JPH08208476A - Nifedipine-containing sustained action drug - Google Patents

Abstract

PURPOSE: To prepare the subject drug preparation having excellent oral absorptivity of nifedipine and sustainability of the concentration in blood plasma and exhibiting sufficient prevention and treatment effect on stenocardia and hypertension at a small number of administration doses. CONSTITUTION: This nifedipine-containing sustained action drug is produced by coating a core particle with a solid dispersion composition composed of (A) nifedipine and (B) a base selected from a water-soluble cellulose ether (preferably hydroxypropyl methylcellulose), polyvinyl pyrrolidone and their mixture and coating the obtained granular composition with (C) a coating film composed of (i) ethylcellulose and (ii) hydroxypropyl, methylcellulose. The amount of the hydroxypropyl, methylcellulose as the component B is 1.5-3 pts.wt. (preferably 1.5 pts.wt.) and the amounts of the component (i) and the component (ii) are 0.6-0.8 pts.wt. (preferably 0.7 pts.wt.) and 0.9-1.2 pts.wt. (preferably 1.05 pts.wt.) based on 1 pt.wt. of the component A, respectively. The preparation is administered once or twice a day.

Description

Detailed Description of the Invention

[0001]

FIELD OF THE INVENTION The present invention relates to a novel long-acting preparation containing nifedipine. For more details, (a)
A granular composition in which core particles are coated with a composition in the form of a solid dispersion comprising nifedipine and (b) a water-soluble cellulose ether, a base material selected from polyvinylpyrrolidone and a mixture thereof is prepared from ethyl cellulose and hydroxypropyl methylcellulose. The present invention relates to a sustained-release preparation containing nifedipine coated with the following film.

[0002]

BACKGROUND OF THE INVENTION Nifedipine is one of the calcium antagonists and is widely used for the prevention and treatment of angina and hypertension. However, it is poorly orally absorbed because it is a poorly water-soluble substance, and its metabolism and excretion are also high. Has the drawback that the duration of action is short due to its fast activity.

In order to overcome the above-mentioned problems, namely, to further improve the preventive and therapeutic effects by keeping the plasma concentration of nifedipine constant for a long time, reduce the frequency of drug administration, and improve patient compliance. To
A long-acting formulation of nifedipine has been developed and is widely used clinically.

[0004]

DISCLOSURE OF THE INVENTION The object of the present invention is to improve the oral absorption of nifedipine and the durability of plasma concentration of nifedipine, and to obtain sufficient prophylactic and therapeutic effects by administration once or twice a day. To provide a sustained-release preparation.

[0005]

Means for Solving the Problems As a result of intensive studies to solve the above problems, the present inventors have found that (i) nifedipine and (b) water-soluble cellulose ether, polyvinylpyrrolidone and a mixture thereof. A granular composition obtained by coating a core particle with a composition in the form of a solid dispersion consisting of a selected base material, a nifedipine-containing sustained-release preparation produced by coating a film consisting of ethyl cellulose and hydroxypropylmethyl cellulose, The present invention has been completed by finding that the object of the present invention is met.

The water-soluble cellulose ether used in the present invention is a water-soluble cellulose ether in which a part of the alcohol group which is a glucose residue in cellulose is replaced with methyl ether and / or hydroxypropyl ether or hydroxyethyl ether. It is soluble in.

As the above water-soluble cellulose ether,
Examples thereof include methyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose and the like.

The above-mentioned methyl cellulose preferably has a methoxyl group content of 26.0 to 33.0%, and it is preferably used in the 12th revised Japanese Pharmacopoeia (Daiichi Law Publication, 1991, hereinafter,
The methylcellulose described on page 1070 of the Japanese Pharmacopoeia) is preferably used. This can be obtained, for example, under the trade name of Metroose SM (manufactured by Shin-Etsu Chemical Co., Ltd.).
The hydroxypropyl cellulose preferably has a hydroxypropoxyl group content of 53.4 to 77.5%, and the hydroxypropyl cellulose described on page 1023 of the Pharmacopoeia is preferably used. This can be obtained, for example, under the trade name Shin-Etsu HPC (manufactured by Shin-Etsu Chemical Co., Ltd.).
Hydroxypropyl methylcellulose has a methoxyl group content and a hydroxypropoxyl group content of 1 each.
It is preferably 9.0 to 30.0%, 4.0 to 12.0%, and among them, the contents of methoxyl group and hydroxypropoxyl group are 28.0 to 30.0% and 7.
Those of 0 to 12.0% are particularly preferable. These hydroxypropyl methylcelluloses are the hydroxypropylmethylcellulose 2208, hydroxypropylmethylcellulose 2906 and hydroxypropylmethylcellulose 2 described on pages 1025 and 1027 of the Pharmacopoeia.
910 is preferably used. For example, a trade name of TC-5 (manufactured by Shin-Etsu Chemical Co., Ltd.) can be obtained. Among the above water-soluble cellulose ethers, hydroxypropylmethyl cellulose is particularly preferable.

