JPH04159222A - Production of solid preparation for oral administration - Google Patents

Abstract

PURPOSE:To obtain a solid drug for oral administration having properly adjusted absorption and immediate effects or prolonged effects, readily being taken, comprising a drug active compound and silicon dioxide or magnesium aluminate metasilicate. CONSTITUTION:A solid or liquid drug active compound (e.g. nifedipine) suitable for oral administration is dissolved in an organic solvent (e.g. ethanol). The solution is blended with fine powder of silicon dioxide or magnesium aluminate metasilicate and generally used preparation auxiliaries such as excipient, binder, disintegrator or dispersant properly and granulated or compression molded to give the objective substance. The weight ratio of the drug active compound and silicon dioxide or magnesium aluminate metasilicate is 1:0.5-5 by weight ratio.

Description

Detailed Description of the Invention [Industrial Field of Application] The present invention relates to a method for producing a solid drug for oral administration, particularly a method for producing a solid drug for oral administration that has an appropriately adjusted absorption property and is immediately effective or sustained-release. Regarding.

Although the present invention is widely applicable to solid or liquid pharmaceutically active compounds suitable for oral administration, the following description will be made with nifedipine selected as a representative example for convenience.

[Technical background: Nifedipine is a calcium antagonist vasodilator created in West Germany, and has traditionally been widely used as a treatment for angina pectoris, but in recent years it has also been increasingly used as a blood pressure lowering agent.] It has become.

However, since nifedipine crystals have extremely poor solubility in water (solubility approximately 1Oμ9/II<1), various attempts have been made to improve bioavailability in formulations, especially when rapid action is required. There is.

For example, nifedipine is dissolved in liquid polyethylene glycol at room temperature and then made into soft capsules, or the solution is adsorbed onto a porous carrier to make tablets (European Patent Publication No. 1247). However, in this case, the dosage form is large, making it difficult to take. Also, attempts have been made to use it as a solid solution formulation.
High-molecular polyethylene glycol that is solid at room temperature
2-167727) and polyvinylpyrrolidone (
JP-A-57-85316, JP-A-62-228
017) is used as the solid medium. However, since this method requires complicated manufacturing operations, there is also a method (Japanese Patent Publication No. 1-41125) in which nifedipine and hydroxyglopylcellulose are co-pulverized in a mixed state without using an organic solvent to produce a solid preparation. Proposed.

On the other hand, attempts to develop so-called long-acting formulations that control the release of nifedipine are becoming more and more popular, with the aim of achieving milder effects and improving dosing compliance.
．． 3 products are covered.

[Objective of the Invention] The object of the present invention is to provide a compact and easy-to-take solid drug, which is quick-acting or sustained-release and whose absorbability is appropriately adjusted, with the essential premise that it is easy to put into practical use, especially nianidibin. The objective is to economically produce the containing formulation.

[Prior Art] In general, methods for controlling drug release basically include:
Methods of dissolving, dispersing, mixing, or coating drugs using poorly water-soluble polymeric materials, or incorporating drugs into porous materials or adsorbing drugs onto adsorbent materials have been adopted.

In the case of poorly water-soluble solid drugs, attempts have also been made to control the release rate by utilizing particle size.

For example, in the case of nifedipine preparation, the specific surface area is 0.5
A method of producing a solid preparation by a conventional method using bulk powder adjusted to a range of 6.0 m'/g (Japanese Patent Publication No. 14446/1983), a method with a specific surface area of 0.1 to 0.4 + m'/g. A method of using raw powder, mixing it with a granular excipient, granulating it, and then coating the surface with an acrylic polymer material (published in 1986-50066).
No. 0 specification), a method of mixing immediate release granules and delayed release granules coated with an enteric polymer substance and filling them into capsules using bulk powder with a particle size of 5 microns or less (Japanese Patent Application Laid-Open No. 1983-1999) 46
019 specification).

However, these methods require considerable effort and advanced formulation technology in terms of production, such as pulverization of the nifedipine bulk powder, particle size adjustment, and granule coating operations, and they also impose a considerable cost burden in terms of quality control. Will.

As a result of intensive research aimed at simplifying the above-mentioned formulation technology, the present invention has been developed to provide a pharmaceutically active compound that can be economically controlled through normal formulation operations without using any special techniques, and whose release properties can be freely controlled. In particular, it has been possible to produce a solid drug containing nifedipine.

