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    • 专利摘要:
    Use of a composition comprising doxycycline in the preparation of a medication for topical administration, for the prevention, improvement and/or treatment of ocular conditions. (Machine-translation by Google Translate, not legally binding)
    公开号:ES2577885A1
    申请号:ES201431854
    申请日:2014-12-16
    公开日:2016-07-19
    发明作者:Enrique VILLEGAS BECERRIL
    申请人:Agencia Publica Empresarial Sanitaria Hospital Alto Guadalquivir；
    IPC主号:
    专利说明:



    Composition of doxycycline in liposomes for the prevention, improvement and / or treatment of eye diseases. FIELD OF THE INVENTION
    The present invention is within the field of biology and medicine, and refers to the use of doxycycline for the prevention, improvement and / or treatment of eye conditions. Preferably, it refers to the topical use of doxycycline in liposomes in the form of stable eye drops for the prevention, improvement and / or treatment of blepharitis, microtrombosis in the anterior pole and chorioretinal vascular disorders. BACKGROUND OF THE INVENTION
    Blepharitis is one of the most common diseases in ophthalmology. It represents a wide spectrum of diseases, acute and chronic, characterized by inflammation of the palpebral free edge. For both patients and ophthalmologists, this disease is
    15 very difficult to understand, frustrating because of its chronicity and very heavy due to the prolonged treatment it requires.
    The palpebral free edge is the origin of the inflammation, which extends to the cornea and the bulbar conjunctiva. This causes different types of patients to be observed: congestion of the vessels of the bulbar conjunctiva, infiltration of the cornea and conjunctiva attached and pannus
    20 (invasion of vessels to the peripheral cornea), especially in the lower cornea.
    It is important to know the different manifestations of blepharitis to apply the appropriate treatment (Raskin et al., 1992. Infect. Dis. Clin. North Am. 6 (4), 777-787).
    More than 80 agents responsible for blepharitis have been identified (Ostler, 1993. Diseases of the external eye and annex, Baltimore, Williiams and Wilkins), the most frequent being 25 Streptococus, Staphilococus, Pseudomonas, Moraxella and Actinomices, in addition to others rare such as Anthrax, Pasteurella, Clostridium and Micobasterium tuberculosis (Groden et al., 1991. Cornea 10 (1), 50-53). There are also other agents of viral origin (Molluscum contagiosum, Herpes simplex and Herpes zoster) and fungi (Coccidioides, Microsporum blastomices, Candida and Aspergillus). There are also allergic disorders (atopy and
    30 contact dermatitis) and other diseases of the Steven-Johnson type, ichthyosis or Lyell's disease


    Currently, there are four alternatives for the treatment of blepharitis: palpebral hygiene, topical antibiotics, systemic antibiotics such as tetracyclines (Neiberg and Sowka, 2008. Optometry 79 (3), 133-137) and corticosteroids.
    The hygiene of the palpebral free edge is essential to eliminate the growing pathogens. Oral tetracyclines are a fundamental complementary treatment for the blepharitis condition to subside (Dougherty et al., 1991. Invest. Ophthalmol. Vis. Sci. 132 (11), 2970-2975). Oral tetracyclines are also used in certain disorders of the corneal apical barrier (De Paiva et al., 2006. Invest. Ophthalmol. Vis. Sci. 47 (7), 2847-56) and in other pathologies of the anterior pole (Pinna et al., 1999. Br. J. Ophthalmol. 83 (7), 771-773). Doxycycline is an antibiotic that belongs to the tetracycline family, it is not usually used topically. From Paiva et al. They have already used topical doxycycline for the treatment of dry eye, although it has never been used for the treatment of blepharitis.
    Doxycycline has an anti-infective effect and an anti-inflammatory effect (Wang et al., 2008. Clin. Experiment. Ophthalmol. 36 (1), 8-12; Dursun et al., 2008. Am. J. Ophthalmol. 132 (1), 8 -13). The amount of tetracycline administered orally may not reach sufficient concentration in the tear film, where it has its usefulness (Smith et al., 2008. Br. J. Ophthalmol. 92 (6), 856-859).
    Doxycycline has a protective effect on the walls of the microvasculature. In fact it is used in the prevention of aortic aneurysms, through the inhibition of enzymes that degrade vessel walls. In certain series of patients undergoing hemodialysis, doxycycline proved effective in preventing thrombosis (Diskin et al., 1998. Nephron 78, 365-368; Saran et al., 2002. Am. J. Kidney Dis. 40 , 1255-1263).
    The protective effect of doxycycline on the vessel wall seems to be given by the inhibition of the activity of the metalloproteinase matrix (Sorsa et al., 1994. Ann. NY. Acad. Sci. 732, 375–378 ).
    In a study in rats, doxycycline was able to prevent aneurysmal dilation, with no subsequent signs of inflammation (Kaito et al., 2003. Surg. Today 33, 426-433). In another study, patients who took doxycycline were found to have less proliferation of the intimate vascular layer, as well as less muscle cell migration (Islam et al., 2003. Am. J. Pathol. 163, 1557–1566).
    The pathophysiology of diabetic retinopathy (RD) has not yet been fully clarified, but most authors focus on vascular changes. Instead, it has recently been discovered that there are changes in the glia and at the neuronal level that could explain part of