Polyvinylpyrrolidone has a molecular weight of about 250.
Those having a molecular weight of about 40,000 can be used, but those having a molecular weight of about 40,000 are preferable, and those having a molecular weight of 1057
Polyvinylpyrrolidone K30 described on page is preferably used.

The sustained-release preparation of the present invention uses water-soluble cellulose ether or polyvinylpyrrolidone as a base. Further, these polymer compounds can be appropriately mixed and used as a base.

The core particles used in the sustained-release preparation of the present invention include one or a mixture of two or more of the usual excipients used in pharmaceuticals (eg starch, sucrose, lactose, mannitol, crystalline cellulose, etc.). Alternatively, granules thereof can be used. Furthermore, in addition to the above-mentioned excipients, binders (eg hydroxypropylmethylcellulose, hydroxypropylcellulose, methylcellulose, gelatin, gum arabic etc.), disintegrants (eg carmellose calcium etc.), lubricants (eg magnesium stearate) , Talc, etc.) and a surfactant (eg, sodium lauryl sulfate, etc.) may be added to prepare a powdery or granulated product, and these may be used as core particles. Further, a commercially available granulated product using the above-mentioned excipient can also be used. Examples of this include Celfia (trade name, manufactured by Asahi Chemical Industry Co., Ltd.), which is a spherical granule of crystalline cellulose, and non-parel (trade name, manufactured by Freund Sangyo), which is a spherical granule of sucrose or sucrose / corn starch. it can. The average particle size of these core particles is 100
The thickness is preferably about 500 μm, but is not particularly limited.

The ethylcellulose used in the film of the sustained release preparation of the present invention has an ethoxyl group of 46.5 to 51.
Those of 0% are preferably used. This can be obtained, for example, under the trade name of Ethocel (manufactured by Dow Chemical Co.). Moreover, as the hydroxypropylmethylcellulose used for the film, the above-mentioned hydroxypropylmethylcellulose is preferably used.

The sustained-release preparation of the present invention can be manufactured by the following manufacturing method. First, a solution of nifedipine, a water-soluble cellulose ether, a base material selected from polyvinylpyrrolidone and a mixture thereof in an organic solvent (this solution is referred to as a solid dispersion solution) is spray-dried on the core particles to form a solid dispersion. A granular composition coated with the body composition is prepared. Next, a liquid in which ethyl cellulose and hydroxypropylmethyl cellulose are dispersed or dissolved in water and / or an organic solvent (this liquid is referred to as a film liquid) is spray-dried to the granular composition to coat the film of the present invention. Sustained-release preparations can be produced.

The amount of the base used in the solid dispersion solution is
It is usually 1 to 7 parts by weight, preferably 1.5 to 3 parts by weight, relative to 1 part by weight of nifedipine.

When the amount of the base compounded is 1 part by weight or less with respect to 1 part by weight of nifedipine, a composition in the form of a solid dispersion cannot be obtained, and when it is 7 parts by weight or more, the volume of the composition becomes large, and However, this is not preferable because the preparation produced using this will be large.

The organic solvent used in the solid dispersion solution is not particularly limited as long as it is a solvent capable of dissolving both nifedipine and the above-mentioned base, and for example, 1 of methanol, ethanol, isopropanol, acetone, chloroform or dichloromethane. One kind or a mixture of two or more kinds can be used. The amount of the organic solvent used is 1.2 to 3 which is the amount required to dissolve the nifedipine and the base at room temperature.
A double dose is appropriate.

The appropriate amount of ethyl cellulose is 0.6 to 0.8 parts by weight per 1 part by weight of nifedipine, and the amount of hydroxypropyl methyl cellulose is
0.9 to 1.2 parts by weight is suitable for 1 part by weight of nifedipine.

The blending ratio of ethyl cellulose and hydroxypropyl methyl cellulose is 1 part by weight of ethyl cellulose and 1 part by weight of hydroxypropyl methyl cellulose.
5 parts by weight is especially preferred.

