JP2003081876A - Method for mixing medicine - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a mixing method by which a speed of mixing a low dose medicinal agent with additives is increased and the homogeneity of the contents of the agent is increased when the low dose medicinal agent is mixed with the additives through a powder mixing process. SOLUTION: The mixing method for increasing the homogeneity of the content of the medicinal agent comprises mixing the agent with a fluidizing modifier (talc, light anhydrous silicic acid or the like) in advance, and subsequently mixing the mixed powder further with other additives.

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to a method for mixing a drug and an additive.

[0002]

2. Description of the Related Art Conventionally, in the direct tableting method in which a drug and an additive are mixed in powder form and the mixed powder is tableted, or when the mixed powder is filled in capsules, or the mixed powder is powdered. In the conventional powder mixing method, when the drug has high cohesiveness, especially when the drug content concentration is low, the mixing speed of the drug and the additive is slow, and it is difficult to improve the drug content uniformity. It is known that there is. Therefore, in such a case, a method of wet granulating the drug and the additive was often used. But,
In the wet granulation method, there are problems that the cost is high and the validation is difficult because many steps are required, and the drug efficacy is lowered for a drug sensitive to moisture and heat. There is an example of study to improve the drug content uniformity by mixing the drug and additives in a powder state, not by wet granulation, but it requires a long time of mixing, or the content variation over time Not enough results have been obtained, such as being large.

[0003]

DISCLOSURE OF THE INVENTION The present invention provides a drug and a predetermined amount as a pre-process for producing a tablet obtained by a direct compression method, a capsule filled with powder, a powder made of powder, or the like. In the case of powder-mixing various additives, the drug content in the final preparation is 20
An object of the present invention is to provide a mixing method for increasing the mixing speed of a drug and an additive and enhancing the content uniformity of the drug when the content is as low as less than or equal to wt%.

[0004]

Means for Solving the Problems As a result of intensive studies to solve the above problems, the present inventors have found that before mixing a drug and an additive, after mixing the drug and a flow modifier in advance. ,
By further mixing the mixed powder with other additives, the mixing speed of the drug is increased and the uniformity of the drug content is improved, that is, the drug-containing mixed powder having a coefficient of variation of the drug content of 5% or less. They have found that they can do so and have completed the present invention.

That is, the present invention is: 1) In mixing a drug and an additive, the drug and the flow modifier are mixed, and then the mixed powder and other additives are mixed. Mixing method: 2) The flow modifier is one kind or two or more kinds selected from the group consisting of talc, light anhydrous silicic acid, hydrous silicon dioxide, and stearate; 3) The method for mixing a drug according to claim 1 or 2, wherein the other additive contains cellulose and / or lactose.

[0006]

BEST MODE FOR CARRYING OUT THE INVENTION The present invention is described in detail below.
The drug used in the present invention is not particularly limited as long as it is formulated as an active ingredient, but when applied to a drug in the form of fine powder having a high cohesive property, the effect of the present invention is remarkable, which is preferable. The average particle size of the drug is preferably 40 μm or less, which is obtained by image analysis from the viewpoint of cohesiveness. It is more preferably 30 μm or less. More preferably, it is 20 μm or less.

Since the concentration of the drug is related to the effective dose of the drug, it cannot be generally stated, but there is no particular limitation as long as it is a concentration which is practically used. However, since the effect of the present invention is more remarkable when the concentration of the drug used is low, it is preferably 20% by weight or less, more preferably 10% by weight or less, particularly preferably 5% by weight in the final preparation. % Or less, more preferably 2% by weight or less. The lower limit of the drug concentration is not particularly limited, but is about 0.01% by weight or more. If necessary, two or more drugs may be used in combination.

Examples of the flow modifier include additives classified into fluidizers and lubricants in "Pharmaceutical Additives Encyclopedia 2000" (published by Yakuhin Jikho Co., Ltd.). Examples of the fluidizing agent include talc, light anhydrous silicic acid, hydrous silicon dioxide, titanium oxide and the like. Examples of the lubricant include magnesium stearate, calcium stearate, stearates such as stearic acid, hydrous amorphous silicon oxide, magnesium silicate, calcium silicate, and magnesium carbonate. Preferred are talc, light anhydrous silicic acid, hydrous silicon dioxide and stearate. The flow modifier may be used alone or in combination of two or more kinds.