    This pathophysiology. (Antonetti et al., 2012. N. Engl. J. Med. 366 (13), 1227-1239). Chronic inflammatory changes that occur in the DR in experimental models, include increased local nitric oxide production, increased intracellular molecular adhesion, leukostasis and increased cell expression by cytokines that in turn are associated with tissue damage and neuronal loss and damage (Adamis et al., 2008. Semin. Immunopathol. 30 (2), 65-84; Tang et al., 2011. Prog. Retin. Eye Res. 30 (5), 343-358).
    The microglia represent the first line of the immune system against aggressions and usually remain inactive, but in situations such as RD it is activated by inducing inflammatory changes (Rungger-Brändle et al., 2000. Invest. Ophthalmol. Vis Sci. 41 (7), 1971-1980; Zeng et al., 2000. Vis Neurosci. 17 (3), 463-471; Zeng et al., 2008. Arch. Ophthalmol. 126 (2), 227-232; Barber et al., 2005. Invest Ophthalmol VisSci. 46 (6), 2210-2218; Gaucher et al., 2007. Vision Res. 47 (5), 612-623; Ibrahim et al., 2007. Diabetes 60 (4), 1122-1133; Krady et al., 2005. Diabetes 54 (5), 1559-1565; Vincent et al., 2007. Diabetes 56 (1): 224-230).
    Tetracycline and its derivatives have been shown in cultures and in animal models, which have an anti-inflammatory effect and neuroprotection effects, in addition to antibacterial effects. With respect to DR, in some studies it has been shown that low-dose doxycycline inhibits inflammatory changes in microglia, metalloproteinase activity and cell apoptosis (Wang et al., 2005. Neurochem Int. 47 (1 -2), 152-158; Federici, 2011. Pharmacol. Res. 64 (6), 614-623; Baptiste et al., 2005. Neuroscience 134 (2), 575-582; Griffin et al., 2011. Pharmacol Res. 63 (2), 102-107).
    In a clinical trial that included 5 patients with foveal involvement due to diabetic macular edema and who were treated with 100 mg oral minocycline twice a day for 6 months, improved their visual acuity, and macular thickness was significantly reduced compared to historical controls from previous studies (Cukras et al., 2012. Invest. Ophthalmol. Vis. Sci. 53 (7), 3865-3874).
    In summary, topical doxycycline can be minimally invasive for the organism, absent undesirable side effects such as lesions to the gastrointestinal tract and that its protective effects on the microvasculature can delay the onset of RD.
    Doxycycline is an antibiotic that presents a stability problem, as do other tetracyclines. When degraded, the microbial activity is lost and can become toxic. Liposomes could be a means of integrating doxycycline that increases its stability.

    BRIEF DESCRIPTION OF THE INVENTION
    The author of the present invention has developed and proved that a topical composition of doxycycline could be useful for the treatment of blepharitis, disorders of the anterior surface of the eye that involve infection and / or inflammation. The topical route would avoid the side effects produced by oral administration.
    Other applications, in addition to those already described, could be:
    - In patients with blepharitis as prophylaxis of intraoperative infections such as endophthalmitis.
    - Dry eye, ocular rosacea.
    - Emergency use for trauma and ulcerations.
    - For treatment, prevention and to prevent the progression of diabetic retinopathy.
    Therefore, a first aspect of the invention relates to the use of a composition, hereinafter composition of the invention, comprising doxycycline or any of its pharmaceutically acceptable salts, esters, tautomers, solvates and hydrates, or any combination thereof. , in the elaboration of a medicine for the prevention, improvement and / or treatment of ocular pathologies. Alternatively, it refers to a composition comprising doxycycline or any of its pharmaceutically acceptable salts, esters, tautomers, solvates and hydrates, or any combination thereof, for use in the prevention, improvement and / or treatment of ocular pathologies.
    In a preferred embodiment of this aspect of the invention, the composition is a topical administration composition. In another preferred embodiment, the ocular pathology is selected from: blepharitis, microtrombosis in the anterior pole and chorioretinal vascular disorders, or any combination thereof.
    In another preferred embodiment of the invention, the ocular pathology is diabetic retinopathy.
    In another preferred embodiment, doxycycline is included in liposomes. More preferably, the liposomes have cationic character, and even more preferably, they have neutral character.
    In another preferred embodiment, the composition of the invention has a concentration of between 0.5 and 50% liposomes, more preferably between 1 and 25%, more preferably between 2 and 10%, even more preferably between 4 and 6%, and even more preferably 5% of liposomes.


    In another preferred embodiment, the liposomes are composed of lecithin with 50 to 99% phosphatidylcholine, more preferably with 70 to 95% phosphatidylcholine, and even more preferably with approximately 90% phosphatidylcholine.
    In another preferred embodiment, the liposomes are stabilized in a solution.
    Ionic, and more preferably in phosphate buffer. In another more preferred embodiment of this aspect of the invention, the pH of the phosphate buffer is adjusted to a value between 4 and 10, more preferably between 5 and 9, and even more preferably between 6 and 8.
    In another preferred embodiment, the liposomes are stabilized in a non-ionic solution. More preferably, the non-ionic solution is selected from a solution of
    10 mannitol and a glucose solution, and more preferably it is a mannitol solution. Even more preferably the mannitol solution has a concentration of 1 to 20%, preferably between 2.5 and 10%, and more preferably about 5% mannitol. Even more preferably the pH of the solution is adjusted to a value between 3 and 9, more preferably between 4 and 8, and even more preferably between 5 and 7.
    In another preferred embodiment, the liposomes have a final size of between 20-1000 nm, more preferably between 50-500 nm, even more preferably between 100-300 nm, and even more preferably about 200 nm.
    In another preferred embodiment, the composition has a doxycycline concentration of between 0.01 and 5%, more preferably between 0.025 and 1%, even more preferably
    20 of between 0.04 and 0.06%, and even more preferably about 0.05%.
    In another preferred embodiment, the composition is a pharmaceutical composition. More preferably the composition further comprises a pharmaceutically acceptable carrier. Even more preferably the composition further comprises another principle.
    25 active.
    In another preferred embodiment, the liposomes comprise antioxidants. More preferably they also comprise antioxidants.
    In another preferred embodiment of this aspect of the invention the composition is sterilized.


