JP4997741B2 - Low melting point drug-containing powder and method for producing the same - Google Patents

Description

  The present invention relates to a granular material containing a low melting point drug, and more specifically, there is no squeezing out of a low melting point substance or aggregation of the granular material during storage at high temperature, and even if a tablet is produced by tableting, a sticking etc. The present invention relates to a low-melting-point drug-containing granule having no tablet trouble and a method for producing the same.

  When a low melting drug having a melting point of 30 ° C. or higher and 80 ° C. or lower is formulated, there is a problem that the drug melts during storage at a high temperature higher than the melting point and the quality is remarkably impaired. In other words, powders and granules cause aggregation due to melting of the drug, and tablets cause problems such as exudation and spots due to melting of the drug. When a tablet containing a low melting point drug is produced using a tableting machine, the low melting point drug is melted by heat generated by the tableting machine and adheres to the surface of the mortar (sticking).

  Various attempts have been made to solve the above problems.

  For example, low melting point drug ubidecalenone is dissolved in an organic solvent, kneaded with an adsorption carrier such as light anhydrous silicic acid and then dried to produce a low melting point drug-containing granular material (Patent Documents 1, 2 and 3). However, this method has a problem that a large amount of an organic solvent is used to dissolve a low melting point drug, and a problem that a long time is required for drying because it is dried at a temperature lower than the melting point of the drug.

  In addition, a method of producing a low-melting drug-containing granular material by spray drying an emulsion of ubidecalenone, which is a low-melting drug (see Patent Document 4). However, the spray drying method is very unfavorable because the apparatus is very large and requires a lot of time for the cleaning operation, and thus the production efficiency is low particularly in the pharmaceutical industry for multi-product small-volume production.

  Furthermore, a method is disclosed in which granules such as macrogol, which is a low melting point substance, and lactose are flowed at a supply temperature equal to or higher than the melting point using a fluidized bed dryer (see Patent Document 5). . However, in this method, the temperature in the fluidized bed dryer (eye plate, wall, bag filter, etc.) is also higher than the melting point, so that the low melting point drug adheres to the container, causing problems such as a decrease in content and difficulty in continuous operation.

  In recent years, a method for producing a low-melting-point drug-containing granule by mixing a low-melting-point drug ubidecarenone and an adsorbent carrier such as light anhydrous silicic acid and pulverizing has been disclosed (see Patent Document 6). However, in this method, ubidecarenone powder that has not been adsorbed is present in the granular material, and sticking to the acetabulum surface (sticking) occurs due to continuous tableting for a long time.

JP-A-55-147219 JP 56-145214 A JP 58-92609 A JP-A-56-103109 JP 58-214333 A Japanese Patent Laid-Open No. 2004-123594

  The present invention relates to a granular material containing a low melting point drug, and more specifically, there is no squeezing out of a low melting point substance or aggregation of the granular material during storage at high temperature, and even if a tablet is produced by tableting, a sticking etc. Disclosed is a low-melting-point drug-containing powder that can be tableted continuously for a long time without any tablet failure.

Furthermore, it is possible to produce in small quantities and many varieties using general granulators and fluidized bed dryers without using a large apparatus such as that used in the spray drying method. A manufacturing method is provided.

  As a result of intensive studies to solve such problems, the present inventors have mixed a low-melting-point drug and an adsorption carrier in a powder state, granulated by a general granulation method, and then used a fluidized bed dryer to obtain a melting point. It has been found that by flowing at the above supply air temperature, a low-melting drug-containing powder particle adsorbed with a low-melting drug can be obtained, and the present invention has been completed.

That is, the present invention is as follows.
(1) It is obtained by flowing a granulated product obtained by granulating a mixed powder containing a low melting point drug having a melting point of 30 ° C. or higher and 80 ° C. or lower and an adsorption carrier at a temperature higher than the melting point. , Low melting point drug-containing powder.
(2) By allowing a granulated product having a particle size of not more than 75 μm to flow at a temperature equal to or higher than the melting point, the granulated product having a ratio of 0.5 parts by mass or less with respect to 1 part by mass of the entire granulated product The obtained low melting point drug-containing granular material according to (1).
(3) The low melting point drug-containing granular material according to (1) or (2) above, wherein the adsorption carrier has a specific surface area of 100 m ² / g or more.
(4) A low-melting-point drug-containing granular material comprising a granulated product in which a low-melting-point drug having a melting point of 30 ° C. or more and 80 ° C. or less is adsorbed on an adsorption carrier having a specific surface area of 100 m ² / g or more.
(5) The low-melting-point drug-containing granular material according to any one of (1) to (4) above, comprising 0.2 to 5 parts by weight of an adsorbing carrier with respect to 1 part by weight of the low-melting-point drug.
(6) The adsorption carrier is one or more selected from the group consisting of light anhydrous silicic acid, hydrous silicon dioxide, calcium silicate, magnesium alumina hydroxide, synthetic aluminum silicate, synthetic hydrotalcite, and magnesium magnesium aluminate metasilicate. The low-melting-point drug-containing granular material according to any one of the above (1) to (5).
(7) The low-melting-point drug substance-containing granular material according to any one of (1) to (6), which is granulated by a wet granulation method.
(8) The low-melting drug-containing granular material according to any one of (1) to (7), wherein the low-melting drug is ubidecarenone.
(9) A low-melting drug having a melting point of 30 ° C. or higher and 80 ° C. or lower and a granulated product obtained by granulating a mixed powder containing an adsorbent carrier are obtained by flowing at a temperature higher than the melting point. A method for producing a low-melting-point substance-containing granular material.

