JP2001302497A - Powdery preparation excellent in miscibility - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a powdery preparation prepared by formulating two or more kinds of powdery preparations and excellent in miscibility. SOLUTION: This powdery preparation is prepared by formulating (1) two or more kinds of powdery preparations with (2) calcium stearate and/or magnesium stearate.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to a powder having excellent mixing properties, which is obtained by mixing 1) two or more powders and 2) calcium stearate and / or magnesium stearate, and a method for producing the same.

[0002]

2. Description of the Related Art Conventionally, when preparing powders by mixing two or more powders having substantially the same average particle diameter and apparent density, silica or talc is often added as a lubricant. Was. However, usually, powders prepared by mixing two or more powders having substantially the same particle diameter with silicic acids often have insufficient mixing properties of the two or more powders. In the case of a powder containing a drug whose chemical decomposition is promoted by contact with silicic acids, it is presently difficult to mix two or more powders.

[0003]

Therefore, development of a powder having excellent mixing properties and a method for producing the powder, which is obtained by mixing two or more kinds of powders, is very much desired. In particular, in the case of a drug having an unpleasant taste such as a bitter taste or a unique taste, a drug-containing powder (or a drug-containing sustained-release powder) and a sweet powder are used in order to make the powder excellent in taking feeling without bitterness in the oral cavity. There has been a long-awaited desire to develop a powder having excellent mixing properties obtained by mixing a powder containing an agent and a method for producing the same. In view of the above situation, the present inventors have conducted intensive research in order to search for a powder having excellent mixing properties, which is obtained by mixing two or more powders, and a production method thereof. As a result, it has been found that the desired object can be achieved by the following configuration, and the present invention has been completed.

[0004]

The present invention is a powder obtained by mixing 1) two or more powders and 2) calcium stearate and / or magnesium stearate. In the powder according to the present invention obtained by mixing 1) two or more powders and 2) calcium stearate and / or magnesium stearate, the coefficient of variation of the degree of mixing of the two or more powders is 2.5% or less. . The method of measuring the degree of mixing is not particularly limited. For example, two or more powders containing the powder and calcium stearate and / or stearin are used as a marker with a specific component (for example, a drug contained) contained in one powder. A test for uniformity of the content of the specific component in a powder obtained by mixing magnesium acid is given. The average particle diameter ratio of the two or more powders is 1 to 1.6, preferably 1 to 1.4, with respect to the average particle diameter 1 of the powder having the smallest average particle diameter. The apparent density ratio of two or more powders is the apparent density 1 of the powder having the smallest apparent density.
Is from 1 to 1.3, preferably from 1 to 1.1. The powder to be mixed in the present invention is not particularly limited as long as it is two or more powders, but it is preferable that at least one or more of the two or more powders is a drug-containing powder. The drug-containing powder to be mixed in the present invention may be one kind, but may be, for example, two or more kinds of drug-containing powders containing different drugs, or two or more kinds containing the same drug but having different elution rates. Drug-containing powders may be mixed and used.

The drug used in the present invention is not particularly limited, but is particularly useful when a drug having an unpleasant taste such as a bitter taste or a unique taste is used. The drug having an unpleasant taste such as a bitter taste or a unique taste according to the present invention includes, for example, ticlopidine hydrochloride, donepezil hydrochloride, ethylephrine hydrochloride, diltiazem hydrochloride, propranolol hydrochloride, indeloxazine hydrochloride,
Examples thereof include aminoguanidine hydrochloride, but are not limited to these compounds. In order to prepare a powder containing a drug having such an unpleasant taste, at least one or more powders among two or more powders to be mixed are drug-containing powders and at least one or more powders. Is a sweetener-containing placebo powder. In addition, the drug-containing powder containing a drug having an unpleasant taste, in order to achieve the elution delay of the drug in the oral cavity,
It is desirable to use a drug-containing sustained release powder.

