are expressly incorporated herein by reference.
[41] 2. Serotonin-Reuptake Inhibitors
[42] As used herein, an "antidepressant" inhibits serotonin reuptake when administered systemically to a mammal ("serotonin-reuptake inhibitor") or is associated with receptor binding properties or serotonin-reuptake inhibitors in standard in vivo or in vitro experiments. Include compounds that exhibit other mechanical properties. One skilled in the art can readily identify serotonin-reuptake inhibitors by in vivo or in vitro experiments.
[43] For example serotonin-retaketake inhibitors include Wong, et al. 8 NEUROPSYCHOPHARMACOLOGY 337 (1993); US Patent No. 6,225,324 (May 1, 2001 Patent) Columns 20, 20-67; And US Pat. No. 5,648,396 (July 15, 1997 patent), columns 15, 33, by modifying the in vitro test method described in column 16, line 44.
[44] Examples of serotonin-reuptake inhibitors include binedaline, m-chloropiperzine, citalopram, duloxetine, etooperidone, femoxetine, Fluoxetine, fluvoxamine, indalpine, indeloxazine, milnacipran, nefazodone, oxaflazone, parosetin (paroxetine) paroxetine, prolintane, ritanserin, sertraline, tandosporone, venlafaxine and zimeldine and their pharmacologically acceptable salts Including but not limited to.
[45] 3. Monoamine-Oxidase Inhibitors
[46] As used herein, "antidepressants" include compounds that act as monoamine oxidase inhibitors (MAOls) or inhibit monoamine oxidase in standard in vivo or in vitro experiments when administered systemically to mammals. One skilled in the art can readily identify serotonin-reuptake inhibitors by in vivo or in vitro experiments. See, eg, 12 Biochem. Pharmacol. 1439 (1963) and Kinemuchi et al. 35 J. NEUROCHEM. 109 (1980); The monoamine oxidase inhibition experiment described in US Pat. No. 6,096,771 (August 1, 2000 patent) can be modified and identified.
[47] Examples of non-selective MAO inhibitors include amifuramine, vanoxerine (boxeprazine), AGN 2253 (Nicholas kiwi), iproniazid, isocarboxazide, M-3 Include, but are not limited to, PPC (Draxis), nialamid, phenelzine, pargyline, and tranylcypromine, and pharmacologically acceptable salts thereof Do not.
[48] Examples of selective MAO A inhibitors are crorgyrine, shimokisatone, befloxatone, brofaromine, bazinaprine, BW-616 U (Burroughs Elcome), BW-1370 U87 (Burroughs Elkham), CS-722 (RS-722) (Sankyo), E-2011 (Ezai), Harmine, Harmaline, moclobemide, PharmaProjects 3975 (Hoechst) RO 41-1049 (Roche), RS-8359 10 (Sankyo), T-794 (Tanabe Pharmaceutical), Troki Sathorn, KY 1349 (Kalir and Youdim)) LY-51641 (Lily), L Y-121768 (Lily), M & B 9303 (May and Baker), MDL 72394 (Marion Merrell), MDL 72392 (Marion Merrell), sercloremine, and MO 1671, and pharmacologically acceptable salts thereof.
[49] Other MAO A inhibitors include budipine, carxazon, D-1711 (Biocodex), pezo1amine, FLA-334 (RAN-ll3) (Astra), FLA-289 (FLA-299, FLA-365, FLA-384, FLA-463, FLA-727) (Astra), K-11566 (Upjohn, Farmitalia), K-11829 (Upjohn, Farmitalia Fannitalia), Metralindole (metralindole), MPCPAM (Yissum), PharmaProjects 227 (Syntex / Roche), PharmaProjects 2806 (Fournier), PharmaProjects 1122, PharmaProjects3311 (Roche), PharmaProjects 4433 (Roche), RS-2232 (Sankyo), and UP-614-04 (Bristol-Myers) And pharmacologically acceptable salts thereof.
[50] Other MAO inhibitors include bifemelane, brofaromide, hypericine, iproclozide, medifoxamine, nialamide, and octamoxin ), Phenoxypropaazine, pivalyl benzhydrazine, prodipine, selegilin and beluoxine and pharmacologically acceptable salts thereof.
[51] 4. Inhibitors of Serotonin- and Noradrenaline Retaketake
[52] As used herein, the term "antidepressant" acts as a serotonin- and noradrenaline-reuptake inhibitor ("SNRIs") when administered systemically to mammals or receptor binding properties or serotonin- and noradrenaline in standard in vivo or in vitro experiments. Include compounds exhibiting other mechanical properties associated with reuptake inhibitors. One skilled in the art can readily identify SNRIs by in vivo or in vitro experiments. The in vitro test method described in US Pat. No. 6,172,097 (January 9, 2001 patent) can be identified by modifying it. Examples of SNRIs include, but are not limited to mirtazapine and venlafaxine and pharmacologically acceptable salts thereof.
[53] 5. Corticotropin-releasing factor antagonists
[54] As used herein, an "antidepressant", when administered systemically to a mammal, acts as an adrenal cortical stimulating hormone antagonist or based on standard assays in vivo or in vitro. When tested, it includes a compound that displays receptor-binding properties or properties associated with CRF antagonists. One skilled in the art can readily identify CRF antagonists by in vivo and ex vivo tests. For example, CRF antagonists are described in US Pat. No. 6,218,391 (patented on January 30, 2005) and can be identified by changing the in vivo test method expressly incorporated herein by reference to the results.
[55] Examples of CRF antagonists are described in US Pat. No. 6,191,131 (2001.2.20. Patented); 6,174,192 (patented on Jan. 2001); 6,133,282 (patented Oct. 17, 2000); PCT Application Publication Nos. WO94 / 13643, WO94 / 13644, WO94 / 13661, WO94 / 13676 and WO94 / 13677, and their pharmaceutically acceptable salts, but not Unless limited, all patents and published patents are expressly incorporated herein by reference.
[56] 6. Alpha-Adrenoreceptor Antagonists
[57] As used herein, an "antidepressant" when administered systemically to a mammal, acts as an α-adrenergic receptor antagonist or tested according to standard assays in vivo or in vitro. and compounds that act as α-adrenergic receptor antagonists. One skilled in the art can readily identify α-adrenergic receptor antagonists by in vivo and ex vivo tests. For example, α-adrenergic receptor antagonists are described in US Pat. No. 6,150,389 (patented Nov. 21, 2000) and can be identified by changing the in vivo test method expressly incorporated herein by reference. .
[58] Examples of α-adrenergic receptor antagonists include, but are not limited to, phentolamine and those described in US Pat. No. 6,150,389 and pharmaceutically acceptable salts thereof.
[59] 7. NK1-receptor antagonists
[60] As used herein, an "antidepressant", when administered systemically to a mammal, acts as a NK1-receptor antagonist (Neurokinin 1 substance P receptor antagonist) or is used in standard or in vitro tests ( When tested according to the assay, it includes compounds that act as NK1-receptor antagonists. One skilled in the art can readily identify NK1-receptor antagonists by in vivo and ex vivo tests. For example, NK1-receptor antagonists are described in US Pat. No. 6,117,855 (patented on Sep. 2, 2000), and the results cited herein clearly alter the NK1-receptor-binding assay, incorporated herein by reference. Can be confirmed by
[61] Examples of NK1-receptor antagonists are those described in PCT Application Publication Nos. WO95 / 16679, WO95 / 18124, WO95 / 23798, and European Patent Specification No. 0 577 394 and their pharmaceutically acceptable salts. All published patents and patents are expressly incorporated herein by reference, including but not limited to these.
[62] 8. 5-HT _1AReceptor agonists, antagonists, and partial agonists
[63] As used herein, an "antidepressant", when administered systemically to a mammal, acts as a 5-HT _1A -receptor agonist, antagonist, and partial agent ("5-HT _1A agonist") or in vivo. When tested according to standard assays in vivo or in vitro, it includes compounds that act as 5-HT _1A -receptor agonists, antagonists, and partial agonists. One skilled in the art can readily identify 5-HT1A drugs by in vivo and ex vivo testing. For example, the 5-HT _1A medicament can be used in the 5-HT1A receptor-binding assay described in US Pat. No. 6,255,302 (patented on July 7, 2001) or 6,239,194 (patented on June 1, 2009). As can be confirmed by the following modifications, these patents are expressly incorporated herein by reference.
[64] Examples of 5-HT _1A agents include busporone, freshsinoxan, gepirone, ipsapirone, and their pharmaceutically acceptable salts and US Pat. No. 6,255,302 ( Patent dated June 2, 2001); And 6,242,448 (patented on June 6, 2001). An example of a 5-HT1A-receptor antagonist / partial agonist active compound is pindolol.
[65] 9. Atypical Antidepressants
[66] "Antidepressants" include atypical antidepressants.
[67] Examples of atypical antidepressants include bupropion, dimethazan, fencamine, fenpentadiol, levophacetoperance, metralindone and myanserine ( mianserin, cotinine, rolicyprine, rolipram, nefopam, lithium, trazodone, viloxazine, and ciputramine sibutramine) and pharmaceutically acceptable salts thereof.
[68] 10. Other Antidepressants
[69] "Antidepressants" include nomifensine, oxitriptan, oxypertine, thiazesim, adrafinil, beactyzine, butacetin, butacetin, dioxad Dioxadrol, febarbamate, hematoporphyrin, hezaporone, tozalinone, tofenacin, l-tryptophan, alaprolate, Amitriptyline-chlordiazepoxide combination, atipamezole, azaamiianserin, bazinaprine, befuraline, vinodaline, Bipenamol, cericlamine, cyanopramine, cimoxatone, clemeprol, clovoxamine, dazepinil, deanol (deanol), enefexine, estazolan, fezolamine, fluorotra (fluotracen), levoprotiline (levoprotiline), litoxetine, monttilin (montirelin), nebracetam, norfluoxetine, orotirelin, oxaflozane, Pinazepam, pirlindone, setiptiline, sulbutiamine, sulbutide, sulpiride, teniloxazine, thymoliberin, and tiflucarbine ), Tofisopam, tomoxetine, veralipride, viqualine, zimelidine and zometapine, and their pharmaceutically acceptable Salts, and various other drugs that are considered to have antidepressant activity, including but not limited to St John's Wort herb or hypericum perforatum or extracts thereof. .
[70] 11. Concentration of Antidepressant in the Composition of the Present Invention
[71] The amount of antidepressant in the composition of the invention varies with the type and nature of the antidepressant, the concentration and nature of the NMDA-receptor antagonist, and the signs of the patient being treated. Dosing and enrichment for specific antagonists are routine experiments using well-known patient models such as those described in J. Sawynok et al., 83 PAIN 149 (1999) and J. Sawynok et al., 80 PAIN 45 (1999). Can be best utilized.
[72] Generally, the amount of antidepressant in the composition of the invention ranges from about 0.1% to about 10% of the total weight of the composition, more preferably from about 0.5% to about 8%, even more preferably from about 1% to about It is within the 5% range.
