EP0365571A1

EP0365571A1 - Drug to treat the eye and suitable carrier material

Info

Publication number: EP0365571A1
Application number: EP88905769A
Authority: EP
Inventors: Christian Bannert
Original assignee: Individual
Current assignee: Individual
Priority date: 1986-01-16
Filing date: 1988-06-23
Publication date: 1990-05-02
Also published as: WO1987004350A1; EP0289512A1; JPS63502186A; DE3601132A1; US5147648A; EP0289512B1; DE3721163A1; WO1988010121A1; JPH02504029A

Abstract

Un médicament comprenant deux constituants qui ensemble forment un gel pour traiter la muqueuse par application simultanée ou successive sur cette dernière est utilisé pour traiter l'oeil.A medicament comprising two constituents which together form a gel for treating the mucosa by simultaneous or successive application to the latter is used to treat the eye.

Description

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Use of a medicinal product for the treatment of the eye and a suitable carrier material

The invention relates to the use of a medicament comprising at least two components capable of gel formation with one another.

To treat diseases of the mucous membranes, it has proven useful to use gels. On the one hand, they can be used to protect and keep mucous membranes moist. On the other hand, they are used to apply disinfectants and drugs to the mucous membrane and let them work there. These gels, which are made from synthetic or vegetable substances and can contain various active ingredients, are applied to the mucous membrane in the nose, mouth, throat or urogenital area.

The disadvantage of the known gels is that they adhere poorly to the mucous membrane, so that they do not stay too long at the place where they are to be applied and act, so that a much larger amount of gel must be used than it does would be necessary for the treatment itself. If less viscous gels are used, they roll off the mucous membrane and cannot achieve the desired effect.

Another problem is the application of drugs to the cornea and conjunctiva of the eye. In ophthalmology, gels used on the cornea and are used to treat diseases of the eye ~ zz -

Conjunctiva of the eye. The residence time of these gels on the cornea and conjunctiva, which for the sake of simplicity are referred to below as mucous membranes, should last as long as possible, on the one hand to keep the eye moist and on the other hand to allow the active ingredients to act locally. A problem with the previously known agents for treating the eye is that they do not adhere sufficiently and are flushed out through the tear duct by the tear fluid. Therefore, the application must be carried out at shorter intervals and in higher doses than would be necessary with good adhesion, which is very uncomfortable for the patient. Especially in diseases such as glaucoma, where constant treatment with drugs is required, it would be desirable to find a form of application that enables less frequent use and lower doses. Other means have the problem that they form a film of smear on the eye which affects vision. In some eye diseases, for example in some cases of the dry eye, there is a mucin deficiency which causes the tears to not adequately wet the corneal surface, which can lead to dry spots on the cornea and to destruction of the epithelium. So far there have been no means to improve this condition.

The object of the invention was therefore to prevent the known disadvantages and to create a method for improving the adhesion of gels to the mucous membrane of the eyes.

This goal is achieved by using a medicament consisting of at least two components capable of gel formation which are applied simultaneously or successively for the treatment of the eye. It has surprisingly been found that if not the finished gel, but components capable of gelation, are applied to the mucous membrane, which then form a gel on the mucous membrane, good adhesion can be achieved. Adhesive gels form for a long time, which do not impair vision.

Furthermore, it has been shown that the viscose layer formed in accordance with the invention is similar to the mucin film usually found on the eye. The oligosaccharide side chains of the mucin, like the polyuronic acids of the alginates, carry a negative charge. The gel films produced according to the invention therefore adhere very persistently to the surface of the cornea and also stabilize the tear film, which thereby adheres better and wets the surface of the cornea better.

The two components capable of gel formation are dissolved separately from one another. The solutions are then applied sequentially or simultaneously. The application can take place in the usual way. The two components are preferably dripped into the lower eyelid crease.

