RU2277411C1 - Pharmaceutical composition for treating eye diseases as a result of microcirculation disorders and/or inflammatory processes - Google Patents

Abstract

FIELD: medicine, ophthalmology, chemico-pharmaceutical industry.

SUBSTANCE: the suggested pharmaceutical composition is indicated for local application and contains an inhibitor angiotensin converting enzyme as an active substance and target additions, moreover, the content of active substance corresponds to about 1-20 mg/ml. The composition suggested could be designed as eye drops, spay, gels, solution for local injections. As target additions one should apply water that contains a buffer agent, an isotonic mixtures, a conservant and a prolongator. Additionally, this composition contains preparations chosen out of the following groups: antibiotics, macro- and microelements, vitamins, adrenoblocking agents. The innovation provides anti-ischemic action, improves reparative processes and accelerates the processes of healing.

EFFECT: higher efficiency.

3 cl, 7 ex

Description

The invention relates to the pharmaceutical industry and relates to a pharmaceutical composition for topical use in the treatment and prevention of eye pathologies associated with impaired microcirculation and / or inflammatory processes.

Disruption of microcirculation is an important pathogenetic link in diseases such as degenerative diseases of the retina and optic nerve, diabetic retinopathy, age-related retinal degeneration, burn conjunctival ischemia, occlusion of the retinal vessels, optical neuropathy, etc. Inflammatory processes include domestic, industrial, and military injuries (mechanical chemical, thermal, radiation, caused by laser exposure), keratitis of various etiologies, uveitis, etc.

Currently, in the world practice for the treatment of such eye pathologies, the following approaches are used. In cases of microcirculatory disorders and, in particular, in dystrophic processes, vasodilator and antispasmodic drugs, fibrinolytics, anticoagulants, biogenic stimulants, and vitamins are used [1-4]. In the treatment of diabetic retinopathy, the main method of treatment remains laser coagulation of the retinal vessels and surgical treatment. In inflammatory processes, non-specific anti-inflammatory drugs (antibiotics, corticosteroids), preparations based on proteinase inhibitors, enzyme preparations, immunomodulators, anti-infective agents, biogenic stimulants of reparative processes, antioxidants, angioprotectors are usually used [5-8]. In the case of tissue necrosis, you have to resort to surgery. However, currently accepted treatment methods are not effective enough, and sometimes have their negative consequences. Corneal ulcers are difficult to treat, often a gross opaque thorn is formed, there are no effective specific topical drugs for topical application that can stop the vascular spasm of the limbal conjunctiva and avoid ischemia of the eye tissue and subsequent necrosis, there is no pharmacological market. In addition, there are no funds that can simultaneously affect tissue repair and restore impaired microcirculation. An advantage of the proposed pharmaceutical composition is its unique integrated antiulcer, anti-ischemic and antioxidant effect.

One of the pathogenetic links uniting the above diseases is the imbalance of the components of the general and local (in the eye) renin-angiotensin systems (ASD). The renin-angiotensin system is one of the most important regulatory systems of the body. The central regulatory element of ASD is the angiotensin converting enzyme (ACE). ACE is a zinc-dependent peptidase that catalyzes the hydrolytic cleavage of dipeptides from the carboxyl end of a number of physiologically active oligopeptide substrates, in particular angiotensin I and bradykinin. As a result of the limited proteolysis by ACE, angiotensin I is converted into a potent vasoconstrictor, angiotensin II, which causes vascular spasm, and the bradykinin vasodilator, which causes vasodilation, is inactivated. ACE inhibitors block ACE activity and thus prevent the formation of angiotensin II and the destruction of bradykinin. Thus, ACE inhibitors create conditions for the accumulation of local tissue bradykinin, which in turn stimulates the release of nitric oxide (NO) and prostaglandins. This mechanism is of great importance for smooth muscle cells of the vascular wall due to the fact that NO can inhibit the mitogenesis and proliferation of these cells [9, 10]. Moreover, prostaglandins and NO have a vasodilating effect, due to which the function of large vessels and tissue perfusion can be improved. ACE inhibitors, along with the ability to improve endothelial function, inhibit the growth and proliferation of smooth muscle cells, have the ability to inhibit the migration and function of macrophages, reduce thrombotic activity by preventing platelet aggregation and enhancing endogenous fibrinolysis [11].

