RU2460517C1 - Pharmaceutical composition for integrated treatment of ocular surface diseases in patients suffering primary open-angle glaucoma - Google Patents

Abstract

FIELD: medicine.

SUBSTANCE: invention refers to pharmacology and represents a pharmaceutical composition for integrated treatment of ocular surface diseases in the patients suffering primary open-angle glaucoma, on the basis of phospholipids and sulphated glycosaminoglycans, differing by the fact that composition represents a liposomal emulsion formed by phospholipids in the form of liposomes, of average particle size 0.05-0.22 mcm, and sulphated glycosaminoglycans with sulphated glycosaminoglycans presented by keratan sulphate sodium salt and chondroitin sulphate sodium salt with the ingredients of the composition taken in certain proportions, wt %.

EFFECT: invention provides preventing lachrymal production from decreasing, reducing tear evaporation, as well as avoiding pathological changes in conjunctival and corneal epithelial cells.

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Description

The invention relates to medicine, in particular to pharmacology, and is a pharmaceutical composition that can be used in ophthalmology for the complex treatment of diseases of the ocular surface in patients with primary open-angle glaucoma.

Recently, much attention has been paid to diseases of the ocular surface and the study of the causes of their occurrence. Numerous studies have confirmed that in patients with primary open-angle glaucoma or intraocular hypertension due to prolonged conservative treatment with anti-glaucoma drops, eye surface diseases (Prevalence of ocular surface disease in glaucoma patients. Leung EW, Medeiros FA, Weinreb RN. Department of Ophthalmology, Hamilton Glaucoma Center, University of California, San Diego, La Jolla, CA 92093-0946, USA). Diseases of the ocular surface can lead to a decrease in the quality of life of patients and to discontinuation of treatment, because due to manifestations of diseases of the ocular surface, patients begin to take drugs at long intervals. A significant proportion of patients with primary open-angle glaucoma or intraocular hypertension show signs of ocular surface disease in at least one eye. The severity of signs of ocular surface disease is also positively correlated with the number of anti-glaucoma drops that the patient uses in the treatment. Thanks to the work of British research groups using epidemiological methods, questions have been raised regarding the causes of ocular surface diseases and the assessment of previously unknown toxic effects of anti-glaucoma drops (Curr Eye Res. 1998 Apr; 17 (4): 419-25. Histopathological effects of topical ophthalmic preservatives on rat corneoconjunctival surface (Becquet F, Goldschild M, Moldovan MS, Ettaiche M, Gastaud P, Baudouin C. Source Department of Ophthalmology, ERCA INSERM, Ambroise Pare Hospital, University of Paris V, Boulogne, France). The toxic effects of eye drops may develop asymptomatically and be clinically implicit. But regardless of the duration of treatment, sooner or later, these lesions can lead to the appearance of clinically noticeable changes in the conjunctival and corneoscleral epithelium. Diseases of the ocular surface in patients with primary open-angle glaucoma or intraocular hypertension are most often manifested in the form of an allergic reaction of the eyelids, blepharitis, dry eye syndrome, the development of pseudopimphegoid, allergic conjunctivitis, diffuse toxic epithelial cornea and conjunctiva.

The classic clinical picture of an acute allergic reaction is the rapid (during the first days of taking the drug) development of acute conjunctivitis, accompanied by severe eczematous inflammation of the eyelids. In the case of taking the drug, these phenomena persist. Allergy should also be assumed in cases where there is a nonspecific impaired tolerance or even mild blepharitis. Along with the development of an acute allergic reaction, symptoms of intolerance to the drug can develop with a significant delay relative to the time of treatment initiation. Signs of intolerance can be detected only after a year or two regular instillation of the drug, even if the local treatment was well tolerated earlier. In some cases, the allergy does not directly affect the surface tissues of the eye or the edges of the eyelids, and you should look for some remote allergic manifestations on the skin of the eyelids. In the area of contact of the skin of the eyelids with fingers contaminated with eye drops, chronic eczema can develop. In addition, the clinical picture of some immunoallergic reactions can be characterized by the development of extremely severe manifestations, such as pseudopimphegoid, which develops as a result of more than a decade of taking antiglaucoma drugs. The clinical picture is very reminiscent of a pemphigoid, but all the classic immunohistological signs are not observed. Due to conjunctival changes, surgical anti-glaucomatous surgery is not effective, and there is no alternative to continued use of anti-glaucoma eye drops. The toxic effects of antiglaucoma drops containing a preservative are much more common than allergic reactions. This toxic mechanism can manifest itself as a mild follicular or non-follicular conjunctivitis, mimicking a prolonged allergic conjunctivitis.

