Title:  Medical uses of in situ formed gels

United States Patent:  6,136,334

Assignee:  MDV Technologies, Inc. (San Diego, CA)

Filed:  June 11, 1999

Balanced pH, hyperosmotic, hypoosmotic, or isoosmotic gels are ideal vehicles for drug delivery. They are especially suited for topical body cavity or injection application of drugs or diagnostic agents; for drug or diagnostic agent delivery to the eye of a mammal; as protective corneal shields; or as ablatable corneal masks useful in laser reprofiling of the cornea. The compositions without the addition of a drug or diagnostic agent are useful as medical devices, for instance, in separating surgically or otherwise injured tissue as a means of preventing adhesions.

SUMMARY OF THE INVENTION

Compositions and a process for drug or diagnostic agent delivery by topical, injection, or body cavity delivery are disclosed. The pharmaceutical compositions in one embodiment of the invention contain pharmacologically active medicaments which are useful in providing treatments to ophthalmic areas of the mammalian body requiring the controlled release application of a medicament or requiring the administration of a diagnostic agent. In addition, the compositions of the invention are useful, with or without the inclusion of a medicament, as injectable compositions for depot drug delivery, as a protective corneal shield, as a second skin for application to wounds, as an ablatable corneal mask in a laser keratectomy process or, as medical devices, for instance, in the separation of organs, injured in surgical procedures or otherwise, in order to prevent the formation of undesirable adhesions as part of the healing process.

The compositions of the invention provide a physiologically acceptable vehicle having a buffered pH and hypoosmotic, hyperosmotic, or isoosmotic characteristics. The pH and osmotic pressure is, preferably, made similar to bodily fluids, such as lacrimal tears. The pH and osmotic pressure of lacrimal tears is about pH 7.4 and 290 mOsm/kg. In addition, the pharmaceutical compositions are, optionally, sterilized so as to insure that the pharmaceutical compositions of the invention do not provide a source of infection.

Polyphase systems are also useful and may contain non-aqueous solutes, non-aqueous solvents, and other non-aqueous additives. Homogeneous, polyphase systems can contain such additives as water insoluble high molecular weight fatty acids and alcohols, fixed oils, volatile oils and waxes, mono-, di-, and triglycerides, and synthetic, water insoluble polymers without altering the functionality of the system.

The compositions of the invention in a preferred embodiment comprise aqueous mixtures of a film forming, water soluble polymer and an ionic polysaccharide, optionally containing a latent counter-ion to gel the polysaccharide upon release of the counter-ion. Alternatively, the compositions of the invention can comprise a two part aqueous system, one of which contains the ionic polysaccharide and film forming polymer and the other part containing an aqueous solution of a counter-ion.

The counter-ion can be provided in latent form by microencapsulation in a heat sensitive medium, for instance, the walls of the microcapsule can be made of mono-, di-, or tri-glycerides or other natural or synthetic heat sensitive polymer medium. Alternatively, ion exchange resins can be incorporated in the compositions of the invention so as to release the desired counter-ion upon contact with an environment opposite in pH to the pH of the ion exchange resin. The aqueous mixture can be delivered to the ophthalmic area of the mammalian body requiring treatment as a low viscosity liquid at ambient temperatures. Activation of the latent form of the counter-ion gels the aqueous mixture in situ. The two part system can be separately applied to gel the mixture in situ. Because the compositions of the invention are low viscosity liquids at ambient temperatures, they easily pass to various ophthalmic areas insuring maximum contact between exposed tissue and the compositions of the invention. The gel compositions of the invention can be either peeled away or allowed to be absorbed over time. The gels are gradually weakened upon exposure to mammalian body pH conditions.

The useful film forming polymers are, preferably, water soluble polymers such as those which have been used in ophthalmic applications. The hydroxyalkyl cellulosics and methyl celluloses, sodium hyaluronate, and polyvinyl alcohol are representative polymers which have been found useful in ophthalmic applications.

The useful ionic polysaccharides are natural polymers such as chitosan, gellan gum or alginates. Aqueous solutions of alginate ionic polysaccharides form gels upon contact with aqueous solutions of counter-ions such as calcium, strontium, aluminum, etc. Aqueous solutions of chitosan form gels upon contact with a metal tripolyphosphate counter-ion. The discovery forming the basis of this application is that when ionic polysaccharides are present in aqueous solutions in admixture with film forming polymers and a counter-ion, that such mixtures form useful gels. The osmolality of which can be calculated by assuming that the film forming polymer, if water soluble, does not contribute to the osmolality in the gel state.

Claim 1 of 8 Claims

The embodiments of the invention in which an exclusive property or privilege is claimed are defined as:

1. An aqueous medical device or vehicle useful for drug delivery, a vehicle for the application of a diagnostic agent, a composition for the prevention of post/operative adhesions, a protective corneal shield, or an ablatable corneal shield, said composition characterized as capable of being gelled in situ to produce an hyperosmotic, hypoosmotic, or isoosmotic gel having a buffered pH, said composition comprising at least one ionic polysaccharide, and at least one film forming agent.

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