JPH1067657A - Multiple unit type long-acting pharmaceutical preparation - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain a pharmaceutical preparation capable of persistently releasing an active ingredient, persistently manifesting pharmacodynamic effects for a long period and suppressing the manifestation of adverse effects by including plural or more specific sustained release tablets therein. SOLUTION: This multiple unit type long-acting pharmaceutical preparation comprises two or more sustained release small tablets prepared by blending (A) 6-[4-(1-cyclohexyl-1H-tetrazol-5-yl)butoxyl]-3,4-dihydrocarbostyril as an active ingredient blended with (B) hydroxypropyl methyl cellulose as a sustained release base. Furthermore, the ingredient B having >=400cP in an amount of 10-90wt.% based on the total amount of the small tablets is preferably blended and 2-20 small tablets having 3-7mm diameter and 10-300mg weight of each small tablet are preferably contained therein.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

TECHNICAL FIELD The present invention relates to 6- [4- (1-
Cyclohexyl-1H-tetrazol-5-yl) butoxy] -3,4-dihydrocarbostyril (generic name cilostazol; hereinafter referred to by the generic name) as a multiple unit type sustained-release preparation, more specifically, cilostazol. A preparation containing two or more sustained-release small tablets comprising an active ingredient and hydroxypropylmethylcellulose as a sustained-release base, and prolonging the efficacy of the active ingredient by sustained release of cilostazol. The present invention relates to a multiple unit-type sustained-release preparation which can be continuously expressed over time and suppress the occurrence of side effects by suppressing rapid absorption of an active ingredient.

[0002]

BACKGROUND OF THE INVENTION Cilostazol has a high inhibitory action on platelet aggregation, a phosphodiesterase inhibitory action, an anti-ulcer action, a hypotensive action,
Since it has an anti-inflammatory effect, it is widely used as an anti-thrombotic agent, cerebral circulation improving agent, anti-inflammatory agent, anti-ulcer agent, antihypertensive agent, anti-asthmatic agent, and also a phosphodiesterase inhibitor. The cilostazol is usually used in the form of a tablet obtained by adding excipients and other components to the tablet, and is orally administered. However, since tablets rapidly disintegrate in vivo, a large amount of cilostazol is released into the body in a short time, resulting in high blood levels, which may cause side effects such as headache, heavy headache, and pain. there were. The present inventors have solved such problems in the conventional formulation, and suppress the rise in the maximum blood concentration by continuously releasing only the amount required for exerting the effect of cilostazol over a long period of time. As a result of various studies to obtain a new type of preparation capable of maintaining an appropriate blood concentration, it was found that a specific multiple unit type sustained-release preparation could achieve the purpose, and the present invention was completed. Reached.

[0003]

That is, the present invention provides a multiple unit comprising two or more sustained-release small tablets prepared by blending hydroxypropylmethylcellulose as a sustained-release base with cilostazol as an active ingredient. The present invention provides a sustained-release formulation, in which the release of the active ingredient from each small tablet is controlled for a long period of time, while simultaneously administering a plurality of small tablets. This makes it possible to maintain the necessary blood concentration of the active ingredient. As shown in the experimental examples described below, the multiple unit type sustained release preparation of the present invention always absorbs the active ingredient in a constant amount without being affected by the physiological conditions of the subject, and thus has a long It also has the feature of maintaining a stable blood concentration over time.

[0004]

BEST MODE FOR CARRYING OUT THE INVENTION The multiple unit type sustained release preparation of the present invention comprises hydroxypropylmethylcellulose (hereinafter referred to as HP) as a sustained-release base in cilostazol as an active ingredient.
MC, which is sometimes abbreviated as MC), and, if desired, is further formulated into small tablets according to a conventional method together with other usual pharmaceutical carriers. Two or more obtained sustained-release small tablets are filled into capsules. It is prepared by such a method.
As the HPMC used as the sustained release base, any commercially available HPMC can be used, but those having a high viscosity are preferable. For example, the viscosity at 20 ° C. as a 2% by weight aqueous solution is 400 cps or more, more preferably 400 to 400 cps. 20
The one of 000 cps is preferably used. The compounding ratio is 10 to 90% by weight, preferably 30 to 80% by weight, based on the total amount of the sustained-release small tablet.