According to studies, glaucoma is often combined with dry eye syndrome: 33.7% of glaucoma patients over the age of 65 have manifestations of corneal conjunctival xerosis. Dry eye syndrome includes a complex of clinical and functional signs of xerosis of the surface of the cornea and conjunctiva of varying severity due to a prolonged violation of the stability of the tear film covering the cornea (V. Brzhesky Diagnosis and treatment of dry eye syndrome: Abstract of Dr. med. Sciences. - St. Petersburg, 1998. - 40 p .; Brzhesky VV, Somov EE Dry Eye Syndrome: Current Aspects of Diagnosis and Treatment // Dry Eye Syndrome. - 2002. - No. 1 . - C.3-10, VV Brzhesky, EE Somov Corneal conjunctival xerosis (diagnostician , Clinic, treatment); second edition, St. Petersburg, 2003).

The causes of decreased tear production in glaucoma include pharmacological inhibition of tear production due to repeated instillation of anti-glaucoma drops. Violation of the stability of the tear film is associated with toxic processes affecting the lipid and mucin layers of the tear film. Disorders in dry eye syndrome are very diverse and may relate to various links in the formation and functioning of the tear film: the production of tears, mucins and lipids, as well as the rate of evaporation of the tear film. A consequence of the violation of one of these processes is the accelerated formation of “dry” spots on the corneal epithelium or the complete absence of the formation of a tear film on the cornea. An unstable, tear film does not fully perform its functions. This causes the development of xerotic changes in the cornea and conjunctiva, which form the clinical picture of dry eye syndrome.

In some cases, the toxicity of antiglaucoma drops containing preservatives is more pronounced in the form of diffuse epitheliopathy, which spreads much wider than the area exposed to the preservative, and also affects the cornea and conjunctiva under the eyelids. As a result of the toxic effects of anti-glaucoma drops containing preservatives, the likelihood of developing diffuse keratitis is high, which in some cases can lead to a significant deficiency of limbal stem cells. This deficiency appears as the front of the cells of the conjunctival epithelium, which is approaching the cornea by successive waves of growth.

Broadway and Hitchings in their work compared the results of predictions of the subsequent course of glaucoma after surgery in patients who were operated on in the early stages with the prognosis of patients who underwent drug treatment before surgery. They observed significant differences in the number of successful outcomes after filtration surgery, depending on whether the conjunctiva was exposed to the long-term effects of one or more anti-glaucoma drugs. The fibrotic process that occurs after filtration surgery is due to changes in the conjunctival and episcleral tissues that occurred before the operation. These processes were recorded in patients who received medication before surgery. The operations were unsuccessful due to fibrosis in the form of collagen deposits, which caused obstruction of the outflow paths of aqueous humor (Curr Opin Ophthalmol. 1996 Apr; 7 (2): 80-6. Side effects of antiglaucomatous drugs on the ocular surface. Baudouin C. Department of Ophthalmology, Hospital Ambroise Pare, Boulogne, France). (Detrimental effect of preservatives in eyedrops: implications for the treatment of glaucoma. Baudouin C. Department of Ophthalmology III, Quinze-Vingts National Ophthalmology Hospital, Paris, France).

Summarizing all of the above, it should be noted that for the optimal treatment of patients with primary open-angle glaucoma and intraocular hypertension, it is necessary to consider the treatment of glaucoma and ocular surface disease together. In this regard, the development of a drug that makes up for the lack of separate layers of the tear film on the eyeball and has the ability to activate reparative and synthetic processes in the corneal cells seems relevant.

The closest in technical essence to the claimed technical solution are eye drops based on phospholipid in a physiological solution of sodium salts, which additionally contain sialic acid, L-carnosine and sulfated glycosaminoglycans (RF patent No. 2302231). Sulfated glycosaminoglycans contain sodium salt of keratan sulfate, as well as sodium salt of chondroitin sulfate, with a certain ratio of components. The pharmaceutical composition is prepared as follows — weighed portions of the components are dissolved in deionized pyrogen-free water in any order, the solution is mixed, filtered through a 0.22 μm filter, packaged in bottles, sealed and autoclaved.