In the method of mixing a drug of the present invention, it is necessary to mix the drug with the above-mentioned flow modifier before mixing it with a predetermined additive. By taking such a method, the drug content in the final preparation obtained from the mixed powder is 20% by weight.
Even when it is as low as below, the variation in the drug content is small, and a tablet having a so-called drug content variation coefficient of 5% or less, which will be described later, excellent in so-called content uniformity can be obtained.

The ratio of the flow modifier added to the drug depends on the type of the modifier and the drug, but is preferably about 0.1 to 200% by weight based on the drug.
If the amount is less than 0.1% by weight, the effect of releasing the aggregation of the drug by the flow modifier is small, so that the effect of the present invention may be difficult to obtain. If it exceeds 200% by weight, the flowability and the adhesion of the flow modifier will be exhibited and the workability will be deteriorated, so that the effects of the present invention will be difficult to obtain. Strictly speaking, the addition amount of the flow modifier differs depending on its type. In the case of talc, it is preferably about 5% by weight to 200% by weight with respect to the drug. More preferably, it is about 20% to 100% by weight. In the case of light anhydrous silicic acid, hydrous silicon dioxide and stearate, preferably 0.1% by weight to 2 based on the drug.
It is about 0% by weight. More preferably, 0.5% by weight
10 to 10% by weight.

When the drug and the flow modifier are mixed, a part of the other additives may be added here to the extent that the effects of the present invention are not lost. The amount of the flow modifier added at that time is based on the total amount of the drug and the additives added at the same time as a guide. The mixing method of the drug and the flow modifier is not particularly limited as long as it is a commonly used powder mixing method. V-type, W-type, double-cone type, container-tank type mixers and other container-rotating type mixers, or high-speed stirring type, universal stirring type, ribbon type, Nauta-type mixers and other stirring type mixers can be used. it can. When the amount of powder is small, it is possible to put the powder in a polyethylene bag and shake it by hand.

The mixing time can be set to a time suitable for each mixing method. Generally, in the case of a container rotary type mixer, mixing for about 1 to 60 minutes is preferable. If the time is shorter than this, the effect of the present invention may not be exhibited depending on the type of drug and flow modifier. It may be used for a longer time than this, but since the effect does not increase further, it is often a waste of labor. About 3 to 20 minutes is more preferable. 0.1-10 for agitated mixers
Mixing for about a minute is preferable, and about 0.5 to 3 minutes is more preferable. When shaking by hand, mixing for about 0.2 to 20 minutes is preferable, and about 0.5 to 5 minutes is more preferable.

In the present invention, the mixed powder of the drug thus obtained and the flow modifier is mixed with other additives. Examples of other additives include excipients, disintegrants, binders, colorants, sweeteners, flavoring agents, wetting agents and the like. Further, it is also free to add a fluidizing agent and a lubricant again. In the case of adding a lubricant here, it is preferable in terms of tablet molding that after the powder mixture of the drug and the flow modifier and other additives are mixed, the lubricant is further added and mixed for a short time. . In the case of a drug having no problem in content uniformity during mixing, the drug can be mixed with other additives here.

As the excipient, celluloses such as crystalline cellulose and powdered cellulose, lactose such as crystalline lactose and granulated lactose, complex compounds of cellulose and lactose, D-mannitol, sucrose, erythritol, trehalose, etc. Sugars and sugar alcohols, corn starch, potato starch, starches such as partially pregelatinized starch, inorganic substances such as calcium hydrogen phosphate, anhydrous calcium hydrogen phosphate, aluminum silicate, and magnesium aluminometasilicate. is there.

Of these, when celluloses are used, the compounding ratio of crystalline cellulose in the excipient is not particularly limited as long as it is a commonly used compounding ratio, but generally 1% by weight in the final preparation. % To 95% by weight is preferred. It is more preferably 5% by weight to 70% by weight, and further preferably 10% by weight to 50% by weight. As a disintegrant, carmellose calcium, low-substituted hydroxypropyl cellulose,
Cellulose derivatives such as croscarmellose sodium, corn starch, sodium carboxymethyl starch, hydroxypropyl starch, starch and starch derivatives such as partially pregelatinized starch,
There are synthetic polymers such as crospovidone. Examples of the binder include cellulose derivatives such as hydroxypropylcellulose, hydroxypropylmethylcellulose, carmellose sodium and methylcellulose, and synthetic polymers such as povidone.

