Formulation of an erodible, gastric retentive oral diuretic
First Claim
1. An erodible, gastric-retentive drug dosage form for delivering a pharmacologically active agent to the stomach, duodenum, and upper small intestine of a patient, the dosage form comprising the pharmacologically active agent incorporated in a matrix of at least one biocompatible, hydrophilic polymer that (a) swells in the presence of water in gastric fluid such that the size of the dosage form is sufficiently increased to provide gastric retention in the stomach of a patient in whom the fed mode has been induced, (b) gradually erodes within the gastrointestinal tract over a determinable time period, and (c) releases the active agent throughout the determinable time period, wherein the dosage form is formulated so as to provide an active agent release profile in vivo that corresponds to a desired active agent release profile obtained for the dosage form in vitro using USP disintegration test equipment;
- wherein the active agent is a diuretic agent.
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Accused Products
Abstract
An erodible, gastric-retentive oral diuretic is provided that is formulated using the in vitro drug release profile obtained with USP Disintegration test equipment rather the USP Dissolution Apparatus. The invention is premised on the discovery that the USP Disintegration Test and modified versions thereof are far more predictive of the in vivo release profile for a controlled release dosage form than is the standard USP Dissolution Test, particularly controlled release dosage forms of the swellable, erodible type. The dosage forms generally comprise particles of a biocompatible, hydrophilic polymer having the active agent incorporated therein, wherein the particles are optionally but preferably compacted into a tablet or loaded into a capsule. The dosage forms can be used to deliver water-insoluble or sparingly soluble drugs as well as water-soluble drugs, providing that the latter are coated with a protective coating or contained in a protective vesicle. Using the controlled release dosage form, adverse side effects associated with peak diuresis are diminished or eliminated, while the overall diuretic effect of the drug is maintained.
350 Citations
54 Claims
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1. An erodible, gastric-retentive drug dosage form for delivering a pharmacologically active agent to the stomach, duodenum, and upper small intestine of a patient, the dosage form comprising the pharmacologically active agent incorporated in a matrix of at least one biocompatible, hydrophilic polymer that (a) swells in the presence of water in gastric fluid such that the size of the dosage form is sufficiently increased to provide gastric retention in the stomach of a patient in whom the fed mode has been induced, (b) gradually erodes within the gastrointestinal tract over a determinable time period, and (c) releases the active agent throughout the determinable time period, wherein the dosage form is formulated so as to provide an active agent release profile in vivo that corresponds to a desired active agent release profile obtained for the dosage form in vitro using USP disintegration test equipment;
wherein the active agent is a diuretic agent. - View Dependent Claims (2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 52, 53, 54)
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40. A gastric-retentive drug dosage form for delivering a pharmacologically active agent to the stomach, duodenum, and upper small intestine of a patient, the dosage form comprising a bilayer tablet having (a) a first layer that swells in the presence of water in gastric fluid such that the size of the dosage form is sufficiently increased to provide gastric retention in the stomach of a patient in whom the fed mode has been induced;
- and (b) a second layer that contains the pharmacologically active agent and gradually erodes within the gastrointestinal tract over a determinable time period, wherein the bilayer tablet provides an active agent release profile in vivo that corresponds to a desired active agent release profile obtained for the dosage form in vitro using USP disintegration test equipment;
wherein the active agent is a diuretic agent.
- and (b) a second layer that contains the pharmacologically active agent and gradually erodes within the gastrointestinal tract over a determinable time period, wherein the bilayer tablet provides an active agent release profile in vivo that corresponds to a desired active agent release profile obtained for the dosage form in vitro using USP disintegration test equipment;
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41. A sustained release oral dosage form for delivering a pharmacologically active agent to the stomach, duodenum, and upper small intestine of a patient, the dosage form comprising a therapeutically effective amount of the pharmacologically active agent in a matrix of at least one biocompatible hydrophilic polymer, wherein the matrix delivers greater than about 80% of the active agent over a time period in the range of about 2 to about 8 hours in vitro as determined using USP disintegration test equipment, and further wherein the tablet is retained in the stomach when administered to a mammal in whom the fed mode has been induced;
wherein the active agent is a diuretic agent. - View Dependent Claims (42, 43, 44, 45, 46)
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47. A method for selecting an optimized controlled release dosage form for administration to a patient such that the dosage form will have a predetermined drug release profile in vivo, the method comprising:
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(a) preparing a plurality of different candidate dosage forms each comprised of a biocompatible, hydrophilic polymer and a pharmacologically active agent incorporated therein;
(b) obtaining the in vitro drug release profile for each candidate dosage form in an aqueous medium in a USP disintegration tester;
(c) comparing the in vitro drug release profiles obtained in (b), and determining which of the in vitro drug release profiles correlates most closely with a desired in vivo drug release profile; and
(d) selecting the dosage form having the determined in vitro drug release profile for administration to a patient;
wherein the pharmacologically active agent is a diuretic agent. - View Dependent Claims (48, 49, 50, 51)
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Specification