Title:  Body cavity drug delivery with thermo-irreversible polyoxyalkylene and ionic polysaccharide gels

United States Patent:  6,346,272

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

Filed:  August 7, 1997

Balanced pH, thermo-irreversible gels are ideal vehicles for drug delivery to a body cavity of a mammal. The gels contain a mixture of a polyoxyalkylene block copolymer or polyether together with an ionic polysaccharide which is thermo-irreversibly gelled in the presence of a counter-ion.

SUMMARY OF THE INVENTION

Compositions and a process are disclosed for pharmaceutical compositions containing pharmacologically active medicaments useful in providing treatments to various body cavities of the mammalian body requiring pharmacological treatment. The pharmaceutical compositions of the invention provide a physiologically acceptable media having a buffered pH and an osmotically balanced vehicle so as to, preferably, provide an isotonic mixture which is iso-osmotic with body fluids and has a similar pH to body fluids, such as blood plasma, lacrimal tears, and the extracellular fluid of exposed tissue, such as found in the area of third degree burn tissue. The pH and osmotic pressure of such bodily fluids is about pH 7.4 and 290 mOsm/kg. In addition, the pharmaceutical compositions are, optionally, sterilized.

The compositions of the invention in one embodiment comprise aqueous mixtures of a polyoxyalkylene polymer, an ionic polysaccharide, and, optionally, a latent counter-ion useful to gel the polysaccharide upon release of the counter-ion. The counter-ion can be microencapsulated 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 body cavities of a mammal requiring treatment as a low viscosity liquid at ambient temperatures which, upon contact with the mammalian body, forms a semi-solid gel having a very high viscosity. Alternatively, the counter-ion, instead of being present in a latent form, can be separately applied in an aqueous solution, for instance, by aerosol or non-aerosol spray application to the semi-solid gel formed by the polyoxyalkylene polymer upon contact with the mammalian body. Because the preferred pharmaceutical compositions of the invention are low viscosity liquids at ambient temperatures, they insure maximum contact between exposed tissue and the pharmaceutical composition of the invention. The pharmaceutical 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 conditions.

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.

A wide variety of polyoxyalkylene polymers are suitable for the preparation of the pharmaceutical compositions of the invention. Generally, it is necessary to adjust the polymer concentration in aqueous solution so as to obtain the desired sol-gel transition temperature in order that the compositions can be provided as low viscosity liquids at ambient temperature, yet form semi-solid gels at mammalian body temperatures. In addition to the concentration of the polymer and the concentration of a water soluble or dispersible pharmacologically active medicament, other suitable excipients must be added so as to provide the desired isotonic, iso-osmotic properties.

The useful polymers which provide the sol-gel characteristics of the pharmaceutical compositions of the invention are, preferably, polyoxyalkylene block copolymers.

The ionic polysaccharides are natural polymers such as chitosan or alginates. Aqueous solutions of these ionic polysaccharides form gels upon contact with aqueous solutions of counter-ions such as calcium, strontium, aluminum, etc., or an aqueous solution of a metal tripolyphosphate.

Claim 1 of 15 Claims

What is claimed is:

1. A method of forming a gel material in situ in contact with at least one biological tissue, in a body cavity, comprising:

preparing a material which comprises an ionic polysaccharide and a polymer, said polymer having polyoxyalkylene blocks comprising a block copolymer of the general formula:

Y[(A)_n --E--H]_x

where A is a polyoxyalkylene moiety having an oxygen/carbon atom ratio of less than 0.5, x is at least 2, Y is derived from water or an organic compound containing x reactive hydrogen atoms, E is a polyoxyethylene moiety constituting at least 60 percent by weight of the polyoxyalkylene block copolymer, n has a value such that the minimum molecular weight of A is between about 500 and about 900, as determined by the hydroxyl number of an intermediate of the general formula:

Y[(A)_n --H]_x

and the average molecular weight of the polyoxyalkylene block copolymer is between about 5000 and about 50,000;

placing said material in contact with at least one biological tissue; and

cross-linking said material in contact with said at lest one biological tissue via, said cross-linking being mediated through a thermal mechanism, a counter-ion mechanism or a combination thereof wherein the cross-linking of said material results in an in situ formation of the gel material.

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