WO2005120481A1

WO2005120481A1 - Propafenone hydrochloride capsules containing microtablets

Info

Publication number: WO2005120481A1
Application number: PCT/CA2005/000863
Authority: WO
Inventors: Bernard Charles Sherman
Original assignee: Bernard Charles Sherman
Priority date: 2004-06-07
Filing date: 2005-06-03
Publication date: 2005-12-22
Also published as: CA2469327A1

Abstract

A capsule for oral administration of propafenone hydrochloride, wherein the capsule contains microtablets, and wherein the amount of lubricant, if any, comprises less than 0.1% of the weight of the microtablets.

Description

PROPAFENONE HYDROCHLORIDE CAPSULES CONTAINING MICROTABLETS

Background

Propafenone hydrochloride is an antiarrythmic agent sold in the United States and elsewhere under the tradename Rythmol™, in the form of immediate-release tablets in strengths of 150 mg, 225 mg and 300 mg. The usual dosing schedule is 3 times daily.

In early 2004, propafenone hydrochloride also became available in the United States and, elsewhere under the tradename Rythmol SR™ in the form of sustained release capsules in strengths of 225 mg, 325 mg and 425 mg. Because the release from Rythmol SR™ is gradual over many hours after ingestion, the dosing schedule for Rythmol SR™ is only twice daily, which is; more convenient for the patient.

Rythmol SR™ capsules are made in accordance with the disclosure of US patent 5,681 ,588. As explained in the disclosure of that patent, the manufacture of sustained release dosage forms usually requires relatively large quantities of excipients (inactive ingredients). This makes it difficult to produce tablets or capsules that contain relatively large amounts of active ingredients but are still small in size. The disclosure further explains that it was surprisingly found that satisfactory sustained release is achieved from microtablets wherein propafenone hydrochloride comprises from 81 to 99.9% of the weight of the microtablets. Gelatin capsules are filled with these microtablets.

TM - Trademark The microtablets actually contained in Rythmol SR™ capsules have a propafenone hydrochloride content of 6.25 mg per microtablet, and a total weight of 6.5 mg per microtablet. Propafenone hydrochloride thus comprises about 96% of the weight of the microtablets. Because the propafenone hydrochloride content is 6.25 mg per microtablet, it follows that the number of microtablets required per capsule is 36 for 225 mg capsules, 52 for 325 mg capsules, and 68 for 425 mg capsules.

Because the propafenone hydrochloride comprises only 96% of the weight of the microtablets in Rythmol SR™ capsules, the microtablets are larger than would be required if the propafenone hydrochloride content were 100%, with the result that the maximum dose can be included in a capsule of any given size is somewhat less than would be achieved if propafenone hydrochloride comprised 100% of the weight of the microtablets. The need to include excipients also increases the cost.

According to the disclosure of U.S. patent 5,681 ,588, the reason that the propafenone hydrochloride content must be less than 100%, is that a lubricant at a level of 0.1% to 5% must be added as an aid in the tabletting process; i.e. to avoid sticking to the tooling in the process of forming the microtablets on a tablet press. Also, the inclusion of a lubricant somewhat softens the tablets, with the result that a binder must be included to enable tablets of adequate hardness. All of the examples of microtablets in U.S. patent 5,681,588 include hydroxypropylmethylcellulose as binder. In light of the foregoing, the objective to the present invention is to enable sustained release propafenone hydrochloride capsules containing microtablets, wherein the excipient content is less than required according to the disclosure of U.S. patent 5,681,588.

Description of the Invention

It has surprisingly been found that pure propafenone hydrochloride, with no excipients added, exhibits relatively little tendency to stick to tooling in a tabletting process, particularly if the tooling has flat faces (i.e. no concavity). This means that, contrary to what is taught by U.S. patent 5,681 ,588, it is not necessary to include in the tablet 0.1% or more of a lubricant. Instead, tablets can be made with less than

0.1% by weight of a lubricant, or even no lubricant at all. ,

The reduction or elimination of a lubricant also has the benefit of increasing tablet hardness, so as to reduce or eliminate the need for a binder.

Accordingly, compositions of the present invention are sustained release propafenone hydrochloride capsules for oral administration containing microtablets, wherein the quantity of lubricant, if any, is less than 0.1% of the microtablets by weight. The microtablets will preferably be lubricant free.

For the purposes of the present disclosure and claims, the word "microtablet" will be defined as meaning a tablet of weight between 2 mg and 30 mg. The microtablets will. optionally contain up to 10 percent by weight of a binder, such

as, for example, povidone, copovidone, cellulose, or a cellulose derivative. However, the microtablets will preferably be free of a binder.

The microtablets will optionally also comprise other excipients.

Most preferably, the microtablets will be comprised entirely of propafenone hydrochloride, with no added excipients at all.

The invention will be illustrated by the following example.

Example 1

Pure propafenone hydrochloride was compacted and then milled into small granules. The granules were then compressed into microtablets of 12.5 mg weight on a rotary tablet press, using flat-faced tooling of diameter 7/64 inch.

Size 0 elongated capsules were filled with 34 of these microtablets per capsule, to give a content of 425 mg of propafenone hydrochloride per capsule.

Claims

1. A capsule for oral administration containing microtablets, wherein the microtablets comprise propafenone hydrochloride, and wherein the amount of lubricant, if any, comprises less than 0.1% of the weight of the microtablets.

2. A capsule of claim 1 wherein the microtablets are free of lubricant.

3. A capsule of claim 2 wherein the microtablets contain no excipients.