United States Patent:  5,942,243

Assignee:  Polytherapeutics, Inc. (Brdigewater, NJ)

Filed:  May 12, 1998

This invention pertains to mucoadhesive compositions for the delivery of pharmacologically active agents, and to polymeric formulations that allow for a prolonged, sustained release of the active agents. More specically the invention pertains to compositions for the delivery of drugs to mucosal tissue, said composition comprising a drug or a plurality of drugs to be delivered and a thermoplastic graft copolymer, said graft copolymer being the reaction product of a polystyrene macromonomer having an ethylenically unsaturated functional group, and at least one acidic hydrophilic monomer having an ethylenically unsaturated functional group.

Summary of the Invention

The present invention pertains to polymeric mucoadhesive compositions consisting essentially of a graft copolymer comprising a hydrophilic main chain and hydrophobic graft chains for controlled release of biologically active agents. The graft copolymer is a reaction product of

(1) a polystyrene macromonomer having an ethylenically unsaturated functional group, and

(2) at least one hydrophilic acidic monomer having an ethylenically unsaturated functional group.

The graft chains consist essentially of polystyrene, and the main polymer chain of hydrophilic monomeric moieties, some of which have acidic functionality. The weight percent of the polystyrene macromonomer in the graft copolymer is between about 1 and about 20% and the weight percent of the total hydrophilic monomer in the graft copolymer is between 80 and 99%, and wherein at least 10% of said total hydrophilic monomer is acidic, said graft copolymer when fully hydrated having an equilibrium water content of at least 90%.

Compositions containing the copolymers gradually hydrate by sorption of tissue fluids at the application site to yielding a very soft jelly like mass exhibiting adhesion to the mucosal surface. During the period of time the composition is adhered to the mucosal surface it provides sustained release of the pharmacologically active agent, which is absorbed by the mucosal tissue.

Mucoadhesivity of the compositions of this invention is, to a large extent, produced by the hydrophilic acidic monomers of the chain in the polystyrene graft copolymer. The acidic monomers include, but are not limited to, acrylic and methacrylic acids, 2-acrylamido-2-methyl-propane sulfonic acid, 2-sulfoethyl methacrylate, and vinyl phosphonic acid. Other copolymerizable monomers include, but are not limited to N,N-dimethylacrylamide, glyceryl methacrylate, polyethylene glycol monomethacrylate, etc.

The compositions of the present invention may optionally contain other polymeric materials, such as poly(acrylic acid), poly,-(vinyl pyrrolidone), and sodium carboxymethyl cellulose plasticizers, and other pharmaceutically acceptable excipients in amounts that do not cause deleterious effect upon mucoadhesivity of the composition. The dosage forms of the compositions of this invention can be prepared by conventional methods.

The various pharmaceutically active agents that may be used include drugs for systemic treatment of conditions as well as local treatment of conditions. Various treatments include drugs for neurological conditions, cardiovascular conditions, inflammatory diseases, pain relief, anticancer drugs, microbial infections, prevention of conception and the like. Peptide and protein drugs are specialty suitable for delivery via the mucosal route, because they are readily destroyed through the gastrointestinal tract when administered orally.

It is an object of the present invention to provide a controlled release polymeric composition for one or more biologically or pharmacologically active agents. Another object of the present invention is to provide a pharmaceutical dosage form which is water swellable but water insoluble. The dosage form can easily be formulated as user friendly articles such as powders, capsules, suppositories, ointments, films, laminates, tablets, solutions, dispersions and the like. In addition, the dosage form may be in a dehydrated state, or plasticized with a suitable plasticizer, or in a partially hydrated state.

A further object of this invention is to provide a pharmaceutical dosage form which exhibits adhesion to the mucous surfaces of animal tissues, but no local side effects or toxicity. Various mucosal sites in the body, to which the compositions of this invention may be applied, include cul-de-sac of the eye, oral mucosa, nose, rectum, vagina, periodontal pocket, intestines and colon.

Another object of the present invention is to provide a composition which is at once both convenient to formulate with a biologically, active agent and economical to manufacture.

The invention also envisions a method of treatment by application of the controlled release composition to a mucosal tissue. The application of the composition to the mucosa of the gastrointestinal tract may be carried out by swallowing the composition.

Claim 1 of 21 Claims

1. A mucoadhesive hydrophilic drug delivery system comprising:

(A) a drug or a plurality of drugs to be delivered, and

(B) a drug delivery vehicle consisting essentially of a thermoplastic graft copolymer, said graft copolymer being a reaction product of:

(1) a polystyrene macromonomer having an ethylenically unsaturated functional group, and

(2) at least one hydrophilic acidic monomer having an ethylenically unsaturated functional group,

wherein the weight percent of the polystyrene macromonomer in the graft copolymer is between about 1 and about 20%, and the weight percent of the total hydrophilic monomer in the graft copolymer is between 80 and 99%, wherein at least about 10% of said total hydrophilic monomer is acidic, said graft copolymer when fully hydrated having an equilibrium water content of at least 90%,

said graft copolymer being present in said drug delivery system in an amount sufficient to cause said drug delivery system to form a water swollen but insoluble jelly like mass upon contact with the biological environment.

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