Substances which lead to gel formation when mixed can be used as components capable of gel formation. They must also be compatible with the mucous membrane and must not be toxic. Combinations of alginic acid, polyguluronic acid, polymannuronic acid, propylene glycol alginic acid, polygalacturonic acid, their salts or esters or mixtures thereof are suitable, for example. Calcium salts are preferably used as gel-forming components together with alginic acid or one of its derivatives or with a pectin with a low degree of esterification. Calcium salts react with alginic acid and pectins and their derivatives and form cross-linkages. With increasing content of the metal salt, thickening and then gel formation occur first. Calcium salts are preferably used as the metal salt, it being possible to use all pharmaceutically acceptable salts as calcium salts, such as calcium chloride or calcium salts with organic anions such as citrate, lactate, aspartate, saccharate, oxovalerate, gluconate, lactobionate and lactogluconate. Calcium gluconate is preferably used.

The preferred alginic acid derivative is sodium alginate, of which all viscosity types can be used. They are classified by the viscosity of the 1% solution. The measurement is carried out at 25 ° C using a Brookfield viscometer. Commercial alginate types are:

very low viscosity sodium alginate (5 cps), low viscosity sodium alginate (50 cps), high viscosity sodium alginate (400 cps), very high viscosity sodium alginate (1350 cps).

In addition to alginic acid, the brown algae also contain other mono- and polysaccharides. Fucose and ester sulfates are important for the mucous membranes. Suitable methods for processing the brown algae can be used to obtain mixtures of alginates, fucose and ester sulfates. These mixtures are also suitable as components for gel formation in the process according to the invention. - r -

The two components are used as a solution. The metal salt is preferably used in a concentration of 0.01 to 2.5 mmol metal / 100 ml and the polysaccharide in a concentration of 0.01 to 1.0% by weight. The concentration to be used can easily be determined. It also depends on the degree of viscosity of the polysaccharide used.

Pharmaceutically acceptable agents which dissolve the respective component well are used as solvents. Distilled water is preferably used, which is provided with a pharmaceutically acceptable preservative.

The gel formed according to the invention can be used as a tear replacement liquid to keep the eye mucosa moist or to protect it. Furthermore, in a further embodiment, a disinfectant and / or pharmaceutical can additionally be applied to the eye mucosa with one of the components used according to the invention.

The gels obtained with the method according to the invention are preferably used as a carrier material for a medicament. For this purpose, the drug in the dose to be administered is then introduced into one of the two component solutions and the solutions of the two components are then applied to the mucous membrane. The two solutions are preferably applied in succession to the conjunctiva.

Another object of the invention is a carrier material for ophthalmic medicinal products which is characterized in that it contains at least two components capable of gel formation which are physically separate from one another. - b -

With the agent according to the invention, gels can be formed in a simple manner on the mucous membrane and adhere long and permanently to the cornea and conjunctiva.

At least one metal salt and at least one polysaccharide are preferably used as components of the agent according to the invention which are physically separate from one another. A calcium salt is preferably used as the metal salt, and calcium chloride or an organic calcium salt is particularly preferably used. Alginic acid, polyguluronic acid, polymannuronic acid, propylene glycol alginic acid, polygalacturonic acid, their salts or esters and mixtures thereof are particularly preferably used as the polysaccharide.

The two components are preferably dissolved in water. One solution preferably contains 0.01 to 2.5 mmol metal / 100 ml, while the other solution preferably contains 0.01 to 1.0% by weight of at least one polysaccharide.

In a preferred embodiment, at least one of the two components of the composition according to the invention additionally contains medicinal substances, buffer substances, disinfectants, humectants and / or preservatives or other customary additives. For example, sorbitol or glycerol is added to the agent to increase the flexibility of the gel. It may also be suitable to add surfactants to improve wetting.

The concentration of the two components of the agent according to the invention is generally approximately the same in each case. In special cases, however, it can be advantageous. -? -

use one of the two solutions with a higher concentration and therefore a smaller volume. The type of gel formed can also be influenced by the concentration.

The particularly adhesive gels obtained with the method according to the invention are particularly suitable for use as a tear replacement fluid and as a carrier material for medicaments or disinfectants. Using the gel obtained with the method according to the invention, drugs and disinfectants can be applied locally in a targeted manner.

The following examples illustrate the invention: All percentages relate to the weight, unless stated otherwise.

