JP3263732B2 - Manufacturing method of granules and granules - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

The present invention relates to a method for producing granules using silicone oil as a lubricant and to the granules.

[0002]

2. Description of the Related Art Granules such as granules are produced by kneading,
It consists of granulation, drying, sizing, and sieving steps. Among these steps, the granulation step largely controls the productivity of the granules and has a great influence on the product quality. In order to facilitate granulation, a lubricant is blended in the formulation. Conventionally, macrogol, propylene glycol, poloxamer, or the like has been used as a lubricant. In addition, a bulking agent, a binder, a disintegrant, and the like are blended as components in the formulation, and crystalline cellulose is also used for ensuring the quality of granules or for performing stable production.

[0003]

However, in the case of a lubricant which has been used in the past, there is a case where a small amount of the kneading liquid and a difference in the kneading state may cause the adhesion of the particles, or the lubricant may be caused by the granulation property. As a result, heat is generated, which causes problems such as deterioration of product quality.

[0004]

SUMMARY OF THE INVENTION The present inventors have found that the above problems have been solved by incorporating silicone oil into the formulation of granules produced by extrusion granulation, or by further using crystalline cellulose in combination. As a result of finding out that the points can be solved and further study, the present invention has been completed. That is, the present invention provides (1) a method for producing a granule, which comprises mixing a silicone oil with a powder containing a main agent and subjecting the powder to extrusion granulation, and (2) subjecting the powder to ball sizing after extrusion granulation. (3) the method of (1) or (2), wherein the powder contains crystalline cellulose; and (4) 0.1 w / w of silicone oil. % To 10w / w%
It is a granule contained.

[0005] The main agent referred to in the present invention is not particularly limited as long as it can be used in the form of granules, such as drugs, agricultural chemicals and animal drugs. Examples of the drug include vitamin based drug preparations (eg, vitamin A, vitamin B ₁ , fursultiamine, vitamin B ₂ , vitamin B ₆ , vitamin B ₁₂ , vitamin C, vitamin D, vitamin E, nicotinamide, pantothene Gastrointestinal drugs (eg, calcium carbonate), gastrointestinal drugs (eg, magnesium carbonate, sodium bicarbonate, magnesium aluminate metasilicate, synthetic hydrotalcite, precipitated calcium carbonate, magnesium oxide, funnel extract, biodiastase, lipase AP, aldioxa, etc.), case drugs
(Eg, acetaminophen, aspirin, chlorpheniramine maleate, dihydrocodeine phosphate, noscapine, methylephedrine hydrochloride, caffeine, serrapeptase, lysozyme chloride), antitussive expectorant (eg, cloperastine hydrochloride, dextro hydrobromide) Metrophan, theophylline, potassium guaiacol sulfonate, etc.), antipyretic analgesics (eg, etenzamid, salicylamide, bromvalerylurea, tinolidine hydrochloride, anhydrous caffeine, etc.), antibiotics (eg, cephalexin, amoxicillin, pivmecillinam hydrochloride, hydrochloric acid) Cefotiam, etc.), Psychoneurologic agents (eg, diazepam, lorazepam, oxazolam, leodopa, etc.), antispasmodics (eg, scopolamine hydrobromide, diphenhydramine hydrochloride, papaverine hydrochloride, aminophylline, etc.) Antihypertensives (eg, ipriflavone, etc.), Antihypertensives (eg, delapril hydrochloride, captopril, manidipine hydrochloride, etc.), Vasodilators (eg, molsidomine, nifedipine, isosorbide dinitrate, diltiazem hydrochloride, etc.), Drugs for allergies (eg, amlexanox , Tranilast, etc.), hypnotic sedatives (eg, estazolam, nitrazebam, phenobarbital sodium, etc.), diuretics
(E.g., isosorbide, furosemide, etc.), bile agents (e.g., trepivton, ursodesoxycholic acid, etc.). Examples of pesticides include cartap hydrochloride, Bassa (BPMC) and etofenprox, and examples of veterinary drugs include chlortetracycline hydrochloride, carobarox, and chlorphenicol.

The term "powder containing the main agent" in the present invention refers to a powder formulation containing the main agent, which is the subject of extrusion granulation, and may be a powdered main agent itself.
Generally, it refers to one composed of a main agent and an auxiliary agent. Here, examples of the auxiliary agent include those generally used together with the main agent in extrusion granulation, such as a diluent, a solvent (kneading liquid), a binder, and a disintegrant. Examples of the diluent include sugars (eg,
Lactose, granulated sugar, corn starch, etc.), sugar alcohols (eg, mannitol, etc.), cellulose (eg, natural cellulose, crystalline cellulose, etc.) and derivatives thereof
(Eg, hydroxypropyl cellulose) and the like. In the present invention, crystalline cellulose is particularly preferably used, and the effect of using it in combination with silicone oil is well exhibited. Crystalline cellulose is conventionally known, that is, a water-insoluble white powder in which the molecular structure of the network is finely divided to some extent by subjecting natural cellulose to, for example, an acid treatment, and further processed while applying a shearing force. Cellulose or crystalline cellulose / carboxymethylcellulose sodium mixed with crystalline cellulose and sodium carboxymethylcellulose (Avicel (trade name) RC (Asahi Kasei Kogyo Co., Ltd.) or Avicel (trade name) RC-591NF (Asahi Kasei Kogyo Co., Ltd.) Etc. can be used.

