WO1998022097A2

WO1998022097A2 - Controlled release matrix composition using polar polymer or monomer and poly(acrylic acid) blend

Info

Publication number: WO1998022097A2
Application number: PCT/US1997/021280
Authority: WO
Inventors: Jane Pei-Fan Bai
Original assignee: Bio Advances, Llc
Priority date: 1996-11-20
Filing date: 1997-11-20
Publication date: 1998-05-28
Also published as: WO1998022097A3

Abstract

A controlled release matrix system comprising a blend of poly(acrylic acid) and a polar polymer or monomer, said polar polymer or monomer having a carbon-oxygen ratio equal to or less than 1.9:1 and a carbon-hydroxyl group ratio of 5:1, the weight ratio of said poly(acrylic acid) to said polar polymer or monomer ranging from 10:90 to 90:10, is useful for the delivery of pharmaceutical agents.

Description

CONTROLLED RELEASE MATRIX COMPOSITION USING POLAR POLYMER OR MONOMER AND POLY(ACRYLIC ACID) BLEND

Field of the invention

This invention relates to mucoadhesive polymer blend compositions of poly(acrylic acid) and a polar polymer or monomer, wherein the polar polymer or monomer has a ratio of carbon atoms to oxygen atoms and of carbon atoms to hydroxyl groups equal to or less than 1.9: 1 and 5: 1 , respectively, to control the release of soluble bioactive agents, including small molecule drugs, peptides, proteins, and antigens, to the mucosal tissues. Preferred embodiments include compositions of carboxymethyl cellulose/poly(acrylic acid), hydroxyethyl cellulose/poly(acrylic acid), propylene glycol alginate/poly(acrylic acid), dextran/poly(acrylic acid), hydroxypropyl cellulose/poly (aery lie acid), alginic acid/poly(acrylic acid), D-mannitol/poly (acrylic acid), and xylitol/poly (acrylic acid).

Background of the invention Hydrogen bonding between polymers facilitates the miscibility of two polymers which have different solubilities in water or polar solvents, and the resulting matrix is transparent and swellable in water. Polymer blends have been designed to control the release of the biologically active agent. The application of these polymer blends to the controlled release of therapeutic agents will be extremely useful if the production method is easy and cost-effective.

Among the polymers desired for pharmaceutical use, poly (acrylic acid)-based polymers with a wide range of molecular weight are particularly useful for the controlled release adjacent to the absorptive mucosal surface, since these polymers are mucoadhesive. For example, Cascone et al. , Biomaterials (1995), 16:569-574 have disclosed the use of hyaluronic/poly(acrylic acid) sponges formed by thermal treatment at 130°C and with protein added after the formation of the sponge. The poly(acrylic acid) utilized has a molecular weight of 250,000 and thermal treatment at a very high temperature, 130°C. is necessary to induce the cross-linking. This is inconvenient and inefficient for the large scale production since one cannot effectively predetermine and control drug loading, and subsequent analysis of the product must be done to ascertain the precise level of such loading. Typically, quality control is a problem, since precise reaction conditions with virtually identical reagents must be maintained in order to replicate the desired loading.

Lee, in U.S. Patent 4,729, 190, discusses membrane-forming polymer systems consisting of a polymeric carboxylic acid with at least 10% of the monomer units containing free carboxyl groups with ethoxylated nonionic surfactants. Polyacrylic acid crosslinked with 1 % polyallyl sucrose and ethoxylated nonionic surfactants are noted as preferred. However, surfactants often cause irritation to the mucosal tissue. Further, the described method is useful only for producing membranes, not a matrix loaded with medicaments.

Chu et al. , J. Applied Polymer Sci. (1993) 47: 1083-1087 discuss the thermal properties of poly(acrylic acid)/Tween-80 and poly(acrylic acid)/poly(ethylene glycol) blends, where Tween-80 and poly(ethylene glycol) have the number ratio of carbon atom to hydroxyl group greater than 20: 1 in their structural compositions. Paladhi et al. , J. Applied Polymer Sci. (1994) 51: 1559-1565, have studied the aqueous solution of poly(ethylene oxide)-poly(acrylic acid) blend, where poly(ethylene oxide) has the number ratio of carbon atom to hydroxyl group greater than 20: 1. Paladhi et al. , Eur. Polym. J. (1994) 30:251-257, studied the aqueous solutions of poly(acrylic acid) with poly(vinyl pyrrolidone) or poly(vinyl alcohol). Poly(vinyl pyrrolidone) has the number ratio of carbon atom to oxygen atom being 6: 1 and has no hydroxyl group. Poly (vinyl alcohol) has the atom number ratio of carbon to oxygen being 2: 1. The interactions in poly (vinyl alcohol)/poly(acrylic acid) blend were also studied by Daniliuc et al , Eur. Polymer J. (1992) 28:(11)1365-1371 and Vazquex-Torres et al , J. Applied Polymer Sci. (1993) 50:777-792.

None of the above patents and publications disclose a controlled release system involving a blend of polar polymer/poly(acrylic acid), wherein the polar polymers have a ratio of carbon atoms to oxygen atoms, and a ratio of carbon atoms to hydroxyl groups equal to or less than 1.9: 1 and 5: 1, respectively.

Carbopol^® and hydroxypropylcellulose were used to form a buoyant hydrogel matrix with citric acid and sodium bicarbonate by Kim et al. , Ackee Hakhoechi, 26: 137-144, 1996. Citric acid and sodium bicarbonate were used to produce CO₂ gas in aqueous solution, thereby inducing buoyancy. This report describes a system with a property which is completely opposite to what is desired for a mucoadhesive matrix. Mucoadhesive polymer blends are for adherence to the mucosal tissue instead of floating in gastric or intestinal fluid.