    A second aspect of the invention relates to a pharmaceutical form, hereafter referred to as the pharmaceutical form of the invention, which comprises the composition of the invention.
    In a preferred embodiment of this aspect the pharmaceutical form of the invention is selected from the list consisting of: plaster, ointment, paste, cream, solution, suspension, emulsion, lotion, liniment, jelly, gel, foam, powder, or any of their combinations. More preferably it is a solution, and even more preferably it is an ophthalmic solution.
    A third aspect of the invention relates to the use of the pharmaceutical form of the invention in the preparation of a medicament for the prevention, improvement and / or treatment of ocular pathologies. Alternatively, it refers to the pharmaceutical form of the invention for use in the prevention, improvement and / or treatment of ocular pathologies.
    In a preferred embodiment of this aspect of the invention, the composition is a topical administration composition. In another preferred embodiment, the ocular pathology is selected from: blepharitis, microtrombosis in the anterior pole and chorioretinal vascular disorders, or any combination thereof. In another preferred embodiment of the invention, the ocular pathology is diabetic retinopathy. DESCRIPTION OF THE FIGURES
    Figure 1. Registration of the eye dryness test by means of a schirmer test in which it can be seen that after the treatment, the hydration of the eye increased as a consequence of it.
    Figure 2. Individual analysis of each patient according to the dry eye questionnaire score. All patients were asked a questionnaire to evaluate the symptoms of blepharitis-dry eye like disease. In all cases there was an improvement in symptoms after doxycycline treatment with a significant decrease in this score.
    Figure 3. Overall results with the sum of all scores in all patients in the dry eye questionnaire. After treatment with doxycycline, the symptoms decreased significantly. It is a complementary figure to figure 2.
    Figure 4. Record of the degrees of hyperemia (red eye, eye redness) that the patient presented before and after treatment with topical doxycycline according to


    Oxford scale. In all cases, this hyperemia was considerably lower after this treatment. DETAILED DESCRIPTION OF THE INVENTION
    The authors of the present invention have developed a doxycycline composition in liposomes with anti-infective and anti-inflammatory effects for topical use.
    Therefore, a first aspect of the present invention relates to the use of a composition comprising doxycycline or any of its pharmaceutically acceptable salts, esters, tautomers, polymorphs, analogs, solvates and hydrates, or any of its
    10 combinations, in the elaboration of a medicine for the prevention, improvement and / or treatment of ocular pathologies. Alternatively, it refers to a composition comprising doxycycline or any of its pharmaceutically acceptable salts, esters, tautomers, polymorphs, analogs, solvates and hydrates, or any combination thereof, for use in the prevention, improvement and / or treatment of pathologies eyepieces
    Preferably, administration of the composition of the invention is topically.
    Doxycycline refers to the antibiotic of the tetracycline group, chemical formula C22H24N2O8. It is a semi-synthetic derivative of adritetracycline. It has a broad spectrum bacteriostatic effect and acts by inhibiting protein synthesis, blocking the binding of transferring RNA to the ribosomal complex. Specifically the union occurs in
    20 30S ribosomal subunit of sensitive organisms. In addition, it has anti-inflammatory action acting on the polynuclear neutrophils involved in the inflammatory phase of certain infections. This antibiotic prevents the growth and spread of both Gram positive and Gram negative bacteria. It has of formula (I):
    Formula (I)


    The IUPAC nomenclature is (2Z, 4S, 4aR, 5S, 5aR, 6R, 12aS) -2- (amino-hydroxymethylidene) -4dimethylamino-5,10,11,12a-tetrahydroxy-6-methyl-4a, 5,5a, 6-tetrahydro-4H-tetracene-1,3,12trione and CAS number 564-25-0.
    The compounds of the present invention represented by formula (I) may include isomers, depending on the presence of multiple bonds, including optical isomers or enantiomers, depending on the presence of chiral centers. The individual isomers, enantiomers or diastereoisomers and mixtures thereof fall within the scope of the present invention, that is, the term isomer also refers to any mixture of isomers, such as diastereomers, racemic, etc., even their optically isomers. assets or mixtures in different proportions thereof. The individual enantiomers or diastereoisomers, as well as mixtures thereof, can be separated by conventional techniques.
    Also, within the scope of this invention are the prodrugs of the compounds of formula (I). The term "prodrug" or "prodrug" as used herein includes any derivative of a compound of formula (I) - for example and not limited to: esters (including esters of carboxylic acids, amino acid esters, phosphate esters, esters of sulphonate of metal salts, etc.), carbamates, amides, etc. - which when administered to an individual can be transformed directly or indirectly into said compound of formula (I) in said individual. Advantageously, said derivative is a compound that increases the bioavailability of the compound of formula (I) when administered to an individual or that enhances the release of the compound of formula (I) in a biological compartment. The nature of said derivative is not critical as long as it can be administered to an individual and provides the compound of formula (I) in a biological compartment of an individual. The preparation of said prodrug can be carried out by conventional methods known to those skilled in the art.
    As used herein, the term "derivative"; It includes both pharmaceutically acceptable compounds, that is, derivatives of the compound of formula (I) that can be used in the manufacture of a medicament or food compositions, as pharmaceutically acceptable derivatives, since these can be useful in the preparation of pharmaceutically derived derivatives. acceptable.
    The compounds of the invention may be in crystalline form as free compounds or as solvates. In this sense, the term "solvate," as used herein, includes both pharmaceutically acceptable solvates, that is, solvates of the compound of formula (I) that can be used in the manufacture of a medicament, such as solvates.