  According to the present invention, there is no squeezing out of a low melting point substance or aggregation of powder particles during high temperature storage, and there is no tableting trouble such as sticking even if a tablet is produced by tableting, and tableting is continued for a long time. Has succeeded in obtaining a low melting point drug-containing powder.

Furthermore, with the production method of the present invention, it is possible to produce using a general granulator and fluidized bed dryer without using a large apparatus such as that used in the spray drying method. Therefore, it is possible to produce a small quantity and a variety of products, and it is possible to manufacture with high productivity.

  In the present invention, the low melting point drug is solid at room temperature and has a melting point of 30 ° C to 80 ° C. Specific examples include tocopherol nicotinate (melting point 38 ° C.), ubidecalenone (melting point 48 ° C.), tocopherol succinate (melting point 75 ° C.), ibuprofen (melting point 75 ° C.), guaifenesin (melting point 80 ° C.), and the like.

The adsorption carrier in the present invention is a substance capable of adsorbing other substances on the surface and is not particularly limited as long as it is generally used in the production of a preparation, but has a specific surface area of 100 m ² / g. The fine particle or porous substance as described above is preferable. Specific examples include light anhydrous silicic acid, hydrous silicon dioxide, calcium silicate, magnesium magnesium aluminate, synthetic aluminum silicate, synthetic hydrotalcite, magnesium magnesium magnesium silicate, and the like. As these adsorption carriers, commercially available ones may be used. For example, Aerosil 130, 150, 200, 300, 380 (manufactured by Nippon Aerosil Co., Ltd.) having a specific surface area of 100 m ² / g or more is preferable. , Adsolider 101, 102 (Freund Sangyo Co., Ltd.), Carplex # 67, # 80 (Shionogi Pharmaceutical Co., Ltd.), Florite RE (Eisai Co., Ltd.), Neusilin UFL2 (Fuji Chemical Co., Ltd.), etc. . The blending amount of the adsorption carrier is preferably 0.2 to 5 parts by mass with respect to 1 part by mass of the low melting point drug. The “specific surface area” is measured by the BET method.

  The low-melting-point drug-containing granular material of the present invention is obtained, for example, by granulating a mixed powder containing a low-melting-point drug and an adsorption carrier, and flowing the obtained granulated material at a temperature equal to or higher than the melting point. Granulated product. Further, the low-melting drug-containing granular material may be a powder obtained by sizing, crushing, and pulverizing the granulated product, or a mixture of the powder and the granulated product.

  The production of the low-melting drug-containing powder granules of the present invention is not particularly limited. For example, the low-melting drug and the adsorption carrier are mixed and pulverized to obtain a mixed powder, and then granulated. The obtained granulated product can be produced by flowing at a supply temperature equal to or higher than the melting point using a fluidized bed dryer. A specific manufacturing method is as described in the examples.

Here, a general granulation method can be used as the granulation method, but a smaller amount of ungranulated fine powder is suitable for the present invention, and a wet granulation method is preferable. In particular, the kneading granulation method, the stirring granulation method, and the extrusion granulation method are preferable as the granulation method of the mixed powder containing the adsorption carrier.
When the granulated product having a particle size of 75 μm or less in the granulated product before flowing at a temperature higher than the melting point is 0.5 part by mass or less with respect to 1 part by mass of the entire granulated product, the desired effect is obtained. In particular, it is preferably 0.05 parts by mass or less.

  The fluidized bed dryer is one in which powder is suspended in hot air blown from below and dried. With this hot air, the low melting point drug can be melted and adsorbed on the adsorption carrier. The supply temperature is preferably 10 ° C. or higher, which is the melting point of the drug.