Another method of preparing microspheres containing poly (acrylic acid) crosslinked with β-cyclodextrin or maltose using olive oil, a heating temperature of 105-115°C, and centrifugation has been described by Bibby et al , Proc. Int. Symp. Controlled Release Bioact. Matr. 24: 545-546, 1997. Though the maltose has the low number ratio of carbon atoms to oxygen atoms and that of carbon atoms to hydroxyl groups, the process involves an oil and tedious centrifugation procedures for encapsulation. Unfortunately, the amount of drugs encapsulated in the microspheres can not be predetermined. It is inconvenient and inefficient for a large scale production. Further, the poly (acrylic acid) used is Carbopol^® 907, which is not pharmaceutical grade.

Dapper et al , in U.S. Patent 5,487,895, disclose a controlled release system of microspheres of collagen/poly(acrylic acid) where the crosslinking reaction involves collagen, cross-linking agent and acetic acid with the aid of the organic solvents, toluene and acetone. Toluene has high toxicity and is, therefore, not suitable for preparation of medications to be used by humans. Acharya, U.S. Patent 5, 110,605, describes a calcium polycarbophil-alginate controlled release system, in which glycol and polyethylene glycol are used as solvents to produce wet mass for granulation. As indicated by Acharby, calcium polycarbophil has no mucoadhesive properties, which offers no advantage of increasing resident time at the absorptive mucosal surface.

Lehr et al , J. Controlled Release, (1990) 113:51-62, studied the mucoadhesive property of blends of poly(acrylic acid) copolymers, Carbopol^® 934P and Carbopol ZX-55 resin, with Eudragit^® RL 100. Carbopol^® 934P is a resin of polyacrylic acid crosslinked with allyl sucrose, and Eudragit^® RL100 is a copolymer of acrylic acid and methacrylic acid containing quaternary ammonium groups. The interaction between Carbopol^® and Eudragit^® is ionic in nature, rather than involving hydrogen bonding, and their interaction would be interfered with by weakly acidic or basic drug molecules which can ionize.

Controlled release of peptides/proteins is specially useful for increasing and prolonging contact with the mucosal tissues, since absorption of these molecules is low. Gombotz et al , in U.S. Patent 5,451,411 , describe a controlled release oral delivery method involving crosslinking of alginate bead with multivalent cation, such as calcium. Poly (aery lie acid) having a molecular weight of 75 to 100 kDa is incorporated in the system to shield the cationic therapeutic agents from interaction with alginate. Dropping of the solution of alginate and poly (acrylic acid) into the calcium solution is necessary to for the beads. The technology is not adaptable for forming a layer on a granule or tablet or suppository or insert or patch.

None of these inventions or reports provide an easy method to produce a controlled release mucoadhesive, swellable gel film involving poly (aery lie acid), which can flexibly form a firm gel layer on any support, such as a tablet, granule, suppository, particle, transdermal patch, or insert, and which is adaptable to any shape or contour.

Poly(acrylic acid) based polymers including poly(acrylic acid) crosslinked with allyl pentaerythritol, such as Carbopol^® 97 IP, are not water-soluble, but swellable once hydrated. Carbopol polymers are produced by BF Goodrich Specialty Chemicals. U.S. Patent 2,798,053 discusses how Carbopol polymers are produced. The Product Bulletins 16 and 17 for Carbopol, published by BF Goodrich Specialty Chemicals (December 1994), particularly describe the use of such polymers in pharmaceutical applications, especially for the preparation of bioadhesive compositions for use in mucosal environment. The Bulletin describes a wide variety of drugs and excipients which can be utilized in combination with the poly (acrylic acid) product, but most surprisingly, indicates that "highly water soluble excipients like sugar should be avoided, as these excipient create osmotic forces that may break up the Carbopol^® gel layer. "

The mucosal surface includes gastrointestinal, nasal, buccal and intra-tracheal mucosae. These mucosal tissues are the major sites for absorption of small molecules and large bioactive macromolecules, and for uptake of antigen to induce immunological responses. Controlled release at the mucosal surface needs to consider the resident time at the site of absorption. A release over several days is not considered optimal or beneficial considering since there typically is less than a 24 hour residence time in mucosal tissues, due to the efficient clearance by mucociliary system of nasal and intra-tracheal mucosal tissues and due to gastrointestinal mobility.

It is known that in rodents oral administration of a soluble antigen induces systemic tolerance to the antigen, which is different from immunity induced by antigen taken up in the form of microparticulates, such as antigen formulated in nanoparticles and microparticles. Such administration has been used to delay /prevent the onset of autoimmune diseases such as insulin-dependent diabetes mellitus (IDDM), experimental autoimmune uveitis (EAU) and encephalomyelitis (EAE)(a disease model induced for the study of multiple sclerosis), adjuvant- and collagen-induced arthritis (Weiner et al , Annu. Rev. Immunol (1994) 12:809-37, 1994). The antigens tested include insulin for IDDM, myelin basic protein and its fragments for EAE, S-antigen for EAU, and collagen and its fragments for arthritis. Though less studied, administration to other mucosal tissues, nasal, tonsil and respiratory, has also been shown to be effective in inducing immunological tolerance to antigen (Weiner et al , Annu. Rev. Immunol (1994) 12:809-37; Staines et al , Clin. Exp. Immunol. (1996) 103:368-375). Intestinal, nasal, tonsil, respiratory mucosal immunological tissues underlying the mucosal layer constitute the common mucosal immune system. The mucosal immune system consists of lymphoid nodules, Peyer's patches, lamina propria, membraneous cells (M cells) specializing in antigen uptake, and others depending the anatomical locations.

