In another embodiment the present invention relates to a pharmaceutical composition in a solid unit dosage form for oral administration in a human or lower animal comprising:

DETAILED DESCRIPTION OF THE INVENTION

The phrase "safe and effective amount", as used herein, means an amount of therapeutically active agent or other component of the present compositions, high enough to provide a significant positive modification of the condition to be treated, but low enough to avoid serious side effects (at a reasonable benefit/risk ratio), within the scope of sound medical judgment. A safe and effective amount of therapeutically active agent or other component of the present compositions, will vary with the particular condition being treated, the age and physical condition of the patient being treated, the severity of the condition, the duration of the treatment, the nature of concurrent therapy, the agent selected and like factors.

Therapeutically Active Agent

The methods and compositions of the present invention comprise a safe and effective amount of the therapeutically active agent. In one embodiment the therapeutic agents suitable for incorporation into dosage forms of the present invention are those for which treatment of the colon is therapeutically advantageous. These include therapeutic agents useful for the treatment of diseases of the colon such as constipation, diarrhea, irritable bowel syndrome (IBS), Crohn's disease, colitis, ulcerative colitis, carcinomas, idiopathic protitis, infection in which systemic absorption of the therapeutic agent is neither required or desired, and other diseases or disorders of the colon or rectum. These include actives for constipation and laxatives such as picosulfate and sennasides, anti-diarrheals such as loperamide, nonsteroidal anti-inflammatory drugs such as salicylates, indomethacin, ibuprofen, flurbiprofen, naproxen, piroxicam 5-amino salicylic acid (or pharmaceutically acceptable salts or esters thereof), balsalazide as well as agents disclosed in U.S. Pat. No. 4,412,992, Chan, issued Nov. 1, 1983, as well as NSAIDS disclosed in U.S. Pat. No. 4,552,899, Sunshine et al., issued Nov. 12, 1985, steriods such as hydrocortisone, prednisone, prednisolone, prednisolone phosphate, prednisolone metasulpho-benzoate sodium, prednisolone sodium phosphate, beclomethasone dipropionate and beclomethasone valerate, glucocorticoids such as dextramethazone, antimicrobials or antiparasitic agents, (especially those effective against anaerobic microbes such as methotrexate), 5-aminosalicylic compounds, 4-aminosalicylic compounds, sulfasalazine, benzalazine, erythromycin, chloroguine, iodochlorhydroxyquin, disodohydroxyquin, neomycin and tetracyclines, immunosupressants such as cyclosporine A, chemotherapeutics for treatment of carcinomas, gastointestinal stimulants and prokinetic agents such as cisapride, peppermint oil and other carminative essential oils, actives for the removal of excess bile acids such as cholestyramine. The above references are herein incorporated by reference in their entirety.

Certain therapeutic agents, particularly peptides and proteins, are subject to lumenal degradation in the stomach and small intestine. The colon may be a preferable site of absorption for such compounds since lumenal enzymatic activity is less in the colon (M. Mackay and E. Tomlinson, in Colonic Drug Absorption and Metabolism, P. R. Bieck, ed., Marcel Dekker, Inc., New York, Basel, Hong Kong, 137-158 (1993)). Peptides and proteins that may exhibit improved systemic bioavailability benefit when released in the colon include calcitonin, insulin, and human growth hormone. In certain cases, the peptide or protein may be formulated with a system than enhances the absorption of the macromolecule (M. Mackay and E. Tomlinson, in Colonic Drug Absorption and Metabolism, P. R. Bieck, ed., Marcel Dekker, Inc., New York, Basel, Hong Kong, 137-158 (1993)).

The therapeutically active agents are present in the solid dosage forms in suitable unit dosage amounts. These amounts will be known by those skilled in the art. In one embodiment the active agent is 5-amino salicylic acid or pharmaceutically acceptable salts or esters thereof at a dosage range of from about 400 mg to about 1.5 grams per tablet, in another embodiment is from about 700 mg to about 900 mg per tablet.

The therapeutically active agent may be incorporated into one of the several substrates described herein in a manner consistent with the physical chemical properties of the drug and its pharmacodynamics, using techniques known to those skilled in the art.

