Patent 6,506,407

A system for releasing a drug specifically in the colon of the gastrointestinal tract, which comprises a drug (b) coated with an organic acid-soluble polymer material (a), and a saccharide (c) which rapidly generates an organic acid by the action of enterobacteria in the lower part of the gastrointestinal tract; a colon-specific drug release oral preparation, which comprises a composition comprising a drug (b) coated with an organic acid-soluble polymer material (a) and a saccharide (c) which rapidly generates an organic acid by the action of enterobacteria in the lower part of the gastrointestinal tract, said composition being coated with an enteric coating polymer material (d). The invention provides a drug release system and a preparation which utilize enterobacteria, which do not form harmful substances due to the release-starting mechanism, show rapid degradation, and have higher colon specificity.

DISCLOSURE OF THE INVENTION

In their study on colon-specific drug release systems, the inventors of the present invention have considered that generation of an organic acid by taking advantage of enterobacteria, if possible, would make it possible to release a drug protected by a coat that is dissolved by an organic acid, thereby providing a colon-specific drug release system which is unaffected by the pH in the vicinity of the cecum and does not rely on time control. Carbohydrates, particularly saccharides, are first to be considered as a material degradable by enterobacteria to generate an organic acid. Saccharides that have conventionally been used as components of preparations are degraded by the digestive enzymes in the gastrointestinal tract or directly absorbed from the gastrointestinal tract. Hence, the inventors paid their notice to the fact that, among the saccharides which have scarcely been used as a component of pharmaceutical preparations, there are saccharides neither digested by digestive enzymes nor absorbed from the gastrointestinal tract. Such saccharides include lactulose, raffinose, cellobiose, stachyose, and fructooligosaccharides.

The inventors have first examined whether lactulose is degraded or not by enterobacteria present in the lower part of the gastrointestinal tract. As a result, it was found unexpectedly that lactulose is degraded rapidly to generate an organic acid. The inventors have then found that, when a drug (b) coated with an organic acid-soluble polymer material (a) is delivered to the lower part of the gastrointestinal tract together with lactulose, lactulose is degraded by enterobacteria to rapidly generate an organic acid, whereupon the polymer material (a) is dissolved to release the drug (b) specifically in the colon. The present invention has been completed based on this finding.

As a result of further investigation, the inventors have found that even a material that is degraded by digestive enzymes or absorbed directly through the gastrointestinal tract can also be used similarly to lactulose as far as it is degradable by enterobacteria to easily generate an organic acid, since it is possible to coat such a material with an enteric coating polymer material (d) (i.e., a polymer material which is not dissolved in the stomach but in the small intestine) so that the material can easily be delivered to the lower part of the gastrointestinal tract. In this case, in order to deliver the material to the lower part of the gastrointestinal tract more efficiently, it is preferable that the material be coated first with the organic acid-soluble polymer material (a) and then with the enteric coating polymer material (d).

From the structural viewpoint, the material which generates an organic acid by the action of enterobacteria is considered to include carbohydrates, particularly saccharides and derivatives thereof such as sugar alcohols. Taking into account the conditions of the lower gastrointestinal tract where enterobacteria live, water solubility would be of importance for the material to generate an organic acid rapidly. As a result of various studies, it was found that lactose having medium water solubility and ribose having low water solubility hardly dissolve with such a small amount of water that has passed through the coating layer of the organic acid-soluble polymer material (a) and therefore show no rapid generation of an organic acid. On the other hand, sucrose, glucose, xylose, fructose, maltose, and galactose having high water solubility were proved to generate an organic acid rapidly, which is similar to lactulose. With reference to sugar alcohols, on the other hand, rapid generation of an organic acid was not observed even with sorbitol and xylitol having high solubility as well as mannitol having medium water solubility and maltol having low solubility. Accordingly, it has now ascertained that saccharides having high water solubility are especially suitable as a material for rapidly generating an organic acid.

That is, the present invention relates to a system for releasing a drug specifically in the colon of the gastrointestinal tract. More particularly, it relates to a colon-specific drug release system, which comprises a drug (b) coated with an organic acid-soluble polymer material (a) and a saccharide (c) which rapidly generates an organic acid by the action of enterobacteria in the lower part of the gastrointestinal tract.