As the solvent, water or an organic solvent (eg, acetone, ethanol, isopropyl alcohol, etc.) is used. Examples of the binder include hydroxypropylcellulose, hydroxypropylmethylcellulose, methylcellulose, dextrin, and pregelatinized starch. Examples of the disintegrant include crosslinked products of carboxymethylcellulose calcium, carboxymethylcellulose, and carboxymethylcellulose sodium (Acdisol),
Polyvinylpyrrolidone cross-linked product (plasdone),
Corn starch or the like is used. As coating bases, long-acting ethyl cellulose (Dome, Germany), Aquacoat (trade name) (FMC, U.S.A.), Eudragit (trade name) E30D, Eudragit (trade name) RL,
Eudragit RS (trade name) (ROHM, Germany), enteric Eudragit (trade name) L30D, Eudragit (trade name) L, Eudragit (trade name) S (ROHM, Germany), hydroxypropyl methylcellulose phthalate, hydroxypropyl Methylcellulose acetate succinate (Shin-Etsu Chemical Co., Ltd.), cellulose acetate phthalate (Wako Pure Chemical Industries, Ltd.), polyvinyl acetate phthalate (Colorcon, UK), Shellac (Nippon Cielac Industry) and the like are used. As the plasticizer, Macrogol 6000, Tween 80, Myvaset (trade name) (Type 9-40) triacetin, triethyl citrate (Citroflex 2), and the like are used. The above-mentioned auxiliary may be appropriately selected in consideration of the type of the main agent and the purpose of use.

[0008] The silicone oil used in the present invention refers to a linear dimethylpolysiloxane obtained by co-hydrolysis and polycondensation of dimethyldichlorosilane and trimethylmonochlorosilane according to a conventional method. Including processed products. Specific examples include silicone resins that are permitted as food additives in the Food Sanitation Act. The resinous material refers to a product obtained by adding fine silicon dioxide (silica) to polysiloxane, and a processed product may be, for example, a product obtained by adding a fatty acid ester to the resinous material and emulsifying the resinous product. In extrusion granulation, these various types of silicone oils are oily or resinous when using an organic solvent as a kneading liquid at the time of kneading, and use a silicone resin / emulsion type when using water as a kneading liquid. It is desirable.

In the production method of the present invention, the apparatus used for the extrusion granulation and its operation may be applied by a technique known per se. The addition ratio of silicone oil in granules is
It is preferably 1 w / w% to 10 w / w%, and may be directly added at the time of powder mixing, or may be diluted into a kneading liquid and charged into the powder. When microcrystalline cellulose is added, the amount of the addition is preferably about 5 to 80 w / w% in the finished granule (in dry matter).

The granules referred to in the present invention include granules, powders and fine granules, and any granules can be produced by selecting a method known per se according to the purpose. After being subjected to extrusion granulation, the granules may be sized, dried and, if necessary, passed through a sieve to select a desired particle size.
These granules, preferably granules that have been subjected to ball sizing, can also be given a long-lasting or enteric function by using a suitable coating base.

[0011]

The present invention will be described in more detail with reference to the following examples. Example 1 Ipriflavone, lactose and crystalline cellulose were charged into a kneading machine, and a silicone resin emulsified type [Shin-Etsu Chemical Co., Ltd.
An aqueous solution containing KM72A, 30% silicone resin, 4% sorbitan fatty acid ester, 2% glycerin fatty acid ester], macrogol 6000 or poloxamer 188 is blended and kneaded as shown in Table 1 (500 rpm, 1 min. ) And granulated (60 rpm) with an extrusion granulator (RG-C125, Kikusui Seisakusho) having a 0.4 mmφ screen. The weight of the granules obtained by this method was measured, and the amount discharged per minute was calculated. The adhesion between the extruded granules was visually observed. Table 1 shows the results.

[0012]

[Table 1] * ¹ Indicates the amount as silicone resin. * ^2- : No adhesion +: Agglomeration after adhesion As is clear from the above results, when granulated using silicone resin, it shows faster discharge compared to using Macrogol 6000 or poloxamer. Was. Further, the adhesion of the particles to each other was smaller than that of the methods of Comparative Examples B and C.

