DD201974A5 - METHOD FOR PRODUCING SOLID MEDICAMENT PREPARATIONS CONTAINING NIFEDIPINE - Google Patents

Abstract

The invention relates to a process for the preparation of solid pharmaceutical preparations containing the compound nifedipine in crystalline form. They are used for the treatment of circulatory diseases. The aim of the invention is the provision of novel pharmaceutical preparations which contain nifedipine without any auxiliary substances in a stable, readily bioavailable form. According to the invention, the new pharmaceutical preparations contain nifedipine crystals with a specific surface of 0.5 to 6 m high 2 / g. They are prepared by passing nifedipine crystals obtained from the synthesis by milling or sieving by conventional methods into a crystal mixture having a specific surface of 0.5 to 6 m high 2 / g and from these nifedipine crystals by conventional methods using Auxiliary and carrier substances formulated solid pharmaceutical preparations. DD # AP

Description

Berlin, 4.5.1982

AP A 61 K / 232 939/6

23 29 3 9 6 - '" ⁵⁹⁴⁶⁴ ' ¹²

Process for the preparation of solid pharmaceutical preparations containing nifedipine

Field of application of the invention

The present invention relates to special solid pharmaceutical preparations containing the known circulation-active compound nifedipine and to processes for their preparation.

characteristics the known technical solutions

It has already been disclosed that the compound nifedipine has very strong effects on the circulation (compare GB-PS 1 173 862). Due to the photosensitivity and the severe solubility of nifedipine, the galenic preparation of proprietary medicinal products presents a number of difficulties, as evidenced by numerous patents and patent applications for specific formulations of this active ingredient. Thus, for example, _# relates to the US-PS 3,784,684 special nifedipine containing Gelatinebeißkapseln through which the coronary action of nifedipine can be used to advantage. In GB-PS 1 456 618 solid pharmaceutical preparations are further described and claimed "which also ensure a good bioavailability of nifedipine. Also in DE-OS 2,822,882 solid dosage forms are described in which by the use of certain solubilizers and surface-active substances, the poor solubility of nifedipine to be compensated. Also in EP-OS 1 247 the absorbability of nifedipine is to be improved by the use of polyethylene glycol and certain porous carrier substances.

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All previous attempts to compensate for the poor solubility of nifedipine by certain measures and at the same time to ensure a good bioavailability, have a number of disadvantages "The use of surface-active substances. Solubilizers and certain excipients which have a particular surface area such as B _{0 are} porous, often lead to administration forms in which the preparations are undesirably large. To facilitate swallowing, such tablets or capsules are often converted into specific forms such as: B, ellipsoids or longitudinal forms, which, however, no longer leads to satisfactory results in preparations with a weight over 400 mg. Even the more frequent intake of smaller preparations is not a satisfactory solution.

For pharmaceutical preparations is that both the number and the amount of excipients and carriers should be kept as low as possible. When comparing two proprietary medicinal products, preference will always be given to those preparations which, in addition to the active substance, contain as few auxiliaries and additives as possible in order to largely avoid undesirable biological effects. "

Another disadvantage of the previously known nifedipine-containing preparations lies in the complex production process, which applies in particular for liquid preparations and capsule preparations · The high photosensitivity and the severe solubility of nifedipine require complex procedures, especially in liquid preparations as light protection, the exclusion of daylight and the use require of sodium light.

05/04/1982

AP A 51 K / 232 939/6 - 3 - 59 464/12

Object of the invention

The aim of the invention is the provision of novel Arzneitnxttelzubereitungen containing the nifedipine without any excipients in a stable, well bioavailable form »

Presentation of the essence the invention

The invention has for its object to produce pharmaceutical preparations containing Nifedipinkristalle with specific high surface area.

The present invention relates to solid, nifedipine-containing pharmaceutical preparations containing nifedipine crystals

with a specific surface area of 0.5 to 6 m / g.

Particularly advantageous are those solid pharmaceutical preparations which Nifedipinkristalle with a specific

Surface of 1 to 4 m / g,

The preparation of the medicament preparations according to the invention is carried out by customary methods by mixing or granulating nifedipine crystals of the specified specific surface area with suitable excipients and preparing solid pharmaceutical preparations from the mixtures or granules by customary methods.

As solid pharmaceutical preparations are preferably mentioned: tablets, pills, dragees, capsules, sachets and multi-phase preparations, such as, for example, two-layer tablets.,

232939 6

The preparation of the nifedipine crystals according to the invention having the specific surface area of 0.5 to 6

m / g is carried out by milling the crystal mixtures obtained from the synthesis of nifedipine. The milling can e.g. done with pin mills or hammer mills. By varying the number of revolutions of the mill, the amount of product and / or the milling time, nifedipine with the desired surface can be obtained.

If a product having a larger specific surface area (for example, 5 gm / g) is desired, it is advantageous to carry out the milling with air jet mills. Low surface area (e.g., 0.5 m2 / g) crystals are advantageously prepared by sieving into purest sieves, preferably 0.1-0.2 mm meshes. In all cases, it is also possible to obtain a product having the desired specific surface area by mixing nifedipine with a different specific surface area.