The system of the present invention is preferably embodied by coating the polymer material (a)-coated drug (b) and the organic acid-generating saccharide (c) with an enteric coating polymer material (d) in order to deliver them to the lower gastrointestinal tract. More specifically, there are two embodiments that the drug (b) and the saccharide (c) can be formulated separately or in the same composition as follows.

1) Formulation in Separate Compositions

A system for releasing a drug specifically in the colon of the gastrointestinal tract, which comprises a composition (1) in which an organic acid-soluble polymer material (a)-coated drug (b) is further coated with an enteric coating polymer material (d), and a composition (2) comprising a saccharide (c) which rapidly generates an organic acid by the action of enterobacteria in the lower part of the gastrointestinal tract, which saccharide may optionally be coated with an enteric coating polymer material (d). [The compositions (1) and (2) can be administered as a single preparation or separately prepared preparations.]

2) Formulation in One Composition

A system for releasing a drug specifically in the colon of the gastrointestinal tract, which comprises a composition containing an organic acid-soluble polymer material (a)-coated drug (b) and a saccharide (c) which rapidly generates an organic acid by the action of enterobacteria in the lower part of the gastrointestinal tract, the composition being coated with an enteric coating polymer material (d).

[In this composition, the saccharide (c) can be used either as a mixture with the drug (b) or as a coating layer on the drug (b). The latter system includes an embodiment in which the polymer material (a)-coated drug (b) is coated with the saccharide (c), an embodiment in which the saccharide (c)-coated drug (b) is coated with the polymer material (a), and an embodiment in which the drug (b) is coated with the saccharide (c) and the polymer material (a).]

The present invention also relates to a colon-specific drug release oral composition, more particularly to a colon-specific drug release oral composition, which comprises a composition comprising a drug (b) coated with an organic acid-soluble polymer material (a), and a saccharide (c) which rapidly generates an organic acid by the action of enterobacteria in the lower part of the gastrointestinal tract, the composition being coated with an enteric coating polymer material (d). In the composition, the saccharide (c) can be used either as a mixture with the drug (b) or as a coating layer on the drug (b). The latter composition includes an embodiment in which the polymer material (a)-coated drug (b) is coated with the saccharide (c), an embodiment in which the saccharide (c)-coated drug (b) is coated with the polymer material (a), and an embodiment in which the drug (b) is coated with the saccharide (c) and the polymer material (a).

More specifically, the present invention relates to the following compositions.

1) A colon-specific drug release oral composition in which a drug (b) and a saccharide (c) which rapidly generates an organic acid by the action of enterobacteria in the lower part of the gastrointestinal tract are coated with an organic acid-soluble polymer material (a), and the coating polymer material (a) is further coated with an enteric coating polymer material (d).

2) A colon-specific drug release oral composition in which a drug (b) is coated with an organic acid-soluble polymer material (a), the coated drug (b) is further coated with a saccharide (c) which rapidly generates an organic acid by the action of enterobacteria in the lower part of the gastrointestinal tract, and the coating saccharide (c) is further coated with an enteric coating polymer material (d).

3) A colon-specific drug release oral composition in which a drug (b) is coated with a saccharide (c) which rapidly generates an organic acid by the action of enterobacteria in the lower part of the gastrointestinal tract, the coated drug (b) is further coated with an organic acid-soluble polymer material (a), the coating polymer material (a) is further coated with an enteric coating polymer material (d).

4) A colon-specific drug release oral composition in which a drug (b) is coated with an organic acid-soluble polymer material (a) and a saccharide (c) which rapidly generates an organic acid by the action of enterobacteria in the lower part of the gastrointestinal tract, and the coated drug (b) is further coated with an enteric coating polymer material (d).

The present invention also relates to a composition according to an embodiment in which separate compositions according to the above-described system are administered as a single preparation, and more particularly to a colon-specific drug release oral composition, which comprises a composition comprising a drug (b) coated with an organic acid-soluble polymer material (a) and a saccharide (c) which rapidly generates an organic acid by the action of enterobacteria in the lower part of the gastrointestinal tract and which may optionally be coated with an organic acid-soluble polymer material (a), the composition being further coated with an enteric coating polymer material (d).

