AP658A - Cisapride extended release oral compositions. - Google Patents

Cisapride extended release oral compositions. Download PDF

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Publication number
AP658A
AP658A APAP/P/1997/000969A AP9700969A AP658A AP 658 A AP658 A AP 658A AP 9700969 A AP9700969 A AP 9700969A AP 658 A AP658 A AP 658A
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Prior art keywords
cisapride
weight
extended release
mixture
release formulation
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APAP/P/1997/000969A
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AP9700969A0 (en
Inventor
Eugene Marie Jozef Jans
Paul Marie Victor Gilis
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Janssen Pharmaceutica Nv
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4468—Non condensed piperidines, e.g. piperocaine having a nitrogen directly attached in position 4, e.g. clebopride, fentanyl
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
    • A61K9/2054—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/08—Drugs for disorders of the alimentary tract or the digestive system for nausea, cinetosis or vertigo; Antiemetics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/14—Prodigestives, e.g. acids, enzymes, appetite stimulants, antidyspeptics, tonics, antiflatulents

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  • Health & Medical Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • Chemical & Material Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Medicinal Chemistry (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Epidemiology (AREA)
  • Organic Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Engineering & Computer Science (AREA)
  • Nutrition Science (AREA)
  • Otolaryngology (AREA)
  • Hospice & Palliative Care (AREA)
  • Medicinal Preparation (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Cosmetics (AREA)
  • Polysaccharides And Polysaccharide Derivatives (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Cereal-Derived Products (AREA)

Abstract

Compounds of the formula being extended release formulations comprising cisapride-(l)-tartrate, in particular an oral formulation, the use thereof as a medecine, especially in treating gastrokinetic disorders.

