DK154326C - Process for the preparation of solid Nifedipine - long-lasting preparations - Google Patents

Description

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The present invention relates to a process for the preparation of long-lasting and high bioavailability solid drug preparations containing Nifedipine crystals. It is already known that the compound Nifedipine has very strong orbital effects, cf. British Patent Specification No. 1,173,862. Due to the sensitivity of Nifedipine to light sensitivity and heavy solubility, there are a number of difficulties in the galenic preparation of drug specialties, as is evident from numerous patents and patent applications for special preparations of this active compound. Thus, e.g. U.S. Patent No. 3,784,684 to special Nifedipine-containing gelatin binder capsules by which Nifedipine's coronary action can be advantageously utilized. British Patent Specification No. 1,456,618 also describes and describes solid drug preparations which also ensure a good bioavailability for Nifedipine. Also, DT-OS 2,822,882 discloses solid pharmaceutical forms in which the use of certain solvents and surfactants must compensate the heavy solubility of Nifedipine. Also in European Publication No. 1.247, the resorbability of Nifedipine is to be improved by the use of polyethylene glycol and certain porous carriers. All attempts to date to compensate for Nifedipine's poor solubility by certain measures while ensuring good bioavailability have a number of disadvantages. The use of surfactants, solvents and certain carriers having a particular surface, e.g. are porous, frequently leading to forms of administration where the compositions are undesirably large. For ease of swallowing, such tablets or capsules are frequently transferred to special forms, e.g. ellipsoids or elongated forms, which, however, also do not produce satisfactory results in preparations weighing more than 400 mg. Nor does a more frequent intake of smaller preparations constitute a satisfactory solution.

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In the case of pharmaceutical preparations, both the number and the amount of excipients and carriers must be kept as low as possible. When comparing two drug specialties, one will always prefer the preparation which, in addition to the active compound, contains as few excipients and additives as possible, to the extent possible to avoid undesirable biological effects.

Another disadvantage of the previously known Nifedipine-containing preparations is the costly preparation method, which is especially true for liquid preparations and capsule preparations. The high sensitivity of light and the heavy solubility of Nifedipine require costly procedural measures which, in particular in liquid preparations such as light protection, require the exclusion of daylight and the use of sodium light.

The process of the invention is characterized in that, by conventional methods, preferably by grinding or sieving, Nifedipine crystals are transferred to a crystal mixture having a specific surface area of from 1 to 4 m / g, and from these Nifedipine crystals at conventional methods using adjuvants and carriers solid drug preparations are prepared.

The preparation of the drug compositions is in accordance with the invention by conventional methods, mixing or granulating Nifedipine crystals with the specified specific surface with suitable excipients and preparing solid drug preparations from the mixtures or granules by conventional methods.

As solid drug preparations, tablets, pills, dragees, capsules, odor pouches and multiphase preparations, e.g. bilayer tablets.

The preparation of those used in the invention

Nifedipine crystals with a specific surface of off. 2 1 to 4 m / g occur as the crystal mixtures obtained from the synthesis of Nifedipine are ground. The grinding can e.g.

happen with staple mills or hammer mills. By variation in the speed of the mill, the amount of product supplied and / or 3

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grinding time, Nifedipine with the desired surface can be recovered.

When a product with a larger specific surface is desired, e.g. at 4 m / g, it is an advantage to carry out.

grinding with air jet mills. Crystals with lower 2 specific surface, e.g. of 1 m / g, is advantageously prepared by sieving in fine sieves, preferably with meshes of 0.1-0.2 mm. In all cases, it is also possible to recover a product with the desired specific surface by mixing Nifedipine with different specific surface.

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

Surprisingly, the solid compositions prepared by the process of the invention show an unexpectedly high bioavailability. In I. Sugimoto et al; Drug Development and Industrial Pharmacy, 6J2), 137-160 (1980) expressly emphasize (p. 139) that crystalline form of nifedipine is poorly absorbed by oral administration and has only a very low bioavailability. Therefore, after oral administration of the preparations containing crystalline Nifedipine containing the crystalline Nifedipine, the plasma concentration could not be expected to rise rapidly and remain at a high value for many hours. In cases where Nifedipine is to be taken over a longer period of time, due to this very high duration of action, it is sufficient to administer 1 or 2 tablets daily. Another significant advantage is that very small tablets with high content of active compound can be produced, as solvents, surfactants and additional excipients can be extensively renounced.

The small size of the tablets and the surprisingly high duration of action of the compositions prepared by the process of the invention enable Nifedipine to be used for the treatment of coronary diseases for a long time and also prophylactically, and in addition these preparations open the possibility 4

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for the use of Nifedipine's blood pressure lowering effect in the treatment of hypertension. The long-lasting blood level of the active compound obtained by the compositions of the invention constitutes an extension of the practical uses of Nifedipine and at the same time facilitates patients.

Knowing the state of the art, which shows that science has for years strived to find fertile forms of preparation for the active compound Nifedipine which is difficult to prepare, it must be considered extremely surprising that when choosing a particular specific surface for the active compound has been found a very simple and effective principle for galenic processing.

The solid compositions prepared by the process of the invention provide relief to the patients upon administration and at the same time enhance the safety of the treatment.

To demonstrate the beneficial effect of the drug compositions prepared by the process of the invention, at the plasma concentration of 8 subjects for each preparation, for several hours after administration, is examined.

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The results are shown in the following table:

Table

Time 1 2 3 4 6 8 10 25.5 hours_____ __

Plasmakonc. p.q / 1 after p.o. administration, 105.8 86.1 65.3 63/9 43.1 46.7 11.8 10.8 tablet of Example 1 (20 mg) do after p.o. administration of the tablets from Example 2 52.1 66.3 60.4 51.3 32.4 25 18.8 11.4 (20 mg)

The following embodiments illustrate the invention. Example 1 200 g of Nifedipine crystals with a specific surface 2 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 of magnesium stearate. From an additional 70 g of starch, water is prepared in a manner known per se, an adhesive which is commonly granulated with said mixture, dried and then pressed into tablets having a single weight of 80 mg. Then these tablets are marked which have a diameter of 6 mm.

For varnishing 800 g tablets, e.g. a suspension of 18 g of hydroxypropyl methyl cellulose, 6 g of polyethylene glycol 5.4 g of titanium dioxide 0.6 g of iron oxide and 370 g of water or ethanol.

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Example 2 200 g of Nifedipine crystals having a specific surface 2 of 1 m / g are pressed analogously to Examples 1 to 80 mg tablets of 6 mm diameter. 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 mixture. Each capsule then contains 10 mg of Nifedipine. By varying the capsule size and weight of the contents, capsules having different dosages can be prepared, e.g. between 5 and 40 mg of active compound per capsule.

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Claims (2)

A process for the preparation of long-lasting and high bioavailability solid drug compositions containing Nifedipine crystals, known by transferring Nifedipine crystals by conventional methods, preferably by grinding or sieving, to a crystal mixture having a specific surface of from 1 to 4 m 2 / g, and from these Nifedipine crystals by conventional methods, using adjuvants and carriers, solid drug preparations are prepared. 2. Use of Nifedipine crystals having a specific surface area of from 1 to 4 m 2 / g for the manufacture of long-lasting and high bioavailability solid pharmaceutical preparations containing Nifedipine in crystalline form 15 together with adjuvants and carriers.