JP2001010950A - Medicinal composition having stable and good drug releasability - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain a medicinal composition stable during production and during preservation thereafter, and good in elutability by covering or mixing a specific amount of hydrophobic low melting-point material on or with an active ingredient, and carrying out a compression molding of the obtained particles with a goodly moldable material. SOLUTION: This medicinal composition is obtained by covering or mixing 0.01-1 pts.wt. hydrophobic low melting-point material (preferably having <=100 deg.C melting point, e.g. stearic acid) on or with 1 pts.wt. active ingredient (preferably an effective component of a medicine having the stability after the compression molding lowered from the stability before the compression molding when carrying out the compression molding, e.g. nicorandil), and carrying out a compression molding of the obtained particles with a goodly moldable material [preferably, the one capable of providing a tablet having >=4 kg hardness when pressing 200 mg material under 2,000/cm2 pressure in a mold having 8 mm diameter, and <=30 min corruption time in a corruption test of the pharmacopoeia of Japan (13 section), and being inert to a medicine, e.g. granulated lactic acid, and preferably added to a preparation at >=10 wt.%] under 20-65 kg/mm2 pressure.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

TECHNICAL FIELD The present invention relates to a pharmaceutical composition, and more particularly, to a compression-molded pharmaceutical composition in which the active ingredient is stable and exhibits good dissolution in a pharmaceutical preparation.

[0002]

2. Description of the Related Art When a certain active ingredient is used as a drug, it is usually possible to obtain a drug having excellent compliance by processing it into various dosage forms. Tablets are widely used as particularly desirable administration forms.

[0003] However, among active ingredients used as pharmaceuticals, in spite of having excellent medicinal properties, in an environment where mechanical stress, moisture, temperature, etc. are simultaneously applied during formulation, they are more unstable than before processing. There is something that becomes. For this reason, for example, as a method of avoiding mechanical stress, there is known a method of coating with a solid brazing substance at room temperature and then performing compression molding to stabilize the crystal lattice of the active ingredient while avoiding distortion ( JP-A-57-145659).

However, according to this method, the stability of the active ingredient was not always sufficient. In addition, in general, it is known that rapid elution is advantageous for the absorption and development of a drug, except for the case where the elution of the active ingredient is intentionally controlled from the preparation such as a sustained release preparation, When the amount of the solid wax at room temperature is increased in order to stabilize the active ingredient by the above-mentioned method, there is a problem that the release of the active ingredient from the preparation is delayed, thereby impairing the expression of the expected medicinal effect.

[0005]

Therefore, mechanical stress,
There has been a strong demand for the development of compression-molded pharmaceutical compositions which exhibit stable active ingredients during storage and subsequent storage, even when moisture, temperature, etc. are given simultaneously, and which exhibit good dissolution.

[0006]

Means for Solving the Problems The present inventors have conducted intensive studies to solve the above-mentioned problems, and as a result, have added a good-forming material to particles obtained by coating or mixing an active ingredient with a hydrophobic low-melting substance. The pharmaceutical composition obtained by compression molding was found to be extremely stable during production and after storage and had good dissolution properties, and completed the present invention.

That is, the present invention is a pharmaceutical composition obtained by compressing and molding particles obtained by coating or mixing 0.01 to 1 part by weight of a hydrophobic low melting point substance with 1 part by weight of an active ingredient together with a good molding substance.

[0008]

BEST MODE FOR CARRYING OUT THE INVENTION There are no particular restrictions on the active ingredient used as the active ingredient in the present invention. However, when compression molded,
The present invention is particularly effective for medicinal ingredients whose stability after compression molding is lower than before compression molding. Examples of such active ingredients include ACE inhibitors, captopril, alacepril, lisinopril, elanapril, delapril, cilazapril, quinapril, ramipril, benazepril,
Examples include imidapril, temocapril, trandolapril, fosinopril, perindopril erbumin and salts thereof, nicorandil as a vasodilator, bisoprolol as a β1 antagonist and salts thereof, and the like.

As the hydrophobic low-melting substance, any substance can be used without particular limitation as long as it is hydrophobic and has a melting point of 100 ° C. or less. Preferred hydrophobic low-melting substances include saturated higher fatty acids (eg, stearic acid and the like) and higher alcohols.
(Eg, stearyl alcohol), higher fatty acid glycerin esters (eg, hardened oil), waxes (eg, carnauba wax), saturated hydrocarbons (eg, paraffin), and the like.

