WO2008002471A2 - Erosion-stabilized bioadhesive polymers functionalized or blended with catechol and derivatives thereof - Google Patents

Abstract

Polymers with improved bioadhesive properties and methods for improving bioadhesion of polymers have been developed. Such bioadhesive polymers can be stabilized against erosion, particularly in the gastrointestinal tract, by incorporating one or more additives selected from (1) polyanhydrides, such as those having a molecular weight average in excess of 20,000, (2) acidic components, (3) metal compounds, (4) stabilizing polymers, and (5) hydrophobic components. By stabilizing bioadhesive polymers against erosion, residence time at tissue surfaces can be further increased. The stabilized polymers are also useful to maintain the drug release rate-controlling properties for a prolonged period of time.

Description

EROSION-STABILIZED BIOADHESIVE POLYMERS FUNCTIONALIZED OR BLENDED WITH CATECHOL AND DERIVATIVES THEREOF

RELATED APPLICATION This application claims the benefit of U.S. Provisional Application No.

60/816,095, filed June 23, 2006, the teachings of which are incorporated herein by reference in their entirety.

BACKGROUND OF THE INVENTION Polymers that adhere well to biological surfaces ("bioadhesives") under a variety of conditions are useful in several branches of medicine. One important use of bioadhesive polymers is in drug delivery systems, particularly oral drug delivery. Such bioadhesive polymers, for example, certain polyanhydrides, are useful for slowing the passage of drug-containing materials through the gastrointestinal tract. U.S. Patent No. 6,197,346 to Mathiowitz et al. describes using bioadhesive polymers that have high concentrations of carboxylic acid groups, such as polyanhydrides, to form microcapsules or as a coating on microcapsules that contain therapeutic or diagnostic agents.

Polyanhydrides are bioadhesive in vivo, for example in the gastrointestinal (GI) tract, and can significantly delay the passage of drug-containing particles through the GI tract, thus allowing more time for absorption of drug by the intestine. The mechanism causing the anhydride polymers or oligomers to be bioadhesive is believed to be a combination of the polymer's hydrophobic backbone coupled with the presence of carboxyl groups at the polymer ends. Interaction of charged carboxylate groups with tissue has been demonstrated with other bioadhesives. In particular, pharmaceutical industry materials considered to be bioadhesive typically are hydrophilic polymers containing carboxylic acid groups, and often containing hydroxyl groups as well. CARBOPOL™, a high molecular weight poly(acrylic acid) available from B. F. Goodrich, Co., is an example of a hydrophilic bioadhesive material. Other classes of bioadhesive polymers are characterized by having moderate to high densities of carboxyl substitution. The relatively hydrophobic anhydride polymers frequently demonstrate superior bioadhesive properties when compared with the hydrophilic carboxylate polymers. (See Drug Delivery Report, Spring/Summer 2006, to Nangia.) For example, hydrophilic bioadhesive polymers tend to lose their effectiveness when wet, and especially when wetting is prolonged. Their reduced adhesion to surfaces in vivo and in vitro tends to diminish their effectiveness in enhancing drug delivery.

Natural adhesives for underwater attachment of mussels, other bivalves and algae to rocks and other substrates are known (see U.S. Patent No. 5,574,134 to Waite, U.S. Patent No. 5,015,677 to Benedict et al., and U.S. Patent No. 5,520,727 to Vreeland et al.). These adhesives are polymers containing poly(hydroxy_^substituted) aromatic groups. In mussels and other bivalves, such polymers include dihydroxy-substituted aromatic groups, such as proteins containing 3,4-dihydroxyphenylalanine (DOPA). In algae, diverse polyhydroxy aromatics such as phloroglucinol and tannins are used. In adhering to an underwater surface, the bivalves secrete a preformed protein that adheres to the substrate thereby linking the bivalve to the substrate. After an initial adherence step, the natural polymers are typically permanently crosslinked by oxidation of adjacent hydroxyl groups.

Extraction of these materials from organisms is not practical for commercial scale production. Attempts to reproduce the adherence have been made, typically using synthetic or genetically engineered polypeptides containing amino acid motifs derived from mussel adhesives, or natural marine materials. The synthetic protein materials have proved to be too expensive, or otherwise inadequate, to sustain commercial applications. For example, U.S. Patent No. 4,908,404 to Benedict et al., describes grafting 3,4-dihydroxyphenylalanine (DOPA) to polyamines. However, the adhesiveness of these cationic water-soluble compounds is not much better than that of the parent polyamines, such as poly-L-lysine. Thus, it is desirable to develop a commercially feasible adhesive polymer that maintains its adhesion when wet over prolonged duration.

BRIEF SUMMARY OF THE INVENTION Polymers and materials with improved and longer lasting bioadhesive properties and methods for improving bioadhesion of polymers have been developed. A compound containing an aromatic group which contains one or more hydroxyl groups is coupled to individual monomers or is grafted onto or blended with a polymer. In one embodiment, the polymer is a biodegradable polymer. In another embodiment, the modified monomers may be polymerized to form any type of polymer, including biodegradable and non-biodegradable polymers. In some embodiments, the polymer is a hydrophobic polymer. In the preferred embodiment, the aromatic compound is catechol or a derivative thereof. In another preferred embodiment, the aromatic compound comprises two or more hydroxyl substituents, methoxy substituents, substituents hydrolyzable to hydroxyl substituents, or a combination thereof, and a primary or secondary amino moiety, where the cumulative amount of the compound (i.e., compound not functionalized to a polymer backbone) that is converted to dopamine when infused into rat striatum is at least 65% less than for an equimolar amount of L-3,4-dihydroxyphenylalanine or where the blood-brain barrier is substantially impermeable to the compound. The polymers may or may not contain reactive functional groups. In the most preferred embodiment, the polymer is a polyanhydride and the aromatic compound is the catechol derivative, DOPA.

These materials display bioadhesive properties superior to conventional bioadhesives used in therapeutic and diagnostic applications. These bioadhesive materials can be used to fabricate new drug delivery or diagnostic systems with increased residence time at tissue surfaces, and consequently increase the bioavailability of a drug or a diagnostic agent. In a preferred embodiment, the bioadhesive material is a coating on a controlled release oral dosage formulation and/or forms a matrix in an oral dosage formulation. Other highly useful embodiments include formulations for delivery to a mucosal surface, for example, vaginal, rectal, nasal, buccal or sublingual, ophthalmic, urethral, or to the pulmonary system, where bioadhesion increases residence times and drug delivery. In another embodiment, the material is used as a delivery vehicle and as the drug, for use in delivering DOPA to an individual in need thereof.

Such bioadhesive polymers can be stabilized against erosion, particularly in the gastrointestinal environment, by incorporating one or more additives that stabilize the polymeric component from erosion, dissolution or both, where, for example, at least 50% by weight of a 1 mm thick film of the bioadhesive material remains after 12 hours in a buffered pH 4.5 or 5 dissolution bath. Typically, the additive is selected from (1) polyanhydrides, (2) acidic components (including precursors thereof), (3) metal compounds, (4) stabilizing polymers, and (5) hydrophobic components. By stabilizing bioadhesive polymers against erosion and/or dissolution, prolonged residence time with close proximity to tissue surfaces can be further achieved. The stabilized polymers are also useful to maintain the drug release rate-controlling properties for a prolonged period of time.

In certain embodiments, the invention provides polymers or materials with improved bioadhesive properties, particularly when the polymers and/or the surfaces are wet. Preferably, the polymers or materials are resistant to erosion and/or dissolution in the gastrointestinal tract, particularly erosion caused by changes in the pH value of the gastrointestinal environment (such as those associated with the presence of absence or food). Erosion and/or dissolution cause a polymer to lose its effectiveness as an adhesive agent and as a drug release rate-controlling agent. In order for a bioadhesive polymer to work effectively in an oral dosage form, it advantageously adheres rapidly, maintains adhesiveness irrespective of the hydrodynamic condition, food and pH changes and does not modify the release of incorporated drug(s). Preferably, the erosion behavior of a polymer for oral use is affected by the aqueous environment and not the pH of the surrounding medium so that its performance remains the same irrespective of the fasted or fed state.

In certain embodiments, the invention provides a method for improving the bioadhesive properties of polymers and compositions thereof.

In certain embodiments, the invention provides a method to stabilize the polymer or material and maintain its performance (bioadhesive and rate controlling) irrespective of pH at various segments of the GI tract (e.g., pH 1-7.4).

In certain embodiments, the invention provides a method to stabilize a catechol grafted polymer with pH dependent solubility, i.e., higher solubility at pH 4.5 and greater. In certain embodiments, the invention provides drug delivery systems with increased residence times in the GI tract, nasal mucosa, pulmonary mucosa, and other mucosal surfaces in a cost-effective manner.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 shows the effects of various acids on the solubility of Spheromer III (poly(butadiene maleic anhydride copolymer)-DOPA) in pH 4.5 buffer.

FIG. 2 shows the effect of metal salts on the solubility of Spheromer III in pH 4.5 buffer. FIG. 3 shows the effect of different levels of poly(fumaric acid-co-sebacic acid)

(poly (FA:SA)) on the solubility of Spheromer III in pH 4.5 buffer.

FIG. 4 shows the effect of different hydrophilic and hydrophobic polymers on the solubility of Spheromer III in pH 4.5 buffer.

FIG. 5 shows the effect of sodium alginate on the solubility of Spheromer HI in pH 4.5 buffer.

FIG. 6 shows the combined effect of ethyl cellulose and citric acid on the solubility of Spheromer III in pH 4.5 buffer.

FIG. 7 shows the effect of various unsaturated acids (propiolic and maleic acids) and saturated acids (butyric and hexanoic acids) on the solubility of Spheromer in in pH 4.5 buffer.

FIGS. 8 A and B show the effect of succinic anhydrides and acetic anhydride, respectively, on the solubility of Spheromer III in pH 4.5 buffer.

FIG. 9 shows the effect of various aliphatic and aromatic dicarboxylic acids on the solubility of Spheromer III in pH 4.5 buffer. FIG. 10 is a bar graph of the tensile work (nJ) required to rupture the bonds formed with Spheromer III alone as compared to Spheromer III combined with the additives described herein.

FIG. 11 shows the dissolution of a Spheromer III coating on placebo tablets, with and without stabilizer. FIG. 12 shows the in vitro dissolution profiles of carbidopa from bioadhesive extended release carbidopa tablets in 0.1 N HCl (pH 1.2) and in pH 4.5 phosphate buffer.

FIG. 13 shows the in vitro dissolution profiles of carbidopa in fed beagle dogs for bioadhesive extended release carbidopa tablets.

DETAILED DESCRIPTION OF THE INVENTION I. Bioadhesives

As generally used herein "bioadhesives" or "bioadhesive materials" refer to the bioadhesive polymers and bioadhesive compositions disclosed herein, including materials that contain one or more additional components in addition to the bioadhesive polymers and bioadhesive compositions of the invention. Bioadhesives also include blends of one or more bioadhesive polymers or blends disclosed herein with one or more other (bioadhesive or non-bioadhesive) polymers or blends. In certain instances, the term "bioadhesive polymers" is used to refer to both compositions where the polymer itself is bioadhesive, as well as compositions where a non- or poorly bioadhesive polymer is combined with a compound that imparts bioadhesive properties to the composition as a whole, as described in detail herein.

As generally used herein "blend" refers to a mixture of two or more polymers or a mixture of one or more polymers with one or more low molecular weight additives containing a catechol functionality. The mixture can be homogeneous or heterogeneous.

As used herein "bioadhesion" generally refers to the ability of a material to adhere to a biological surface for an extended period of time. Bioadhesion requires a contact between the bioadhesive material and the receptor surface, such that the bioadhesive material penetrates into the crevice of the surface (e.g. tissue and/or mucus). Thus the amount of bioadhesive force is affected by both the nature of the bioadhesive material, such as a polymer, and the nature of the surrounding medium. Adhesion of materials to tissues may be achieved by (i) physical or mechanical bonds and/or (ii) secondary chemical bonds (e.g., ionic). Physical or mechanical bonds can result from deposition and inclusion of the adhesive material in the crevices of the mucus or the folds of the mucosa. Secondary chemical bonds, contributing to bioadhesive properties, consist of dispersive interactions (e.g., Van der Waals interactions) and stronger specific interactions, which include hydrogen bonds and ionic bonds. The hydrophilic functional groups typically responsible for forming hydrogen bonds are the hydroxyl (-OH) and the carboxylic groups (-COOH).

