US 2007/0190145 A1 · DRUG DELIVERY SYSTEMS COMPRISING WEAKLY BASIC SELECTIVE SEROTONIN 5-HT3 BLOCKING AGENT AND ORGANIC ACIDS

Abstract

A pharmaceutical dosage form such as a capsule, a conventional or orally disintegrating tablet capable of delivering a weakly basic, nitrogen (N)-containing selective serotonin 5-HT3 blocking agent having a pKa in the range of from about 5 to 14 and a solubility of not more than about 200 μg/mL at pH 6.8 into the body in a sustained-released fashion, suitable for a once-daily dosing regimen, comprises at least one organic acid, which solubilizes said weakly basic selective serotonin 5-HT3 blocking agent prior to releasing it into the hostile intestinal environment wherein the blocking agent is practically insoluble. The unit dosage form may be composed of a multitude of multicoated particulates (i.e., immediate-release beads, sustained-release beads and/or one or more timed, pulsatile-release bead populations) and is designed in such a way that the weakly basic blocking agent and the organic acid do not come into close contact during processing and/or storage thereby avoiding in-situ formation of acid addition compounds while ensuring that the acid is not depleted prior to completion of the drug release.

Claims25

Dependent claims

A pharmaceutical multiparticulate dosage form comprising immediate release (IR) beads, sustained-release (SR) beads and/or one or more populations of timed, pulsatile release (TPR) beads of a weakly basic drug, wherein the weakly basic drug comprises a nitrogen (N)-containing selective serotonin 5-HT3 blocking agent having a pKa in the range of from about 5 to 14 and a solubility of not more than about 200 μg/mL at pH 6.8 and at least one pharmaceutically acceptable organic acid as a solubilizer wherein the weakly basic active and the organic acid do not come into contact with each other during manufacturing or in storage in the solid state thereby avoiding in-situ formation of an acid addition compound and the organic acid is not depleted until completion of the drug release from the dosage form when dissolution tested by United States Pharmacopoeia (USP) dissolution methodology using a two-stage dissolution medium (first 2 hours in 0.1N HCl followed by testing in a buffer at pH 6.8).

A method for the preparation of a multiparticulate dosage form comprising a weakly basic, nitrogen (N)-containing selective serotonin 5-HT3 blocking agent having a pKa in the range of from about 5 to 14, a solubility of not more than 200 μg/mL at a pH of 6.8, and a ratio of optimal highest dose to solubility at pH 6.8 of not less than about 100, and at least one pharmaceutically acceptable organic acid as a solubilizer comprising:

a) preparing organic acid cores;
b) preparing SR-coated organic acid cores by coating the organic acid cores with a SR coating comprising a water-insoluble polymer alone or in combination with a water-soluble polymer or an enteric polymer at a ratio of from about 95:5 to about 50:50 for a weight gain of up to about 20%, to provide a sustained-release profile;
c) preparing IR (immediate-release) beads by layering the weakly basic or pharmaceutically acceptable salt thereof from a polymer binder solution onto the SR-coated organic acid cores and optionally applying a protective seal-coat with a water-soluble polymer;
d) preparing SR beads by applying a barrier (SR) coating of a water-insoluble polymer alone or in combination with a water-soluble polymer at a ratio of from about 95:5 to about 50:50 for a weight gain of from about 1.5% to 20% by dry weight of the coated bead;
e) preparing TPR beads by applying an outer lag-time coating comprising a water-insoluble polymer in combination with an enteric polymer at a ratio of from about 9:1 to 1:3 for a weight gain of from about 10% to 60% by weight of the coated bead;
and
f) filling into a gelatin capsule or compressing into a conventional tablet or an orally disintegrating tablet a mixture of IR beads, SR beads and/or one or more TPR bead populations at appropriate amounts to achieve target pharmacokinetics profiles in order to be suitable for a once-daily dosing regimen in patients in need of such a medication.

4 more elements

Dependencies are inferred from the claim text.

Drug delivery systems comprising weakly basic selective serotonin 5-ht3 blocking agent and organic acids

Life of this patent

Drug delivery systems comprising weakly basic selective serotonin 5-ht3 blocking agent and organic acids

Life of this patent

Abstract

Claims25