JPH07277978A - Nifedipine solid particle composition for tablet production - Google Patents

Abstract

PURPOSE:To obtain a nifedipine salid particle composition capable of producing any kind of tablets, rapid release or sustained release ones, by improving its solubility through wet grinding process. CONSTITUTION:This composition is obtained by wet grinding of nifedipine in an aqueous solution of polysorbate 80 followed by evaporating the resultant suspension to dryness. The resultant solid particle composition is incorporated with a vehicle, disintegrant and hydroxypropyl cellulose to prepare a material, which is, in turn, granulated so as to be 5-20wt.% in the fractional mechanical strength of the resultant granulated product followed by drying, and the dried granulated product is blended with a disintegrant and lubricant followed by tableting, and the resultant raw tablets are coated with a coating agent, thus obtaining sustained release nifedipine tablets.

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to a nifedipine solid particle composition used as a medicine for treating hypertension and angina. More specifically, the present invention relates to a nifedipine solid particle composition capable of producing both immediate release and sustained release tablets by improving the solubility by wet milling.

[0002]

BACKGROUND ART Nifedipine has an excellent coronary vasodilatory effect and is widely used as a therapeutic drug for hypertension and angina attacks. However, since it is a drug that is poorly soluble in water, it is bioavailable. It is quite difficult to prepare high rate tablets. Until now, various methods have been proposed in order to solve the problem of the solubility of nifedipine, which is poorly soluble, in water. For example, a method of dissolving nifedipine in polyethylene glycol and filling the solution into a soft capsule (see Japanese Patent Publication No. 54-34048) or a method of formulating nifedipine as a solid solution (Japanese Patent Laid-Open No. 54-231).
This is the case (see Japanese Patent Publication No. 6). In the preparation produced by such a method, the plasma concentration of nifedipine increases immediately after administration. However, since the preparations obtained by these treatments are quick-release preparations, they are useful for sublingual administration in cases such as hypertensive emergencies, but have the drawback that a sustained antihypertensive effect cannot be expected. is doing.

Further, as a method for controlling the release characteristics of nifedipine for the purpose of obtaining a sustained antihypertensive action, the following methods are mentioned (1).
A method in which an immediate-release preparation composition and a delayed-release preparation composition are combined to achieve sustainability (see JP-A-58-46019), (2) Nifedipine is co-ground with casein, and then enteric-coated. A method in which granulation is carried out by co-grinding with a plasticizer and a plasticizer to measure the sustainability (JP-A-60-255).
719), (3) a method for increasing and maintaining absorption by using nifedipine crystals obtained by dry pulverization (see Japanese Patent Publication No. 59-14446).
Have been proposed. However, these proposed methods have the following drawbacks. In the method (1), the variation in mixing the immediate-release composition and the slow-release composition becomes the variation in the sustained action as it is. In the method (2), since the enteric coating agent is used, the sustained action is affected by the individual difference in pH of the gastrointestinal tract content liquid. In the method of (3),
Depending on the treatment method of nifedipine after pulverization, preferable sustainability may not be obtained. Further, since nifedipine is a drug that is easily decomposed by light, the light-shielding property during work is a problem in the open dry pulverization method, forcing a worker to work in a dark place. Furthermore, handling of the powder not only has poor workability, but also has the drawback of causing health problems for workers.

On the other hand, Japanese Patent Publication No. 63-112519 proposes a nifedipine preparation in which nifedipine is wet-milled with a water-soluble polymer substance to improve the solubility, and this preparation contains the amount of water used. When the amount is small, the concentration of the water-soluble polymer increases, and the viscosity of the solution increases, which makes it difficult to formulate the preparation. Further, the preparation described in the publication is intended as an immediate-release nifedipine preparation, and is not a sustained-release nifedipine preparation. As described above, the conventional technique is a method for producing either an immediate-release preparation or a sustained-release preparation, and the method of nifedipine varies greatly depending on which preparation is produced.