The Inner and Outer Coating Layers

In one embodiment the coating layers of the present invention do not contain any therapeutically active agent of the present invention. In addition, the "coating layers" described herein refer to completely encasing or coating all of the solid unit dosage form (does not include coated microcrystal spheres, coated pellets, coated beads, coated microparticles or particles, or coated granules, of the therapeutically active agent).

Inner Coating Layer

The inner coating layer is selected from the group consisting of poly(methacrylic acid, methyl methacrylate) 1:2, poly(methacrylic acid, methyl methacrylate) 1:1, and mixtures thereof. Generally the inner coating layer is selected based on the preferred delivery site desired and is applied to the core of the unit dosage form to achieve a minimum coating thickness from about 20 μm to about 120 μm. The coating thickness depends on the actual size of the unit dosage form, but in one embodiment the minimum coating thickness of the inner coating layer is from about 20 μm to about 50 μm.

In one embodiment the inner coating layer comprises poly (methacrylic acid, methyl methacrylate) 1:2 (Eudragit® S), or other enteric polymer material which has the same pH release characteristics in aqueous media as Eudragit® S. Eudragit® S, an anionic copolymer derived from methacrylic acid and methyl methacrylate, with a ratio of free carboxyl groups to the ester groups of approximately 1:2, and a mean molecular weight of approximately 135,000, from Rohm Tech. In one embodiment the inner coating layer is any other polymer with the same aqueous pH release charcteristics as Eudragit® S.

Outer Coating Layer

The outer coating layer comprises an enteric polymer or film coating material, wherein the inner coating layer is not the same as the outer coating layer. Generally, if the inner coating layer is poly(methacrylic acid, methyl methacrylate) 1:1 (Eudragit® L) then the outer coating layer is not poly(methacrylic acid, methyl methacrylate) 1:2 (Eudragit(® S) or is not a mixture of poly(methacrylic acid, methyl methacrylate) 1:1 and poly(methacrylic acid, methyl methacrylate) 1:2. The outer coating material can be any coating material that protects the inner coating layer from fractures during handling and that dissolves or is removed in the gastrointestinal tract prior to the inner coating layer. The outer coating layer is either a single coating or multiple coatings of either an enteric polymer material or film coating material. In another embodiment the unit dosage form has a single outer coating layer. In another embodiment the outer coating layer is an anionic copolymer. In one embodiment the outer coating cannot comprise an enteric polymer or mixtures thereof with the same pH of release in aqueous media as Eudragit® S. If the inner coating is poly(methacrylic acid, methyl methacrylate 1:2, then the outer coating layer can only comprise poly(methacrylic acid, methyl methacrylate 1:2 (Eudragit® S) if it is mixed with another enteric polymer or film coating material such that the pH of release, in aqueous media, for the mixture is less than the pH of release (aqueous media) for poly(methacrylic acid, methyl methacrylate 1:2 (Eudragit® S) alone.

In another embodiment the outer coating layer is an enteric polymer material that begins to dissolve in an aqueous media at a pH of less than about 7, in another embodiment at a pH of less than about 6.8. Generally the outer coating layer is applied to the core of the unit dosage form to achieve a minimum thickness of from about 10 μm to about 200 μm, in another embodiment is from about 30 μm to about 150 μm.

In one embodiment the outer coating layer is selected from the group consisting of film coatings, cellulose derivatives, cellulose ethers, methyl cellulose, ethylcellulose, carboxymethylcellulose, carboxymethylethylcellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, low viscosity hydroxypropyl cellulose, low viscosity hydroxypropyl methylcellulose, wax or wax like substance, such as carnauba wax, fatty alcohols, hydrogenated vegetable oils, zein, shellac, sucrose, Arabic gum, polyethylene glycol, polyvinylpyrolidone, gelatin, sodium alginate, dextrin, psyllium husk powder, polymethacrylates, anionic polymethacrylates, poly(methacrylic acid, methyl methacrylate) 1:1, mixtures of poly(methacrylic acid, methyl methacrylate) 1:2 and poly(methacrylic acid, methyl methacrylate) 1:1, cellulose acetate phthalate, cellulose acetate trimelliate, hydroxypropyl methylcellulose phthalate (HPMCP), cellulose propionate phthalate, cellulose acetate maleate, polyvinyl alcohol phthalate, hydroxypropyl methylcellulose acetate succinate (HPMCAS), hydroxypropyl methylcellulose hexahydrophthalate, polyvinyl acetate phthalate, poly(methacrylic acid, ethyl acrylate) 1:1, and compatible mixtures thereof.