Bioadhesive forces are measured in units of N/m², by methods defined in U.S. Patent No. 6,197,346 to Mathiowitz et al., which is herein incorporated by reference. Bioadhesive forces, especially those exhibited by tablets, can also be measured using a Texture Analyser, such as the TA-TX2 Texture Analyser (Stable Micro Systems, Haslemer, Surrey, UK). As described in Michael J. Tobyn et al, Eur. J. Pharm.

Biopharm., 41(4):235-241 (1995), a mucoadhesive tablet is attached to a probe on the texture analyzer and lowered until it contacts pig gastric tissue, which is attached to a tissue holder and exposed to liquid at 37 ⁰C to simulate gastric medium. A force is applied for a set period of time and then the probe is lifted at a set rate. Area under the force/distance curve calculations are used to determine the work of adhesion. (See also Michael J. Tobyn et al., Eur. J. Pharm. Biopharm., 42(1):56-61 (1996) and David S. Jones, et al., International J. Pharmaceutics, 151: 223-233 (1997)).

As used herein "catechol" refers to a compound with a molecular formula of C₆Hβθ2 and the following structure:

Catechol.

Bioadhesive materials may contain a polymer with a catechol functionality or a polymer blended with catechol or a catechol derivative. For materials that contain polymers that have been modified with a catechol functionality, the molecular weight of the bioadhesive materials and percent substitution of the polymer with the aromatic compound may vary greatly. The degree of substitution varies based on the desired adhesive strength, it may be as low as 10%, 20%, 25%, 50%, or up to 100% substitution. On average at least 50% of the monomers in the polymeric backbone are substituted with at least one aromatic group. Preferably, 75-95% of the monomers in the backbone are substituted with at least one aromatic group or a side chain containing an aromatic group. In the preferred embodiment, on average 100% of the monomers in the polymeric backbone are substituted with at least one aromatic group or a side chain containing an aromatic group. The resulting bioadhesive material is a polymer with a molecular weight ranging from about 1 to 2,000 kDa, preferably 1 to 1 ,000 kDa, more preferably 10 to 1,000 kDa, most preferably 100 to 1,000 kDa, such as 200 to 1,000 kDa or 300 to 800 kDa. For materials in which a polymer has been blended with catechol or a catechol derivative, the ratio of polymer to catechol can be varied in order to vary the bioadhesive properties of the material. The catechol or catechol derivative can be present in an amount from about 0.5% to about 95% by weight of the polymer, typically about 10% to about 75%, preferably about 10% to about 50% and more preferably about 10% to about 30%. a. Polymers

The polymer that is derivatized or blended with catechol or a catechol derivative may be any non-biodegradable or biodegradable polymer. The polymers can be homopolymers or copolymers. The polymers that are copolymers can be block, alternating or random copolymers. The backbone of the bioadhesive polymer is preferably flexible in order to penetrate or interact with mucus and/or epithelial tissue. In the preferred embodiment, the polymer is a hydrophobic polymer. In one embodiment, the polymer is a biodegradable polymer and is used to form an oral dosage formulation.

Examples of biodegradable polymers suitable for use in the invention include synthetic polymers such as poly hydroxy acids, such as polymers of lactic acid and glycolic acid, polyanhydrides, poly(ortho)esters, polyesters, polyurethanes, poly(butyric acid), poly( valeric acid), poly(caprolactone), poly(hydroxybutyrate), poly(lactide-co-glycolide) and poly(lactide-co-caprolactone), and natural polymers such as alginate and other polysaccharides, collagen, chemical derivatives thereof (substitutions, additions of chemical groups, for example, alkyl, alkylene, hydroxylations, oxidations, and other modifications routinely made by those skilled in the art), albumin and other hydrophilic proteins, zein and other prolamines and hydrophobic proteins, copolymers and mixtures thereof. In general, these materials degrade either by enzymatic hydrolysis or exposure to water in vivo, by surface or bulk erosion. The foregoing materials may be used alone, as physical mixtures (blends), or as co-polymers. In one aspect of the invention, a bioadhesive polymer is formed by first coupling a compound to a monomer and then polymerizing the coupled monomer. In this embodiment, the monomers are polymerized to form a polymer, including biodegradable and non-biodegradable polymers. Suitable polymers include, but are not limited to: polyanhydrides, polyamides, polycarbonates, polyalkylenes, polyalkylene oxides such as polyethylene glycol and poloxamers, polyalkylene terepthalates such as poly(ethylene terephthalate), polyvinyl alcohols, polyvinyl ethers, polyvinyl esters, polyethylene, polypropylene, poly(vinyl acetate), poly vinyl chloride, polystyrene, polyvinyl halides, polyvinylpyrrolidone, polyhydroxy acids, polysiloxanes, polyurethanes and copolymers thereof, modified celluloses, alkyl cellulose, hydroxyalkyl celluloses, cellulose ethers, cellulose esters, nitro celluloses, chitosan, chitin, polymers of acrylic and methacrylic esters, methyl cellulose, ethyl cellulose, hydroxypropyl cellulose, hydroxy-propyl methyl cellulose, hydroxybutyl methyl cellulose, cellulose acetate, cellulose propionate, cellulose acetate butyrate, cellulose acetate phthalate, carboxylethyl cellulose, cellulose triacetate, cellulose sulfate sodium salt, and polyacrylates such as poly(methacrylate) poly(methyl methacrylate), ρoly(ethylmethacrylate), poly(butylmethacrylate), poly(isobutylmethacrylate), poly(hexylmethacrylate), poly(isodecylmethacrylate), poly(lauryl methacrylate), poly(phenyl methacrylate), poly(methyl acrylate), poly(isopropyl acrylate), poly(isobutyl acrylate) and poly(octadecyl acrylate). In some embodiments, one can use non-biodegradable polymers, especially hydrophobic polymers. Examples of preferred non-biodegradable polymers include ethylene vinyl acetate, poly(meth)acrylic acid, copolymers of maleic anhydride with other unsaturated polymerizable monomers, poly(butadiene maleic anhydride), polyamides, copolymers and mixtures thereof, and dextran, cellulose and derivatives thereof. Hydrophobic polymers include polyanhydrides, poly(ortho)esters, and polyesters such as polycaprolactone. In the preferred embodiment, the polymer is sufficiently hydrophobic that it is not readily water soluble, for example, the polymer should be soluble up to less than about 1% w/w in water, preferably about 0.1% w/w in water, at room temperature or body temperature. In the most preferred embodiment, the polymer is a polyanhydride, such as a poly(butadiene maleic anhydride) and other copolymers of maleic anhydrides.

Polyanhydrides may be formed from dicarboxylic acids as described in U.S. Patent No. 4,757,128 to Domb et al. Suitable diacids include: aliphatic dicarboxylic acids, aromatic dicarboxylic acids, aromatic-aliphatic dicarboxylic acids, combinations of aromatic, aliphatic and aromatic-aliphatic dicarboxylic acids, aromatic and aliphatic heterocyclic dicarboxylic acids, and aromatic and aliphatic heterocyclic dicarboxylic acids in combination with aliphatic dicarboxylic acids, aromatic-aliphatic dicarboxylic acids, and aromatic dicarboxylic acids of more than one phenyl group. Suitable monomers include sebacic acid (SA), fumaric acid (FA), bis(p- carboxyphenoxy)propane (CPP), isophthalic acid (IPh), and dodecanedioic acid (DD).

A wide range of molecular weights are suitable for the polymer backbone of the bioadhesive composition or for the polymer used in the bioadhesive composition. The molecular weight may be as low as about 200 Da (for oligomers) up to about 2,000 kDa. Preferably the polymer (backbone) has a molecular weight of at least 1,000 Da, more preferably at least 2,000 Da, most preferably the polymer has a molecular weight of up to 20 kDa or up to 200 kDa or greater (e.g., 20 kDa to 1,000 kDa, 20 kDa to 200 kDa). The molecular weight of the polymer may be up to 2,000 kDa. For polymers that are blended with catechol or a catechol derivative, the molecular weight is in the range of 20,000 to 1 ,000,000 Daltons, preferably 20,000 to 200,000 Daltons.

Polymers that are copolymers can be block, alternating or random copolymers, such as the maleic anhydride copolymer disclosed above. Polymers can be crosslinked or uncrosslinked.

The backbone of bioadhesive polymers is advantageously sufficiently flexible to interpenetrate mucus and/or epithelial tissue, preferably both. The range of substitution on the polymer backbone of a bioadhesive polymer varies greatly and depends on the polymer used and the desired bioadhesive strength. For example, a butadiene maleic anhydride copolymer that is 100% substituted with DOPA will have the same number of DOPA molecules per chain length as a 67% substituted ethylene maleic anhydride copolymer. Typically, the polymer backbone has a percent substitution ranging from 1% to 100%, preferably greater than 5%, such as ranging from 5% to 75%.

The polymers and copolymers that form the backbone of the bioadhesive material contain reactive functional groups which interact with the functional groups on the aromatic compound.

Polymers used in blends preferably have functional groups that are not reactive with the compounds included in the compositions. The lack of reactivity can be absolute or can be lack of reactivity under the conditions to which the composition is exposed.

b. Reactive Functional Groups

For the polymers modified with a catechol functionality, it is important that the polymer or monomer that forms the polymeric backbone contains accessible functional groups that readily react with functional groups contained in the aromatic compounds, such as amines and thiols. In a preferred embodiment, the polymer contains amino reactive moieties (i.e., moieties that react with an amine, preferably to form a covalent linkage), such as aldehydes, ketones, carboxylic acid derivatives, anhydrides (e.g. cyclic anhydrides), alkyl halides, acyl azides, isocyanates, isothiocyanates, and succinimidyl esters. A polymer used in a blend (physical mixture) of the invention need not, and preferably does not, contain functional groups to react with a primary amino moiety. c. Sidechains containing aromatic groups with one or more hydroxy! groups

Aromatic groups containing one or more hydroxyl groups are attached to the polymeric backbone. The aromatic groups can be part of a compound that is grafted to the polymer backbone or the aromatic groups may be part of larger sidechains that are grafted to the polymer backbone. In one embodiment, the aromatic group containing one or more hydroxyl groups is catechol or a derivative thereof. Optionally the aromatic compound is a polyhydroxy aromatic compound, such as a trihydroxy aromatic compound (e.g. phloroglucinol and benserazide) or a multihydroxy aromatic compound (e.g. tannin). The aromatic moiety can also be an aromatic moiety that includes two or more (e.g., three or more) hydroxyl substituents, methoxy substituents, substituents hydrolyzable to hydroxyl substituents, or a combination thereof, more typically, hydroxyl substituents or substituents hydrolyzable to hydroxyl substituents. A substituent hydrolyzable to a hydroxyl substituent is a substituent, which when cleaved by water (optionally mediated by an enzyme), that leaves a hydroxyl substituent attached to the phenyl ring. Common examples of such substituents include esters (-O- C(O)-R), carbamates (-O-C(O)-NRR') and carbonates (-O-C(O)-OR).

The catechol derivative also generally contains a reactive group, such as an amino, thiol, or halide group. Suitable sidechains which can be grafted to the polymer backbone include poly(amino acids), peptides, or proteins, having a molecular weight of 20 kDa or less, where at least 10% of the amino acids contain catechol residues; preferably, greater than 50%, more preferably 75%, and most preferably 100% of the amino acids contain catechol residues. Common amino acids with catechol-like residues are phenylalanine, tyrosine and tryptophan. Additionally, synthetic amino acids that contain catechol residues may be prepared.

A preferred catechol derivative is 3,4-dihydroxyphenylalanine (DOPA), which contains a primary amine. L-DOPA is known to be pharmaceutically active and is used as a treatment for Parkinson's disease. Tyrosine, the immediate precursor of DOPA, which differs only by the absence of one hydroxyl group in the aromatic ring, can also be used. Tyrosine is capable of conversion (e.g. by hydroxylation) to DOPA.