[73] C. N-Methyl-D-Aspartate Receptor Antagonist
[74] NMDA receptors are cell-surface protein complexes that are widely distributed in the central nervous system of mammals belonging to the ionotroic-glutamate receptor class. It is associated with excitatory-synaptic delivery and neuronal growth regulation. The structure has a ligand-gated / voltage sensitive ion channel. NMDA receptors are very complex and have at least five binding (activating) sites: glycine-binding sites, glutamate-binding sites (NMDA-binding sites); It is believed to accept PCP-binding sites, polyaminc binding sites, zinc-binding sites. As used herein, an NMDA-receptor antagonist means any compound or composition known or found to inhibit the flow of ions through an NMDA-receptor ion channel when contacted with an NMDA receptor in vivo or ex vivo.
[75] NMDA-receptor antagonists include one or more chiral centers and / or double bonds and, therefore, double-bond isomers (ie, geometric isomers), enantiomers, or diastereos Exist as stereoisomers such as diastereomers and the like. As used herein, the term NMDA-receptor antagonist refers to all such enantiomers and stereoisomers, ie, stereomerically-pure forms (eg, geometrically pure, ethanethiomerically pure). And also diastereomerically pure) and mixtures of enantiomers and streoisomers such as racemates. The term NMDA-receptor antagonist includes all pharmaceutically acceptable salts, all complexes (e.g., hydrates, solvates, and clathrate-type compounds), and all prodrugs of NMDA-receptor antagonists. It includes more.
[76] NMDA-receptor antagonists suitable for use in the present invention can be identified by NMDA-receptor antagonist testing for local anesthetic and peripheral anticiceptive properties according to standard patient models. See, for example, J. Sawynok et al., 82 Pain 149 (1999); See J. Sawynok et al., 80 Pain 45 (1999).
[77] Preferably, the NMDA-receptor antagonist is a non-competitive NMDA-receptor antagonist, more preferably ketamine, even more preferably ketamine hydrochloride.
[78] 1.N-methyl-D-aspartate receptor antagonist that interferes with the NMDA receptor at glycine binding sites
[79] As used herein, the meaning of an NMDA-receptor antagonist phrase includes any compound and composition that antagonizes an NMDA receptor by binding at the glassine site. For an overview of glycine-site NMDA-receptor antagonists, see LEESON, P.D., GLYCINE SITE N-METHYL-D-ASPARTATE RECEPTOR ANTAGONISTS, Chapter 13 DRUG DESIGN FORr NEUROSCIENCE, (Kozikowski, A.P. ed. 338-381, 1993). Glycine-site NMDA-receptor antagonists can be identified by in vivo and ex vivo standard tests. See, for example, US Pat. No. 6,251,903 (Patented 26.26. 2); 6,191,165 (patented on Feb. 9, 2001); Grimwood et al. 4 MOLECULAR PHARMACOLOGY 923 (1992); Yoneda et al. 62 J. NEUROCHEM. 102 (1994); And Mayer et al. J. NEUROPHYSIOL. See the tests described in 645 (1988), all of which are expressly incorporated herein by reference.
[80] Glycine-site NMDA-receptor antagonists are glycinamide, tereonine, D-serine, felbamate, 5,7-dichlorokynurenic acid, and 3-amino-1-hydroxy-2-pyrrolidone (HA-966), diethylenetriamine, 1,10-diaminodecane, 1,12-diamino degree Diaminododecane, and ifenprodil and US Pat. No. 6,252,903; 5,914,403 (patented on June 6, 1999); 5,863,916 (January 1, 1999); 5,783,700 (patented on July 7, 1998); And 5,708,168 (patented on January 13, 1998), all of which are expressly incorporated herein by reference.
[81] 2. N-methyl-D-aspartate receptor antagonist that interferes with the NMDA receptor at the glutamate binding site
[82] As used herein, the meaning of "NMDA-receptor antagonist" includes any compound and composition that antagonizes an NMDA receptor by binding to a glutamate site referred to herein as a "competitive NMDA-receptor antagonist"; See, eg, Olney & Farber, 13, NEUROPSYCHOPHARMACOLOGY 335 (1995).
[83] Competitive NMDA antagonists include 3-((1) -2-carboxypiperazin-4-ylpropyl-1-phosphate (CPP); 3- (2-carboxypiperazin- 4-yl) -prpenyl-1-phosphonate (CPP-ene); 1- (cis-2-carboxypiperidine-4-yl) methyl-1-phosphonic Phosphonic acid (CGS19755), D-2-amido-5-phosphonopentanoic acid (AP5); 2-amino-phosphonohcptanoate (AP7); D, L- (E) -amino-4-methyl-5-phosphono-3-enoic acid carboxyethyl ester (CGP39551); 3-((phosphonylmethyl ) -Sulfinyl-D, L-alanine; amino- (4-phosphonomethyl-phenyl) -acetic acid (PD 132477); 2-amino -3- (5-chloro-l-phosphonomethyl-lH-benzoimidazol-2-yl) -propionic acid; 2-amino-3- (5-phosphonomethyl-biphenyl-3-yl) -propionic acid (SDZ EAB 515); 2-amino-3- [2- (2-Phospho-ethyl-cyclohexyl] -propionic acid (NPC17742); 4- (3-phosphone-propyl) -piper Pyrazine-2-carboxylic acid (D-CPP); 4- (3-phosphono-allyl) -piperazine-2-carboxylic acid acid) (CGS 19755); 3 (2-phosphono-acetyl) -piperidine-2-carboxylic acid (MDL100,925); 5-phosphono-1,2,3,4-tetrahydro-isoquinoline-3-carboxylic acid (SC 48981); 5- (2-phosphono-ethyl) -1,2,3,4-tetrahydro-isoquinoline-3-carboxylic acid (PD 145950 ); 6-phosphonomethyl-decahydro-isoquinoline-3-carboxylic acid (LY 274614); 4- (1H-tetrazol-5-ylmethyl) -piperidine-2-carboxylic acid (LY 233053 and 235723); 6- (1H-tetrazol-5-ylmethyl) -decahydro-isoquinoline-3-carboxylic acid (LY 233536) It is not limited. References describing other competitive NMDA-receptor antagonists as well as tests to identify competitive NMDA-receptor antagonists are described in Jia-He Li, et al., 38 J. MED. CHEM. 1995 (1995); Steinberg et al., 133 NEUROSCI. LETT. 225 (1991); Meldrum et al., 11 TRENDS PHARMACOL. SCI., 379 (1990); Willetts et al., 11 TRENDS PHARMACOL. SCI. 423 (1990); Faden et al., 13 TRENDS PHARMACOL. SCI. 29 (1992); Rogawski 14 TRENDS PHARMACOL. SCI. 325 (1993); Albers et al., 15 CLINICAL NEUROPHARM. 509 (1992); Wolfe et al., 13 AM. J EMERG. MED., 174 (1995); And Bigge, 45 BIOCHEM. PHARMACOL. 1547 (1993), all of which are expressly incorporated herein by reference.
[84] 3. N-methyl-D-aspartate receptor antagonist that interferes with the NMDA receptor at the PCP binding site
[85] As used herein, the meaning of NMDA-receptor antagonist is to antagonize the NMDA receptor by binding at the PCP (phencyclidine) site referred to herein as a "non-competitive NMDA-receptor antagonist." It includes any compound and composition. For example, Bigge 45 BIOCHEM. PHARMACOL. See 1547 (1993).
[86] Non-competitive NMDA antagonists include conventional tests, for example, US Pat. No. 6,251,948 (Patented 1.6.25.200); 5,985,586 (patented November 16, 1999); And 6,025,369 (patented on February 5, 2000); Jacobson et al., 110 J. PHARMACOL. EXP. THER. 243 (1987); And Thurkauf et al., J. MED. CHEM. 2257 (1988), all of which citations are expressly incorporated herein by reference.
[87] Examples of noncompetitive NMDA-receptor antagonists that bind at the PCP site include ketamine, phencyclidine, dextromethorphan, dextrophan, dexosadrol, die Dizocilpine (MK-801), remacemide, thienylcyclohexylpiperidine (TCP), N-allylometazocine (SKF 10,047), cyclazine (cyclazocine), etoxadrol, (1,2,3,4,9,9a-hexahydro-fluorene-4a-yl) -methyl-amine (PD137889) ; PD 138558, tiletamine, kynurenic acid, 7-chloro-kynurenic acid, and memantine; And 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX) and 6,7-dinitro-quinoxaline-2,3- Quinoxalinediones such as dione, including but not limited to.
[88] 4. N-methyl-D-aspartate receptor antagonists that interfere with NMDA receptors and other NMDA-receptors at polyamine or zinc binding sites
[89] As used herein, the meaning of NMDA-receptor antagonist means NMDA by polyamine binding site, a compound that interferes with NMDA-receptor at zinc-binding site, and by a specific binding site or by another mechanism. Other NMDA-receptor antagonists that interfere with the receptor. Examples of NMDA-receptor antagonists that bind at polyamine sites include, but are not limited to, spermine, spermidine, putrescine and arcane. Examples of tests used to identify NMDA-receptor antagonists that function at zinc or polyamine binding sites are disclosed in US Pat. No. 5,834,465 (patented Nov. 10, 1998), which is expressly incorporated herein by reference. .
[90] Other NMDA-receptor antagonists include amantadine, eliprodil, iamotrigine, riluzol, aptiganel, flupirtine, celfotel , Levemopamil, 1- (4-hydroxy-phenyl) -2- (4-phenylsulfanyl-piperidine-1-yl) -propane ( propan) -1-one; 2- [4- (4-fluoro-benzoyl) -piperidin-1-yl] -1-naphthalen-2-yl-ethanone (E 2001) ); 30 (1,1-dimethyl (heptyl) -9-hydroxymethyl-6,6-dimethyl-6a, 7,8,10a-tetrahydro- 6H-Benzo [c] chromen-1-ol (HU-211); 1-4- [1- (4-Chloro-phenyl) -1-methyl-ethyl] -2 -Methoxy-phenyl-1H- [1,2,4] triazole-3-carboxylic acid amide (CGP 31358); acetic acid 10-hydroxy-7,7,7 ' , 9'tetramethoxy-3,3'dimethyl-3,4,3 ', 4'tetrahydro
[91] -1H, 1'H- [5,5 '] bi [benzo [g] isochromenyl] -4-yl ester (ES 242-1); 14-hydroxy-11-isopropyl-10-methyl-5-octyl-10,13-diaza-tricyclo [6.6.1.04,15] pentadeca-1,4, 6,8 (15) -tetraen-12-one; and 4,5-dioxo-4,5-dihydro-1H-benzo [g] indole-2 , 7,9-tricarboxylic acid (PQQ) and pharmaceutically acceptable salts thereof.
[92] 5. Concentration of NMDA-Receptor Antagonists in Compositions of the Invention
[93] The amount of NMDA-receptor antagonist in the compositions of the present invention will vary depending on the type and nature of the NMDA-receptor antagonist, the concentration and nature of the antidepressant, and the signs of the patient being treated. Dosing and enrichment for certain NMDA-receptor antagonists is performed using well known patient models, for example, those described in J. Sawynok et al., 82 PAIN 149 (1999) and J. Sawynok et al., 80 PAIN 45 (1999). It can be best used based on routine experimentation.