Example 2 Magnesium carbonate, sodium hydrogen carbonate and crystalline cellulose were charged into a kneading machine, and silicone oil [Shin-Etsu Chemical Co., Ltd.
Co., Ltd.), silicone resin [Shin-Etsu Chemical Co., Ltd., KS6
6], polyvinyl acetal diethylaminoacetate
An ethanol solution containing [Sankyo Co., Ltd.] was blended and kneaded (500 rpm, 1 min.) As shown in Table 2 and extruded with a 0.4 mmφ screen (Fuji Paudal, EX).
K-1) was granulated (60 rpm). The weight of the granules obtained by this method was measured, and the amount discharged per minute was calculated. The adhesion between the granules was visually observed.

[Table 2] * ¹ See Table 1. As is clear from the above results, when macrogol 600 was granulated using silicone oil or silicone resin,
It showed a quick discharge property as compared with the use at 0.

Example 3 Ipriflavone, lactose, and crystalline cellulose were charged into a kneading machine, and a silicone resin / emulsion type [Shin-Etsu Chemical Co., Ltd. KM7
2A] was mixed and kneaded (500 rpm, 1 min.) As shown in Table 3 and granulated (60 rpm) with an extrusion granulator (Kikusui Seisakusho, RG-C125) having a 0.4 mmφ screen. )did. The weight of the granules obtained by this method was measured, and the amount discharged per minute was calculated. The adhesion was visually observed. Table 3 shows the results.

[Table 3] * ^1- ; no adhesion ±; adheres but can be loosened +; solidifies after adhesion As evident from the above results, the effect of addition of silicone resin on dischargeability is enhanced in the presence of crystalline cellulose. . It was also found that the addition of crystalline cellulose increased the amount of discharge and prevented adhesion.

Example 4 Ipriflavone, lactose, crystalline cellulose and crystalline cellulose / carboxymethylcellulose sodium (Avicel (trade name) RC) were charged into a kneading machine, and a silicone resin emulsified type [Shin-Etsu Chemical Co., Ltd. KM72A] or macro An aqueous solution containing any of Goal 6000 was blended and kneaded (500 rpm, 1 min.) As shown in Table 4 to obtain 0.4 mm.
Extrusion granulator with φ screen (Kikusui Seisakusho)
RG-C125) for granulation (60 rpm). The weight of the granules obtained by this method was measured, and the amount discharged per minute was calculated. The adhesion between the extruded granules was visually observed. Table 4 shows the results.

[0016]

[Table 4] * ¹ : Indicates the amount as a silicone resin. * ² ; see Table 1 It is clear that A (the present invention) is superior. Next, only the granulated product of A in Table 4 was ball-adjusted (1000 r.
pm), and then dried (intake air temperature: 70 ° C.) using a fluidized bed drier (Powrex FD-3S), and the coating liquid having the composition shown in Table 5 was flowed to 1000 g of the obtained spheres (fine particles). Layer coating machine (Powrex FD-3S)
Coated with The particles (coated fine particles) and fine particles obtained by this method were tested by the Japanese Pharmacopoeia 11, the dissolution test, the second method, and the dissolution of ipriflavone was determined as follows:
Table 6 shows the results of evaluation using high performance liquid chromatography. From this, it was found that the dissolution property of the coated fine particles was controlled as compared with the fine particles. further,
Filling the coated fine particles into a No. 0 capsule results in a sustained capsule.

Coating conditions Absorption temperature: 70 ° C. Spray air pressure: 2.0 kg / cm ² Injection speed: 10 g / min. Absorption amount: 0.8 m ³ / min. Dissolution test conditions Eluate; 2% sodium dodecyl sulfate 900 ml Rotation speed; 100 rpm high performance liquid chromatography condition column ; μ-Bondepack C ₁₈ mobile phase; acetonitrile / water = 60/40 Detection wavelength;

[Table 5]

[Table 6]

[0018]

According to the present invention, it is possible to obtain excellent effects of extruding granulation (exhaustability) during the manufacturing process and also of reducing adhesion between granulated materials. Further, the obtained granules are advantageous in that the particle size distribution is small and granules having a target particle size range can be obtained efficiently. In addition, by spheronizing after granulation, sustainability and enteric solubility can be efficiently imparted.

────────────────────────────────────────────────── (5) References JP-A-61-260029 (JP, A) JP-A-58-171454 (JP, A) JP-A-51-123814 (JP, A) US Patent 3,773,920 (US) , A) (58) Surveyed fields (Int. Cl. ⁷ , DB name) A61K 9/00-9/72 A61K 47/00-47/48 B01J 2/00-2/30

Claims (2)

(57) [Claims] 1. A method for producing granules, comprising mixing a silicone oil with a powder containing a main ingredient and crystalline cellulose and subjecting the mixture to extrusion granulation. 2. The method according to claim 1, wherein the granulation is carried out after extrusion granulation.