In the induction of oral tolerance, larger doses of antigens are required when a single dose is given while small doses of antigens are sufficient when intermittent doses are given. Oral tolerance is transient and usually disappears not long after feeding of antigen is terminated. Therefore, continued, repeated oral administration of the tolerogenic antigen is required to maintain systemic tolerance (Weiner et al , Annu. Rev. Immunol 12:809-37, 1994); likewise for other mucosal administrations. Clearly, a continuous exposure of mucosal immune systems to small doses of antigen is necessary to maintain immunological tolerance. This is also supported by in vitro cell culture experiments testing lymphocyte proliferative response and secretion of cytokines, which usually involve a prolonged incubation (Javed et al , J. Immunol. 155: 1599-1605, 1995; Bitar and Whitacre, Cell. Immunol. 112:364-370, 1988). The use of mucoadhesive polymers in controlled release of antigens will increase the contact of mucosal immune system with antigens.

In order to induce immunological tolerance, antigens have to be taken up in soluble form, and microspherical controlled release systems taken up by mucosal tissues are not desirable. Controlled release of soluble antigen from poly (acrylic acid)-based polymer blends will prolong interaction with the mucosal lymphoid tissues. They are suitable for maximizing the in vivo contact of the antigen with mucosal immune tissues and to increase the number of mucosal lymphoid cells exposed to the antigen. While many drug delivery formulations presently exist, none of these utilize the mild conditions which are necessary for the efficient administration of sensitive bioactive proteins, peptides, and antigens to the mucosal tissues at the desired rate of delivery. Therefore, a need exists for a suitable mucoadhesive composition which can incorporate into its matrix a bioactive agent during the process of matrix formation.

Controlled release of small molecule drugs at the mucosal tissues in the oral cavity, intestine, stomach, rectum and vagina can often provide convenience to the patient and minimize the fluctuation of drug levels in blood with minimal dosing frequency. A need exists for an easy, cost-effective method which can be used for the large scale manufacturing process using solvents which are safe and can be easily removed at low temperature. A need exists for a method producing a firm controlled release matrix at temperatures which do not degrade the active agents, for instance, at temperature of about 37 °C. A need exists for a cost-effective method producing a firm controlled release matrix of any thickness and any shape, and on the surface or interior of any dosage forms.

BRIEF DESCRIPTION OF THE DRAWINGS FIGURE 1A is a graph showing the release profile of insulin-FITC from the polymer blend matrix of Carbopol 97 IP NF and hydroxyethylcellulose. FIGURE IB is a graph showing the release profile of insulin-FITC from the polymer blend matrix of Carbopol 97 IP NF and hydroxyethylcellulose. FIGURE 2 is a graphical presentation of the release profile of diltiazem, a cardiovascular drug, from the polymer blend matrix of Carbopol 971 P NF and hydroxyethylcellulose . FIGURE 3 is a graphical presentation of the release profile of triamterene, a diuretic, from the polymer blend matrix of Carbopol 97 IP NF and hydroxyethylcellulose . SUMMARY OF THE INVENTION

The present invention relates generally to a novel poly(acrylic acid) blend useful for drug delivery to the mucosal tissues. More particularly, this invention relates to a mucoadhesive controlled-release matrix composition which comprises a bioactive agent incorporated in the matrix comprising a poly(acrylic acid) and a water-soluble polymer or monomer, with the carbon-oxygen ratio of the polymer or monomer being less than or equal to 1.9: 1 and the carbon-hydroxyl group ratio of the polymer or monomer being less than or equal to 5: 1 , the weight ratio or the poly (acrylic acid) to water-soluble polymer or monomer ranging from 1 :90 to 90: 1 , and preferably from 20:80 to 80:20, said composition being prepared at a temperature of less than about 120°C. In a highly preferred embodiment, the invention comprises a mucoadhesive controlled-release matrix composition wherein the bioactive agent is a small molecule drugs or protein/peptide, or antigen, in an amount of about 0.01-80%, and preferably, about 1-40%, by weight of the composition.

The present invention also extends to the process for preparing a mucoadhesive composition under mild conditions, and to therapeutic methods of using the so-prepared compositions.

It is thus an object of the invention to thus develop a controlled release system for the mucosal delivery of bioactive agents, including proteins, peptides and antigens, for controlled release on the surface of mucosal tissues.

It is a further object of the present invention to develop methods of preparation for such system, which utilize sufficiently mild reaction conditions so as to avoid denaturation of the bioactive agents.

It is a further object of the present invention to develop methods of preparation for such a system, which utilize safe and cost-effective conditions. It is yet a further object of the invention to utilize the novel composition in therapeutic methods where such controlled release of a bioactive agent is both necessary and preferable to other standard drug delivery techniques so as to ensure patient compliance and enhance overall therapeutic performance of the bioactive agent.

It is yet a further object of the invention to create a versatile method for forming controlled release matrix layers on objects of various shapes, which can be used for any nonparenteral dosage form.

