JPS58109412A - Nifedipine solid preparation - Google Patents

Abstract

PURPOSE:A nifedipine solid preparation that is made by adding carboxymethylethylcellulose and/or ethylcellulose to nifedipine, which is used as a remedy for stenocardia attack, thus having improved disintegration, elution and absroption. CONSTITUTION:1pt.wt. of nifedipine, which expands coronary blood vessels to improve the balance in oxygen feed in cardiac muscles is combined with 0.2- 30, preferably 1-15pts.wt. of carboxymethylethylcellulose and/or ethylcellulose, preferably with 0.05-30 preferably 0.5-20wt% of at least one selected from surfactants, propylene glycol, glycerol, polyethylene glycol, hydroxypropylcellulose, hydroxypropylmethylcellulose and vegetable oil to produce the objective solid preparation of nifedipine with ease disintegration, high elution and easy absorption, with no use of organic solvents except ethanol.

Description

DETAILED DESCRIPTION OF THE INVENTION It has the effect of improving balance and is used as a therapeutic agent for angina pectoris attacks. It is desirable that this type of drug be a formulation that exhibits rapid and reliable effects when administered sublingually or orally. However, nifedipine is sparingly soluble, resulting in low bibis availability when administered orally (4), making it difficult to develop a formulation that meets the purpose.

Methods for producing preparations that have improved these drawbacks include a method of dissolving nifedipine in polyethylene glycol 400 etc. to make our capsules (see Japanese Patent Application Laid-Open No. 48-28621), and dissolving nifedipine together with polyvinylpyrrolidone in an organic solvent. A method in which nifedipine is dissolved in liquid polyethylene glycol and polyethylene rubitan monooleate to form a solution (see JP-A-54-46837), and a method in which nifedipine is dissolved in liquid polyethylene glycol and polyethylene rubitan monooleate (JP-A-55-1989) -22631) and the like are known.

However, liquid preparations are limited in their formulation form, require more complicated operations to manufacture than solid preparations, and soft capsules have the drawback of being relatively large in size due to constraints in the manufacturing process. Furthermore, solid preparations containing nifedipine and polyvinylpyrrolidone alone have the disadvantage of delayed disintegration.

The present inventors have discovered that a solid preparation of nifedipine that is easily disintegrated (disintegrated quickly) and easily absorbed can be obtained by incorporating specific components into nifedipine.

The present invention is a solid nifedipine preparation containing nifedipine and carboxymethylethylcellulose and/or ethylcellulose.

Furthermore, the present inventors have found that by blending carboxymethylethylcellulose and/or ethylcellulose with nifedipine in combination with one or more components selected from the group consisting of bilmethylcellulose and vegetable oil, nifedipine solid form can be obtained. It was found that the quality of the formulation was further improved.

The nifedipine solid preparation of the present invention can be manufactured as follows.

Nifedipine and carboxymethylethylcellulose and/or ethylcellulose (components are dissolved in an organic solvent while heating as necessary, and optionally a surfactant, propylene glycol, glycerin, polyethylene glycol, hydroxypropylcellulose, hydroxypropylmethylcellulose and/or A mixed solution is prepared by adding and dissolving vegetable oil (component ①).The solid preparation of the present invention is then obtained by removing the organic solvent from this mixed solution by an appropriate means.

In addition, the disintegration and absorption properties of the solid preparation can be further improved by blending the ingredients, and the amounts of ingredient (1) and organic solvent used can be reduced.

As organic solvents, nifedipine, component ① and component 11
(Usually, methanol, ethanol, impropatol, chloroform, dichloromethane, and mixtures thereof are used, and ethanol is particularly preferred.The organic solvent is used in at least an amount necessary to dissolve each component.) used in

Another manufacturing method is to preheat and melt (40 to 90°C)
nifedipine and component (2) are added to component (2) to form a solution, which is cooled and solidified and then pulverized to obtain a nifedipine-containing powder with low bulk and excellent fluidity without using an organic solvent.

To remove the organic solvent, there are two methods: putting excipients in a fluidized bed granulator and spraying, drying, and granulating the mixed solution, concentration method under reduced pressure or normal pressure, spray drying method, and after granulating the product. A method of drying, etc. can be used.

The preparation of the present invention may optionally contain fillers such as lactose, starch, light anhydrous silicic acid, crystalline cellulose, calcium hydrogen phosphate, synthetic aluminum silicate, magnesium aluminate metasilicate, talc, etc., and light-shielding agents such as oxidized Titanium, etc., flavoring agents such as sugars, fragrances, etc., plasticizers such as triacetin, vegetable oils, etc. can be added.

The blending ratio of component (■) to 1 part by weight of nifedipine is 0.
．． The amount is 2 to 60 parts by weight, preferably 1 to 15 parts by weight.

When using a mixture of carboxymethylethylcellulose and ethylcellulose, the blending ratio of both is generally such that carboxymethylethylcellulose is greater than or equal to ethylcellulose - but is not limited to this, depending on the solubility in the organic solvent used, It is desirable to change it appropriately depending on the viscosity and the intended formulation. The blending ratio of component H to 1 part by weight of nifedipine is 0.05 to 60 parts by weight, preferably 0.5 to 20 parts by weight.

The blending ratio of component (■) to component (I) is not limited to (but is not limited to)
It can be changed as appropriate depending on the intended formulation.

As ethyl cellulose, 5 to 10 (1 c
ps (ethoxy group content: 44-51% by weight), especially those having a viscosity of 50 cps at 25° C. (ethoxy group content: 48-49% by weight). As carboxymethylethylcellulose, one having an ethoxy group content of 15 to 50% by weight is preferable. Examples of the surfactant include nonionic surfactants such as polyoxyl stearate-140, polysorbate 80, ethylene oxide-propylene oxide copolymer, glycerin fatty acid ester, and anionic surfactants such as sodium alkyl sulfate.

