JPS59101422A - Solid pharmaceutical preparation of nifedipine having improved dissolution property - Google Patents

Abstract

PURPOSE:The titled pharmaceutical preparation having extremely improved dissolution properties of nifedipine, useful for remedying angina pectoris or hypertension, obtained by blending nifedipine with hydroxypropyl cellulose, followed by crushing them together. CONSTITUTION:The titled pharmaceutical preparation containing ultrafine composition obtained by crushing nifedipine [chemical name: 2,6-dimethyl-4-(2-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylic acid dimethyl ester] in combination with hydroxypropyl cellulose in a mixed state. In a blending ratio of the composition, 1pt.wt. nifedipine is usually blended with >=0.65pts.wt. hydroxypropyl cellulose in case of hydroxypropyl cellulose alone and they are preferably crushed. The composition has extremely improved dissolution properties, and shows no reduction in dissolution ratio in a long period preservation.

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention describes the use of nifedipine (chemical name 2,6-cymethyl-4-(2-nitrophenyl)), which is useful as a vasodilator.
This invention relates to a novel solid preparation of 1,4-dihydrobiricin-3,5-dicarboxylic acid dimethyl ester).

More specifically, the present invention relates to a novel solid preparation of nifedipine with excellent dissolution properties.

Nifedipine is an excellent vasodilator, widely used to treat angina pectoris, and is a promising drug for the treatment of high blood pressure. Formulation techniques, such as techniques for making granules or tablets by adding excipients, have the disadvantage that dissolution from the prepared formulation is extremely poor, and as a result, rapid absorption from the gastrointestinal tract cannot be expected.

In general, as a means to improve the dissolution of poorly soluble pharmaceutical substances, (a) convert the substance into a soluble derivative and use the derivative; Possible methods include (b) micronization during formulation, and (c) addition of solubilizing agents during formulation. This method has not yet yielded satisfactory results. For example, in the case of nifedipine, soluble derivatives have not yet been put to practical use, and the purpose cannot be achieved simply by pulverization. Even with the use of surfactants such as polyoxyl stearate 40, the elution effect is small, and although some of these can achieve experimental effects if used in large quantities, it is difficult to put them into practical use. 1. There are methods such as dissolving it in a dissolving agent such as polyethylene glycol or propylene glycol and then making it into soft capsules, or adsorbing it to excipients and making it into tablets, but in this case, The drawback is that the mesh becomes larger (large capsules and tablets are difficult to swallow).

As a result of intensive research into improving the dissolution properties of solid preparations of nifedipine, the present inventors found that the dissolution properties of nifedipine in solid preparations can be significantly improved by adding hydroxypropylcellulose to nifedipine and co-pulverizing it. I found it. The present invention is based on such knowledge. That is, the present invention contains a fine powder composition obtained by co-pulverizing nifedipine and hydroxypropyl cellulose in a mixed state. It provides:

The present invention will be explained in detail below.

Solid of the present invention! ! ! The fine powder composition that is characteristic of cutting is obtained by co-pulverizing nifedipine and hydroxypropylcellulose in a mixed state.
parts, when using hydroxypropyl cellulose alone, it is more than 0.8 parts by weight, preferably 0.8 to 1 part by weight (1 part by weight).
If the amount exceeds 1 part by weight, lumps may occur during crushing).

Ru. When preparing this fine powder composition, co-pulverization can be carried out by adding water-bath sugars such as grape saccharide, fructose, mannitol, sorbitol, quinlitol, maltose, lactose, and sucrose as excipients. The amount of hydroxypropyl cellulose used can be reduced from the above amount. For example, when 61 parts of lactose is used as an excipient for 1 part by weight of nifedipine, it is sufficient that the amount of hydroxypropyl cellulose used is not less than oj Mrt parts. The advantages of the formulation obtained according to the invention are:
By using a small amount of hydroxypropyl cellulose and co-pulverizing it with nifedipine, the purpose of improving dissolution is achieved, making it possible to provide small capsules and tablets. In preparing the above-mentioned fine powder composition, when the obtained fine powder composition is tested by the Japanese Pharmacopoeia Dissolution Test Method 2 (paddle method) under the conditions shown in Example 1 below, 10 min. It is necessary to obtain a dissolution rate of 90% or higher, and using this as an indicator, the grinding conditions can be set, and these conditions are based on the mixing ratio of nifedipine and hydroxypropylcellulose, the type of grinding equipment, and the grinding time. It is not limited depending on the The fine powder composition obtained in this way is further added with excipients, disintegrants, binders, lubricants, etc., and processed by conventional formulation methods to form powders, fine granules, granules, etc. It can be prepared into solid dosage forms for internal use such as capsules and tablets.