[0005] Said sustained-release small tablets are prepared by mixing an appropriate amount of HPMC with a predetermined amount of cilostazol as an active ingredient and, if desired, further adding a commonly used preparation carrier. It is manufactured by molding into a small tablet form by a wet granulation method or a dry granulation method. As the pharmaceutical carrier, those conventionally known in the art can be widely used, for example, lactose, sucrose, sodium chloride, glucose, starch, calcium carbonate, kaolin, crystalline cellulose,
Excipients such as silicates, water, ethanol, propanol,
Simple syrup, glucose solution, starch solution, gelatin solution,
Binders such as carboxymethylcellulose Na, shellac, methylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, polyvinyl alcohol, dried starch, agar powder, carboxymethylcellulose calcium, sodium hydrogencarbonate, calcium carbonate, polyoxyethylene sorbitan fatty acid esters, lauryl sulfate Disintegrators such as sodium, stearic acid monoglyceride and starch; absorption promoters such as quaternary ammonium bases; lubricants such as purified talc, stearates, boric acid powder, polyethylene glycol, colloidal silicic acid, and glycerin fatty acid esters And plasticizers such as dioctyl phthalate, dibutyl phthalate, triacetin and castor oil. These pharmaceutical carriers can be appropriately selected and used.

[0006] The sustained-release small tablet thus prepared is usually about 3 to 7 mm in diameter, preferably 4 to 6 mm.
Particularly preferably, it has a size of 5 to 6 mm, and the weight of one small tablet is usually 10 to 300 mg, preferably 20 to 300 mg.
１２０120 mg, particularly preferably 40-80 mg.
A multiple unit type sustained release preparation containing two or more small tablets, preferably 2 to 20, more preferably 3 to 10, and particularly preferably 4 to 7 small tablets. This multiple-unit sustained-release preparation may be in any form as long as it contains two or more of the sustained-release small tablets per unit administration. 1
A capsule filled in one capsule or a sealed packaging in which a desired number of sustained-release small tablet preparations are sealed in a heat-sealed packaging is suitable.

The dose of the active ingredient cilostazol in the preparation of the present invention can vary depending on the age, sex, weight, and further symptoms of the patient.
The dosage is 00 mg, preferably 50 to 200 mg, more preferably 100 to 200 mg, and is mixed with the multiple unit type sustained release formulation of the present invention so as to have the above-mentioned dose per day. For example, in order to obtain a multiple-unit sustained-release preparation containing 100 mg of cilostazol per day, a sustained-release small tablet containing 10 mg of cilostazol is prepared, and a capsule prepared by filling 10 small tablets in a capsule is prepared. Well, or 5 small tablets each into 2 capsules, 2 capsules a day at the same time,
Alternatively, administration may be performed in two divided doses. Alternatively, cilostazol 50m per sustained-release small tablet
g, and the two small tablets may be filled into a capsule to give a capsule with a daily dose of 100 mg. As described above, the multiple-unit sustained-release preparation of the present invention also has an advantage that the daily dose and the unit dose of cilostazol can be freely adjusted by appropriately adjusting the amount of the active ingredient.

[0008] The multiple unit type sustained release preparation of the present invention may contain only a plurality of the above-mentioned sustained release small tablets.
Without using C, small tablets prepared by blending with the active ingredient cilostazol using the usual pharmaceutical carrier as described above (hereinafter referred to as “immediate release small tablets”) may be combined and formulated. Good. Such quick release small tablets are blended in an amount of 60% or less, preferably 10 to 60%, more preferably 10 to 40%, based on the total amount of the multiple unit type sustained release preparation. For example, five sustained-release small tablets containing 10 mg of cilostazol and five short-release tablets containing 10 mg of cilostazol
Each of the capsules was filled into a capsule to obtain a multiple unit-type sustained-release preparation containing 100 mg of cilostazol. Of course,
It is also possible to freely change the amount of cilostazol between the sustained release tablet and the quick release tablet. By appropriately combining such a sustained-release small tablet and a quick-release small tablet, it is possible to freely control the release of cilostazol and, consequently, the blood concentration.