In addition to ethyl cellulose and hydroxypropylmethyl cellulose, the film liquid contains a plasticizer (for example,
Triacetin, triethyl citrate, macrogol 60
00 or the like) or a suitable mixture of two or more thereof.

The organic solvent used for the coating solution is not particularly limited, and for example, one or more of methanol, ethanol, isopropanol, acetone, chloroform and dichloromethane can be used as a mixture.
When using a mixed solvent of water and an organic solvent, it is necessary to select an organic solvent in which the solvents are mixed.

In order to maintain the stability of nifedipine, which is unstable to light, titanium oxide, iron sesquioxide, yellow sesquioxide, edible yellow dye No. 4 or edible yellow dye 5 is used as a light-shielding agent in the coating solution. No. etc. can be added.

For the above-mentioned light shielding, for example, hydroxypropylmethylcellulose and titanium oxide, iron sesquioxide, yellow iron sesquioxide, edible yellow dye No. 4 or edible yellow dye No. 5 are added to water and / or an organic solvent after coating the coating solution. It can also be achieved by dissolving or dispersing and further coating the solution.

For the purpose of preventing and treating hypertension and angina, the sustained-release preparation of the present invention is orally administered in an amount equivalent to 10 to 40 mg of nifedipine per day for an adult once or twice a day.

[0024]

The sustained-release preparation of the present invention gradually releases nifedipine over a long period of time (Test Example 1 described later).
When administered orally to humans, the plasma concentration of nifedipine lasts for an extremely long time after administration (see Test Example 2 below).

Therefore, the nifedipine-containing sustained-release preparation of the present invention is useful as a preparation for administration once or twice a day.

Further, since the sustained-release preparation of the present invention is in the form of granules, it is easy to adjust the dose according to the symptoms, age, etc., and by filling them into capsules, It can also be taken all at once as a drug.

The working effects of the present invention will be described in detail below with reference to test examples.

[Test Example 1] (Dissolution test) (1) Sample (a) Formulation of Example 1 (b) Formulation of Example 2 (2) Test method The second liquid described in the Japanese Pharmacopoeia was used as a test liquid. Each sample was added to this in an amount equivalent to 5 mg of nifedipine, and the test was carried out according to the second dissolution test method (paddle method) described in the Japanese Pharmacopoeia. The rotation speed of the paddle was 50 rpm. After adding the sample to the test solution, the sample was added for a certain period of time (0.5, 1, 2, 3, 4, 6, 8, 10, 12, 1
The elution amount of nifedipine was measured by measuring the absorbance at a wavelength of 325 nm and a wavelength of 500 nm using an automatic dissolution test system (manufactured by Toyama Sangyo Co., Ltd.) every time 4, 16, 18, 20 hours). (3) Test Results The time course of the elution rate of nifedipine (average value of 6 cases) is shown in FIG.

[Test Example 2] (Drug administration test) (1) Sample (a) Capsule of Example 3 (b) Capsule of Example 4 (2) Test method Samples (nifedipine 20 mg of 20 mg) were given to four healthy males. Considerable amount)
Was orally administered for a certain period of time (2, 4, 6, 8, 1
Blood was collected every time (0, 12, 15, 24 hours), and the obtained blood was centrifuged to obtain plasma. The concentration of nifedipine in the obtained plasma was measured by gas chromatography [detector: electron capture detector, column: 3% OV-17 (3 mm × 3.1).
m, manufactured by GL Sciences Inc.), column temperature: 270
° C]. (3) Test Results The time course of plasma nifedipine concentration (average value) is shown in FIG.

[0030]

EXAMPLES The present invention will be described below with reference to examples.

Example 1 200 g of nifedipine and hydroxypropylmethyl cellulose (trade name: TC-5E, manufactured by Shin-Etsu Chemical Co., Ltd.)
300 g of dichloromethane 1620 g and ethanol 10
Dissolve in 80 g of mixed solvent to obtain a solid dispersion solution. Spherical granules of crystalline cellulose (trade name: Celphia CP-2
03, manufactured by Asahi Kasei Kogyo Co., Ltd.) in a fluidized bed granulation dryer (device name: GPCG-1, manufactured by Fuji Paudal Co., Ltd.), and the solid dispersion solution is spray-dried by a bottom spray method to obtain a solid dispersion. After coating the granular composition, it was sized with a 30-mesh sieve to obtain 1350 g of a granular composition.