    Pharmaceutically unacceptable, which may be useful in the preparation of pharmaceutically acceptable solvates or salts. The nature of the pharmaceutically acceptable solvate is not critical as long as it is pharmaceutically acceptable. In a particular embodiment, the solvate is a hydrate. Solvates can be obtained by conventional solvation methods known to those skilled in the art.
    For application in therapy, the compounds of formula (I), their salts, prodrugs or solvates, will preferably be found in a pharmaceutically acceptable or substantially pure form, that is, having a pharmaceutically acceptable level of purity excluding pharmaceutical additives. normal such as diluents and carriers, and not including material considered toxic at normal dosage levels. The purity levels for the active ingredient are preferably greater than 50%, more preferably greater than 70%, and still more preferably greater than 90%. In a preferred embodiment, they are greater than 95% of the compound of formula (I), or of its salts, solvates or prodrugs.
    In another preferred embodiment, the ocular pathology is selected from: blepharitis, microtrombosis in the anterior pole and chorioretinal vascular disorders, or any combination thereof. In another preferred embodiment of the invention, the ocular pathology is diabetic retinopathy.
    In this report blepharitis is understood as inflammation of the tissue that forms the eyelid. Normally, its origin is due to irregular functioning of the glands of the eyelid margin, which leads to irritation and crusting, which provides optimal conditions for the growth of bacteria that further irritate the eyelid and aggravate the process. If the process is not stopped, progressive worsening occurs with painful swelling of the eyelid margin, severe discomfort in the ocular surface and even decreased vision. Blepharitis can be of two types:
     Squamous blepharitis: shows flaky eyelids due to their appearance and is characterized by the formation of scales between the eyelashes, which often fall into the eyes producing the sensation that there is something inside them. The eyes appear red. The edges of your eyelids are reddened most of the time, giving the impression that you have been crying, and may produce local itching. It is the cause of local infection of bacteria and fungi in a seborrheic skin.


     Allergic blepharitis: It is a form of expression of a contact allergy to cosmetic products for the most part, for example shaders, pencils and blushers, as well as cosmetic solvents to eliminate them. But in reality any substance that contaminates the fingers and that by means of the hands is brought to the eyes can cause acute or chronic eyelid dermatitis, such as plants and their juices, vegetables, acrylic plastics or even medicines for the legs or feet, to give some examples.
    In this report, microtrombosis of the anterior pole is understood as the formation of thrombi in capillaries and small vessels located in the anterior part of the eyeball: conjunctiva, cornea and lens.
    In this report, chorioretinal vascular disorder is understood as the situation where blood does not circulate as it should due to any eventuality in the chorioretinal area.
    In this report, diabetic retinopathy is understood as an ocular complication of diabetes that is caused by the deterioration of blood vessels that supply the retina. Damage to the blood vessels of the retina can result in them leaking fluid or blood. If the disease progresses, new blood vessels form and fibrous tissue proliferates in the retina, which results in vision deterioration, as the image sent to the brain becomes blurred.
    In a preferred embodiment of this aspect of the invention, doxycycline is included in liposomes.
    In this report, liposomes are understood as spherical vesicles with a membrane composed of phospholipids. The arrangement of phospholipids in their formation generates that both the interior and the exterior are water soluble, while the interior is liposoluble. Its use has been described as transporters of substances between the exterior and the cellular interior, hence its interest in biotechnology. Normally, liposomes are made from lecithins obtained from soy, egg yolk and brain tissue, although other lipids are added to increase their stability. The size of the liposomes usually ranges between 20nm-500µm and can be classified by their size: those ranging from 20 to 70 nm are called Small Unillamelar Vesicles (SUV), those ranging from 70 to 400 nm are called Large Unillamelar Vesicles ( LUV). It is also possible to form a special type of liposomes of size well above the previous ones, their diameter varies between approximately 10 and 100 µm which are called Giant Unillamelar Vesicles (GUV). On the other hand are the Oligollamelar Vesicles (OLV), which have a few overlapping layers, and


    the Multillamelar Vesicles (MLV), which has many overlapping layers. These liposomes have distributions of very variable size, and can range from 500 nm to 2000 nm in approximately the same sample.
    In a preferred embodiment of this aspect of the invention, the liposomes have cationic character. In another preferred embodiment of this aspect of the invention, the cationic character is achieved by preparing the liposomes with physiological serum.
    In the present specification it is understood by physiological serum or physiological solution to an aqueous solution that is compatible with living organisms thanks to its defined characteristics of osmoticity, pH and ionic strength. It is usually composed of water, electrolytes, and additionally other substances such as glucose. Its biochemical composition is 0.9% NaCl.
    In another preferred embodiment of this aspect of the invention, the liposomes have a neutral character. In another preferred embodiment of this aspect of the invention, the neutral character is achieved by making the liposomes with purified water.
    In the present specification it is understood by purified water, the water corrected or enriched in the laboratory with some agent. They are treated waters for specific use in science or engineering. Three types can be distinguished: distilled, double distilled and deionized.
    In a preferred embodiment of this aspect of the invention, the composition has a concentration between 0.5-50% liposomes, more preferably between 1-25%, more preferably between 2-10%, more preferably between 4- 6%, and even more preferably about 5%.
    In a preferred embodiment of this aspect of the invention, the liposomes are composed of lecithin with 50-99% phosphatidylcholine, more preferably with 7095% phosphatidylcholine, and even more preferably with approximately 90% phosphatidylcholine.
    Phosphatidylcholine is a phospholipid and, normally, the major component of lipid bilayers. The phospholipid is composed of a group of choline-headed and glycerophosphoric acid, with a variety of fatty acids, one of them being a saturated fatty acid, and one of them an unsaturated fatty acid. Phospholipase D catalyzes the hydrolysis of phosphatidylcholine to form phosphatidic acid, releasing the soluble choline head group in the cytosol. Phosphatidylcholine is a neutral lipid, but it does, however, have an electric dipole moment of ~ 10 D.


