JP2011213606A - Method for producing solid preparation containing donepezil - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a method for producing a solid preparation containing donepezil by which the discoloration caused by the influence of heat or light is reduced.SOLUTION: The method for producing the solid preparation containing the donepezil includes forming granules of donepezil hydrochloride free from crystalline cellulose, mixing the crystalline cellulose and other additives therewith, and tableting the resultant mixture. The obtained tablet is prevented from the discoloration caused by the influence of the heat or the light, and the content of the main drug is maintained stably without using a coloring agent or other stabilizers.

Description

The present invention relates to a method for producing a solid preparation containing donepezil and crystalline cellulose.

Donepezil hydrochloride, which is known as a therapeutic agent for Alzheimer-type dementia, is marketed in Japan in various types of oral preparations such as tablets, fine granules, orally disintegrating tablets, and jelly agents. However, as will be described later, formulations containing donepezil hydrochloride are known to be easily altered by the influence of light, temperature, etc., and care must be taken during the distribution process and storage of the formulations. In particular, when the formulation changes color, even if the change does not affect the drug efficacy, the patient's appetite may be reduced and compliance may deteriorate. Various techniques have been studied to solve such problems.

Patent Document 1 discloses that a donepezil solution containing an organic acid was more stable to light than that containing no organic acid, that is, a decrease in the content of the main agent and a change in appearance were suppressed. ing. However, among the types of organic acids listed in the same document, there are some types in which the appearance is clearly changed by the influence of light. In the same document, the thermal stability was not mentioned. However, in Patent Document 2 disclosed later, the donepezil tablet to which citric acid, which is an organic acid, is added has a degradation product in terms of thermal stability. There is a description that it has been increased, and it seems that the method of adding an organic acid cannot ensure thermal stability even if light stability is improved. On the other hand, this Patent Document 2 only considers decomposition products in thermal stability, and does not mention stability to light and changes in appearance.

In general, as a method for solving the discoloration over time of the preparation, in addition to the method of blending a stabilizer as in Patent Document 1, a method of blending a colorant (Patent Document 3), There is a method of coating (Patent Document 4), etc., but all of them are only the effect of suppressing discoloration to light, do not mention the effect of suppressing discoloration to heat, and examples of application to solid preparations containing donepezil are also known. It is not done. In addition, in order to use such a method, it is necessary to examine the influence of the substance used on the active ingredient and other additives, and a manufacturing process and apparatus for coating the preparation surface are required. There are problems such as becoming.

As described above, for a solid preparation containing donepezil, a simple solution for simultaneously suppressing discoloration due to light and heat has not been known.

JP-A-11-106353 Special table 2008-525313 JP 2008-273870 A JP 2007-22938 A

The subject of this invention is providing the manufacturing method of the solid formulation containing the donepezil by which the discoloration by the influence of a heat | fever or light was suppressed.

In general, when manufacturing tablets, granulation is performed by adding additives such as excipients and binders to the active ingredient as a pretreatment, and the granules have good fluidity and compactness and have appropriate plasticity and particle size. This is known to facilitate compression molding. In addition, crystalline cellulose is one of the widely used excipients at that time, and this is because it is excellent in compression moldability, disintegration, and granulation properties, so that it can be used in the manufacturing process of tablets and capsules. Often wet granulated with additives. Although the present inventors manufactured donepezil hydrochloride tablets, they were previously mixed with donepezil hydrochloride and crystalline cellulose in a dry state, and it was confirmed that there was no particular problem even if the two contacted. First, it was discovered that tablets obtained by wet granulating both donepezil hydrochloride and crystalline cellulose by a conventional method are significantly discolored by heat or light.

As a result of intensive studies, the present inventors obtained granules of donepezil hydrochloride not containing crystalline cellulose, and then mixed crystalline cellulose with other additives and obtained by tableting the mixture. The tablet has been found to be capable of suppressing discoloration due to the influence of heat and light without using colorants or other stabilizers, and maintaining the content of the active ingredient in a stable manner.