DETAILED DESCRIPTION OF THE INVENTION The poly (aery lie acid) utilized in the present invention can be any of the commercially available poly (acrylic acid) polymers. The poly (aery lie acid) can be loosely crosslinked or have no cross-linking. Poly (acrylic acid) polymers with crosslinking or with no crosslinking are commercially available from a number of sources. Highly preferred poly (acrylic acid) polymers are those crosslinked with less than 10% allyl pentaerythritol, which are available from BFGoodrich specialty Chemicals, Cleveland, Ohio, under the tradename of Carbopol^®. Especially preferred are the pharmaceutical grade Carbopol^® 971P, Carbopol^® 934P and Carbopol^® 974P poly(acrylic acid) polymers. These polymers are crosslinked, and swell up to 1000 times their original volume (and ten times their original diameter) in water to form a gel when exposed a pH environment above 4-6. Above their pKa of 6 _.+0.5, the carboxylate groups on the polymer backbone ionize, resulting in repulsion between the anions and further increasing the swelling of the polymer. These crosslinked polymers do not dissolve in water, but instead form colloidal gel dispersions. These polymers can absorb water of more than 15% their dry weight when swelling (Bulletin 17, December, 1994, BF Goodrich Specialty Chemicals). According to available product literature, these polymers possess an approximate molecular weight of 3.5 million, due to their cross-linked nature. Poly(acrylic acid), poly(acrylic acid) crosslinked with about 10% or less allyl pentaerythritol, Carbopol 97 IP, Carbopol 974P, sodium carboxymethyl cellulose, hydroxy ethyl cellulose, hydroxypropyl cellulose are bioadhesive polymers. These polymers can thus provide a prolonged close contact with mucosal surface to increase absorption through mucosal tissues and interaction with mucosal immune systems.

To insure strong hydrogen bonding interaction in the blend of a polar polymer and poly(acrylic acid), the preferred polymers should have a low number ratio of carbon atom to oxygen atom, that of carbon atom to nitrogen atom, and that of carbon atom to hydroxyl group. This principle can extend to the blend of monomer with similar characteristics and poly (acrylic acid).

In a controlled release formulation, the Carbopol" polymers are usually mixed with bioactive agents, and other pharmaceutical excipients, such as diluents, disintegrants and coloring agents, and the resulting mixture is directly compressed into tablet. Once such tablets are hydrated, discrete microgels of the matrix form a gelatinous layer on the tablet, which deters diffusion of drug molecules dispersed between polymer particles, thereby controlling drug release. In the hydration process, the matrix microparticles are often partially hydrated with the inner core unhydrated because of water penetration into the core being deterred by the strong hydrogen bonding network with water in the outer hydrated layer. This irregular hydration can cause irregularity in drug release; further, the heterogeneous dispersion of drug molecules between polymer particles can cause unpredictable drug release kinetics. Compression into tablets is a very limited method and does not have a broad application to formulations for various nonparenteral routes. There exists a need for a method of linking the microparticles of Carbopol polymers to form a firm gel matrix film which is applicable and adaptable to various nonparenteral formulations, such as granules, particles, tablets, inserts, suppositories, and transdermal patches. The Carbopol polymers, especially Carbopol^® 971P, Carbopol^® 934P, and 974P with low level crosslinking, are preferred for use in the matrix compositions of the present invention to provide a versatile method for the control of the release of the bioactive agent. The Carbopol^®/polar polymer matrix containing the bioactive agent can be compressed into tablets, optionally containing other excipients and active agents. The Carbopol^®/polar polymer mixture containing the bioactive agent can be spray-dried onto sugar/starch seeds to form particles and granules or spray-dried onto inserts or suppositories, or sprayed to form a controlled release layer on the transdermal or buccal patches. Preferably, the Carbopol^®/polar polymer mixture can be coated on to the surface of any object to form a controlled release layer for any non-parenteral administration.

The polar polymers and monomers utilizable in the present invention are those which contain numerous carboxyl and hydroxyl groups so as to form blends with poly (aery lie acid) and have a carbon-oxygen ratio of less than or equal to 1.9: 1 , and the carbon-hydroxyl group ratio of the polymer or monomer being less than or equal to 5: 1. Examples of such polar polymers include, but are not limited to, sodium carboxymethyl cellulose, carboxymethyl cellulose, calcium carboxymethyl cellulose, propylene glycol alginate, hydroxy ethyl cellulose, dextran, hydroxypropyl cellulose, alginic acid, and sodium alginate. Examples of such polar monomers with capability to form extensive hydrogen bonding can also be mixed with the swellable polymers. Those of pharmaceutical grade are especially desirable, including, but not limited to, those such as D-mannitol and xylitol. Preferred for use in the practice of this invention are the polar polymers and monomers, sodium carboxymethyl cellulose, calcium carboxymethyl cellulose, hydroxy ethyl cellulose, hydroxypropyl cellulose, dextran, alginate, propylene glycol alginate, xylitol and D-mannitol. Hydroxyethyl cellulose and hydroxypropyl cellulose of various molecular weights and viscosity are also within the scope of the present invention. The bioactive agent utilized in the mucoadhesive compositions of the present invention can be any molecule possessing biological activity, including, but not limited to small molecule drugs, proteins, peptides and antigens. The mild reaction conditions utilized in the preparation of the composition of the instant invention provide a facile and easy formulation. Thus, the present invention finds particular utility in the formulation of proteins, peptides, and antigens, where high heat conditions varying from physiological conditions can cause a partial, if not total loss of bioactivity.

Representative bioactive agents which can be utilized in the present invention thus include, but are not limited to antiarthritics, antacids, anti-inflammatory substance, (including but not limited to non-steroidal anti- inflammatory drugs, NSAIDs, vasodilators, coronary vasodilators, and peripheral vasodilators), anti-infectives, psychotropics, antimanics, stimulants, antihistamines, laxatives, decongestants, vitamins, gastrointestinal sedatives, anti-diarrheal preparations, anti-anginal drugs, anti-arrhythmics, anti-hypertensive drugs, vasoconstrictors and migraine treatments, anticoagulants, and anti-thrombotic drugs, analgesics, anti-pyretics, hypnotics, sedatives, anti-emetics, anti-nauseants, anticonvulsants, neuromuscular drugs, hyper- and hypoglycemic agents, thyroid and antithyroid preparations, diuretics, b-blockers, antispasmodics, diuretics, uterine relaxants, mineral and nutritional additives, anti-obesity drugs, anabolic drugs, erythropoietic drugs, antiasthmatics, expectorants, cough suppressants, mucolytics, antiuricemic drugs, and other drugs or substances acting locally in the mouth, such as topical analgesics, local anesthetics, etc. The bioactive agents must be physically and chemically compatible with the polar polymer or monomer, as well as with the poly(acrylic acid) polymer utilized in the present invention. Preferably, the active medicament will be at least very slightly soluble in water, and more preferably, slightly soluble in water (as defined in Remingto 's Pharmaceutical Sciences, X 8^th edition, Chapter 16, page 208).