According to the present invention, there is provided (a) a drug-containing sustained-release powder in which a drug is contained in a matrix of fats and oils, a water-insoluble polymer and / or a water-soluble polymer; Or a drug-containing sustained-release powder coated with a water-soluble polymer film, or (c) a drug-containing sustained-release in which the drug is contained in a matrix of fats and oils, a water-insoluble polymer and / or a water-soluble polymer. To produce a drug-containing sustained-release powder coated with an oil, a water-insoluble polymer and / or a water-soluble polymer on a water-soluble powder, a generally known sustained-release preparation is used. Manufacturing method can be used,
There is no particular limitation. As a granulating solvent when performing a granulating operation of the drug-containing powder according to the present invention, water, an organic solvent,
Any of water-containing organic solvents may be used. Examples of the organic solvent include ethanol, propanol, isopropanol and the like. Furthermore, kneading and granulating operations performed by adding a formulation aid and adding a solvent can be performed by a commonly used apparatus, for example, a fluidized bed granulator, a tumbling granulator or an extrusion granulator. Can be used. The coating operation can be usually performed using a fluidized bed granulator, a centrifugal fluidized granulator, or the like. The fats and oils in the present invention are not particularly limited, and include, for example, hardened oils. The hardened oil preferably has a melting point of 80 ° C. or lower, more preferably 50 to 70 ° C., and more preferably 50 to 65 ° C. Further, the water-soluble polymer in the present invention, for example, hydroxypropylmethylcellulose, methylcellulose, hydroxypropylcellulose, sodium carboxymethylcellulose, gum arabic, agar, gelatin, sodium alginate,
Examples include polyvinylpyrrolidone, carboxyvinyl polymers, polyvinyl alcohol and / or macrogol. Further, examples of the water-insoluble polymer in the present invention include ethyl cellulose, aminoalkyl methacrylate copolymer, methacrylic acid copolymer, hydroxypropylmethylcellulose phthalate, hydroxypropylmethylcellulose acetate succinate and / or cellulose acetate phthalate. In the present invention, these can be used alone or in combination of two or more.

The sweetener contained in the sweetener-containing placebo powder of the present invention includes, for example, mannitol, aspartame, licorice, saccharin, saccharin sodium, stevia extract and the like, and preferably mannitol.

The powder according to the present invention, which is obtained by mixing 1) two or more powders and 2) calcium stearate and / or magnesium stearate, belongs to the particle size regulation described in the thirteenth revised Japanese Pharmacopoeia. Powders of any particle size distribution may be used as long as they are fine, but fine powders belonging to powder having a small particle size are particularly desirable.

[0009] The calcium stearate according to the present invention and
The mixing ratio of magnesium stearate is 0.1 to 2% by weight, preferably 0.1 to 1% by weight, based on the total weight of two or more powders mixed. still,
If it is more than 2%, the dissolution of the drug from the mixed powder is delayed, which is not preferable.

According to the present invention, 1) two or more powders,
2) A powder obtained by mixing calcium stearate and / or magnesium stearate has a surprising property that two or more powders are extremely excellent in mixing properties. Therefore, the present invention is a method for preparing a powder having excellent mixing properties, characterized by adding calcium stearate and / or magnesium stearate when mixing two or more powders. The mixing is not particularly limited as long as it is a commonly used mixing method.
Cylindrical mixer, rotating container mixer, mixer with low-speed stirring device (ribbon blender, planetary mixer, etc.)
And the like. The powder and the method for preparing the powder according to the present invention have an excellent property that a good mixing property can be imparted even to a drug whose decomposition is accelerated by contact with a lubricant. For example, when ticlopidine hydrochloride is contacted with a lubricant such as light anhydrous silicic acid that has been often used in the past, warming, a change in the appearance of the color is observed during storage under humidified conditions. By adding calcium stearate and / or magnesium stearate, there is no change in coloring of the appearance of the preparation, and improvement in chemical stability is recognized. Further, the calcium stearate and / or magnesium stearate according to the present invention has an effect of preventing generation of static electricity, and is easily packaged in a product or a hospital preparation prepared by packaging the powder according to the present invention with glassine paper or the like. In addition, it has a feature that the powder is easily taken out from the sachet and easily taken. Furthermore, the mixed powder according to the present invention is stably present without causing blocking (aggregation) between the powders under humid storage conditions. That is, the mixed powder according to the present invention also has an extremely excellent property that blocking between powders can be prevented.