Currently, ACE inhibitors are widely used orally or intravenously for the treatment of hypertension and cardiovascular failure [5]. In the literature there is evidence of a positive effect with the oral administration of ACE inhibitors in atherosclerosis [12] and in insulin-dependent diabetes mellitus [13].

Current data indicate the existence, in addition to humoral generalized ASD, of local tissue factor systems in various organs and many physiological functions of ASD are associated with its local action - paracrine, autocrine and intracrine. To date, many components of ASD have been found in tissue structures and liquid media of the eye, which can play a significant role in the pathogenesis of various eye diseases [14]. Currently, there is evidence of a positive effect of the oral administration of ACE inhibitors in senile retinal degeneration [15] and diabetic retinopathy [16]. There are indications of the possible local use of ACE inhibitors to reduce intraocular pressure in glaucoma [17] and the treatment of corneal ulcers [18]. However, currently ACE inhibitors are not topically used to treat eye diseases.

The objective of the present invention is to prevent the development of microcirculatory disorders, as well as the restoration of impaired microcirculation in the tissue structures of the eye. Another important feature of the invention, in addition to anti-ischemic action, is the ability to improve the course of reparative processes in case of tissue damage, prevent the development of deep ulcers, and accelerate healing processes. This is especially important for the treatment of eye injuries, given the fine structural organization of tissues and the need to maintain the transparency of a number of tissues and environments of the eye.

To solve this problem, a pharmaceutical composition for topical application is proposed, the active principle of which is an ACE inhibitor. The inhibitor should be in active form, for example, containing a sulfhydryl group (captopril, methioprilat, zofenoprilat, etc.), containing a carboxyalkyl group (enalaprilat, lisinopril, ramiprilat, trandolaprilat, etc.) or containing a phosphinyl group (fosinoprilat, etc.). The composition may contain known ophthalmic carriers as a medium, including water containing a buffering agent, isotonic mixtures, antibacterial components, preservatives, prolongators, thickeners, gels. The composition may also contain one or more additional approved therapeutic drugs, for example, such as antibiotics, macro- and microelements, vitamins and vitamin-like agents, adrenergic blockers, etc. The claimed composition is proposed to be administered topically in the form of eye drops, spray or local injection.

Tests of the pharmaceutical composition were carried out on rabbits. Experimental studies were conducted on models of eye burns of various localization, which are accompanied by conjunctival ischemia, corneal ulcers and the inflammatory process, as well as on a model of diabetes in rabbits, in the early stage of which there are disturbances in the microcirculation in the conjunctiva. We found that in experimental animals in the tear fluid, the metabolism of which reflects the nature of the course of biochemical processes in the eye, ACE activity increases with eye injuries and diabetes. A correlation was established between the activity of ACE in the tear and the severity of the clinical manifestations of the pathological process. ACE activity in a tear was evaluated by the initial rate of hydrolysis of the substrate Cbz-Phe-His-Leu, determining the reaction product (His-Leu) fluorimetrically after modification with orthophthalaldehyde [19]. The clinical picture of the course of the disease was evaluated using biomicroscopy, photoregistration of limb vessels, ophthalmoscopy and vascular caliberometry. The depth and area of ulceration, the degree of edema and hyperemia of the eyelids, the presence of discharge, tissue infiltration, the length and density of newly formed vessels, and the presence of signs of uveitis were also evaluated.

The concentration of an ACE inhibitor can vary from 1 mg / ml to 20 mg / ml, depending on whether the surface or internal tissues of the eye are affected.

The pharmaceutical composition has the following composition (wt.)

