JPH037645B2 - - Google Patents

Description

[Detailed description of the invention]

The present invention relates to solid formulations containing nifedipine. Nifedipine has an excellent coronary vasodilator effect,
It is a compound useful as a therapeutic agent for so-called anginal stroke. Anginal attacks cannot be predicted, so you may have to treat them yourself at the time of the attack.For this reason, this type of therapeutic agent is not only easy to take, but also works quickly and reliably. It is particularly desirable to have a formulation that can However, since nifedipine is poorly soluble and has low bioavailability when administered orally, it has been extremely difficult to develop an oral formulation of nifedipine with excellent bioavailability. Conventionally, tablets, pills, and mouth-release capsules have been known as oral preparations of nifedipine (see, for example, West German Patent Publication No. 2400819 and Japanese Patent Application Laid-open No. 28621/1983). It has been reported that tablets and pills have very slow absorption and are not very effective. In particular, the tablets reported in the above-mentioned West German patent publication are made by adsorbing a solution of nifedipine in polyethylene glycol onto an inert carrier to form a solid form, which is then molded into a tablet. Crystals precipitate over time, and the dissolution of nifedipine is also inferior to the formulation of the present invention. On the other hand, the oral-release capsule disclosed in the above-mentioned Japanese Patent Application Laid-Open No. 48-28621 is a liquid composition containing nifedipine, polyalkylene glycol, and glycerin encapsulated in a colored light-shielding gelatin capsule, and has no effect. However, since it is a liquid preparation, the formulation form is limited, and its production is much more complicated than that of solid preparations. Therefore, as a result of repeated research into solid preparations of nifedipine, the present inventors have now developed a new solid preparation of nifedipine that has an efficacy comparable to that of the orally-released capsule preparations by combining nifedipine with a specific base. The present invention was completed based on the discovery that the present invention can be obtained. Accordingly, the present invention provides a nifedipine-containing solid preparation characterized by containing a vitreous or solid solution-like homogeneous composition consisting of nifedipine and polyvinylpyrrolidone. The glassy or solid solution-like homogeneous composition described above can be prepared according to the invention by dissolving nifedipine and polyvinylpyrrolidone in an organic solvent and then removing the organic solvent. The mixing ratio of nifedipine and polyvinylpyrrolidone is generally 1 part or more of polyvinylpyrrolidone, usually 1 to 50 parts, to 1 part of nifedipine.
Preferably 1 to 20 parts, more preferably 1 to 10 parts
parts, and most preferably within the range of 3 to 10 parts. The organic solvent used in producing the above composition is not particularly limited as long as it can substantially dissolve nifedipine and the base, and the amount used is the amount necessary for dissolution. Generally, organic solvents such as methyl alcohol, ethyl alcohol, acetone, chloroform, dichloromethane, and carbon tetrachloride are preferably used alone or in an appropriate mixture in an amount of 3 parts or more per 1 part by weight of nifedipine. A mixture of nifedipine and polyvinylpyrrolidone dissolved in the above organic solvent may contain colorants, flavoring agents, flavoring agents, and fillers (for example, lactose, starch, crystalline cellulose, low-substituted hydroxypropylcellulose, synthetic silicone), if necessary. aluminum acid, magnesium aluminate metasilicate, calcium hydrogen phosphate, magnesium silicate stearate anhydride), disintegrants (e.g. cross-linked polyvinylpyrrolidone), etc., and preferably crystalline cellulose and starch are used. Can be done. The organic solvent is then removed from the dissolved mixture prepared as described above by a suitable method, such as freeze drying, heating drying under normal pressure or reduced pressure, spray drying, fluidized bed granulation drying, and the like. In this way, a solid nifedipine-containing composition is obtained, and its properties vary depending on the amount of polyvinylpyrrolidone used, but in general, a uniform solid composition in the form of a glassy or solid solution in which nifedipine is dissolved in polyvinylpyrrolidone is obtained. is forming. In such a solid composition,
Nifedipine is characterized by being difficult to decompose, and no crystal precipitation is observed even when stored for a long period of three years or more. Therefore, the composition of the present invention is extremely suitable for preparing solid oral preparations of nifedipine in the form of tablets, powders, and the like. The above-mentioned solid composition of the present invention can be formulated into a dosage form such as powder, granules, tablets, pills, etc. by a conventional method. Such preparations are not only easier to measure, package, take, etc. than liquid preparations, but also convenient to handle, as the dosage can be increased or decreased as appropriate. Next, in order to prove the effectiveness of the solid preparation of the present invention, the time course of the plasma concentration of nifedipine when the preparation is orally administered to dogs will be described together with the experimental method. Experimental method: A male beagle dog weighing approximately 10 kg that had been fasted for 16 hours was given the solid product obtained in Example 3 below or a commercially available liquid capsule containing nifedipine (trade name: Adalat, manufactured by Bayer) as a control. It was orally administered at 3 mg/Kg. Administration was performed at one-week crossover intervals, and after administration
Plasma nifedipine concentrations were measured at 0.5, 1, 2, 4 and 7 hours. Measurement of nifedipine concentration was performed as follows. Add 0.5 ml (300 ng) of an aqueous solution of deuterated nifedipine as an internal standard to 1 ml of plasma, then add 2 ml of 0.1 N hydrochloric acid and 0.3 ml of 1% sodium nitrite aqueous solution, and react at 45°C for 60 minutes to convert nifedipine into pyridine. oxidizes to the body. Thereafter, 0.5 ml of a 2N aqueous sodium hydroxide solution was added to make it alkaline, and 4 ml of benzene was added, followed by shaking for 1 minute and extraction. The organic layer of the extract is distilled off under reduced pressure, 50μ of ethyl acetate is added to the residue, 1μ of this is injected into a gas chromatograph-mass spectrometer, and nifedipine is quantified from the peak height ratio obtained. The results are shown in Table 1 below.