Example 1

A means of treating the eye has been prepared. Two solutions were prepared with the following composition:

Solution 1: calcium gluconate "H ₂ 0 0.1%

Benzalkonium chloride 0.01%

Cooking salt 0.9% distilled water ad 100

Solution 2: sodium alginate (very high viscosity) 0.1% thiomersal 0.01%

Sodium chloride 0.9% distilled water ad 100. Of these two solutions, a drop of solution 1 and then solution 2 was instilled into the conjunctival sac of the eye. A viscous liquid was formed, which remained on the mucous membrane of the eyes for a long time and can be used as an artificial tear fluid.

Example: 2

Eye drops for the treatment of glaucoma were produced. Two solutions with the following composition were prepared:

Solution 1: sodium alginate (very highly viscous) 0.1% isotonic borate buffer, pH 7.6, 50 ml sodium chloride 0.45% thiomersal 0.01% distilled water ad 100.

Solution 2: Calcium gluconate ^* H_0 0.1% sodium chloride 0.7% benzalkonium chloride 0.01% pilocarpine hydrochloride 1% distilled water ad 100.

To treat glaucoma, first a drop of solution 1 and then immediately afterwards a drop of solution 2 was placed in the eye. Another possibility is to let a drop of solution 1 and a drop of solution 2 flow together and then let this mixture immediately drip into the eye. In both applications, a fine film is created that floats on the eye and remains there for a long time. Example 3

A patient with chronic kerato conjunctivitis Sicca and with missing eyelashes (trichiasis), which had to be pulled regularly at certain intervals, was treated with a tear replacement fluid, as was produced in example 1. The dropping was carried out three times a day. After application of the drops, there was less irritation and a considerably lower disturbing effect due to the eyelashes on the eye. Therefore, the intervals at which the eyelashes had to be removed due to the disturbance reaction could be increased from approximately one week to two weeks. These results could not be achieved with the artificial tear fluid previously used.

Example 4

A patient with chronic glaucoma was treated with drops according to Example 2. The drops were applied every 12 hours. Normalization of eye pressure has been observed with this therapy. With the pilocarpine eye drops previously used, which had to be applied four to five times a day, the eyes were severely irritated. Nevertheless, normalization of the eye pressure could not be achieved.

Example 5

A patient who has suffered from blepharoconjunctivitis with Sicca symptoms since 1979 and has tried numerous eye drops and eye ointments without success during this time has been treated with eye drops for 4 months - lo -

Example 1 treated. The application frequency could be reduced. The subjective condition improved and the burning and reddening of the eyes subsided. The foreign body feeling in the eye also decreased.

Example 6

A patient who had been suffering from chronic recurrent conjunctivitis sicca with burning and reddening, especially in dry air, was treated with eye drops according to Example 1. The patient became symptom-free through two to three applications. Monthly checks confirmed this diagnosis.

Example 7

A patient with chronic conjunctivitis with a pronounced blepharochalasis, who had suffered from burning and reddening of the eyes for years and applied various eye preparations to the eyes with moderate success in some cases, was treated with the eye drops according to Example 1. By applying the agent according to the invention three times a day, the condition could be significantly improved.

Example 8

A child who has had severe shrinking conjunctivitis and Sicca syndrome after Lyell's syndrome has been suffering from eye drops for a year - 1 / -

Example 1 treated. The eye drops are well tolerated when applied two or three times a day. Since then, the child has been much more free of complaints than before. Monthly checks confirmed this.

Example: 9

A patient who had suffered from chronic conjunctivitis sicca with burning and reddening for years and responded to various preparations only with temporary improvement was treated with eye drops according to Example 1. He tolerated these drops very well. The burning eyes disappeared completely.

Example 10

A patient with chronic fibrosing conjunctivitis after Lyell syndrome had expired was treated with eye drops prepared according to Example 1. The drops were very well tolerated. The drip frequency could be significantly reduced compared to other agents. The burning of the eyes practically completely subsided.

Example: 11

A patient with Sjögren's syndrome had had massive symptoms, especially burning eyes, for years, which made him unable to read. He used numerous preparations without success. The application of the according - 1 1 -

Example 1 eye drops produced a sudden improvement. The patient applied the eye drops four to five times a day. He has been reading for the first time in years. A check carried out after one month showed that the patient was free of symptoms.