[94] Generally, the amount of NMDA-receptor antagonist in the composition of the invention is in the range of about 0.1% to about 5%, more preferably in the range of about 0.3% to about 0.5% of the total weight of the composition.
[95] D. Lipophilic Ingredients
[96] In the compositions of the present invention, the fat-soluble component may be a hydrophobic organic substance or a mixture thereof capable of forming a stable emulsion comprising an anti-depressant and an NMDA-receptor antagonist suitable for intradermal administration. Preferably the fat soluble component is from about 15% to about 40% by weight of the total composition and more preferably about 20% by weight.
[97] Suitable fat-soluble ingredients are well known in the art and include vegetable oils, nuts, and seed oils (eg almond oil, castor oil, palm oil, corn oil, cottonseed oil, jojoba oil, flaxseed oil, grape seed oil, rape seed oil, mustard oil, olive oil, Palm oil and palm core oil, peanut oil, safflower oil, sesame oil, soybean oil, sunflower-seed oil, crampbe oil, bran oil and cacao butter); Animal fats and oils (eg lanolin, tallow, lard, beef fat, fats, minks and fish oils); hydrocarbons and essential oils (petrolatum, mineral oils and liquid paraffins); And higher fatty acids (e.g. lauric acid, myristic acid, palmitic acid, stearic acid, behenic acid, oleic acid, 12-hydroxy stearic acid (Undecylenic acid), tall acid, lanolin fatty acid, isostearic acid, linoleic acid and lino) The oil soluble component is preferably an essential oil such as mineral oil, mineral oil, or liquid paraffin, with mineral oil being most preferred.
[98] Preferably the fat-soluble component further comprises a "curing agent" (i.e. solid phase but hydrophobic material which melts in the range 40 ° C.-80 ° C.) to provide a creamy texture to the composition of the present invention. The preferred amount of curing agent is about 1% to about 10% of the total weight of the composition. Examples of suitable curing agents are cetyl alcohol, cetyl ester wax, microcrystalline wax, paraffin, stearyl alcohol, lauryl alcohol, miracle alcohol, cetostearyl alcohol, white wax, yellow wax, beeswax, candelilla ( candelil1a) wax, cotton wax, carnauba wax, bayberry wax, rice bran wax. Cetyl alcohol is a preferred curing agent.
[99] Preferably the fat soluble component further comprises a hydrophobic substance which facilitates absorption of antidepressants and NNDA-receptor antagonists into the skin, referred to hereinafter as " lipophilic intradermal penetration enhancers. &Quot; Preferred amounts of intradermal penetration enhancer are from about 1% to about 15% by weight of the total composition and suitable fat-soluble intradermal penetration enhancers are isopropyl myristate, glycerol monolaurate, glycerol monooleate, glycerol monolino Monooleate, isopropyl isotearate, isopropyl linoleate, isopropyl myristate / fatty acid monoglyceride mixture, isopropyl myristate / ethanol / L-lactate mixture, isopropyl Palmitate, methyl acetate, methyl caprate and methyllaurate.
[100] Preferably the fat soluble phase further comprises a hydrophobic surfactant. The preferred amount of hydrophobic surfactant is from about 2% to about 8% by weight of the total composition weight. Hydrophobic surfactants are well known in the art and include, for example, emulsifying waxes, polyoxyethylene acids, polyoxy ethylene alcohols, glycerol monosterates, sorbitan tristerates, sorbitan motopalmi Mate (monopalmitate), sorbitan sesquiloleate and other sorbitan fatty acid esters.
[101] E. Surfactants
[102] The composition of the present invention comprises a surfactant for stabilizing the emulsion. The surfactant can be cationic, nonionic, anionic, or amphoteric. For surfactants and emulsions, see Gillian M. Eccleston, Emulsion in 5 ENCYCLOPEDIA OF PHARMACEUTICAL TECHNOLOGY 137-184 (James C. Swarbrick & James C. Boylan eds. 1988). For the use of the present invention, the surfactant may be an intradermal acceptable hydrophilic or hydrophobic substance or mixture of substances which may stabilize the oil-in-water type emulsion. One skilled in the art can readily select a suitable surfactant or mixture of surfactants based on the hydrophilic-lipophilic balance (HLB) of the surfactant and the fat soluble component.
[103] Preferred amounts of surfactant are from about 2% to about 15% by weight of the total composition, with about 10% being most preferred. As is well known in the art, the "hydrophilic-lipophilic balance" or "HLB" refers to a shackle assigned to a surfactant according to Griffin's method to facilitate surfactant selection prior to emulsion preparation. For a table of numerical values and a detailed HLB system, see Griffin 1 SOC. COSMET.CHEM. 311 (1949); 1 REMINGTON: THE SCIENCE AND PRACTICE OF PHARMACY 286-289 35 (Alfonso R: Genennaro ed., 19th edition 1995); TRANSDERMAL AND TOPICAL DRUG DELIVERY SYSTEMS 542-546 (Tapash K. Ghosh et al., 1997 ), And all citations are expressly incorporated herein. In general, emulsion preparation is essentially a trial and error run, but if an oil-in-water type emulsion is desired, the formula begins with a composition having a surfactant system having an HLB value in the range of about 8 to 18 (± 2). Should be. On the other hand, if a water-in-oil type emulsion is desired, the formula should start with a composition with a surfactant system having an HLB value in the range of about 4 to 6 (± 2).
[104] Materials that are generally used as components of the hydrophobicity of the emulsion can assign "essential HLB values". In order to effectively emulsify a particular material, the essential HLB value is the HLB value that the surfactant or surfactant system should have. For example, a surfactant system having an HLB of about 10.5 (± 2) should be used to prepare an oil-in-water emulsion of fat-soluble material with an essential HLB of l0.5. Preferred surfactants having HLB values in the range of 8 to 18 (± 2) are sorbitan monolaurate, glycero monosterate, PEG 20 sorbitan monolaurate, PEG 20 sorbitan monopalmitate, PEG 20 sorb Non-elastic monosterate, PEG 20 sorbitan monoorate, PEG 20 sorbitan triorate, PEG 8 sterate, PEG 40 sterate, PEG-100 sterate and other PEG sterates; PEG 4 lauryl ether, PEG 21 stearyl ether, PEG 2 oleyl ether.
[105] In addition, mixtures of surfactants are suitable for the use of the present invention. In general, when a mixture of surfactants is used, the HLB value of the surfactant mixture should be in the range of ± 2 (typically between 8 and 18 (± 2)) to the required HLB value for the fat soluble component. HLB values add logarithmically to make such calculations relatively simple. Preferred surfactant mixtures include sorbitan tristerate and PEG 20 sorbitan monosterate; Sorbitan monopalmitate and PEG 20 sorbitan monopalmitate; Sorbitan sesquiorate and PEG 20 lauryl ether.
[106] F. Preservatives
[107] In a preferred embodiment the composition of the invention further comprises a preservative. In general, topical preparations need to be preserved from microbial contaminants that affect the stabilization of the formulation and can infect the handler. The amount of preservative when present in the composition of the present invention is preferably about 0.001% to about 1% by weight, more preferably about 0.01% to about 0.5% by weight of the total weight of the composition. In some instances it is advantageous to include antioxidants to preserve the agents and excipients present in topical formulations. Some agents and excipients can react with oxygen and undergo oxidation. The amount of antioxidant when present in the composition of the present invention is preferably about 0.001% to about 1% by weight, more preferably about 0.01% to about 0.5% by weight of the total weight of the composition.
[108] Examples of preservatives include quaternary amines (eg quaternium 15, benzalkonium chloride, celimide, benzetium chloride); And imidizolidinyl urea; Organic acids (eg sorbic acid, p-hydroxy benzoic acid, and benzoic acid; parabens (eg methylparaben and propylparaben); alcohols (eg benzyl alcohol and isopropyl alcohol); phenols (eg triclosan ( triclosan, chlorhexidine and thimerosal; hydantoin derivatives; chloromethylthiazoline; methylisothiazoline; phenylisothiazoline; phenyoxyethol; Cetidine; chlorohexydingluconate; and imidazolidinylurea, preferably preservatives such as methylparaben, propylparaben, or mixtures thereof to be.
[109] Examples of antioxidants include ascorbate and its esters, sodium bisulfide, sodium metabisulfide, thiourea, butylated hydroxytoluene, butylated hydroxyanisole, tocopherols, alkyl molars And chelating agents such as EDTA or citric acid.
[110] G. Antifoam
[111] In a preferred embodiment the composition of the invention further comprises an antifoaming agent which facilitates preparation. Defoamers destabilize the air-liquid system surface to remove bubbles and remove liquid from the air pockets. The amount of antifoaming agent when present in the composition of the present invention is preferably about 0.001% to about 1% by weight, more preferably about 0.01% to about 0.5% by weight of the total weight of the composition.
[112] Examples of antifoaming agents include simethicone, dimethicone, ethanol), and ethers. Preferably the antifoaming agent is simethicone.
[113] H. Emollients. Humidants, and Skin Protectants
[114] In a preferred embodiment the composition of the invention further comprises an emollient, humectant, or skin protectant, preferably a humectant that softens and hydrates the skin. The amount of wetting agent, skin protector or emollient when present in the composition of the present invention is preferably about 1% to about 10% by weight, more preferably about 2% to about 5% by weight of the total weight of the composition.
[115] Examples of wetting agents include, but are not limited to, glycerin, sorbitol, polyethylene glycol, urea, propylene glycol, 1,3-butylene glycol, ethanol, and isopropanol. In a preferred embodiment sorbitol is a humectant and a 70% aqueous humectant solution is preferred.
[116] Examples of emollients include, but are not limited to, cholesterol and glycerol. Examples of skin protectants include vitamin E oils, aratoin, glycerin, zinc oxide, vitamins A, B (eg biotin and pantothenic acid) C, E, F, H, and P, and esters thereof One is not limited thereto.
[117] I. Permeation Enhancer
[118] In another embodiment, the composition of the present invention further comprises a penetration enhancer. The amount of permeation enhancer present in the composition of the present invention is preferably in the range of about 0.1% to about 10% by weight, more preferably in the range of about 2% to about 5% by weight of the total weight of the composition.
[119] Permeation enhancers can be included in the compositions of the present invention to optimize delivery of the antidepressant and NMDA receptor antagonist through the stratum corneum into the dermis to provide a topical effect. For information on the use of permeation enhancers in topical formulations, see PERCUTANEOUS PENETRATION ENHANCER (Eric W. Smith and Howard I. Maybach eds. 1995); Ghosh, T.K. et al. 17 PHARM. TECH. 72 (1993); Ghosh, T.K. et al. 17 PHARM. TECH. 62 (1993); Ghosh, T.K. et al. 17 PHARM. See TECH.68 (1993).