[0005]

DISCLOSURE OF THE INVENTION As a result of intensive studies on the factors affecting the release characteristics of tablets containing nifedipine, the present inventors have found that by using wet-ground nifedipine in an aqueous solution of polysorbate 80, rapid release or It has been found that sustained-release tablets can be made arbitrarily without the use of special formulation techniques. The present invention has been made based on such findings.

The present invention provides a nifedipine solid particle composition for tablet production, which is obtained by wet milling nifedipine in an aqueous solution of polysorbate 80 and drying the resulting suspension. By using the above nifedipine solid particle composition, both sustained-release and immediate-release tablets can be produced.

To obtain a long-acting nifedipine tablet,
The nifedipine solid particle composition obtained by wet grinding in an aqueous solution of polysorbate 80, to which an excipient, a disintegrating agent and hydroxypropylcellulose were added, was used as a material, and the strength of the granulated product was from 5% by weight to 20% by weight. The granules are granulated so that the content of the granules becomes 100%, dried, and then the obtained granules are added with a disintegrating agent and a lubricant to form tablets, and the obtained uncoated tablets are coated with a coating agent to maintain durability. And nifedipine tablets. On the other hand, in the case of obtaining an immediate release nifedipine tablet, an excipient, a disintegrating agent, a binder, a lubricant, etc. are added to the nifedipine solid particle composition obtained by wet pulverization, and the mixture is tableted after mixing. Then, the obtained plain tablets are coated with a coating agent to give immediate release nifedipine tablets.

The present invention will be described in detail below. In the method of the present invention, first, nifedipine is polysorbate 8
It is wet-ground in an aqueous solution containing 0. Nifedipine cannot be obtained by dry pulverization or wet pulverization in an aqueous solution containing a water-soluble polymer substance to obtain tablets having desired release characteristics. The wet pulverization is performed by, for example, a ball mill, and the nifedipine raw material is added together with the aqueous solution of polysorbate 80 and pulverized. The polysorbate 80 used at this time is added by about 4 to 6% by weight with respect to nifedipine. This polysorbate 80 enhances the dispersibility (aggregation prevention) of the nifedipine raw material in water during wet pulverization, contributes to pulverization efficiency as a pulverization aid, and further suppresses the foaming of the nifedipine suspension during pulverization to handle after pulverization. Improve.
The polysorbate 80 also covers the surface of the nifedipine particles dried after pulverization to enhance the solubility in water and improve the absorption of nifedipine in vivo.

It is preferable that the wet pulverization in the present invention is generally carried out using an aqueous solution of polysorbate 80 having a concentration of 4 to 6% by weight. Even if the concentration of polysorbate 80 is further increased and used, there is no problem in the operation, but if the concentration is 3% by weight or less, the dispersibility of nifedipine is deteriorated, which is not preferable. Then, wet pulverization can be performed only by using an approximately equal weight of this aqueous solution of polysorbate 80 with respect to the nifedipine raw material.

The wet pulverization is controlled by changing the particle diameter of the nifedipine particles in the suspension to a saturated aqueous solution of nifedipine (methanol: 0.5% by weight, polysorbate 80:
(Containing 0.05% by weight) is used to measure the particle size distribution by a sedimentation method.
If it is less than μm, it is sufficient. The wet-milled nifedipine suspension is dried by a general drying method such as heat drying or freeze-drying, and nifedipine is obtained in the state of a nifedipine solid particle composition coated or mixed with polysorbate 80. For the purpose of immediate release nifedipine tablets, freeze drying is more suitable than heat drying. The nifedipine solid particle composition thus obtained is made into a sustained-release or immediate-release nifedipine tablet by the following formulation method.

(1) Method for Producing Sustained Tablets The nifedipine suspension containing polysorbate 80 after wet pulverization was mixed with an excipient and a disintegrant to the nifedipine solid particle composition obtained by drying, and further mixed. An aqueous solution of hydroxypropyl cellulose, which is a water-soluble polymer substance, is added as a binder to granulate. As the excipient to be used, D-mannitol, crystalline cellulose, corn starch and the like can be used, and as the disintegrant, carboxymethyl cellulose and the like can be used.