Description

Cisapride extended release oral compositions
The present invention concerns extended release formulations comprising cisapride-(L)tartrate, in particular for oral administration, the use thereof as a medicine, especially in treating gastro-intestinal disorders.
European Patent No. 0,076,530 discloses the gastroprokinetic agent cisapride and classic compositions thereof. Cisapride has the following structural formula :
The systematic chemical name of cisapride is cis-4-amino-5-chloro-N-i 1-13-(415 fluorophenoxy)propyl]-3-methoxy-4-piperidinyl]-2-methoxybenzamide. Cisapride is a racemic mixture of two enantiomers. Cisapride has excellent gastro-intestinal motility stimulating properties and is reported to be devoid of antidopaminergic activity. Its utility in a variety of gastro-intestinal disorders has already been reported extensively.
Useful extended release formulations of cisapride for oral administration should release the active ingredient, i.e. cisapride, over a long period of 15 to 24 hours, that is through the whole gastro-intestinal tract with its varying pH values. However, the solubility of cisapride depends very much on the surrounding pH. The solubility of cisapride is the highest in a strongly acidic medium at pH 1 to 2, such as for example in gastric juice.
The solubility diminishes rapidly when the pH of the (physiological) medium increases, for example in the intestines. An effective sustained release formulation of cisapride should therefore function not only in highly acidic but also in less acidic or neutral media. Moreover an extended release formulation should release the active ingredient as soon as the formulation is administered and should release the active ingredient in a constant manner, preferably following zero order to first order kinetics. This profile is desired because it provides relief to the patient very soon after administration and overdosing is avoided when administering the formulation for a consecutive time.
A solution to this problem was found in the use of (+)-cis-4-amino-5-chloro-N-[l-[3-(435 fluorophenoxy)propyl]-3-methoxy-4-piperidinyl]-2-methoxybenzamide [R(R*,R*)]2,3-dihydroxybutanedioate (1:1) - referred to hereinunder as cisapride-(L)-tartrate - in
AP/P/ 9 7 / 0 0 9 6 9
AP . Ο Ο 6 5 8
-2a matrix formulation as described hereinafter. Cisapride-(L)-tartrate is the salt of racemic cisapride with (+)-L-tartaric acid and is exemplified in European Patent No. 0,076,530 as compound number 241.
An additional aspect of this invention is the fact that the production process for the present extended release formulations is very simple as is shown in the examples hereinunder. This is in contrast to the production processes known in the an for preparing extended release formulations.
In comparison with other salts of cisapride the salt form with [R(R*,R*)]-2,3dihydroxybutanedioic acid, i.e. (+)-L-tartaric acid (the natural form of tartaric acid) shows a remarkably good solubility in water. Cisapride being a racemic mixture and Ltartaric acid being one single enantiomer, the resulting salt form is in principle a mixture of two diastereomeric salts : (+)-cisapride-(L)-tartrate and (-)-cisapride-(L)-tartrate.
Unexpectedly, it was shown that the salt cisapride-(L)-tartrate is a mixture of the diastereomers [(3R4S)(2R3R)] and [(3S4R)(2R3R)], that crystallize as a double salt in a 1:1 ratio. (This is confirmed by X-ray.) The (3R4S) and (3S4R) refer to the respective enantiomers of cisapride and the (2R3R) refers to the optically pure L-tartrate.
Unexpectedly, it was found that formulations containing cisapride-(L)-tanrate released cisapride in a racemic form, i.e. equal amounts of (+)-cisapride and (-)-cisapride or in o±er words the diastereomeric salt forms (+)-cisapride-(L)-tartrate and (-)-cisapride-(L)tartrate unexpectedly have equal dissolution rates.
Moreover, it was also found that during the preparation of cisapride-(E)-tartrate no enrichment of one of the two diastereomeric salt forms could be detected.
Compositions according to the present invention comprise pharmaceutically acceptable carriers and excipients, such as fillers, e.g. lactose, sucrose, mannitol, maize starch, preferably lactose; lubricants e.g. stearic acid, magnesium stearate, talc or silica or mixtures thereof; preferably a mixture of magnesium stearate, talc and colloidal silicon dioxide (Aerosil ®). Also other pharmaceutically acceptable additives such as colorants or flavorings and the like may be present.