[120] Permeation enhancers should be pharmacologically inactive, nontoxic, non-allergic, show signs of rapid and reversible action, and be compatible with the compositions of the present invention.
[121] Examples of penetration enhancers are described in US Pat. No. 4,755,535; As described in 4,801,586, 4,808,414 and 4,920,101, transcutol P, ethyl alcohol, isopropyl alcohol, lauryl alcohol, salicylic acid, octolyphenylpolyethylene glycol, polyethylene glycol 400, propylene glycol, N-decylmethylsulfoxide, DMSO and azacyclo compounds, including but not limited to. Preferably the permeation enhancer is transcutol P.
[122] J. Other Local Anesthetics
[123] The compositions of the present invention may further comprise one or more additional local anesthetics in addition to the antidepressant and the NMDA-receptor antagonist. As used herein, "local anesthetic" refers to a compound or composition that provides topical relief or analgesia or a medicament that provides local inhibition of the painful pathway (afferent and / or centrifugal). Local anesthetics may be known or developed local anesthetics. The amount of local anesthetic when present in the composition of the present invention is preferably in the range of about 0.1% to about 10% by weight of the total weight of the composition.
[124] Examples of suitable local anesthetics for use in the present invention include sodium channel blockers. Sodium channel blockers, such as lidocaine, reduce or interfere with the large transient increase in the excitatory membrane of sodium ions, thus interfering with the generation and conduction of nerve impulses. Examples of sodium channel blockers include ambucaine, amolanone, amylcaine, benoxysinate, benzocaine, betosicaine, biphenamine, bepivacaine, buta Butacaine, butamben, butanilicaine, butaniamine, butethamine, butoxycaine, carticaine, chloroprocaine, cocaethylene ( cocaethylene, cocaine, cyclomethycaine, dibucaine, dimethisoquin, dimethisoquine, dimethocaine, diperodon, diclonine, Ecogonidine, ecogonine, euprocine, euprocine, fenalcomine, formocaine, hexylcaine, hydroxyteteracaine, iso Butyl p-aminobenzoate, leucinocaine, levoxadol adrol, lidocaine, mepivacaine, meprylcaine, mebutrylcaine, metabutoxycaine, methyl chloride, myrtecaine, myrapine, napaine, Octacaine, orthocaine, orthocaine, oxethazaine, parenthoxycaine, phenacaine, phenol, piperocaine, pyridocaine, piridocaine, poridocaine Polidocanol, pramoxine, prilocaine, procaine, procaine, propanocaine, propparacaine, propipocaine, propoxycaine ), Pseudococaine, pyrrocaine, ropivacaine, salicyl alcohol, tetracaine, tolycaine, trimecaine, zoramin (zolamine), or a pharmacologically acceptable salt thereof and mixtures thereof It is not limited to this. Preferred sodium chopping blockers include bupivacaine, dibucaine, ethidocaine, lidocaine, procaine, prerocaine, mepivacaine, lopivacaine and pharmacologically acceptable salts thereof and mixtures thereof. Most preferred local anesthetics are lidocaine and its pharmacologically acceptable salts.
[125] Opioids such as morphine are known to have local anesthetic properties when administered to mammals (see US Pat. No. 5,948,389 (September 7, 1999); and Christoph Stein & Alexander Yassouridis 71 Pain 119 (1997)).
[126] As used herein, "opioids" refers to mu (μ), kappa (κ), and delta (δ) opioid receptors and all agents and antagonists of subtypes thereof. GOODMAN & GILMAN'S THE for opioid receptors and subtypes thereof
[127] See PHARMACOLOGICAL BASIS OF THERAPEUTICS 521-525 (Joel G. Hardman et al., 9 nd. 1996). Opioids can be opioid receptor agonists or antagonists that can be known or developed. Preferred opioids are mu-opioid receptors, kappa-opioid receptors, or both, preferably opioids are opioid-receptor agonists.
[128] Examples of suitable opioids are alfentanil, allylprodine, alphaprodine, anileridine, benzylmorphine, benzitramide, nor-binaltor Nor-binaltorphimine, bremazocine, buprenorphine, butophanol, butorphanol, clonitazene, codeine, CTOP, DAMGO, desomorphine , Dextromoramide, dezocine, diampromide, dihydrocodeine, dihydrocodene enol acetate, dihydromorphine, dimenosaldol, dimepetanol ( dimepheptanol, dimethylthiambutene, dioxaphetyl butylate, dipipanone, diprenorphine, DPDPE, eptazocine, ethoheptazine Ethyl ketocyclazosin (ethylketocyc1azocine), Ethylmethylthiambutene, etonitazene, etorphine, fentanyl, hydrocodone, hydromorphine, hydroxypethidine, isomethadone, Ketobemidone, levorphanol, lofentanil, loperamide, loperamide, meperidine, meptazinol, metazocaine, methadone (methadone), metopon, morphine, morphine, myropine (myrophine, nalbuphine), naltrindole, benzoylhydrazone, naltrexone and narcane narceine, nicomorphine, norlevorphanol, normethadone, normethadone, normorphine, norpipanone, opium, oxycodone, oxymorphine oxymorphone, papaveretum, papaverine, pentazocine, phenadoxone, Phenazocine, phenoperidine, piminodine, pitramide, proheptazine, promedol, propiram, propofiphen propoxyphene, remifentannil, spiradoline, spentanyl, tilidine, U50,488, and U69,593, amifenazol, cyclazosin, levarorphan, narmefen, nalor Pins, naloxone, and naltrexone or pharmacologically acceptable salts thereof and mixtures thereof.
[129] Examples of peptide opioids include Tyr-Gly-Gly-Phe-Leu ([Leu ⁵ ] enkeparin), Tyr-Gly-Gly-Phe-Met ([Met ⁵ ] enkeparin), Tyr-Gly-Gly-Phe -Leu-Arg-Arg-Ile-Arg-Pro-Lys-Leu-Lys-Trp-Asp-Asn-Gln (Dynorphin A) Tyr-Gly-Gly-Phe-Leu-Arg-Arg- Gln-Phe-Lys-Val-Val-Thr (dynorphine B), Tyr-Gly-Gly-Phe-Leu-Arg-Lys-Tyr-Pro-Lys (alpha-neoendorphin, Tyr-Gly- Gly-Phe-Leu-Arg-Lsy-Tyr-Pro (beta-neoendodolphin), Tyr-Gly-Gly-Phe-Met-Thr-Ser-Glu-Lys-Ser-Gln-Thr-Pro-Leu-Val- Thr-Leu Phe-Lys-Asn-Ala-Ile-Ile-Lys-Asn-Ala-Tyr-Lys-Lys-Gly-Glu (beta _h -endorphin), [D-Ala ² , MePhe ⁴ Gly (ol) ⁵ ] Enkephalin (DAMGO), [D-Pen ² , D-Pen ⁵ ] Enkephalin (DPDPE), [D-Ser ² , Leu ⁵ ] Enkephalin (DSLET), [D-Ala ² , D-Leu ⁵ ] Enkephalin (DADL ) D-Phe-Cys-Tyr-D-Trp-Orn-Thr-Pen-Thr-NH ₂ (CTOP), [D-Ala ² , N-MePhe ⁴ , Met (O) ⁵ -ol] enkephalin (FK- 33824) Tyr-D-Ala-Phe-Asp-Val-Val-Gly-NH ₂ ([D-Ala ² ] Deltorphin 1), Tyr-D-Ala-Phe-Glu-Val-Gal-NH ₂ ( [D-Ala ² Glu ⁴ ] Deltorphin (Deltorphin II)), Tyr-Pro-Phe-Pro-NH ₂ (Morphiceptin), Tyr-Pro-MePhe-D-Pro-NH 2 (PL-017), [D-Ala ² , Leu ⁵ , Cys ⁶ ] Enkephalin (DALCE) or pharmacologically acceptable salts thereof.
[130] Preferred opioids are morphine, loperamide and loperamide derivatives (e.g., U.S. Pat. As described) or pharmacologically acceptable salts thereof or mixtures thereof. Most preferred opioids are morphine or pharmacologically acceptable salts thereof. Other agents with local anesthetic properties include analgesics such as nonsteroidal anti-inflammatory drugs ("NSAIDs") (see, for example, TRANSDERMAL AND TOPICAL DRUG DELIVERY SYSTEMS 87-93 (Tapash K. Ghosh et al., 1997). Examples of brittle analgesics include, but are not limited to, acetylsalicylic acid, ketoprofen, piroxicam, dichlofenac, indomethacin and ketorolac.
[131] Another embodiment may include a medicament that sustains the local anesthetic effect of a composition of the present invention, such as a saccharide adrenal corticosteroid (eg US Pat. No. 5,922,340) or a vasocontract such as catecholamines.
[132] K. Other Excipients
[133] Compositions of the present invention may comprise one or more thickening agents, pharmaceuticals or pharmaceuticals, bioadhesive polymers, inert carriers, lipid adsorbents, viscosity stabilizers, chelating agents, buffers, anti-fading agents, stabilizers, moisture It may further comprise one or more additional ingredients such as absorbents, fragrances, colorants, film forming materials, and resurfacing agents. One skilled in the art can readily select such additional excipients based on the desired physical and chemical properties of the final topical formulation. Of course, a single excipient can have a variety of functions and properties.
[134] 1. Thickener
[135] The composition of the present invention may further comprise one or more thickening agents. Thickeners can be used to increase viscosity and improve bioadhesiveness. The amount of thickener when present in the composition of the present invention is preferably in the range of about 1% to about 10% by weight, more preferably in the range of about 2% to about 5% by weight of the total weight of the composition.
[136] Examples of thickening agents include cellulose, hydroxy propyl cellulose, methyl cellulose, polyethylene glycol, sodium carboxymethyl cellulose, polyethylene oxide, xanthan gum, guana gum, agar, carrageenan gum, gelatin, karaya, pectin, and locust-bean gum. , But not limited to, aliginic acid, bentonite carbomer, povidone and tragacanth.
[137] 2.drugs
[138] The compositions of the present invention may comprise medicaments or their pharmacologically acceptable salts.
[139] Those skilled in the art can readily select the agent to be inserted into the composition of the present invention and its appropriate concentration according to the indication and the desired effect.
[140] Examples of medicaments include antibacterial agents (e.g., cycloclorox, crorocyrenor, triacetin, sulconazole, nystatin, undecylenic acid, tornafate) , Miconizole, clotrimazole, oxiconazole, griseofulvin, econazole, ketoconozole and anpoterisin B; antibiotics ( For example mupirocin, erythromycin, clindamycin, gentamicin, polymyxin, bacitracin and silver sulfadiazine; preservatives (e.g. iodine, poppydine) Iodine, benzalkonium chloride, benzoic acid, chlorhexidine, nitrofurazone, benzoyl peroxide, hydrogen peroxide, hexachlorophene, phenol, resorcinol, and cetylpyridinium chloride And anti-inflammatory agents (eg hydrocortis) , Prednisone (prednisone), a tree implied theory (triamcilolone), beta mesa zone, dexamethasone) to include, but not limited thereto.