    In a preferred embodiment of this aspect of the invention, the liposomes are stabilized in an ionic solution, preferably phosphate buffer. In another preferred embodiment of this aspect of the invention, the pH of the phosphate buffer is adjusted between 4-10, more preferably between 5-9, and even more preferably between 6-8.
    In a preferred embodiment of this aspect of the invention, the liposomes are stabilized in a non-ionic solution. In a preferred embodiment of this aspect of the invention, the non-ionic solution is preferably selected from a mannitol solution and a glucose solution, preferably a mannitol solution. In a preferred embodiment of this aspect of the invention, the mannitol solution is 1-20%, preferably 2.5-10%, and more preferably about 5%. In another preferred embodiment of this aspect of the invention, the pH of the mannitol solution is adjusted between 3-9, more preferably between 4-8, and even more preferably between 5-7.
    In a preferred embodiment of this aspect of the invention, the liposomes have a final size between 20-1000 nm, more preferably between 50-500 nm, even more preferably between 100-300 nm, and even more preferably about 200 nm.
    In a preferred embodiment of this aspect of the invention, the liposomes have a doxycycline concentration between 0.01-5%, more preferably between 0.025-1%, more preferably 0.04-0.06%, and even more preferably approximately 0.05%.
    In a preferred embodiment of this aspect of the invention, the composition is a pharmaceutical composition.
    In a preferred embodiment of this aspect of the invention, the composition further comprises a pharmaceutically acceptable carrier.
    In a preferred embodiment of this aspect of the invention, the composition further comprises another active ingredient.
    As used herein, the term "active ingredient", "active substance", "pharmaceutically active substance", "active ingredient" or "pharmaceutically active ingredient" means any component that potentially provides a pharmacological activity or other different effect on the diagnosis, cure, mitigation, treatment, or prevention of a disease, or that affects the structure or function of the body of man or other animals. The term includes those components that promote a chemical change in the preparation of the drug and are present therein in a modified form intended to provide the specific activity or effect.


    In a preferred embodiment of this aspect of the invention, the liposomes contain antioxidants.
    In a preferred embodiment of this aspect of the invention, the liposomes contain stabilizers.
    In a preferred embodiment of this aspect of the invention, the composition is sterilized. The sterilization process of the composition can be carried out by any sterilization method known in the state of the art. In a preferred embodiment of this aspect of the invention, sterilization is achieved by filtration.
    The compositions of the present invention can be formulated for administration to an animal, and more preferably to a mammal, including man, in a variety of ways known in the state of the art. Thus, they can be, without limitation, in sterile aqueous solution or in biological fluids, such as serum. Aqueous solutions may be buffered or unbuffered and have additional active or inactive components. Additional components include salts to modulate ionic strength, preservatives and other substances including, but not limited to, antimicrobial agents, antioxidants, chelators, and the like, and nutrients including glucose, dextrose, vitamins and minerals. Alternatively, the compositions can be prepared for administration in solid form. The compositions may be combined with various inert vehicles or excipients, including but not limited to; binders such as microcrystalline cellulose, gum tragacanth, or gelatin; excipients such as starch or lactose; dispersing agents such as alginic acid or corn starch; lubricants such as magnesium stearate, glidants such as colloidal silicon dioxide; sweetening agents such as sucrose
    or saccharin; or flavoring agents such as peppermint or methyl salicylate.
    A second aspect of the invention relates to a pharmaceutical form, hereafter referred to as the pharmaceutical form of the invention, which comprises the composition according to the first aspect of the invention.
    In this specification, "pharmaceutical form" means the mixture of one or more active ingredients with or without additives that have physical characteristics for proper dosage, preservation, administration and bioavailability.
    In a preferred embodiment of this aspect of the invention, the pharmaceutical form is selected from the list comprising: plaster, ointment, paste, cream, solution, suspension, emulsion, lotion, liniment, jelly, gel, foam, powder, or any of their combinations.


    A "plaster" or "patch" is a pharmaceutical form that consists of a solid or semi-solid form that contains the active ingredient or additives, spread on a cloth, plastic or adhesive tape, which serves as a support and protection, in addition to having an occlusive effect and macerating action that also allows direct contact with the skin and softens with body temperature.
    An “ointment” or “ointment” is a pharmaceutical form that consists of a soft consistency preparation that contains the active ingredient or additives incorporated into an appropriate base that gives it mass and consistency. It adheres and is applied to the skin and mucous membranes. This base can be liposoluble or water soluble, it is generally anhydrous or with a maximum of 20 percent water. It is also called hydrophilic ointment when it contains a washable or removable base with water.
    A "paste" is a pharmaceutical form consisting of a semi-solid form containing the active ingredient or additives, made from a high concentration of insoluble powders (20 to 50 percent), in fatty or aqueous bases, absorbents or weak abrasives combined with soaps.
    A "cream" is a pharmaceutical form that consists of a liquid or semi-solid preparation containing the active ingredient or additives necessary to obtain an emulsion, generally oil in water, with a water content greater than 20 percent.
    A "solution" is a pharmaceutical form consisting of a liquid, transparent and homogeneous preparation, obtained by dissolving it or the active ingredients and additives in water, and which is used for external or internal use. In the case of injectable, ophthalmic and otic solutions they must be sterile solutions. The term "solution" includes the solutions.
    A "suspension" is a pharmaceutical form consisting of a dispersed system, composed of two phases, which contain the active ingredient or additives. One of the phases, the continuous or the external one, is generally a liquid or a semi-solid and the dispersed or internal phase consists of insoluble solids (active principles), but dispersible in the external phase. In the case of injectables they must be sterile.
    An "emulsion" is a pharmaceutical form consisting of a heterogeneous system, generally consisting of two liquids not miscible with each other; in which the dispersed phase is composed of small globules distributed in the vehicle in which they are immiscible. The dispersed phase is also known as internal and the dispersion medium is known as the external or continuous phase. There are emulsions of the water / oil or oil / water type and can