That is, the features of the present invention are as follows.
[1] A method for producing a solid preparation containing donepezil and crystalline cellulose,
(A) a step of producing granules containing donepezil and no crystalline cellulose;
Manufacturing method.
[2] A method for producing a solid preparation containing donepezil and crystalline cellulose,
(A) a step of producing granules containing donepezil and no crystalline cellulose;
(B) a step of mixing crystalline cellulose with the granules obtained in (a),
Manufacturing method.
[3] A method for producing a solid preparation containing donepezil and crystalline cellulose,
(A) a step of producing granules containing donepezil and no crystalline cellulose;
(B) a step of mixing crystalline cellulose with the granules obtained in (a),
(C) Tableting the mixture obtained in (b),
Manufacturing method.
[4] A method for producing a solid preparation containing donepezil and crystalline cellulose,
(A) a step of producing granules containing donepezil and no crystalline cellulose;
(B) a step of mixing crystalline cellulose with the granules obtained in (a),
(C) Tableting the mixture obtained in (b),
(D) coating the tablet obtained in (c),
Manufacturing method.
[5] A solid preparation obtained by the method according to [1] to [4].
[6] A solid preparation containing donepezil and crystalline cellulose,
(A) granules containing donepezil and no crystalline cellulose;
(B) crystalline cellulose,
A solid formulation comprising a mixture of
[7] The solid preparation according to [6], wherein the solid preparation is a tablet.
[8] The solid preparation according to [6], wherein the solid preparation is a coated tablet.
[9] A method for suppressing discoloration of a solid preparation containing donepezil and crystalline cellulose, wherein neither donepezil and crystalline cellulose are wet granulated.

In the solid preparation obtained by the production method of the present invention, discoloration due to the influence of heat or light is suppressed without using a colorant or other stabilizer, and the content of donepezil as the main agent is also stably maintained. . Moreover, the tablet obtained by the production method of the present invention has good tablet hardness and disintegration.

The solid preparation in the present invention includes tablets, powders, granules, pills and the like, and tablets are particularly desirable. There are no particular limitations on the type of tablet, and uncoated tablets, coated tablets, orally disintegrating tablets, intraoral quick dissolving tablets, chewable tablets and the like are included.

The donepezil in the present invention is preferably donepezil hydrochloride. The content of donepezil contained in the solid preparation is preferably 0.2% to 30% of the preparation weight.

The kind and grade of the crystalline cellulose in the present invention are not particularly limited. For example, in the case of Theolas (registered trademark) manufactured by Asahi Kasei Chemicals Corporation, powder grades PH-101, PH-102, UF-702, UF-711, PH-301, PH-302, PH-F20JP , KG-802, and KG-1000. PH-101 is particularly preferred. When the preparation to be finally produced is a granule or a powder, crystalline cellulose may be granulated by a conventional method or a commercially available granule. The content of crystalline cellulose contained in the solid preparation is preferably 3% to 70%, more preferably 5% to 50% of the preparation weight.

In addition to crystalline cellulose, the solid preparation in the present invention may contain, if necessary, excipients, binders, disintegrants, lubricants, surfactants, sweeteners, flavoring agents, fragrances, coloring agents, and the like. An agent can be contained. The solid preparation in the present invention includes a coated tablet. In this case, the components of the coating film are enteric polymer, gastric polymer, water-soluble polymer, water-insoluble polymer, plasticizer, surfactant, moisture-proof agent. Further, a polishing agent, a lubricant, a coloring agent, etc. may be used in combination as appropriate.