Two or more kinds of powders constituting the powder according to the present invention, for example, a drug-containing sustained-release powder and a sweetener-containing placebo powder may contain, if necessary, commonly used excipients such as saccharides. Agents, disintegrants, binders, lubricants and / or colorants can be added. Examples of the excipient include lactose, sucrose, corn starch, mannitol, erythritol, xylitol, trehalose, starch, partially pregelatinized starch, crystalline cellulose, dextrin, hydroxypropyl starch, various cyclodextrins (α-cyclodextrin, β -Cyclodextrin, γ-cyclodextrin) and its derivatives, pullulan, gum arabic and the like. Disintegrators include, for example, light anhydrous silicic acid, crystalline cellulose, crospovidone, low-substituted hydroxypropylcellulose, croscarmellose sodium, calcium silicate, magnesium metasilicate aluminate, carboxymethylcellulose, carboxymethylcellulose calcium, hydroxypropyl starch , Sodium carboxymethyl starch, partially pregelatinized starch, sodium alginate, corn starch and the like. Lubricants include, for example, magnesium stearate, calcium stearate, stearic acid, talc, sodium stearate fumarate and the like, and coloring agents include, for example, yellow iron sesquioxide, yellow iron oxide, edible yellow 4.
No. 5, Food Yellow No. 5, Food Yellow No. 4 Aluminum Lake and Vengara, iron sesquioxide, Food Red No. 2, Food Red No. 3, Food Red No. 102, and the like. In the present invention, these can be used alone or in combination of two or more.

The powder having excellent mixing properties according to the present invention can be produced, for example, as follows. 800 g of ticlopidine hydrochloride, 680 g of hardened oil, hydrous silicon dioxide 1
After precisely weighing 60 g and 120 g of Macrogol 6000 and thoroughly mixing them in a mixer, 160 g of hydroxypropyl cellulose and 40 g of anhydrous citric acid were added to 2000 g of purified water.
The fluidized-bed granulation is performed by spraying the aqueous solution dissolved in the liquid. Next, a heat treatment (supply air temperature 100 ° C., exhaust temperature 65 ° C.) is performed, and a methacrylic acid copolymer L-containing solution is sprayed and sized to 1715 g of the obtained powder to form a drug-containing sustained release powder. Is prepared. Separately, D-mannitol 489
For 7 g, 140 g of hydroxypropyl cellulose
Is dispersed in 2660 g of purified water, and the mixture is sprayed to form a fluidized-bed granulator and sized to prepare a sweetener-containing placebo powder. By precisely weighing 504 g of the drug-containing sustained-release powder and 1290.6 g of the sweetener-containing placebo powder, and adding and mixing 5.4 g of calcium stearate, an unpleasant taste-masked powder excellent in mixing property is obtained. Can be manufactured.