3,4-dihydroxyphenylalanine (DOPA) In a preferred embodiment, the aromatic group is an amine-containing aromatic compound, such as an amine-containing catechol derivative. Other suitable compounds for forming polymers or blends include 3,4-dimethoxyphenyl-2-hydrazino-2-methyl propanoic acid, 2-aminocarbonyl-amino-3-(3,4-dimethoxyphenyl)-2-methylpropanoic acid, 2-amino-3-(3,4-dimethoxyphenyl)-2-methyl hydrochloride, 2-amino-3-(3,4- dimethoxyphenyl)-2-methyl propane nitrile, methyl-DOPA, 3-O-methylcarbidopa and 4-O-methylcarbidopa, and enantiomers and mixtures thereof.

In another preferred embodiment, the aromatic group is a compound comprising: a) an aromatic moiety comprising two or more hydroxyl substituents, methoxy substituents, substituents hydrolyzable to hydroxyl substituents, or a combination thereof, and b) a primary or secondary amino moiety, where the cumulative amount of the compound (i.e., compound not functionalized to a polymer backbone) that is converted to dopamine when infused into rat striatum is at least 65% less than for an equimolar amount of L-3,4- dihydroxyphenylalanine or where the blood-brain barrier is substantially impermeable to the compound. In certain embodiments, the compounds used to form residues are selected such that the cumulative amount of the compound converted to dopamine when infused into rat striatum is at least 70%, 75%, 80%, 85%, 90%, 95% or 100%

(i.e., the compound is not converted to dopamine) less than an equimolar amount of L- 3,4-dihydroxyphenylalanine. The cumulative amount of a compound converted to dopamine when infused into rat striatum can be measured according to the method described in Brannan, et al., Brain Res. 718:165-168 (1996), the contents of which are incorporated herein by reference. Briefly, a microdialysis probe is lowered into the corpus striatum of anesthetized rats. The probe generally has a tip length of 3 mm and is perfused with an artificial cerebrospinal fluid solution. Concentrations of dopamine in the microdialysis samples are monitored at regular intervals by HPLC or another suitable analytical method. Once the dopamine concentration reaches a basal level, a 1 mM solution of a sidechain residue compound is perfused into the striatum via the probe, with continued monitoring of the dopamine concentration. Separately or in addition to selection of aromatic compounds based upon their ability to be converted into dopamine, aromatic compounds can be selected such that the blood-brain barrier is substantially impermeable to these compounds when present as free molecules (i.e., not covalently attached to a polymer). Typically, less than 10%, such as less than 5%, 4%, 3%, 2% or 1%, of a substantially impermeable compound is able to cross the blood-brain barrier. A suitable assay for determining permeability of the blood-brain barrier to a compound is described by Gomes and Soeares-da-Silva in Brain Res. 829:143-150 (1999), the contents of which are incorporated herein by reference. Briefly, the assay measures the uptake of a compound by immortalized rat capillary cerebral endothelial cells (RBE 4), which represent the blood-brain barrier. The endothelial cells are seeded in collagen-treated 24-well plastic culture clusters (16 mm internal diameter) at a density of 40,000 cells per well (20,000 cells/cm²). For 24 hours prior to an experiment, the cell medium is free of fetal bovine serum and basic fibroblast growth factor. Uptake experiments are typically performed 6 days after seeding. On the day of the experiment, the growth medium is aspirated and the cells are washed with Hanks' medium at 4 ⁰C, followed by incubating the cells in Hanks' medium at 37 ⁰C for 30 minutes. The cells are incubated for 6 minutes with 2 mL of 1 μM substrate (e.g., sidechain residue compound) in Hanks' medium. Uptake is terminated by rapid removal of uptake solution with a vacuum pump connected to a Pasteur pipette, followed by a rapid wash with cold Hanks' medium and the addition of 250 μL of 0.2 mM perchloric acid. The acidified samples are stored under appropriate conditions until the substrate concentration is measured (e.g., via HPLC).

In another embodiment, the aromatic compounds include all sidechain residue compounds having the moieties discussed above, except L-DOPA and/or DL-DOPA. Typically, the aromatic moiety is a monocyclic aromatic moiety that includes two or more hydroxyl substituents, methoxy substituents, substituents hydrolyzable to hydroxyl substituents, or a combination thereof, more typically, hydroxyl substituents or substituents hydrolyzable to hydroxyl substituents. Preferably, the aromatic moiety is a phenyl moiety that includes two or more (e.g., three or more) hydroxyl substituents, methoxy substituents, substituents hydrolyzable to hydroxyl substituents, or a combination thereof, more typically, hydroxyl substituents or substituents hydrolyzable to hydroxyl substituents. An exemplary aromatic moiety is catechol. The aromatic moiety can include other substituents in addition to those indicated, but typically does not include additional substituents.

A substituent hydrolyzable to a hydroxyl substituent is a substituent, which when cleaved by water (optionally mediated by an enzyme), that leaves a hydroxyl substituent attached to the phenyl ring. Common examples of such substituents include esters (-O-C(O)-R), carbamates (-O-C(O)-NRR') and carbonates (-O-C(O)-OR).

The primary or secondary amino moiety can be directly attached to a carbon atom or can be part of a hydrazinyl moiety (-NH-NHR).

Suitable compounds for forming residues include D-3,4- dihydroxyphenylalanine (D-DOPA), (D-, L- or a mixture thereof) carbidopa and (D-, L-, or a mixture thereof) benserazide, which have the following structures, respectively:

Other suitable compounds for forming residues include 3,4-dimethoxyphenyl-2- hydrazino-2-methyl propanoic acid, 2-aminocarbonyl-amino-3-(3,4-dimethoxyphenyl)- 2-methylpropanoic acid, 2-amino-3-(3,4-dimethoxyphenyl)-2-methyl hydrochloride, 2- amino-3-(3,4-dimethoxyphenyl)-2-methyl propane nitrile, methyl-DOPA, 3-0- methylcarbidopa and 4-O-methylcarbidopa, including enantiomers and mixtures thereof. d. Blends containing a catechol or a catechol derivative In one embodiment, the catechol or catechol derivative described in the preceding section is blended with a biodegradable or non-biodegradable polymer to form a bioadhesive composition. The polymer is preferably a hydrophobic polymer. Suitable hydrophobic polymers include ethyl cellulose, poly(anhydrides), and polyesters. The preferred catechol derivatives are 3,4-dihydroxyphenylalanine (DOPA), which contains a primary amine, or carbidopa. The catechol derivative can be present in an amount from about 0.5% to about 95% by weight of the polymer. For example, blending polycaprolactone with L-DOPA in a ratio of 2:1 w/w results in a bioadhesive material with an adhesive force of 491 mN/cm² compared to 50 mN/cm² for polycaprolactone alone. II. Method of Forming Bioadhesives

Three general methods are used to form the bioadhesive materials. In one embodiment, a compound containing an aromatic group which contains one or more hydroxyl groups is grafted onto a polymer. In this embodiment, the polymeric backbone is a biodegradable polymer. In a second embodiment, the aromatic compound may be coupled to individual monomers and then polymerized. In a third embodiment, the polymer is blended with a compound containing an aromatic group which contains one or more hydroxyl groups. Any chemistry which allows for the conjugation of a polymer or monomer to an aromatic compound containing one or more hydroxyl groups may be used. For example, if the aromatic compound contains an amino group and the monomer or polymer contains an amino reactive group, this modification to the polymer or monomer is performed through a nucleophilic addition or a nucleophilic substitution reaction, such as a Michael-type addition reaction, between the amino group in the aromatic compound and the polymer or monomer. Additionally, other procedures can be used in the coupling reaction. For example, carbodiimide and mixed anhydride based procedures form stable amide bonds between carboxylic acids or phosphates and amino groups, bifunctional aldehydes react with primary amino groups, bifunctional active esters react with primary amino groups, and divinylsulfone facilitates reactions with amino, thiol, or hydroxy groups. a. Polymer Grafting

The aromatic compounds are grafted onto the polymer using standard techniques to form the bioadhesive polymer. An example of the grafting procedure is schematically depicted in Reaction 1, which depicts a nucleophilic substitution reaction between the amino group in the aromatic compound and the polymer. L-DOPA is grafted to maleic anhydride copolymers by reacting the free amine in L-DOPA with the maleic anhydride bond in the copolymer.

A variety of different polymers can be used as the backbone of the bioadhesive material. Representative polymers include random copolymers (e.g., 1 :1 copolymers) of maleic anhydride with ethylene, vinyl acetate, styrene, or butadiene. The variable portions of the backbone structures are designated as the R groups at the bottom of Reaction 1. In addition, a number of other compounds containing aromatic rings with hydroxy substituents, such as tyrosine or derivatives of catechol, can be used in reaction 1.

Reaction 1

b. Polymer Synthesis

In another embodiment, the polymers are prepared by conjugate addition of a compound containing an aromatic group and an amine functionality to one or more monomers containing an amino reactive group. In the preferred method the monomer is an acrylate or a polymer acrylate. In one example, the monomer is an acrylate or a polymer acrylate. Particular monomers include a diacrylate such as 1,4-butanediol diacrylate; 1,3-propanediol diacrylate; 1,2-ethanediol diacrylate; 1,6-hexanediol diacrylate; 2,5-hexanediol diacrylate; and 1,3-propanediol diacrylate. In the coupling reaction, the monomer and the compound containing an aromatic group are each dissolved in an organic solvent (e.g., tetrahydrofuran (THF), CH₂Cl₂, methanol (MeOH), ethanol (EtOH), CHCI₃, hexanes, toluene, benzene, CCU, glyme, diethyl ether, etc.) to form two solutions. The resulting solutions are combined, and the reaction mixture is heated to yield the desired polymer. The molecular weight of the synthesized polymer can be determined by the reaction conditions (e.g., temperature, starting materials, concentration, solvent, etc) used in the synthesis.

For example, a monomer, such as 1,4 phenylene diacrylate or 1,4 butanediol diacrylate having a concentration of 1.6 M, and DOPA or another primary amine containing aromatic molecule are each dissolved in an aprotic solvent such as DMF or DMSO to form two solutions, the solutions are mixed in a 1 : 1 molar ratio between the diacrylate and the amine group and heated to 56⁰C to form a bioadhesive material. c. Blending a Polymer with a Catechol or Catechol Derivative Blends of a biodegradable or non-degradable polymer with a catechol or catechol derivative can be prepared by mixing, such as by dissolving the polymer and the catechol or catechol derivative in a suitable solvent and then removing the solvent under controlled conditions of temperature and rate of solvent removal. The resulting blends can be spray dried or dried at room temperature. Alternatively, the blend can be prepared by melt blending the polymer and the catechol or catechol derivative at a temperature corresponding to the melting point of the polymer. For example, polycaprolactone can be melt-blended with L-DOPA (m.p. 295°C) at a temperature of 58-60⁰C, which corresponds to the meting point of polycaprolactone. The blends can be also coated onto a substrate using melt extrusion, a fluidized bed, or any method of coating known in the art. The catechol or catechol derivative is present in amount from about 0.5% to about 95% by weight of the polymer. III. Method for Stabilizing Bioadhesives

The invention includes a bioadhesive material comprising (1) a polymeric component selected from (a) a polymeric backbone and a side chain or side group containing an aromatic group substituted with one or more hydroxyl groups and (b) a polymer blended with an aromatic compound substituted with one or more hydroxyl groups and (2) an additive that stabilizes the polymeric component from erosion, dissolution or both, where at least 50% by weight of a 1 mm thick film of the bioadhesive material remains, e.g., after 12 hours in a buffered pH 4.5 dissolution bath.

In certain embodiments, the bioadhesive material film is exposed to the dissolution bath for 6 hours, 8 hours, 10 hours, 12 hours, 14 hours, 16 hours, 18 hours, 20 hours, 24 hours or longer. In certain such embodiments, the amount of bioadhesive material film remaining after exposure to the dissolution bath is at least 50% by weight, at least 60% by weight, at least 70% by weight, at least 80% by weight, at least 90% by weight, at least 95% by weight, at least 97% by weight, at least 98% by weight or even at least 99% by weight of the polymer prior to exposure. A suitable dissolution bath, a USP π apparatus, is described below in the Examples. In certain embodiments, the dissolution bath is stirred at 50 rpm and the temperature is 37° C.