The granulation is performed by a method such as a kneading extrusion granulation method, a stirring granulation method or a fluidized bed granulation method. Drying of the granulated product may be carried out by an ordinary drying method such as a tray system or heat drying with a fluidized bed. After drying, the particles are sized by passing through a JIS standard 20 mesh screen. The kneading extrusion granulation method is suitable for obtaining a hard granulated product having a granulated product strength of 15% by weight or more.
The fluidized bed granulation method is suitable for obtaining a soft granulation product of 5% by weight or less. In addition, the agitation granulation method can obtain granules having a wide range of granule strength from 5% by weight to 30% by weight. At this time, by increasing the amount of water added or increasing the granulation time, a granulated product with high granule strength can be obtained, and conversely, decrease the amount of water or shorten the granulation time. As a result, a granulated product having a low granulated product strength can be obtained.

The strength of the granulated product is measured by the following method (see Omura et al., Avicel Bulletin No. 12 (1966) p. 31). Passed through a JIS standard 20 mesh screen and 2
20g of granules that do not pass through an 8-mesh sieve was used as a sample, and this sample was put into a Kayagaki-type friability tester containing 150 steel balls with a diameter of 0.45mm and a weight of 0.5g and rotated for 5 minutes. After destroying some of the granules,
Sieve with a 28-mesh sieve, and calculate the ratio of the rest to the whole. The ratio is defined as the granulated product strength. The sustained-release nifedipine tablet using the solid particle composition according to the present invention has the granule strength adjusted in the range of 5% by weight to 20% by weight. If the strength of the granulated product deviates from this range, a sufficient sustaining effect cannot be expected. The fact that sustainability is achieved by adjusting the strength of the granulated product in this manner is surprising and completely unexpected from the prior art in the method for producing a sustained-release formulation of nifedipine.

Next, a lubricant such as light anhydrous silicic acid or magnesium stearate and a disintegrating agent such as carboxymethyl cellulose are added to the granulated product, and the tableting pressure is 500 to 500.
Tableting is performed with 1,500 kg. By adding the disintegrant, the disintegration time of the tablet does not largely change even if the tableting pressure changes. Next, for the purpose of shielding light, film coating is performed according to a conventional method to produce a nifedipine-containing sustained-release tablet. For the coating agent, it is desirable to use iron sesquioxide, titanium oxide, or the like, which is highly safe to the human body and has an excellent light shielding effect, as a light shielding agent.

(2) Method for Producing Immediate-Release Tablets Nifedipin tablets having immediate-release properties are obtained by drying the wet-milled polysorbate 80-containing nifedipine suspension, preferably by freeze-drying. Then, various additives usually used for tablets are added and kneaded, and then tableted by a conventional method to produce plain tablets. In this case, granulation using hydroxypropyl cellulose, which is a water-soluble polymer substance, as a binder before tableting is not preferable in many cases because it gives a sustained tablet, but granulation with a granule strength of about 4% by weight or less is preferable. The granules may be added with a water-soluble polymer substance and granulated, so that the immediate release property is maintained, which is no problem.

The additives used are D as an excipient.
-Mannitol, crystalline cellulose, corn starch and the like, disintegrants such as carboxymethyl cellulose and the like, and lubricants such as light anhydrous silicic acid and magnesium stearate can be used. Then, the obtained plain tablets are coated by a conventional method with a light-shielding agent composed of iron sesquioxide and titanium oxide, which has an excellent light-shielding effect as in the case of the sustained-release tablet. Next, the present invention will be described in more detail with reference to Examples of the present invention together with Comparative Examples and test examples. The present invention is not limited to these examples.

[0017]

【Example】

Example 1 (immediate release tablet) 200 g of nifedipine raw material was mixed with polysorbate 801.
0 g was suspended in a solution prepared by dissolving 200 g of purified water and placed in a pot for a resin ball mill having an internal volume of 1 liter,
Using YTZ zirconia balls (diameter 10 mm),
It was crushed. At this time, the rotation speed of the ball mill was 100 rotations per minute. After that, a part of the contents of the ball mill was sampled and the particle size distribution was measured by the sedimentation method to confirm that the median diameter was 10 μm or less. Then, the contents of the ball mill were taken out and dried with a freeze dryer to obtain nifedipine solid particles. 195 g of composition was obtained.