The retard-effect or extended release effect is due to the fact that the cisapride-(L)tartrate is embedded in a mixture of two viscous polymers. Hence, the formulation
AP/P/ 97/00969
AP . Ο Ο 6 5 8
-3comprises a mixture of a highly viscous hydrophilic polymer and a viscous hydrophilic polymer, which releases the active ingredient gradually from the formulation. For the present active ingredient, cisapride-(L)-tartrate, this can conveniently be achieved using a mixture of hydroxypropyl methylcellulose and another viscous cellulose derivative such as, hydroxypropylcellulose, ethylcellulose, hydroxyethylcellulose, hydroxyethyl methylcellulose, methylcellulose, preferably hydroxypropylcellulose.
These two hydrophilic polymers swell when in contact with water, thus creating a porous matrix from which the cisapride can gradually be released. The said polymers themselves also dissolve slowly in the aqueous medium. Consequently, the surface of the formulation is also constantly dissolving and so the aqueous medium can reach the more inward mixture of polymers, that in turn begins swelling and releasing active ingredient thus providing for a continous release of active ingredient following a zero order to first order kinetics.
The hydroxypropyl methylcellulose used in the above mentioned mixture preferably has a viscosity of about 15,000 mPa.s, e.g. hypromellose 2208.
The hydroxypropylcellulose used in the above mentioned mixture should preferably have a viscosity ranging from 150 to 700 mPa.s, preferably from 200 to 600 mPa.s, e.g. Klucel EF ®.
The relative amount of said mixture of viscous hydrophilic cellulose polymers in a formulation ranges preferably between 15 % and 35 % of the total composition weight.
The relative amount of mixture of viscous hydrophilic cellulose polymers correlates with the period during which the active ingredient is released. The lowest limit, i.e. 15 %, gives a reasonably extended release period of about 900 minutes. The highest limit, i.e.
% leads to longer release periods yet still releasing all of the active ingredient present in the formulation. At relative amounts higher than 35 % there is expected to be an incomplete release of the active ingredient.
The ratio of the weight hydroxypropyl methylcellulose over weight of the other cellulose polymer ranges from 0.33 to 3. In particular the ratio of the weight of hydroxypropyl methylcellulose over the weight hydroxypropyl cellulose ranges from 0.33 to 3. The preferred ratio is 1, i.e. equal amounts of hvdroxypropyl methyl cellulose and hydroxypropylcellulose are present.
The preferred oral formulation of the present invention is a tablet.
AP/P/ 97/00969
AP.00658
-4Said tablets may have different kinds of shapes, e.g. oblong or right circular. The shape of the tablet influences the release period, because of the fact that different shapes have a different ratio of surface over volume.
A person skilled in the art will appreciate that the volume of the tablet is function of other parameters such as, the actual composition, shape, intended period of release and the intended dose. The exemplified compositions are given for right circular tablets with a diameter of about 11.5 mm diameter and a height of about 5.2 mm.
Said tablets may have lines or break-marks and may bear a symbol or other markings.
Said tablets can optionally be coated with art-known coating compositions. Coated tablets are the preferred formulation in this invention. The above ingredients and ratios apply for the formulation-core in general, the tablet-core in particular, the compositions of these formulation-cores willed be called core-compositions hereinafter.
Suitable coating formulations comprise a filmforming polymer such as, for example, hydroxypropyl methylcellulose, e.g. hypromellose 2910 (5 mPa.s); a plasticizer such as, for example, a glycol, e.g. propylene glycol; an opacifier, such as titanium dioxide; a film smoothener, such as talc. Water is added as a solvent.
AP/P/ 9 7 / 0 0 9 6 9
Suitable core compositions are : 25 cisapride-(L)-tartrate ; filler:
hydrophilic polymer mixture ;
lubricants:
Interesting core compositions are :
cisapride-(L)-tartrate : filler:
hydrophilic polymer mixture : lubricants :
from 2 to 15 % by weight from 50 to 70 % by weight from 15 to 35 % by weight from 0.5 % to 10 % by weight from 5 to 15 % by weight from 50 to 70 % by weight from 15 to 35 % by weight from 0.5 % to 10 % by weight