The invention further relates to a colon-specific drug release oral composition, which comprises a composition comprising a drug (b) coated with an organic acid-soluble polymer material (a) and a saccharide (c) which rapidly generates an organic acid by the action of enterobacteria and which may optionally be coated with a water-insoluble release-controlling material (e), the composition being coated with a water-insoluble release-controlling material (e) and optionally with a hole-making material (f) and further coated with an enteric coating polymer material (d). In this composition, a coating layer comprising a water-permeable release-controlling material (e) (optionally with coexistence with a hole-making material (f)) is optionally provided on the inner side of the coating layer comprising an enteric coating polymer material (d) so as to increase the efficiency of organic acid generation by the action of enterobacteria, dissolution of the polymer material (a), and release of the drug (b). Provision of the coating layer (e) on the inside of the coating layer (d) is applicable to any composition of the present invention.

The present invention furthermore relates to a method for releasing a drug specifically in the colon of the gastrointestinal tract, more particularly to a method for releasing a drug specifically in the colon of the gastrointestinal tract, which comprises coating a composition comprising a drug (b) coated with an organic acid-soluble polymer material (a) and a saccharide (c) which rapidly generates an organic acid by the action of enterobacteria in the lower part of the gastrointestinal tract with an enteric coating polymer material (d).

The present invention will now be illustrated in more detail.

The basic concept of the colon-specific drug release system of the present invention is diagrammatically explained by referring to FIG. 1.

The system of the present invention consists of (1) a unit comprising an organic acid-generating saccharide (c) and (2) a unit comprising a drug (b) coated with an organic acid generated by enterobacteria (a), which are further coated with an enteric coating polymer material (d), i.e., a polymer material which is not dissolved in the stomach but in the small intestine. If desired, a saccharide (c) which is degraded and generates an organic acid by the action of enterobacteria may be coated with an enteric coating polymer material. When orally administered to humans or mammals simultaneously, these two units pass the stomach almost unaffectedly and reaches the small intestine since the pH in the stomach is generally 6 or lower. In the small intestine having a pH of 6 to 7, the outermost coating layer which dissolves at pH 6 or higher, i.e., the coating layer made of the enteric coating polymer material (d) dissolves. Since the drug (b) in the unit (2) is protected by an inner coating layer which dissolves at a pH lower than 6, i.e., the coating layer made of the organic acid-soluble polymer material (a), the drug is not released in the small intestine. On the other hand, a saccharide (c) which is degraded and generates an organic acid by the action of enterobacteria and which is a component of the unit (1), dissolves in the small intestine. The saccharide (c) thus dissolved moves from the ileum, to the cecum, and then to the colon, it undergoes degradation by the action of drastically increasing enterobacteria to generate an organic acid. With respect to the unit containing the drug (b), the organic acid thus produced dissolves the membrane which dissolves at a pH of lower than 6, i.e., the organic acid-soluble polymer material (a), whereby the drug (b) is released specifically in the colon.

That is, the present invention provides a colon-specific drug release system characterized in that it specifically and rapidly releases a drug in the colon and that it comprises a combination of a saccharide (c) which generates an organic acid on decomposition by enterobacteria in the lower part of the gastrointestinal tract, a polymer material (a) which is dissolved by an organic acid, i.e., at a pH of lower than 6, an enteric coating polymer material (d), i.e., a polymer material which is dissolved at a pH of 6 or higher, and a drug (b).