Specific representative bioactive peptides and peptidiomimetics include, but not limited to, TRH, DDAVP, LHRH agonists, LHRH agonists, DADLE, metkephamid, oxytocin, insulin-like growth factors, growth hormone releasing factor, sleep inducing peptide, opiate antagonists, opiate agonists, DGAVP, somatostatin, peptide T, vasoactive intestinal polypeptide, gastric inhibitory peptide, cholecystokin and its active fragments, gastrin releasing peptide, ACTH and its analogues, and enkephalins.

Specific representative bioactive proteins include, but not limited to, growth hormones, interferons, interleukins, calcitonin, insulin-like growth factors, insulin, colony stimulating factor, tumor inhibitory factors, transforming growth factors, epidermal growth factor, atrial naturetic factor, proinsulin, nerve growth factor, calcitonin, transforming growth factor beta, and glucagon.

Specific representative antigens include, but are not limited to, self-antigens and nonself-antigens implicated in autoimmune diseases, and their effective tolerogenic fragments, such as insulin, glutamic acid decarboxylase, heat shock protein 65, bovine serum albumin, carboxypeptidase H, ICA-69, type II collagen and its effective tolerogenic fragments, myelin basic protein and its effective tolerogenic fragments, and many others implicated in autoimmune diseases. The autoimmune diseases include, but not limited to, systemic lupus erythematosus, dermatomyositis, Sydenham's chorea, rheumatoid arthritis, rheumatic fever, thrombocytopenic purpura, polyglandular syndromes, bullous pemphigoid, diabetes mellitus, henoch-schonlein purpura, post-streptococcal nephritis, systemic lupus erythematosus, erythema nodosum, Takayasu's arteritis, myasthenia gravis, thrombocytopenic purpura, Addison's disease, rheumatoid arthritis, multiple sclerosis, sarcoidosis, ulcerative colitis, erythema multiforme, IgA nephropathy, polyarteritis nodosa. ankylosing spondylitis, goodpasture's syndrome, thromboangiitis obliterans, Sjogren's syndrome, primary biliary cirrhosis, thyrotoxicosis, scleroderma, chronic active hepatitis, polymyositis/dermatocyositis, polychondritis, pemphigus vulgaris, Wegener's granulomatosis, Henoch-Schonlein purpura, membranous nephropathy, amyotrophic lateral sclerosis, tabes forsalls, giant cell arteritis/polymyalgia, pernicious anemia, bullous pemphigoid, rapidly progressive glomerulonephritis, myasthenia gravis and fibrosing alveolitis. Examples of specific active medicaments include aluminum hydroxide, prednisolone, dexamethasone, aspirin, acetaminophen, ibuprofen, isosorbide dinitrate, nicotinic acid, tetracycline, ampicillin, dexbrompheniramine, chlorpheniramine. albuterol, pseudoephedrine, loratadine theophylline, ascorbic acid, tocopherol, pyridoxine, metoclopramide, magnesium hydroxide, verapamil, procainamide hydrochloride, propranolol, captopril, ergotamine, flurazopam, diazepam, lithium carbonate, insulin, furosemide, hydrochlorothiazide, guaiphenesin, dextromethorphan, triamterene, diltiazem and benzocaine, although any active medicament which is physically and chemically compatible with the water-soluble polymer or monomer and poly (acrylic acid) polymer may be used in the present invention.

The weight percentage of the bioactive agent loaded into the matrix of the present invention ranges from 0.01% to 80%, preferably from 0.1 % to 80%, and most preferably, from about 1-35%), by weight of total composition. The weight percentage of drug loading depends upon the particular bioactive agent, and the desired dose to be administered within the time period.

To prepare the polymer blend based controlled release matrix of the instant invention, the poly(acrylic acid) polymer and the polar polymer are mixed in water or an aqueous miscible solvent such as ethanol, glycerol, polyethylene glycol, glycol or mixtures thereof. The weight%> of the polymer mixture in the solution is in the range of about 0.05 to about 95% W/W, preferably about 0.5 to about 80% W/W, and most preferably about 0.5 to about 5%> W/W, and then the bioactive agent is added. The amount ratio of poly(acrylic acid) to the polar polymer or monomer can range from 1 :90 to 90: 1, depending on the desired release pattern of the bioactive agent. Preferably, the ratio is from 20:80 to 80:20, and most preferably from 1 :10 to 10:1, but this can vary depending upon the particular poly(acrylic acid) and the polar polymer or monomer utilized in the composition. In a highly preferred composition of the present invention, a base which ionizes at a pH below 8, including but not limited to basic amino acids, such as lysine, polylysine, histidine, and arginine, is added to modify the release profile of cationic pharmaceutical active agents to create individual unique release rates and durations. In a further preferred embodiment, the weight % of a base is in the range of 1-40%), based on the weight of the total composition.

