Title:  Bioadhesive composition

United States Patent:  6,824,792

Issued:  November 30, 2004

Inventors:  Foreman; Paul B. (Somerville, NJ); Richardson; Paul (Plainsboro, NJ); Tsai; John (Belle Mead, NJ); Remon; Jean Paul (Melle, BE); Voorspoels; Jody (Reningelst, BE); Ameye; Dieter (Waregem, BE); Callens; Catherine (Ploegsteert, BE)

Assignee:  Universiteit Gent (Ghent, BE); National Starch and Chemical Investment Holding Corporation (New Castle, DE)

Appl. No.:  907413

Filed:  July 17, 2001

Abstract

This invention relates to a method of producing a bioadhesive composition comprising the steps of preparing a solution of a solvent and a polymer mixture wherein the polymer mixture comprises at least one natural or synthetic polycarboxylated polymer and at least one polysaccharide; drying the solution to form a solid; and heat treating the solid to effect cross-linking and to form the bioadhesive composition.

Description of the Invention

FIELD OF THE INVENTION

This invention relates to a method for the preparation and use of a bioadhesive composition.

BACKGROUND OF THE INVENTION

Carboxylated polymers, such as poly(acrylic) acid, are known to be effective as bioadhesive compositions, but their use is limited owing to problems associated with mucosa irritation. To overcome these problems, it is known to blend these polymers with other materials such as starch (as described in U.S. Pat. No. 5,643,603 (Janssen Pharmaceuticals)).

Known bioadhesive compositions are described in WO 98/22097 (Bio Advances); EP 410,696 (E. R. Squibb); U.S. Pat. No. 5,643,603 (Janssen Pharmaceuticals); and U.S. Pat. No. 4,915,948 (Warner-Lambert).

WO 98/22097 refers to compositions of poly(acrylic) acid and a polar polymer or monomer produced under conditions that ensure hydrogen bonding interactions, rather than cross-linking, occur.

EP 410,696 discloses a mucoadhesive delivery system comprising poly(acrylic) acid crosslinked with 1 percent to 20 percent by weight of a polyhydroxy compound and a therapeutically effective amount of a drug. This invention is concerned with the use of low molecular weight polyhydroxy compounds.

U.S. Pat. No. 5,643,603 describes a bioadhesive carrier composition which is a tablet formulated from pregelatinized starch, synthetic polymer such as poly(acrylic) acid and a drug. The pregelatinized starch is used as a substitute adhesive allowing for lower loading of poly(acrylic) acid to reduce corresponding irritation effects.

U.S. Pat. No. 4,915,948 refers to a tablet with bioadhesive properties prepared from a blend of xanthan gum and/or a pectin combined with a solid polyol. The blend is prepared without any form of heating.

Prior art methods of crosslinking polycarboxylated polymers with polysaccharides include the method described in U.S. Pat. No. 5,895,804 (National Starch and Chemical) wherein polysaccharide and polycarboxylated polymer are combined under conditions effective to induce crosslinking of the polycarboxylated polymer.

None of the above patents or references provide a method of preparing bioadhesive compositions having the high loading of poly(acrylic) acid and corresponding adhesion and low irritation properties described in this invention.

SUMMARY OF THE INVENTION

The present invention relates to a method of producing a bioadhesive composition which comprises the steps of preparing a solution of at least one solvent and a polymer mixture wherein the polymer mixture comprises from about 10 percent by weight to about 90 percent by weight of at least one natural or synthetic polycarboxylated polymer and about 10 percent by weight to about 90 percent by weight of at least one polysaccharide; drying the solution to form a solid; and heat treating the solid at a temperature from about 60^oC. to about 200^oC. to effect cross-linking and to form the bioadhesive composition.

Any suitable aqueous or organic solvent may be used in this invention. The preferred solvent is water.

Solid, as used herein, is intended to mean a material having less than about 20 percent by weight of solvent present, and includes powders.

Solution, as used herein, is intended to mean a partial or total solubilization.

