DE4113048A1 - Controlled release pharmaceuticals - have PVA partially acetalised with butyraldehyde as matrix former - Google Patents

Abstract

A pharmaceutical prepn. with controllable delayed release of active ingredient contains, as the matrix former, a polyvinylalcohol which is partially acetalised with butyraldehyde and which has a stepped deg. of acetalisation of 0-21%. In the case of sparingly soluble low dose pharmaceuticals, the deg. of acetalisation is e.g. 0-4% or 15-21% and for readily soluble high dosed substances, the deg. of acetalisation is 5-10%. The active ingredient, the partially acetalised polyvinyl alcohol and conventional lubricants are mixed and pressed into tablets by direct tableting. USE/ADVANTAGE - The active ingredient can be uniformly and completely released over a period of at least 8 hrs. The retardation is achieved using readily available, easily worked, non-toxic auxiliaries. The matrix swells under physiological conditions and dissolves step-wise and gives controllable release of the active ingredient by working in hydrophilic auxiliaries.

Description

The invention relates to a pharmaceutical preparation in the form of a carrier material with an active pharmaceutical ingredient with controlled and delayed drug release and a method of manufacturing the same. Peroral Retarded drug forms contribute significantly to the improvement of Therapy for chronic diseases by passing through a constant blood levels of the Ensure active ingredient. According to the invention Such medicinal forms can be used when known certain key figures with minimal effort for any drugs can be produced.

The invention relates to a pharmaceutical preparation in the form of a carrier material with an active pharmaceutical ingredient with controlled delayed drug release and a manufacturing process. An ideal sustained release drug form must act similar to an intravenous continuous infusion, d. H. through the even and complete release of the active ingredient from the pharmaceutical form over a certain Period becomes a constant therapeutic blood level discontinued, the long-term effect of the drug  guaranteed reduction in side effects. The invention is applicable in the pharmaceutical industry.

It is known that the release of active substances from pharmaceutical forms by wrapping or coating, embedding or delay matrix processes. The applicability one of these processes is primarily dependent on the physico-chemical properties of the active substance and the clinical-pharmacological requirements for the Retarded drug form. A method is described in this way (DE-OS 21 26 810), in which the active ingredient in a three-dimensional Network made of plastic and / or wax-like material is embedded. Other procedures (WP / DD 2 64 850 A1) use a mixture of partially saponified and fully saponified Polyvinyl alcohols as matrix formers. Although with such Dosage forms have a good therapeutic effect, d. H. long-lasting, even blood levels have been achieved the technical implementation of the process is complex. There are usually various intermediate operations (pre-granulation) required. The process is unfavorable in to assess such cases when easily soluble and high-dose drugs processed into sustained-release medicinal products should be. In such cases, tablets are created with a relatively high tablet mass, which is bad are applicable. In addition, the process is only significant Development work on other drugs transferable.

The aim of the invention is a pharmaceutical preparation in Form of a carrier material with an active pharmaceutical ingredient with controlled delayed drug release and their Manufacturing. The pharmaceutical preparation is said to be the drug evenly and for at least 8 hours release completely, with the drug retardation by  suitable, industrially available, pharmaceutical-technological easy to process and non-toxic auxiliaries he follows.

The invention has for its object the liberation of the active ingredient by incorporating it into an under physiological conditions swellable, gradually to delay soluble matrix framework, taking control the release of the active ingredient by incorporated hydrophilic Auxiliaries should be made. According to the invention Object achieved in that partially acetalized by butyraldehyde Polyvinyl alcohols with a graded Degree of acetalization from 1.5 to 21.5% as matrix former Find use. Surprisingly, it was found that tablets made from the pure matrix formers in Dependence on the degree of acetalization of the partially acetalized Polyvinyl alcohol changes after different times in the disintegration tester (AB - DDR). This occurs the phenomenon that the moldings develop to a degree of acetalization of the adjuvant of approx. 15% always initially loosen more slowly and then disintegrate faster again (see Table 1).

The time course of the mass loss caused by erosion of the surface in the liquid medium (disintegration tester AB - DDR) is shown in Fig. 1.

From these surprisingly found contexts there arises the possibility for poorly soluble and for low-dose drugs a partially acetalized Polyvinyl alcohol with a degree of acetalization of e.g. B. 0-4% or from 15-21% and for easily soluble and high doses Substances with partially acetalized polyvinyl alcohols a degree of acetalization of 5-10% as a matrix former use.

In the development of tablet formulations for prolonged-release drug forms then proceed in such a way that first the characteristic Drug data are collected. Corresponding the solubility and the dosage then becomes a corresponding one  partially acetalized polyvinyl alcohol as matrix former selected and with the help of usual tableting aids, such as B. magnesium stearate, on the Ways of direct tableting processed into tablets. The The advantage of this procedure is that it is essential Saving time when developing recipes.

The principle is explained in more detail using a few examples. The partially acetalized were used to produce the compacts Polyvinyl alcohols with a grain size <0.5 mm are used.