In a preferred process, a solution of the poly(acrylic acid) and a polar polymer or monomer containing the bioactive agent is spray-dried onto a support, such as a sugar seed or other support particle, a tablet, the surface of a baking or supporting layer of a transdermal or buccal patch, or an insert. A heating temperature ranging from 37 °C to 1 10°C is applied during the spraying process, depending on the nature of the composition and bioactive agent. Preferably, the temperature is less than about 120°C, more preferably from about 37°C to 120°C, and most preferably, between 37°C to 80°C.

In an alternate embodiment, the solution of the polymer mixture can be spray-dried onto a surface to form a solid matrix layer in an automated system . The solid matrix composition can be formed as a flake, pellet, spheres, or irregular particulate. Alternately, the solid matrix composition can be formed into tablets or capsules or other pharmaceutical dosage forms using standard pharmaceutical procedures, optionally, using additional inactive pharmaceutical excipients such as binders, diluents, and disintegrants, for making the tablets, capsules or other pharmaceutical dosage forms.

In an alternate embodiment, the solution of the polymer mixture can be spray-dried onto sugar/starch seeds in a conventional coating pan as indicated, or alternatively, using an automated system such as a CF granulator, for example, a FREUND® CF granulator. a GLATT® fluidized bed processor, an AEROMATIC®, a modified ACCELA-COTA® or any other suitably automated bead coating equipment to form particulates or particles or granules of about 0.1 mm or larger. In these spraying processes, the above-noted thermal ranges apply.

In a still further embodiment, the solid matrix composition can additionally include an enteric or pH-dependent or enzyme- sensitive (such as azopolymer) coating to control the release at a certain site in the GI tract.

Depending upon the particular bioactive agent utilized, and the therapy for which it is to be used, the solid matrix composition can be adapted for intranasal, oral, buccal, intratracheal, transdermal, vaginal or rectal administration.

In the matrix composition of the present invention, plasticizers, i.e., either small molecules or large molecules often used to change the permeability of polymer films, can also be included to manipulate the release rate of the bioactive agent from the polymer blend matrix. Useful plasticizers include, but not limited to, organic plasticizers with low molecular weight, such as glycerol, glycerol monoacetate, glycerol diacetate, glycerol triacetate; low molecular polyalkylene oxides, such as polyethylene oxide, polyethylene-propylene glycols, polypropylene glycols; diethyl phthalate, propylene glycol, sodium diethylsulfosuccinate, sorbitol, tributyl citrate, and triethylcitrate. Preferred plasticizers include propylene glycol, sorbitol, triethylcitrate. Preferably, the weight percentage of plasticizer ranges from 0.5 to 50 weight %, and most preferably 0.5 to 30 weight %>, by weight of total composition. Other excipients, such as coloring agents, lubricants, binders, disintegrants, and flavorings may also be added at the discretion of the skilled pharmaceutical formulator.

To prevent extensive degradation of peptides, proteins, autoantigens, antigens and tolerogenic fragments, protective excipients which are able to inhibit lumenal degradation of these sensitive agents in the intestine are preferably added to the polymer blends. Preferably, such excipients include, but are not limited to, organic acids. Typically, such organic acids are citric acid and malic acid. In a preferred embodiment, the weight %> of the organic acid is 1% to 30%, and most preferably, 1-5%), by weight of total composition.

The invention will be further illustrated by the following Examples, which are to be considered illustrative of the invention, and not limited to the precise embodiments shown.

EXAMPLE 1 The following suspensions were prepared: Carbopol 97 IP (0.15 g) and hydroxyethyl cellulose (0.15 g) suspended in 30 ml water, Carbopol 971 P (0.3 g) and hydroxyethyl cellulose (0.3 g) suspended in 15 ml ethanol, Carbopol 971P (0.6 g) and hydroxyethyl cellulose (0.6 g) suspended in 15 ml ethanol, Carbopol 971 P (0.15 g) and hydroxypropyl cellulose (0.15 g) suspended in 30 ml water, and Carbopol 971P (0.3 g) and hydroxypropyl cellulose (0.3 g) suspended in 15 ml ethanol. Aluminum pans with a diameter of 7.5 cm and 3 cm were used for 30 ml and 15 ml of each suspension, respectively. A drying temperature of 60°C, 80°C, and 100°C was applied to a suspension. The resulting gel film from each suspension at a drying temperature was then soaked in water for more than 48 hours. Three suspensions of each kind were each dried at a temperature. The gel films from all suspensions dried at each temperature remained intact after 48 hours soaking.

EXAMPLE 2

Carbopol 971P (0.15 g) and a polar polymer or monomer (0.15g) were suspended in 30 ml water. The suspension was poured into a aluminum pan with a diameter of 7.5 cm and then vacuum dried at 40°C over 48 hours. The films obtained was then soaked in 100 ml water. The film was weighed before and after soaking in water. After swelling for 1 hour, the firmness of gel film was judged visually and touching with forceps. The results are summarized in Table 1 below. From these results, it is clear that at 40°C, polyvinylalcohol, Eudragit® S-100, Eudragit® L-100 and many other polymers, which are excluded from the present invention by virtue of the limitations with respect to carbon-oxygen ratio and cargon-hydroxy group ratio, do not form a firm gel film with a poly(acrylic acid) polymer such as Carbopol® 97 IP, as compared to D-mannitol, hydroxyethylcellulose, and propylene glycol alginate which do form the necessary firm gel film. A firm gel film is essential for maintaining the shape throughout the release duration.

Table 1 Comparison of the characteristics of gel films made from the blend of individual polymers with Carbopol 97 IP Polymer blend Comments

Carbopol® 97 IP: 0.15 g The gel film was firm when the drying Natrosol®: 0.15 g temperature was equal to or greater than 37 °C. The gel swelled upon hydration.