[141] 3. Bioadhesive Polymer
[142] The composition of the present invention may comprise one or more bioadhesive polymers.
[143] Bioadhesive polymers in the present invention can also be usefully used to hydrate the skin and increase its permeability.
[144] Bioadhesive polymers also function as thickening agents. Bioadhesive polymers include polysorbates such as pectin, alginic acid, chitosan, hyaluronic acid, polysorbate-20, -21, -40, -60, -61, -65, -80, -81, -85; PEG-7 , -14, -16, -18, -55, -90, -100, -135, -180, -4, -240, -6, -8, -9, -10, -12, -20 or Polyethylene glycol such as 32; Oligosaccharides and polysaccharides (e.g. gellan, carrageenan, xanthan gum, gum arabic, and dextran; cellulose esters and cellulose ethers; modified cellulose polymers (e.g. carboxymethyl cellulose, hydroxyethylcellulose) , Hydroxy propyl methyl cellulose, hydroxy ethyl ethylcellulose); poly etherpolymers and oligomas (e.g. polyoxy ethylene); compounds having long hydrophobic chains (e.g. aliphatic chains having about 12 to 20 carbon atoms) Condensation products of poly (ethylene oxide) with various reactive hydrogens, for example condensation products of poly (ethylene oxide) with fatty acids, fatty alcohols, fatty acid amides, polyhydric alcohols; poly (methyl vinyl ether), repeat units of 10 or less Polyether propylene compounds such as polyoxypropylene;
[145] Poly ether compounds (eg block copolymers of ethylene oxide and propylene oxide); Mixtures of block copolymers of ethylene oxide and propylene oxide with other excipients such as pluronic lecithin organogel (1 INTERNATIONAL JOURNAL OF PHARMACEUTICAL CONPOUNDING 71 (1997)); Poly (vinyl alcohol); polyacrylamide; hydrolyzate of polyacrylamide; Poly (vinyl pyrrolidone); poly (methacrylic acid);
[146] Homopolymers of poly (acrylic acid) or crosslinked poly acrylic acid (for example carbomers, ie allyl ether of pentaerythritol, allyl ether of sucrose or allyl ether of propylene and crosslinked acrylic acid (Acrisint® 400, 410 or 430 (NJ) available from Weehawkin); Orabase® (ie a mixture of gelatin, pectin, and carboxymethylcellulose in plasticized hydrocarbon gels, from Hoyt laboratories, Needhm, MA) Carafate® (sulfurized sucrose and aluminum hydroxide, commercially available from Marion Laboratories, Kansas City, MO) Block copolymers of ethylene oxide and propylene oxide are particularly preferred.
[147] L. Manufacturing Method
[148] Compositions of the present invention are prepared according to standard methods well known in the art for preparing oil-in-water emulsions for topical administration.
[149] For example, the method is described in 1 REMINGTON: THE SCIENCE AND PRACTICE OF PHARMACY 289 (Alfenso R. Gennaro ed., 19th edition, 1995). In addition, the Example manufacturing method is explained in full detail in the following Example.
[150] For example, the components can be separated into water-soluble and zucchini. The water-soluble components can be mixed with each other in one container to make a solution, and the fat-soluble components can be mixed together and heated (70-80 ° C.) in a separate container to make a solution. The next two solutions can be mixed and the mixture cooled. This method requires nothing more than two or more beakers and heating tools.
[151] Homogenization is achieved using high shear rate blenders or other suitable instruments. Suitable droplet sizes include those described in 1 REMINGTON: THE SCIENCE AND PRACTICE OF PHARJY1 ACY 282-283 (Alfenso R. Gennaro ed, 19th edition 1995), and Allen and Terence, PARTICLE SIZE MEASUREMENT 483 (4th edition 1990). Likewise, this is accomplished by standard control of shear rate and droplet size analysis during high speed mixing. Suitable tools and methods for making emulsions and compositions of the present invention, such as high shear rate branders, are described in 2 REMINGTON: THE SCIENCE AND PRACTICE OF PHARMACY 1509-1515 (Alponso R. Gennaro ed., 19th edition 1995). It is. Methods of preparing topical emulsions suitable for the preparation of the compositions of the present invention are also described in Bernard Idson, Pharmaceutical Emulsions in 1 PHARMACEUTICAL DOSAGE FORMS: DISPERSE SYSTEMS 199 (Herbert A. Lieberman et al., 1988).
[152] The composition of the present invention is then packaged and stored in known manner. For example, the packaging process is described in 1 REMINGTON: THE SCIENCE AND PRACTICE OF PHARMACY 390-391 (Alfenso R. Gennaro ed., 19th edition 1995). If desired, the compositions of the present invention can be sterilized according to known methods. For example, the method is described in 2 REMINGTON: THE SCIENCE AND PRACTICE OF PHARMACY 1463-1486 (Alfonso R. Genennaro ed., 19th edition 1995).
[153] M. Methods of Administration
[154] 1. Topical application
[155] The compositions of the present invention can be administered topically by a medical professional or patient simply by mechanically touching the site of application. When applying these compositions to the skin, the area to which the composition will be administered is first washed with astringents such as standard commercial preservatives or alcohols for maximum effectiveness and increased absorption. The area is then dried for a few seconds and the composition of the invention is applied to the target area (pain area) of complete skin and gently but firmly massaged with the fingertips until all visible gel or cream is absorbed.
[156] The application site after application of the composition of the invention can be covered with a dressing. As used herein, "dressing" refers to a covering designed to protect a previously applied drug product. "Dressing" includes a variety of inert coverings such as porous or nonporous bandages and plastic film wraps or other non-absorbent films, for example. "Dressing" also refers to nonwovens, especially elastomeric coverings capable of heat and water vapor transfer. (non-woven) or woven coverings. These dressings cool the pain spot and give greater comfort. In another embodiment, a composition of the present invention can be included in a dressing and the dressing can be applied to the skin or pain area.
[157] 2. Administration via Intradermal Patch
[158] In one embodiment of the present invention the composition of the present invention is included in a patch applied adjacent to the skin area to be treated. As used herein, a "patch" includes at least the composition and covering layer of the present invention such that the patch can be located above the skin area to be treated. Preferably the patch is designed to maximize drug clouding through the stratum corneum into the epidermis or dermis, minimize absorption in the circulatory system, reduce lag time, promote the same absorption, and reduce mechanical rub-off. .
[159] Preferably the patch composition resembles the viscoelasticity of the skin and depends on the skin during exercise to prevent excessive shear and foliation.
[160] Patches comprising the compositions of the present invention have advantages over conventional methods of administration. One advantage is that the capacity is controlled by the patch surface area. Other advantages of the patch include: constant dosing rate, long duration of action (the ability to stick to the skin for 1, 3, 7 days or longer); Improved patient compliance, non-invasive dosing, and reversible action (ie, patches can simply be removed).
[161] Examples of patches suitable for use in the compositions of the present invention include (1) matrix-form patches; (2) reservoir-form patches; (3) multi-layered drug-in-adhesive patches; (4) monolithic drug-in-adhesive patches; And (5) hydrogel patches; generally Ghosh, T.K .; Pfister, W. R .; Yum, S.L Transdermal and Topical Drug Delivery Systems, Interpharm Press, Inc. See p. 249-297, which is hereby incorporated by reference. These patches are well known in the art and are commercially available.
[162] In one embodiment, the composition of the present invention is included in a low-form patch. The low-form patch features a low compartment comprising an backing film coated with an adhesive and a composition of the present invention ( See, eg, US Pat. No. 4,615,699, which is incorporated herein by reference. An adhesive inwardly extending layer extends around the area of low water to maintain intensive sealing with the skin and low skin adjacent water.
[163] In one embodiment the compositions of the present invention are included in a drug-in-adhesive or hydrogel patch. The monolithic drug-in-adhesive patch design is characterized by the inclusion of a medicament in the skin contact adhesive layer, the underlying film, and preferably in the release liner. The adhesive secretes anesthetics and functions both as the anesthetic matrix adheres to the skin. The drug-in-adhesion system does not require a tacky overlay so the patch size is minimized. In addition, drug-in-adhesive patches are thin and comfortable (see, eg, US Pat. No. 4,751,087, hereby incorporated by reference).
[164] The multi-layered drug-in-adhesive patch design further includes an additional semi-permeable membrane or a multi-drug-in-adhesive layer under a single inner padded film between two separate drug-in-adhesive layers (Peterson, TA and Dreyer, SJ Proceed.Intern.Symp.Control.Rel.Bioact.Mater. 21: 477-478, hereby incorporated by reference).
[165] Semipermeable membranes useful for low or multi lamination patches include thin nonporous ethylene vinyl acetate thin membranes or thin microporous films of polyethylene used in microlaminate solid phase low phase patches.
[166] Adhesives for use with drug-in-adhesive patches are well known in the art and can be readily selected by those skilled in the art. The three basic forms commonly used are polyisobutylene, silicone, acrylic resins and hydrogels. Adhesives useful in the present invention can operate in a wide range of conditions such as high and low humidity, bathing, sweating and the like. Preferably the adhesive is a natural or synthetic rubber, polyacrylate, polyvinylacetate, polybutylacrylate, polymethylacrylate, polydimethylsiloxane, and hydrogel (For example, high molecular weight polyvinylpyrrolidone, polyethylene oxide of Origoma, or mixtures thereof). Most preferred are polyacrylates and hydrogels. Most preferred adhesives are hydrogels and polyacrylates. In one embodiment the hydrogel is electron beam crosslinked polyvinylpyrrolidone (“PVP”) and the PVP has a molecular weight of about 500,000-about 2,000,000 Daltons, preferably about 900,000 Daltons to about 1,500,000 Daltons. PVP-G hydrogels exemplified for use herein include WO 93/1 0163 published May 27, 1993, page 12, line 24, page 3; US Patent No. 4,989,607, column 13, lines 10-25; EP 0 107 376 (published February 5, 1984) pages 19, lines 10-30; D. Darwis 42 RADIAT. PHYS.CHEM. 907 (1993); And Olgun Guven and Murat Sen 32 POLYMER 2491 (1991), whereby all citations are expressly incorporated herein by reference.
[167] Suitable release linings include, but are not limited to, occlusive, opaque, transparent polyester films (e.g., silicon-fluoric silicone and perfluorocarbon based polymers) with pressure sensitive release linings in thin coatings. .
[168] The inner film can be occluded or permeable and can come from polyolefin oil polyesters, artificial polymers such as polyethylene, polyvinylidene, chloride, and polyurethane, or natural materials such as cotton, wool, and the like. Films that line the occlusion, such as synthetic polyester, cause hydration of the outermost layer of the stratum corneum, while non-occluded lining breathes in the area (ie, promotes water vapor transfer at the skin surface).
[169] The most preferred inner film is a closed polyolefin pin foil (Alevo, Dreieich, Germany). The polyolefin pins preferably have a thickness from about 0.6 to about 1 mm.
