KR20070110068A - Alfuzosin controlled-release formulations - Google Patents

Abstract

A solid controlled-release pharmaceutical formulation containing alfuzosin hydrochloride and the use thereof in the treatment of prostate hypertrophy.

Description

ALFUZOSIN CONTROLLED-RELEASE FORMULATIONS}

The present invention relates to solid dosage forms in the form of controlled-release tablets comprising alfuzosin, methods for their preparation and the use of prostate hypertrophy.

Alfuzosin (hydrochloride) is a molecule that can intensify alpha-adrenergic contractions. Alfuzosin and its salts, in particular, are potent blockers of alpha-adrenergic receptors and are known to selectively act on the urethra. Since alfuzosin has a short duration, it is desirable to provide an oral pharmaceutical form in which the active ingredient can be administered once daily to maintain an effective plasma concentration for at least 24 hours.

) 기술인데, 이는 두 층에 알푸조신이 분산되어 있는 세개의 층으로 이루어진 정제로 구성된 것이다. 세 번째 층은 알푸조신 방출을 막는 장벽(barrier)의 역할을 하는 반면, 기성-방출층(ready-relaese layer)은 전체 알푸조신의 일부분을 포함하고, 두 번째 층은 지연된 방출을 할 수 있도록 잔류 약물을 포함한다(EP 938318). 이러한 기술은 동력학적인 방출을 유연하게 조절하는 것이지만, 높은 생산 비용과 방출 동력학을 재생성하는 과정에서의 어려움과 같은 문제점을 가지고 있고, 따라서 다른 메커니즘의 결과라고 볼 수 있는 약물 혈장 농도는 제형의 단일한 서브컴포넌트(sub-component)에 의해 결정된다.Other technical solutions have been proposed to solve this problem, and one of them is Geomatrix.

Technology, which consists of three layers of tablets with alfuzosin dispersed in two layers. The third layer acts as a barrier against alfuzosin release, while the ready-relaese layer contains part of the total alfuzosin, while the second layer allows for delayed release. Residual drug (EP 938318). While this technique flexibly regulates the dynamic release, there are problems such as high production costs and difficulties in regenerating the release kinetics, and thus drug plasma concentrations, which can be seen as a result of other mechanisms, are unique to the formulation. It is determined by sub-components.

Protracted-release formulations exhibiting the "fluctuating" nature of alfuzosin are reported in WO 02/06231; This property allows for longer gastrointestinal absorption and absorption of the released drug for an extended time in vivo.

These attempts have been known for some time, but they do not ensure the reproducibility of plasma concentrations to rule out preconceptions about the efficacy and stability of the drug, which is very specific for gastric emptying and within the same patient. It is due to the fact that even it depends on physio-pathological conditions that can be varied.

WO 2004/037228 relates to alfuzosin delayed-release formulations of formulations in which there are one or more layers, only one of which contains alfuzosin.

Another patent application deals with alfuzosin solid controlled release formulations, which in most cases comprise a number of layers in various spatial arrangements with different release behaviors (see eg EP 673650 and HU 9903428).

Disclosure of the Invention

The daily release of alfuzosin in a pharmacologically effective amount is possible by tablets comprising the active ingredient in combination with a mixture of hydrophilic polymer, polyvinylpyrrolidone and lactose.

The hydrophilic polymer according to the present invention is a mixture of hydroxypropyl methylcellulose. The compound form forms a gel in the presence of water, the rate of dissolution / erosion decreases with increasing viscosity. Mixtures of these polymers with different viscosities make it possible to control the release rate of the drug, which is determined by the diffusion mechanism of the hydrated matrix and the advanced disintegration / erosion of the matrix.

 According to a preferred embodiment, hydroxypropyl methylcellulose (HPMC) mixtures with different degrees of viscosity are 5 to 10% (w / w) HPMC KlOO (USP definition: hypromellose type, based on the final weight of the tablet). 2208); nominal viscosity: 100,000 cP), 20 to 35% HPMC K15M (USP definition: Hypromellose type 2208; nominal viscosity: 15,000 cP) and 15 to 25% HPMC KlOOM (hypromellose type) 2910 nominal viscosity: 100 cP). In particular, formulations comprising 7.87% HPMC KlOO, 19.68% HPMC KlOOM and 27.56% HPMC K 15M are preferred.

In addition to the hydroxypropyl methylcellulose mixture and alfuzosin, the tablets of the present invention may include ingredients that contribute to controlling active ingredient release, and are preferably present in an amount of 1 to 4% by weight of the total tablet. Examples are polyvinylpyrrolidone and lactose present in an amount of 15 to 25%.