The saccharide (c) used in the present invention, which is degraded by enterobacteria in the lower part of the gastrointestinal tract to generate an organic acid, is not limited by whether it is a monosaccharide or a polysaccharide as long as it is rapidly degraded by enterobacteria to generate an organic acid. Di- or polysaccharides which are not degraded by digestive enzymes in the gastrointestinal tract or not absorbed directly from the gastrointestinal tract are preferred. It is preferable for the saccharide which rapidly generates an organic acid to be rapidly dissolved and degraded to generate an organic acid. Accordingly, those having high water solubility are preferred. Specifically, the amount of water which is required to dissolve a 1 g portion of saccharides is preferably less than 5 ml, that is, saccharides having a water solubility of higher than 20 weight (w)/volume (v) % are preferred. Examples of such saccharides include lactulose, raffinose, cellobiose, stachyose, and fructooligosaccharides (which are synthetic disaccharides which show a high rate of degradation by enterobacteria). The fructooligosaccharides preferably include lactosucrose, such as Nyuka Oligo LS-55p (Hayashibara Syoji K. K.).

Saccharides which are degraded by digestive enzymes or directly absorbed from the gastrointestinal tract are also employable similarly to the above-described lactulose, etc., if coated with an enteric coating polymer material (d) which does not dissolve in the stomach but in the small intestine.

In order to deliver this type of saccharides to the lower part of the gastrointestinal tract more efficiently, it is preferable that the saccharide be previously coated with an organic acid-soluble polymer material (a) and then coated with an enteric coating polymer material (d). Examples of saccharides of this type are sucrose, glucose, xylose, fructose, maltose, and galactose.

As noted above, bacteria which live within the body are abundant in the oral cavity, rare in the stomach due to the acidicity, and also scarce in the upper part of the small intestine. Enterobacteria are increasing dramatically in the order of the ileum, the cecum, and the colon. A remarkable feature observed is an increase of anaerobic bacteria. In humans, Bacteroidaceae, Bifidobacterium sp., Eubacterium sp., Clostridium sp., and Peptococcaceae constitute main microbial flora, and Enterobacteriaceae sp., Streptococcus sp., Lactobacillus sp., and Veillonella sp. are detected next. The intestinal microbial flora does not so change within a healthy individual but varies among individuals or with stress, a diet or a disease. The variation is limited to specific bacteria and is not so large that all the microbial flora contributing to degradation of saccharides cannot be detected. While the bacteria absorb and metabolize saccharides, various organic acids are generated. The organic acids generated mainly include acetic acid, propionic acid, and butyric acid, while varying according to the saccharide. These organic acids are absorbed from the intestinal tract and become an energy source for humans or animals.

In the present system, the enteric coating polymer material (d) (a polymer material that dissolves at pH 6 or higher) dissolves in the vicinity of the duodenum, and enterobacteria enter the inside of the preparation together with water. The organic acid-generating saccharide (c) dissolves in water, and the enterobacteria degrade the saccharide to generate an organic acid. The pH thus decreases, and the organic acid-soluble polymer material (a) (a polymer material that dissolves at pH lower than 6) dissolves. As water enters, the saccharide (c) exudes and undergoes degradation by the action of the enterobacteria. If the enteric coating polymer material (d) is solely used, the organic acid-generating saccharide (c) may dissolve and diffuse and there is a fear that the organic acid generated does not produce sufficient effects as expected. It is recommended therefore that a composition containing the organic acid-generating saccharide (c) and a drug (b) is coated with the organic acid-soluble polymer material (a) or a composition comprising a drug (b) coated with the polymer material (a) and the organic acid-generating saccharide (c) are coated with a water permeable release-controlling material (e). If the water permeability is insufficient, the saccharide cannot dissolve sufficiently, and organic acid generation is retarded, tending to fail to manifest sufficient effects. In order to accelerate dissolution of the saccharide, the water permeable release-controlling layer (e) may contain a hole-making material (f), or the organic acid-soluble polymer material (a) may contain a substance having higher water permeability than the polymer material (a), i.e., the water permeable material (e). Where the organic acid-generating material (c) is present between the coating layer of the organic acid-soluble polymer material (a) and the coating layer of the enteric coating polymer material (d), the preparations include an embodiment in which the organic acid-generating saccharide (c) is coated with the organic acid-soluble polymer material (a) and may optionally be further coated with a water permeable release-controlling material (e) and an embodiment in which a composition containing the organic acid-generating saccharide (c) and the organic acid-soluble polymer material (a) is coated.

