OPHTHALMIC COMPOSITION CONTAINING RHAMSAN GUM

Abstract: The present invention concerns a pharmaceutical and/or cosmetic composition designed to be applied on the skin or the mucosae, characterized in that it contains Rhamsan gum.

Description: The present invention relates to an ophthalmic composition for topical use, the formulation of which permits a slow and gradual release of the active principle on the mucosae, in particular on the conjunctiva. One of the main penetration routes for ophthalmic compositions is the cornea. The cornea is, in effect, a fibrous membrane which is non-vascularized but permeable to all water-soluble substances. This membrane is protected by a mucosa, the conjunctiva, on which the ophthalmic compositions are applied. Various known processes enable the contact time between the eye lotion and the conjunctiva to be prolonged. It has been known for a long time that the act of depositing drops of eye lotion in the outer corner of the eye enables lachrymal drainage to be delayed. It is also known to use viscous solutions, gels, eye ointments or even occular implants for the purpose of prolonging the residence time of the eye lotion in the eye. To increase the contact time between the ophthalmic compositions and the conjunctiva, the use of special adjuvants, such as gums or polymers, is also recommended. For example, C. Rosenblum et al. (Arch Ophthal, 77: 234-237, 1967) describes the use of hydroxyethylcellulose for increasing the systemic absorption of dexamethasone by the eye tissues. Y.F. Maichuk (Am. J. Ophthal, 74: 694, 1972) shows that the use of polyvinyl alcohol enhances the pharmacological response to medicinal products such as erythrocin propionate and sulphapyridazine sodium. Similarly, guar gum has been shown to increase the absorption of tropicamide via the cornea (Lee et at., J. Pharm. Sci. 63: 721, 1974). The use of combinations between gum and polymer is also described, and in particular by way of a bactericidal cleaning agent, a lubricant and a wetting agent. Thus, for example, German Patent No. 2,051,369 describes a solution containing polyethylene glycol, poly(ethylene oxide) and an ophthalmic medicinal product. Similarly, British Patent No. 1,337,105 describes a different combination of polymers designed to be used in solutions for cleaning the eyes and containing hydroxyethylcellulose and polyvinyl alcohol. Another example relates to British Patent No. 1,340,518, which describes ophthalmic compositions containing an ophthalmic medicinal product, a polyalkylene glycol, a cellulose derivative or a mixture of these derivatives with, where appropriate, polyvinylpyrrolidone. Similarly, U.S. Patents No. ,944,427 and 3,700,451 describe compositions which are capable of gelation and in gel form, containing agar, xanthan gum and carob gum in a liquid medium which is usable by way of a vehicle in therapeutic solutions. U.S. Patent 4,136,177 also describes the use of xanthan gum in ophthalmic compositions. Xanthan gum, however, has the disadvantage of being partially degraded under the effect of heat; with an instability of this kind, it is difficult to achieve compatibility with sterilization in the autoclave, which is required in the formulation of eye lotions. Gellan gum has been described in the French Patent n° 2 588 189, for its use in liquid ophthalmic compositions which possess the property of undergoing a liquid-gel phase transition in situ . The present invention relates to an ophthalmic composition designed to be applied on the mucosae, characterized in that it contains Rhamsan gum. It has been shown, in effect, altogether unexpectedly, that Rhamsan gum prolongs the period of action of pharmaceutical and/or cosmetic compositions designed to be applied on the mucosae. In the ophthalmic compositions according to the invention, Rhamsan gum enables the residence time of the said compositions in the pre-corneal area, that is to say at the conjunctival level, to be very substantially prolonged. The bioavailability of the medicinal product therein is consequently greatly improved, thereby permitting a substantial parallel decrease in the side effects. Furthermore, Rhamsan gum shows exceptional thermal stability; this stability enables the compositions according to the invention to be sterilized in the autoclave. Rhamsan