The specific surface area is determined by the gas adsorption method (BET method; see S. Brunauer: The Adsorption of Gases and Vapors, Princeton (1945).

Surprisingly, the solid preparations according to the invention show an unexpectedly high bioavailability. In the publication by I. Sugimoto et al., Drug Development and Industrial Pharmacy, 6J2), 137-160 / 1980), it is expressly emphasized (page 139) that nifedipine is poorly absorbed in crystalline form upon oral administration

Le A 20 447

232939 6

and has only a very low bioavailability. It could therefore not be expected that after oral administration of the preparation according to the invention, which contains crystalline nifedipine, the plasma concentration increases rapidly and keeps for many hours at a high value. In cases where nifedipine has to be taken for prolonged periods of time, it is sufficient because of this very high duration of action if 1 or 2 tablets are administered daily. A further significant advantage consists in the fact that very small tablets with a high active ingredient content can be prepared since it is largely possible to dispense with solubilizers, surface-active substances and additional auxiliaries.

The small size of the tablet and the surprisingly long duration of action of the formulation according to the invention make it possible to use nifedipine for the treatment of coronary disorders over longer periods of time and also prophylactically, and moreover this formulation opens up the possibility of using the antihypertensive effect of nifedipine for the treatment of hypertension. The long-lasting blood levels obtainable by the formulation according to the invention. of the drug represent an extension of the practical applications of nifedipine and at the same time provide relief to the patient.

With knowledge of the state of the art, from which it can be seen that the experts have been endeavoring for years,

Le A 20 447

, 04.05.1982

AP A 61 K / 232 939/6

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To find useful preparation forms for the difficult-to-formulate active ingredient nifedipine, it is to be described as extremely surprising that a very simple and effective principle for galenic processing has been found by selecting a very specific specific surface area of the active ingredient *

The solid preparation forms according to the invention represent a relief for the patient in the application and at the same time increase the assurance of his treatment,

In order to demonstrate the advantageous effect of the pharmaceutical preparations according to the invention, the plasma concentration was determined in each case for 8 persons for several hours after the application. The values are shown in the following table:

Table:

Time 1 2 3. 4 6 8 10 25.5

(Hours)

Plasmakonz. > ig / l according to p # o # application of the Ta 105.8 86.1 65.3 63.9 43.1 46.7 11.8 10ß bletten aus Example 1 (20 mg)

dto »to p _# o.

Application of 52.1 66.3 60.4 51.3 32.4 25 18.8 llfi

Tablets off

Example 2 (20 mg)

AusfOhrungsbeispiel

The following "embodiments illustrate the invention,

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example 1

200 g of nifedipine crystals having a specific surface area of 4 m / g are mixed with 348 g of microcrystalline cellulose, 100 g of lactose, 10 g of Twen 80, 70 g of starch

* and 2 g magnesium stearate mixed. From a further 70 g of starch, a paste is prepared with water in a well-known manner, the with the o.g. The mixture is usually granulated, dried and then pressed into tablets with a single weight of 80 mg.

Then these tablets are marked, they have a diameter of 6 mm.

For coating 800 g tablets, e.g. a suspension from

18 g of hydroxypropylmethylcellulose, 6 g of polyethylene glycol

5.4 g of titanium dioxide

0.6 g of iron oxide and 370 g of water or ethanol "

used. ·

Example 2

200 g of nifedipine crystals having a specific surface area of 1 m / g are pressed analogously to Example 1 to 80 mg tablets with a diameter of 6 mm.

Le A 20 447

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Example 3

200 g of nifedipine with a specific surface area of 1.2 m / g are mixed with 800 g of lactose, 960 g of starch and 40 g of magnesium stearate. The mixture is filled into hard gelatin capsules of size "3" to 100 mg. "Fro capsule then contains 10 mg of nifedipine Capsules may be prepared by varying the capsule size and content weights at different dosages, for example between 5 mg and 40 mg of active ingredient per capsule.

Example 4

Two-layer tablets are produced. One layer consists of 7.5 mg nifedipine with a specific surface area of 6 m2 / g 7.5 mg lactose, 30 mg starch,

'*' 3 mg polyvinylpyrrolidone and 2 mg magnesium stearate (together 100 mg), the second layer has the same composition but with nifedipine with a specific surface area of 0.6 m2 / g. The compressed bilayer tablets with a total weight of

200 mg can be provided with a dividing notch to allow individual dosage for the patient.

Le A 20 447

Claims (2)

4.5.1982 3 2 9 3 9 6 Ap A 611 </ 232 939/6 - 9 - 59 464/12 - Invention claim 1. A process for the preparation of solid pharmaceutical preparations containing nifedipine, characterized in that one obtains from the synthesis Nifedipinkristalle by milling or sieving by conventional methods in a Kristallgeraisch with the specific surface area of 0.5 2
transferred to 6 in / g and formulated from these Nifedipinkristallen by conventional methods using excipients and carriers solid pharmaceutical preparations «