Among the above additives, celluloses, lactose, and their composites are excellent in improving mixing speed and content uniformity. Particularly, crystalline cellulose is excellent among celluloses, and granulated lactose is excellent among lactose. It is presumed that both of them have a relatively rough particle surface, so that the dispersed drug is trapped on the surface and the reaggregation of the drug is suppressed. As the mixer used here, an apparatus which is normally used may be used, like the mixer used for mixing the drug and the flow modifier.

The mixing time can be set to a time suitable for each mixing method. Generally, in the case of a container rotary type mixer, mixing for about 3 to 60 minutes is preferable. If the time is shorter than this, the effect is difficult to obtain. It doesn't matter if you do it longer than this, but since the effect is less likely to increase further,
It is a waste of labor. About 5 to 30 minutes is more preferable.
In the case of a stirring mixer, mixing for about 0.5 to 10 minutes is preferable, and about 1 to 5 minutes is more preferable.

The drug-containing mixed powder having a small coefficient of variation of drug content obtained by the method of the present invention may be added with a fluidizing agent or a lubricant, if necessary, and then filled into capsules as they are, to give capsules. It may be used as an agent or a powder. A commonly used tablet manufacturing method can be applied to the drug-containing mixed powder obtained by the method of the present invention. Particularly, when the drug content is low, the direct tableting method, which has been shunned as being inferior in the uniformity of the drug content in the final preparation, is particularly preferably used in the present invention because of its simple operation. Is.

In the above-mentioned tablet production, it is possible to use other techniques which have been often used conventionally. For example, by appropriately using a disintegrant, it is also free to produce an orally disintegrating tablet with a small variation in drug content. In addition, a sustained-release tablet can be prepared by adding a gel-forming substance such as hydroxypropylmethylcellulose as another additive, and further, the tablet may be masked with a bitter taste, or the sustained-release coating or intestine may be added. It is also free to apply a soluble coating.

[0020]

EXAMPLES The present invention will be described in detail below with reference to examples, but the technical scope and embodiments of the present invention are not limited thereto. In addition, the method regarding physical property evaluation in Examples and Comparative Examples is as follows. [Average particle size of drug] Digital microscope (Co., Ltd.)
Images taken with KEYENCE, VH-7000) or an electron microscope (Hitachi, Ltd.) were obtained using image processing analysis software. [Damping method of drug mixed powder] In the step of mixing the powder mixed with the drug and the flow modifier with other additives, a powder sampler (manufactured by Tsutsui Rikagaku Co., Ltd., sample volume 0.8 ml) In the case of a V-type blender as a mixer, the mixer is stopped after 5 minutes, 15 minutes, and 30 minutes of mixing, and 3 points are sampled from 3 predetermined points at each time point, and a total of 9 points are sampled. To do. When the mixer is a high-speed stirring mixer, the measurement is performed only after 5 minutes of mixing.

[Tabletting method] A rotary tabletting machine (Clean Press Collect 12HUK, manufactured by Kikusui Seisakusho Co., Ltd.) was used and a turntable rotation speed of 50r was obtained by a predetermined method.
It was formed into a tablet having a diameter of 8 mm and a diameter of 200 mg. [Determination method of drug] 200m from sampled powder
g is precisely weighed, put in a 100 ml measuring flask, and made up to 100 ml with pure water. After filtering the insoluble matter in the aqueous solution with a resin filter, the drug concentration in the filtrate was quantified from the absorbance using a spectrophotometer (manufactured by JASCO Corporation). In the case of tablets, about 200 mg of each tablet was precisely weighed, and then the same operation was performed to quantify.

[Evaluation Method of Content Uniformity] In the case of evaluating a drug mixed powder, the drug concentration of each of the nine samples collected by the mixed powder sampling method is measured, and in the case of evaluating a tablet, the above method is used. The weight and drug concentration of each of 10 arbitrarily prepared preparations obtained by the tableting method were measured, and defined as (standard deviation / average value) * 100 from the standard deviation and average value of those measured values. Content uniformity was evaluated from the coefficient of variation (%). The lower the coefficient of variation, the higher the content uniformity.