[Problem to be Solved by the Invention 1] In order to further simplify the formulation technology and increase productivity, the present inventors have conducted intensive research on pharmaceutical raw materials and manufacturing methods to satisfy the following conditions.

■ To easily obtain fine particles of nifedipine without using a special pulverizer or adjusting particle size such as classification.

■ The degree of release control can be controlled freely.

■ Products of stable quality can be easily obtained.

■ Make the dosage form easy to take.

■ The above can be done economically.

[Means for solving the problem] As a result of various studies, we dissolved nifedipine bulk powder in an organic solvent with a high dissolution ability, especially a mixed solvent of methylene chloride and ethanol, and created a fine powder of silicon dioxide or magnesium aluminate metasilicate, which has a high oil absorption ability. In addition, the powdered material is mixed with auxiliaries for preparing solid drugs, such as excipients, binders, disintegrants, etc.
We have discovered that a method of blending a dispersant, a lubricant, etc. and granulating or compression molding can easily produce a solid drug that satisfies the above conditions and has an arbitrary release property, and has developed the present invention. It was completed.

The fine powder of silicon dioxide and magnesium aluminate metasilicate is a bulky powder with a particle size of 4 microns or less (filling volume 5-2h/100+++Q) and a large oil absorption capacity (oil absorption 150-400rnQ/1009). It is widely used in various fields as a powder for oily substances and as a solidification base. However, these fine powders are generally referred to as solid acids and are relatively acidic, and therefore, when a pharmaceutically active compound is supported, there is a fear that the pharmaceutically active compound will decompose; however, as a result of the application of the present invention, It was confirmed that it did not have as much of an adverse effect on pharmaceutically active compounds, particularly nianidipine, as initially feared.

In the present invention, in order to easily micronize nifedipine without using large-scale machinery and energy, the crude crystals of nifedipine are dissolved in a solvent and incorporated into a fine powder of silicon dioxide or magnesium aluminate metasilicate. In this case, since the final product is intended to be miniaturized, it is desirable that the concentration of nianidipine be as high as possible. Therefore, as a result of searching for a solvent system with a high ability to dissolve nifedipine, it was found that using a mixed solvent with a mixing ratio of methylene chloride and ethanol in a volume ratio of 1:1 to 9:11, preferably 4:1, yields 20% (w/V). Since the above nifedipine is solubilized, it becomes possible to add a solution within the oil absorption capacity range (1.5 to 4 times) of silicon dioxide and magnesium aluminate metasilicate fine powder, making it possible to economically add nifedipine at a high concentration ( 40 to 60%) of silicon dioxide or magnesium aluminate metasilicate can be obtained. Production is carried out using a conventional mixer with a jacket and stirring blades, and stirring (10100-40 Orp, Impregnation of nifedipine into the base, removal of the solvent, and pulverization can be easily achieved by applying high temperature (30 to 40°C) and reduced pressure.

There are hydrated and anhydrous forms of silicon dioxide, but the anhydrous form, so-called silicic anhydride, is preferable because the surface acidity of the hydrated form due to silanol groups may adversely affect the stability of the drug. Moreover, since some magnesium aluminate metasilicate has strong alkaline properties, it is also preferable to use a neutral one from the viewpoint of drug stability.

The thus obtained fine powder of nifedipine-containing silicon dioxide or magnesium aluminate metasilicate is extremely fine, so that the dissolution of nifedipine in water is extremely high, so rapid action can be expected.

On the other hand, the fine powder of nifedipine-containing silicon dioxide or magnesium aluminate metasilicate obtained here,
By mixing it with appropriate formulation aids and granulating it or compression molding it, forming it into appropriate agglomerated particles and redispersing it at the required location after taking it, the release control can be controlled and sustained release can be achieved. You can. To this end, important factors are the selection and blending ratio of formulation aids to be blended, such as excipients, binders, disintegrants, dispersants, etc., that is, optimization of the blending formulation, and strength during compression molding.

Formulation aids are not particularly limited, but are commonly used in the pharmaceutical formulation field, such as excipients such as crystalline cellulose, lactose, mannitol, and starch, and binders such as HFCI xypropylcellulose, Polyvinylpyrrolidone and gum arabic are preferred; disintegrants include low-substituted hydroxypropyl cellulose, calcium carboxymethyl cellulose, and croscarmellose sodium; and dispersants include polysorbate 80 and sodium lauryl sulfate. In addition, the load adjustment in compression molding is ultimately carried out based on, for example, the tablet hardness, and a tablet hardness of 3 to 8 kg/CII+2 is preferable, taking into consideration factors such as the formulation and the size of the tablet.

