JP5650956B2 - Method for producing mixed granules - Google Patents

Description

  The present invention relates to a mixed granule and a method for producing the same. More specifically, the present invention relates to a mixed granule containing drugs or nutritional components that are contraindicated with each other and a method for producing the same.

When blended into the same formulation, the drug or nutritional component accelerates the decomposition of the drug or nutritional component, resulting in a blending change such as a decrease in the melting point of the drug, a strange odor, or a color change in the formulation. There are so-called contraindicated drugs.
As a method for producing a granule containing a contraindicated drug or a nutritional component, there is a method in which two or more types of granules containing a contraindicated drug are separately produced and then mixed in order to prevent a change in the formulation. Furthermore, an additive may be coated on the surface of the granule to prevent a change in formulation due to contact between the granules and to suppress the bitterness of the drug itself (hereinafter, the additive is coated in this specification). The previous granule is referred to as “original granule”, and a granule prepared by mixing two or more contraindicated drugs or nutritional components may be referred to as “mixed granule”). In the case of producing a mixed granule coated with an additive, conventionally, in order to prevent a change in formulation, each of the coated granules is mixed after the additive is coated on each original granule.

Patent Document 1 discloses a method for producing a mixed granule of isopropylantipyrine (IPA) and acetaminophen which is a contraindicated drug for IPA. In patent document 1, the original granule which mix | blended the masking agent with IPA and the original granule which mix | blended acetaminophen are mixed, and it is set as the mixed granule.
Further, Patent Document 2 discloses a method in which a raw granule is once individually prepared and then coated in a mixed fluidized tank.
That is, as shown in these patent documents, conventionally, it has been considered that the denaturation of a contraindicated drug can be suppressed by coating the surface of an original granule with an additive. However, it has already been found that this alone cannot achieve the purpose of suppressing change in formulation. The biggest cause is the moisture derived from the raw materials used in preparing the raw granule or the moisture derived from the granulation process. For this reason, at present, it is a common method that the raw granules are kneaded and granulated and then dried in an apparatus to reduce the water content to about 5% before coating. Then, the mutual contact between the drugs or nutritional components is suppressed by blocking the contact between the drugs by the coating.

JP 2001-19639 A JP 2005-60276

  However, as in the above prior art, even if the mixed granule is prepared by reducing the moisture of each original granule of incompatible drugs and nutritional ingredients to about 5% and coating it, the granules react with each other. Often browning or solidification occurred. For example, in the present specification, in the combination of γ-aminobutyric acid (GABA) and vitamin C exemplified below, or the combination of capsules encapsulated seamlessly with ginseng and gelatin film, the raw granule is mixed. Immediately thereafter, solidification and browning of the granules occur, which makes it difficult to use in a short time.

From the situation as described above, the present inventors conducted research on the cause of the mixing change in the mixed granule preparation of contraindicated drugs and nutritional components. Discovered that it plays an important role in the interaction.
In the case of coating an original granule containing a contraindicated drug or nutritional component with an additive, the present inventors set the moisture content of each original granule to 2% or less and then coat it with the additive to change the formulation. It was found that the manufacturing process could be made more efficient and the present invention was completed.

That is, this invention provides the following mixed granule and its manufacturing method.
(A) In a method for producing a mixed granule in which a granule containing a drug or a nutritional component that is contraindicated with each other is mixed,
(1) For each drug or nutrient component, separately produce two or more kinds of original granules by the same or similar granulation method,
(2) Each of the above original granules is dried so that the water content is 2% or less,
(3) Each dried original granule is coated with additives,
(4) Mix each coated original granule,
(5) A method for producing a mixed granule, wherein the mixed original granule is hermetically packaged with a packaging material having no moisture permeability.
(B) One of the granulation methods in the said process (1) is the kneading granulation method by a triaxial kneading apparatus, The manufacturing method of the mixed granule as described in said (A) characterized by the above-mentioned.
(C) The method according to (A) or (B), wherein the additive in the step (3) is a polyglycerin fatty acid ester.
(D) The method according to any one of (A) to (C), wherein the drying in the step (2) is performed by a vacuum drying method, a blow drying method, or a combination thereof. .
(E) After the step (3), any one of the above (A) to (D), further comprising a step of further drying so that the water content of each original granule becomes 2% or less. The manufacturing method as described in.
(F) a mixture of a plurality of types of granules containing a contraindicated drug or nutritional component, wherein one or more or all of the plurality of types of granules have a moisture content of 2% or less, A mixed granule, wherein the surface of the granule is coated with a polyglycerol fatty acid ester.
(G) A combination of a contraindicated drug or nutritional component is a γ-aminobutyric acid and vitamin C, a seamless encapsulating agent having ginseng and a gelatin coating, a seamless encapsulating agent having vitamin C and a gelatin coating, or a metal salt The mixed granule according to (F) above, which is a seamless encapsulating agent encapsulating eicosapentaenoic acid.