More interesting core compositions are :
AP.00658
-5cisapride-(L)-tartrate : filler :
hydrophilic polymer mixture : lubricants :
Particular core compositions are :
from 8 to 12 % by weight from 55 to 65 % by weight from 20 to 25 % by weight from 2.5 % to 8 % by weight cisapride-(L)-tartrate: filler:
hydrophilic polymer mixture : lubricants :
about 9 % by weight about 61 % by weight about 23.5 % by weight about 6.5 % by weight
Preferred core compositions are :
cisapride-(L)-tartrate : about 9 % by weight lactose : about 61 % by weight hydroxypropyl methylcellulose: from 5.5 % to 18 % (*) hydroxypropyl cellulose from 5.5 % to 18 % (*) lubricants: about 6.5 % by weight (*) the total amount of cellulose derivatives in weight percent being about 23.5 %
In view of the gastro-intestinal motility stimulating properties of cisapride, the present invention provides the use of the present formulation as a medicine, in particular in treating gastro-intestinal disorders.
Experimental part
Example 1
To a stirred solution of cis-4-amino-5-chloro-N-[l-[3-(4-fluorophenoxy)propyl]3-methoxy-4-piperidinyl]-2-methoxybenzamide (4 g) in ethanol (81 ml) was added a solution of [R(R*,R*)]-2,3-dihydroxybutanedioic acid (1.4 g) in ethanol (20 ml) and the product was allowed to crystallize. It was filtered off and dried, yielding 4.8 g (89%) of
5 (+) -cis-4-amino- 5 -chloro-N- [ 1 - [ 3-(4-fluorophenoxy)propy 1] - 3- methoxy-4-piperidiny 1] 2-methoxybenzamide [R(R*,R*)]-2,3-dihydroxybutanedioate (1:1), i.e. cisapride-(L)20 tatrate. Melting point is 197.1 *C and [α]β is 6.7 (c = 0.1 % methanol).
AP/P/ 9 7 / 0 0 969
AP.00658
-6Example 2
Ingredients for the preparation of 1000 tablets (570 mg) of formulation 1 :
5 Ingredient amount % of tablet weight
cisapride-(L)-tartrate 52.92 g 9.3 %
Lactose 346.08 g 60.7 %
10 Hydroxypropylmethylcellulose 2208 66 g 11.6 %
Klucel EF ® 67.95 g 11.9 %
water (*) 60 g
isopropanol (*) 140 g
magnesium stearate 2.85 g 0.5 %
15 Aerosil ® 5.7 g 1.0 %
talc 28.5 g 5.0 %
(*) these ingredients are not comprised in the final composition of the tablet.
Preparation :
The above mentioned amounts of cisapride-(L)-tartrate, lactose, hvdroxypropylmethylcellulose, Klucel EF® were sieved over a stainless-steel frame sieve (mesh 0.95 mm) and were mixed in a planetary powder mixer during 5 minutes. The mixture was wetted with isopropanol and water. The wetted mixture was again sieved over a frame sieve (mesh : 1.8 mm). The mixture was dried overnight at a temperature of 45 °C. The dried granulate was sieved over a frame sieve (mesh : 0.95 mm). The dried and sieved granulate was mixed with sieved magnesium stearate, Aerosil ® and talc in a planetary powder mixer during 5 minutes.
Preparation of tablets:
Using the above described mixture 1000 tablets were compressed.
Example 3
AP/P/ 97/00969
AP.00658
-7Ingredients for the preparation of 1000 tablets (tablets of 570 mg) of formulation 2 :
Ingredient amount % of tablet weight
cisapride-(L)-tartrate 52.92 g 9.3 %
lactose 346.08 g 60.7 %
Hypromellose 2208 40 g 7.0 %
Klucel EF ® 93.95 g 16.5 %
water (*) 45 g
isopropanol (*) 105 g
magnesium stearate 2.85 g 0.5 %
Aerosil ® 5.7 g ' 1.0 %
talc 28.5 g 5.0 %
(*) these ingredients are not comprised in the final composition of the tablet.
Preparation is completely analogous to the preparation as described for formulation 1.
Example 4
AP/P/ 97/00969
Ingredients for the preparation of 1000 tablets of fonmulation
cisapride-(L)-tartrate 52.92 mg
25 lactose monohydrate 346.08 mg
Hypromellose 2208 15000mPa.s 66 mg
Hydroxypropylcellulose 67.95 mg
water (*)
isopropanol (*)
30 magnesium stearate 2.85 mg
Aerosil® 5.7 mg
Talc 28.5 mg
Coating composition
Hypromellose 2910 5mPa.s propylene glycol mg 3 mg
AP.00658
-8titanium dioxide talc water (*) mg 2 ms
120 ms
Preparation
Cisapride-(L)-tartrate, lactose, Hypromellose and Klucel® are mixed in a high shear mixture- granulator and wetted with a mixture of isopropanol and water. The granulate thus formed is dried by heating in vacuo. After calibrating the dried granulate aerosil, talc and magnesium stearate are added and mixed till a homogeneous mixture is obtained. Biconvex tablets with a diameter of 11.5 mm weighing about 570 mg are compressed.
The tablets are coated in a suitable coating vessel with a coating suspension consisting of hypromellose (5 mPa.s), propyleneglycol, titanium dioxide, talc and water.
AP/P/ 9 7 / 0 0 969