[170] Generally, the inventive compositions have about 0.5% to 40% of the patch weight, preferably from about 10% to about 30%, more preferably from about 15% to about 25%, and most preferably about 18% of the patch weight. Will contain about 22 percent from.
[171] Patches for use with the compositions of the present invention can be prepared, packaged, stored and labeled in a standard order. For example, Product Development and Technology Transfer for Transdermal Therapeutic Systems in TRANSDERMAL CONTROLLED SYSTEMIC MEDICATIONS 379-396. (YW Chien ed. 1987); See H-M Wolf et al., Development of Processes and Technology for Adhesive-Type TRANSDERMAL CONTROLLED SYSTEMIC MEDICATIONS 365-378 (YW. Chien ed. 1987), all citations expressly incorporated herein by reference.
[172] 3. Dosage
[173] It is important to choose a suitable dose for the site of application. The rate of intradermal anesthetic administration from topical agents or patches is a function of skin permeability, and skin permeability has been shown to vary between anatomical sites, depending on the thickness of the stratum corneum. For example, generally permeable planter leg arches, transverse ankles, palms, ventral forearm, dorsal forearm, back, chest, thighs, abdomen, scalp, armpits, forehead And scrotum in order; R.C.Wester. & H.I. Maibach Regional variation in Percutaneous Absorption in PERCUTANEOUS ABSORPTION, MECHANISM, METHODOLOGY, DRUG DELIVERY 111-119 (R.L.Bronaugh and H.I. Maibach eds., 2nd edition, ed. 1989), hereby expressly incorporated herein by reference. The dose and frequency of administration can of course be determined by a trained medical professional and depend on many factors such as the application site and size and the severity of the indication.
[174] Gels, creams or ointments typically require 1 to 4 applications per day.
[175] In general, 0.5 g to 5 g, preferably 1 g to 2 g, of the composition of the present invention per cm 2 of skin is administered around and around the application site. If necessary after administration, the area can be covered with a dressing.
[176] When a patch is used to administer a composition of the present invention, the dose that achieves analgesia is determined by the active surface area of the site of administration of the patch in direct contact with the skin. Various dose strengths are available depending on the severity of the wound. In general, doctors can initiate dosing with a low or medium intensity patch and, depending on the effect, a dose by prescribing a higher or lower active concentration patch, or a larger or smaller surface area or in some cases multiple patches. Can be adjusted. Generally, the compositions of the present invention will preferably comprise from about 0.5 percent to about 20 percent by weight of the patch, preferably from about 5 percent to about 25 percent by weight of the patch, in the weight of the patch. The composition of the present invention in an in-adhesive) patch may comprise from about 0.5 percent to about 20 percent by weight of the patch. In a patch comprising a hydrogel, the compositions of the present invention may comprise from about 0.5 percent to about 10 percent by weight of the patch in the weight of the patch. The new patch can be administered several times per day but is administered about every 18 to every 48 hours, more preferably daily.
[177] The invention and its many attendant advantages can be understood from the foregoing description, and various changes in form, configuration, and arrangement of parts of the invention are possible without departing from the spirit or scope of the invention or the advantages thereof. It is evident that the foregoing is a simple exemplary embodiment thereof.
[178] All reagents used for the examples below are commercially available from standard donors (eg, Spectrum Laboratory Products, Inc. Gardena, Calif.). Amitriptyryl hydrochloride was purchased from Spectrum Laboratory Products, and ketamine hydrochloride was purchased from Medisca, Plattsburg, NY. As used throughout the examples, "high-strength composition" means containing about 2% ketamine and about 4% amitriptyline, and "low-strength composition" means about Meaning 0.5% ketamine and about 1% amitriptyline.
[179] Example 1 Compositions A and B of the Invention Including Amitriptyline and Ketamine
[180] Compositions A and B are compositions according to the invention. Topical amitriptyline-ketamine cream compositions A and B comprising amitriptyryl hydrochloride and ketamine hydrochloride were prepared according to the following method using the ingredient weights listed in Table 1 It became. The holding phase is detailed in Table 2.
[181]
[182] * The composition of the oil phase is shown in Table 2.
[183]
[184] Aqueous-Phase Solution : Sorbitol solution, water and PEG-l00 stearate were added to a Groen vessel (Model "TDB / 8-20 CFC", Groen Division, Dover Corporation, Elk Grover Village, IL). The container has a self-sufficient water jacket. The temperature is maintained in the range of about 70 ° C to 80 ° C. The vessel was covered and the mixture was heated and stirred.
[185] When in solution, methylparaben, ketamine hydrochloride and amitriptylene hydrochloride are added. Stirring and heating are continued until all components are dissolved.
[186] Oil-Phase Solution : Cetyl alcohol, isopropyl myristate, glycerol stearate and mineral oil were added to a stainless steel vessel submerged in a hot water bath. The water-bath temperature was maintained in the range of about 70 ° C. to about 80 ° C. using hot plate. The solution was heated and stirred until homogeneous (Lab-Stirrer, Model LR 400 C, Fisher Scientific Inc, Pittsburgh, PA). Propylparaben was then added and stirring and heating continued until the propylparaben was completely dissolved.
[187] The oil phase (70 ° C.) was slowly injected into the water phase (70 ° C.) and the mixture was stirred for 10 minutes using a kettle-stirrer. The kettle stirring device was separated and the mixture was oiled for 15 minutes using a high shear homogenizer (powerGen Homogenizer, Model 700 D, Fisher, Scientific, Pittsburgh, P A). The kettle stirrer was recombined to agitate the emulsion when hot water was replaced with cold water in the kettle jacket to cool the emulsion. After the emulsion temperature dropped below 40 ° C., simethicone was added and the emulsion was mixed for another 15 minutes using a kettle stirring device. The Grisona MA filling machine (NAG Nahma AG, Unterageri, Austria) was used to fill the emulsion into 60 grams of aluminum tubes (Peerless Tube Company, Bloomfield, NJ).
[188] The oil phase-liquid droplet diameter (weight average diameter) was measured by laser-light diffraction (Malvern Mastersizer S Laser Diffractor, Malvern Instruments, Malvern, UK). Before analysis, the emulsion sample was prepared in 6.5% solution of PEG-I00 stearate in purified water. Dispersed at a rate.
[189] Sample refractive index and carrier fluid refractive index were set to 1.5295 and 1.33, respectively. The default settings for the Presentation and Analysis Model were "OHD" and "Polydisperse". The droplet size was determined within the range of 0.2 microns to 100 microns and the average droplet size was 0.34 microns.
[190] Example 2 Compositions C and D of the Invention Comprising Amitrifthilin and Ketamine and Transcutol-P as Permeation Enhancer
[191] The method described in Example 1 above was used to prepare amitriptyline-ketamine emulsion compositions C and D, where C and D were Permeation Enhancer Transcutol-P (eg Gattesfosse, Westwood). , Ethoxydiglycol), available from NJ. Transcutol-P was mixed with water, sorbitol solution and PEG-l00 stearate during the water formulation.
[192]
[193] The composition of the oil-fat phase is shown in Table 2 of Example 1.
[194] Example 3: Present Topical Pluronic-Gel Formulations E and F Including Amitrifthilin and Ketamine and Permeation Enhancer (Transcutol-P)
[195] Topical prunonic gel compositions E and F were prepared for skin penetration rates compared to compositions A-D of the present invention. The formula and component weights of the compositions E and F are shown in Table 4.
[196] Amitriptyline hydrochloride and ketamine hydrochloride were dissolved in water in a glass beaker. Methylparaben and propylparaben were mixed with Transcutol-P in another beaker. Transcutol-P solution containing methylparaben and propylparaben was placed into amitriptyline hydrochloride / ketamine hydrochloride solution. A glass beaker containing the solution was placed in an ice bath to cool the solution to about 5 ° C. Pluronic F127 was added to the solution with continuous mixing (Lab-Stirrer, 400 C Model LR, Fisher Scientific, Pittsburgh, PA) and mixed for nearly 12 hours until a clear solution was obtained. The clear solution was filled in an aluminum tube while maintaining the temperature below about lO < 0 > C. If the solution temperature is equilibrated to room temperature it is clear gelled.
[197]
[198] Example 4 Present Topical Pluronic-Gel Formulations G and H Including Amitrifthilin and Ketamine and Permeation Enhancer (Transcutol-P)
[199] Pluronic-Lecithin-Gel (PLO) Compositions G and H further comprise the permeation enhancer Transcutol-P and were prepared for skin penetration rates compared to Compositions A-D of the present invention. The formulation and component weights of Compositions G and H are shown in Table 5 below.
[200] Place a fixed amount of amitriptyline hydrochloride and ketamine hydrochloride and transcutol-P in a 200 ml glass beaker and keep the temperature at about 5 ° C using an ice bath and use a mechanical mixer (Lab-Stirrer, 400 C Model LR). (Fisher Scientific, Pittsburgh, PA) was used to stir until a solution was obtained.
[201] Methylparaben, propylparaben, vitamin E, lecithin, and isopropyl myristate were mixed in a separate beaker through grinding with free mortar and pestle until a solution was obtained. The two solutions were mixed in glass mortar and mixed under vigorous grinding for about 5 minutes. The final product was a pale yellow soft gel.
[202]
[203] Example 5 In Vitro Permeation Through Human Bodies Fibules of Ketamine-Amitriptyline Cream and Gel Formulation (Composition AJ)
[204] For permeation studies, a system with six improved Franz diffusion cells with a 1.767 cm 2 diffusion area (FDC-400, Crown Glass, Somerville, NJ) was used. The receptor phase volume was 13 ml and the receptor temperature was maintained at 37 ± 0.5 ° C. in a water jacket. PEG 400 / Water (40/60) was used as the receptor medium.
[205] Human body skin at 375 μm (New York Firefighters Skin Bank, New York) was hydrated with normal saline for 15 minutes at room temperature. The skin samples were placed in the donor and receptor compartments of the cells and the dermal surface in contact with the receptor culture was fixed. About 150 mg of Composition A-J was applied to the stratum corneum side. Samples of receptor fluid (1 ml) were drawn at 2, 4, 6, 8 and 24 hours to take each sample and replaced with the same volume of receptor medium. The experiment for each formulation was repeated three times. The ketamine and amitriptyline concentrations of the samples were analyzed by the HPLC analysis method described below. The cumulative amount of permeate ketamine and amitrifthilin per unit area of the skin was plotted against time and the permeation rate (flux = μg / cm 2 / hr) was determined for the ketamine and amitrifthilin.