[0009] The multiple unit sustained release preparation of the present invention includes the following multiple unit sustained release preparation. (1) 6- [4- (1-cyclohexyl-1H-tetrazol-5-yl) butoxy] -3,4-dihydrocarbostyril as an active ingredient, and hydroxypropylmethylcellulose as a sustained-release base, A sustained-release multiple unit preparation comprising two or more sustained-release small tablets. (2) The viscosity of hydroxypropyl methylcellulose is 4
The multiple unit continuous preparation according to the above (1), which is not less than 00 cps and contains 10 to 90% by weight of hydroxypropylmethylcellulose based on the total amount of the sustained-release small tablet. (3) The multiple according to (2), wherein the sustained-release small tablets have a diameter of 3 to 7 mm and 2 to 20 sustained-release small tablets each weighing 10 to 300 mg. Unit-type sustained-release preparation. (4) The viscosity of hydroxypropyl methylcellulose is 4
The multiple unit-type sustained-release preparation according to the above (3), which has a drug content of 00 to 200,000 cps. (5) The multiple-unit sustained-release preparation according to the above (4), wherein the weight of one sustained-release small tablet is 20 to 120 mg. (6) The multiple-unit sustained-release preparation according to the above (5), which comprises 3 to 10 sustained-release small tablets whose diameter is 4 to 6 mm. (7) The above (6) wherein hydroxypropyl methylcellulose is blended in an amount of 30 to 80% by weight based on the total amount of the sustained-release small tablet.
2. The multiple unit-type sustained-release preparation according to [1]. (8) The multiple unit sustained-release preparation according to the above (7), comprising 4 to 7 sustained-release small tablets. (9) The multiple-unit sustained-release preparation according to the above (8), wherein the size of the sustained-release small tablet is 5 to 6 mm and the weight of one small tablet is 40 to 80 mg. (10) The multiple-unit sustained-release preparation according to the above (7), wherein the weight of one sustained-release small tablet is 40 to 80 mg. (11) The multiple-unit sustained-release preparation according to the above (10), comprising 4 to 7 sustained-release small tablets. (12) The multiple-unit sustained-release preparation according to the above (7), wherein the sustained-release small tablet has a diameter of 5 to 6 mm. (13) The multiple unit-type sustained-release preparation according to the above (5), wherein hydroxypropylmethylcellulose is mixed in an amount of 30 to 80% by weight based on the total amount of the sustained-release small tablet. (14) The multiple-unit sustained-release preparation according to the above (13), wherein the size of the sustained-release small tablet is 4 to 6 mm in diameter and the weight of one small tablet is 40 to 80 mg. (15) The multiple unit-type continuous preparation according to the above (13), comprising 4 to 7 sustained-release small tablets. (16) In addition to the two or more sustained-release small tablets, 6- [4-
(1) The multiple unit type according to the above (1), which comprises one or two or more quick-release small tablets containing (1-cyclohexyl-1H-tetrazol-5-yl) butoxy] -3,4-dihydrocarbostyril as an active ingredient. Sustained preparation. (17) The multiple unit type according to the above (16), wherein the rapid release small tablets are blended in an amount of not more than 60% based on the total amount of the multiple unit type sustained-release preparation in addition to the 2 to 20 sustained release small tablets. Sustained preparation. (18) The multiple unit according to the above (17), wherein in addition to the 3 to 10 sustained-release small tablets, the rapid-release small tablets are blended in an amount of 10 to 60% based on the total amount of the multiple-unit-type sustained-release preparation. Type sustained-release preparation. (19) The multiple unit-type sustained release preparation according to the above (18), wherein the quick release small tablet is blended in an amount of 10 to 40% based on the total amount of the multiple unit-type continuous preparation.

[0010]

EFFECT OF THE INVENTION The multiple unit type sustained release preparation of the present invention controls the release of cilostazol as an active ingredient and gradually releases the same, thereby suppressing a rapid increase in blood concentration, leading to headache and headache sensation. Can prevent the undesirable side effects of
It has the advantage of reducing the number of doses. The multiple unit type sustained-release preparation of the present invention also has no significant difference in the dissolution rate in either the fasting or postprandial administration, and is almost always unaffected by changes in the patient's physiological condition and, consequently, individual differences. It has the advantage that a nearly constant amount of cilostazol is continuously absorbed.