Neutralization, as used herein, may be partial or total. Such neutralization may be carried out by, but is not limited to, the use of ammonia, or any metal cations of the Group I or Group II elements of the Periodic Table.

The drying and heat treating steps may be carried out together as a one step process or individually as a two step process.

The chemistry of the natural or synthetic polycarboxylated polymer may be selected by one skilled in the art to control the degree and location of ester crosslinking.

The bioadhesive compositions produced by the method of this invention do not contain residual monomer or chemical residue, and therefore do not require a post-washing step. As the natural or synthetic polycarboxylated polymer is cross-linked to the polysaccharide backbone higher levels of natural or synthetic polycarboxylated polymer, such as poly(acrylic) acid, may be incorporated into the composition to provide good adhesion properties and low mucosa irritation.

By bioadhesive composition is meant a component that provides bioadhesive properties to a bioadhesive system in which it is included rather than, for instance, an excipient in a bioadhesive system. Bioadhesive properties mean that adhesive properties are developed on contact with animal or human mucosa, skin or body tissue or vegetable or plant tissues wherein some water or an aqueous solution is present. Typical, but non-limiting, examples of types of bioadhesives include intestinal, nasal, buccal, sub-lingual, vaginal and ocular bioadhesives. Bioadhesion compositions may be neutralized by known means.

Bioadhesion, as used herein, is intended to mean the ability of a material (synthetic or biological) to adhere to biological tissue. Bioadhesion stages can be summarized as follows. First an intimate contact must exist between the bioadhesive and the receptor tissue. Such contact results either from a good wetting of the bioadhesion surface or from the swelling of the bioadhesive. When contact is established, the penetration of the bioadhesive into the crevice of the tissue surface then takes place, or there is interpenetration of bioadhesive chains with those of the mucus, and there is formation of weak chemical bonds between entangled chains. A general description of bioadhesion may be found in the publication Bioadhesive Drug Delivery Systems, 1999, pp. 1-10, Published by Marcel Dekker.

Controlled release, as used herein, is intended to mean a method and composition for making an active ingredient available to the biological system of a host. Controlled-release includes the use of instantaneous release, delayed release, and sustained release. "Instantaneous release" refers to immediate release to the biosystem of the host. "Delayed release" means the active ingredient is not made available to the host until some time delay after administration. "Sustained Release" generally refers to release of active ingredient whereby the level of active ingredient available to the host is maintained at some level over a period of time. The method of effecting each type of release can be varied. For example, the active-ingredient can be associated physically and/or chemically with a surfactant, a chelating agent, etc. Alternatively, the active ingredient can be masked by a coating, a laminate, etc. Regardless of the method of providing the desired release pattern, the present invention contemplates delivery of a controlled-release system that utilizes one or more of the "release" methods and compositions. Moreover, the present invention can be an element of the release method and/or composition, especially with respect to sustained release systems.