In another embodiment the outer coating layer is selected from the group consisting of cellulose derivatives, cellulose ethers, methyl cellulose, ethylcellulose, carboxymethylcellulose, carboxymethylethylcellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, low viscosity hydroxypropyl cellulose, low viscosity hydroxypropyl methylcellulose, fatty alcohols, hydrogenated vegetable oils, zein, shellac, sucrose, Arabic gum, polyethylene glycol, polyvinylpyrolidone, gelatin, sodium alginate, dextrin, psyllium husk powder, polymethacrylates, anionic polymethacrylates, poly(methacrylic acid, methyl methacrylate) 1:1, mixtures of poly(methacrylic acid, methyl methacrylate) 1:2 and poly(methacrylic acid, methyl methacrylate) 1:1, cellulose acetate phthalate, cellulose acetate trimelliate, hydroxypropyl methylcellulose phthalate (HPMCP), cellulose propionate phthalate, cellulose acetate maleate, polyvinyl alcohol phthalate, hydroxypropyl methylcellulose acetate succinate (HPMCAS), hydroxypropyl methylcellulose hexahydrophthalate, polyvinyl acetate phthalate, poly(methacrylic acid, ethyl acrylate) 1:1, and compatible mixtures thereof.

In another embodiment the outer coating layer is selected from the group consisting of anionic polymethaclylates, poly(methacrylic acid, methyl methacrylate) 1:1, mixtures of poly(methacrylic acid, methyl methacrylate) 1:2 and poly(methacrylic acid, methyl methacrylate) 1:1, cellulose acetate phthalate, cellulose acetate trimelliate, hydroxypropyl methylcellulose phthalate (HPMCP), cellulose propionate phthalate, cellulose acetate maleate, polyvinyl alcohol phthalate, hydroxypropyl methylcellulose acetate succinate (HPMCAS), hydroxypropyl methylcellulose hexahydrophthalate, polyvinyl acetate phthalate, poly(methacrylic acid, ethyl acrylate) 1:1, and compatible mixtures thereof.

In another embodiment the outer coating layer is a single layer of a mixture of poly(methacrylic acid, methyl methacrylate) 1:1 (Eudragit® L) and poly(methacrylic acid, methyl methacrylate) 1:2 (Eudragit® S) in a ratio of about 1:10 to about 10:1, preferably about 1:5 to about 1:3 more preferably about 2:3. The coating thickness depends on the actual size of the unit dosage form, but in one embodiment the minimum coating thickness of the outer coating layer is from about 10 μm to about 50 μm, in another embodiment is from about 20 μm to about 40 μm.

In another embodiment the outer coating layer is a single coating of an enteric polymer that begins to dissolve in aqueous media at a pH between about 5 to about 6.3, in another embodiment at a pH between about 5 to about 6, in even another embodiment at a pH between about 5 to about 5.5.

In one embodiment, the function of the outer coating layer is to prevent or minimize fractures of the inner coating layer during formulation processing, manufacturing, and packaging, and the function of the inner coating layer is to maintain the desired point of release of the therapeutic active agent in the gastrointestinal tract. For example if the inner coating is poly(methacrylic acid, methyl methacrylate) 1:2 (Eudragit® S), the present invention maintains the desired point of release, as described, for example, in U.S. Pat. Nos. 5,541,170 and 5,541,171, Rhodes et al., which are incorporated herein by reference in their entirety.

In one embodiment the total coating thickness (both the inner and outer coating layers together) is from about 5 mg/cm² to about 40 mg/cm², in another embodiment is from about 10 mg/cm² to about 15 mg/cm².

Specific examples of the outer coating layer follow.