[Example 1] The present invention will be explained in more detail with reference to Examples, Reference Examples, and Test Examples below, but these do not limit the present invention in any way.

Example 1 Nianizibin crystal (specific surface area 0.1 m”/y or less) 50
1 part was dissolved in a mixed solvent of 115 parts of methylene chloride and 25 parts of ethanol to obtain fine silicon dioxide powder (70 Indian Industries:
Add 55 parts of light anhydrous silicic acid azolida (101) and mix with a jacketed mixer. Then, the temperature inside the container was set to 35
Continue stirring while warming to ℃ to completely remove the solvent. Furthermore, crystalline cellulose (Asahi Kasei Industries: Avicel 101) 9
0 parts, lactose (Gokyo Sangyo: 200M) 144 parts, low 11
Diluted hydroxypropylcellulose (Shin-Etsu Chemical: L-
RPC), 15 parts of carboxymethyl cellulose calcium (Gotoku Pharmaceutical: ECG505), and 2 parts of sodium lauryl sulfate were added and mixed, and 250 parts of a lθ% ethanol solution of hydroxypropyl cellulose (Shin-Etsu Chemical: HPC-EFG) was added as a binder. Granulate using After drying, a predetermined amount of magnesium stearate is added to the granulated product and pressed into tablets weighing 80 mg (diameter 5.5 mm). One ice crystal tablet contains 10111 g of nifedipine.

To film-coat tablets, for example, a coating liquid consisting of the components shown below is used. Hydroxypropyl methylcellulose (Shin-Etsu Chemical: TC-5) 7
．． Part 5, Macrogol 6000 (Sanyo Chemical: Powder) 1
．． 2 parts, titanium oxide (70 Indian industry: FW-1) 2
．． 5 parts, iron sesquioxide (Hatsumi Kasei) 0.3 parts, magnesium stearate 0.1 part, methylene chloride 250 parts, ethanol 50 parts.

Example 2 Nifedipine crystal (specific surface area 0.1+n2/g or less) 6
0 parts was dissolved in a mixed solvent of 140 parts of methylene chloride and 30 parts of ethanol, and added to 66 parts of silicon dioxide fine powder.
Mix in a jacketed mixer. Next, the temperature inside the container was increased to 3.
Completely remove the solvent by stirring while heating to 5°C.

Furthermore, 94.5 parts of lactose, 3 parts of crystalline cellulose, 12 parts of low-11-converted hydroxypropyl cellulose, 18 parts of carboxymethyl cellulose, and 1.5 parts of sodium lauryl sulfate were added and mixed, and 8 parts of hydroxypropyl cellulose was added as a binder. % ethanol solution. After drying, a predetermined amount of magnesium stearate was added to the granulated product, and the weight was 10100 l1 diameter 6.0
Press into tablets. 2 nifedipine in 1 ice crystal tablet
Contains 0.11g.

To film-coat the tablets, a coating liquid consisting of the components shown in Example 1 is used.

The formulation aids in this Example 2 are all the same as in Example 1 except for what is specifically described.

Example 3 Nifedipine crystal (specific surface area 0.111”/9 or less) 5
0 parts was dissolved in a mixed solvent of 115 parts of methylene chloride and 25 parts of ethanol, added to 50 parts of silicon dioxide fine powder, and mixed with a jacketed mixer. Then, the temperature inside the container was set to 35
Continue stirring while warming to ℃ to completely remove the solvent. Further, 303 parts of D-mannitol (Nippon Bulk Yakuhin), 20 parts of gum arabic powder (Sanei Pharmaceutical), 15 parts of low-substituted hydroxypropyl cellulose, 10 parts of calcium carboxymethylcellulose, and 2 parts of sodium lauryl sulfate were mixed, and polyvinyl was added as a binder. Pyrrolidone to 25 (Gokyo Sangyo Nikoliton to -25) 20% ethanol (50% water)
250 parts of the solution (including 250%) were kneaded, and the particles were sieved using a No. 30 sieve. After drying, the particles are sieved using a No. 30 to No. 80 sieve to obtain granules having a nifedipine content of 100 mt/g.