Examples of the present invention are shown below.

Example 1 Nifedipine 11 and hydroxypropylcellulose 0
．． 82 was weighed and co-pulverized using a vibrating rod mill (Model Tl-200 manufactured by Heiko Seisakusho). Operation is capacity 3
07rnl! This was carried out by placing an alumina rod with a length of 65mm and a diameter of 4.5α into a container, and pulverizing it for 90 minutes. Lactose was added to the pulverized product and mixed evenly to prepare a powder containing 20t+y of nifedipine in 1 vol. When the obtained powder was tested according to the second dissolution test method (paddle method) of the Japanese Pharmacopoeia, it showed good dissolution, and after 5 minutes, 1
A dissolution rate of 0.00% was obtained. Figure 1 shows a powder (4) produced using co-pulverized products and a powder produced using individually ground products (4).
The elution curve of B) is shown.

The dissolution test was conducted as follows.

Using water 200°C as the test solution, an amount of sample corresponding to nifedipine IDIIIHC was added while maintaining the temperature at 67 ± 05°C, and the paddle was rotated at 100 r, p, m, and the eluate was collected at regular intervals. , and filtered using a glass filter (G3). Filtrate 5trL1. After extracting with ether and distilling off the ether, methanol 5- was added and quantified by ultraviolet absorption spectrophotometry (wavelength 350 nm).

In addition, the powder made using the co-pulverized product should be placed in an airtight container.
Even after being left at 40° C. and 75% RH for 6 months, almost no decrease in the dissolution rate was observed.

Example 2 Nifedipine 11, hydroxypropylcellulose 0.
61 and sucrose 61 were weighed and co-pulverized under the same conditions as in Example 1. 5. Add potato starch to this crushed product.
Add 571 and 0.13f of magnesium stearate, mix evenly, and use a capsule filling machine to fill υ per capsule.
1011011I as nifedipine in 130ffig
"A hard capsule was prepared by filling the capsule. When the obtained hard capsule was tested according to the dissolution test method 2 (paddle method) of the Japanese Pharmacopoeia, it showed good dissolution.
An elution rate of 90- was obtained after 0 minutes. Figure 2 shows the capsules prepared using the co-pulverized product and the above (4) prepared by separately grinding nifedipine, hydroxypropyl cellulose, and sucrose and adding potato starch and magnesium stearate. The dissolution curve of a hard capsule (B) having the same composition is shown.

The dissolution test was conducted as follows.

Using 200°C of water as the test liquid and keeping it at 3Z ± 0.5°C, add 10mg of fuedipintocite per capsule.
The solution was added using a sinker, and the subsequent steps were carried out in the same manner as in the dissolution test method shown in Example 1.

Incidentally, even when the capsules prepared using the co-pulverized product were placed in an airtight container and allowed to stand at 40° C. for 75% w-c66, almost no decrease in the dissolution rate was observed.

Example 6 0.5 kg of nifedibine, 0.15 kg of hydroxypropylcellulose, and 3y4 of lactose were weighed and co-pulverized using a vibrating ball mill (Model MB-50, manufactured by Chuo Kakoki Kohata). Operation is 20cP in diameter in a container with a capacity of 158t.
This was carried out by adding 13,000 n alumina poles and grinding for 90 minutes. This co-pulverized product contains 1 kg of lactose.
, corn starch 2.025 Kf, carboxymethylcellulose calcium 0.75 Ky and magnesium stearate 0075 ~ were added and mixed evenly, and one tablet was prepared using a rotary tablet machine (HT-AP38SIIl type manufactured by Hata Iron Works): ji' (150 mg tablet containing 10 g of ferribin) was prepared. The obtained tablets were tested according to the Japanese Pharmacopoeia's dissolution test method 2 (paddle method), and showed good dissolution, with a 90% dissolution after 20 minutes.
After 45 minutes, an elution rate of 98% was obtained. Figure 6 shows the tablet (a) prepared using the co-pulverized product and nifedipine, hydroxypropyl cellulose, and lactose were separately crushed in the same manner as above, and then lactose, corn starch,
The dissolution curve of a tablet (B) having the same composition as the above (4) prepared by adding carboxymethyl cellulose calcium and magnesium stearate is shown.

The dissolution test was conducted as follows.

Using 20 ml of water as a test solution, 10Q) as nifedipine was added to one tablet while maintaining the temperature at 37±0.5°C, and the same dissolution test method as shown in Example 1 was carried out.