In particular,
Starches such as corn starch, lactose, sucrose, mannitol, xylitol, erythritol, sorbitol, maltitol, calcium citrate, calcium phosphate, magnesium carbonate, calcium carbonate, magnesium aluminate metasilicate, light anhydrous silicic acid, anhydrous calcium hydrogen phosphate Excipients such as;
Binders such as sucrose, gelatin, gum arabic powder, methylcellulose, hydroxypropylcellulose, hypromellose, povidone, macrogol, carmellose, crystalline cellulose / carmellose sodium, dextrin, pullulan, tragacanth, sodium alginate, pregelatinized starch;
Disintegrants such as crospovidone, carmellose sodium, croscarmellose sodium, carmellose calcium, carmellose, low-substituted hydroxypropylcellulose, sodium carboxymethyl starch;
Lubricants such as magnesium stearate, calcium stearate, sodium stearyl fumarate, talc, light anhydrous silicic acid, hydrous silicon dioxide, sucrose fatty acid ester, hydrogenated oil;
Surfactants such as glycerin fatty acid ester, sorbitan fatty acid ester, polyoxyethylene fatty acid ester, polyoxyethylene sorbitan fatty acid ester, polyoxyethylene hydrogenated castor oil, polyoxyethylene alkyl ether, sodium lauryl sulfate, polyoxyethylene polyoxypropylene glycol ;
Sweeteners such as aspartame, saccharin, saccharin sodium, acesulfame potassium, sucralose, sorbitol, sucrose, glucose, maltitol;
Flavoring agents such as citric acid, sodium citrate, tartaric acid, DL-malic acid, glycine, DL-alanine;
Perfumes such as strawberry, lemon, lemon lime, orange, l-menthol, mint oil;
Coloring agents such as yellow ferric oxide, ferric oxide, titanium oxide, edible tar dyes, natural dyes;
Enteric polymers such as cellulose acetate phthalate, hypromellose phthalate, hypromellose acetate succinate, methacrylic acid copolymer L, methacrylic acid copolymer LD, methacrylic acid copolymer S;
Gastric soluble polymers such as polyvinyl acetal diethylaminoacetate, aminoalkyl methacrylate copolymer E;
Water-soluble polymers such as hydroxypropylcellulose, polyvinyl alcohol, povidone, hypromellose;
Water-insoluble polymers such as ethyl cellulose, aminoalkyl methacrylate copolymer RS, ethyl acrylate / methyl methacrylate copolymer;
Plasticizers such as macrogol, triethyl citrate, cetanol;
Moisture-proofing agents such as purified shellac and white shellac;
Polishing agents such as carnauba wax;
Etc.

(About step (a))
In the present invention, the step (a) includes a step of producing granules containing donepezil and not containing crystalline cellulose. The granules are produced by the following procedure.

First, necessary additives other than donepezil and crystalline cellulose, such as excipients, disintegrants, and binders, are mixed and granulated by a kneading granulation method or a stirring granulation method. This operation can be performed using a mixer, a kneading granulator, a stirring granulator, or the like. In particular, it is desirable to use a stirring granulator that can perform consistently from mixing to the end of granulation. The apparatus to be used may be a conventional one. Specifically, a high speed mixer such as a high speed mixer (trade name, manufactured by Fukae Powtech Co., Ltd.) or a vertical granulator (trade name, manufactured by Pou Lec Co., Ltd.) is used. An example is a grain device. The granulating liquid used for granulation is preferably purified water, but may contain alcohols such as ethanol or a solution in which a binder is dissolved, if necessary.

After completion of granulation, the granulated product is dried. This drying step is usually preferably performed at a temperature of about 20 to 80 ° C. The equipment used in the drying process is not particularly limited, and a shelf-type dryer, a rolling fluidized bed apparatus, a fluidized bed granulating dryer, and the like can be selected.

Then, if necessary, the granulated product in the step (a) can be produced by sizing the dried granulated product with a crushing device, a sizing device, a sieve or the like.

(About step (b))
In the present invention, the step (b) includes a step of mixing crystalline cellulose with the granules obtained in (a). This mixing may be performed by a commonly used method, for example, using a V-type mixer or the like. At this time, additives other than crystalline cellulose, for example, a lubricant, a surfactant, a sweetener, a corrigent, a fragrance, a colorant, and the like are added and mixed as necessary.

(About step (c))
In the present invention, a tablet can be produced by tableting the mixture obtained in step (b). The apparatus used in the tableting process is not particularly limited as long as it is commonly used, and examples thereof include a rotary tableting machine and a single tableting machine.

(About step (d))
In the present invention, a coated tablet can be produced by coating the tablet obtained in step (c). By applying an appropriate coating, it is possible to improve the appearance and mask bitterness and odor. In addition, it is possible to obtain a sustained-release preparation in which the active ingredient gradually elutes by stabilizing the active ingredient with a film that prevents moisture absorption and light, or coating with a substance having an appropriate solubility.