The saccharide for use in the present invention, for example, lactulose that is a synthetic disaccharide, is degraded by enterobacteria mainly comprising Bifidobacterium, Lactobacillus, and Streptococcus in the lower part of the gastrointestinal tract, i.e., the colon to produce lactic acid, acetic acid, etc. Diabetics show a slight reduction in Bifidobacterium and Streptococcus, but such does not seem to have large influence on the degradation of lactulose because no change is observed in Lactobacillus. Raffinose, cellobiose, stachyose, maltose, and fructooligosaccharides are rapidly degraded by the main microbial flora in the colon similarly to lactulose, while there are slight differences in enterobacteria by which they are degraded. Accordingly, it is considered that their degradation is not subject to large variation with slight variation of the microbial flora. The same seems to apply to sucrose, glucose, xylose, fructose, maltose, and galactose.

The organic acid which is generated by the action of enterobacteria serves to intentionally decrease the pH to dissolve the inner coating layer of the polymer material (a) and also to contribute to improvement in drug absorption.

The amount of the saccharide which is degraded by enterobacterial to generate an organic acid to be used in the present invention is not particularly limited as long as it is in the range for general use as excipients of preparations. A suitable amount is 1 to 99.9%, preferably 5 to 99.9%, still preferably 10 to 99.9%.

The organic acid-soluble polymer material (a), which is used in the present invention, is not particularly limited as far as it is pharmaceutically acceptable. Polymer materials which dissolve at pH lower than 6 are preferable, and those dissolve at pH 5.5 or lower are more preferable. Specific examples of such polymer materials include a dimethylaminoethyl methacrylate-methyl methacrylate-butyl methacrylate copolymer (product name: Eudragit E), polyvinyl acetal diethylaminoacetate (product name: AEA, by Sankyo Co., Ltd.), and chitosan. If desired, the polymer material (a) may contain a water permeable release-controlling material (e). While not limiting as far as pharmaceutically acceptable, examples of the water permeable release-controlling material include a copolymer of ethyl acrylate, methyl methacrylate, and trimethylammonioethyl methacrylate chloride (product name: Eudragit RS, produced by Rohm & Haas Co.), ethyl cellulose (product name: Ethocel, produced by Dow Chemical Co., Ltd.), hydroxypropylmethylcellulose (product name: TC-5, produced by Shin-Etsu Chemical Co., Ltd.), hydroxypropylcellulose (product name: HPC, produced by Nippon Soda Co., Ltd.), polyethylene oxide, and polyvinylpyrrolidone. These materials may be used either individually or as an appropriate mixture thereof. If desired, it may contain a plasticizer. While not limiting as far as pharmaceutically acceptable, the plasticizer includes triacetin, Macrogol 400, triethyl citrate, Tween 80, and castor oil, etc.

The water-insoluble and water-permeable release-controlling material (e) serves as a protecting layer for controlling the release of the organic acid-generating saccharide (c) from tablets or granules containing the same or for preventing diffusion of the tablets or granules contained therein. In this case, this layer may be provided between the coating layer of the organic acid-soluble polymer material (a) and the coating layer of the enteric coating polymer material (d).

The hole-making material (f) is used for acceleration of water permeation or for making holes through which enterobacteria can pass sufficiently in the release-controlling membrane. The hole-making material is not particularly limited as long as it is water-soluble and has a particle size greater than the size of enterobacteria (about 4 .mu.m) when laminated. Salts (e.g., NaCl) and easily water-soluble saccharides (e.g., glucose) are preferred.

The coating amount of the organic acid-soluble polymer material (a) to be used is not particularly limited as long as it is within the range for general use as a polymer material in pharmaceutical preparations. Such an amount is usually 1 to 50%, preferably 2.5 to 40%.