[0010] Good molding materials used in the present invention include:
A material with good moldability, more specifically, a diameter of 8 mm
Pharmaceutically inert, the tablet hardness is 4 kg or more when 200 mg of the substance is compressed at 2000 / cm ² in the mold of the above, and the disintegration time is within 30 minutes in the disintegration test of the Japanese Pharmacopoeia Law (13 stations). Substances. Specific examples of preferable good molding substances include granulated lactose (for example, manufactured by Freund Corporation, product name: Dilactose R, S), and spray-dried and granulated lactose (for example, manufactured by DMV, product name: Ph)
armatose DCL11), spray-dried and granulated anhydrous calcium hydrogen phosphate (eg, Fuji Chemical Co., Ltd., product name: Fujicalin), calcium citrate (eg, Tanabe Seiyaku, product name: xetamine K), spray-dried sorbitol (For example, Merck Japan, product name: sorbitol instant), calcium silicate (for example,
Tokuyama Soda, product name: Fluorite RE).

The compounding amount of the hydrophobic low-melting substance in the pharmaceutical composition of the present invention is preferably 1 part by weight or less, for example, about 0.01 to 1 part by weight per 1 part by weight of the active ingredient.
In particular, the range of 0.05 to 0.5 parts by weight is more preferable.
When more than 1 part by weight of a hydrophobic low-melting substance is blended, the stability of the active ingredient is not problematic, but the dissolution may be insufficient.

[0012] The good molding substance is preferably added to the preparation at least 10% by weight or more, more preferably at least 50% by weight.

The pharmaceutical composition of the present invention is obtained by coating the active ingredient with a hydrophobic low-melting substance, or mixing the active ingredient with the hydrophobic low-melting substance, and then adding a good moldable substance and compression molding. It is manufactured by

The coating of the active ingredient with the hydrophobic low-melting substance can be carried out according to a conventional method, and preferable methods include a spray coating method and a melting method. In the case of the spray coating method, coating can be performed after dissolving or suspending a hydrophobic low-melting substance in a solvent. As the solvent, a solvent having a boiling point of about 40 to 100 ° C. is preferable. From the viewpoint of operability and safety, particularly, ethanol is preferred.
And methanol or the like. As a device used for spray coating, a tumbling fluidized bed granulator [for example, New / Malmerizer (made by Fuji Paudal)] is preferable. When the melting method is used, it is desirable that the particle size of the hydrophobic low-melting substance is smaller than the particle size of the active ingredient.
As an apparatus used for the melt coating, an agitation granulator [e.g., a high-speed mixer (manufactured by Fukae Kogyo)] having a warm water jacket and having crushing blades on the inner surface of the agitator is preferable. The temperature in the container is preferably about 50 to 100 ° C., and preferably around the melting point (about ± 5 ° C.) of the hydrophobic low melting point substance to be used.

The mixing of the hydrophobic low-melting substance and the active ingredient can be carried out according to a conventional method. At the time of mixing, it is preferable that the physical force of the active ingredient on the crystal be small. For example, it is preferable to use a mixing device such as a V-type mixer to mix for about 20 to 60 minutes.

The particle diameter of the particles coated or mixed with the hydrophobic low-melting substance is preferably about 5 μm to 2000 μm, more preferably about 75 μm to 500 μm.

The addition of a good molding substance and compression molding can be carried out by a conventional method, but the pressure during compression molding is preferably about ²⁰ to 65 kg / mm ² , preferably 25 to 50 kg / mm ^2.
It is more preferably about kg / mm ² . The hardness of the formed tablet is generally 3 to 15 kg in the case of a round tablet, and a particularly preferred tablet has a hardness of 4 to 9 kg.

In formulating the composition of the present invention, various additives usually used in the preparation of pharmaceuticals such as crystalline cellulose, starch, carboxymethylcellulose, hydroxypropyl are used as long as the effects of the present invention are not impaired. Cellulose, light silicic anhydride, magnesium stearate, calcium stearate, stearic acid, talc,
Polyethylene glycol, polysorbate 80 and the like can be used.