In certain embodiments, the bioadhesive materials are stabilized against erosion by incorporating one or more additives selected from (1) polyanhydrides, such as those having a molecular weight average in excess of 20,000, (2) acidic components

(including precursors thereof), (3) metal compounds, (4) stabilizing polymers, and (5) hydrophobic components. a. Polyanhydrides

Suitable polyanhydrides for stabilizing the bioadhesive materials discussed above are described in U.S. Patent No. 4,757,128 to Domb et al. and U.S. Patent No. 5,955,096 to Mathiowitz et al., the contents of which are incorporated herein by reference. Polymers may be synthesized from highly pure isolated prepolymers formed from: aliphatic dicarboxylic acids, aromatic dicarboxylic acids, aromatic-aliphatic dicarboxylic acids, combinations of aromatic, aliphatic and aromatic-aliphatic dicarboxylic acids, aromatic and aliphatic heterocyclic dicarboxylic acids and aromatic and aliphatic heterocyclic dicarboxylic acids in combination with aliphatic dicarboxylic acids, aromatic-aliphatic dicarboxylic acids, and aromatic dicarboxylic acids of more than one phenyl group. For example, the following monomers are suitable for synthesizing bioadhesive copolymers: bis(p-carboxyphenoxy)alkanes; hydroquinone- O,O' diacetic acid; 1,4-bis-carboxymethyl benzene; 2,2-bis(4-hydroxphenyl)propane- O,O'-diacetic acid; 2,2-bis(4-carboxyphenyl)propane; terephthalic acid; bis(4- carboxyphenyl)alkanes; 1 ,4-phenylene dipropionic acid; cyclohexane dicarboxylic acids, adipic acid, sebacic acid (SA), bis(p-carboxyρhenoxy)propane (CPP), isophthalic acid (IPh), and dodecanedioic acid (DD). A particular polyanhydride is poly(fumaric acid-co-sebacic acid) (pFA:SA) (e.g., a 20:80 copolymer of p(FA:SA)). Another particular polyanhydride is polyadipic anhydride.

As used herein, the term "anhydride oligomer" refers to a diacid or polydiacid linked by anhydride bonds, and having carboxy end groups linked to a monoacid such as acetic acid by anhydride bonds. The anhydride oligomers have a molecular weight less than about 5000, typically between about 100 and 5000 daltons, or are defined as including between one to about 20 diacid units linked by anhydride bonds. The anhydride oligomer is hydrolytically labile. As analyzed by gel permeation chromatography, the molecular weight may be, for example, on the order of 200-400 for fumaric acid oligomer (FAPP) and 2000-4000 for sebacic acid oligomer (SAPP). In one embodiment, the diacids are those normally found in the Rrebs glycolysis cycle. The anhydride oligomer compounds preferably have high chemical reactivity.

Anhydride oligomers can be used alone or incorporated into a polyanhydride by combining a finely ground dispersion of particles of oligomer in a solution or dispersion or physical blend with the polyanhydride. Alternatively, the oligomer compound can be incorporated into the polymer by dispersing the polyanhydride in a solution or dispersion of the oligomer compound and then removing the solvent by evaporation or filtration. Alternatively, the oligomer compound can be incorporated into the polymer by blending with polyanhydride by grinding and coextruding through an extruder.

While Applicants do not wish to be bound by theory, it is believed that free carboxylic acid groups of the polyanhydrides (including anhydride oligomers) form hydrogen bonds with hydroxyl group in the polymers functionalized or blended with catechol and derivatives thereof and/or create a local acidic environment, thereby stabilizing the polymers. It is also believed that the erosion of polyanhydrides is less affected by pH than the polymers functionalized or blended with catechol or a derivative, such that a polyanhydride selected for use herein advantageously erodes at a largely pH-independent rate and/or erodes slowly upon hydration.

Typically, the amount of polyanhydride added to a bioadhesive polymer is from about 0.5% to about 75% by weight, preferably about 5% to about 50% and more preferably about 10% to about 25%. b. Acidic Components The bioadhesive materials can additionally be stabilized by the incorporation of a small molecule (i.e., non-polymeric or oligomeric) acidic component, preferably a slow release acidic component. Typically, the acid is a weak organic acid, for example, an acid having a pKa of about 1 to about 7, such as about 1 to about 5.5, typically about 1.2 to 4.5. Preferably, the acid is poorly soluble in water as defined in the USP, but miscible with the bioadhesive polymer. The acid advantageously has a relatively long chain (e.g., 6-10 or 6-8 carbon atoms), and is preferably aliphatic, and in certain embodiments, saturated. The acid may contain one or more carboxylic, phosphonic, phosphoric, sulfonic, sulfuric or sulfenic acid moieties, preferably two or more acid moieties. Typically, the acid contains two or more carboxylic acid moieties. Exemplary acids include glutaric acid, succinic acid, fumaric acid, citric acid, sebacic acid, adipic ^■ acid, lactic acid, malic acid, propiolic acid, butyric acid, hexanoic acid, ascorbic acid, tartaric acid and sorbic acid. In certain embodiments, the acid is not citric acid. In certain such embodiments, the acid is not citric acid, fumaric acid, sebacic acid or lactic acid. In other embodiments, the acid is not a sugar. A combination of two or more such acids may be incorporated into a polymer.

The acid may be an acid precursor, such as an anhydride. An acid precursor is a molecule that is hydrolyzed or metabolized into an acid. Suitable anhydrides includes symmetrical anhydrides (e.g., acetic anhydride, cyclohexanecarboxylic anhydride, hexanoic anhydride, chloroacetic anhydride, thiobenzoic anhydride, thiopropionic anhydride, 2-chloroethanesulfinic anhydride, benzenesulfonic anhydride and cyclic anhydrides formed from two acid groups attached to the same molecule such as succinic anhydride, cyclohexane-l,2,3,4-tetracarboxylic acid 3,4-anhydride and phthalic anhydride), unsymmetrical (mixed) anhydrides (e.g., acetic propionic anhydride, benzoic thioacetic anhydride, acetic chloroacetic anhydride, benzenesulfinic ethanesulfonic anhydride, chloroacetic-4-nitrobenzenesulfonic anhydride) and chalcogen analogues of anhydrides (e.g., benzoic thioanhydride, 4-chlorocyclohexane- 1-carbothioic thioanhydride, acetic propionic thioanhydride, acetic thiopropionic anhydride, propionic thioacetic anhydride, acetic thiopropionic thioanhydride, propionic thioacetic thioanhydride, thioacetic thiopropionic anhydride). Preferably, the anhydride is succinic anhydride, phthalic anhydride, maleic anhydride, adipic anhydride, butyric anhydride, isobutyric anhydride, propionic anhydride or another carboxylic acid anhydride. More preferably, the anhydride is a cyclic anhydride such as succinic anhydride.

The acids advantageously are present in a bioadhesive polymer for an extended period of time (e.g., not washed away in an aqueous environment), which is typically achieved either by virtue of low water solubility or by virtue of coating the acids with an appropriate coating. Such acids are collectively referred to herein as slow-release acid components. Acids selected on the basis of solubility typically have a solubility in water of less than 10 mg/mL at pH 4.5 and below. Coatings for an acid are selected such that they do not appreciably dissolve at pH 4.5 or below or such that they coat the acid until the formulation (i.e., polymer) into which the coated acid is incorporated has passed through the stomach (e.g., an enteric coating).

Typically, the amount of an acidic component (including acid precursors) added to a bioadhesive material is from about 0.5% to about 75% by weight, such as about 1% to about 65%, preferably about 5% to about 50% (about 5% to about 45%, about 10% to about 30%) and more preferably about 10% to about 25%. c. Metal Compounds

The bioadhesive materials described above can also be stabilized by the incorporation of a metal compound, as described in U.S. Patent No. 5,985,312 to Jacob et al. The metal compounds preferably are water-insoluble metal compounds, such as water-insoluble metal oxides and hydroxides, including oxides of calcium, iron, copper and zinc. The metal compounds can be combined with a wide range of hydrophilic and hydrophobic polymers including proteins, polysaccharides and synthetic biocompatible polymers.

Metal compounds which can be incorporated into materials preferably are water-insoluble metal compounds, such as water-insoluble metal oxides and metal hydroxides, which are capable of becoming combined with a polymer to thereby improve the bioadhesiveness of the material. As defined herein, a water-insoluble metal compound is defined as a metal compound with little or no solubility in water, for example, less than about 0.0 to 0.9 mg/ml. The water-insoluble metal compounds can be derived from a wide variety of metals, including, but not limited to, calcium, iron, copper, zinc, cadmium, zirconium and titanium. The water insoluble metal compound preferably is a metal oxide or hydroxide. Water insoluble metal compounds of multivalent metals are preferred. Representative metal oxides suitable for use in the compositions described herein include cobalt oxide (I) (CoO), cobalt oxide (1I)(Co₂Os), selenium oxide (SeO₂), chromium double oxide (CrO₂), manganese oxide (MnO₂), titanium oxide (TiO₂), lanthanum oxide (La₂O₃), zirconium oxide (ZrO₂), silicon oxide (SiO₂), scandium oxide (Sc₂O₃), beryllium oxide (BeO), tantalum oxide (Ta₂Os), cerium oxide (CeO₂), neodymium oxide (Nd₂O₃), vanadium oxide (V₂Os), molybdenum oxide (MO₂O₃), tungsten oxide (WO), tungsten trioxide (WO₃), samarium oxide (Sm₂Os), europium oxide (EU2O₃), gadolinium oxide (Gd₂Os), terbium oxide (Tb₄O?), dysprosium oxide (DV₂O₃), holmium oxide (Ho₂O₃), erbium oxide (Er₂Os), thulium oxide (Tm₂Os), ytterbium oxide (Yb₂Os), lutetium oxide (LU₂O₃), aluminum oxide (AI₂O₃), indium oxide (Inθ₃), germanium oxide (GeO₂), antimony oxide (Sb₂Os), tellurium oxide (TeO₂), nickel oxide (NiO), and zinc oxide (ZnO). Other oxides include barium oxide (BaO), calcium oxide (CaO), nickel oxide (III) (Ni₂Os), magnesium oxide (MgO), iron oxide (JT) (FeO), iron oxide (TLT) (Fe₂Os), copper oxide (II) (CuO), cadmium oxide (CdO), and zirconium oxide (Zrθ2). In certain embodiments, the metal compound is ferric oxide, copper oxide or zinc oxide or a combination thereof. In other embodiments, the metal compound is a zirconate, such as magnesium zirconate or calcium zirconate. In yet other embodiments, the metal compound is a silicate, such as magnesium silicate (e.g., a hydrated magnesium silicate such as talc) or calcium silicate. Advantageously, metal compounds which are incorporated into polymers are metal compounds which are already approved by the FDA or an equivalent agency as either food or pharmaceutical additives, such as zinc oxide or talc. The water-insoluble metal compounds can be incorporated into a material by, for example, one of the following mechanisms: (a) physical mixtures which result in entrapment of the metal compound; (b) ionic interaction between metal compound and polymer; (c) surface modification of the polymers which would result in exposed metal compound on the surface; and (d) coating techniques such as fluidized bed, pan coating, or any similar methods known to those skilled in the art, which produce a metal compound enriched layer on the surface of the device. In one embodiment, nanoparticles or microparticles of the water-insoluble metal compound are incorporated into the material, preferably as a uniform dispersion.

Fine metal oxide particles can be produced, for example, by micronizing a metal oxide by mortar and pestle treatment to produce particles ranging in size, for example, from 10.0 to 300 run. The metal oxide particles can be incorporated into a material, for example, by dissolving or dispersing the particles into a solution or dispersion of the material.

Metal compounds are optionally coated with a protective coating, such as an enteric coating or a rate controlling coating. Such coatings are selected in order to release the metal compound only when the system is exposed to gastric fluid or another targeted environment.

Typically, the amount of a metal compound added to a bioadhesive material is from about 1% to about 65% by weight, preferably about 5% to about 45% and more preferably about 10% to about 30%. d. Stabilizing Polymers

The bioadhesive materials described above can also be stabilized by the incorporation of certain polymers, particularly a hydrophilic polymer (hydrogel) that forms a rigid gel at pH 4.5 and higher or a hydrophobic polymer. Preferably, a hydrogel has little or no swelling at pH 4.5 or less. One group of suitable polymers includes polymers with pendant hydroxyl, carboxylic acid, amine, amide and/or urea moieties (or, more generally, hydrogen bond donors and/or acceptors). Specific examples of stabilizing polymers include polyvinyl alcohol, polyacrylamide, polyacrylonitrile, polymethacrylic acid, polyacrylic acid (e.g., Carbomer), alginate (e.g., sodium alginate), chitin, chitosan, zein and shellac. Typically, the hydrogel is Carbomer or an alginate. In certain embodiments, the stabilizing polymer is not an alginate. In certain embodiments, the stabilizing polymer is not ethyl cellulose, cellulose acetate and/or zein.