[0023]

[Example 1] Acetaminophen (a powder type manufactured by Yoshitomi Fine Chemical Co., Ltd.) was crushed and used by a small crusher.
Average particle size 16 μm. ) 30 g, talc (Wako Pure Chemical Industries, Ltd.)
15 g in a polyethylene bag and shaken by hand for 3 minutes to mix, and then 30 g of the mixed powder, crystalline cellulose "Avicel" PH-101 (manufactured by Asahi Kasei Co., Ltd.) 4
00g, 100 mesh lactose (manufactured by DMV) 1570g
Were weighed (mixing ratio; crystalline cellulose / lactose / acetaminophen / talc = 20 / 78.5 / 1/0.
5) The mixture was put into a V-type mixer (manufactured by Dalton) having a capacity of 5 liters (filling rate was set to about 65%) and mixed for 30 minutes. The coefficient of variation of drug concentration is shown in Table 1.

[0024]

Example 2 Acetaminophen 3 used in Example 1
0 g of light anhydrous silicic acid "Aerosil 200" (manufactured by Nippon Aerosil Co., Ltd.) was placed in a polyethylene bag and shaken by hand for 3 minutes to mix, and then 22 g of the mixed powder,
400 g of "Avicel" PH-101 and 1578 g of 100 mesh lactose were weighed (mixing ratio; crystalline cellulose / lactose / acetaminophen / light anhydrous silicic acid = 20 /
78.9 / 1 / 0.1) and mixed with a V-type mixer in the same manner as in Example 1. The coefficient of variation of drug concentration is shown in Table 1.

[0025]

Example 3 Acetaminophen 3 used in Example 1
0 g and 15 g of talc were placed in a polyethylene bag and shaken by hand for 3 minutes to mix, and then 25.3 g of the mixed powder,
675.6 g of "Avicel" PH-101 and 988.1 g of 100 mesh lactose were weighed (mixing ratio; crystalline cellulose / lactose / acetaminophen / talc = 40/5).
8.5 / 1 / 0.5) and mixed with a V-type mixer in the same manner as in Example 1. The coefficient of variation of drug concentration is shown in Table 1.

[0026]

Example 4 Acetaminophen 3 used in Example 1
0 g and talc 15 g were put in a polyethylene bag and shaken by hand for 3 minutes to mix, then 27.1 g of the mixed powder,
361.9 g of crystalline cellulose "Ceorus" KG-802 (manufactured by Asahi Kasei Corporation), 100 mesh lactose 142
9.4 g was weighed (mixing ratio; crystalline cellulose / lactose / acetaminophen / talc = 20 / 78.5 / 1 /
0.5) and mixed with a V-type mixer in the same manner as in Example 1. The coefficient of variation of drug concentration is shown in Table 1.

[0027]

Example 5 Acetaminophen 3 used in Example 1
0 g and 2.1 g of magnesium stearate were put in a polyethylene bag and shaken by hand for 3 minutes to mix, and then 14.8 g of the mixed powder, 55 of "Ceorus" KG-802.
2.5 g and 813.9 g of 100 mesh lactose were weighed (mixing ratio; crystalline cellulose / lactose / acetaminophen / magnesium stearate = 40 / 58.93 / 1)
/0.07) and mixed with a V-type mixer in the same manner as in Example 1. The coefficient of variation of drug concentration is shown in Table 1.

[0028]

Example 6 Acetaminophen 3 used in Example 1
0 g and talc 15 g were put in a polyethylene bag and shaken by hand for 3 minutes to mix, and then 31.2 g of the mixed powder,
2050 g of granulated lactose “Super-Tab” (Lactose New Zealand) was weighed (mixing ratio; lactose / acetaminophen / talc = 98.5 / 1/0.
5) and mixing with a V-type mixer as in Example 1. The coefficient of variation of drug concentration is shown in Table 1.