Claims (9)

Claims
1. An extended release formulation comprising cisapride-(L)-tartrate suitable for oral administration.
2. An extended release formulation as claimed in claim 1 comprising a mixture of hydroxypropyl methylcellulose and another viscous cellulose polymer.
3. An extended release formulation as claimed in claim 2 comprising a mixture of
10 hydroxypropyl methylcellulose and hydroxypropyl cellulose.
4. An extended release formulation as claimed in claim 2 wherein the core of the formulation comprises from 15 % to 35 % of the mixture of hydroxypropyl methylcellulose and another viscous cellulose polymer.
5. An extended release formulation as claimed in claim 4 wherein the ratio of the weight of hydroxypropyl methylcellulose over the weight of hydroxypropylcellulose ranges from about 0.33 to about 3.
20
6. An extended release formulation as claimed in claim 5 wherein the ratio of the weight of hydroxypropyl methylcellulose over the weight of hydroxypropylcellulose is about 1.
7. An extended release formulation as claimed in any of claims 1 to 4 comprising :
25 cisapride-(L)-tartrate : about 9 % by weight lactose : about 61 % by weight hydroxypropyl methylcellulose: from 5.5 % to 18 % hydroxypropyl cellulose from 5.5 % to 18 % lubricants : about 6.5 % by weight,
30 the total weight percent of cellulose derivatives being about 23.5 %.
8 · Process of preparing an extended release formulation as claimed in any of the claims 1 to 7 characterized in that the active ingredient is intimately mixed with the other pharmaceutically acceptable ingredients.
9. Use of a composition as claimed in any of claims 1 to 7 for use as a medicine, especially for treating gastro-intestinal disorders.
APAP/P/1997/000969A 1994-11-02 1995-10-25 Cisapride extended release oral compositions. AP658A (en)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
EP94203184 1994-11-02
PCT/EP1995/004198 WO1996014070A1 (en) 1994-11-02 1995-10-25 Cisapride extended release oral compositions

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AP9700969A0 AP9700969A0 (en) 1997-04-30
AP658A true AP658A (en) 1998-08-17

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APAP/P/1997/000969A AP658A (en) 1994-11-02 1995-10-25 Cisapride extended release oral compositions.

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US (2) US6153623A (en)
EP (1) EP0789572A1 (en)
JP (1) JP3182423B2 (en)
KR (1) KR100255521B1 (en)
AP (1) AP658A (en)
AR (1) AR001765A1 (en)
AU (1) AU704284B2 (en)
BG (1) BG63244B1 (en)
BR (1) BR9509565A (en)
CA (1) CA2203663C (en)
CZ (1) CZ287844B6 (en)
EE (1) EE03510B1 (en)
FI (1) FI971856A0 (en)
HR (1) HRP950539A2 (en)
HU (1) HUT77887A (en)
IL (1) IL115843A0 (en)
MY (1) MY113092A (en)
NO (1) NO312538B1 (en)
NZ (1) NZ295166A (en)
OA (1) OA10419A (en)
PL (1) PL181470B1 (en)
RO (1) RO116042B1 (en)
RU (1) RU2143890C1 (en)
SK (1) SK54297A3 (en)
TR (1) TR199501351A2 (en)
TW (1) TW466114B (en)
UA (1) UA50721C2 (en)
WO (1) WO1996014070A1 (en)
ZA (1) ZA959221B (en)

Families Citing this family (13)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
ZA959221B (en) * 1994-11-02 1997-04-30 Janssen Pharmaceutica Nv Cisapride extended release
EP0866707A1 (en) * 1995-12-01 1998-09-30 Janssen Pharmaceutica N.V. Cisapride sustained release
DE69713948D1 (en) * 1996-04-23 2002-08-22 Janssen Pharmaceutica Nv Rapidly releasing pH-independent solid dosage forms containing cisapride
AU7888298A (en) * 1997-01-03 1998-07-31 Elan Corporation, Plc Sustained release cisapride minitablet formulation
CA2292628A1 (en) * 1997-06-11 1998-12-17 Janssen Pharmaceutica, N.V. Immediate release ph-independent solid dosage form of (+)- or (-)-cisapride
TW407058B (en) * 1998-07-17 2000-10-01 Dev Center Biotechnology Oral cisapride dosage forms with an extended duration
ATE313319T1 (en) 1999-03-31 2006-01-15 Janssen Pharmaceutica Nv PREGELATINATED STARCH IN A CONTROLLED RELEASE FORMULATION
EP1060743A1 (en) * 1999-06-17 2000-12-20 Development Center For Biotechnology Oral cisapride dosage forms with an extended duration
SI1345595T1 (en) * 2000-09-29 2007-08-31 Solvay Pharm Bv Ion-strength independent sustained release pharmaceutical formulation
ES2312525T3 (en) * 2002-05-21 2009-03-01 Watson Laboratories, Inc. PHARMACEUTICAL FORMULATION WITH PROLONGED RELEASE.
ES2557165T3 (en) 2006-04-12 2016-01-22 Nippon Soda Co., Ltd. Method to produce a sustained-release tablet
RU2356532C2 (en) * 2007-06-01 2009-05-27 Открытое Акционерное Общество "Отечественные Лекарства" Controlled-release pharmaceutical proxodolol composition
US20120065221A1 (en) 2009-02-26 2012-03-15 Theraquest Biosciences, Inc. Extended Release Oral Pharmaceutical Compositions of 3-Hydroxy-N-Methylmorphinan and Method of Use