  In addition, active ingredients and additives other than the low melting point drug can be added within a range not impairing the effects of the present invention. For example, Asenayaku powder, Achacha powder, Aloe powder, Fennel powder, Ages powder powder, Ogon powder powder, Owaku powder powder, Auren powder powder, Onji powder powder, Kakon powder powder, Kanoko powder powder, Japanese licorice powder powder, Kuji powder powder, Keihi powder powder, Gentian powder powder, Gennoshoko powder, Kojin powder, Kobushi powder, Koboku powder, Gouo powder, Goshi mushroom powder, Psycho powder powder, Saishin powder powder, Sankirai powder powder, Sanshishi powder powder, Sansho powder powder, Sanyaku powder powder, Giant powder powder, Jikitaris powder powder, Peonies powder powder, Shukusha powder powder, Showa Kyou powder, Senegal powder, Senkyu powder, Senna powder, Sembli powder, Sojutsu powder, Soyo powder, Daio powder, Taiso powder, Takusha powder, Chikutsujinjin mushroom powder, Clove powder powder, Chorei powder powder, Chimpi powder powder, Pepper powder powder, Toki powder powder, Tounin powder, Tokon powder, Tragant powder, Nigaki powder, carrot powder, sandalwood powder Herbal powders such as powdered powder, powdered rice powder, bowie powder, button powder powder, borei powder powder, yakuinin powder powder, ryutan powder powder, fennel oil, licorice extract, Chinese berry extract, cinnamon oil, clove oil, belladonna extract, funnel extract, etc. , Chlorpheniramine maleate, L-aspartic acid, potassium L-aspartate, magnesium L-aspartate, L-isoleucine, L-glutamine, L-phenylalanine, L-methionine, L-histidine hydrochloride, ascorbic acid , Aspirin, sodium azulenesulfonate, acetaminophen, aminoethylsulfonic acid, aldioxa, isopropylantipyrine, ursodeoxycholic acid, etenzamide, ergocalciferol, octothiamine, caffeine, guaiacol sul Potassium phosphate, dipotassium glycyrrhizinate, cholecalciferol, sodium chondroitin sulfate, salicylamide, cyanocobalamin, dibrofilin, sucralfate, semi-alkaline proteinase, albumin tannate, berberine tannate, thiamine disulfide, theophylline, dehydrocholic acid, tranexamic acid, Nicotinamide, noscapine, retinol palmitate, calcium pantothenate, biotin, sodium picosulfate, bisacodyl, bisibutamine, bisbenchamine, tipepidine hibenzate, dextromethorphan phenol phthalate, cloperastine fendizoate, clemastine fumarate , Ferrous fumarate, fursultiamine, bromvalerylurea, hesperidin, hepronicart , Benfotiamine, carbinoxamine maleate, chlorpheniramine maleate, pheniramine maleate, mequitazine, methylmethioninesulfonium chloride (VU), iodopropamide, riboflavin, codeine phosphate, dihydrocodeine phosphate, dimemorphan phosphate, pyridoxal phosphate , Riboflavin sodium phosphate, calcium hydrogen phosphate, sodium benzoate caffeine, carnitine chloride, berberine chloride, arginine hydrochloride, isothipentyl hydrochloride, cloperastine hydrochloride, chlorhexidine hydrochloride, dicyclomine hydrochloride, dicetiamine hydrochloride, diphenidol hydrochloride, diphenylpyraline hydrochloride, diphenhydramine hydrochloride , Cetraxate hydrochloride, thiamine hydrochloride, triprolidine hydrochloride, trimethquinol hydrochloride, noscapi hydrochloride , Papaverine hydrochloride, hydroxocobalamin hydrochloride, pyridoxine hydrochloride, phenylpropanolamine hydrochloride, phenylephrine hydrochloride, fursultiamine hydrochloride, bromhexine hydrochloride, meclizine hydrochloride, methoxyphenamine hydrochloride, ranitidine hydrochloride, lysine hydrochloride, loperamide hydrochloride, magnesium oxide, gallic acid Bismuth, alimemazine tartrate, butyl scopolamine bromide, methyl atropine bromide, methyl octatropine bromide, methyl benactidium bromide, scopolamine hydrobromide, dextromethorphan hydrobromide, thiamine nitrate, tocopherol acetate, hydroxo acetate Cobalamin, aluminum hydroxide / sodium bicarbonate coprecipitate, magnesium hydroxide, magnesium carbonate, sodium bicarbonate, precipitated calcium carbonate, copper chlorophyllin sodium Herbal ingredients such as calcium lactate, anhydrous caffeine, folic acid, riboflavin butyrate, excipients such as lactose, sucrose, mannitol, starch, crystalline cellulose, binders such as hydroxypropylcellulose, hydroxypropylmethylcellulose 2910, polyvinylpyrrolidone, low Degree of substitution such as hydroxypropylcellulose, croscarmellose sodium, crospovidone, aminoalkyl methacrylate copolymer E, aminoalkyl methacrylate copolymer RS, coating agents such as ethylcellulose, magnesium stearate, calcium stearate, talc, etc. Agents, fragrances, pigments, and flavoring agents. The types and addition amounts of these active ingredients and additives are not particularly limited.