Examples

This was always the case with the development of sustained-release formulations proceed that a readily soluble active ingredient with a sparingly soluble partially acetalized polyvinyl alcohol and conversely, a poorly soluble drug with a slightly soluble partially acetalized polyvinyl alcohol combined has been.

example 1

30 g of the active ingredient cafaminol (easily soluble), 17.5 g partially acetalized polyvinyl alcohol C and 0.5 g magnesium stearate are mixed in the mortar. The mixture will then at a pressing force of 10 kN to tablets coated with tablets with a diameter of 11 mm, a mass of 480 mg and an active ingredient content of 300 mg pressed.

Example 2

20 g of the active ingredient quinidine sulfate (moderately soluble), 26.5 g partially acetalized polyvinyl alcohol B and 0.5 g magnesium stearate are mixed in the mortar. The mixture is at a pressing force of 10 kN to form tablets with a tablet Diameter of 11 mm, a mass of 470 g and one Active ingredient content of 200 mg pressed.

Example 3

6.4 g of the active ingredient codeine phosphate (easily soluble), 13.3 g partially acetalized polyvinyl alcohol G and 0.3 g magnesium stearate are mixed in the mortar. The mixture is at 20 kN to vaulted tablets with a diameter of 9 mm, a mass of 200 mg and an active substance content of 64 mg pressed.

Example 4

10.0 g of the active ingredient diclofenac Na (easily soluble in Water, but very sparingly soluble at pH 1.3), 10.8 g  partially acetalized polyvinyl alcohol B and 0.2 g magnesium stearate are mixed in the mortar. The mixture is at 10 kN to vaulted tablets with a diameter of 7 mm, a mass of 210 mg and an active substance content of 100 mg pressed.

Example 5

40.0 g of the active ingredient pentoxifylline (easily soluble), 22.4 g of partially acetalized polyvinyl alcohol G and 0.6 g Magnesium stearate is mixed in a mortar. The mixture becomes a tablet with a compression force of 10 kN with a diameter of 11 mm, a mass of 630 mg and an active ingredient content of 400 mg pressed.

Example 6

7.0 g of the active ingredient pholedrine sulfate (soluble), 12.7 g partially acetalized polyvinyl alcohol D and 0.3 g magnesium stearate are mixed in the mortar. The mixture is at with a pressing force of 20 kN to form tablets with a tablet a diameter of 9 mm, a mass of 200 mg and a Active ingredient content of 70 mg pressed.

Example 7

28.0 g of the active ingredient theophylline (moderately soluble), 36.4 g partially acetalized polyvinyl alcohol B and 0.6 g magnesium stearate are mixed in the mortar. The mixture is at with a pressing force of 10 kN to form tablets with a tablet a diameter of 11 mm, a mass of 650 mg and an active ingredient content of 280 mg pressed.

Example 8

12.0 g of the active ingredient verapamil hydrochloride (easily soluble in water, but hardly soluble at pH 7.5), 19.7 g  partially acetalized polyvinyl alcohol C and 0.3 g magnesium stearate are mixed in the mortar. The mixture becomes vaulted at a pressing force of 10 kN Tablets with a diameter of 9 mm, a mass of 320 mg and an active ingredient content of 120 mg.  

Table 1

Decay characteristics of the compacts made from partially acetalized polyvinyl alcohols depending on the degree of acetalization

Table 2

Characteristics of the drugs used

Example 1 (Cafaminol)

Drug liberation from Cafaminol prolonged-release tablet  

Example 2 (Quinidine Sulfate)

Drug liberation from quinidine sulfate prolonged-release tablets  

Example 3 (Codeine Phosphate)

Drug liberation from codeine phosphate prolonged-release tablet  

Example 4 (Diclofenac Sodium)

Drug liberation from diclofenac Na prolonged-release tablet  

Example 5 (pentoxifylline)

Drug liberation from pentoxifylline prolonged-release tablets  

Example 6 (Pholedrine Sulfate)

Drug liberation from pholedrine sulfate prolonged-release tablets  

Example 7 (Theophylline)

Drug liberation from theophylline prolonged-release tablets  

Example 8 (Verapamil · HCl)

Drug liberation from verapamil hydrochloride prolonged-release tablets

Claims (4)

1. Pharmaceutical preparation with controllable delayed release of active ingredient, characterized in that partially acetalized polyvinyl alcohols with a graded degree of acetalization of 0 to 21% are contained as matrix formers with butyraldehyde. 2. Pharmaceutical preparation according to claim 1, characterized characterized that poorly soluble and low-dose Drugs with a partially acetalized polyvinyl alcohol with a degree of acetalization of 0 to 4% or 10 to 21% can be combined as matrix formers. 3. Pharmaceutical preparation according to claim 1 with easily soluble and high-dose drugs, characterized, that they partially acetalized as matrix formers Polyvinyl alcohols with a degree of acetalization of 5 to 10% included. 4. Process for the preparation of pharmaceutical preparations according to claim 1, characterized in that medicinal substances polyvinyl alcohol partially acetalized with butyraldehyde mixed as a matrix and common lubricants and on the way of direct tableting to tablets be pressed.