Drug – bio-affecting and body treating compositions – Preparations characterized by special physical form – Tablets – lozenges – or pills
Reexamination Certificate
1999-07-07
2001-04-24
Page, Thurman K. (Department: 1615)
Drug, bio-affecting and body treating compositions
Preparations characterized by special physical form
Tablets, lozenges, or pills
C424S474000, C424S490000, C424S494000, C424S497000
Reexamination Certificate
active
06221396
ABSTRACT:
BACKGROUND OF THE INVENTION
1. Field of the Invention
The present invention relates to bioavailable sustained release cisapride formulations which provide an extended duration of effect when orally administered.
2. Description of Related Prior Art
Formulations which can provide sustained release (slow release) of pharmacologically active substances when administrated orally to humans or animals are well-known in the pharmaceutical art. A sustained release formulation is used to delay absorption of an active substance until it has reached a desired area in the gastrointestinal tract. Sustained release preparations provide a longer period of the drug substances in blood after the administration of the substance than traditional rapid release dosage forms.
EP 0076530 A2 and U.S. Pat. No. 4,962,115 disclose cisapride, i.e., (±)-cis-4-amino-5-chloro-N-1-[3-(4-fluorophenoxy)propyl]-3-methoxy-4-piperidine-2-methoxybenzamide monohydrate, as a gastroenterokinetic promoter and the synthesis thereof, which are incorporated herein by reference. Cisapride has two enantiomers consisting of (+)-cisapride and (−)-cisapride. Cisapride is known to be able to enhance the propelling activity of esophagus, increase the tensile force of lower esophageal sphincter, and promote the gastrointestinal emptying. With respect to therapeutic applications, cisapride can be used in therapy of a variety of diseases associated with gastroenterokinesia (such as reflective reflux of esophagus, anorexia, nausea and emesis), gastroparesis resulted from neurectomy and vagal neurectomy, pseudo-ileus and chronic constipation. The pharmacological mechanism of cisapride is mainly involved in stimulating plexus myentericus to enhance physiological secretion of acetylcholine.
There are many inherent advantages on the development of long-term effective sustained release formulations. Among the advantages, sustained release dosage forms increase the compliance of patients. It is more convenient for patients to receive long-term effective sustained release cisapride dosage forms once or twice a day than the conventional cisapride dosage forms administered four times a day. Another advantage of sustained release formulations is to greatly reduce various adverse side effects caused by drug administration. A desired modulation of local or systemic drug concentrations in patients would be resulted from the slow release of the sustained release dosage forms. Appropriate modulation of the adverse effects upon administering conventional cisapride dosage forms, such as diarrhea and colic, can be alleviated to a great extent.
A major issue during the development of a sustained release cisapride dosage form was how to overcome the problem of the solubility of cisapride. It is known in the art that a better solubility of cisapride was observed under acidic conditions, while a very poor solubility, almost insoluble, in a pH condition near neutral (i.e., the pH of intestinal fluid) was observed. A good sustained release dosage form should meet the goal to allow an appropriate amount of a drug substance sustained-release in every area of the gastrointestinal tract. The major technical concerns during developing a cisapride sustained release dosage form focus on a possible solution to the existing problem that an effective level of drug in the blood cannot be maintained for a long period. The dissolution of cisapride in a neutral pH condition in the intestinal tract is so poor as not to allow cisapride persistently released in an adequate amount.
There are a number of techniques for promoting solubility and dissolution of drugs. For example, U.S. Pat. No. 5,646,131 describes a method for the solubility improvement of water insoluble or almost insoluble drugs where a composition comprising a cyclodextrin, a carboxylic acid and a drug was provided to enhance the solubility of the drug or its complex.
U.S. Pat. No. 5,582,837 discloses a formulation capable of increasing the residence time in the stomach in view of the feature of cisapride (good solubility the stomach) to provide a resolution to the little solubility in the intestine. The prior formulation was a drug composition in the tablet or capsule form including hydroxyethylcellulose, hydroxypropylcellulose, and the like. The drug composition would be disintegrated into small particulates in the stomach. The particulates absorb water and swell to form hydrogel-like materials which can extend the residence time in the stomach such that the slow-release effect can be achieved.
WO 96/14070 describes a method of improving the solubility of cisapride by forming a cisapride-(L)-tartrate from cisapride and tartaric acid. A sustained release tablet comprising hydroxypropylmethylcellulose with high viscosity (e.g., 15000 mPa.s) and the thus-formed cisapride-(L)-tartrate was also provided in WO 96/14070. Hydroxypropylmethylcellulose with high molecular weight would form a hydrogel in water to achieve slow release of cisapride.
All of the literature references and publications as mentioned herein are incorporated by reference.
The prior approaches, such as a complex of cyclodextrin and cisapride or a salt of tartaric acid and cisapride, may enhance the solubility of cisapride in the stomach to some extent. However, the problem resulted from the pharmacokinetic profile of cisapride (i.e., good solubility in an acidic environment, while poor solubility in a neutral or basic environment) has not been resolved yet. Furthermore, whether the pharmacodynamic properties of the prior cisapride complex or salt are comparable to cisapride still needs to undergo time-consuming and expensive experiments.
Therefore, there is a need in the art for a long-term effective cisapride formulation, such as suitable for once- or twice-a-day administration, which would be more convenient for administration to patients. The formulation would be expected to have enhanced solubility in the intestinal tract and retain the pharmacodynamic characteristics of cisapride.
SUMMARY OF THE INVENTION
An objective of the present invention is to provide an oral pharmaceutical dosage form of cisapride, which is suitable for once- or twice-a-day administration.
Another objective of the present invention is to provide a sustained release cisapride preparation which is bioavailable and can provide a patient an effective steady-state blood level for longer than 12 hours, preferably at least 24 hours.
Another objective of the present invention is to provide a method for treating a patient with an oral cisapride dosage form which is bioavailable and can provide a desired effective period of longer than 12 hours, preferably at least 24 hours.
More particularly, yet another objective of the present invention is to provide a once-a-day oral sustained release cisapride dosage form, which comprises a plurality of pharmaceutically acceptable substrates in a unit dosage. The unit dosage of the substrates comprise an effective amount of cisapride. The unit dosage is bioavailable and provides an effective blood level of cisapride for at least 24 hours. The unit dosage of the substrates, for example, can be encapsulated within a hard gelatin capsule for oral administration.
The present invention further relates to a bioavailable sustained release cisapride dosage form which comprises pharmaceutically acceptable substrates coated with one or more layers comprising an effective amount of cisapride and one or more enteric polymers. The enteric polymer is selected from the group consisting of:
(i) an enteric acrylic polymer, such as copolymer of methyl methacrylate and methacrylic acid;
(ii) a phthalic acid derivative of vinyl polymer or copolymer, such as copolymers of vinyl alcohol, vinyl acetate and vinyl phthalate; and
(iii) a phthalic acid derivative of cellulose, such as hydroxypropylmethyl cellulose phthalate or cellulose acetate phthalate.
The dosage form according to the present invention is capable of providing a sustained release of cisapride in an aqueous medium at least 24 hours.
The present invention further relat
Chang Hui-Fang
Chao Shouchung
Chen David
Lu Shu-Bin
Tseng Wen-Pao
Development Center for Biotechnology
Ladas & Parry
Page Thurman K.
Tran S.
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