The bioadhesive composition of the present invention may take up and controllably release active components such as drugs. Active components may be added using any of the known methods described in the prior art, and such addition may be carried out during and/or after the production of the bioadhesive composition. Typical active components may include, but are not limited to, a therapeutic substance or a pharmaceutically active agent such as a drug, a non-therapeutic substance such as a cosmetic substance, a local or general anesthetic or pain killer, or an opiate, a vaccine, an antigen, a microorganism, a sterilizing substance, a contraceptive composition, a protein or peptide such as insulin, an insecticide, a herbicide, a hormone such as a growth hormone or a seed germination hormone, a steroid, a toxin, or a marker substance. A non-limiting list of possible active components includes hydrochlorothiazide, acetazolamide, acetylsalicyclic acid, allopurinol, alprenolol, amiloride, antiarrhythmics, antibiotics, antidiabetics, antiepileptics, anticoagulants, antimycotics, atenolol, bendroflumethiazide, benzbromarone, benzthiazide, betamethasone, bronchodilators, buphenine, bupranolol, chemotherapeutics, chlordiazepoxide, chlorquine, chloro thiazide, chlorpromazine, chlortalidone, clenbuterol, clomipramine, clonidine, co-dergocrine, cortisone, dexamethasone, dextropropoxyphene, diazepam, diazoxide, diclofenac, diclofenamide, digitalisglycoside, dihydralazine, dihydroergotamine, diltiazem, iron salt, ergotamine, ethacrynic acid, ethinylestradiol, ethoxzolamide, fenoterol, fludrocortisone, fluphenazine, fluorosemide, gallopamil, guanethidine, hormones, hydrochlorothiazide, hydrocortisone, hydroflumethiazide, immunosuppresives, ibuprofen, imipramine, indomethacine, coronartherapeutics, levodopa, lithium salt, magnesium salt, medroxyprogesteron acetate, manadione, methaqualone, 8-methoxypsoralen, methylclothiazide, methyidopa, methylprednisolone, methyltestosterone, methylthiouracil, methylxanthine, metipranolol, molsidomine, morphine, naproxen, nicergline, nifedipine, norfenefrine, oxyphenbutazone, papaverine, parmathasone, pentobarbital, perphenazine, phenobarbital, phenylbutazone, phytomenadione, pirenzepine, polythiazide, prazosine, prednisolone, prednisone, probenecid, propranolol, propylthiouracil, rescinnamine, reserpine, secbutabarbital, secobarbital, spironolactone, sulfasalazine, sulfonamide, testosterone, thioridazine, triamcinolon, triamteren, trichloromethiazide, trifluoperazine, trifluopromazine, tuberculostatic, verapamil, virustatics, zytostatics, bromocriptine, bromopride, carbidopa, carbocromen, quinine, chlorprothixene, cimetidine, clofibrat, cyclizine, desipramine, disulfiram, domperidone, doxepine, fenbufen, flufenamine acid, flunarizine, gemfibrocil, haloperidol, ketoprofen, labetalol, lorazepam, mefenamine acid, melperone, metoclopramide, nortriptyline, noscapine, oxprenolol, oxymetholone, pentazocine, pethidine, stanozolol, sulindac, sulpiride, tiotixen.

The term "bioadhesive system" as used herein includes any system or product comprising the bioadhesive composition of this invention.

DETAILED DESCRIPTION OF THE INVENTION

This invention provides compositions having improved bioadhesion properties, where such compositions are prepared from a solution of a natural or synthetic polycarboxylated polymer and a polysaccharide molecule by means of drying the solution to form a solid and heat treating the solid to induce cross-linking.

The bioadhesive compositions produced by the method of this invention do not contain residual monomer or chemical residue, and therefore do not require a post-washing step. As natural or synthetic polycarboxylated polymer is cross-linked to the polysaccharide backbone higher levels of the natural or synthetic polycarboxylated polymer, such as poly(acrylic) acid, may be incorporated into the composition to provide good adhesion properties and low mucosa irritation properties. The bioadhesive compositions may be neutralized.

Preparation of the bioadhesive composition of this invention may be accomplished by preparing a solution by means of charging at least one solvent, preferably water, and a polymer mixture comprising about 10 percent by weight to about 90 percent by weight of polysaccharide and about 10 percent by weight to about 90 percent by weight of natural or synthetic polycarboxylated polymer into a reaction vessel. In order to partially or totally solubilize the mixture, the solution may be heated and stirred for a short period.

The mixture is then dried by conventional means, including, but not limited to, spray drying, freeze drying, air drying, drum drying and extrusion, to provide a solid. The solid produced during the drying stage preferably has a moisture content of less than about 20 percent by weight. The resultant solid is then heat treated at a temperature of about 60^oC. to about 200^oC., preferably from about 80^oC. to about 120^oC., by a suitable method to induce cross-linking. Suitable methods of heat treatment include, but are not limited to, oven heat treatment, drum drying, extrusion, fluidized bed and IR radiation. The time required to complete cross-linking is determined by the means of heating and by the composition of the solid. For those skilled in the art, comparable cross-linking may be achieved by lowering the heat treatment temperature and increasing heat treatment time and visa versa. As determined by one skilled in the art, the overall time may vary from about 1 second to 6 hours dependent upon the degree of cross-linking required. Less heat treatment is generally required for mixtures containing higher levels of natural or synthetic polycarboxylated polymer. The drying and heat treating process may be carried out in one step or two steps.