Next, ethyl cellulose (trade name: Etocel standard-10, manufactured by Dow Chemical Co.) 2
8 g and 42 g of hydroxypropylmethyl cellulose (trade name: TC-5E, manufactured by Shin-Etsu Chemical Co., Ltd.) were dissolved in 930 g of a mixed solvent of dichloromethane and ethanol [1: 1 (weight ratio)] to give a film solution. 280 g of the above granular composition was fluidized in a fluidized bed granulation dryer, and the coating solution was spray-dried by a bottom spray method to coat the coating, and then sized with a 30-mesh sieve to continuously contain nifedipine. 329 g of a sex preparation was obtained.

Example 2 200 g of nifedipine and hydroxypropylmethyl cellulose (trade name: TC-5E, manufactured by Shin-Etsu Chemical Co., Ltd.)
300 g of dichloromethane 1620 g and ethanol 10
Dissolve in 80 g of mixed solvent to obtain a solid dispersion solution. 150 of crystalline lactose (trade name: 80M lactose, manufactured by Asahi Kasei Corporation)
900 g of the product sieved to μm to 300 μm was made to flow in a fluidized bed granulation dryer (apparatus name: GPCG-1, manufactured by Fuji Paudal Co., Ltd.), and the solid dispersion solution was spray-dried by the bottom spray method to disperse the solid. After coating the body-shaped composition, it was sized with a 30-mesh sieve to obtain 1370 g of a granular composition.

Next, ethyl cellulose (trade name: Etocel standard-10, manufactured by Dow Chemical Co.) 2
8 g and 42 g of hydroxypropylmethyl cellulose (trade name: TC-5E, manufactured by Shin-Etsu Chemical Co., Ltd.) were dissolved in 930 g of a mixed solvent of dichloromethane and ethanol [1: 1 (weight ratio)] to give a film solution. 280 g of the above-mentioned granular composition was fluidized in a fluidized bed granulation dryer, and the coating solution was spray-dried by a bottom spray method to coat the coating, and then synthetic aluminum silicate (trade name: synthetic silicic acid). 7 g of aluminum (light aluminum, manufactured by Kyowa Chemical Industry Co., Ltd.) was added, and the particles were sized with a 30-mesh sieve to obtain 322 g of a nifedipine-containing sustained-release preparation.

Example 3 No. 2 hard capsule was filled with 175 mg of the sustained-release preparation of Example 1 to prepare a capsule.

Example 4 178.5 mg of the sustained-release preparation of Example 2 was filled in a No. 2 hard capsule to prepare a capsule.

[Brief description of drawings]

FIG. 1 shows the time-dependent transition (average value) of the elution rate of nifedipine from the preparation of Example 1 and the preparation of Example 2.

FIG. 2 shows the time course (average value) of plasma nifedipine concentration when the capsule of Example 3 and the capsule of Example 4 were orally administered to humans.

[Explanation of symbols]

 Formulation of Example 1 Formulation of Example 2 □ Capsule of Example 3 ■ Capsule of Example 4

─────────────────────────────────────────────────── ─── Continuation of front page (51) Int.Cl. ⁶ Identification number Office reference number FI technical display area // C07D 211/90

Claims (5)

[Claims] 1. A granular composition in which core particles are coated with a composition in the form of a solid dispersion comprising (i) nifedipine and (b) a base selected from water-soluble cellulose ether, polyvinylpyrrolidone and mixtures thereof. A long-acting nifedipine-containing preparation coated with a film of ethyl cellulose and hydroxypropylmethyl cellulose. 2. The nifedipine-containing sustained-release preparation according to claim 1, wherein the water-soluble cellulose ether is hydroxypropylmethyl cellulose. 3. A granular composition in which core particles are coated with a composition in the form of a solid dispersion comprising (i) 1 part by weight of nifedipine and 1.5-3 parts by weight of (b) hydroxypropylmethylcellulose, and ethyl cellulose 0.6-0.8 parts by weight and hydroxypropylmethylcellulose 0.9-
A continuous formulation containing nifedipine coated with 1.2 parts by weight of a film. 4. A granular composition in which core particles are coated with a composition in the form of a solid dispersion comprising (i) 1 part by weight of nifedipine and 1.5 parts by weight of (b) hydroxypropylmethyl cellulose is added to a granular composition of ethyl cellulose A continuous formulation containing nifedipine coated with a film consisting of 7 parts by weight and 1.05 parts by weight of hydroxypropylmethylcellulose. 5. A nifedipine-containing sustained-release preparation obtained by filling a capsule with the sustained-release preparation according to any one of claims 1 to 4.