Polyvinylpyrrolidone allows drug concentrations to maintain a high gradient between the hydrated matrix and the solution. Lactose promotes the rapid influx of water and digestive fluid into the tablets due to its high solubility in water, which results in rapid hydration in the center and the difference in drug concentration between the non-hydrated matrix, the hydrated matrix and the surrounding environment.

In addition, ingredients that increase efficiency at the manufacturing stage, such as diluents, lubricants and film-forming agents, may be added to the formulation.

In another embodiment of the invention, tablets are water-insoluble film-forming polymers, preferably ethylcellulose (e.g., NlO and NlOO) and poly- which are present in amounts of 0.5 to 10% by weight of the tablet. Coated with poly-methylmethacrylates (eg Eudragit RS).

The solid dosage form according to the invention preferably

(a) preparing a mixture comprising a hydrophilic polymer, alfuzosin and polyvinylpyrrolidone;

(b) wet-granulating the mixture obtained in step (a) through a 14 wire mesh extruder;

(c) adding an excipient, in particular a diluent and a lubricant, to the mixture of granules obtained in step (b);

(d) compressing the product obtained in step (c) and optionally

(e) film-coating the obtained tablet with a polymer that is water-insoluble in water in an amount ranging from 0.5 to 10% by weight relative to the tablet.

The use of granules of the size calibrated with precisely calibrated scales causes differences in alfuzosin concentrations in the matrix, as the osmotic pressure difference occurs throughout the disintegration process.

While the solubility of alfuzosin hydrochloride is pH dependent, the tablets of the present invention exhibit a disintegration profile that is not dependent on the pH of the disintegration medium.

In addition, the tablets of the present invention are readily obtainable and easy to manufacture by inexpensive equipment.

Another aspect of the invention relates to the use of said tablet for use in the treatment of malignant prostate hyperplasia.

100 g of alfuzosin hydrochloride were mixed with 200 g of hydroxypropyl methylcellulose K100, 700 g of hydroxypropyl methylcellulose K15M and 500 g of hydroxypropyl methylcellulose K100M.

The resulting mixture was kneaded with povidone solution, granulated with a calibrated wire extruder and dried.

The resulting granules were mixed with 500 g lactose monohydrate, 500 g microcrystalline cellulose, 4 g colloidal silica and 6 g magnesium stearate.

The resulting mixture was compressed in a round die of 10 mm diameter to make tablets each containing 10 mg of alfuzosin hydrochloride.

Tablets were optionally coated with various types of film-forming agents to improve friability and flowability.

Tablets may optionally be coated with an insoluble polymer in an amount in the range of 0.5 to 10% by weight relative to the tablet, to better control the ex vivo disintegration pattern.

Claims (12)

A solid pharmaceutical composition in the form of a tablet comprising alfuzosin hydrochloride, a hydrophilic polymer, polyvinylpyrrolidone and lactose. According to claim 1, Wherein said tablet is coated with a film-forming polymer that is insoluble. The method of claim 2, The insoluble film-forming polymer is present in the range of 0.5 to 10% by weight, based on the weight of the tablet. According to claim 1, Wherein said hydrophilic polymer is hydroxypropyl methylcellulose (HPMC) with a different degree of viscosity. The method of claim 4, wherein A composition comprising a mixture of HPMC KlOO, HPMC KlOOM, and HPMC K15M. The method of claim 5, The mixture comprises 5 to 10% HPMC KlOO, 15 to 25% HPMC KlOOM and 20 to 35% HPMC K15M. The method of claim 6, Said mixture comprising 7.87% HPMC KlOO, 19.68% HPMC KlOOM and 27.56% HPMC K15M. According to claim 1, A composition comprising 1 to 4% polyvinylpyrrolidone. According to claim 1, A composition comprising 15 to 25% lactose. According to claim 1, A composition further comprising an excipient selected from diluents, lubricants and film-forming agents. (a) preparing a mixture comprising a hydrophilic polymer, alfuzosin and polyvinylpyrrolidone; (b) wet granulating the mixture obtained in step (a) through a 14 wire mesh extruder; (c) adding an excipient, in particular a diluent and a lubricant, to the mixture of granules obtained in step (b); (d) compressing the product obtained in step (c) and optionally (e) film coating the obtained tablet with a polymer that is insoluble in water and permeable to water. Use of a solid dosage form according to claims 1 to 10 for the manufacture of a medicament for the treatment of enlarged prostate.