The pharmaceutical preparation obtained according to the present invention can be prepared in accordance with Japanese Pharmacopoeia Law (13 stations) Dissolution Test Method 2
When the dissolution test was performed at 0 mL and at a paddle rotation speed of 50 rotations (per minute), the active ingredient was 75% within 60 minutes of the test start.
The elution characteristics are shown above. A more preferable dissolution property is a preparation in which 85% or more of the active ingredient is dissolved within 30 minutes from the start of the test. In addition, Pharmaceutical Research Vol.
13, No. 5, p1116-1117 (1982) employs a dissolution test for estimating bioequivalence. In the case of a preparation within 60 minutes when the dissolution of the active ingredient shows 75%, the dissolution test is used. Are described as being comparable. However, the paddle rotation speed in the test is as high as 100 rotations (per minute), which is not enough to confirm the dissolution characteristics of the preparation.

[0020]

The present invention will be described in more detail with reference to the following examples and test examples, but the present invention is not limited by these examples.

EXAMPLE 1 500 g of nicorandil and 50 g of hardened oil were placed in a stirring granulator equipped with a warm water jacket, the vessel was heated to 65 ° C. with stirring, mixed for 5 minutes while maintaining the temperature at 65 ° C., and then stirred. The mixture was allowed to cool to room temperature while continuing to obtain particles. After mixing 215 g of these particles with 2215 g of Dilactose R (manufactured by Freund Corporation) and 10 g of calcium stearate, the mixture was compression-molded under a pressure of 720 kg to give a diameter of 5 mm, a hardness of 5 kg, and a tablet of 50 mg.
Tablets were obtained.

Comparative Example 1 To 250 g of nicorandil, 2240 g of Dilactose R (manufactured by Freund Corporation) and calcium stearate
After mixing 10 g, the mixture was compression-molded under a pressure of 720 kg to obtain a tablet having a diameter of 5 mm, a hardness of 5 kg, and a tablet of 50 mg.

Comparative Example 2 50 g of stearyl alcohol was dissolved in 250 mL of chloroform, mixed with 500 g of nicorandil using a stirring granulator, and dried at 50 ° C. for 12 hours to obtain particles (particle I). ). Apart from this, Mannitol 4
04 g, carboxymethyl cellulose calcium 25
g and 8 g of hydroxypropyl cellulose were placed in a stirring granulator, granulated with water, and then dried at 60 ° C. for 12 hours to obtain particles (particle II). Particle I 49.5
g, 393.3 g of particles II and 7.2 g of magnesium stearate, and then compression-molded under a pressure of 720 kg to give a diameter of 5 mm, a hardness of 4.5 kg, and a hardness of 4.5 kg.
50 mg tablets were obtained.

Example 2 150 g of enalapril maleate and 300 g of lactose powder
And 75 g of the hardened oil were placed in a stirring granulator equipped with a warm water jacket, and the vessel temperature was raised to 65 ° C. while stirring.
The mixture was mixed for 10 minutes while maintaining the temperature at 5 ° C, and allowed to cool to room temperature while stirring was continued to obtain particles. These particles 175
g to 815 g of Dilactose S (Freund Sangyo)
And after mixing 10 g of calcium stearate,
Compression molding with a pressure of 1000 kg gives a diameter of 6.
A tablet having a size of 5 mm, a hardness of 4.5 kg, and a tablet of 100 mg was obtained.

Comparative Example 3 Enalapril maleate 50 g, Dilactos S
After mixing 940 g (manufactured by Freund Corporation) and 10 g of calcium stearate, the mixture was compression-molded under a pressure of 1000 kg to give a diameter of 6.5 mm and a hardness of 4.5 k.
g, 100 mg tablets were obtained.

Example 3 436 g of lisinopril and 40 g of setanol were placed in a stirring granulator equipped with a warm water jacket, the vessel was heated to 65 ° C. with stirring, mixed for 5 minutes while maintaining the temperature at 65 ° C., and stirred. The mixture was allowed to cool to room temperature while continuing to obtain particles. 1341 g of Fujicalin (manufactured by Fuji Chemical Co., Ltd.), 670 g of crystalline cellulose, 100 g of croscarmellose sodium and 20 g of calcium stearate were mixed with 119 g of the particles, and the mixture was compression-molded under a pressure of 1200 kg to give a diameter of 8 mm and a hardness of 7 kg. 1 tablet 2
25 mg tablets were obtained.