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0076530A2 (en) * 1981-10-01 1983-04-13 Janssen Pharmaceutica N.V. Novel N-(3-hydroxy-4-piperidinyl)benzamide derivatives
WO1993018755A1 (en) * 1992-03-25 1993-09-30 Depomed Systems, Incorporated Alkyl-substituted cellulose-based sustained-release oral drug dosage forms
WO1996014070A1 (en) * 1994-11-02 1996-05-17 Janssen Pharmaceutica N.V. Cisapride extended release oral compositions

Family Cites Families (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5057525A (en) * 1981-10-01 1991-10-15 Janssen Pharmaceutica N.V. Novel N-(3-hydroxy-4-piperidinyl) benzamide derivatives
JPH08502032A (en) * 1992-07-07 1996-03-05 セプラコア インコーポレーテッド Method of using ▲ (−) ▼ cisapride for treating gastroesophageal reflux disease and other disorders

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0076530A2 (en) * 1981-10-01 1983-04-13 Janssen Pharmaceutica N.V. Novel N-(3-hydroxy-4-piperidinyl)benzamide derivatives
WO1993018755A1 (en) * 1992-03-25 1993-09-30 Depomed Systems, Incorporated Alkyl-substituted cellulose-based sustained-release oral drug dosage forms
WO1996014070A1 (en) * 1994-11-02 1996-05-17 Janssen Pharmaceutica N.V. Cisapride extended release oral compositions

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AU704284B2 (en) 1999-04-15
FI971856A (en) 1997-04-30
WO1996014070A1 (en) 1996-05-17
JP3182423B2 (en) 2001-07-03
CA2203663C (en) 2002-04-30
RO116042B1 (en) 2000-10-30
SK54297A3 (en) 1997-10-08
ZA959221B (en) 1997-04-30
AP9700969A0 (en) 1997-04-30
CA2203663A1 (en) 1996-05-17
BR9509565A (en) 1997-09-16
KR100255521B1 (en) 2000-05-01
IL115843A0 (en) 1996-01-31
NO971832L (en) 1997-04-21
HUT77887A (en) 1998-09-28
FI971856A0 (en) 1997-04-30
CZ287844B6 (en) 2001-02-14
NO312538B1 (en) 2002-05-27
US6274599B1 (en) 2001-08-14
UA50721C2 (en) 2002-11-15
TR199501351A2 (en) 1996-06-21
PL181470B1 (en) 2001-07-31
MY113092A (en) 2001-11-30
US6153623A (en) 2000-11-28
EE03510B1 (en) 2001-10-15
TW466114B (en) 2001-12-01
EP0789572A1 (en) 1997-08-20
NZ295166A (en) 1999-03-29
BG101401A (en) 1997-12-30
MX9703249A (en) 1997-07-31
HRP950539A2 (en) 1997-08-31
AU3844795A (en) 1996-05-31
EE9700105A (en) 1997-12-15
NO971832D0 (en) 1997-04-21
CZ124497A3 (en) 1997-08-13
OA10419A (en) 2001-12-06
AR001765A1 (en) 1997-12-10
BG63244B1 (en) 2001-07-31
PL319948A1 (en) 1997-09-01
RU2143890C1 (en) 2000-01-10
JPH09511760A (en) 1997-11-25

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