The natural or synthetic polycarboxylated polymers of this invention may be modified or unmodified and have a weight average molecular weight of at least 1,000 Daltons. Such modifications may include, but are not limited to cross-linking, neutralization, hydrolysis, enzyme treatment and partial esterification.

Exemplary synthetic polycarboxylated polymers which may be used in the present invention include without limitation poly(acrylic acid) and carboxylic-acid-functionalized polyesters. Also included are polymers containing carboxyl groups and prepared from monomers such as, vinyl acetate (VA), (meth)acrylic acid (M)AA, the C₁ to C₈ alkyl esters of (meth)acrylic acid, maleic anhydride (MAnh), maleic acid, itaconic acid (IA), crotonic acid (CA), and beta-carboxy ethyl acrylate (BCEA). (Meth)acrylic is used herein to denote both acrylic and methacrylic acids and esters thereof. These examples are not limiting and the polysaccharides according to the present invention may be used in combination with virtually any natural or synthetic polycarboxylated polymer.

Natural polycarboxylated polymers include, but are not limited to xanthan, low methoxyl pectin, alginate, hyaluronic acid, polyaspartic acid, polyglutamic acid and pectic acid. The term "natural polycarboxylated polymers" also encompasses modified natural polycarboxylated polymers including, but not limited to, carboxymethylated starch, oxidized guar, oxidized starch and carboxymethylcellulose.

Typical synthetic polycarboxylated polymers of this invention include acrylic acid polymers crosslinked with allyl ethers of sucrose, pentaerythritol or divinyl glycol. Such polymers are available from B F Goodrich Specialty Chemicals, Cleveland, Ohio under the trade names CARBOPOL.RTM. and NOVEON.RTM.. Particularly suitable are the pharmaceutical grades CARBOPOL.RTM. 971P, CARBOPOL.RTM. 934P and CARBOPOL.RTM. 974P.

The amount of natural or synthetic polycarboxylated polymer may vary from about 10 percent to about 90 percent, preferably from about 25 percent to about 83 percent, by weight of the final bioadhesive composition of this invention.

The polysaccharides of the present invention are derived from natural products, including plant, animal and microbial sources. Examples of polysaccharides include starch, cellulose and gums such as galactomannans. Polysaccharide starches include maize or corn, waxy maize, potato, cassava, tapioca and wheat starch. Other starches include varieties of rice, waxy rice, pea, sago, oat, barley, rye, amaranth, sweet potato, and hybrid starches available from conventional plant breeding, e.g., hybrid high amylose starches having amylose content of 40 percent or more, such as high amylose corn starch. Also useful are genetically engineered starches such as high amylose potato and waxy potato starches.

The polysaccharides may be modified or derivatized, such as by etherification, esterification, acid hydrolysis, dextrinization, crosslinking, pregelatinization or enzyme treatment (e.g., with alpha-amylase, beta-amylase, pullulanase, isoamylase, or glucoamylase).

The preferred polysaccharide of the present invention has a weight average molecular weight of at least 10,000 Daltons.

Other materials known in the art may be added to the mixture of polysaccharide and the natural or synthetic polycarboxylated polymer as desired to aid in the efficiency of the cross-linking.

Claim 1 of 21 Claims

What is claimed is:

1. A method of producing a bioadhesive composition comprising preparing a solution of at least one solvent and a polymer mixture wherein the polymer mixture comprises at least one natural or synthetic polycarboxylated polymer and at least one polysaccharide having a molecular weight of at least 10,000 Daltons; drying the solution to form a solid; and heat treating the solid at a temperature and for a time sufficient to effect cross-linking and form a bioadhesive composition.

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