Hydrogel-forming sustained-release preparation

Abstract

The invention provides a hydrogel-type sustained-release preparation comprising (1) at least one drug, (2) an additive which insures a penetration of water into the core of the preparation and (3) a hydrogel-forming polymer, wherein said preparation is capable of undergoing substantially complete gelation during its stay in the upper digestive tract such as stomach and small intestine and is capable of releasing the drug in the lower digestive tract including colon. By the preparation of the invention, the drug is efficiently released and absorbed even in the colon so that a steady and sustained release effect can be achieved.

Description

[0001] 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.[0002] 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 etc. comprisi...

AI Technical Summary

Benefits of technology

[0008] 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.

[0015] The additive for allowing water to penetrate into the core of the preparation according to the present invention (this additive for insuring a penetration of water into the preparation core will hereinafter be referred to as "hydrophilic base") is such that the amount of water required to dissolve 1 g of the hydrophilic base is not more than 5 ml and preferably not more than 4 ml at the temperature of 20.+-.5.degree. C. The higher the solubility of the hydrophilic base in water, the more effective is the base in allowing water into the core of the preparation. The hydrophilic base includes, inter alia, highly hydrophilic polymers such as polyethylene glycol (PEG; e.g. PEG400, PEG1500, PEG4000, PEG6000 and PEG20000, produced by Nippon Oils and Fats Co.) and polyvinylpyrrolidone (PVP; e.g. PVP K30, the trade name of BASF), sugar alcohols such as D-sorbitol, xylitol, etc., sugars such as sucrose, anhydrous maltose, D-fructose, dextran (e.g. dextran 40), glucose, etc., surfactants such as polyoxyethylene-hydrogenated castor oil (HCO; e.g. Cremophor RH40 produced by BASF, HCO-40 and HCO-60 produced by Nikko Chemicals Co.), polyoxyethylene-polyoxypropylene glycol (e.g. Pluronic F68 produced by Asahi Denka Kogyo K.K.), polyoxyethylene-sorbitan high molecular fatty acid ester (Tween; e.g. Tween 80 produced by Kanto Kagaku K.K.), etc.; salts such as sodium chloride, magnesium chloride, etc.; organic acids such as citric acid, tartaric acid, etc.; amino acids such as glycine, .beta.-alanine, lysine hydrochloride, etc.; and amino sugars such as meglumine.

[0067] It was found that the rate of dissolution could be controlled by varying the proportion of the hydrogel-forming base POLYOX303. It was also found that when 50 mg of acetaminophen was used as the principal agent and not less than 100 mg (50% of tablet weight) of POLYOX303 was added, a sustained release of the drug lasting for not less than 12 hours was realized even under vigorous agitation (paddle speed 200 rpm, pH 6.8). Similarly, when 80 mg of Pd was used as the principal agent, the inclusion of not less than 96 mg (37.5% of tablet weight) of POLYOX303 insured a sustained release lasting for not less than 12 hours even under vigorous agitation (paddle speed 200 rpm, pH 1.2).

[0096] Depending on the intended use, the product of the invention can be provided in the form of a dry coated tablet. For example, when a high blood concentration at a definite time after administration is desired, the core tablet is manufactured according to a formulation providing for rapid drug release (with an increased amount of the drug, a reduced amount of the hydrogel-forming base, and / or an increased amount of the hydrophilic base) and, then, the outer layer is formed using a formulation providing for retarded release (with a reduced amount of the drug, an increased amount of the hydrogel-forming base and / or a reduced amount of the hydrophilic base) so that the rate of drug release may be accelerated after a predetermined time.

Problems solved by technology

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.

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 colon (Pharm. Tech. Japan 8 (1), (1992), 41).

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).

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