Example 1 (mg / ml) Captopril 1,2 Monosubstituted Sodium Phosphate 6.0 Disubstituted Sodium Phosphate 0.88 Benzalkonium chloride 0.3-1.0 Sodium chloride 3.0-9.0 Distil. water 1 ml

Example 2

Lisinopril twenty Sodium hydroxide pH 6.0-7.5 Benzalkonium chloride 0.3-1.0 Sodium chloride 3.0-9.0 Distil. water 1 ml

Example 3

Lisinopril 5 Sodium hydroxide pH 6.0-7.5 Sodium chloride 3.0-9.0 Calcium chloride twenty Distil. water 1 ml

Example 4

Captopril 2 Monosubstituted Sodium Phosphate 6.0 Disubstituted Sodium Phosphate 0.88 Sodium chloride 3.0-9.0 Riboflavin 0.2 Distil. water 1 ml

Example 5

Enalaprilat 10 Sodium hydroxide pH 6.0-7.5 Sodium chloride 3.0-9.0 Ciprofloxacin 3.0 Distil. water 1 ml

Example 6

Enalaprilat twenty Sodium hydroxide pH 6.0-7.5 Sodium chloride 3.0-9.0 Trimolol maleate 2.5-5.0 Distil. water 1 ml

Example 7

Enalaprilat 1,0 Sodium hydroxide pH 6.0-7.5 Sodium chloride 3.0-9.0 Cellulose 10 Distill water 1 ml

Animal experiments have shown that topical application of the claimed composition improves microcirculation during ischemic processes, reduces inflammation, improves outcomes and accelerates the course of reparative processes after an injury.

Given that the physiological characteristics of the eye of a rabbit and a human are identical, this pharmaceutical composition can be recommended for use in both veterinary medicine and in the clinic.

LITERATURE

1. Morozov V.I., Yakovlev A.A. Pharmacotherapy of Eye Diseases: A Guide. Moscow, (2001), 336 p.

2. Patent EP 1297849 A1 (2001).

3. Patent US 4,795,423 (1989).

4. Patent US 5431907 (1995).

5. Mashkovsky M.D. Medicines M., UN “New Wave”, (2002) t.1, 420-425.

6. S.C. Brodovsky, C.A. McCarty, G. Snibson et al. Management of alkali burns. Ophtalmology (2000) 107, 1829-1835.

7. Patent RU 2145229 C1, (1997).

8. Patent RU 2073523 C1, (1977).

9. Tereshchenko S.N. EUROPA opens up new horizons for the use of ACE inhibitors. Pharmacotherapy in Cardiology (2003) 05.

10. Drexler H., Kurz S. et al. Am. J. Cardiol (1995) 76, 13E-18E.

11. Yusuf S., Lonn E. Eur. Heart J. (1998) 19 (Suppl. J.), J36-J44.

12. Jacobsson L., Persson K., Aberg G., Anderson R., Karlberg B., Olsson A.J. Antiatherosclerotic effects of the angiotensin-converting enzyme inhibitors captopril and fosinopril in hypercholesterolemic minipigs. Cardiovasc. Pharmacol (1994) 24, 670-677.

13. L.H. Opie. Angiotensin-converting enzymes inhibitors: the advance continius. N.-Y., 1999, 275 p.

14. Deinum J., Derkx F.H., Danser A.H., Schalekamp M.A. Identification and quantification of renin and prorenin in the bovine eye. Endocrinology (1990) 126, 1673-1682.

15. Patent US 4,656,188 (1987).

16. Chaturvedi H., Sjolie A.K., Stephenson J.M. et al. Effect of lisinopril on progression of retinopathy in normotensive people with type 1 diabetes. The EUCLID Study Group. EURODIAB Controlled Trial of Lisinopril in Insulin-Dependent Diabetes Mellitus. Lancet (1998) 351, 28-31.

17. Patent EUR. 0099239 (1984).

18. RF patent 2119314 (1996).

19. Eliseeva Yu.E., Orekhovich VN, Pavlikhina LV Isolation and properties of carboxicatepsin (peptidyl dipeptidase) from bovine lung tissue. (1976) Biochemistry, 41, 506-512.

Claims (4)

1. The pharmaceutical composition for the treatment and prevention of eye diseases associated with impaired microcirculation and / or inflammatory processes, characterized in that it is intended for local use and contains as an active substance an angiotensin-converting enzyme inhibitor and target additives, while the content of the active substance ranges from 1 to 29 mg / ml. 2. The composition according to claim 1 can be made in the form of eye drops, spray, gels, solution for local injection. 3. The composition according to claim 1, where as the target additives can be used water containing a buffering agent, isotonic mixtures, preservative, prolongator. 4. The composition according to claim 1 additionally contains preparations selected from the groups: antibiotics, macro- and microelements, vitamins, adrenergic blockers.