The enteric coating polymer material (d), i.e., the polymer material which does not dissolve in the stomach but in the small intestine, is not particularly limited as far as it is pharmaceutically acceptable. Polymer materials which dissolve at pH 6 or higher are preferred. Examples thereof include methyl methacrylate-methacrylic acid (1:1) copolymer (product name: Eudragit L, produced by Rohm & Haas Co.), a methyl methacrylate-methacrylic acid (2:1) copolymer (product name: Eudrogit S, produced by Rohm & Haas Co.), an ethyl acrylate-methacrylic acid (1:1) copolymer (product name: Eudragit LD-55, produced by Rohm & Haas Co.), hydroxypropylmethylcellulose (JPXII), cellulose acetate phthalate (JPXII), and shellac (JPXII). These materials may be used either individually or as an appropriate mixture thereof. If desired, the enteric coating polymer material (d) may contain a plasticizer. Useful plasticizers include triacetin, Macrogol 400, triethyl citrate, Tween 80, and castor oil, etc.

The term "the lower part of the gastrointestinal tract" as used herein means the part from the ileum to the colon. The term "colon" as used herein means the part of the large intestine of from the cecum to the rectum. The "cecum" is a cecal pouch from which the large intestine starts and at one side of which the ileum is open.

The term "the upper part of the gastrointestinal tract" as used herein means the part from the stomach to the duodenum, inclusive of the jejunum.

The drug (b) which can be used in the present invention is not particularly limited.

Representative drugs which can be used effectively as a main active ingredient of the preparation include various polypeptides, proteins and derivatives thereof which are easily degraded in the upper part of the gastrointestinal tract and are absorbed in the lower part of the gastrointestinal tract to exhibit pharmacological activities. Examples of the drugs include insulin, calcitonin, angiotensin, vasopressin, desmopressin, LH-RH (luteinizing hormone-releasing hormone), somatostatin, glucagon, oxytocin, gastrin, ciclosporin, somatomedin, secretin, h-ANP (human artial natriuretic peptide), ACTH (adrenocorticotropic hormone), MSH (melanocyte-stimulating hormone), .beta.-endorphin, muramyl dipeptide, enkephalin, neurotensin, bombesin, VIP (vasoacive intestinal polypeptide), CCK-8 (cholecystokinin-8), PTH (parathyroid hormone), CGRP (calcitonin gene-related peptide), TRH (thyrotropin-releasing hormone), endocerine, hGH (human growth hormone), cytokines (e.g., interleukin, interferon, colony-stimulating factor, and tumor necrosis factor), as well as derivatives thereof.

The above peptides and proteins include not only naturally occurring substances but pharmacologically active derivatives thereof and analogues thereof. For example, calcitonin used in the present invention includes not only naturally occurring products, such as salmon calcitonin, human calcitonin, porcine calcitonin, eel calcitonin, and fowl calcitonin, and also includes analogues, such as [Asul,7]-eel calcitonin (Elcatonin). Further, insulin includes human insulin, porcine insulin, bovine insulin as well as their analogues, such as recombinants.

Drugs effective on diseases of the lower part of the gastrointestinal tract, such as Crohn disease, ulcerative colitis, irritable colitis, and colic cancer, are also useful in the present invention. Examples of such drugs include salazosulfapyridine, 5-aminosalicylic acid, cortisone acetate, triamcinolone, dexamethasone, budesonide, tegafur, fluorouracil, and derivatives thereof.

In addition to these physiologically active substances, other various physiologically active substances can be used as a main active ingredient that is absorbed efficiently from the lower part of the gastrointestinal tract. For example, antitussive expectorants, such as theophylline; vasodilators, such as nicardipine hydrochloride and nifedipine; coronary vasodilators, such as isosorbide nitrite; antipyretic analgesics, such as acetaminophen, indomethacin, hydrocortisone, ibuprofen, and salazopyrin can be used.

In order to make these drugs easily absorbable in the colon, it is possible to add one or more pharmaceutically acceptable additives to the drug. Suitable additives include surface active agents, such as sucrose fatty acid esters (e.g., Sugar Ester L1695, produced by Mitsubishi Chemical Foods Co., Ltd.), sodium laurylsulfate, polyoxyethylene hydrogenated castor oil (e.g., HCO-60), and polyoxyethylene sorbitan higher fatty acid esters (e.g., Tween 80); cholic acids and salts thereof, such as sodium glycocholate and chenodeoxycholic acid; organic acids and salts thereof, such as citric acid, tartaric acid, benzoic acid, and capric acid; dissolution aids, such as .beta.-cyclodextrin; pH adjusters, such as sodium citrate, meglumine, and MgO; trypsin inhibitors, such as camostat mesilate; enzyme inhibitors, such as aprotinin; antiinflammatory agents, such as salicylic acid, aspirin, sodium dichlofenac; aromas, such as peppermint oil; and antibiotics, such as bacitracin and amphotericin B.