The disadvantage of these drops is that the mixture of phospholipids with sulfated glycosaminoglycans is unstable in time, and the complex of phospholipids with sulfated glycosaminoglycans precipitates for a short time. The authors also propose a sterilization method - autoclaving, but it is known that phospholipids are destroyed by heat treatment.

The objective of the invention is the creation of a pharmaceutical composition intended for the complex treatment of diseases of the ocular surface in patients with primary open-angle glaucoma, which should have a protective effect on the ocular surface, activate reparative processes in the cornea and conjunctiva, restore the tear film, have anti-allergic and anti-inflammatory properties.

The technical result of the claimed invention is to prevent a decrease in tear production, reduce the evaporation of the tear film, as well as prevent pathological changes in the epithelial cells of the conjunctiva and cornea, which may be followed by damage to the corneal stroma.

The technical result is achieved in that the pharmaceutical composition based on phospholipids and sulfated glycosaminoglycans, according to the invention, is a liposome emulsion formed by phospholipids in the form of liposomes, with an average particle size of 0.05-0.22 microns and sulfated glycosaminoglycans. As sulfated glycosaminoglycans it contains keratan sulfate sodium salt and chondroitin sulfate sodium salt, in the following ratio, wt.%:

Phospholipid 0.001-2 Keratan Sulfate Sodium 0.002-0.2 Chondroitin Sulfate Sodium 0.006-0.1 Saline Rest,

while sulfated glycosaminoglycans are located both inside the liposomes and outside the liposomes in physiological saline.

Liposomal emulsion has several advantages, namely it is stable in time, can be sterilized under aseptic conditions using a sterilization 0.22 micron filter and does not require autoclaving. In addition, liposomes at a temperature of 37 degrees disintegrate over an extended period of time, forming monolamellar layers, similar to a tear film. This provides a longer effect compared to a simple mixture of phospholipids with sulfated glycosaminoglycans in an aqueous medium and the achievement of a therapeutic effect (restoration of a tear film and relief of dry eye syndrome) with lower doses of injected substance (instillation).

The hydroxyl groups of the head groups of these phospholipids participate in hydrogen bonding with the aqueous portion of the tear fluid film and thus stabilize the tear film formed on the surface of the eye for a long time. Phospholipids are available from various sources such as egg yolk, soybeans, etc. These sources usually contain a mixture of components, including natural lipids, such as glycerides, cholesterol and cholesterol esters; phospholipids having a total zero charge, such as, for example, phosphatidylcholine, phosphatidylethanolamine, various unsaturated and saturated fatty acids, and charged phospholipids, such as phosphotidylglycerol and phosphatidylinositol. The most preferred phospholipid for the purposes of this invention is a polyalcohol. The most preferred polyalcoholic phospholipids are phosphatidylglycerols, including cardiolipins and phosphatidylinosites, as well as serine, phosphatidylcholine, sphignomelin.

The concentration of phospholipids cannot be less than 0.001% due to a decrease in the longevity effect of the tear fluid film and cannot be more than 2% due to the fact that blurring of vision can occur at such a concentration.

Sulfated glycosaminoglycans stimulate reparative processes and normalize metabolism in the cornea of the human eye, have the property of reducing the inflammatory and exudative reaction. The sulfated glycosaminoglycans of the corneal stroma include keratan sulfate, chondroitin sulfate, heparan sulfate, heparin. Sulfated glycosaminoglycans stimulate the regeneration and activate synthetic processes in keratitis of the stroma of the cornea in case of damage, normalize water-salt metabolism and contribute to the restoration of transparency of the corneal stroma, which determines their use in drugs.

Sulfated glycosaminoglycans used in different amounts and in different ratios provide different therapeutic effects. The fastest repair of eye tissue with dry eye syndrome occurred when using sodium salt of keratan sulfate in an amount of 0.002-0.2 wt.%, And sodium salt of chondroitin sulfate 0.006-0.1 wt.%. The therapeutic effect we discovered occurred when using both the minimum and maximum doses of each of the sulfated glycosaminoglycans, which indicates the presence of a synergistic effect. Dosages of keratan sulfate below 0.002 wt.% And chondroitin sulfate below 0.006 provided a sharp decrease in the reparative effect. The use of doses above the indicated upper values of keratan sulfate and chondroitin sulfate did not give any noticeable enhancement of the reparative effect, and is excessive.