    present as semi-solids or liquids. The active ingredient or additives may be in the external or internal phase.
    A "lotion" is a pharmaceutical form that can be presented as a solution, suspension
    or emulsion, which contains the active ingredient or additives, and whose dispersing agent is predominantly water.
    A "liniment" is a pharmaceutical form that consists of a liquid presentation, solution
    or emulsion containing the active ingredient or additives whose vehicle is aqueous, alcoholic or oily.
    A "jelly" is a pharmaceutical form that consists of a semi-solid colloid that contains the
    or the active ingredients and additives, whose water-soluble base usually consists of gums such as tragacanth, other bases used are: glycerin, pectin, alginates, boroglycerinated compounds, synthetic derivatives or natural substances such as carboxymethylcellulose.
    A "gel" is a pharmaceutical form consisting of semi-solid preparation, which contains the
    or the active ingredients and additives, solid in a liquid that can be water, alcohol or oil, such that a network of particles trapped in the liquid phase is formed.
    A "foam" is a pharmaceutical form consisting of a semi-solid preparation, consisting of two phases: a liquid that carries the active ingredient (s) and additives, and another gas that carries propellant gas so that the product comes out in the form of a cloud.
    The "powder" is a pharmaceutical form that consists of a solid form that contains the active ingredient (s) and finely ground and mixed additives to ensure homogeneity.
    In a preferred embodiment of this aspect of the invention, the pharmaceutical form is a solution, preferably an ophthalmic solution or eye drops.
    A third aspect of the invention relates to the use of the pharmaceutical form of the invention in the preparation of a medicament for the prevention, improvement and / or treatment of ocular pathologies. Alternatively, it refers to the pharmaceutical form of the invention for use in the prevention, improvement and / or treatment of ocular pathologies.
    In a preferred embodiment of this aspect of the invention, the composition is a topical administration composition. In another preferred embodiment, the ocular pathology is


    Select from: blepharitis, microtrombosis in the anterior pole and chorioretinal vascular disorders, or any combination thereof.
    The term "medication", as used herein, refers to any substance used for prevention, diagnosis, relief, treatment or cure of diseases in man and animals. In the context of the present invention, the disease is an eye disease, preferably it is a blepharitis, a microtrombosis in the anterior pole and / or chorioretinal vascular disorders.
    Throughout the description and the claims the word quot; comprehequot; and its variants are not intended to exclude other technical characteristics, additives, components or steps. For those skilled in the art, other objects, advantages and features of the invention will be derived partly from the description and partly from the practice of the invention. The following examples and drawings are provided by way of illustration, and are not intended to be limiting of the present invention.
    EXAMPLES OF THE INVENTION Example 1: Experimental study of 0.05% doxycycline in eye drops in blepharitis
    MATERIAL AND METHODS
    We set out to evaluate the experience of the use of doxycycline in blepharitis in the first moment prior to the design of a clinical trial. We included 12 patients with this disease whose cornea hyperaemia and contact lens research lab score was maximum (4) and signs of staphylococcal infection were present (collaretes and telangiectasias) and objectified the disease by this bacterium.
    RESULTS
    Conjunctival culture
    The twelve patients had a staphylococcus positive culture before doxycycline treatment. After treatment with this 0.05% eye drops for three weeks, said culture was repeated, at that time none of the twelve patients had a staphylococcus positive culture.
    Schimer test


    This test is used to assess the status of dry eye in blepharitis (in millimeters). As can be seen - although even in the absence of validated statistical tests, all patients had a basal tear secretion lower than that presented after treatment. This makes us think about the possible usefulness of doxycycline against this dry syndrome (figure 1).
    Symptom score according to the dry eye questionnaire
    This test was designed (see bibliography in trial design) to assess the symptoms that the patient perceives and to capture them through a score based on some questions about them. You can see how in each and every patient there is a higher score prior to treatment, which tells us that all the patients in the sample had at least moderate symptoms, being mostly severe. After instillation of doxycycline in eye drops 0.05%, these symptoms decrease in all cases until they are mild (Figure 2).
    The sum of all pre and post treatment scores is presented in Figure 3. You can also see the total decrease in points in terms of symptoms.
    Hyperemia according to the Cornea scale and contact lens research lab
    This scale allows us to include the patient in this study because of the hyperemia (ocular redness) caused by this staphylococcal infection. Its range fluctuates depending on the severity of hyperemia between grade I and IV. As can be seen in the following graph, almost all patients had severe degrees of hyperemia prior to treatment. Subsequently all returned to minimum levels of hyperemia (Figure 4).
    In addition to these parameters, others such as the safety of the drug and its side effects were evaluated. In no case there were abandonments of the treatment, keratitis or epithelial toxicities in the anterior ocular pole due to this treatment, nor were there significant increases in intraocular pressure.
    The negativity in all the cultures against staphylococcus after the treatment, the absence of side effects and the improvement of the symptoms of the patients, made us think about the effectiveness that this drug can have in the long term in blepharitis, since This disease has no specific treatment at this time. Their results are very promising and lead us to the realization of a prospective clinical trial with an increase in sample size.


    Example 2: Patient with blepharitis and glycemic decompensation.
    A 72-year-old male patient attended in consultation for ocular redness referred for years. He has received treatment that he provides in consultation, from his family doctor but has not noticed improvement so he has requested specialized assistance with
    5 ophthalmology. As a history of interest, the patient reports being diabetic with poor glycemic control. In all reviews, fundus monitoring was done for his diabetes.
    First consultation on March 5, 2008: Signs of both anterior and posterior chronic blepharitis, ocular redness, telangiectasias, collaterals, secretions and mild-moderate grade keratitis are observed in both eyes. Treatment is established at that time
    10 with tobramycin and dexamethasone in eye drops and artificial tears.
    In this period of time and as a result of the blepharitis he suffers, infectious palpebral granules (styes) have appeared that have had to be operated in the operating room (chalazion). It is then cataloged of severe blepharitis with poor response to usual treatment.
    15 As a point of interest, their blood glucose levels are provided during the years 2007 and 2008 below:
    Table 1. Patient's blood glucose during the years 2007-2008
    Date 1 Feb 2007Feb 20, 2008March 29, 2008Jul 19, 200818 Sep 2008
    Blood glucose (mg / dl) 172159141150153
    Remember that a fasting blood glucose test, a level between 70 and 100 milligrams per
    20 deciliter (mg / dl) is considered normal. If it is a random blood glucose test, a normal result depends on when you last ate. Most of the time, the blood glucose level will be below 125 mg / dl. This patient frequently presented figures up to twice what was considered normal in the diabetes process.
    No retinal injuries from diabetes at that time.