The equipment used in the coating process is not particularly limited, and a commonly used fluidized bed granulator, rolling fluidized bed granulator, centrifugal rolling granulation coating apparatus, composite granulation coating apparatus, or the like may be used.

EXAMPLES Hereinafter, although a reference example, an Example, and a test example demonstrate this invention in detail, the scope of the present invention is not limited to the following example.

(Reference example)
The contact test of donepezil hydrochloride and various additives was performed according to the following procedure. Donepezil hydrochloride and various additives were weighed at a weight ratio of 1: 1 and mixed in a mortar. The various additives used here are crystalline cellulose, lactose, corn starch, hydroxypropyl cellulose, magnesium stearate, talc, light anhydrous silicic acid, and hypromellose. Samples of these mixtures and samples containing only donepezil hydrochloride drug substance without additives were placed in a brown glass bottle in an environment of 25 ° C. and 50% RH, stoppered, and stored in an environment of 60 ° C. Two weeks later and four weeks later, the properties of each sample were visually compared with the initials. As a result, none of the samples showed any change in properties.

In a high speed agitation granulator (high speed mixer, LFS-GS-2J, manufactured by Fukae Pautech Co., Ltd.), donepezil hydrochloride 5.0 g, lactose hydrate 86.3 g, corn starch 13.0 g, hydroxypropylcellulose 1.2 g was mixed and kneaded and granulated with purified water. The granulated product obtained by sieving this with a No. 16 sieve is dried in a mini jet oven, sized with a No. 22 sieve, and finally mixed with 19.0 g of crystalline cellulose and 0.5 g of magnesium stearate. A lock powder was obtained. This powder was tableted with a single tableting machine at a tableting pressure of about 700 kg to prepare tablets of 125.0 mg per tablet. The obtained tablet had a hardness of 3.8 kg and a disintegration time of 0.8 minutes. The hardness was measured using a Schleuniger hardness tester (Dr. Schleuniger Pharmatron AG), and the disintegration time was measured according to the 15th revised Japanese Pharmacopoeia Disintegration Test Method using purified water as a test solution. The hardness and disintegration time described below are also the same.

In a high speed agitation granulator (high speed mixer, LFS-GS-2J, manufactured by Fukae Pautech Co., Ltd.), donepezil hydrochloride 10.0 g, lactose hydrate 172.6 g, corn starch 26.0 g, hydroxypropylcellulose 2.4 g was mixed and kneaded and granulated with purified water. The granulated product obtained by sieving this with a No. 16 sieve is dried in a mini jet oven, sized with a No. 22 sieve, and finally mixed with 38.0 g of crystalline cellulose and 1.0 g of magnesium stearate. A lock powder was obtained. This powder was tableted with a single tableting machine at a tableting pressure of about 700 kg to prepare tablets of 250.0 mg per tablet. The obtained tablet had a hardness of 4.4 kg and a disintegration time of 1.2 minutes.

(Comparative Example 1)
In a high speed agitation granulator (high speed mixer, LFS-GS-2J, manufactured by Fukae Pautech Co., Ltd.), donepezil hydrochloride 5.0 g, lactose hydrate 86.3 g, corn starch 13.0 g, hydroxypropylcellulose 1.2 g and 19.0 g of crystalline cellulose were mixed and kneaded and granulated with purified water. The granulated product obtained by sieving this with a No. 16 sieve was dried in a mini jet oven, sized with a No. 22 sieve, and finally mixed with 0.5 g of magnesium stearate to obtain a pre-tablet powder. This powder was tableted with a single tableting machine at a tableting pressure of about 700 kg to prepare tablets of 125.0 mg per tablet. The obtained tablet had a hardness of 3.6 kg and a disintegration time of 1.4 minutes.