In addition, this product can be placed in a size 3 hard gelatin capsule containing 10
When filled with hg, hard capsules containing 10111 g of nifedipine in 1 capsule are obtained.

In addition, by changing the size and content weight of the capsule, the content of nianidipine per 1 capsule can be changed, for example, by changing the content of 5
It can also be adjusted to 11g to 30II1g.

The formulation aids in this Example 3 are all the same as in Example 1 except for what is specifically described.

Example 4 Nifedipine crystal (specific surface area 0.111”/9 or less) 5
0 parts was dissolved in a mixed solvent of 100 parts of methylene chloride and 30 parts of ethanol, and added to 50 parts of silicon dioxide fine powder,
Mix in a jacketed mixer. Next, the temperature inside the container was increased to 3.
Continue stirring while heating to 5°C to completely remove the solvent.

Furthermore, 75 parts of crystalline cellulose, 169 parts of lactose (Megre Japan: Tabletose), 25 parts of low-substituted hydroxypropylcellulose methyl starch sodium (Wood Industry: Explotab), 2 parts of sodium lauryl sulfate, and 4 parts of magnesium stearate. Mix. The above mixture had a weight of 80 mg (diameter 5, 51+I+11
) directly into tablets. One ice crystal tablet contains nifedipine LOWry.

To film-coat the tablets, a coating liquid consisting of the components shown in Example 1 is used. The formulation aids in this Example 4 are all the same as in Example 1 except for what is specifically described.

Example 5 The tablet obtained in Example 4 was crushed to have a particle size of 0.18 to 0.
Prepare 51 parts m of granules. Nianidipine limg is included in 1g of Favorite 8oII.

Furthermore, if 80 mg of Honjima is filled into a size 3 hard capsule, a hard capsule containing IOmy of nifedipine in one capsule can be obtained. By changing the size of the capsule and the weight of the contents, the content of nianidipine per capsule can be adjusted to, for example, 5 to 30 Il/g.

Example 6 27 Edipine crystal (specific surface area 0.1 m”/y or less) 1
00 parts was dissolved in a mixed solvent of 210 parts of methylene chloride and 40 parts of ethanol, and added to 110 parts of Magfusoum metasilicate aluminate (Fuji Chemical Industry: Neusilin US2),
Mix gently with a jacketed mixer. Next, stirring is continued while heating the container to a temperature of 35° C. to completely remove the solvent. Additionally, 50 parts of crystalline cellulose, 182.5 parts of lactose (Megre Japan: Tabletose), 20 parts of low-substituted hydroxypropylcellulose, 30 parts of croscarmellose sodium type A (Asahi Kasei Niaczisol), 2.5 parts of sodium lauryl sulfate, and stearin. Mix 5 parts of Acid Magfusoum.

The above mixture has a weight of loOmg (without wet granulation).
Press directly into tablets with a diameter of 6 mm. One ice crystal tablet contains 20 mg of nifedipine.

To film-coat the tablets, a coating liquid consisting of the components shown in Example 1 is used.

The formulation aids in Example 6 are all the same as in Example 1 except for what is specifically described.

Shiny Yuni Nijibin crystal (specific surface area 0.25/9) 100
part, crystalline cellulose 200 parts, lactose (Megre Japan:
Tabletose), 100 parts of low-substituted hydroxypropylcellulose, 4 parts of sodium lauryl sulfate, and 8 parts of magnesium stearate were mixed, and the weight was 80++.
Press directly into +9 (diameter 5.5 dragon) tablets.

One ice crystal tablet contains Nianidipine 101119.

To film-coat the tablets, a coating liquid consisting of the components shown in Example 1 is used.

Note that all the formulation aids in this reference example are the same as in Example 1 except for what is specifically described.

[Test Example] The results of comparing the release properties of nifedipine and blood concentration when administered to humans with commercially available immediate-release nifedipine preparations for the present invention preparations and reference preparations obtained in Examples are explained below. .

Test Example 1 (Dissolution test in water) Using a Japanese Pharmacopoeia dissolution tester, the dissolution rate of Nianidipine was compared using the paddle method. The test liquid is polysorbate 80
Using Pharmacopoeia No. 1 liquid (pH 1.2) containing 0.1% of Nifedipine, the liquid volume was 10mg tablets of nifedipine and 10++1g granules (
19), 500mQ1 nifedipine nidipine 20 and 900+++72 were used. The set temperature was 37°C, the paddle rotation speed was 100 rpm, and the amount of nianidipine eluted into the test solution was determined by ultraviolet absorption spectrophotometry. The test results are shown in Table 1, and the values are the average of six measurements.

