JPH03169814A - Production of long-acting nifedipine formulation - Google Patents

Abstract

PURPOSE:To industrially advantageously obtain the subject formulation useful for stenocardia, etc., having excellent stability by a favorable method by dissolving a specific amount of nifedipine and a water-soluble polymer in an organic solvent, adding a specific amount of water-insoluble polymer and pelletizing by a wet method. CONSTITUTION:1 pt.wt. nifedipine and 0.5-3.0 pts.wt. water-soluble polymer are dissolved in an organic solvent (e.g. chloroform, dichloromethane or carbon tetrachloride) and 3.0-10.0 pts.wt. water-insoluble polymer is added, then the resultant solution is pelletized by a wet method to afford the objective nifedipine solid formulation. One, two or more of polyvinylpyrrolidone, hydroxypropyl cellulose and hydroxypropyl methylcellulose are used as the water-soluble polymer. Furthermore, crystalline cellulose is used as water-insoluble polymer.

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention provides novel solid formulations containing nifedipine.
li! This article describes a method for producing nifedipine solid preparations that are fast-acting, long-lasting, small in size, and easy to take. Nifedipine has excellent coronary vasodilatory and antihypertensive effects, but it has the disadvantages of being poorly soluble in water, poorly absorbed into the body, and rapidly metabolized and excreted. To date, nifedipine has been formulated with the aim of improving bioavailability by dissolving it in polyethylene glycol and encapsulating it in soft capsules, or by forming it into a solid solution with water-soluble polymers. By the way, after taking these fast-acting preparations, they are quickly absorbed and reach high blood concentrations, so they are suitable for treating angina attacks.
On the other hand, since nifedipine is rapidly metabolized and excreted, it causes a rapid drop in blood concentration, so it must be administered three times a day if the purpose is to prevent angina or lower blood pressure. ．． On the other hand, conventional methods for sustaining drugs include those that utilize the solubility and dissolution rate of the drug itself, those that release from a matrix made of hydrophobic substances or water-insoluble polymers, and those that suppress release by applying a semi-permeable film. It has been known. However, because nifedipine crystals are extremely insoluble in water and difficult to absorb from the gastrointestinal tract, there is a risk that bio◆availability may decrease with these conventional sustainability methods. In addition, even if nifedipine is processed into an easily soluble form and its release is controlled by the method described above, a decrease in bioavailability can be prevented, but the concept of side effects due to dose dumping, which is commonly seen in long-acting preparations, pH
Judging from the drug characteristics of nifedipine, such as inter-individual variation due to dependence and quality control problems due to the complicated manufacturing process, it is difficult to say that it is a desirable dosage form for immediate use. To address this problem, we have developed a combination of nifedipine and water-soluble polymers.
After dissolving it in a solvent, adding a water-insoluble polymer and granulating it using a wet method, it has both fast-acting and long-lasting properties without reducing bioavailability, and also has dose dumping and We have discovered that it is possible to obtain a small-sized solid preparation that is highly safe, pH-independent, has no manufacturing complexity, and has excellent stability, and has completed the method of the present invention. That is, the method of the present invention is a method for producing a solid nifedibine preparation, which comprises dissolving nifedipine and a water-soluble polymer in an organic solvent, adding a water-insoluble polymer, and granulating the mixture by a wet method. In the method of the present invention, the water-soluble polymer includes one or more components selected from the group consisting of polyvinylpyrrolidone, hydroxybububil cellulose, hydroxybububu methylcellulose, and methylcellulose, and the amount thereof is determined by nifedipine. It is desirable to use 0.5 to 3.0 parts by weight per 1 part by weight. Examples of the organic solvent include chloroform, dichloromethane, carbon tetrachloride, ethanol, methanol, or a mixed solution thereof. In addition, examples of water-insoluble polymers include crystalline cellulose, and the amount of the water-insoluble polymer is 1.1 m [parts] of nifedipine.