[0029]

Example 7 1.9 g of acetaminophen used in Example 1, 1.9 g of talc, "Avicel" PH-101
/ 19g was put in a polyethylene bag and shaken by hand for 3 minutes to mix, and then the total amount of the mixed powder and "Avicel" PH-101 / 361g, "Super-Tab"
Weigh 1516.2 g (mixing ratio; crystalline cellulose / lactose / acetaminophen / talc = 20 / 79.8)
/0.1/0.1) and mixed with a V-type mixer in the same manner as in Example 1. The coefficient of variation of drug concentration is shown in Table 1.

[0030]

[Embodiment 8] 800 g of ethenzamid (P type manufactured by Yoshitomi Fine Chemical Co., Ltd. is crushed and used by a small crusher. The average particle size is 24 μm) and 160 g of talc are a high speed stirring mixer (manufactured by Paulec Co., VG10 type). ),
Impeller rotation speed 400 rpm, cross screw 150
Stir at 0 rpm and mix for 2 minutes. Then, 102 g of the mixed powder, and "Avicel" PH-302 / 102
0 g and 578 g of Mannitol (manufactured by Towa Kasei Co., Ltd.) were weighed (mixing ratio; crystalline cellulose / mannite / ethenzamid / talc = 60/34/5/1), Example 1
And mixed with a V-type mixer in the same manner. The coefficient of variation of drug concentration is shown in Table 1.

[0031]

Example 9 50 g of phenylpropanolamine hydrochloride (manufactured by Alps Chemical Co., Ltd. was used after crushing with a small crusher. Average particle size is 28 μm) and 25 g of talc were placed in a polyethylene bag and shaken manually for 3 minutes. It was mixed. Then, 57 g of mixed powder, and "Avicel" PH-101 /
380 g, 100 mesh lactose 703 g, partially pregelatinized starch "PCS" (manufactured by Asahi Kasei Co., Ltd.) 380 g, and mannitol 380 g were weighed (mixing ratio; crystalline cellulose / lactose / partially pregelatinized starch / mannite / phenylpropanol hydrochloride) Amine / talc = 20/37/20/20/2
/ 1), and mixed with a V-type mixer in the same manner as in Example 1. The coefficient of variation of drug concentration is shown in Table 1.

[0032]

[Example 10] 30 g of acetaminophen used in Example 1 and 15 g of talc were placed in a polyethylene bag and shaken by hand for 3 minutes to mix, and then 30 g of the mixed powder, and "Avicel" PH-101 / 400 g, 1570 g of 100 mesh lactose were weighed (mixing ratio; crystalline cellulose / lactose / acetaminophen / talc = 20/78.
5/1 / 0.5), charged into a high speed stirring mixer, impeller rotation speed 400 rpm, cross screw 1500 rpm
Stir and mix for 5 minutes. Table 2 shows the coefficient of variation of drug concentration
Shown in.

[0033]

[Embodiment 11] After mixing was carried out in the same manner as in Example 1 except that the mixing time of the V-type mixer was 15 minutes, 10 g of magnesium stearate (manufactured by Taihei Chemical Co., Ltd.) was further added to the V-type mixer. And mixed for 5 minutes. Table 3 shows the coefficient of variation of the drug concentration after mixing. A mixed powder having a small variation in the drug content was obtained. Subsequently, the obtained all-drug mixed powder was tabletted by the above-mentioned method, and the tablet weight and the coefficient of variation of the drug content in the tablet were determined. The results are shown in Table 3.
Tablets with small variations in tablet weight and drug content were obtained.

[0034]

[Example 12] After mixing was performed in the same manner as in Example 3 except that the mixing time of the V-type mixer was 15 minutes, 8.5 g of magnesium stearate was further added to the V-type mixer, and
Mix for minutes. Table 3 shows the coefficient of variation of the drug concentration after mixing. A mixed powder having a small variation in the drug content was obtained. Then, the same operation as in Example 11 was carried out to determine the tablet weight and the coefficient of variation of the drug content in the tablet. The results are shown in Table 3. Tablets with small variations in tablet weight and drug content were obtained.

[0035]

Comparative Example 1 Acetaminophen 20 g and talc 10 g were directly charged into a V-type mixer without pre-mixing acetaminophen and talc, and "Avicel" PH-10
Mixing with 1,100 mesh lactose was performed in the same manner as in Example 1 (mixing ratio is the same as in Example 1). The coefficient of variation of drug concentration is shown in Table 1.