Stabilizing polymers can be combined with a bioadhesive material by combining a finely ground dispersion of particles in a solution or dispersion with the bioadhesive material. Alternatively, the stabilizing polymer can be combined with the bioadhesive material by dispersing the bioadhesive polymer in a solution or dispersion of the hydrogel and then removing the solvent by evaporation or filtration.

Typically, the amount of a stabilizing polymer added to a bioadhesive material is from about 1% to about 90% by weight, preferably about 5% to about 70% and more preferably about 10% to about 50%. e. Hydrophobic Components

The bioadhesive materials described above can also be stabilized by combination with one or more hydrophobic components. Examples of hydrophobic molecules include waxy materials (e.g., carnauba wax, beeswax, Chinese wax, spermaceti, lanolin, bayberry wax, Candelilla wax, castor wax, esparto wax, Japan wax, jojoba oil, ouricury wax, rice bran wax, ceresin waxes, montan wax, ozocerite, peat waxes, paraffin wax, polyethylene waxes) and polyglycerol fatty acid esters. Examples of hydrophobic polymers include ethyl cellulose, cellulose acetate, cellulose acetate butarate and chitin. Typically, the amount of a hydrophobic component added to a bioadhesive material is from about 1% to about 25% by weight, preferably about 2% to about 10%. f. Combinations of Additives

The stability of bioadhesive materials can also be enhanced by incorporating materials from two or more of the classes of materials described above. Thus, the invention includes combinations including: (1) a polyanhydride and an acidic component, (2) a polyanhydride and a metal compound, (3) a polyanhydride and a stabilizing polymer, (4) a polyanhydride and a hydrophobic component, (5) an acidic component and a metal compound, (6) an acidic component and a stabilizing polymer, (7) an acidic component and a hydrophobic component, (8) a metal compound and a stabilizing polymer, (9) a metal compound and a hydrophobic component, (10) a stabilizing polymer and a hydrophobic component, (11) a polyanhydride and an acidic component and a metal compound, (12) a polyanhydride and an acidic component and a stabilizing polymer, (13) a polyanhydride and an acidic component and a hydrophobic component, (14) a polyanhydride and a metal compound and a stabilizing polymer, (15) a polyanhydride and a metal compound and a hydrophobic component, (16) a polyanhydride and a stabilizing polymer and a hydrophobic component, (17) an acidic component and a metal compound and a stabilizing polymer, (18) an acidic component and a metal compound and a hydrophobic component, (19) an acidic component and a stabilizing polymer and a hydrophobic component, (20) a metal compound and a stabilizing polymer and a hydrophobic component, (21) a polyanhydride and an acidic component and a metal compound and a stabilizing polymer, (22) a polyanhydride and an acidic component and a metal compound and a hydrophobic component, (23) a polyanhydride and a metal compound and a stabilizing polymer and a hydrophobic component, (24) an acidic component and a metal compound and a stabilizing polymer and a hydrophobic component and (25) at least one material from each of the five categories. In a one embodiment, a combination of an acidic component and a hydrophobic component are incorporated into a bioadhesive material, particularly citric acid and ethylcellulose.

The proportion of additives, when there is a combination of additives, typically falls within the ranges for the individual classes of additives disclosed above. IV. Applications for Bioadhesives

Bioadhesive materials described herein may be used in a wide variety of drug delivery, tissue engineering, and other medical and diagnostic applications. Bioadhesive materials may be formed into microparticles, such as microspheres or microcapsules, or may be a coating on such microparticles. The bioadhesive materials may be applied to tissue engineering matrices or medical implants. In the preferred embodiment, the material is applied as a coating to a solid oral dosage formulation, such as a tablet or gel-capsule or to multiparticulates. The coating may be applied by direct compression or by applying a solution containing the material to the tablets or gel-capsules. In one embodiment, the bioadhesive material is in the matrix of a tablet or other drug delivery device. Optionally, the tablet or drug delivery device contains a coating, such as a coating containing the bioadhesive material, another bioadhesive polymer, a rate-controlling coating or an enteric coating. The thickness of the coating varies depending upon the formulation and where the formulation is to be targeted. For example, the coating on a microparticle is typically about 1-100 microns, such as 25-75 microns. In general, the coating on a tablet or capsule is significantly thicker, such as from 200 microns to 1 mm.

Bioadhesive materials used as coatings preferably do not appreciably swell upon hydration, such that they do not substantially inhibit or block movement (e.g., of ingested food) through the gastrointestinal tract, as compared to the polymers disclosed by Duchene et al. Generally, polymers that do not appreciably swell upon hydration include one or more hydrophobic regions, such as a polymethylene region (e.g., (CH₂),,, where n is 4 or greater). The swelling of a polymer can be assessed by measuring the change in volume when the polymer is exposed to an aqueous solution. Polymers that do not appreciably swell upon hydration expand in volume by 50% or less when fully hydrated. Preferably, such polymers expand in volume by less than 25%, less than 20%, less than 15%, less than 10% or less than 5%. A polymer that does not appreciably swell upon hydration can be mixed with a polymer that does swell (e.g., Carbopol™, poly(acrylic acid), provided that the amount of swelling in the polymer does not substantially interfere with bio adhesiveness.

In one embodiment, the bioadhesive coating consists of two layers, an inner bioadhesive layer that does not substantially swell upon hydration and an outer bioadhesive layer that is readily hydratable and optionally bioerodable, such as one comprised of Carbopol™.

A tablet or a drug eluting device can have one or more coatings in addition to the bioadhesive coating. These coatings and their thickness can, for example, be used to control where in the gastrointestinal tract the bioadhesive coating becomes exposed. In one example, the additional coating prevents the bioadhesive coating from contacting the mouth or esophagus. In another example, the additional coating remains intact until reaching the small intestine.

Examples of coatings include methylmethacrylates, zein, cellulose acetate, cellulose acetate phthalate, HPMC, sugars, enteric polymers, gelatin and shellac. Premature dissolution of a tablet in the mouth can be prevented with hydrophilic polymers such as HPMC or gelatin.

Coatings used in tablets of the invention, typically include a pore former, such that the coating is permeable to the drug. Tablets, capsules and drug eluting devices of the invention can be coated by a wide variety of methods. Suitable methods include compression coating, coating in a fluidized bed or a pan, hot melt (extrusion) coating and enrobing. Such methods are well known to those skilled in the art.

In one embodiment, the bioadhesive material is used in drug depot or reservoir systems, such as an osmotic drug delivery system. In one aspect of this embodiment, the bioadhesive material is present in a matrix surrounding the drug to be delivered and/or as a coating on the surface of the system. The depot or reservoir systems contain a microporous or macroporous membrane that separates the outside environment from the drug inside the system. The osmotic delivery system contains osmotic agents, which bring water into the system, causing a swellable material, such as a polymeric matrix or separate polymeric layer, to swell. When the material inside the system swells, it pushes the drug against the semi-permeable membrane and out of the system.

The bioadhesive coating adheres to the mucosa in the aqueous environment of the gastrointestinal tract. As a result, the bioavailability of therapeutic agents is enhanced through increased residence time at the target absorption rate. Typically, the solid oral dosage form contains rate controlling agents, such as hydroxypropylmethyl cellulose (HPMC) and polyethylene oxide (Poly-ox). Optionally, the drug may be in the form or microparticles or nanoparticles. In one embodiment, a tablet contains a core containing a nanoparticulate drug and enhancers in a central matrix of rate controlling agents, such as hydroxypropylmethyl cellulose (HPMC) and microcrystalline cellulose (MCC). The core is surrounded on its circumference by bioadhesive polymer (preferably DOPA-BMA polymer) or composition of the invention. Optionally, the final tablet is coated with an enteric coating, such as Eudragit Ll 00-55 Acryl-Eze, to prevent release of the drug until the tablet has moved to the small intestine. The bioadhesive materials may be used in or as a coating on prosthetics, such as dental prosthetics. The materials may be used as dental adhesives, or bone cements and glues. The materials are suitable for use in wound healing applications, such as synthetic skins, wound dressings, and skin plasters and films.

In order to alter the physical properties of bioadhesive materials, additional components can be added to a composition. Such components include bioadhesive modifiers, solvents, thermoplastic polymers and plasticizers.

Bioadhesive materials can be mixed with one or more plasticizers or thermoplastic polymers. Such agents typically increase the strength and/or reduce the brittleness of polymeric coatings. Plasticizers can be hydrophobic or hydrophilic. Examples of plasticizers include dibutyl sebacate, polyethylene glycol, triethyl citrate, dibutyl adipate, dibutyl fumarate, diethyl phthalate, ethylene oxide-propylene oxide block copolymers such as Pluronic™ F68 and di(sec-butyl) fumarate. Example of thermoplastic polymers include polyesters, poly(caprolactone), polylactide, poly(lactide-co- glycolide), methyl methacrylate (e.g., EUDRAGIT™), cellulose and derivatives thereof such as ethyl cellulose, cellulose acetate and hydroxypropyl methyl cellulose (HPMC) and large molecular weight polyanhydrides. The plasticizers and/or thermoplastic polymers are mixed with a bioadhesive polymer to achieve the desired properties. Typically, the proportion of plasticizers and thermoplastic polymers, when present, is from 0.5% to 50% by weight. Bioadhesive modifiers include both natural and synthetic bioadhesive modifiers, which can be swellable or non-swellable and gellable or non-gellable. Swellable modifiers include fluid-imbibing displacement polymers (osmopolymers), such as poly(alkylene oxide), hydrogels (CARBOPOL^®), polyacrylamide, crosslinked poly(indene-co-maleic anhydride), poly(acrylic acid), polysaccharides and polyglucan. Gellable or non-gellable modifiers include karaya gum, guar gum, okra gum, gum arabic, acacia gum, pectina gum, ghatti gum, tragacanth gum, xanthan gum, locust bean gum, psyllium seed gum, tamarind gum, destria gum, casein gum and other gums.

Natural bioadhesive modifiers include cellulose compounds (cellulose, ethylcellulose, methylcellulose, nitrocellulose, propylcellulose, hydroxypropyl cellulose, hydroxyethylcellulose, carboxymethylcellulose and hydroxypropylmethylcellulose, including alkyl and hydroxyalkyl derivatives), karaya gum, prolamines (zein), L-DOPA, benserazide, carbidopa, dopamine, 3-O-methyldopa and other L-DOPA metabolites. In certain embodiments, the natural bioadhesive modifiers exclude L-DOPA and/or its metabolites.

The bioadhesive modifiers can, for example, be blended with the bioadhesive materials of the invention during the preparation of a pharmaceutical composition. For tablets, a bioadhesive modifier is generally blended with a bioadhesive material though dry or wet mixing prior to tablet preparation. As disclosed in U.S. Patent Nos. 5,985,312, 6,123,965 and 6,368,586, the contents of which are incorporated herein by reference, bioadhesive polymers and compositions, such as those named above, having a metal compound combined therewith have a further improved ability to adhere to tissue surfaces, such as mucosal membranes. The metal compound combined with the polymer can be, for example, a water-insoluble metal oxide. The combination of metal compounds with a wide range of different polymers, even those that are not normally bioadhesive, improves their ability to adhere to tissue surfaces such as mucosal membranes.