Next, tablets cA) made using the above-mentioned co-pulverized products and tablets (B) made using the individually ground products were prepared with a weight of 2.3 to 2.9 to
One tablet of nifedipine (10 + y/rabbit) was orally administered to 4 Japanese white rabbits with 30 - of water immediately before administration and on 05.1.15.2.3 after administration.
．． 5.8 hours later, blood was collected from the ear vein and the nifedipine concentration in plasma was measured. The results are shown in FIG. 4 as a plasma concentration transition curve (graph). The vertical axis shows the concentration of nifedipine in plasma [unit: amount of nifedipine in plasma (μg)
)], and the elapsed time after administration of the nifedipine tablet is plotted on the horizontal axis. As shown in the curve, the tablet (A) prepared using the co-pulverized product was absorbed quickly after administration and maintained a high concentration for a long time. Tablets made using individually crushed materials (B
), it can be seen that absorption is slow and the concentration remains low, as shown in curve (B). When the area under the plasma concentration/time curve (A, UC) is calculated from these curves using the trapezoidal formula, it is 4.10 μg for the tablet made using the co-milled product (B).
-hr/-, tablets made using individually crushed products (B
), the absorption was 1.62 μg-hr/vt, and the tablet (4) made using the co-pulverized product showed about 2.5 times the absorption [7
Ta.

Note that the tablets (A) manufactured using the co-pulverized product were stable even when left in an airtight container at 40° C. and 75% BH for 6 months, and no decrease in dissolution rate was observed.

[Brief explanation of the drawing]

Figures 1, 2, and 3 are diagrammatic representations of the dissolution test results for nifedipine solid preparations, and Figure 4 shows plasma concentration changes when nifedipine solid preparations (tablets) are administered to rabbits. It is a curve. Patent applicant: Takada Pharmaceutical Co., Ltd. Purification of drawings (No changes to 1, Figure 1, Figure 3, 1J7tl/l'n 1) Figure 2, Figure 4) Procedures Amendment (Method) Date of 1939 (Showa 5G), Kazuo Wakasugi, Commissioner of the Japan Patent Office 1. Indication of the case 1933 Patent Application No. 210 O/g 2. Name of the invention Solid preparation of nifedipine with excellent dissolution 3. Relationship with the case by the person making the amendment Patent applicant address Torigoe, Taito-ku, Tokyo 2-chome/3-10th P. 4. Date of amendment order: March 9, 1939 (Shipping date: March 29, 1939) 5. Target of amendment: Drawing 6: Drawing No. 1 attached with the details of the amendment. Submit the drawings first 9-Drawings Continued Amendment Written by Mr. Kazuo Wakasugi, Commissioner of the Japan Patent Office, dated 2C, Showa SG, 1996 Patent Application No. 210 Otsu/g No. 2, Title of the invention Nifedipine solid preparation with excellent dissolution properties 3 Relationship with the person making the amendment Patent applicant address 2-3-104 Torigoe, Taito-ku, Tokyo Date of amendment order Initiator 5, subject of amendment Brief description of the drawings in the specification After section 6 of the explanation, page 11, line 12 of the statement of contents of the amendment, add the following sentence on a new line. [Figure 1 is a diagram showing the dissolution curve obtained from the dissolution test of the powder described in Example 1. The vertical axis shows the dissolution amount (%).
, the dissolution time (minutes) is plotted on the horizontal axis, and the amount dissolved at each dissolution time is shown. In the figure, −・− indicates the powder (c) prepared using the co-pulverized product.
-Δ- indicates each elution curve of the powder (B) produced using the individual pulverized products. FIG. 2 is a diagram showing the dissolution curve obtained by the dissolution test of the capsule described in Example 2, and FIG. 3 is a diagram showing the dissolution curve obtained by the dissolution test of the tablet described in Example 6. It is a figure showing an elution curve. -・-1-△ in the vertical axis, horizontal axis and in the figure
- indicates the case where the co-pulverized product and the individually pulverized product were used, respectively, as in FIG. FIG. 4 is a diagram showing a concentration transition curve showing the results of measuring the concentration transition of nifedipine in rabbit plasma using the tablet described in Example B. The vertical axis is the plasma concentration (μ ?/mI, and time (hr) is shown on the horizontal axis. In the figure, the meanings of -・- and -mu are respectively
It is similar to the figure. "that's all

Claims (1)

[Claims] A solid nifedipine preparation characterized by containing a fine powder composition obtained by co-pulverizing nifedipine and hydroxypropyl cellulose in a mixed state.