  Hereinafter, the present invention will be described in more detail with reference to Examples, Comparative Examples, and Test Examples.

Example 1
Low melting point drug (ubidecalenone), adsorption carrier (light anhydrous silicic acid (Freund Sangyo Co., Ltd. Adsolider 101)), excipient (lactose, crystalline cellulose), binder (hydroxypropylcellulose) are weighed in the proportions shown in Table 1. After mixing with vinyl, the mixture was pulverized using No. 22 sieve to obtain a mixed powder. Next, kneading granulation was carried out with anhydrous ethanol using a kneading granulator (Kneader NW-5, manufactured by POWREC) to obtain a granulated product having a No. 200 sieve passing rate of 3%. Next, ubidecalenone was melted while drying at a supply air temperature of 80 ° C. for 1 hour with a fluidized bed dryer (FD-3S, manufactured by Paulek). After cooling, the particle size was adjusted using a 0.7 mmφ screen using a granulator (Speed Mill ND-10, manufactured by Okada Seiko Co., Ltd.) to obtain a low-melting-point drug-containing granular material.

Example 2
It was produced in the same manner as in Example 1 except that the amount of absolute ethanol was reduced and a granulated product having a No. 200 sieve passing rate of 34% was obtained.

Comparative Example 1
The mixed powder before granulation in Example 1 was used as a low-melting drug-containing powder granule.

Comparative Example 2
Granulation of Example 1 was not carried out, and the mixed powder was melted, cooled and sized in the same manner as in Example 1 using a fluidized bed dryer to obtain a low-melting drug-containing powder granule.

Comparative Example 3
It was produced in the same manner as in Example 1 except that the adsorption carrier (light anhydrous silicic acid) in Example 1 was replaced with lactose.

Test example 1
The adhesion state of ubidecarenone to the plate and bag filter of the fluidized bed dryer after melting was observed to consider whether continuous production is possible.

  The results are shown in Table 1. Adhesion occurred when the pre-melting powder had a high rate of passing through a No. 200 sieve (75 μm). In Example 1 where the No. 200 sieve passage rate was 3% by mass, no adhesion occurred, but in Example 2 where the No. 200 sieve passage rate was 34% by mass, slight adhesion occurred. However, there was no problem in continuous production. In Comparative Example 2 in which granulation was not performed and the passing rate of No. 200 sieve was 73% by mass, a large amount of adhesion occurred, and continuous production was difficult.

  From the above results, granulation is performed before melting, and granulation with a particle size of 75 μm or less in the granulation is preferable when the amount of granulation is 0.5 part by mass or less with respect to 1 part by mass. It turns out that a granule can be obtained. In particular, in the case of 0.05 parts by mass or less, adhesion of the low melting point substance can be almost completely suppressed.

  On the other hand, in Comparative Example 3 in which light anhydrous silicic acid as an adsorption carrier was not blended, adhesion occurred even though the No. 200 sieve passage rate was as small as 6% by mass. From this result, it can be seen that an adsorption carrier is necessary to prevent adhesion.

Test example 2
The low melting point drug-containing granules of Examples 1 and 2 and Comparative Examples 1 to 3 were heated at 70 ° C. for 1 hour and then cooled to 5 ° C. to evaluate the storage stability.

  The results are shown in Table 1. Examples 1 and 2 were stable with no caking or spots. On the other hand, in Comparative Example 1 where melting was not performed, solidification and spots were generated.

  From this result, it can be seen that adsorbing is insufficient by mixing and crushing ubidecalenone and an adsorption carrier, and stable low-melting-point drug-containing particles cannot be obtained.

  On the other hand, in Comparative Example 3 in which no adsorbent carrier was blended, no spots were generated, but solidification occurred. From this result, it can be seen that the adsorption carrier is also necessary for obtaining a stable low-melting-point drug-containing granular material.