[206] HPLC was performed using a commercially available HPLC apparatus (Platinum EPS colunm ㏇ 18,100 A 5 u, 150 × 4.6 mm Part No. 32214, Alltech Associates, Deerfield, IL). Mobile phase A was 10/90 (v / v) Acetonitrile / 40 mM potassium phosphate buffer (pH 2.5) with 10 mM heptanesulfonic acid sodium salt as the ion pairing material. Mobile phase B was 50/50 (v / v) Acetonitrile / 40 mM potassium phosphate buffer (pH 2.5) with 10 mM heptanesulfonic acid sodium salt as the ion pairing material. The gradient program consists of 70% A solution and 30% B solution at 0 minutes; 100% B solution at 10 minutes; 100% B solution at 17 minutes; 70% A solution and 30% B solution at 18 minutes; At 22 minutes 70% A solution and 30% B solution were used. The moving speed was 1.0 ml per minute; Column temperature 40 ° C .; Sample temperature was room temperature; Injection volume of 25 μl; Wavelength 260 nanometers; The compressive pressure was about 40 kg / cm 3. The retention time for the run time of 22 minutes under these conditions is as follows; methylparaben 5.3 minutes; ketamine hydrochloride, 7.6 minutes; Propylparaben, 10.3 min; Amitriptylene hydrochloride, 14.5 min.
[207]
[208]
[209] Representative compositions A-D of the present invention provide increased ketamine and amitriptylene permeation rates compared to standard topical formulation E-H. The effect is more pronounced at low intensity concentrations.
[210] Example 6: Chemical and Physical Stability Studies
[211] September 4, ICH Process, October 27, 1993, by the Harmonisation (ICH) Guidelines Conference on ICH Steering Committee to assess the physical and chemical stability of Composition A, a representative composition of the present invention, and to test the stability of new drug substances and products. Comparison), thereby expressly inserting it here by reference. Samples of the compositions of the present invention were prepared in Stability oven, Model No. It was maintained in a storage chamber under controlled temperature and relative humidity ("RH") using ES2000, Environmental Specialties, Raleigh, NC. Three different storage conditions, 25 ° C./60% RH, 30 ° C./60% RH and 40 ° C./75% RH were used in this study. In one month and two months the allerquat was removed and amitriptyline, ketamine, methylparaben and propylparaben were extracted with methanol. The extracts were analyzed by HPLC to determine the percentage of amitriptyline, ketamine, methylparaben and propylparaben remaining in the composition. It was determined whether the composition lost activity due to degradation or other causes. Extraction and HPLC analysis were performed as follows.
[212] One gram of a composition or gel of the present invention to which they are compared was placed in a glass beaker. For low intensity samples, about 30 ml of methanol was added as extraction solvent. Samples were stirred for 5 minutes in a hot water bath at 70 ± 10 ° C. and sonicated for 5 minutes in hot tap water (60 ± 10 ° C.). 10 ml of methanol was added to replace the evaporated and the sample was stirred and sonicated as above. It was then taken out of a bical water bath and stirred to cool to room temperature. The sample was then transferred to a volumetric flask and methanol was added to 50 ml. For high-strength samples, the same method was used except that the amount of methanol used for extraction was about four times. The sample was then filtered through a 0.2 μm PTFE syringe filter. The first 2 ml of filtrate was discarded and the rest was transferred to an HPLC vial. The amounts of amitrifthilin, ketamine, methylparaben and propylparaben in the extraction solvent were determined using HPLC. The chemical stability of the active ingredients and preservatives in emulsion composition A (prepared by Example 1) is shown in Table 8 as percentage of residual active agent. This value can be compared with the percentage of active agent calculated before storage according to the HPLC method.
[213]
[214] The stability test shows that Composition A, a representative composition of the present invention, is chemically stable under storage conditions of at least 2 months even at high temperatures. Thus the compositions of the present invention exhibit good chemical stability.
[215] After storage of the sample under the above conditions, the sample was measured for viscosity and oil phase droplet size to evaluate physical stability. Brookhaven ™ viscometer (Model RVT, Helipath standing setting, Brookhaven, Engineering laboratories Inc., Middleboro, Mass.) Was used to analyze the viscosity of Composition A. The T spindle was used at 5 rpm speed. Sample temperature was maintained at 25 ° C. during the analysis. The effect of storage of the emulsion viscous phase is shown in Table 9.
[216] The maintenance phase droplet diameter (“D” weight average diameter) was measured via laser-light diffraction (Malvern Mastersizer S Laser Diffractor, Malvern Instruments, Malvern, UK).
[217] Emulsion samples were dispersed for 6.5% PEG-100 stearate in a solution of purified water prior to analysis. Sample refractive index and carrier fluid refractive index were set to 1.5295 and 1.33, respectively. The default settings for the Presentation and Analysis Model were "OHD" and "Polydisperse". The effect of storage on the droplet size distribution is shown in Table 9.
[218] When the same experiment was performed on pluronic lecithin gels G and H, the sample turned yellow during storage and phase separation occurred. This indicates physical and chemical instability.
[219]
[220] The data in Table 9 shows that after two months under storage conditions, composition A, the representative composition of the present invention, exhibited minimal changes in viscosity and internal droplet size. Thus, the compositions of the present invention exhibit excellent physical stability.
[221] Example 7: Another Composition of the Invention
[222] Using the method of Example 1, a composition (composition I) of the present invention having the following composition was prepared. Brij 721, stearyl alcohol and mineral mineral oils include oily phases.
[223]
[224] The present invention is not to be limited in scope by the specific embodiments described in the embodiments which describe some aspects of the present invention, and any functionally equivalent embodiment is within the scope of the present invention. Indeed, various modifications of the invention in addition to those described and shown herein will be apparent to those skilled in the art and are within the scope of the appended claims.
[225] All references cited here are inserted here in their entirety by reference.

权利要求:
Claims (57)
[1" claim-type="Currently amended] (a) an antidepressant or a pharmacologically acceptable salt thereof;
(b) an NMDA-receptor antagonist or a pharmacologically acceptable salt thereof;
(c) fat-soluble components;
(d) water; And
(e) an emulsion comprising a surfactant.
Wherein said emulsion is an oil-in-water emulsion.
[2" claim-type="Currently amended] The emulsion of claim 1 wherein the average oil droplet size ranges from about 0.01 to about 100 microns.
[3" claim-type="Currently amended] The emulsion of claim 1 wherein the average oil droplet size ranges from about 0.1 to about 10 microns.
[4" claim-type="Currently amended] The antidepressant of claim 1, wherein the anti-depressant is a norepinephrine reuptake inhibitor, a selective serotonin reuptake inhibitor, a monoamine oxidase inhibitor, a serotonin and noradrenaline reuptake inhibitor, a corticotropin release factor antagonist, an alpha adrenoreceptor antagonist , 5 HT _1A receptor partial agonist, atypical antidepressant, or other antidepressant or pharmacologically acceptable salt thereof.
[5" claim-type="Currently amended] The emulsion of claim 4 wherein the antidepressant is a norepinephrine reuptake inhibitor or a pharmacologically acceptable salt thereof.
[6" claim-type="Currently amended] 2. The emulsion of claim 1 wherein the antidepressant is a tricyclic depressant or a pharmacologically acceptable salt thereof.
[7" claim-type="Currently amended] The method of claim 6, wherein the tricyclic anti-depressant is amitriptyline, desmethylamitriptyline, crimipramine, doxepin, imipramine, imipramine N-oxide (imipramine-oxide), trimipramine, adinazolam, amitriptylinoxide, amoxapine, desipramine, maprotiline, nordone Nortriptyline, protriptyline, amineptine, amineptine, buttriptyline, dimesiptiline, dibenzepin, dimethzerine, dimetacrine, docepin (dothiepine), fluacizine, iprindole, lofepramine, lofepramine, meritracene, metapramine, norclolipramine, noxiptilin ), Opipramol, perlapine, pizotyline, fr Blood benzodiazepine (propizepine), kwinu plastic Min (quinupramine), ribonucleic paroxetine (reboxetine), or thiazol neptin (tianeptine), or its pharmacologically acceptable salt, characterized in that the emulsion.
[8" claim-type="Currently amended] The emulsion of claim 1, wherein the antidepressant is amitriptyline or a pharmacologically acceptable salt thereof.
[9" claim-type="Currently amended] The emulsion of claim 1 wherein the amount of antidepressant is in the range of about 0.1% to about 10% by weight of the total weight of the emulsion.
[10" claim-type="Currently amended] The method of claim 1, wherein the NMDA receptor antagonist is a binding to the NMDA receptor at the glycine binding site, glutamate binding site, PCP binding site, polyamine binding site, or zinc binding site, or a pharmacologically acceptable salt thereof. Emulsion.
[11" claim-type="Currently amended] The emulsion of claim 10, wherein the NMDA receptor antagonist is one that binds to the NMDA receptor at the PCP binding site or a pharmacologically acceptable salt thereof.
[12" claim-type="Currently amended] The method of claim 1, wherein the NMDA receptor antagonist is ketamine, phencyclidine, estromesorophan, dextropane, exosadrol, dizocilpin, recemide, cyenylcyclohesylpiperidine, N-allyl Normetazosin, cyclazosin, etosadrol, (1,2,3,4,9,9a-hexahydro-furren-4a-yl) -methyl-amine, PD 138558, tyretamine, kynurenic acid, 7-chloro-kinurenic acid, memantine, 6-cyano-7-nitroquinosarin-2,3-dione, or 6,7-dinitro-quinosarin-2,3-dione or Emulsion, characterized in that its pharmacologically acceptable salt.
[13" claim-type="Currently amended] The emulsion of claim 1 wherein the NMDA receptor antagonist is ketamine or a pharmacologically acceptable salt thereof.
[14" claim-type="Currently amended] The emulsion of claim 1, wherein the amount of NMDA receptor antagonist is in the range of about 0.1% to about 10% by weight of the total weight of the emulsion.
[15" claim-type="Currently amended] The emulsion of claim 1, wherein the NMDA receptor antagonist is ketamine or a pharmacologically acceptable salt thereof and the antidepressant is amitriptyline or a pharmacologically acceptable salt thereof.
[16" claim-type="Currently amended] The emulsion of claim 1 wherein the fat soluble component comprises petrolatum.
[17" claim-type="Currently amended] The emulsion of claim 1 wherein the fat soluble component comprises a curing agent.
[18" claim-type="Currently amended] 18. The emulsion of claim 17 wherein the curing agent is cetyl alcohol.
[19" claim-type="Currently amended] The emulsion of claim 1 further comprising a fat soluble intradermal penetration enhancer.
[20" claim-type="Currently amended] 20. The method according to claim 19, wherein the fat-soluble intradermal penetration enhancer isopropyl myristate, glycerol monolaurate, glycerol monooleate, glycerol monolinoleate, isopropyl isostearate, Isopropyl linoleate, isopropyl myristate / fatty acid monoglyceride mixture, isopropyl myristate / ethanol / L-lactate mixture, isopropyl palmitate, methyl acetate, methyl caprate or Emulsion, characterized in that methyl laurate (methyllaurate).
[21" claim-type="Currently amended] The emulsion of claim 1 further comprising a humectant or an anti-foaming agent.
[22" claim-type="Currently amended] (a) an antidepressant or a pharmacologically acceptable salt thereof;
(b) an NMDA-receptor antagonist or a pharmacologically acceptable salt thereof;
(c) fat-soluble components;
(d) water; And
(e) patches comprising surfactants.
Wherein said emulsion is an oil-in-water emulsion.