[Table] Note: Values in the table indicate average values.
Furthermore, as a clinical test, 10 mg each of the nifedipine-containing solid preparation of the present invention and a commercially available nifedipine liquid-containing capsule (trade name: Adalat, manufactured by Bayer AG) were orally administered to healthy volunteers. 8
Plasma concentrations of nifedipine were measured over time. The results are shown in Table 2 below.

[Table] Prepared by:
d) Solid formulation B: Contains 10 mg of nifedipine, 40 mg of polyvinylpyrrolidone, and 105 mg of microcrystalline cellulose. tablet.
Nifedipine and polyvinylpyrrolidone were dissolved in dichloromethane, the solution was mixed with microcrystalline cellulose, and then the solvent was removed.
The resulting granular solid composition contains 4 parts by weight of starch and 0.04 parts by weight of magnesium stearate per 1 part by weight of nifedipine.
prepared by adding 2.46 parts by weight of cross-linked insoluble polyvinylpyrrolidone and tableting.
As is clear from the results shown in the table above, the solid preparation of the present invention has approximately the same absorption pattern and area under the plasma concentration curve as the control adalate. The method for producing the solid composition of the present invention will be explained in more detail below with reference to Examples. Example 1 Nifedipine 1 g and polyvinylpyrrolidone 10
After dissolving 50 g of methanol in 50 g, the mixture is heated at normal pressure and the solvent is distilled off to obtain a solid. Example 2 Nifedipine 1 g and polyvinylpyrrolidone 5
g to methyl alcohol-carbon tetrachloride (weight ratio 2:
8) After adding and dissolving 20 g of the mixed solution, the organic solvent is distilled off using a spray drying method to obtain a powdery substance. Example 3 Nifedipine 1g and polyvinylpyrrolidone 20
After dissolving 100 g of methyl alcohol in g, the organic solvent is removed by freeze-drying to obtain a solid. Example 4 1 g of nifedipine and 4 g of polyvinylpyrrolidone are dissolved in 60 g of dichloromethane, and then the organic solvent is removed under reduced pressure (maximum 0.3 atm) to obtain a solid coprecipitate. Example 5 1 g of nifedipine and 5 g of polyvinylpyrrolidone are dissolved in 80 g of acetone, and then the organic solvent is removed in the same manner as in Example 4 to obtain a solid product.

Claims (1)

[Scope of Claims] 1. It is characterized by containing a vitreous or solid solution-like homogeneous composition containing nifedipine in a substantially non-crystalline state, consisting of (a) nifedipine and (b) polyvinylpyrrolidone. Solid preparation containing nifedipine. 2. A glassy or solid solution-like homogeneous composition is prepared by dissolving (a) nifedipine and (b) polyvinylpyrrolidone in an organic solvent and then removing the organic solvent. Preparations as described in section. 3. The preparation according to claim 1 or 2, wherein the glassy or solid solution-like homogeneous composition comprises (a) 1 part by weight of nifedipine and (b) 1 to 20 parts by weight of polyvinylpyrrolidone. . 4. The preparation according to claim 1 or 2, wherein the glassy or solid solution-like homogeneous composition comprises (a) 1 part by weight of nifedipine and (b) 1 to 10 parts by weight of polyvinylpyrrolidone. . 5. Claim 2 in which the organic solvent is methyl alcohol, ethyl alcohol, chloroform, dichloromethane, carbon tetrachloride, or a mixture thereof.
Preparations as described in section.