Drug – bio-affecting and body treating compositions – Preparations characterized by special physical form – Matrices
Reexamination Certificate
1995-03-20
2002-08-20
Webman, Edward J. (Department: 1617)
Drug, bio-affecting and body treating compositions
Preparations characterized by special physical form
Matrices
C424S487000, C424S484000, C424S468000, C424S465000
Reexamination Certificate
active
06436441
ABSTRACT:
TECHNICAL FIELD
The present invention relates to a sustained-release preparation capable of releasing a drug for a prolonged period of time. More particularly, the invention relates to a hydrogel-type sustained-release preparation capable of satisfactorily releasing a drug not only in the upper digestive tract but also in the lower digestive tract, particularly in the colon.
BACKGROUND ART
A variety of hydrogel-type preparations have heretofore been proposed for realizing sustained release of drugs. For example, JP-A-62-120315 discloses a preparation obtained by compression-molding a drug, a hydrogel-forming water-soluble polymer and an enteric coating base (the term “JP-A”as used herein means an “unexamined published Japanese patent application”). JP-A-63-215620 discloses a hydrogel-type preparation which comprises a core comprising a drug and a water-soluble polymer and an outer layer comprising a water-soluble polymer as a base. JP-B-40-2053 discloses a sustained-release preparation comprising a mixture of a drug and a high polymer of ethylene oxide and, as an optional component, a hydrophilic substance (the term “JP-B” as used herein means an “examined Japanese patent publication”).
However, all of these preparations are designed to release a drug continuously while the administered preparation is still retained in the upper digestive tract, typically in the stomach and small intestine, and are not intended to provide for a release of the drug in the lower digestive tract, typically in the colon, where little water is available. Thus, for any sustained-release preparation designed to release a drug for absorption during its descent down in the digestive tract, the extent of drug release and absorption in the upper digestive tract has a major influence on the bioavailability of the drug. However, it is generally believed that the release of the drug in the colon can hardly be expected because of the paucity of water and the influence of spodogenous contents etc. and actually, little research has been undertaken on drug release in the colon (Pharm. Tech. Japan 8 (1), (1992), 41).
Furthermore, the biological half-life of a drug per se is also an important factor in the design of sustained-release preparations. It has been generally considered difficult to design a preparation providing for dramatic sustained release for a drug having a short half-life period (The Pharmaceuticals Monthly 25 (11), (1983), 29).
DISCLOSURE OF INVENTION
As a result of extensive studies on the sustained-release of a drug, the inventors of the present invention discovered that the release of a drug in the colon, which is low in water content, can be achieved by providing a preparation adapted to absorb water into its core to undergo substantially complete gelation during its stay in the upper digestive tract such as the stomach and small intestine, and then move in the form of the gel down to the lower digestive tract. The present invention was achieved based on the above finding.
Thus, the present invention relates to a hydrogel-type sustained-release preparation comprising (1) at least one drug, (2) an additive providing for a penetration of water into the core of the preparation, and (3) a hydrogel-forming polymer, which preparation undergoes a substantially complete gelation during its stay in the upper digestive tract such as the stomach and small intestine and is capable of releasing a drug in the colon.
The term “substantially complete gelation” of the preparation as used in this specification refers to the state in which not less than about 70%, preferably not less than about 80%, of the preparation is gelled.
Since even the colon can be utilized as a site of absorption, the sustained-release preparation of the present invention prolongs the absorption period of the drug to a remarkable extent and, hence, insures a steady blood level of the drug. Thus, the preparation of the present invention absorbs water during its stay in the upper digestive tract to undergo a substantially complete gelation and then moves down into the lower digestive tract with its surface being constantly eroded, and maintains drug release by further erosion in the lower digestive tract, with the result that a sustained and sufficient absorption of the drug is achieved even in the colon where little water is available.
The sustained-release preparation of the present invention is described in further detail hereinafter.
The drug or drugs which can be used in the preparation according to the present invention are not particularly limited in kind, provided that they are used for sustained-release system.