[0011]

EXAMPLES Next, the preparations of the present invention and the effects thereof will be described more specifically with reference to examples and experimental examples. Example 1 Ingredient weight cilostazol 1000 g HPMC 2910 1,940 g (Shin-Etsu Chemical Co., Ltd., Metolose 60SH4000; 2% 20 ℃ Viscosity 4000 cps) hydroxypropyl cellulose (manufactured by Nippon Soda Co., HPC-L) 30g Magnesium stearate 30g The above sustained release according to the formula Prepare small tablets. That is, 1000 g of cilostazol and HPMC1940
g of water, and 30 g of an aqueous solution of hydroxypropylcellulose as a binder is added thereto, and wet granulation is performed by a kneading granulator (Vertical Granulator VG-25 manufactured by Powrex). After drying and sizing the granulated product, 30 g of magnesium stearate as a lubricant is added and mixed to obtain a tableting powder. This tableting powder was crushed with a continuous tableting machine (812HUK manufactured by Kikusui Seisakusho) using a punch and die having a diameter of 5 mm.
The tablets are compressed to a tablet weight of 60 mg (cilostazol content: 20 mg). The capsules are filled with the sustained-release small tablets obtained as described above so that five tablets per capsule are obtained to prepare a multiple unit type sustained-release preparation (containing 100 mg of cilostazol in one capsule).

Examples 2 to 3 and Comparative Examples 1 to 6 According to the formulation shown in Table 1 below, sustained-release small tablets (Examples 2 to 3 and Comparative Examples 1, 3 and 5 (1 tablet weighs 50 mg, Comparative Examples 2, 4 and 6 each weighs 60 mg, cilostazol content 20 mg)
Is prepared, and each of the five small tablets is filled into one capsule to obtain a multiple unit type preparation.

[0013]

[Table 1]

[0014]

[Table 2]

Comparative Examples 7 and 8 Tablets are prepared in the same manner as in Example 1 according to the formulation shown in Table 2 below. However, each tablet weighs 1 tablet
70 mg (cilostazol content: 100 mg), and the tablet is used as a single unit dosage form to give a single unit preparation.

[0016]

[Table 3]

Examples 4 to 24 According to the formulation shown in Table 3 below, small tablets are prepared in the same manner as in Example 1 (compounding unit of each component: g). The weight of one tablet and the cilostazol content of each small tablet and the number of small tablets in the preparation (1 capsule) of the present invention are shown in the table, respectively.

[0018]

[Table 4]

[0019]

[Table 5]

[0020]

[Table 6]

[0021]

[Table 7]

[0022]

[Table 8]

[0023]

[Table 9]

[0024]

[Table 10]

Example 25 (1) Production of immediate release small tablets 1000 g of cilostazol, 750 g of corn starch (manufactured by Nippon Shokuhin Kako Co., Ltd.) and 500 g of crystalline cellulose (manufactured by Asahi Kasei Corporation) were mixed, and hydroxypropyl as a binder was added thereto. Cellulose (HPC-L, manufactured by Nippon Soda Co., Ltd.) 2
5 g of an aqueous solution is added, and wet granulation is performed using a kneading granulator (Vertical Granulator VG-25, manufactured by Baurek). After drying and sizing the granules, disintegrant carmellose calcium (ECG505, manufactured by Nichirin Chemical Co., Ltd.)
200 g and 25 g of magnesium stearate (manufactured by Taihei Chemical Industry Co., Ltd.) as a lubricant are added and mixed to give a tableting powder. This tableting powder was weighed 50 mg per tablet using a continuous tableting machine (812 HUK, manufactured by Kikusui Seisakusho) using a punch and die having a diameter of 5 mm.
(A cilostazol content of 20 mg) to give a quick-release small tablet. (2) Production of Multiple Unit Type Sustained Release Formulation The sustained-release small tablets obtained in Example 1 were 3 per capsule, and the quick-release small tablets were 2 per capsule.
A multiple unit type sustained-release preparation (containing 100 mg of cilostazol in one capsule) is prepared by filling individually.

Example 26 The punch and die having a diameter of 5 mm of Example 1 were replaced with 3 mm and 4 mm in diameter.
A multi-unit sustained-release preparation was prepared in the same manner as in Example 1 except that the preparation was changed to 5.2 mm, 5.5 mm, 6 mm and 7 mm.