In addition, commercially available nifedipine 5rng soft capsules were used as a comparative formulation.

Test Example 2 (Human administration test) Nifedipine preparations 1hy and 20 were administered to 6 healthy male adults.
A dose equivalent to mg was administered, and blood was collected over time after administration, and the blood nifedipine concentration was determined by high performance liquid chromatography. The test results are shown in Table 2, and the values represent the average of 6 test subjects.

[Effect of the invention 1] As is clear from the above test results, the preparations of the present invention shown in Examples have a higher concentration of nianidipine in an acidic aqueous solution, which is assumed to be a human gastric solution, than conventional immediate-release preparations. Because the elution rate is moderately controlled, when administered to humans, the blood concentration gradually increases without a rapid level increase, and the effective blood concentration (> lOng/mQ) also decreases to 2.
Lasts for more than 4 hours.

Therefore, the frequency of side effects associated with transient absorption is low.
Furthermore, since the short-lived effective time due to rapid excretion is improved, the preparation of the present invention can be said to be a highly safe solid nifedipine preparation that can reduce compliance to administration.

Examples of embodiments falling within the technical scope of the present invention are as follows: 1. The amount of the organic solvent is in the range of 2 to 201 parts by weight,
5. The method according to claim 1, wherein the amount is sufficient to dissolve 1 part by weight of nianidipine.

2. The method according to claim 1 or 4, wherein the organic solvent is selected from ethanol, methanol, acetone, methylene chloride, chloroform, and mixed solvents thereof.

3. The method according to claim 4, wherein the solid drug preparation auxiliaries are excipients, binders, disintegrants, and dispersants.

4. The method according to claim 4, wherein the solid drug preparation auxiliary is an excipient, and the excipient is selected from crystalline cellulose, lactose, mannitol, sucrose, glucose, starch, calcium phosphate, and calcium carbonate.

5. The method of claim 4, wherein the solid drug preparation auxiliary or binder is selected from among methylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, starch, dextrin, polyvinylpyrrolidone and gum arabic.

6. The solid drug preparation aid is a disintegrant, and the disintegrant includes low-substituted hydroxypropyl cellulose, carboxymethyl cellulose, carboxyl methyl cellulose calcium, hydroxypropyl starch, sodium carboxymethyl starch, croscarmellose sodium, polyvinyl poly 5. The method of claim 4, wherein the method is selected from pyrrolidone and partially pregelatinized starch.

7. The method according to claim 4, wherein the solid drug preparation aid is a dispersant selected from polysorbate 8o, polyquine 40 stearate and sodium lauryl sulfate.

8. The method according to claim 4, wherein the solid drug is in the form of granules, tablets, pills or capsules.

Patent applicant Taisho Pharmaceutical Co., Ltd.

Claims (1)

[Claims] 1. A solid or liquid pharmaceutically active compound suitable for oral administration is dissolved in a volatile organic solvent in which it can be dissolved, and this solution is mixed with a fine powder of silicon dioxide or magnesium aluminate metasilicate. . A method for producing a fast-acting solid drug for oral administration, which comprises removing the solvent and pulverizing it. 2. The method for producing a fast-acting solid drug for oral administration according to claim 1, wherein the weight ratio of the pharmaceutically active compound to silicon dioxide or magnesium aluminate metasilicate is 1:0.5 to 5. 3. The method for producing a fast-acting solid drug for oral administration according to claim 1 or 2, wherein the pharmaceutically active compound is nifedipine. 4. A solid or liquid pharmaceutically active compound suitable for oral administration is dissolved in a volatile organic solvent in which it can be dissolved, and this solution is mixed with fine powder of silicon dioxide or magnesium aluminate metasilicate, and the solvent is removed to form a powder. 1. A method for producing a sustained-release solid drug for oral administration, which comprises blending the obtained powder with an auxiliary agent for solid drug preparation and granulating or compression molding the resulting powder. 5. The method for producing a sustained-release solid drug for oral administration according to claim 4, wherein the weight ratio of the pharmaceutically active compound to silicon dioxide or magnesium aluminate metasilicate is 1:0.5 to 5. 6. The method for producing a sustained-release solid drug for oral administration according to claim 4 or 5, wherein the pharmaceutically active compound is nifedipine.