Without depending on whether a drug is acidic or basic, it is possible to adjust the pH of the system at the time when tablets dissolve, by using an organic acid or a basic substance. The organic acids include citric acid and tartaric acid, and the basic substances include solid bases (e.g., MgO), basic amino-sugars (e.g., meglumine), and basic amino acids (e.g., lysine and arginine).

Where a drug has low solubility at pH 6 or lower, a dissolution aids can be added. The dissolution aid is not limited as far as it is pharmaceutically acceptable. Examples include nonionic surface active agents, such as sucrose fatty acid esters, glycerol fatty acid esters, sorbitan fatty acid esters (e.g., sorbitan trioleate), polyethylene glycol, polyoxyethylene hydrogenated castor oil, polyoxyethylene sorbitan fatty acid esters, polyoxyethylene alkyl ethers, methoxypolyoxyethylene alkyl ethers, polyoxyethylene alkylphenyl ethers, polyethylene glycol fatty acid esters, polyoxyethylene alkylamines, polyoxyethylene alkyl thioethers, polyoxyethylene polyoxypropylene copolymers, polyoxyethylene glycerol fatty acid esters, pentaerythritol fatty acid esters, propylene glycol monofatty acid esters, polyoxyethylene propylene glycol monofatty acid esters, polyoxyethylene sorbitol fatty acid esters, fatty acid alkylolamides, and alkylamine oxides; bile acid and salts thereof (e.g., chenodeoxycholic acid, cholic acid, deoxycholic acid, dehydrocholic acid and salts thereof, and glycine or taurine conjugate thereof); ionic surface active agents, such as sodium laurylsulfate, fatty acid soaps, alkylsulfonates, alkylphosphates, ether phosphates, fatty acid salts of basic amino acids; triethanolamine soap, and alkyl quaternary ammonium salts; and amphoteric surface active agents, such as betaines and aminocarboxylic acid salts.

For the purpose of controlling the drug release from tablets, water-soluble polymers, such as polyethylene oxide, hydroxypropylcellulose, hydroxypropylmethylcellulose, and polyvinylpyrrolidone, may be added.

In addition, pharmaceutically acceptable excipients, such as stabilizers and bulking agents, may also be added.

The kind of these additives may be altered according to the drug.

The colon-specific drug release system of the present invention is a preparation comprising, as basic constituents, a saccharide (c) which is degraded by enterobacteria to generate an organic acid, a polymer material (a) which is dissolved by an organic acid generated on degradation of the saccharide by the action of enterobacteria, and an enteric coating polymer material (d). The preparation may have any dosage form, such as tablets, granules, fine granules, powders, and capsules.

Claim 1 of 56 Claims

What is claimed is:

1. An oral drug delivery system for releasing a drug specifically in the colon of the gastrointestinal tract, wherein said system comprises a drug (b) coated with a pharmaceutically acceptable acrylic or cellulosic organic acid-soluble polymer material which dissolves at a pH lower than 6 (a), in an amount of from 2.5% to 40% and a saccharide (c), which rapidly generates an organic acid by the action of enterobacteria in the lower part of the gastrointestinal tract in an amount of from 10% to 99.9%, wherein said composition comprising the drug (b) coated with the organic acid-soluble polymer material (a) and saccharide (c), is further coated with a pharmaceutically acceptable enteric coating polymer material which dissolves at a pH not lower than 6 (d) and wherein said composition when orally administered, is delivered to the lower part of the gastrointestinal tract without releasing the drug (b) at the upper part of the gastrointestinal tract and, at the lower part of the gastrointestinal tract, the polymer (a) coating the drug (b) is dissolved by organic acids generated by degradation of the saccharide (c), by the enterobacteria.

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