To reduce complications when using eye drops, it is necessary to use balanced solutions that are closest in composition to chamber moisture and have protective properties. The most physiologically acceptable and balanced salt composition is physiological saline with a pH of 6.8-7.8.

The method of obtaining the invention

Phospholipids and sulfated glycosaminoglycans are mixed in an aqueous medium, all water is evaporated at a temperature of 37 degrees, then dissolved in physiological saline, after which the resulting emulsion is pressed 50 times through filters (Teflon with a pore diameter of 0.1 μm) until uniform opalescence and no noticeable the eye of the particles. The resulting emulsion is sterilized by filtering through a 0.22 μm filter, then poured into vials.

The following components are used to prepare a pharmaceutical composition of the claimed composition:

Phospholipid;

Keratan sulfate sodium salt;

Chondroitin Sulfate Sodium;

Saline solution - the rest.

All the starting components used to obtain the pharmaceutical composition meet the requirements of the Pharmacopoeia.

Examples

Example 1. Patient D., 71, diagnosis: OU Primary open-angle compensated glaucoma. For 3 years, the patient received Sol. Timololi maleati 0.25% 2 times a day. She complained of a foreign body sensation, a feeling of dryness, burning and pain in the eyes, visual impairment in the evening, redness of the eyes. The examination revealed conjunctival hyperemia, a decrease in the lacrimal menisci at the edges of the eyelids, folds of the bulbar conjunctiva at the free edge of the eyelids, staining of the conjunctiva and cornea portions when treated with a 1% solution of pink Bengal (degeneration of epithelial cells), mucous "threads" in the conjunctival cavity. The time of rupture of the tear film according to Norn was 6.4 ± 0.6 seconds with a norm of 10 seconds or more. Schirmer's test (total tear production) was 10.1 ± 0.1 mm ³ with a norm of 15.8 ± 0.4 mm ³ . The patient for a month 3 times a day in both eyes received a pharmaceutical composition prepared according to the above method, the following composition, wt.%:

Cardiolipin 0.001 Keratan Sulfate Sodium 0.002 Chondroitin Sulfate Sodium 0.006 Saline Rest

A month later, the level of subjective discomfort decreased, the eye was calm, the size of the lacrimal menisci normalized, the fold value of the bulbar conjunctiva at the edge of the eyelids decreased. When treated with Bengal pink, staining of the conjunctiva and cornea was not observed. The time of rupture of the tear film according to Norn increased to 8.8 ± 0.6 sec, the total tear production increased to the norm of 14.5 ± 1.1 mm ³ .

Example 2. Patient S., 62 years old, diagnosis: OU Primary open-angle compensated glaucoma. For 4 years, the patient received Sol. Timololi maleati 0.5% 2 times a day. He complained about the presence of a foreign body, burning and redness of the eyes, a pronounced reaction to the dustiness of the room, bright light, wind. During the examination: conjunctival hyperemia, decrease in lacrimal menisci at the edges of the eyelids, folds of the bulbar conjunctiva at the free edge of the eyelids, staining of the conjunctiva and cornea sections with 1% Bengal pink solution, the time of tear film rupture according to Norn was 7.6 ± 0.4 s at normal 10 s or more, Schirmer's sample was 11.1 ± 1.1 mm ³ with a norm of 15.8 ± 0.4 mm ³ .

The patient for 2 weeks 3 times a day received a pharmaceutical composition prepared according to the above method, the following composition, wt.%:

Cardiolipin 0.05 Keratan Sulfate Sodium 0.002 Chondroitin Sulfate Sodium 0.006 Saline Rest

After 1 month, complaints and discomfort disappeared. The eye is calm, the folds of the bulbar conjunctiva at the edge of the eyelids were not determined, the values of the lacrimal menisci at the edges of the eyelids returned to normal. When treated with Bengal pink, staining of the conjunctiva and cornea was not observed. Samples of Norn and Schirmer normalized.