[0013]

According to the present invention, it is possible to produce a powder having excellent mixing properties by mixing two or more powders. Particularly, in the case of a drug having an unpleasant taste such as a bitter taste or a unique taste, a powder containing a drug (or a sustained-release powder containing a drug) is used in order to obtain a powder excellent in taking feeling without feeling bitterness in the oral cavity.
And a sweetener-containing powder can be mixed to produce a powder having excellent mixing properties. The effect example is shown below. Experimental example

Good Mixability of Powder According to the Present Invention A sustained-release powder containing a drug and a placebo powder containing a sweetener are mixed, and magnesium stearate is added in an amount of 0.1% each.
(Example 1), 0.3% (Example 2), powder containing 0.5% (Example 3), 0.3% calcium stearate
The mixed powder (Example 4) was evaluated for mixability of two types of powder (drug-containing sustained-release powder and sweetener-containing placebo powder). As a control experiment, a powder containing no lubricant (Control Example 1) and 0.3% of light anhydrous silicic acid were added.
A blended powder (Comparative Example 2) and a powder blended with 0.3% talc (Control Example 3) were produced in the same manner as in Example 2 and evaluated. The average particle size ratio of the drug-containing sustained-release powder and the sweetener-containing placebo powder (the drug-containing sustained-release powder)
/ Placebo powder containing sweetener) and the apparent density ratio (sustained release powder containing drug / placebo powder containing sweetener) are 1.2 respectively.
9, 0.97 powder was used, and ticlopidine hydrochloride was used as the drug in the drug-containing sustained release powder. The evaluation of the degree of mixing of the two powders (sustained-release powder containing a drug and placebo powder containing a sweetener) was conducted by randomly extracting 6 samples of 1 g each from the mixed powder and then testing the content uniformity of ticlopidine hydrochloride. Then, the coefficient of variation of the degree of mixing was determined using the content as an index. The content of ticlopidine hydrochloride was measured by high performance liquid chromatography. Table 1 shows the coefficient of variation of the prescription in each powder and the degree of mixing of the two powders (the drug-containing sustained-release powder and the sweetener-containing placebo powder).

[0015]

[Table 1]

As shown in the results of the coefficient of variation of the degree of mixing in Examples 1 to 3, as the amount of magnesium stearate was increased, the coefficient of variation became smaller, and the mixing property was improved (coefficient of variation). Value: 0.1% blend (Example 1) = 2.24%, 0.3% blend (Example 2) = 1.68
%, 0.5% blending (Example 3) = 1.88%). In addition, the coefficient of variation of the powder containing 0.3% calcium stearate (Example 4) was 1.35% smaller, and good mixing properties were obtained. In addition, in the case of the powder containing no lubricant (Comparative Example 1), the coefficient of variation was as large as 27.9%, and the mixing property was extremely poor. A powder containing 0.3% of light silicic anhydride (Comparative Example 2) and a powder containing 0.3% of talc (Example 4)
Then, the coefficient of variation of the mixture degree is 4.04% and 4.97, respectively.
%, And sufficient mixing was not obtained. The powder obtained by mixing 1) two or more powders and 2) calcium stearate and / or magnesium stearate according to the present invention has an excellent property of being excellent in mixing property of two or more powders. It is clear that

[0017]

EXAMPLES The present invention will be described in more detail with reference to the following Examples, but it should not be construed that the present invention is limited thereto.