Carbopol® 97 IP: 0.15g The gel film was firm when the drying Propylene glycol alginate: 0.15 g temperature was equal to or greater than 40°C. The gel swelled upon hydration.

Carbopol® 97 IP: 0.15g The gel film was firm when the drying D-mannitol: 0.15 g temperature was equal to or greater than 40°C. The gel swelled upon hydration.

Carbopol® 971P: 0.15g No firm gel film with a defined shape was Polyvinylalcohol : 0.15 g formed at 40°C. The gel mass was loose and dissipated once hydrated.

Carbopol® 971P: 0.15g No firm gel film with a defined shape was Polyvinylpyrrolidone: 0.15 g formed at 40°C. The gel mass was loose.

Carbopol® 971P: 0.15g No firm gel film with a defined shape was Hydroxypropylmethylcellulose formed at 40°C. The gel mass was loose.

Carbopol® 971 P: 0.15g No firm gel film with a defined shape was Hydroxypropylmethylcellulose formed at 40°C. The gel mass was loose. Carbopol® 97 IP: 0.15§ No firm gel film with a defined shape was Eudragit S-100 formed at 100°C. The gel mass was loose and dissipated once hydrated. Carbopol® 97 IP: 0.15g No firm gel film with a defined shape was Eudragit® LI 00 formed at 100°C. The gel mass was loose and dissipated once hydrated.

30 ml water was used as the solvent.

Natrosol®(99-250 L NF) is a commercially available hydroxyethylcellulose.

EXAMPLE 3 Each of hydroxypropylcellulose (0.15g), carboxymethylcellulose(0.15g), hydroxyethylcelluose (0.15g), and propylene glycol alginate (0.15g) was mixed with 0.15 g Carbopol® 97 IP NF in 30 ml water, and then dried at various temperatures for 48 hours under vacuum. The drying temperature for the hydroxypropylcellulose mixture was 100°C, for the carboxymethylcellulose mixture, 40°C, for propylene glycol alginate mixture, 100°C, and for hydroxyethylcellulose mixture, 100°C. In another experiment, hydroxyethylcelluose (0.15 g) was mixed with Carbopol® 97 lp NF (0.15 g) in 15 ml ethanol and dried at 60°C. for 48 hours. Each gel film was soaked in 30 ml water until the weight of the wet gel reached a constant. The percentage of swelling was determined by the following equation: [(weight of wet gel - weight of dried gel)/weight of dried gel ] X 100%>= Swelling

Table 2 The percentage swelling of various polymer blends

Polymer Blend Swelling hydroxypropylcellulose (100°C) 725% carboxymethylcellulose (40°C) 2283 % hydroxyethylcelluose (100°C) 259% propylene glycol alginate (100°C) 450 % hydroxyethylcelluose (60°C) 3600%

EXAMPLE 4 Insulin-FITC (2 mg), Carbopol® 971P NF (100 mg), and hydroxyethylcelluose (100 mg) were suspended in 15 ml ethanol and then dried in aluminum pan of a diameter of 3 cm at 37°C for 48 hours. Insulin-FITC (M.W.: 6,380) is bovine pancreas insulin coupled to fluorescein isothiocyanate. The release of insulin-FITC in pH 7.5 phosphate buffer (250 ml) was studied over a 24 hour period using a water bath shaker (Prevision) at 37°C with a shaking frequency of 90 rpm. Insulin-FITC was quantified using a UV/visible spectrophotometer (Genesys® 2, Fisher Scientific) at 495 nm. The results of the percentage of insulin released from over time of this formulation are shown in FIGURES 1A and IB.

EXAMPLE 5 Carbopol® 971P NF (0.6 g), hydroxyethylcellulose (0.6g ), and diltiazem (0.015 g) were mixed in 15 ml ethanol and then dried as described in Example 1. The release of diltiazem was studied in 30 ml pH 7.5 phosphate buffer as described in Example 2. The concentration of diltiazem in sampled aliquot was determined at 290 nm. The results are summarized in FIGURE 2. A controlled release of diltiazem was completed by 97 hours.

EXAMPLE 6 Diltiazem formulated in the polymer blend of Carbopol® 97 IP NF and hydroxyethylcellulose was as described in Example 5. The release of diltiazem at different levels of loading was compared. Results are summarized in the following table.

Table 3 - -

%> loading Time required for 100 % release

1.3% > 50 hr

67% 24 hr EXAMPLE 7 Triamterene formulated in the polymer blend of Carbopol® 97 IP NF and hydroxyethylcellulose was as described in Example 5. The release profile of triamterene from this polymer blend matrix over time is shown graphically in FIGURE 3.

EXAMPLE 8 Diltiazem formulated in the polymer blend of Carbopol 97 IP NF and hydroxyethylcellulose was as described in Example 5. The release profile of diltiazem at a loading of 67% is shown in Table 4.

Table 4

Time (hr) % release

6 27% 8 47% 12 93%

24 100 %

EXAMPLE 9 Diltiazem formulated in the polymer blend of Carbopol 97 IP NF and hydroxyethylcellulose was as described in Example 5. The release of diltiazem was affected by the addition of lysine to the composition. The results are listed in Table 5 below.

Table 5

Composition Rate of release (mg /hr)

Carbopol 97 IP (0.6g) Hydroxyethylcellulose (0.6g)

Diltiazem (0.015g) 1.59 (1.2)

Carbopol 97 IP (0.6g) Hydroxyethylcellulose (0.6g) Diltiazem (0.015g) Lysine (0.3g) 2.52 (0.6) EXAMPLE 10

Each of Carbopol 971P (0.3 g), Carbopol® 974P (0.3 g) and Carbopol® 934P was mixed with hydroxyethylcellulose (0.3 g) in 15 ml ethanol. Poly(acrylic acid)

(MW: 450,000; Polysciences, Inc., Warrington, PA) (1 g) was mixed with hydroxyethylcellulose (0.5g) in 15 ml ethanol. After drying at 60°C for 48 hours, the gel films of all three compositions remained intact after 24 hours in water at 37

°C. This demonstrates that all three Carbopols® and poly(acrylic acid) without cross-linking are able to form firm gel films with hydroxyethylcelluose.