gum endows the compositions according to the invention with a more or less viscous consistency, or even a gel consistency, a, consistency of this kind depending on the concentration of this polymer in the said compositions. Rhamsan gum is an extracellular anionic heteropolysaccharide produced by the organism ATCC 31961. This polymer is manufactured by Kelco Co. It is also known under the code names S-194 or KI A 112. It is described in U.S. Patent 4,401,760. Its structure comprises a linear tetrasaccharide skeleton bearing a disaccharide side chain, and it may be represented in the following manner: The Rhamsan gum used according to the present invention is preferably of clarified grade. The ophthalmic compositions according to the present invention preferably contain Rhamsan gum in the proportion of between 0.05% and 3%(w/w). The viscosity of these compositions increases with the percentage of gum to become a gel at the strongest concentrations. These ophthalmic compositions can be used in very varied fields of application, and in particular for maintaining satisfactory hydration of the eye (treatment of the dry eye syndrome). It appears that the ophthalmic compositions according to the invention are especially suitable for the administration of any pharmacologically active substance for curative or diagnostic purposes. The present invention relates more especially to ophthalmic compositions containing 0.001% to 5% (w/w) of at least one pharmacologically active substance. By pharmacologically active substance, there are understood one or more medicinal substances. Water-soluble substances are preferably chosen, but lipid-soluble active principles can also be appropriate to compositions according to the present invention, in particular in the form of suspensions or emulsions in the aqueous polysaccharide solutions of the present invention. Among water-soluble substances, some are more readily solubilized in the aqueous polysaccharide solutions of the present invention, and their use is hence especially preferred. Other advantages and characteristics will emerge on reading the following examples: EXAMPLE 1 : Composition for the delivery of a carbonic anhydrase inhibitor per gram L-651,465-OOX 20.6 mg Rhamsan 6.00 mg Sodium acetate 3H₂O 8.98 mg Sodium edetate 0.50 mg Benzalkonium chloride 0.011 mg Hydrochloric acid (0.1 N solution) 4.760 mg Water for injection qs 1 g Concentrations of L-650,719 (active metabolite) are measured in the aqueous humour of unanaesthetized albino rats following single instillations of 50 µl of 2% strength L-651,465 formulations containing 0.6% of Rhamsan gum and 0.5% of hydroxyethylcellulose QP 52000H, which is a widely used viscosity-enhancing agent. The results given below show that the bioavailability of the medicinal product is significantly increased by using the Rhamsan formulation. EXAMPLE 2 Composition containing timolol in solution Timolol (maleate) 0.250 g Rhamsan gum 0.600 g Monobasic sodium phosphate 0.721 g Dibasic sodium phosphate 1.158 g Benzalkonium chloride 0.010 g Distilled water qs 100 ml EXAMPLE 3 Composition for delivery of timolol in a gel Timolol (maleate) 0.250 g Rhamsan gum 3.000 g Monobasic sodium phosphate 0.721 g Dibasic sodium phosphate 1.158 g Benzalkonium chloride 0.010 9 Distilled water qs 100 g EXAMPLE 4: Composition containing Norfloxacine in the form of a gel Norfloxacine 0.300 g Rhamsan 3.000 g Disodium EDTA 0.010 g Benzalkonium chloride 0.0025 g Sodium acetate trihydrate 0.0272 g Sodium chloride 0.742 g Hydrochloric acid to adjust the pH to 5.2-6 Distilled water qs 100 g The above examples, and in particular the results which appear in the table, clearly demonstrate the prolonged pharmacological effects of the compositions containing Rhamsan gum according to the invention.

Claims: Ophthalmic composition containing Rhamsan gum. Ophthalmic composition according to claim 1, characterized in that it contains Rhamsan gum in the proportion of between 0.05 % and 3 % (w/w). Ophthalmic composition according to claim 2, characterized in that it contains 0.001 % to 5 % (w/w) of at least one pharmacologically active substance.

Inventors: MAZUEL, CLAUDE
Applicants: LABORATOIRES MERCK, SHARP & DOHME-CHIBRET
Application year: 1988
Main classification: A61K9
IPC codes: A61K9, A61K8, A61Q19, A61K47