As polyethylene glycol, the average molecular weight is 200~
6000 is preferred. Examples of vegetable oils include soybean oil, sesame oil, and olive oil.

Additives such as excipients, disintegrants, lubricants, binders, etc. are mixed with the powder or granules of the nifedipine solid preparation thus obtained, and fine granules, granules, hard capsules, etc. are prepared by a conventional method. It can be made into tablets.

A solid preparation containing nifedipine and carboxymethylethylcellulose or ethylcellulose has not been known so far. The nifedipine solid preparation of the present invention is produced by blending nifedipine with component I and, if desired, component The elution rate of nifedipine is significantly improved compared to when it exists in a crystalline state, and it is rapidly absorbed from the gastrointestinal tract. In terms of the manufacturing method, it is possible to manufacture using only ethanol, which is highly safe, as an organic solvent. The advantage is that an excellent nifedipine solid preparation can be produced.

In an example, 10 g of fuedipine and 40 g of carboxymethylethyl cellulose were dissolved in 500 ml of ethanol in VCM, and then poured into 200 g of lactose. This is kneaded, granulated, and dried to obtain granular powder.

Example 2 50 g of ethanol was added to 10 g of nifedipine, 30 g of ethyl cellulose, and 30 g of polyoxyl-40 stearate.
Add 0ml of lactose and dissolve by heating to 45℃, then add 1ml of lactose.
It is poured into a mixed powder of 50 g and silicic anhydride 209, and kneaded, granulated, and dried. Talc io is added to the resulting granular powder.
g is added, mixed uniformly, and packed into capsules (No. 1 capsule, filling amount 250 mg) to prepare hard capsules.

Example 6 10 g of nifedipine, 40 g of carboxymethylethyl cellulose, 40,020 g of polyoxyl stearate, and 5 g of hydroxypropyl cellulose with 40 g of ethanol.
After adding and dissolving 0 ml, the mixed solution is sprayed onto 118 g of lactose and 49.9 g of crystalline cellulose using a fluidized bed granulator to obtain granules. To 120 g of the granules thus obtained, 2 g of talc, 1 g of magnesium stearate and 2 g of calcium carboxymethyl cellulose are added and mixed uniformly, and tablets each weighing 250 Da are prepared by a conventional method.

Example 4 Nifedipine 20,9. Carboxymethylethyl cellulose 60I and polyethylene glycol 4000/10
．． ! 400 ml of -1-tanol was added to i' and dissolved with stirring. This solution is spray dried to obtain a powder. To 45 g of the powder thus obtained, 20 g of crystalline cellulose, 19 g of 2-2-ruboxymethylcellulose calcium and 1 g of magnesium stearate are added and mixed uniformly to form tablets of 85 square centimeters each in a conventional manner.

Example 5 Nifedipine IQ, 9. 20 g of ethyl cellulose, 30 g of carboxymethyl ethyl cellulose and 159 of polyethylene glycol 1500, 500 me of ethanol.
After complete dissolution, 10 g of magnesium aluminate metasilicate was added to this solution and dispersed uniformly, and then 165 g of lactose and 60 g of crystalline cellulose were added using a fluidized bed granulator.
to obtain granules. The granules thus obtained are sieved to form fine granules.

Example 6 20 g of nifedipine and 20.9 g of carboxymethylethyl cellulose are added to a mixed solution of 80.9 g of sita polyethylene glycol 6000 and 20.9 g of polyethylene glycol 400, melted by heating (55° C.), and stirred to dissolve. This solution was cooled and solidified, and then ground to a powder of 10
Take 5 g, add 60 g of lactose, 10 g of crystalline cellulose, and 5 g of Merck, mix uniformly, and fill in capsules (No. 2 cell, filling amount: 1 jom 9) to prepare hard capsules.

Test Example A dissolution test was conducted using the formulations of Examples 1 to 6 and the following formulation as a comparative example. The test was conducted by adding a sample equivalent to 20 mg of nifedipine to 900 ml of distilled water (37°C) in a 1-e beaker and using the Japanese Pharmacopoeia X paddle method (rotation speed 10 Orpm). The amount of nifedipine eluted was measured using a spectrophotometer. The results are shown in the table below. The formulation of the present invention had a better initial dissolution rate and a much higher dissolution rate than the comparative example.

The formulation of the comparative example was prepared by dissolving hydroxypropyl cellulose 6I in ethanol, 10 g of nifedipine, and 51 g of lactose.
, potato starch 10.9, and crystalline cellulose 6f1, the mixture was kneaded, granulated, and dried to form granules.

11- Elution test results: Applicant: Toa Nutritional Chemical Industry Co., Ltd. Agent Patent Attorney Tadashi Kobayashi 12-

Claims (1)

[Claims] 1. A solid nifedipine preparation containing nifedipine and carboxymethylethylcellulose and/or ethylcellulose.5. 2. Carboxymethylethylcellulose and/or ethylcellulose to nifedipine, a surfactant selected from the group consisting of propylene glycol, glycerin, polyethylene glycol, hydroxypropylcellulose, hydroxyglobil methylcellulose and vegetable oil 1
Nifedipine solid preparation formulated in combination with seeds or two or more ingredients. 6. 0.2 parts of carboxymethylethylcellulose and/or ethylcellulose per 1N part of nifedipine.
~60 parts by weight, one or more components selected from the group consisting of surfactant, propylene glycol, glycerin, polyethylene gdroxyglobil methylcellulose, and vegetable oil in a ratio of 0.05 to 30 parts by weight. A solid preparation of nifedipine according to claim 2.