[23" claim-type="Currently amended] 23. The patch of claim 22, wherein said NMDA receptor antagonist is ketamine or a pharmacologically acceptable salt thereof and said antidepressant is amitriptyline or a pharmacologically acceptable salt thereof.
[24" claim-type="Currently amended] (a) a therapeutically effective amount of an antidepressant or a pharmacologically acceptable salt thereof;
(b) a therapeutically effective amount of an NMDA-receptor antagonist or a pharmacologically acceptable salt thereof;
(c) fat-soluble components;
(d) water; And
(e) A method of treating mammalian pain comprising topically administering an emulsion comprising a surfactant to the skin of a mammal in need thereof.
Wherein said emulsion is an oil-in-water emulsion.
[25" claim-type="Currently amended] 25. The method of claim 24, wherein said average oil droplet size ranges from about 0.01 to about 100 microns.
[26" claim-type="Currently amended] 25. The method of claim 24, wherein said average oil droplet size ranges from about 0.1 to about 10 microns.
[27" claim-type="Currently amended] 25. The method of claim 24, wherein the anti-depressant is a norepinephrine reuptake inhibitor, a selective serotonin reuptake inhibitor, a monoamine oxidase inhibitor, a serotonin and noradrenaline reuptake inhibitor, a corticotropin release factor antagonist, an alpha adrenoreceptor antagonist , 5 HT _1A receptor partial agonist, atypical antidepressant, or other antidepressant or pharmacologically acceptable salt thereof.
[28" claim-type="Currently amended] The method of claim 27, wherein the antidepressant is a norepinephrine reuptake inhibitor or a pharmacologically acceptable salt thereof.
[29" claim-type="Currently amended] The method of claim 24, wherein the antidepressant is a tricyclic depressant or a pharmacologically acceptable salt thereof.
[30" claim-type="Currently amended] 30. The method of claim 29, wherein the tricyclic antidepressant is amitriptyline, desmethylamitriptyline, crimipramine, doxepin, imipramine, imipramine N-oxide (imipramine-oxide), trimipramine, adinazolam, amitriptylinoxide, amoxapine, desipramine, maprotiline, nordone Nortriptyline, protriptyline, amineptine, amineptine, buttriptyline, dimesiptiline, dibenzepin, dimethzerine, dimetacrine, docepin (dothiepine), fluacizine, iprindole, lofepramine, lofepramine, meritracene, metapramine, norclolipramine, noxiptilin ), Opipramol, perlapine, pizotyline, fr A method of treating pain, characterized in that it is propizepine, quinupramine, reboxetine, or tianeptine, or a pharmacologically acceptable salt thereof.
[31" claim-type="Currently amended] The method of claim 24, wherein the antidepressant is amitriptyline or a pharmacologically acceptable salt thereof.
[32" claim-type="Currently amended] The method of claim 24, wherein the amount of antidepressant is in the range of about 0.1% to about 10% by weight of the total weight of the emulsion.
[33" claim-type="Currently amended] The method of claim 24, wherein the NMDA receptor antagonist is a binding to the NMDA receptor at a glycine binding site, glutamate binding site, PCP binding site, polyamine binding site, or zinc binding site, or a pharmacologically acceptable salt thereof. How to treat pain.
[34" claim-type="Currently amended] 34. The method of claim 33, wherein said NMDA receptor antagonist is a binding to NMDA receptor at a PCP binding site or a pharmacologically acceptable salt thereof.
[35" claim-type="Currently amended] 25. The method of claim 24, wherein the NMDA receptor antagonist is ketamine, phencyclidine, estromesorophan, dextropane, exosadrol, dizocilpin, recemide, cyenylcyclohesylpiperidine, N-allyl Normetazosin, cyclazosin, etosadrol, (1,2,3,4,9,9a-hexahydro-furren-4a-yl) -methyl-amine, PD 138558, tyretamine, kynurenic acid, 7-chloro-kinurenic acid, memantine, 6-cyano-7-nitroquinosarin-2,3-dione, or 6,7-dinitro-quinosarin-2,3-dione or It is a pharmacologically acceptable salt thereof.
[36" claim-type="Currently amended] The method of claim 24, wherein the NMDA receptor antagonist is ketamine or a pharmacologically acceptable salt thereof.
[37" claim-type="Currently amended] The method of claim 24, wherein the amount of NMDA receptor antagonist is in the range of about 0.1% to about 10% by weight of the total weight of the emulsion.
[38" claim-type="Currently amended] 25. The method of claim 24, wherein said NMDA receptor antagonist is ketamine or a pharmacologically acceptable salt thereof and said antidepressant is amitriptyline or a pharmacologically acceptable salt thereof.
[39" claim-type="Currently amended] The method of claim 24, wherein the emulsion further comprises a fat soluble intradermal penetration enhancer.
[40" claim-type="Currently amended] 40. The method according to claim 39, wherein the fat-soluble intradermal penetration enhancer isopropyl myristate, glycerol monolaurate, glycerol monooleate, glycerol monolinoleate, isopropyl isostearate, Isopropyl linoleate, isopropyl myristate / fatty acid monoglyceride mixture, isopropyl myristate / ethanol / L-lactate mixture, isopropyl palmitate, methyl acetate, methyl caprate or Pain treatment method characterized in that the methyl laurate (methyllaurate).
[41" claim-type="Currently amended] (a) a therapeutically effective amount of an antidepressant or a pharmacologically acceptable salt thereof;
(b) a therapeutically effective amount of an NMDA-receptor antagonist or a pharmacologically acceptable salt thereof;
(c) fat-soluble components;
(d) water; And
(e) A method of inducing local anesthesia in a mammal comprising topically administering an emulsion comprising a surfactant to the skin of the mammal in need thereof.
Wherein said emulsion is an oil-in-water emulsion.
[42" claim-type="Currently amended] 42. The method of claim 41 wherein the average oil droplet size ranges from about 0.01 to about 100 microns.
[43" claim-type="Currently amended] 42. The method of claim 41 wherein the average oil droplet size ranges from about 0.1 to about 10 microns.
[44" claim-type="Currently amended] 42. The method of claim 41, wherein the anti-depressant is a norepinephrine reuptake inhibitor, a selective serotonin reuptake inhibitor, a monoamine oxidase inhibitor, a serotonin and noradrenaline reuptake inhibitor, a corticotropin release factor antagonist, an alpha adrenoceptor antagonist , 5 HT _1A receptor partial agonist, atypical antidepressant, or other antidepressant or pharmacologically acceptable salt thereof.
[45" claim-type="Currently amended] 45. The method of claim 44, wherein the antidepressant is a norepinephrine reuptake inhibitor or a pharmacologically acceptable salt thereof.
[46" claim-type="Currently amended] 42. The method of claim 41, wherein the antidepressant is a tricyclic depressant or a pharmacologically acceptable salt thereof.
[47" claim-type="Currently amended] 47. The method of claim 46, wherein the tricyclic antidepressant is amitriptyline, desmethylamitriptyline, crimipramine, doxepin, imipramine, imipramine N-oxides. (imipramine-oxide), trimipramine, adinazolam, amitriptylinoxide, amoxapine, desipramine, maprotiline, nordone Nortriptyline, protriptyline, amineptine, amineptine, buttriptyline, dimesiptiline, dibenzepin, dimethzerine, dimetacrine, docepin (dothiepine), fluacizine, iprindole, lofepramine, lofepramine, meritracene, metapramine, norclolipramine, noxiptilin ), Opipramol, perlapine, pizotyline, fr Blood benzodiazepine (propizepine), kwinu plastic Min (quinupramine), ribonucleic paroxetine (reboxetine), or thiazol neptin (tianeptine), or induce local anesthesia method as acceptable salt thereof, wherein in its pharmacologically.
[48" claim-type="Currently amended] 42. The method of claim 41, wherein the antidepressant is amitriptyline or a pharmacologically acceptable salt thereof.
[49" claim-type="Currently amended] 42. The method of claim 41, wherein the amount of antidepressant is in the range of about 0.1% to about 10% by weight of the total weight of the emulsion.
[50" claim-type="Currently amended] 42. The method of claim 41, wherein the NMDA receptor antagonist is a binding to the NMDA receptor at a glycine binding site, glutamate binding site, PCP binding site, polyamine binding site, or zinc binding site, or a pharmacologically acceptable salt thereof. Local anesthesia induction method.
[51" claim-type="Currently amended] 51. The method of claim 50, wherein said NMDA receptor antagonist is a binding to NMDA receptor at a PCP binding site or a pharmacologically acceptable salt thereof.
[52" claim-type="Currently amended] 42. The method of claim 41, wherein the NMDA receptor antagonist is ketamine, phencyclidine, estromesorophan, dextropane, exosadrol, dizocilpin, recemide, cyenylcyclohesylpiperidine, N-allyl Normetazosin, cyclazosin, etosadrol, (1,2,3,4,9,9a-hexahydro-furren-4a-yl) -methyl-amine, PD 138558, tyretamine, kynurenic acid, 7-chloro-kinurenic acid, memantine, 6-cyano-7-nitroquinosarin-2,3-dione, or 6,7-dinitro-quinosarin-2,3-dione or It is a pharmacologically acceptable salt thereof.
[53" claim-type="Currently amended] 42. The method of claim 41, wherein said NMDA receptor antagonist is ketamine or a pharmacologically acceptable salt thereof.
[54" claim-type="Currently amended] 42. The method of claim 41, wherein the amount of NMDA receptor antagonist is in the range of about 0.1% to about 10% by weight of the total weight of the emulsion.
[55" claim-type="Currently amended] 42. The method of claim 41, wherein said NMDA receptor antagonist is ketamine or a pharmacologically acceptable salt thereof and said antidepressant is amitriptyline or a pharmacologically acceptable salt thereof.
[56" claim-type="Currently amended] 42. The method of claim 41, wherein the emulsion further comprises a fat soluble intradermal penetration enhancer.
[57" claim-type="Currently amended] 57. The method of claim 56, wherein the fat-soluble intradermal penetration enhancer isopropyl myristate, glycerol monolaurate, glycerol monooleate, glycerol monolinoleate, isopropyl isostearate, Isopropyl linoleate, isopropyl myristate / fatty acid monoglyceride mixture, isopropyl myristate / ethanol / L-lactate mixture, isopropyl palmitate, methyl acetate, methyl caprate or Local anesthesia induction method, characterized in that methyl laurate (methyllaurate).

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引用文献:

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公开号 | 申请日 | 公开日 | 申请人 | 专利标题

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法律状态:
2001-08-17|Priority to US09/931,293

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2001-08-17|Priority to US09/931,293

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2002-08-14|Application filed by 에피셉트 코포레이션

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2002-08-14|Priority to PCT/US2002/025871

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2004-06-23|Publication of KR20040053112A

优先权:

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申请号 | 申请日 | 专利标题

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US09/931,293|2001-08-17|

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US09/931,293|US6638981B2|2001-08-17|2001-08-17|Topical compositions and methods for treating pain|

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PCT/US2002/025871|WO2003015699A2|2001-08-17|2002-08-14|Topical compositions and methods for treating pain|