Metal compounds which can be incorporated into polymers to improve their bioadhesive properties preferably are water-insoluble metal compounds, such as water- insoluble metal oxides and metal hydroxides, which are capable of becoming incorporated into and associated with a polymer to thereby improve the bioadhesiveness of the polymer. As defined herein, a water-insoluble metal compound is defined as a metal compound with little or no solubility in water, for example, less than about 0.0 to 0.9 mg/ml. The water-insoluble metal compounds can be derived from a wide variety of metals, including, but not limited to, calcium, iron, copper, zinc, cadmium, zirconium and titanium. The water insoluble metal compound preferably is a metal oxide or hydroxide. Water insoluble metal compounds of multivalent metals are preferred. Representative metal oxides suitable for use in the compositions described herein include cobalt (I) oxide (CoO), cobalt (II) oxide (CO2O₃), selenium oxide (SeO₂), chromium (IV) oxide (CrO₂), manganese oxide (MnO₂), titanium oxide (TiO₂), lanthanum oxide (La₂Os), zirconium oxide (ZrO₂), silicon oxide (SiO₂), scandium oxide (SC₂O₃), beryllium oxide (BeO), tantalum oxide (Ta₂Os), cerium oxide (CeO₂), neodymium oxide (Nd₂Oa), vanadium oxide (V2O5), molybdenum oxide (MO2O₃), tungsten oxide (WO), tungsten trioxide (WO3), samarium oxide (Sm₂θ3), europium oxide (EU2O₃), gadolinium oxide (Gd₂Os), terbium oxide (Tb₄O₇), dysprosium oxide (DV₂O₃), holmium oxide (HO₂O₃), erbium oxide (Er₂O₃), thulium oxide (Tm₂O₃), ytterbium oxide (YtøCb), lutetium oxide (L11₂O₃), aluminum oxide (AI2O₃), indium oxide (InO₃), germanium oxide (Geθ2), antimony oxide (Sb2θ₃), tellurium oxide

(TeO₂), nickel oxide (NiO), and zinc oxide (ZnO). Other oxides include barium oxide (BaO), calcium oxide (CaO), nickel oxide (III) (Ni₂Os), magnesium oxide (MgO), iron (II) oxide (FeO), iron (III) oxide (Fe₂Os), copper oxide (II) (CuO), cadmium oxide (CdO), and zirconium oxide (ZrO₂). Preferred properties defining the metal compound include: (a) substantial insolubility in aqueous environments, such as acidic or basic aqueous environments (such as those present in the gastric lumen); and (b) ionizable surface charge at the pH of the aqueous environment.

The water-insoluble metal compounds can be incorporated into the material by one of the following mechanisms: (a) physical mixtures which result in entrapment of the metal compound; (b) ionic interaction between metal compound and polymer; (c) surface modification of the polymers which would result in exposed metal compound on the surface; and (d) coating techniques such as fluidized bed, pan coating, or any similar methods known to those skilled in the art, which produce a metal compound enriched layer on the surface of the device. In one embodiment, nanoparticles or microparticles of the water-insoluble metal compound are incorporated into the polymer.

Advantageously, metal compounds which are incorporated into materials to improve their bioadhesive properties can be metal compounds which are already approved by the FDA as either food or pharmaceutical additives, such as zinc oxide.

Bioadhesive materials with further enhanced bioadhesive properties can be obtained by incorporating anhydride monomers or oligomers into one of the bioadhesive materials disclosed herein by dissolving, dispersing, or blending, as taught by U.S. Patent Nos. 5,955,096 and 6,156,348, the contents of which are incorporated herein by reference. The anhydride oligomers are formed from organic diacid monomers, preferably the diacids normally found in the Krebs glycolysis cycle. Anhydride oligomers which enhance the bioadhesive properties of a polymer have a molecular weight of about 5000 or less, typically between about 100 and 5000 daltons, or include 20 or fewer diacid units linked by anhydride linkages and terminating in an anhydride linkage with a carboxylic acid monomer.

The oligomer excipients can be blended or incorporated into a wide range of hydrophilic and hydrophobic polymers including proteins, polysaccharides and synthetic biocompatible polymers, including those described above. In one embodiment, anhydride oligomers may be combined with metal oxide particles, such as those described above, to improve bioadhesion even more than with the organic additives alone. Organic dyes, because of their electronic charge and hydrophobicity or hydrophilicity, can either increase or decrease the bioadhesive properties of polymers when incorporated into the polymers.

As used herein, the term "anhydride oligomer" refers to a diacid or polydiacid linked by anhydride bonds, and having carboxy end groups linked to a monoacid such as acetic acid by anhydride bonds. The anhydride oligomers have a molecular weight less than about 5000, typically between about 100 and 5000 daltons, or are defined as including between one to about 20 diacid units linked by anhydride bonds. In one embodiment, the diacids are those normally found in the Krebs glycolysis cycle. The anhydride oligomer compounds have high chemical reactivity. Control of the rate that an active drug (e.g., a sustained release or controlled delivery form of a drug) is introduced to a targeted delivery site and its residence time at the targeted delivery site (e.g., site of absorption) is typically achieved, at least in part, by using excipients such as polymeric excipients. The exact mechanism by which a polymer interacts with the mucosa or controls the delivery of the drug is at least partially dependent on the rate of polymer hydration and swelling, which is related to its molecular weight. Therefore, any process that significantly reduces the molecular weight of the polymer is likely to affect its ability to control the drug delivery. Oxidative degradation can lead to a loss in molecular weight for several polymers commonly used in controlled release applications (Waterman, K. C, et. al., Pharm.

Dev. Technol., 2002, 1-32). In addition to a loss in molecular weight, such degradation in polymers can produce reactive impurities and end groups to compromise the chemical stability of drugs and also their effectiveness as a bioadhesive polymer or release controlling agent. An example of class of controlled release polymers that can degrade to compromise the drug release rate is the polyoxyethylenes, including poly(ethylene oxides) (Polyox™), poly(ethylene glycols), and poly(oxyethylene) alkyl ethers. The polyethylene oxide is usually treated by the manufacturer (Dow chemicals) with 100-1000 ppm of butylated hydroxy toluene (BHT) to reduce such degradation. While this antioxidant is quite effective, it is volatile and can be lost during any heating steps and therefore it is advisable to include an additional antioxidants to the formulation matrix to retain the polymer behavior intact (Waterman, K. C, et. al., Pharm. Dev. Technol., 2002, 1-32).

Hence, it is advisable to incorporate some stabilizers, preferably antioxidants or chelating agents, to inhibit any impurity-related degradation of drugs. Antioxidants can reduce formation of peroxides, but may be less effective in eliminating of peroxides already present in a dosage form. Currently, the marketed form of bupropion hydrochloride is stabilized with an antioxidant like L-cysteine hydrochloride. In contrast, chelating agents such as citric acid, edetic acid, fumaric acid and malic acid are recommended for inhibition of any metal induced oxidation. Chelating agents are generally more effective when added during a granulation step or by coating particles using fluid bed technology, rather than simply during physical mixing. Suitable antioxidants and chelating agents are disclosed in U.S. Pat. No. 6,423,351, the contents of which are incorporated herein by reference, which discloses prevention of drug oxidation using a ferrous ion source. Other suitable antioxidants include vitamin E, vitamin C, butylated hydroxytoluene, and butylated hydroxyanisole. The pH to which a polymer is exposed can play a significant role in the stabilization of the polymer to oxidation. It is in general more difficult to remove an electron from a polymer when it is positively charged. For this reason, stability against oxidation is often greater under low pH conditions, which promote protonation of polymers if protonation is possible. In the converse, higher pH conditions, which deprotonate a polymer, generally make a drug more susceptible to oxidation.

U.S. Pat. Nos. 5,358,970; 5,541,231; 5,731,000 and 5,763,493 to Ruff et al, the contents of which are incorporated herein by reference, describe a stabilized bupropion hydrochloride formulation having a stabilizer selected from group consisting of L- cysteine hydrochloride, glycine hydrochloride, malic acid, sodium metabisulfite, citric acid, tartaric acid, L-cystine dihydrochloride, ascorbic acid, and isoascorbic(erythorbic) acid. Such stabilizers are useful herein as antioxidants and/or chelating agents. U.S. Pat. No. 6,652,882 to Odidi et. al describes stabilization of drug by a saturated polyglycolised glyceride like Gelucire™, and such compounds are suitable for use in the present invention. Other oxidation stabilization strategies for bupropion formulations, which are suitable for use herein, include the addition of inorganic acids like hydrochloric acid, phosphoric acid, nitric acid and sulfuric acid (U.S. Pat. No. 5,968,553, the contents of which are incorporated herein by reference); dicarboxylic acids like oxalic acid, succinic acid, adipic acid, fumaric acid, benzoic acid and phthalic acid (U.S. Pat. Nos. 6,194,002; 6,221,917; 6,242,496; 6,482,987 and 6,652,882, the contents of which are incorporated herein by reference); sulfites like potassium metabisulfite and sodium bisulfite (U.S. Pat. No. 6,238,697, the contents of which are incorporated herein by reference); organic esters like L-ascorbic acid palmitate, tocopherol solution in alcohol, butylated hydroxy anisole, tocopherol or tocopherol , vitamin E succinate, vitamin E 700 acetate, and L-ascorbic acid G palmitate (U.S. Pat. No. 6,312,716, the contents of which are incorporated herein by reference). The use of acidified granules of microcrystalline cellulose (U.S. Pat. No. 6,153,223, the contents of which are incorporated herein by reference); salts of organic bases like creatinine hydrochloride, pyridoxine hydrochloride and thiamine hydrochloride and inorganic acid like potassium phosphate monobasic (U.S. Pat. No. 6,333,332, the contents of which are incorporated herein by reference) is also suitable for the present invention.

Antioxidants (also sometimes referred to as free radical absorbers) self- sacrificially stabilize materials against free radicals (for example, free radicals generated from photooxidation as a result of exposure to sunlight). Typically, antioxidants used in the present invention are selected from ascorbyl palmitate, butylated hydroxyanisole, butylated hydroxytoluene, malic acid, propyl gallate, sodium bisulfite, sodium sulfite, sodium metabisulfite, potassium metabisulfite, potassium bisulfite, sodium thiosulfate, sodium formaldehyde sulfoxylate, L-ascorbic acid, D- ascorbic acid, acetylcysteine, cysteine, thioglycerol, thioglycollic acid, thiolactic acid, thiourea, dithiothreitol, dithioerythreitol, glutathione, nordihydroguaiaretic acid, tocopherol, fumaric acid and succinic acid.

The term "acidification" refers to any method of lowering the pH of the bioadhesive polymers either before or after combination with a compatible pharmaceutical drug. Preferably, acidification employs a pharmaceutically acceptable acid to lower pH. Suitable pharmaceutically acceptable acids are well known in the art and include, by way of example only, hydrochloric acid, phosphoric acid, acetic acid, citric acid, fumaric acid, succinic acid, lactic acid, and the like.

Preferably, an antioxidant or a chelating agent is added to a bioadhesive polymer prior to formulating it with a drug. The antioxidant or chelating agent can be added as a dry material or during wet granulation or following the extrusion or annealing process.

The antioxidant and the bioadhesive polymer are preferably maintained in sufficiently close proximity such that a synergistic effect on stability of the polymer is achieved. In that regard, a bioadhesive polymer (e.g., a carbidopa-BMA polymer) can be maintained in sufficiently close proximity to the antioxidant moiety to enhance the stability of the polymer in an environment in which photo-oxidation can occur. Such close proximity is not typically obtained upon mere physical mixing of antioxidant and UV-absorber.

In order to further protect a drug formulation, an antioxidant can be present in combination with a UV-absorber such as PABA or BHT. These components can be localized such that the UV-absorber is within a single molecule (for example, within a single oligomeric or polymer chain). For example, the antioxidant and the UV-absorber can be localized through covalent bonding by reacting (for example, copolymerizing) at least one monomer including or incorporating the antioxidant with at least one monomer including or incorporating the UV-absorber. Antioxidants and UV-absorbers can also be conjugated to a suitably reactive polymer.

Antioxidants, chelating agents and UV-absorbers should be selected such that they do not react with a drug planned to be delivered with the polymer.

Typically, about 0.1% to about 20% by weight, such as about 0.5% to about 10% or about 1% to about 5%, of antioxidant and/or chelating agent is added to a bioadhesive polymer. a. Materials that can be Incorporated into the Bioadhesive Materials There is no specific limitation on the material that can be encapsulated within the bioadhesive materials. Any kind of therapeutic, prophylactic or diagnostic agent, including organic compounds, inorganic compounds, proteins, polysaccharides, nucleic acids, or other materials can be incorporated using standard techniques. Flavorants, nutraceuticals, and dietary supplements are among the materials that can be incorporated in the bioadhesive material. In one embodiment, L-3,4- dihydroxyphenyl alanine ("levodopa" or "L-dopa") is incorporated into the bioadhesive material for delivery to a patient. The bioadhesive material may contain carbidopa. In one embodiment, levodopa and carbidopa are both incorporated in the bioadhesive material. In a preferred embodiment, the bioadhesive material is a coating on an oral dosage formulation which contains levodopa and carbidopa in separate drug layers.