Next, to 105 g of this solid particle composition, 315 g of D-mannitol as an excipient, 200 g of corn starch and 160 g of carboxymethyl cellulose as a disintegrant were added and mixed, and 10 g of light anhydrous silicic acid as a lubricant and stearin. 10 g of magnesium acidate was added and mixed, and using a punch having a diameter of 5.5 mm, a tableting pressure of 1,000 kg was obtained with a single-shot tableting machine N-30E manufactured by Okada Seiko Co.
Thus, 80 mg of uncoated tablets were obtained. This plain tablet was coated with a coating solution having the following composition to give a film-coated tablet (83 mg).

Coating liquid composition Hydroxypropyl methylcellulose 2910 5.6 parts Macrogol 6000 0.6 part Titanium oxide 1.2 parts Iron sesquioxide 0.1 part Purified water 92.5 parts Dissolution test is conducted on this film-coated tablet. As a result, as shown in the dissolution test example 1 described later, it was confirmed that the tablets had an immediate release property.

Example 2 (persistent tablet) 2,000 g of nifedipine raw material was added to polysorbate 80.
100 g of the product was suspended in a solution prepared by dissolving 2,000 g of purified water, the suspension was put in a pot for a resin ball mill having an internal volume of 10 liters, and pulverized using YTZ zirconia balls (diameter 10 mm). went. At this time, the rotation speed of the ball mill was 95 rotations per minute. After that, a part of the contents of the ball mill was sampled and the particle size distribution was measured by the sedimentation method to confirm that the median diameter was about 10 μm or less. Drying was carried out for 15 hours with a machine to obtain 1,950 g of a nifedipine solid particle composition.

Next, 130 g of D-mannitol, 390 g of crystalline cellulose, 130 g of corn starch and 52 g of carboxymethyl cellulose as a disintegrating agent were added to and mixed with 273 g of the solid particle composition 263 g of hydroxypropyl cellulose as a binder. Was added to a solution of 300 g of purified water and stirred and granulated for 1 minute, followed by drying for 15 hours with a shelf-type dryer having an internal temperature of about 50 ° C., and then sizing with a 20-mesh sieve. Thus, a granulated product having a granulated product strength of 10% by weight was obtained.

Next, 231 g of the obtained granules were mixed with 3 g of carboxymethyl cellulose as a disintegrating agent, 3 g of light anhydrous silicic acid and 3 g of magnesium stearate as a lubricant, and mixed, and using a pestle having a diameter of 6 mm, Okada Seiko Using a single-shot tableting machine N-30E manufactured by Co., Ltd., a plain tablet weighing 80 mg was obtained at a tableting pressure of 1,000 kg. This plain tablet was coated with a coating solution having the following composition to give a film-coated tablet (83 mg).

Coating liquid composition Hydroxypropyl methylcellulose 2910 5.6 parts Macrogol 6000 0.6 part Titanium oxide 1.2 parts Iron sesquioxide 0.1 part Purified water 92.5 parts

This film-coated tablet was used as a healthy person 14
As shown in the following plasma concentration test (Table 1), it was stably administered to plasma for about 12 ng / ml, which is said to be the minimum effective blood concentration of nifedipine, for 12 hours. Was recognized.

[0025]

[Table 1]

Example 3 Nifedipine solid particle composition 273 obtained in Example 2
26 g of hydroxypropylcellulose as a binder in the same formulation as in Example 2, using 300 g of purified water.
After stirring and granulating for 30 seconds using the solution dissolved in 1 to obtain a granulated product having a granulated product strength of 5% by weight, the granulated product was tableted and filmed according to the method of Example 2. Coating was performed to obtain a film-coated tablet weighing 83 mg.

