Nifedipine-containing pharmaceutical compositions and process for the preparation thereof.

Method for preparing a pharmaceutical composition containing nifedipine - Preparation of a pharmaceutical composition containing a nifedipine pharmaceutical composition

This invention relates to a process for the preparation of a pharmaceutical composition containing nifedipine, in particular a slow-release formulation containing nifedipine.

Nifedipine is currently used as a drug in the form of a rapidly available pharmaceutical dose for the treatment of acute myocardial infarction (angina) and in the form of a slowly available pharmaceutical dose for the treatment of chronic hypertension. It would be apparent that for the treatment of acute angina, it would be desirable to rapidly achieve plasma nifedipine concentrations of about 100 ng / ml or greater, and the need is currently met with a preparation containing a solution of nifedipine in low molecular weight polyethylene glycol encapsulated in soft gelatin capsules. It is apparent that for the treatment of hypertension, it would be better to maintain plasma concentrations of nifedipine in the therapeutic range of about 20 to 80 ng / ml, and slow release formulations are available for this purpose.

The reason why two significantly different types of formulations are needed is that nifedipine itself is very sparingly soluble in water. This has led to a somewhat strange situation in the patent literature, where patents describing controlled release systems for nifedipine actually describe ways to increase, rather than decrease, the solubility of nifedipine.

Thus, in EP 0047899 (corresponding to CA 1180277), the dissolution of nifedipine is achieved by treating the material with a high specific surface area of ​​0.5 to 6 m²/ G. The publication discloses the preparation of such nifedipine crystals by grinding and screening, but not by other means.

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Similarly, in WO PC / EP85 / 00481, the control of the dissolution of nifedipine is carried out by limiting its specific surface area to 0.1 to 0.4 m.²/ g and by coating the nifedipine crystals, in admixture with the same amount of filler, on inert spheres with suitable binders.

Further increase in the solubility of nifedipine has been achieved by treating the material as a solution absorbed on a solid support (as described in GB).

1456618), or by forming a solid solution (also known as co-precipitation) with a high molecular weight polyethylene glycol (EP patent application 0220760) or an ester or ether of polyethylene glycol (EP patent application 0249587) or other selected materials, including polyvinylpyrrolidone-15

This ability of polyvinylpyrrolidone to increase the solubility characteristics of certain materials by forming co-precipitates is now fully documented. It is also generally accepted that an excess of polyvinylpyrrolidone relative to the active material must be used to form such co-precipitates. In fact, Sugimoto et al. (Drug Dev. Ind. Pharm. 1980. 6, 139-160), in particular on the co-precipitation of nifedipine and polyvinylpyrrolidone25, found that the amount of polyvinylpyrrolidone should be at least 75% for consistency.

In view of the above work with polyvinylpyrrolidone, it was therefore surprising that in the present invention, polyvinylpyrrolidone, when used in an amount lower than the amount of nifedipine, actually significantly retarded the dissolution of nifedipine from the final solid dosage form.

The present invention therefore relates to a process for preparing a pharmaceutical composition comprising finely divided pharmaceutically acceptable water-soluble diluent particles coated with nifedipine particles in the presence of polyvinylpyrrolidone, wherein the main particle size of the nifedipine particles is:

(i) dissolving nifedipine and polyvinylpyrrolidone in a suitable solvent, wherein polyvinylpyrrolidone is used in an amount of 10 to 90% by weight of nifedipine;

(ii) coating fine particles of a pharmaceutically acceptable water-soluble diluent which is insoluble in said solvent with a nifedipine / polyvinylpyrrolidone solution; and (iii) evaporating the solvent from the surface of the coated diluent particles.

The amount of polyvinylpyrrolidone in this pharmaceutical composition is 10 to 90% by weight, preferably 20 to 50% by weight of nifedipine.

In the present invention, more than 50% of the particles have a particle size smaller than the stated limit, preferably more than 60% have a smaller size than the indicated limit, more preferably 80% of the particles have a smaller size than the stated limit.

In the pharmaceutical composition according to the invention, the majority of the nifedipine microcrystalline particles preferably have a particle size of less than 25 μια, more preferably a particle size in the range of

- 25 gm.