Examples of useful proteins include hormones such as insulin, growth hormones including somatomedins, transforming growth factors and other growth factors, antigens for oral vaccines, enzymes such as lactase or lipases, and digestive aids such as pancreatin. Examples of useful drugs include ulcer treatments such as Carafate from Marion Pharmaceuticals, antihypertensives or saluretics such as Metolazone from Searle Pharmaceuticals, carbonic anhydrase inhibitors such as Acetazol amide from Lederle Pharmaceuticals, insulin-like drugs such as glyburide, a blood glucose lowering drug of the sulfonylurea class, hormones such as Android F from Brown

Pharmaceuticals and Testred (methyltestosterone) from ICN Pharmaceuticals, and antiparasitics such as mebeandazole (VERMOX™, Jannsen Pharmaceutical). Other drugs for application to the vaginal lining or other mucosal membrane lined orifices such as the rectum include spermacides, yeast or trichomonas treatments and anti- hemorrhoidal treatments.

Drugs may be classified using the Biopharmaceutical Classification System (BCS), which separates pharmaceuticals for oral administration into four classes depending on their aqueous solubility and their permeability through the intestinal cell layer. According to the BCS, drug substances are classified as follows: Class I - High Permeability, High Solubility

Class π - High Permeability, Low Solubility

Class HI - Low Permeability, High Solubility

Class IV - Low Permeability, Low Solubility.

The interest in this classification system stems largely from its application in early drug development and then in the management of product change through its life- cycle. In the early stages of drug development, knowledge of the class of a particular drug is an important factor influencing the decision to continue or stop its development. Examples of various BCS Class of drugs can be found in the following two articles: Kasim N. A. et al., Molecular Pharmaceutics 1:85-96, (2004) and Rinaki E. et al, Pharm. Res. 20(12):1917-1925 (2003), the contents of which are incorporated herein by reference.

Class π drugs are drugs that are particularly insoluble, or slow to dissolve, but that readily are absorbed from solution by the lining of the stomach and/or the intestine. Hence, prolonged exposure to the lining of the GI tract is required to achieve absorption. Such drugs are found in many therapeutic classes. Many of the known Class π drugs are hydrophobic, and have historically been difficult to administer. Moreover, because of the hydrophobicity, there tends to be a significant variation in absorption depending on whether the patient is fed or fasted at the time of taking the drug. This in turn can affect the peak level of serum concentration, making calculation of dosage and dosing regimens more complex.

Both Class in and IV drugs are often problematic or unsuitable for sustained release or controlled release. Class III and Class IV drugs are characterized by insolubility and poor biomembrane permeability and are commonly delivered parenterally. Traditional approaches to parenteral delivery of poorly soluble drugs include using large volumes of aqueous diluents, solubilizing agents, detergents, nonaqueous solvents, or non-physiological pH solutions. These formulations, however, can increase the systemic toxicity of the drug composition or damage body tissues at the site of administration.

In one embodiment, one or more Class I, II, III, or FV drugs are included in a core of a solid oral dosage formulation, and the core is surrounded on at least its circumference by one or more bioadhesive polymers.

Drugs suitable for use in the invention include caffeine, carbamazepine, fluvastatin, Ketoprofen, Metoprolol, Naproxen, Propranolol, Theophylline, Verapamil, Diltiazem, Gabapentin, Levodopa, Carbidopa, Benserazide, Topiramate, Pramipexole, Oxcarbazepine, Prednisolone, Diflunisal, Bezafibrate, Fenofibrate, Nortriptyline,

Mometasone furoate, Amoxapine, Dipyridamole, Divalproex sodium, itraconazole and its relatives, fluoconazole, terconazole, ketoconazole, and saperconazole, griseofulvin and related compounds such as griseoverdin, some anti malaria drugs (e.g. Atovaquone), immune system modulators (e.g. cyclosporine), cardiovascular drugs (e.g. digoxin and spironolactone), ibuprofen, danazol, albendazole, clofazimine, acyclovir, carbamazepine, proteins, peptides, polysaccharides, nucleic acids, nucleic acid oligomers, viruses, Neomycin B, Captopril, Atenolol, Valproic Acid, Stavudine, Salbutamol, Acyclovir, Methotrexate, Lamivudine, Ergometrine, Ciprofloxacin, Amiloride, Caspofungin, Clorothiazide, Tobramycin, Cyclosporin, Allopurinol, Acetazolamide, Doxycyclin, Dapsone, Nalidixic Acid, Sulfamethoxazole, Tacrolimus, And Paclitaxel. Both Class III and IV drugs are often problematic or unsuitable for sustained release or controlled release. Class III and Class IV drugs are characterized by insolubility and poor biomembrane permeability and are commonly delivered parenterally. Traditional approaches to parenteral delivery of poorly soluble drugs include using large volumes of aqueous diluents, solubilizing agents, detergents, nonaqueous solvents, or non-physiological pH solutions. These formulations, however, can increase the systemic toxicity of the drug composition or damage body tissues at the site of administration.

In one embodiment, one or more Class I, II, III, or IV drugs are included in a core of a solid oral dosage formulation, and the core is surrounded on at least its circumference by one or more bioadhesive polymers.

In a preferred method for imaging, a radiopaque material such as barium is coated with a bioadhesive material. Radioactive materials or magnetic materials could be used in place or, or in addition to, the radiopaque materials. b. Tablets

The bioadhesive materials may be used as one or more layers in a bioadhesive drug delivery tablet formulation.

EXAMPLES

Example 1 : Enhancing stability of bioadhesive polymers

Levodopa was reacted with poly(l,4-butadience-α/Mnaleic anhydride) according to the procedure described in U.S. Patent Publication No. 2005/0201974 and PCT Publication No. WO 2005/056708, the contents of which are incorporated herein by reference, to produce Spheromer III. Polymer films were prepared using Spheromer III and various additives at different amounts. The solubility of Spheromer III in buffers was determined at various time points by UV- Vis spectrophotometry.

Film Casting and Solubility Testing Procedures Films were prepared by mixing appropriate quantities of Spheromer III and additives in a 50 mL beaker. To each beaker was added 5 mL of methanol, which was stirred using a magnetic stir bar. The additive was added slowly to the beaker and allowed to dissolve completely, followed by Spheromer III. After the materials were completely dissolved into solution, the solution was transferred into a non-stick muffin pan, and methanol was allowed to evaporate overnight at room temperature. Films were subsequently dried at 60° C overnight to remove the residual solvent.

Additives having low solubility in methanol were mixed with Spheromer III in methanol and blended to form a suspension. The suspension was subsequently dried in films as described above.

The solubility study was performed in a USP dissolution apparatus (Venkel Industries). Dry films weighing approximately 27±0.5 mg were transferred to dissolution vessels containing 900 mL of pH 4.5 phosphate buffer maintained at 37±0.5° C with the paddle rotating at 50 rpm. At regular intervals, 10 mL of the buffer solution was removed and transferred into a 15 mL test tube. The amount of Spheromer III dissolved at different time intervals was determined by measuring the absorbance of the aliquots collected at various intervals at 283 nm using a UV -Vis spectrophotomer. A linear regression analysis was performed by plotting the absorbance of various solutions containing different concentrations of a Spheromer III standard. The corresponding concentration was calculated from the absorbance measured.

In a first example, the effect of adding various acids, citric acid, succinic acid and fumaric acid, on the stability of Spheromer HI was measured. As shown in Figure 1 , each acid either reduces the rate of solubilization and/or the maximum solubility of Spheromer III. Succinic acid was particularly effective in enhancing the stability of Spheromer III.

In a second example, the effect of adding various metals salts, magnesium hydroxide, aluminum oxide, talc and calcium zirconate, on the stability of Spheromer III was measured. As shown in Figure 2, each metal salt either reduces the rate of solubilization and/or the maximum solubility of Spheromer III. Calcium zirconate and talc were particularly effective in enhancing the stability of Spheromer III.

In a third example, poly(fumaric acid-eø-sebacic acid) (p(FA:SA)) was blended with Spheromer III. As shown in Figure 3, increasing the p(FA:SA) decreased levels in the membrane and the solubility of Spheromer III in buffer. In a fourth example, the ability of a hydrophilic polymer, Poloxamer 188 (poly(oxyethylene-α//-oxypropylene-α//-oxyethylene)) to stabilize Spheromer III was compared that of a hydrophobic polymer, ethylcellulose. As shown in Figure 4, ethyl cellulose reduced the solubility of Spheromer HI to greater extent than did Lutrol. In addition, the solubility of Spheromer HI was further reduced by adding a greater proportion of ethylcellulose.

In a fifth example, the effect of adding a rigid-gelling polymer, sodium alginate, on the stability of Spheromer IH was measured. As shown in Figure 5, sodium alginate reduced the maximum solubility of Spheromer HI, and this effect was increased by adding a larger proportion of sodium alginate.

In a sixth example, the effect of adding two additives on the solubility of Spheromer III was investigated. As shown in Figure 6, increasing the amount of additives decreased the solubility of Spheromer and reduced the rate at which it dissolved in buffer. In a seventh example, the effect of additive molecular weight on Spheromer in solubility was investigated, including for acids having similar pKa values. As shown in Figure 7, maleic acid (MW = 116.07) caused Spheromer in to be less soluble than with an equal amount of propiolic acid (MW = 70.05). Similarly, hexanoic acid caused Spheromer in to be less soluble that with butyric acid, even though the two acids have similar pKa values. In an seventh example, the effect of additive structure on Spheromer HI solubility was investigated. As shown in Figures 8 A and B, succinic anhydride had a greater ability to lower the solubility of Spheromer IH than acetic anhydride. It is believed that the cyclic ring structure of succinic acid contributes to the stability of the Spheromer III. In a eighth example, the effect of additive molecular weight on Spheromer πi solubility was investigated again (Figure 9). The acids tested were glutaric (MW 132.11, PKa₁ = 4.31), adipic (MW 146.11, pKa, = 4.43) and phthalic (MW 166.13, pKa, = 2.94).

The examples demonstrated that acids used to stabilize bioadhesive polymers such as Spheromer III are preferably dicarboxylic instead of monocarboxylic, aliphatic instead of aromatic and have a relatively high molecular weight. In addition, stabilizers preferably have a flexible chain (e.g., saturated).

Figure 10 shows the tensile work performed when various additives described in this invention were added to Spheromer III. The tensile work was determined according to the procedure described in U.S. Patent Publication No. 2005/0201974 and PCT Publication No. WO 2005/056708.

Example 2. Dissolution Profile of Stabilized Spheromer III Coating

Placebo round tablets were coated with a coating compositions containing Spheromer HI alone or in combination with acid stabilizer, succinic acid. The coating solution was prepared by dissolving 48 g of Spheromer III, 3 g of dibutyl sebacate as plasticizer and 9 g of succinic acid in 1200 mL of methyl alcohol. The coating solution was applied to the compressed placebo tablets for a theoretical weight gain of 20% w/w in the pan coater. Placebo tablets were also coated with Spheromer III composition at the target 20% weight gain but without succinic acid. The coated tablets were dried for about 15 minutes at a bed temperature of about 70° C. These coated tablets were evaluated for the dissolution of Spheromer III in pH 6.5 phosphate buffer using USP apparatus II. As shown in Figure 11, the Spheromer III coating dissolved rapidly in about 4 hours while stabilized Spheromer III coating dissolved evenly in a slow manner over an extended duration and only 20% of the coating was dissolved in 10 hours.

Example 3. Bioadhesive Extended Release Carbidopa Tablets, 100 mg

A bioadhesive trilayer extended release tablet formulation of carbidopa (100 mg) consisting of carbidopa extended release granules and a stabilized Spheromer III bioadhesive polymer composition, was prepared and its in vitro and in vivo pharmacokinetic performance was evaluated. Tablets consisted of an active controlled release (CR) layer laminated between two stabilized bioadhesive layers. The weight and composition of the CR and bioadhesive layers are given below in Table 1. Table 1. Weight and Composition of Controlled Release and Biaodhesive

Layers of Carbidopa Extended Release Tablet

Carbidopa controlled release granules are produced by a high-shear granulation method, consisting of the following steps:

(1) Weighing carbidopa and various other excipients.

(2) Blending the weighed ingredients from step (1) excluding a lubricant in a 2- or 4-liter product bowl of Pharmx High Shear Granulator and Mixer (Fluid Air Inc., Aurora, IL) at a mixing speed of 100-200 rpm for 3-5 min, forming a uniform dry mix.