Experiment 1 (Dissolution Test) The preparations of Examples 1 and 2 and Comparative Examples 1 to 6 were subjected to a dissolution test by the following paddle method and paddle bead method. (1) Buddle method This test method was set as a fasting administration model. A 0.3% aqueous solution of sodium lauryl sulfate was used as a test solution, the preparation to be tested was added thereto, and the test was carried out at 75 revolutions per minute according to the Japanese Pharmacopoeia Method 2 Paddle Method. The drug elution amount was continuously measured by a flow cell, and the time (P) at which 75% of the total drug amount was released was determined. (2) Buddle bead method This test method was set as a postprandial administration model in which a mechanical destructive force was added to the preparation. A 0.3% aqueous solution of sodium lauryl sulfate was used as a test solution, placed in a dissolution test container together with the preparation to be tested, and 2,000 plastic beads having a diameter of about 6 mm were further placed in the container. The test was performed at 50 revolutions per minute according to the method. The drug elution amount was continuously measured by the flow cell, and 75% of the total drug amount was measured.
% Release time (PB) was determined. Table 4 shows the results.

[0028]

[Table 11]

[0029]

[Table 12]

As is clear from the results shown in Table 4 above,
In the multiple unit type sustained release preparation of the present invention, when the dissolution rate (75% drug dissolution time) between the buddle method as a fasting administration model and the buddle bead method as a postprandial administration model was compared, there was no significant difference in the dissolution time. Good sustained release was shown without significant difference in pharmacokinetics depending on physiological conditions. In contrast, in the preparations of Comparative Examples 1 to 6 prepared without using the sustained release base of the present invention,
The drug release behavior is significantly different between fasting and postprandial administration, leading to differences in pharmacokinetics. In the case of a preparation using methylcellulose (Comparative Examples 1 and 2) or sodium alginate (Comparative Examples 3 and 4) as a sustained-release base, the drug dissolution rate was high, and the drug release could not be sufficiently controlled.

Experiment 2 (Pharmacokinetics in postprandial administration) In order to examine the pharmacokinetics of the test preparation in postprandial administration,
After breakfast to volunteers, test preparations shown in Table 5 below (all cilostazol content: 100 mg) were orally administered once, and blood was collected over time to measure cilostazol blood concentration, and the maximum cilostazol blood concentration (C _max ), the time to maximum blood concentration (T _max ), and the amount of cilostazol absorbed within 72 hours after administration (AUC _{0-72 hr} ).
As a control, plestar tablets 100 (manufactured by Otsuka Pharmaceutical Co., Ltd., cilostazol content 1
00 mg) 1 tablet was orally administered, and the C _max , T _max and AUC _{0-72 hr} of each _tablet were _defined as C _max , T _{max
The max} and AUC _{0-72 hr} % were calculated. Table 5 shows the results.

[0032]

[Table 13]

As is clear from the results shown in Table 5 above, the multiple unit type sustained release preparation (Example 1,
2) and 3) show a sufficient absorption (AUC), but have a higher blood concentration (C
_max ), and side effects such as headache caused by high blood levels were suppressed. On the other hand, the single-unit preparations (Comparative Examples 7 and 8) have the drawback that the maximum blood concentration is suppressed, but at the same time the drug elution is suppressed, so that a sufficient absorption amount cannot be obtained. In addition, the multiple unit type sustained release preparation showed a remarkable delay in the time to reach the maximum blood concentration (T _max ) as compared to the commercially available Pletal tablet.
In contrast, no sufficient delay was observed for the single-unit preparation.

──────────────────────────────────────────────────の Continued on the front page (51) Int.Cl. ⁶ Identification code Agency reference number FI Technical display location A61K 9/22 A61K 9/22 BFC 31/47 AED 31/47 AED 47/38 47/38 C C07D 401/12 257 C07D 401/12 257 // (C07D 401/12 215: 22 257: 04)

Claims (3)

[Claims] 1. A method for preparing 6- [4- (1-cyclohexyl-1H)
-Tetrazol-5-yl) butoxy] -3,4-dihydrocarbostyril as an active ingredient, and two or more sustained-release small tablets comprising hydroxypropylmethylcellulose as a sustained-release base. Characteristic multiple unit type sustained release preparation. 2. Hydroxypropylmethylcellulose having a viscosity of 400 cps or more is added to the sustained-release small tablet in an amount of 1%.
0 to 90% by weight, the diameter of the sustained-release small tablet is 3 to 7 m
m and the small tablet weighs 10 to 300
The multiple-unit sustained-release preparation according to claim 1, wherein the sustained-release small tablet is 2 to 20 mg. 3. In addition to the two or more sustained-release small tablets, 6
-[4- (1-cyclohexyl-1H-tetrazole-
The multiple unit-type sustained-release preparation according to claim 1, comprising one or more quick-release small tablets containing 5-yl) butoxy] -3,4-dihydrocarbostyril as an active ingredient.