The pharmaceutically acceptable water-soluble diluent may be any diluent commonly used in the preparation of pharmaceutical compositions, for example lactose, sucrose, mannose, sorbitol or a mixture thereof.

The pharmaceutically acceptable water-soluble diluent preferably has a particle size of less than 250 μm and preferably also has a specific surface area of ​​more than 0.5 m²/ G.

Although polyvinylpyrrolidone is known as a binder for use in the preparation of various pharmaceutical compositions,

9534 / se acts as a retardant in the compositions of this invention by delaying the dissolution of the microcrystalline nifedipine particles.

The solvent used in the process of the invention must be a solvent for nifedipine and polyvinylpyrrolidone, but should not dissolve a pharmaceutically acceptable diluent. Examples of suitable solvents are chloroform, lower aliphatic alcohols and methylene chloride.

The most preferred solvent for use is chloroform.

The solvent evaporates from the surface of the coated diluent particles, leaving nifedipine microcrystals in the presence of polyvinylpyrrolidone coated on the particles of a pharmaceutically acceptable water-soluble diluent.

The pharmaceutical compositions prepared in accordance with this invention may be formulated in a solid unit dosage form such as tablets or capsules in a conventional manner. Conventional additives such as lubricants, binders, stabilizers and the like can be used in the preparation of such formulations.

The pharmaceutical compositions prepared in accordance with this invention have good stability and are easily reproducible. Microcrystalline nifedipine particles are formed during manufacture without the need for mill use, and this prevents the formation of nifedipine dust.

It is conceivable that dry milling techniques are laborious and expensive, and further that dust from a drug such as nifedipine is potentially harmful to health. Thus, the process of the present invention provides an economical and simple way to prepare a nifedipine-containing pharmaceutical composition.

Example 1

A batch of 5000 nifedipine tablets was prepared according to the following formulation:

nifedipine 100 g polyvinylpyrrolidone 25 g chloroform 500 ml lactose (area 0.52 m^e/ g) 1000 g of hydrogenated vegetable oil 11.25 g talc 22.50 g

Nifedipine and polyvinylpyrrolidone were dissolved in chloroform in this preparation. The solution was then uniformly coated on the lactose particles using a large agitator, and then the coated lactose particles were dried to remove the chloroform solvent therefrom.

The coated lactose particles were mixed with hydrogenated vegetable oil and talc, and then formed into tablets by standard tableting methods. The coated lactose particles prepared as described above were imaged by scanning electron microscopy. Figure 2 is a micrograph taken at higher magnification, showing the microcrystalline characteristics of the larger crystals more clearly.

The in vitro solubility properties of the tablets were measured by the Paddle method described in U.S. Pharmacopaeia XX Manual at 37 ° C and 50 rpm. The following results were obtained.

time Chl solute '/.-proportion

71

Tablets prepared according to this method were also tested against the slow release formulation of niTedipine marketed by Bayer under the trademark Adalat Retard. In the accompanying drawings, Figure 3 shows the steady-state plasma concentrations of nifedipine when SO 5 mg nifedipine is administered twice daily using Adalat Retard or tablets prepared in accordance with this invention.

The product of this invention showed good maintenance of nifedipine plasma levels throughout the IS-h period and showed more uniform plasma levels than using Adalat Retard.

SO

A comparative example

A batch of 5000 nifedipine tablets was prepared according to the following formulation:

100 g 500 ml 1000 g 11.35 g SS, 50 gni fed ipii ni k 1 chloroform lactose hydrogenated vegetable oil talc

Tablets were prepared according to the procedure of Example 1. It should be noted, however, that polyvinylpyrrolidone was omitted from the above formulation.

The in vitro solubility of these tablets was tested as detailed in Example 1. The following results were obtained.

ai ka C h 3 is the X fraction of the solute

From this rapid dissolution of the tablets, it can be seen that the polyvinylpyrrolidone added to the tablets of Example 1 acts as a dissolution rate control agent and slows down the dissolution rate of nifedipine. Figure 4 is a micrograph of the composition of the above tab5 tablets, while Figure 5 is a photomicrograph of the same sample at higher magnification, showing the microcrystalline characteristics more clearly. From these micrographs, it is clear that this product is microcrystalline, despite the absence of polyvinylpyrrolidone in the formulation.