EXAMPLE 1 1 Dextran (Sigma) (0.3g) was mixed with Carbopol® 971P NF (0.3g) in 30 ml water and dried at 60 °C. The gel film was transparent and able to maintain its shape after several hours' soaking in water.

EXAMPLE 12

Carbopol (0.4%o (W/V) and citric acid (12 mM) or maleic acid (20 mM) were dissolved in intestinal fluid. The degradation of insulin in simulated intestinal fluid was studied at 37°C using the TCA method and iodinated insulin (Amershan). The results of protection of insulin from degradation by intestinal enzymes by various combinations of organic acid and Carbopol® polymers are summarized in the following Table 5.

Table 5

The effects of excipients on insulin degradation in the intestinal fluid

Treatment %> inhibition

Control 0

Citric acid (20 mM) 97 Malic acid (20 mM) 96

Carbopol®974 P NF (0.4%) & citric acid (12 mM) 96

Carbopol 97 IP (0.4%) & citric acid (12 mM) 97

Carbopol 934 P (0.4%) & malic acid (20 mM) 97 The results indicate that Carbopol® polymers did not interfere the actions of organic acids in inhibiting degradation of insulin by intestinal enzymes.

The invention is described above in detail with reference to the preferred embodiments. Variations resulting from modifications are within the scope of the invention.

Claims

WHAT IS CLAIMED IS: 1. A mucoadhesive controlled-release matrix composition which comprises a bioactive agent incorporated in the matrix comprising a poly(acrylic acid) and a polar polymer or monomer, said polar polymer or monomer having a carbon- oxygen ratio equal to or less than 1.9:1 and a carbon-hydroxyl group ratio of 5:1, the weight ratio of said poly(acrylic acid) to said polar polymer or monomer ranging from 10:90 to 90:10.

2. A composition according to Claim 1 which is prepared at a temperature of less than 120°C.

3. A composition according to Claim 1 wherein the bioactive agent is a pharmaceutically active agent.

4. A composition according to Claim 3 wherein said agent is selected from the group consisting of proteins, peptides, antigens, anti-anginal drugs, decongestants, autoantigens, oligonucleotides, analgesics, anti-inflammatory agents, diuretics, hyper- and hypoglycemic drugs, anti-congestion agents, antibiotics, anti-depressants, anti-epileptics, anti-hypertensive agents, anti-arrhythmics, corticosteroids, lipid regulating agents, antacids, laxatives, anti-ulcer agents and mixtures thereof.

5. A composition according to Claim 1 wherein the bioactive agent is a pesticide.

6. A composition according to Claim 1 wherein the bioactive agent is present in amount of about 0.1 to 80%) by weight of the total composition.

7. A composition according to Claim 1 wherein the polar polymer or monomer is selected from the group consisting of calcium carboxymethyl cellulose, carboxymethyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, alginic acid, propylene glycol alginate, dextran, D-mannitol, xylitol, and the water-soluble salts of carboxymethylcellulose and alginic acid.

8. A composition according to Claim 1 wherein the poly(acrylic acid) has no cross-linking and has molecular weight above 450,000.

9. A composition according to Claim 1 wherein the poly(acrylic acid) is a poly(acrylic acid) polymer crosslinked with about 10%> or less allyl pentaerythritol, said poly(acrylic acid) has an approximate molecular weight above 3 million.

10. A composition according to Claim 9 wherein the poly(acrylic acid) is selected from the group consisting of Carbopol® 97 IP poly(acrylic acid), Carbopol® 974P poly(acrylic acid) and Carbopol® 934P poly(acrylic acid) polymers.

1 1. A composition according to Claim 1 further comprising a plasticizer in an amount of about 0.5 - 30% by weight of the total composition.

12. A composition according to Claim 11 wherein the plasticizer is selected from the group consisting of polyethylene glycols, propylene glycols, polyethylene-polypropylene glycol, glycerol, glycerol monoacetate, glycerol diacetate, glycerol triacetate, propylene glycol, sorbitol, triacetin, tributyl citrate, diethyl phthalate, sodium diethylsulfosuccinate, and triethylcitrate.

13. A composition according to Claim 1 further comprising an organic acid in an amount of about 1 - 30% by weight of the total composition.

14. A composition according to Claim 13 wherein the acid is selected from the group comprising citric acid and maleic acid.

15. A composition according to Claim 1 further comprising a basic amino acid monomer or polymer in an amount of about 1 to 40%) by weight of the total composition.

16. A composition according to Claim 15 wherein the basic amino acid is selected from the group comprising lysine, histidine, arginine, and polylysine.

17. A composition of Claim 7 wherein the polar polymer or monomer is hydroxyethyl cellulose.

18. A composition according to Claim 1 wherein the solid matrix composition is formed into a nonparenteral dosage forms selected from the group consisting of tablets, capsules, suppositories, inserts, or transdermal patches.

19. A composition according to Claim 1 wherein the bioactive agent is an antigen, and which additionally contains an immunoadjuvant to enhance the immunological response to the soluble antigen released.

20. A method for the preparation of a composition of Claim 1 using the solvent casting method with a solvent selected from the group of consisting of water, ethanol, glycol, polyethylene glycol, glycerol, and mixtures thereof.