DRUG DELIVERY SYSTEMS COMPRISING WEAKLY BASIC DRUGS AND ORGANIC ACIDS
First Claim
1. A pharmaceutical multiparticulate dosage form comprising immediate release (IR) beads, one or more populations of sustained-release (SR) beads and/or one or more populations of timed, pulsatile release (TPR) beads of at least one weakly basic drug, wherein the weakly basic drug comprises a pharmaceutically acceptable nitrogen (N)-containing therapeutic agent having a pKa in the range of from about 5 to 14, and a solubility of not more than about 200 μ
- g/mL at pH 6.8 and at least one pharmaceutically acceptable organic acid as a solubilizer wherein the weakly basic therapeutic agent 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).
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Abstract
A pharmaceutical dosage form such as a capsule, a conventional or orally disintegrating tablet capable of delivering a nitrogen (N)-containing therapeutic agent having a pKa in the range of from about 5 to 14 into the body in a sustained-released fashion, in order to be suitable for a twice- or once-daily dosing regimen, comprises at least one organic acid, which solubilizes the therapeutic agent the drug prior to releasing it into the hostile intestinal environment wherein said weakly basic drug is practically insoluble. The unit dosage form is 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) is designed in such a way that said weakly basic drug and said organic acid do not come into close contact during processing and/or storage for in-situ formation of acid addition compounds while ensuring that the acid is not depleted prior to completion of the drug release.
91 Citations
28 Claims
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1. A pharmaceutical multiparticulate dosage form comprising immediate release (IR) beads, one or more populations of sustained-release (SR) beads and/or one or more populations of timed, pulsatile release (TPR) beads of at least one weakly basic drug, wherein the weakly basic drug comprises a pharmaceutically acceptable nitrogen (N)-containing therapeutic agent having a pKa in the range of from about 5 to 14, and a solubility of not more than about 200 μ
- g/mL at pH 6.8 and at least one pharmaceutically acceptable organic acid as a solubilizer wherein the weakly basic therapeutic agent 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).
- 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, 25, 26, 28)
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24. A method for the preparation of a multiparticulate dosage form comprising a weakly basic, nitrogen (N)-containing therapeutic agent having a pKa in the range of from about 5 to 14 and a solubility of not more than about 200 μ
- g/mL at pH 6.8, and at least one pharmaceutically acceptable organic acid as a solubilizer comprising;
a. preparing organic acid cores; b. preparing barrier-coated organic acid cores by coating the organic acid cores with a barrier-coating comprising a polymer, more particularly 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 one or more weakly basic or pharmaceutically acceptable salts thereof from a polymer binder solution onto the barrier-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; andf. 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. pharmacokinetics profiles in order to be suitable for a twice- or once-daily dosing regimen in patients in need of such a medication. - View Dependent Claims (27)
- g/mL at pH 6.8, and at least one pharmaceutically acceptable organic acid as a solubilizer comprising;
Specification