Example 12

A patient with Sicca syndrome in Sjögren's syndrome has had symptoms for years. He used various preparations that often had to be applied. For 3 months it has been treated with the eye drops prepared according to Example 1, which it tolerates very well. The symptoms disappeared after two to four applications.

Example: 13

A patient with Sicca syndrome used eye drops according to Example 1 two to three times a day. The eye drops were well tolerated. Since then, the patient has been symptom-free.

Example 14

A patient with chronic Staphylococcal Blepharo keratitis with Sicca syndrome had been treated with the eye drops obtained according to Example 1 for 8 months. The eye drops were well tolerated. The patient has been using the drops two to three times a day with unchanged good success for 8 months. - ii -

Example 15

Two solutions of the following composition were prepared as starting solutions for eye drops for glaucoma treatment:

Solution 1

Sodium alginate (very high viscosity) 0.1% isotonic borate buffer, pH 8.5 *, 40 ml

Sodium chloride 0.55% thiomersal 0.01% distilled water to 100 ml

Solution 2

Calcium gluconate 0.1% ^* H »0 sodium chloride 0.8% benzalkonium chloride 0.01% pilocarpine hydrochloride 0.2% distilled water to 100 ml

* Isotonic borate buffer was produced according to the "Borax buffer according to Palitzsch" in OPTHALMICA, Volume 1, Pharmaceutical principles and their preparation, Wissenschaftliche Verlagsgesellschaft mbH Stuttgart, page 95, Table 3.2./7, (1975).

To treat glaucoma, a drop of solution 1 was placed in the eye and immediately afterwards a drop of solution 2. - ι ₇ -

Example 16

A patient with right-left angular block glaucoma was administered with eye drops obtained twice daily (8 a.m. / 8 p.m.) according to Example 15 in the right eye and 0.5% timolol (beta-blocker) in the same period in the left eye. The measurement of the eye pressure gave the following values:

Basis daily pressure measurement 8.00 10.00 12.00 14.00 16.00

(Hour)

right eye 22 21 21 22 21

(drops according to the invention at 8 a.m. / 8 p.m.)

left eye 26 28 30 26 26

Timolol (8 a.m. / 8 p.m.)

With the same application over time, the eye drops according to the invention provide a better activity profile than known eye drops.

Example 17

A patient with right-left angular block glaucoma with an identical pressure position on the right and left was applied twice in the right eye, at 8:00 a.m. and at 8:00 p.m., eye drops according to Example 15. For comparison, spersacarpine 0.5% and at 8.00 p.m. for the night Pilocarpol 2% was applied to his left eye for comparison three times, at 8:00 a.m., 12:00 p.m. and 6:00 p.m. The values for the pressure measurement of both eyes can be found in the following table: - i -

Basis daily pressure measurement 8.00 10.00 12.00 14.00 16.00

(Hour)

right eye 17 16 19 18 17

(drops according to the invention at 8 a.m. / 8 p.m.)

left eye 15 16 16 18 17

Comparison (8 a.m. / 12 p.m. / 6 p.m. / 8 p.m.)

As these values show, the pressure curve is practically identical for both agents. According to the invention, the pilocarpine dose can be reduced by a factor of 10 and at the same time the frequency of use can be reduced. In contrast, the eye drops of the prior art must be applied more frequently, which is uncomfortable for the patient. In addition, the amount of pilocarpine must be 10 times higher to achieve the same result.

Claims

- \ b -Patent claims

1. Use of a medicament consisting of at least two components capable of gel formation which are applied simultaneously or successively for the treatment of the eye.

2. Use of a medicament according to claim 1, which also comprises a metal salt and a polysaccharide as components capable of gel formation.

3. Use according to claim 2, that a combination of a calcium salt and sodium alginate is used as the components capable of gel formation.

4. Use according to claim 2 or 3, that the metal salt is used in a concentration of 0.01 to 2.5 mmol per 100 ml and the polysaccharide in a concentration of 0.01 to 1% by weight.

5. Use according to one of the preceding claims, d a d u r c h g e k e n n z e i c h n e t that one of the components or both additionally contain disinfectants and / or drugs.

6. Carrier material for ophthalmic medicinal products, due to the fact that it contains at least two components capable of gel formation that are physically separate from one another.