It is preferable to use 3.0 to 10.0 parts by weight. In the method of the present invention, nifedipine and a water-soluble polymer are dissolved in an organic solvent, a water-insoluble polymer is added, and the mixture is stirred and mixed in a granulator, granulated, and then dried to form a solid preparation (powder granules). body) is obtained. Here, a lubricant such as stearic acid or magnesium stearate may be added together with the water-insoluble polymer. Next, a disintegrant such as carboxymethyl cellulose is added to the resulting powder and granules, and then tablets are obtained by a conventional method, and film tablets can be obtained by further applying a water-soluble coating. Furthermore, the above-mentioned powder or granules can be used to make granules and capsules. It has been found by thermal analysis and X-ray analysis that 20-80% (V/W) of the nifedipine in the nifedipine solid preparation obtained by the method of the present invention is ultrafine particles. The long-acting preparation of nifedipine obtained by the method of the present invention described above is a long-acting preparation that has both quick-acting and long-lasting effects without reducing bioavailability, and also has the following characteristics: dose dumping, pH It is a highly safe, time-dependent preparation with no dependence, and is a small solid preparation with excellent stability. Furthermore, as described above, the method of the present invention is a simple method, does not involve any complicated manufacturing process, and is an industrially useful method. Next, the present invention will be further explained in detail by giving Examples, Comparative Examples, and Test Examples. Example l. 200 g of nifedibine and 20 g of polyvinylpyrrolidone
08 to 600 liters of dichloromethane and 200 liters of ethanol
It was dissolved in the mixture of I. Crystalline cellulose 99% is added to this solution.
08 and 10 g of stearic acid were added thereto, granulated in a granulator, and dried at 50°C to obtain powder. Next, carboxymethyl cellulose 15 was added to this granule 7008.
0g was mixed uniformly and pressed into tablets weighing 85mg each using a rotary tablet press.
Tablets containing BB were obtained. Example 2. 200 g of nifedipine and 150 g of hydroxybubuvir methylcellulose were dissolved in 500 ml of dichloromethane, a mixture of methanol + 70 + al. This melt tα
15 g of crystalline cellulose IO and 35 g of magnesium stearate were added to the mixture, and the mixture was granulated in a molding machine, followed by drying at 50°C to obtain granules. Next, 700 g of this granule was uniformly mixed with IOOg of carboxymethyl cellulose, and pressed into tablets each weighing 801 Bg using a rotary tablet press to obtain tablets each containing IOmg of nifedibine. Furthermore, a water-soluble coating was applied to the obtained tablets to obtain film tablets. Comparative Example: 2 g of nifedibine, 2 g of vorivinyl pyrolidone, 600 ml of dichloromethane, 9.0 g of crystalline cellulose. 9g
, A mixed powder of 0.1 g of stearic acid and 38 g of carboxymethylcellulose was made into a tablet with a weight of 85 g.
-g of tablets to obtain tablets containing IOmg of nifedibine in each tablet. Test Example Using the formulation (tablet) obtained in Example 1 and the formulation obtained in Comparative Example, a dissolution test was conducted under the following conditions. (Test method) Dissolution test method; Eluate; Test material; Temperature; Stirring speed; Quantitative method; 10th revised Japanese IK circumferential dissolution test method (paddle method) 1 tablet 27th 0.5℃ 100rp ■ Absorbance measurement method (test results) Figure 1 shows the test results. r! ! :i, the vertical axis represents the elution rate, and the horizontal axis represents time. The preparation (tablet) obtained by the method of the present invention exhibits a higher dissolution rate than the preparations of comparative examples, and is an excellent preparation that has both quick-acting and long-lasting effects without reducing bioavailability. It was also revealed that the tablets obtained by the method of the present invention showed similar dissolution patterns for both the first and second liquids, and were time-dependent preparations with no pH dependence. Ta.

[Brief explanation of the drawing]

Figure 1 is a diagrammatic representation of the results of the dissolution test described in the test example.

Claims (3)

[Claims] (1) 1 part by weight of nifedipine and 0.5 to 3 parts of water-soluble polymer
．． A method for producing a solid preparation of nifedipine, which comprises dissolving 0 parts by weight in an organic solvent, adding 3.0 to 10.0 parts by weight of a water-insoluble polymer, and granulating by a wet method. (2) The water-soluble polymer is selected from the group consisting of polyvinylpyrrolidone, hydroxypropylcellulose, hydroxypropylmethylcellulose, and methylcellulose.
or 2 or more components. (3) The method for producing a nifedipine solid preparation according to claim 1, wherein the water-insoluble polymer is crystalline cellulose.