Example 3
Low melting point drug (Ubidecarenone), adsorption carrier (light anhydrous silicic acid (Freund Sangyo Co., Ltd. AdSolider 101)), additives are weighed in the proportions shown in Table 2, mixed with vinyl, and Yarya crusher (Yaya Yuki Machinery Co., Ltd.). ) To obtain a mixed powder.

  Next, kneading granulation is performed using the granulation liquid shown in Table 2 using a kneading granulator (kneader NW-5, manufactured by Paulek), and a fluidized bed dryer (FD-3S manufactured by Paulek). And melted while drying at 80 ° C. for 60 minutes.

  Subsequently, the particle size was adjusted using a 0.7 mmφ screen using a granulator (Speed Mill ND-10, manufactured by Okada Seiko Co., Ltd.) to obtain a low melting point drug-containing powder [A granule]. Separately, B granules containing other active ingredients are stirred and granulated with purified water using a stirring granulator (Vertical Granulator VG-5 manufactured by Paulek), and then fluidized bed dryer (FD-3S manufactured by Paulec). ) And dried at 80 ° C. and then sized with a No. 22 sieve.

  Next, the A granule, B granule and the latter additive component were added in the proportions shown in Table 2, mixed with vinyl, and 1 tablet weight shown in Table 2 using a rotary tableting machine (Collect 12 HUK, manufactured by Kikusui Seisakusho). Then, continuous tableting of 7200 tablets was performed for 40 minutes using 6 ridges of 30 rpm, compression pressure 900 kgf, 8.5 mmφ and sugar-coated surface.

Test example 3
After the tablet of Example 3 was manufactured, the presence or absence of adhesion of a mortar, pestle and turntable of a tableting machine was observed to evaluate the sticking property of the low melting point drug-containing granular material. Adhesion is not recognized at all, and it can be seen that the low melting point drug-containing granular material according to the present invention does not cause sticking even during long-time continuous tableting.

Test example 4
After the tablet obtained in Example 3 was stored at 65 ° C., 50 ° C., and 40 ° C. for a predetermined period, the presence or absence of spots due to ubidecalenone exudation was observed. As shown in Table 3, no spots were observed under all conditions, and it can be seen that the low-melting drug-containing granular material of Example 3 stably adsorbs ubidecalenone.

According to the present invention, there is no squeezing out of a low melting point substance or aggregation of powder particles during high temperature storage, and there is no tableting trouble such as sticking even if a tablet is produced by tableting, and tableting is continued for a long time. Thus, it has become possible to provide a low-melting-point drug-containing powder. In addition, since the low-melting drug-containing granular material can be produced using a general granulator and a fluidized bed dryer without using a large apparatus such as that used in the spray drying method, A small quantity of many varieties can be manufactured with good productivity.

Claims (5)

Melting point 30 ° C. or more and light anhydrous silicic acid specific surface area for low-melting drug and low melting drug 1 part by mass is 100 m ² / g or more is 80 ° C. or less, hydrated silicon dioxide, calcium silicate, hydroxide Wet granulating a mixed powder containing 0.2 to 5 parts by mass of one or more adsorbents selected from the group consisting of alumina magnesium, synthetic aluminum silicate, synthetic hydrotalcite and magnesium metasilicate aluminate The ratio of the granulated product having a particle diameter of 75 μm or less obtained by the above is 0.05 parts by mass or less with respect to 1 part by mass of the entire granulated product, and the low-melting-point drug is adsorbed to the adsorption unit. A low-melting drug-containing granule obtained by allowing a granulated product to flow at a temperature equal to or higher than the melting point of the low-melting drug.   The low-melting-point drug-containing granule according to claim 1, wherein the wet granulation is kneading granulation, stirring granulation or extrusion granulation. The low-melting-point drug-containing powder according to claim 1 or 2 , wherein the low-melting-point drug is ubidecarenone. Low melting drug melting point of 30 ° C. or higher and 80 ° C. or less, and the low melting point drug 1 mass specific surface area of 100 m ² / g or more with respect to part of light anhydrous silicic acid, hydrated silicon dioxide, calcium silicate, water Wet granulate mixed powder containing 0.2 to 5 parts by mass of one or more adsorbent carriers selected from the group consisting of alumina magnesium oxide, synthetic aluminum silicate, synthetic hydrotalcite and magnesium metasilicate aluminate The ratio of the granulated product having a particle diameter of 75 μm or less obtained by the above is a granulated product having a mass of not more than 0.05 parts by mass with respect to 1 part by mass of the total granulated product. A method for producing a low-melting-point drug-containing granule obtained by flowing at a temperature of The method for producing a low-melting drug-containing powder granule according to claim 4 , wherein the wet granulation is kneading granulation, stirring granulation or extrusion granulation.