    Consultation of November 21, 2008: The patient reports not having noticed excessive improvement with the previous treatment, even with its withdrawal, worsening. Treatment begins with tobramycin and dexamethasone in eye drops, improving the improvement of its symptoms with zaditen eye drops (topical antihistamine).
    No retinal injuries from diabetes at that time.
    Consultation of February 11, 2009: In this consultation and due to new worsening of symptoms with squamous blepharitis, seborrheic and new episodes of styes, specific treatment with oral doxycycline is decided at high doses for 20 days plus topical treatment with diclofenac eye drops and tobramycin with dexamethasone.
    No retinal injuries from diabetes at that time.
    Consultation of May 12, 2009: Go back to consultation with worsening symptoms and report that you have not taken the full treatment for oral doxycycline intolerance. He refers to an episode of gastritis as a consequence of oral doxycycline and therefore its abandonment of treatment. As doxycycline is especially indicated for this pathology, it is then decided to prescribe 0.05% master formula of doxycycline in eye drops with dexamethasone and topical treatment in eye drops with 0.05% doxycycline solution and dexamethasone is indicated.
    No retinal injuries from diabetes at that time.
    Consultation of June 15, 2009: The patient goes to the consultation for review of this treatment, literally referring to “that it is much better” (figure in history). On examination, there was an objective absence of telangiectasias, collarettes and minor inflammation and redness. At that time and given the good result of therapy with doxycycline in eye drops 0.05% with dexamethasone, treatment is prescribed and prescriptions are given for 40 more days given the chronicity of the process. In these future preparations, dexamethasone is excluded from the formulated product since applied topically in eye drops more than 25 days, it can cause glaucoma, so it is excluded and left alone with topical preparation of doxycycline eye drops 0.05 %.
    No retinal injuries from diabetes at that time.
    Consultation of February 9, 2010: The patient after the previous cycle of topical treatment of doxycycline, remains asymptomatic although it appears after withdrawal when he is


    They finished the recipes, new episode of seborrheic blepharitis. New topical doxycycline treatment is scheduled until the next November review and prescriptions are given.
    No retinal injuries from diabetes at that time.
    Consultation of November 8, 2010: The patient comments that he has maintained the treatment,
    5 because when you leave it for a period of weeks, the symptoms of blepharitis reappear and you are very upset about what continues with doxycycline in eye drops indefinitely. He asks the pharmacy for doxycycline eye drops.
    No retinal injuries from diabetes at that time.
    Consultation of August 1, 2011: Go for reviews of your diabetes and blepharitis. He
    10 says that doxycycline eye drops are put on demand according to the symptoms, but administering it almost continuously because if it is not put on, the discomfort and the red eye reappear.
    No retinal injuries from diabetes at that time.
    As a point of interest, their blood glucose levels are provided during the years 2010, 2011 and 2012 to 15 below:
    Table 2. Patient's blood glucose during the years 2010-2012
    Date May 14, 2010Nov 14, 2010Nov 18, 2010Dec 20, 20109 Sep 2011Sep 22, 201118 Sep 2012
    Blood glucose (mg / dl) 146232170175201219147
    In all the time this patient was treated with doxycycline both orally and in eye drops, there were no signs of diabetic retinopathy, since February 11, 2009
    20 to the present.
    In 2013 and given the improvement of its symptoms, the abandonment of doxycycline in eye drops as well as the control of its blood glucose levels began.
    He currently has no changes in the retina due to his diabetes and his blood glucose levels are normal.


    With all this we can conclude that the patient, diabetic with high blood sugar levels and with poor endocrine-metabolic control, did not develop his diabetic disease towards his retinopathy form.
    We can also think based on the results obtained in the administration of
    5 Doxycycline to this patient, that there is a cause and effect relationship between the administration of doxycycline and the non-occurrence of diabetic retinopathy despite having high blood sugar levels for years, apart from the cure of blepharitis, which currently remains inactive .
    Example 3: Composition of doxycycline eye drops in liposomes
    10 The eye drops used contain doxycycline in liposomes. These liposomes have been made using the sonication method with a posterior extrusion. Liposomes have a final diameter of 200nm. Fundamentally, the composition of these liposomes is based on soy lecithin with 90% phosphatidylcholine and they are made with purified water or with physiological serum, depending on this preparation the liposomes will have character
    15 neutral or positive, respectively. Thus, the final concentration of phospholipids in the coliro is 5%.
    Doxycycline is found in a concentration of 0.05% within the liposome.
    The use of antioxidants and / or stabilizer has been contemplated. It has also been sterilized by a filtration procedure, using 0.22 µm filters.