Thus, representative examples of the drugs include antiinflammatory, antipyretic, anticonvulsant and/or analgesic agents such as indomethacin, diclofenac, diclofenac Na, codeine, ibuprofen, phenylbutazone, oxyphenbutazone, mepirizol, aspirin, ethenzamide, acetaminophen, aminopyrine, phenacetin, scopolamine butylbromide, morphine, etomidoline, pentazocine, fenoprofen calcium, etc; tuberculostats such as isoniazid, ethambutol hydrochloride, etc.; cardiocirculatory system drugs such as isosorbide dinitrate, nitroglycerin, nifedipine, barnidipine hydrochloride, nicardipine hydrochloride, dipyridamole, amrinone, indenolol hydrochloride, hydralazine hydrochloride, methyldopa, furosemide, spironolactone, guanethidine nitrate, reserpine, amosulalol hydrochloride, etc.; antipsychotic agents such as chlorpromazine hydrochloride, amitriptyline hydrochloride, nemonapride, haloperidol, moperone hydrochloride, perphenazine, diazepam, lorazepam, chlordiazepoxide, etc.; antihistaminic agents such as chlorpheniramine maleate, diphenhydramine hydrochloride, etc.; vitamins such as thiamine nitrate, tocopherol acetate, cycothiamine, pyridoxal phosphate, cobamamide, ascorbic acid, nicotinamide, etc.; antigout agents such as allopurinol, colchicine, probenecid, etc.; hypnotic sedatives such as amobarbital, bromovalerylurea, midazolam, chloral hydrate, etc.; antineoplastic agents such as fluorouracil, carmofur, aclarubicin hydrochloride, cyclophosphamide, thiotepa, etc.; anticongestants such as phenylpropanolamine, ephedrine, etc.; antidiabetics such as acetohexamide, insulin, tolbutamide, etc.; diuretics such as hydrochlorothiazide, polythiazide, triamterene, etc.; bronchodilators such as aminophylline, formoterol fumarate, theophylline, etc; antitussives such as codeine phosphate, noscapine, dimemorfan phosphate, dextromethorphan, etc; antiarrhythmic agents such as quinidine nitrate, digitoxin, propafenone hydrochloride, procainamide, etc.; surface anesthetics such as ethyl aminobenzoate, lidocaine, dibucaine hydrochloride, etc.; antiepileptics such as phenytoin, ethosuximide, primidone, etc.; synthetic adrenocortical steroids such as hydrocortisone, prednisolone, triamcinolone, betamethasone, etc.; digestive system drugs such as famotidine, ranitidine hydrochloride, cimetidine, sucralfate, sulpiride, teprenone, plaunotol, etc.; central nervous system drugs such as indeloxazine, idebenone, tiapride hydrochloride, bifemeline hydrochloride, calcium hopantenate, etc.; hyperlipemia treating agents such as pravastatin sodium etc.; and antibiotics such as ampicillin phthalidyl hydrochloride, cefotetan, josamycin and so on. A typical drug among the above drugs is nicardipine hydrochloride. Drugs having short biological half-lives can also be utilized. The amount of the drug may be any of pharmaceutically effective amount, but is usually below 85 weight %, and preferably below 80 weight % based on the total weight of the preparation.
In order that these drugs may be readily absorbed in the colon which is low in water content, it is preferable to improve their solubilities in advance. Known techniques for improving the solubility of a drug which can be applied to hydrogel preparation can be employed. Among such techniques (solubilizing treatment) can be mentioned the method comprising adding a surfactant (e.g. polyoxyethylene-hydrogenated castor oils, polyoxy-ethylene-sorbitan higher fatty acid esters, polyoxyethylene polyoxypropylene glycols, sucro
Fukui Muneo
Nakashima Hiroshi
Okada Akira
Sako Kazuhiro
Sawada Toyohiro
Sughrue, Mion, Zinn Macpeack & Seas, PLLC
Webman Edward J.
Yamanouchi Pharmaceutical Co. Ltd.
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