(Comparative Example 2)
In a high speed agitation granulator (high speed mixer, LFS-GS-2J, manufactured by Fukae Pautech Co., Ltd.), donepezil hydrochloride 10.0 g, lactose hydrate 172.6 g, corn starch 26.0 g, hydroxypropylcellulose 2.4 g and crystalline cellulose 38.0 g were mixed and kneaded and granulated with purified water. The granulated product obtained by sieving this with a No. 16 sieve was dried in a mini jet oven, sized with a No. 22 sieve, and finally mixed with 1.0 g of magnesium stearate to obtain a pre-tablet powder. This powder was tableted with a single tableting machine at a tableting pressure of about 700 kg to prepare tablets of 250.0 mg per tablet. The obtained tablet had a hardness of 3.3 kg and a disintegration time of 1.1 minutes.

As shown in Table 1, Example 1 and Comparative Example 1, Example 2 and Comparative Example 2 are tablets composed of the same components, but Example 1 and Example 2 are mixed after granulating crystalline cellulose. On the other hand, in Comparative Example 1 and Comparative Example 2, crystalline cellulose is mixed during granulation.

(Test Example 1)
10 tablets each prepared in Example 1, Example 2, Comparative Example 1 and Comparative Example 2 were put into a brown glass bottle (No. 6) in an environment of 25 ° C. and 50% RH and stoppered. Stored in the environment. Two to four weeks later, the color tone of the tablet was visually observed, and the change in color tone relative to the initial was measured with a spectroscopic color difference meter (SE-2000, manufactured by Nippon Denshoku Industries Co., Ltd.). The results are shown in Table 2. Here, the numerical value in the parenthesis represents the color difference ΔE with respect to the initial.

From the above results, in the tablets of Example 1 and Example 2 produced according to the present invention, discoloration under high temperature conditions was significantly suppressed as compared with the tablets of Comparative Example 1 and Comparative Example 2. In addition, when the tablet of Example 2 was stored in an environment of 60 ° C. for 2 weeks, the content of donepezil hydrochloride was quantified by HPLC, and 99.5% or more of the initial was maintained. Was confirmed.

(Test Example 2)
Ten tablets each prepared in Example 2 and Comparative Example 2 were placed in a petri dish and stored in an environment irradiated with light of 25 ° C., 50% RH and 2000 lux at all times. Four weeks later, the color tone of the tablet was visually observed, and the color tone change relative to the initial was measured with a spectroscopic color difference meter (SE-2000, manufactured by Nippon Denshoku Industries Co., Ltd.). The results are shown in Table 3. Here, the numerical value in the parenthesis represents the color difference ΔE with respect to the initial.

From the above results, the discoloration due to light was remarkably suppressed in the tablet of Example 2 produced according to the present invention as compared with the tablet of Comparative Example 2. In addition, when the tablet of Example 2 was stored for 4 weeks in an environment irradiated with 2000 lux light, the content of donepezil hydrochloride was quantified by HPLC. It was confirmed that it was leaning.

In a high speed agitation granulator (high speed mixer, LFS-GS-2J, manufactured by Fukae Pautec Co., Ltd.), donepezil hydrochloride 10.0 g, lactose hydrate 128.4 g, corn starch 56.0 g, hydroxypropylcellulose 5.6 g was mixed and kneaded and granulated with purified water. The granulated product obtained by sieving this with a No. 16 sieve is dried in a mini jet oven, sized with a No. 22 sieve, and finally mixed with 68.8 g of crystalline cellulose and 1.2 g of magnesium stearate. A powder before tableting was obtained. This powder was tableted with a single tableting machine at a tableting pressure of about 800 kg to prepare tablets of 270.0 mg per tablet. The obtained tablet had a hardness of 10.8 kg and a disintegration time of 1.1 minutes.

Ten tablets obtained were put in a brown glass bottle (No. 6) in an environment of 25 ° C. and 50% RH, stoppered, and stored in an environment of 60 ° C. Separately, the obtained 10 tablets were placed in a petri dish and stored in an environment irradiated with light of 25 lux, 50% RH, and 2000 lux at all times. After 4 weeks, the color tone of each tablet was visually observed.

As a result, those stored at 60 ° C. and those always irradiated with 2000 lux remained white as the initial color tone.