(3) Granulating the dry mix from step (2) under high shear with a binder solution of

Hypromellose 2910, 5 cps, forming a wet granulation. The granulation is conducted at an impeller speed of 100-150 rpm and a chopper speed of 1000- 2000 rpm.

(4) Drying the wet granulation from step (3) in a Vector MFL.01 Micro Batch Fluid Bed System, operating at an inlet air flow rate of 100-300 lpm (liters per minute) and an inlet air temperature of 50⁰C, for 1-3 h. Alternatively, the wet granulation is dried in a Fluid Air Fluid Bed System, Model 5 (Fluid Air Inc., Aurora, IL).

(5) Milling and sieving the ground material through a U.S. Std. mesh # 20 screen.

(6) Blending the sieved granulation from step (5) with a lubricant in Maxiblend V- shell blender with a 0.5-, 1-, or 2-qt V-shell, for 5-15 min, forming a uniformly lubricated dry mix ready for compression.

(7) Optionally, passing the lubricated dry mix from step (6) through a U.S. Std. mesh # 20 screen.

Bioadhesive Granules are produced by a fluidized bed granulation method, consisting of the following steps:

(1) Weighing of Spheromer III and Poly(FA:SA) (Spheromer I) hydrophobic polymer, optionally a hydrophilic polymer composition, and pharmaceutically acceptable excipients. (2) Transferring the weighed ingredients from step (1) excluding a lubricant to the product bowl of a Fluid Air Fluid Bed System, Model 5 (Fluid Air Inc., Aurora, IL) and pre-heating by fluidization at an inlet air temperature of 30-40⁰C and flow rate of 15-25 scfrn (standard cubic feet per minute) for 2-5 min. (3) Granulating the pre-heated material mix from step (2) under fluidization with a granulation fluid in a top-spray mode. The granulation fluids are mainly selected from a group consisting of purified water, an aqueous solution of a mineral or organic acid, an aqueous solution of a hydrophilic polymer composition, a pharmaceutically acceptable alcohol, a ketone or a chlorinated solvent, a hydro-alcoholic mixture, an alcoholic or hydro-alcoholic solution of a hydrophilic or hydrophobic polymeric composition, a solution of a hydrophilic or hydrophobic polymeric composition in a chlorinated solvent or in a ketone. The granulation is conducted at an inlet air temperature of 30-60⁰C and flow rate of 15-25 scfin. (4) Drying the granulation from step (3) under fluidization at an inlet air temperature of 30-6O⁰C and flow rate of 15-25 scfrn. (5) Milling and sieving the ground material through a U.S. Std. mesh # 20 screen.

(6) Optionally, blending the sieved granulation from step (5) with a lubricant in Maxiblend V-shell blender with a 0.5-, 1-, or 2-qt V-shell, for 5-15 min, forming a uniformly lubricated dry mix ready for compression.

(7) Optionally, passing the lubricated dry mix from step (6) through a U.S. Std. mesh # 20 screen.

The CR layer granulation and bioadhesive layer granulations were blended separately with magnesium stearate in a cylindrical vessel mounted on an ATR rotator for 5 min. A 0.3287" x 0.8937" capsule-shaped die and punch set was installed on GlobePhaπna Manual Tablet Compaction Machine MTCM-I. The CR and two bioadhesive layers were pre-compressed together at a pressure of 500 psi (pounds per square inch) for 2 seconds and then pressed at 4000 psi for 2 seconds.

In vitro Dissolution and In vivo Pharmacokinetic Performance of Bioadhesive Trilayer Extended Release Carbidopa Tablets, 100 mg

The in vitro dissolution profile of bioadhesive extended release tablets containing 100 mg carbidopa was obtained under simulated gastric conditions. The dissolution tests were performed in 900 mL of both 0.1 N HCl (pH 1.2) and phosphate buffer saline (PBS) (pH 4.5) solutions in a USP II apparatus at a temperature of 37±0.5°C. The paddle speed was set at 50 rpm. Samples of dissolution media were collected at predetermined intervals and analyzed by HPLC. The dissolution profiles of carbidopa obtained from HPLC analysis are shown in Figure 12. As shown in Figure 12, in the presence of pH buffer 4.5, the release profile of extended release tablets was identical to that observed in 0.1 N HCl, further indicating that the outer bioadhesive layer was intact due to the incorporation of poly (FA:SA) in the Spheromer III composition. The in vivo performance of bioadhesive extended release tablets was also evaluated in beagle dogs. The tablets were administered to separate cohorts of six beagle dogs in the fed state. Plasma levels of carbidopa were measured using LC/MS/MS analysis. Figure 13 shows the plasma concentration profiles of cabidopa in the fed state. The pharmacokinetic data including the area under the plasma carbidopa vs. time curve (AUC), maximum concentration (C_m3x) and time required to achieve Cmax (Tmax) are provided in Table 2.

Table 2. Pharmacokinetic Data for Bioadhesive Carbidopa 100 mg Trilayer Tablets, in Fed Beagle Dogs; the area under the plasma levodopa vs. time curve (AUC), maximum concentration (C_m2x), and time required to achieve Cm_0x (Tm_3x)

The teachings of U.S.S.N. 11/009,327, filed December 9, 2004, which claims the benefit of U.S.S.N. 60/528,042, filed December 9, 2003, U.S.S.N. 60/605,201, filed August 27, 2004, U.S.S.N. 60/605,199, filed August 27, 2004, U.S.S.N. 60/604,990, filed August 27, 2004, and U.S.S.N. 60/607,905, filed September 8, 2004, are incorporated herein by reference in their entirety. It is understood that the disclosed invention is not limited to the particular methodology, protocols, and reagents described as these may vary. It is also to be understood that the terminology used herein is for the purpose of describing particular embodiments only, and is not intended to limit the scope of the present invention which will be limited only by the appended claims. Those skilled in the art will recognize, or be able to ascertain using no more than routine experimentation, many equivalents to the specific embodiments of the invention described herein. Such equivalents are intended to be encompassed by the following claims.

Claims

We claim:

1. A bioadhesive material comprising (1) a polymeric component selected from (a) a polymeric backbone and a side chain or side group containing an aromatic group substituted with one or more hydroxyl groups and (b) a polymer blended with an aromatic compound substituted with one or more hydroxyl groups and (2) an additive that stabilizes the polymeric component from erosion, dissolution or both, wherein at least 50% by weight of a 1 mm thick film of the bioadhesive material remains after 12 hours in a buffered pH 4.5 dissolution bath.

2. A bioadhesive material comprising (1) a polymeric component selected from (a) a polymeric backbone and a side chain or side group containing an aromatic group substituted with one or more hydroxyl groups and (b) a polymer blended with an aromatic compound substituted with one or more hydroxyl groups and (2) an additive selected from one or more of a polyanhydride, an acidic component, a metal compound, a stabilizing polymer and a hydrophobic component.

3. The material of claim 2, wherein the aromatic compound is present in an amount from about 0.5% to about 95% by weight of the polymeric component.

4. The material of claim 3, wherein the aromatic compound is catechol.

5. The material of claim 4, wherein the aromatic compound is a derivative of catechol.

6. The material of claim 5, wherein the derivative of catechol is 3,4 - dihydroxyphenylalanine (DOPA).

7. The material of claim 2, wherein the polymer or polymeric backbone is a hydrophobic polymer or polymeric backbone.

8. The material of claim 7, wherein the hydrophobic polymer or polymeric backbone is selected from polyanhydrides, polyacrylates, polyorthoesters, polyesters, and polyhydroxy acids.

9. The material of claim 8, wherein the hydrophobic polymer or polymeric backbone is a polyanhydride.

10. The material of claim 8, wherein the hydrophobic polymer or polymeric backbone is a polyester.

11. The material of claim 10, wherein the polyester is poly(caprolactone).

12. The material of claim 2, further comprising a therapeutic, prophylactic, or diagnostic agent.

13. The material of claim 12, wherein the therapeutic agent is L-3,4- dihydroxyphenylalanine (levodopa).

14. The material of claim 1 or 2, wherein the additive is a polyanhydride.

15. The material of claim 14, wherein the polyanhydride is poly(fumaric acid-co- sebacic acid).

16. The material of claim 14, wherein the polyanhydride is polyadipic anhydride.

17. The material of claim 13, wherein the additive is about 1% to about 75% by weight of the material.

18. The material of claim 14, wherein the polyanhydride comprises an anhydride monomer or oligomer.

19. The material of claim 1 or 2, wherein the additive is an acidic component.

20. The material of claim 19, wherein the acidic component is a weak organic acid.

21. The material of claim 20, wherein the acid has a pKa of 1 to 7.

22. The material of claim 21, wherein the acid has a pKa of 1.2 to 4.5.

23. The material of claim 19, wherein the acidic component is poorly soluble in water and is miscible with the polymeric component.

24. The material of claim 19, wherein the acidic component is an acid comprising two or more acid moieties.

25. The material of claim 24, wherein the acid moieties comprise carboxylic acid moieties.

26. The material of claim 19, wherein the acid component is an aliphatic acid.

27. The material of claim 26, wherein the acid component is a saturated aliphatic S acid.

28. The material of claim 19, wherein the acid component comprises 6 to 10 carbon atoms.

29. The material of claim 19, wherein the acidic component is succinic acid or succinic anhydride. 0

30. The material of claim 19, wherein the acidic component is not citric acid.

31. The material of claim 19, wherein the additive is about 1% to about 65% by weight of the material.

32. The material of claim 19, wherein the acidic component is a slow-release acidic component. 5

33. The material of claim 32, wherein the acidic component is coated.

34. The material of claim 1 or 2, wherein the additive is a metal compound.

35. The material of claim 34, wherein the metal compound is water-insoluble.

36. The material of claim 34, wherein the metal compound is a zirconate.

37. The material of claim 34, wherein the metal compound is a silicate.

38. The material of claim 34, wherein the metal compound is coated with a protective coating.

39. The material of claim 34, wherein the additive is about 1% to about 65% by weight of the material.

40. The material of claim 1 or 2, wherein the additive is a stabilizing polymer.

41. The material of claim 40, wherein the stabilizing polymer is a gel-forming hydrophilic polymer having little or no swelling at pH 4.5 or less.

42. The material of claim 41, wherein the gel- forming hydrophilic polymer comprises one or more hydrogen bond donors, acceptors or a combination thereof.

43. The material of claim 40, wherein the gel- forming hydrophilic polymer is S polyacrylic acid or an alginate.

44. The material of claim 40, wherein the additive is about 1% to about 65% by weight of the material.

45. The material of claim 1 or 2, wherein the additive is a hydrophobic component.

46. The material of claim 45, wherein the hydrophobic component is a waxy0 material or a polyglycerol fatty acid ester.

47. A device for tissue engineering, wound healing or bone repair or regeneration comprising a bioadhesive material comprising (1) polymeric component selected from (a) a polymeric backbone and a side chain or side group containing an aromatic group substituted with one or more hydroxyl groups and 5 (b) a polymer blended with an aromatic compound substituted with one or more hydroxyl groups and (2) an additive selected from one or more of a polyanhydride, an acidic component, a metal compound, a stabilizing polymer, and a hydrophobic component.

48. The device of claim 47, wherein the device adheres to mucosal surfaces.

49. A formulation comprising a therapeutic, diagnostic or prophylactic agent, in a bioadhesive material comprising (1) polymeric component selected from (a) a polymeric backbone and a side chain or side group containing an aromatic group substituted with one or more hydroxyl groups and (b) a polymer blended with an aromatic compound substituted with one or more hydroxyl groups and (2) an additive selected from one or more of a polyanhydride, an acidic component, a metal compound, a stabilizing polymer and a hydrophobic component, and a pharmaceutically acceptable carrier for administration of the agent vaginally, orally, rectally, nasally, sublingually, buccally or pulmonary.

0. A formulation for administering L-dopa to an individual in need thereof comprising a bioadhesive material comprising (1) polymeric component selected from (a) a polymeric backbone and a side chain or side group containing an aromatic group substituted with one or more hydroxyl groups and (b) a polymer blended with an aromatic compound substituted with one or more hydroxyl groups and (2) an additive selected from one or more of a polyanhydride, an acidic component, a metal compound, a stabilizing polymer and a hydrophobic component, wherein the aromatic group or compound is L- dopa.