Example 4 Nifedipine solid particle composition 273 obtained in Example 2
26 g of hydroxypropylcellulose as a binder in the same formulation as in Example 2, using 300 g of purified water.
The solution dissolved in 1 was stirred and granulated for 2 minutes to prepare a granulated product having a granulated product strength of 20% by weight. Then, tableting and film coating of the granulated product 1
83 mg of film-coated tablets were obtained.

Example 5 Using the granulated product obtained in Example 2 and having a strength of 10% by weight, an uncoated tablet of 80 mg per tablet was prepared at a tableting pressure of 500 kg. Film coating was performed according to the operation method of Example 2 to obtain 83 mg of film-coated tablets.

Example 6 Using the granulated product obtained in Example 2 and having a strength of 10% by weight, an uncoated tablet of 80 mg per tablet was prepared at a tableting pressure of 1,500 kg. Then, film coating was carried out according to the operation method of Example 2 to obtain 83 mg of film-coated tablets.

[0030]

[Control example]

Control Example 1 Nifedipine solid particle composition 273 obtained in Example 2
Granules having the same formulation as in Example 2 but having a granule strength of 2% by weight were tableted according to the method of Example 2 and then film-coated to obtain 83 mg film. A coated tablet was obtained.

Control Example 2 Nifedipine solid particle composition 273 obtained in Example 2
Using g, a granulated product having the same formulation as in Example 2 and a granulated product strength of 30% by weight was prepared. The granulated product was tabletted according to the method of Example 2 and then film-coated to obtain 83 mg of film-coated tablet.

[Dissolution Test Example 1] With respect to the tablets of Examples 1 to 4 and Control Examples 1 and 2, a dissolution test of nifedipine was carried out according to the dissolution test method 2 (paddle method: see Japanese Pharmacopoeia No. 12). It should be noted that the test liquid is the 12th Bureau No. 1 of the Japanese Pharmacopoeia
Liquid: A mixture of anhydrous ethanol (37: 9) (900 ml) was used and the liquid temperature was 37 ° C. The results of this dissolution test are shown in Table 2. As a result, in the case of Example 1 in which granulation is not performed,
It shows a rapid release elution behavior of 95% or more in 15 minutes, and when granulation is performed, a good correlation is shown between the granule strength and the elution rate. In the wt% granules, a sustained dissolution suitable for sustained release tablets was observed.

[0033]

[Table 2]

[Dissolution Test Example 2] Example 2 and Example 5
The tablets of No. 6 were subjected to the dissolution test by the same test method as that of the dissolution test example 1. The results are shown in Table 3.

[Table 3]

There is no difference in the dissolution rate of nifedipine between Example 2 and Examples 5-6, and the dissolution rate of the tablets was not affected by the tableting pressure when the tableting pressure was between 50 and 1,500 kg. Was recognized. As is clear from the results of the dissolution test examples 1 and 2, the dissolution characteristics of nifedipine of nifedipine tablets are hardly affected by the tableting pressure and depend on the strength of the granulated product before tableting. Admitted.

 ─────────────────────────────────────────────────── ─── Continuation of the front page (72) Yoichi Tojima, 37, Minamiurawa, 37-chome, Urawa-shi, Saitama Prefecture, Room 18, Room No. 204 (72) Daizen Sakakibara 1-2-2-504, Aoba, Kuki-shi, Saitama Prefecture (72) ) Inventor Shigeru Yokoi 2-15-24 Shimura, Itabashi-ku, Tokyo

Claims (2)

[Claims] 1. A nifedipine solid particle composition for tablet production, which is obtained by wet milling nifedipine in an aqueous solution of polysorbate 80, and drying the resulting suspension. 2. Nifedipine is wet-milled in an aqueous solution of polysorbate 80, the resulting suspension is dried to obtain a nifedipine solid particle composition, and an excipient and a disintegrant are added to the obtained solid particle composition. The granulated product was granulated so that the strength of the granulated product was 5% by weight to 20% by weight and then dried, and the resulting granulated product was disintegrated with a lubricant. A method for producing a long-acting nifedipine tablet, which comprises adding a lubricant to tableting, and coating the obtained plain tablet with a coating agent.