(Comparative Example 3)
In a high speed agitation granulator (high speed mixer, LFS-GS-2J, manufactured by Fukae Pautec Co., Ltd.), donepezil hydrochloride 10.0 g, lactose hydrate 128.4 g, corn starch 56.0 g, hydroxypropylcellulose 5.6 g was mixed and kneaded and granulated with purified water. The granulated product obtained by sieving this with a No. 16 sieve is dried in a mini jet oven, sized with a No. 22 sieve, and finally 22.0 g of low-substituted hydroxypropyl cellulose as a disintegrant, magnesium stearate. 1.2g was mixed and the powder before tableting was obtained. This powder was tableted with a single tableting machine at a tableting pressure of about 400 kg to prepare 223.2 mg tablets per tablet.

The disintegration time of the obtained tablets was good at 0.8 minutes, but the hardness was very brittle at 1.8 kg.

(Comparative Example 4)
In a high speed agitation granulator (high speed mixer, LFS-GS-2J, manufactured by Fukae Pautec Co., Ltd.), donepezil hydrochloride 10.0 g, lactose hydrate 128.4 g, corn starch 56.0 g, hydroxypropylcellulose 5.6 g was mixed and kneaded and granulated with purified water. The granulated product obtained by sieving this with a No. 16 sieve is dried in a mini jet oven, sized with a No. 22 sieve, and finally, 10.5 g of crospovidone and 1.2 g of magnesium stearate as disintegrants. By mixing, a powder before tableting was obtained. This powder was tableted with a single tableting machine at a tableting pressure of about 400 kg to produce 211.7 mg tablets per tablet.

The obtained tablets had a slow disintegration time of 4 minutes 30 seconds.

Comparative Examples 3 and 4 are examples in which crystalline cellulose is not used, but tablets that satisfy both hardness and disintegration time can be obtained simply by adjusting the amount of each disintegrant and the tableting pressure. There wasn't.

A film coating solution was prepared by dissolving and dispersing 29.0 g of hypromellose, 3.0 g of macrogol 6000, 3.0 g of talc, and 6.0 g of titanium oxide in 261.0 g of purified water. The film coating solution was coated on the tablets prepared in Example 1 using a coating machine (Hi-Coater Lab, HC-LABO, Freund Sangyo Co., Ltd.), and 129.0 mg of film-coated tablets per tablet. Obtained.

Ten obtained film-coated tablets were put in a brown glass bottle (No. 6) in an environment of 25 ° C. and 50% RH, stoppered, and stored in an environment of 60 ° C. Separately, 10 obtained film-coated tablets were placed in a petri dish and stored in an environment irradiated with light of 25 lux, 50% RH, and 2000 lux at all times. After 4 weeks, the color tone of each tablet was visually observed.

As a result, those stored at 60 ° C. and those always irradiated with 2000 lux remained white as the initial color tone.

Claims (9)

A method for producing a solid preparation containing donepezil and crystalline cellulose,
(A) a step of producing granules containing donepezil and no crystalline cellulose;
Manufacturing method. A method for producing a solid preparation containing donepezil and crystalline cellulose,
(A) a step of producing granules containing donepezil and no crystalline cellulose;
(B) a step of mixing crystalline cellulose with the granules obtained in (a),
Manufacturing method. A method for producing a solid preparation containing donepezil and crystalline cellulose,
(A) a step of producing granules containing donepezil and no crystalline cellulose;
(B) a step of mixing crystalline cellulose with the granules obtained in (a),
(C) Tableting the mixture obtained in (b),
Manufacturing method. A method for producing a solid preparation containing donepezil and crystalline cellulose,
(A) a step of producing granules containing donepezil and no crystalline cellulose;
(B) a step of mixing crystalline cellulose with the granules obtained in (a),
(C) Tableting the mixture obtained in (b),
(D) coating the tablet obtained in (c),
Manufacturing method. A solid preparation obtained by the method according to claim 1. A solid preparation containing donepezil and crystalline cellulose,
(A) granules containing donepezil and no crystalline cellulose;
(B) crystalline cellulose,
A solid formulation comprising a mixture of The solid preparation according to claim 6, wherein the solid preparation is a tablet. The solid preparation according to claim 6, wherein the solid preparation is a coated tablet. A method for suppressing discoloration of a solid preparation containing donepezil and crystalline cellulose, wherein neither donepezil and crystalline cellulose are wet granulated.