Example 1 The drug-containing sustained-release powder obtained in 1) and the sweetener-containing placebo powder obtained in 2) are mixed by the method described in 3) to obtain excellent mixing properties. An unpleasant taste of the masked granule was obtained. 1) Preparation of drug-containing sustained release powder 800 g of ticlopidine hydrochloride, hardened oil 6 having a melting point of about 60 ° C.
80 g, 160 g of hydrated silicon dioxide and 120 g of Macrogol 6000 were precisely weighed and thoroughly mixed in a mixer. Next, in a fluidized bed granulator, for this mixture,
An aqueous solution in which 160 g of hydroxypropylcellulose and 40 g of anhydrous citric acid were dissolved in 2000 g of purified water was sprayed, and granulation and drying were performed. After the granulation and drying, a heat treatment (supply air temperature 100 ° C., exhaust temperature 65 ° C.) was performed, and the mixture was sized with a 30-mesh sieve. Granulated powder 1715
g of methacrylic acid copolymer L-containing solution (700 g of Eudragit L30D) in a fluidized bed granulator.
After adding and dispersing 35 g of triethyl citrate in the −55 dispersion, a solution in which 665 g of purified water was added and sufficiently dispersed and mixed) was sprayed, dried, and then sized with a 30-mesh sieve and a 150-mesh sieve. Thus, a drug-containing sustained-release powder coated with a film (a powder that was sieved through a 30-mesh sieve and remained on a 150-mesh sieve) was obtained. 2) Preparation of placebo powder containing sweetener 5000 g of D-mannitol was crushed in a mixer.
Next, in a fluidized bed granulator, hydroxypropyl cellulose 1 was added to 4897 g of the crushed D-mannitol.
An aqueous solution in which 40 g was dissolved in 2660 g of purified water was sprayed, and granulation and drying were performed. After granulation and drying, the mixture was sized with a 30-mesh sieve to obtain a sweetener-containing placebo powder (powder sieved with a 30-mesh sieve). 3) Preparation of mixed powder The drug-containing sustained-release powder 30 coated with a film
g, 70 g of a sweetener-containing placebo powder and 0.1 g of magnesium stearate were mixed in a mixer to obtain a powder (fine granules).

Example 2 30 g of the drug-containing sustained-release powder obtained in 1) of Example 1
70 g of the sweetener-containing placebo powder obtained in 2) and 0.3 g of magnesium stearate were mixed in a mixer to obtain a powder (fine granules).

Example 3 30 g of the drug-containing sustained-release powder obtained in 1) of Example 1
70 g of the sweetener-containing placebo powder obtained in 2) and 0.5 g of magnesium stearate were mixed in a mixer to obtain a powder (fine granules).

Example 4 30 g of the drug-containing sustained-release powder obtained in 1) of Example 1
70 g of the sweetener-containing placebo powder obtained in 2) and 0.3 g of calcium stearate were mixed in a mixer to obtain a powder (fine granules).

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Claims (10)

[Claims] 1. A powder obtained by mixing 1) two or more powders and 2) calcium stearate and / or magnesium stearate. 2. In a powder obtained by mixing 1) two or more powders and 2) calcium stearate and / or magnesium stearate, the mixing coefficient of the two or more powders is not more than 2.5%. The powder according to claim 1, 3. The powder according to claim 1, wherein at least one of the two or more powders is a drug-containing powder. 4. The powder according to claim 1, wherein at least one of the two or more powders is a drug-containing powder, and at least one or more powders is a sweetener-containing placebo powder. Powder 5. The drug according to claim 3 or 4, wherein the drug contained in the drug-containing powder is ticlopidine hydrochloride, donepezil hydrochloride, etilephrine hydrochloride, diltiazem hydrochloride, propranolol hydrochloride, indeloxazine hydrochloride or aminoguanidine hydrochloride. Powder 6. The powder according to any one of claims 3 to 5, wherein the drug-containing powder is a drug-containing sustained-release powder. 7. A drug-containing sustained-release powder comprising: (a) a drug-containing sustained-release powder containing a drug in a matrix of fats and oils, a water-insoluble polymer and / or a water-soluble polymer; Drug-containing sustained-release powder coated with a film of a water-insoluble polymer and / or a water-soluble polymer, or (c) containing a drug in a matrix of fats and oils, a water-insoluble polymer and / or a water-soluble polymer. On the drug-containing sustained-release powder,
The powder according to claim 6, which is a drug-containing sustained-release powder coated with a film of a water-insoluble polymer and / or a water-soluble polymer. 8. The powder according to claim 1, wherein the powder is a fine granule. 9. The method according to claim 1, wherein the mixing ratio of calcium stearate and / or magnesium stearate is 0.1 to 2% by weight based on the total weight of the mixture of two or more powders. Powder described in item 10. A method for preparing a powder having excellent mixing properties, comprising adding calcium stearate and / or magnesium stearate when mixing two or more powders.