[0036]

[Comparative Example 2] Acetaminophen and "Aerosil 20"
0 "without pre-mixing with acetaminophen,
2 g of "Aerosil 200" was charged as it was into a V-type mixer, and mixing with "Avicel" PH-101, 100 mesh lactose was carried out in the same manner as in Example 2 (the mixing ratio is the same as in Example 2). The coefficient of variation of drug concentration is shown in Table 1.

[0037]

Comparative Example 3 Acetaminophen 16.9 g, “Avicel” PH-101 / 675.6 without adding talc.
g, 100 mesh lactose 996.5 g were mixed in the same manner as in Example 3 (mixing ratio; crystalline cellulose / lactose / acetaminophen = 40/59/1). The coefficient of variation of drug concentration is shown in Table 1.

[0038]

Comparative Example 4 Acetaminophen 13. Acetaminophen was not premixed with magnesium stearate.
8 g and 1 g of magnesium stearate were charged into a V-type mixer as they were, and mixed with "Ceorus" KG-802, 100 mesh lactose in the same manner as in Example 5 (mixing ratio is the same as in Example 5). The coefficient of variation of drug concentration is shown in Table 1.

[0039]

Comparative Example 5 1.9 g of acetaminophen and "Avicel" PH-101 / 19 g were put in a polyethylene bag without adding talc, and the mixture was shaken by hand for 3 minutes to mix,
The total amount of the mixed powder, and "Avicel" PH-101 /
361 g and “Super-Tab” 1518.1 g were weighed (mixing ratio; crystalline cellulose / lactose / acetaminophen = 20 / 79.9 / 0.1), and mixed with a V-type mixer in the same manner as in Example 7. did. The coefficient of variation of drug concentration is shown in Table 1.

[0040]

Comparative Example 6 Without pre-mixing acetaminophen and talc, 20 g of acetaminophen and 10 g of talc were directly charged into a high-speed stirring mixer, and "Avicel" PH-1
Mixing with 01,100 mesh lactose was carried out in the same manner as in Example 10 (mixing ratio is the same as in Example 10). The coefficient of variation of drug concentration is shown in Table 2.

[0041]

Comparative Example 7 After mixing was carried out in the same manner as in Comparative Example 1 except that the mixing time of the V-type mixer was 15 minutes, 10 g of magnesium stearate was further added to the V-type mixer and mixed for 5 minutes. . Table 3 shows the coefficient of variation of the drug concentration after mixing.
Then, Table 3 shows the coefficient of variation of the tablet weight and the drug content in the tablet, which were obtained in the same manner as in Example 11.

[0042]

[Comparative Example 8] Tablet weight and tablet content obtained in the same manner as in Example 12 after mixing was performed in the same manner as in Comparative Example 3 except that the mixing time of the V-type mixer was 15 minutes. The coefficient of variation of the drug content of is shown in Table 3. Table 4 shows a list of mixed powder compositions and mixing conditions of the above Examples and Comparative Examples. In the table, "amount" represents% by weight.

[0043]

[Table 1]

[0044]

[Table 2]

[0045]

[Table 3]

[0046]

[Table 4]

[0047]

[Effects of the Invention] When the method of mixing the drug and the flow modifier of the present invention and then mixing the mixed powder with other additives is used, the drug content is 20% by weight or less based on the final preparation. Even with a low content, the coefficient of variation of the drug content can be reduced to 5% or less, preferably 2.5% or less in a very short time. That is, the mixing time for suppressing the coefficient of variation of the drug content to be low can be shortened to about ⅕ as compared with the conventional method in which the drug, the flow modifier and the other additive are added all at once. Further, when the drug is mixed using the method of the present invention, a mixed powder having a small variation in the drug content can be obtained in a short time, and therefore, even when the drug content is low, tablets can be directly produced by the tableting method. Is easy.

Claims (3)

[Claims] 1. A method of mixing a drug, which comprises mixing the drug and a flow modifier, and then mixing the powder mixture and other additives. 2. The flow modifier is talc, light anhydrous silicic acid,
2. The mixing method according to claim 1, which is one or more selected from the group consisting of hydrous silicon dioxide and stearate. 3. The other additives are celluloses, and / or
Alternatively, the method for mixing a drug according to claim 1 or 2, further comprising lactose.