Example 3. Patient K., 72 years old, diagnosis: OU Primary open-angle compensated glaucoma. For 6 years, the patient received Sol. Betaxololi 2 times a day. Discomfort in the eye, irritation in bright light, in a smoky or dusty room are disturbing. During the examination: flaccid hyperemia of the conjunctiva of the eye, a decrease in the lacrimal menisci at the edges of the eyelids, folds of the bulbar conjunctiva at the free edge of the eyelids, staining of the conjunctiva and cornea when treated with 1% Bengal pink solution, Norn test - 6.7 ± 0.3 s at a rate of 10 sec and more, Schirmer's test - 9.1 ± 0.9 mm ³ with a norm of 15.8 ± 0.4 mm ³ .

The patient for a month 2 times a day received a pharmaceutical composition prepared according to the above method, of the following composition, wt.%:

Phosphatidylcholine 2.0 Keratan Sulfate Sodium 0.002 Chondroitin Sulfate Sodium 0.006 Saline Rest

At the end of treatment, the complaints disappeared, the eye was calm, the tear meniscus at the edges of the eyelids returned to normal, the folds of the bulbar conjunctiva at the free edge of the eyelids were not determined. Samples of Norn and Schirmer normalized.

Example 4. Patient K., 69 years old, diagnosis: OU Primary open-angle compensated glaucoma. For 5 years, the patient received Sol. Betaxololi 2 times a day. He complained of the presence of a foreign body, burning and redness of the eyes, irritation in bright light. During the examination: flaccid hyperemia of the conjunctiva of the eye, a decrease in the lacrimal menisci at the edges of the eyelids, folds of the bulbar conjunctiva at the free edge of the eyelids, staining of the conjunctiva and cornea when treated with 1% Bengal pink solution, Norn test - 6.5 ± 0.3 s at a rate of 10 sec, Schirmer's test - 8.2 ± 0.9 mm ³ with a norm of 15.8 ± 0.4 mm ³ .

The patient for a month 2 times a day received a pharmaceutical composition prepared according to the above method, of the following composition, wt.%:

Serine 0.2 Keratan Sulfate Sodium 0.01 Chondroitin Sulfate Sodium 0.03 Saline Rest

Two months later, the complaints disappeared, the eye was calm, the tear meniscus at the edges of the eyelids returned to normal, the folds of the bulbar conjunctiva at the free edge of the eyelids were not detected. Samples of Norn and Schirmer normalized.

Example 5. Patient S., 74 years old, diagnosis: OU Primary open-angle compensated glaucoma. For 3.5 years, the patient received Sol. Timololi maleati 0.5% 2 times a day. He complained of the presence of a foreign body, burning and redness of the eyes, a pronounced reaction to the wind. During the examination: conjunctival hyperemia, decrease in lacrimal menisci at the edges of the eyelids, folds of the bulbar conjunctiva at the free edge of the eyelids, staining of the conjunctiva and cornea sections with 1% Bengal pink solution, the time of tear film rupture according to Norn was 7.1 ± 0.5 s at normal 10 s or more, Schirmer's test was 12.1 ± 1.2 mm ³ with a norm of 15.8 ± 0.4 mm ³ .

The patient for 2 weeks 3 times a day received a pharmaceutical composition prepared according to the above method, the following composition, wt.%:

Sphignomelin 0.005 Keratan Sulfate Sodium 0.2 Chondroitin Sulfate Sodium 0.1 Saline Rest

After 1.5 months, complaints and discomfort disappeared. The eye is calm, the folds of the bulbar conjunctiva at the edge of the eyelids were not determined, the values of the lacrimal menisci at the edges of the eyelids returned to normal. When treated with Bengal pink, staining of the conjunctiva and cornea was not observed. Samples of Norn and Schirmer normalized.

Claims (1)

A pharmaceutical composition for the complex treatment of ocular surface diseases in patients with primary open-angle glaucoma based on phospholipids and sulfated glycosaminoglycans, characterized in that the composition is a liposome emulsion formed by phospholipids in the form of liposomes, with an average particle size of 0.05-0.22 microns, and sulfated glycosaminoglycans, while as sulfated glycosaminoglycans it contains keratan sulfate sodium salt and chondroitin sulfate sodium salt when the following ratio of components, wt.%:
Phospholipid 0.001-2 Keratan Sulfate Sodium 0.002-0.2 Chondroitin Sulfate Sodium 0.006-0.1 Saline Rest,
while sulfated glycosaminoglycans are located both inside the liposomes and outside the liposomes in physiological saline.