Example 4 500 g of bisoprolol fumarate was placed in a fluidized bed granulator, and 5 g of cetanol was dissolved in 500 mL of hot ethanol to obtain coated particles. 50.5 g of these particles were mixed with xetamine K (manufactured by Tanabe Seiyaku) 900
g, 34.5 g of corn starch and 15 g of stearic acid, and then compression-molded under a pressure of 800 kg to give a diameter of 6.5 mm, a hardness of 6 kg, and one tablet.
00 mg tablets were obtained.

Example 5 300 g of delapril hydrochloride was placed in a fluidized bed granulator, and a solution in which 3 g of stearic acid was dissolved in 500 mL of ethanol was sprayed to obtain coated particles. These particles 15
To 1.5 g, Dilactose S (manufactured by Freund Corporation)
588.5 g, 100 g of mannitol, 100 g of low-substituted hydroxypropylcellulose and 50 g of hydroxypropylcellulose were added, and the mixture was placed in a fluidized-bed granulator. Granulated by spraying. After drying at 80 ° C for 1 hour,
Mix 10g of magnesium stearate, 1000k
A tablet having a diameter of 6.5 mm, a hardness of 5 kg and a tablet of 100 mg was obtained by compression molding under a pressure of g.

Test Example 1 The preparations obtained in Example 1 and Comparative Examples 1 and 2 were sealed together with a desiccant in a brown glass bottle and stored at 50 ° C. for 7 days. The raw active ingredient was also tested at the same time. At this time, the residual ratio of the nicorandil content was compared. Table 1 shows the results.

[0030]

Table 1 ────────────────────────────────── Example 1 Comparative Example 1 Comparative Example 2 Active ingredient 残存 Residual rate after 7 days at 50 ° C (%) 90.5 53.7 70.2 90.7 ──────────────────────────────────

Test Example 2 The preparations obtained in Example 2 and Comparative Example 3 were sealed in a brown glass bottle and stored at 60 ° C. for 21 days. The raw active ingredient was also tested at the same time. At this time, the residual ratio of the elanapril maleate content was compared. Table 2 shows the results.

[0032]

２ Example 2 Comparative Example 3 Raw Active Ingredient ─── {Residual rate (%) after 21 days at 60 ° C 97.5 46.7 98.9} ───────────────────────────────

Test Example 3 The preparations obtained in Examples 1 and 2 were used in accordance with the Japanese Pharmacopoeia method (13
Department) Dissolution test method 2 (paddle method, 50 rotations). The test was performed with 900 mL of test liquid water. As shown in Table 3, the active ingredient was rapidly dissolved.

[0034]

[Table 3] ──────────────────────────Dissolution rate ───────────────Time Example 1 Example 2 5 minutes 35.5% 79.2% 10 minutes 62.1% 97. 7% 15 minutes 85.1% 98.3% 30 minutes 100.1% 99.7% ──────────────────────────

[0035]

According to the present invention, the active ingredient of a drug, particularly an active ingredient consisting of a medicinal ingredient whose stability after compression molding is lower than that before compression molding when compression molded, can be obtained even under severe conditions. It can be formulated stably. In addition, since the compression-molded pharmaceutical composition of the present invention exhibits rapid dissolution characteristics, it is presumed that the absorption and the onset of the drug effect after administration to a living body are also good. that's all

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Claims (4)

[Claims] 1. A pharmaceutical composition obtained by compression-molding particles obtained by coating or mixing 0.01 to 1 part by weight of a hydrophobic low melting point substance with 1 part by weight of an active ingredient together with a good molding substance. 2. The hydrophobic low-melting substance is one or a mixture of two or more selected from saturated higher fatty acids having a melting point of 100 ° C. or lower, higher alcohols, higher fatty acid glycerin esters, waxes and saturated hydrocarbons. The pharmaceutical composition according to claim 1. 3. The good molding material is selected from granulated lactose, spray-dried granulated lactose, spray-dried granulated anhydrous calcium hydrogen phosphate, calcium citrate, spray-dried sorbitol and calcium silicate. The pharmaceutical composition according to claim 1, wherein the composition is one kind or a mixture of two or more kinds. 4. When the active ingredient is subjected to a dissolution test with 900 mL of test liquid water and a paddle rotation speed of 50 rotations (per minute),
The pharmaceutical composition according to any one of claims 1 to 3, wherein 75% or more is eluted within 60 minutes from the start of the test.