    权利要求:
    Claims (40)
    [1]
    1.-The use of a composition comprising doxycycline or any of its pharmaceutically acceptable salts, esters, tautomers, solvates and hydrates, or any combination thereof, in the preparation of a medicament for topical administration for prevention, improves and / or treatment of eye diseases.
    [2]
    2. The use of a composition according to the preceding claim, wherein the ocular pathology is selected from: blepharitis, microtrombosis in the anterior pole and chorioretinal vascular disorders, or any combination thereof.
    [3]
    3. The use of a composition according to any of claims 1-2, wherein the doxycycline is included in liposomes.
    [4]
    4. The use of a composition according to any of claims 1-3, wherein the liposomes have cationic character.
    [5]
    5. The use of a composition according to any of claims 1-4, wherein the liposomes have a neutral character.
    [6]
    6. The use of a composition according to any of claims 1-5, wherein the composition has a concentration of between 0.5 and 50% liposomes.
    [7]
    7. The use of a composition according to any of claims 1-6, wherein the composition has a concentration of between 1 and 25% liposomes.
    [8]
    8. The use of a composition according to any of claims 1-7, wherein the composition has a concentration of between 2 and 10% liposomes.
    [9]
    9. The use of a composition according to any of claims 1-8, wherein the composition has a concentration of between 4 and 6% liposomes.
    [10]
    10. The use of a composition according to any of claims 1-9, wherein the composition has a concentration of approximately 5% liposomes.
    [11]
    11. The use of a composition according to any of claims 1-10, wherein the liposomes are composed of lecithin.
    [12]
    12. The use of a composition according to any of claims 1-11, wherein the liposomes are composed of lecithin with 50 to 99% phosphatidylcholine.

    [13]
    13. The use of a composition according to any of claims 1-12, wherein the liposomes are composed of lecithin with 70 to 95% phosphatidylcholine.
    [14]
    14. The use of a composition according to any of claims 1-13, wherein the liposomes are composed of lecithin with approximately 90% phosphatidylcholine.
    15. The use of a composition according to any of claims 1-14, wherein the liposomes are stabilized in an ionic solution.
    [16]
    16. The use of a composition according to any of claims 1-15, wherein the liposomes are stabilized with phosphate buffer.
    [17]
    17. The use of a composition according to claim 16, wherein the pH of the phosphate buffer 10 is adjusted to a value between 4 and 10.
    [18]
    18. The use of a composition according to any of claims 16-17, wherein the pH of the phosphate buffer is adjusted to a value between 5 and 9.
    [19]
    19. The use of a composition according to any of claims 16-18, wherein the pH of the phosphate buffer is adjusted to a value between 6 and 8.
    20. The use of a composition according to any of claims 1-14, wherein the liposomes are stabilized in a non-ionic solution.
    [21]
    21. The use of a composition according to claim 20, wherein the non-ionic solution is selected from a mannitol solution and a glucose solution.
    [22]
    22. The use of a composition according to claim 21, wherein the non-ionic solution is a mannitol solution.
    [23]
    23. The use of a composition according to claim 22, wherein the mannitol solution has a concentration of 1 and 20% mannitol.
    [24]
    24. The use of a composition according to claim 22, wherein the mannitol solution has a concentration of between 2.5 and 10% mannitol.
    25. The use of a composition according to claim 22, wherein the mannitol solution has a concentration of approximately 5% mannitol.
    [26]
    26. The use of a composition according to any of claims 20-25, wherein the pH of the solution is adjusted to a value between 3 and 9.

    [27]
    27. The use of a composition according to any of claims 20-26, wherein the pH of the solution is adjusted to a value between 4 and 8.
    [28]
    28. The use of a composition according to any of claims 20-27, wherein the pH of the solution is adjusted to a value between 5 and 7.
    29. The use of a composition according to any of claims 1-28, wherein the liposomes have a final size of between 20-1000 nm.
    [30]
    30. The use of a composition according to any of claims 1-29, wherein the liposomes have a final size of between 50-500 nm.
    [31]
    31. The use of a composition according to any of claims 1-30, wherein the 10 liposomes have a final size of between 100-300 nm.
    [32]
    32. The use of a composition according to any of claims 1-31, wherein the liposomes have a final size of approximately 200 nm.
    [33]
    33. The use of a composition according to any of claims 1-32, wherein the composition has a concentration of doxycycline of between 0.01 and 5%.
    34. The use of a composition according to any of claims 1-33, wherein the composition has a concentration of doxycycline of between 0.025 and 1%.
    [35]
    35. The use of a composition according to any of claims 1-34, wherein the composition has a doxycycline concentration of between 0.04 and 0.06%.
    [36]
    36. The use of a composition according to any of claims 1-35, wherein the composition has a doxycycline concentration of approximately 0.05%.
    [37]
    37. The use of a composition according to any of claims 1-36, wherein the composition is a pharmaceutical composition.
    [38]
    38. The use of a composition according to any of claims 1-37, wherein the composition further comprises a pharmaceutically acceptable carrier.
    The use of a composition according to any of claims 1-38, wherein the composition further comprises another active ingredient.
    [40]
    40. The use of a composition according to any of claims 1-39, wherein the liposomes comprise antioxidants.

    [41]
    41. The use of a composition according to any of claims 1-40, wherein the liposomes comprise stabilizers.
    [42]
    42. The use of a composition according to any of claims 1-41, wherein the composition is sterilized.
    5 43. A pharmaceutical form comprising a composition according to any of claims 1-42.
    [44]
    44. The pharmaceutical form according to the preceding claim that is selected from the list consisting of: plaster, ointment, paste, cream, solution, suspension, emulsion, lotion, liniment, jelly, gel, foam, powder, or any of its combinations
    10. The pharmaceutical form according to any of claims 43-44, which is a solution.
    [46]
    46. The pharmaceutical form according to claim 45, wherein the solution is an ophthalmic solution.
    [47]
    47. The use of a pharmaceutical form according to any of claims 43-46, in the
    15 preparation of a medication for topical administration for the prevention, improvement and / or treatment of eye diseases.
    [48]
    48. The use of a composition according to the preceding claim, wherein the ocular pathology is selected from: blepharitis, microtrombosis in the anterior pole and chorioretinal vascular disorders, or any combination thereof.

    Fig. 1
    Fig. 2

    Fig. 3
    Fig. 4
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    IT201600078872A1|2016-07-27|2018-01-27|Fb Vision S R L|OIL AND DEVICE FOR HYGIENE OF THE EYE AND PERIOCULAR AREA|
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