  According to the present invention, it is possible to produce a mixed granule that does not cause a blending change such as a browning change even though it contains two or more types of granule containing a contraindicated drug or nutritional component in an arbitrary ratio. . Furthermore, in the present invention, if the granulation method using a triaxial kneader is used instead of the granulation method generally employed in the conventional medicine, not only the production process can be simplified but also the components can be homogenized. Granules contained in can be prepared.

Hereinafter, the present invention will be described in detail.
The method for producing a mixed granule according to the present invention is a method for producing a mixed granule in which a granule containing drugs or nutritional components that are contraindicated with each other is mixed.
(1) For each drug or nutrient component, separately produce two or more kinds of original granules by the same or similar granulation method,
(2) Each of the above original granules is dried so that the water content is 2% or less,
(3) Each dried original granule is coated with additives,
(4) Mix each coated original granule,
(5) The mixed raw granule is hermetically packaged with a packaging material having no moisture permeability.

  The drug or nutritional component used in the mixed granule of the present invention contains two or more drugs or nutritional components that are contraindicated. Combinations of contraindicated drugs or nutritional components are not limited. For example, γ-aminobutyric acid and vitamin C, ginseng and eicosapentaenoic acid-containing seamless capsule, eicosapentaenoic acid-containing seamless capsule and vitamin C, ginseng And a seamless capsule agent having a gelatin film with vitamin C, a seamless capsule agent having a vitamin C and gelatin film, or a seamless capsule agent containing a metal salt and eicosapentaenoic acid. The mixed granule of the present invention can also contain drugs and nutritional ingredients other than incompatible drugs or nutritional ingredients, and the types thereof are not limited.

In addition to drugs or nutritional components, the original granule can contain pharmaceutically acceptable additives such as excipients, binders, and disintegrants.
As the excipient, those known in the art can be widely used. For example, lactose, sucrose, glucose, D-mannitol, powdered reduced maltose starch syrup, maltitol, xylitol, erythritol, D-sorbitol, Maltose, starch and starch derivatives, aspartame, glycyrrhizic acid and salts thereof, saccharin and salts thereof, stevia and salts thereof, sucralose, acesulfame potassium, calcium hydrogen phosphate and the like, among which lactose, sucrose, D-mannitol, Starch is preferred. These excipients can be used alone or in combination of two or more.

  A wide variety of binders known in the art can be used, such as hydroxypropylcellulose, hydroxypropylmethylcellulose, polyvinylpyrrolidone, methylcellulose, dextrin, starch and starch derivatives, guar gum, gum arabic, tragacanth, Examples include alginic acid and salts thereof, pullulan, carrageenan, gelatin, agar, carboxyvinyl polymer, carmellose sodium and the like. Among them, hydroxypropylcellulose, hydroxypropylmethylcellulose, polyvinylpyrrolidone and methylcellulose are preferable. These binders can be used alone or in combination of two or more.

  As the disintegrating agent, those widely known in the art can be used, and examples thereof include sodium carboxymethyl starch, carmellose sodium, and low-substituted hydroxypropylcellulose. These disintegrants can be used alone or in combination of two or more.

In the present invention, raw granules containing mutually contraindicated drugs or nutritional components and preferably the above-mentioned additives and the like are produced separately. In the production of the original granule, each drug or nutritional component can be produced by the same or similar granulation method.
The production method of the original granule is not particularly limited, and a wide variety of methods known in the art can be used. Specifically, extrusion granulation method, rolling granulation method, stirring granulation method, Examples thereof include a fluidized bed granulation method, a rolling fluidization granulation method, and a kneading granulation method. Among these, the kneading granulation method is preferable.

  As a granulator for kneading and granulating, it is preferable to use a granulator using an apparatus equipped with a kneading blade and a crushing blade. Examples of such a granulator include a triaxial kneading granulator provided by Shinagawa Kogyo Co., Ltd. This apparatus is disclosed in JP-T-2008-529755, and the production method of the present invention can be carried out based on the method described in this publication. In the present invention, when it is produced using a granulation method using a triaxial kneader, each granule can be granulated at an arbitrary ratio, and not only the production process can be simplified, but each component of the granule is contained homogeneously. Granules can be prepared and are preferred.

  In the present invention, when two or more kinds of original granules are separately produced for each drug or nutritional component by the same or similar granulation method, incompatible drugs or nutritional components are granulated separately. In this case, each granule may contain other drugs or nutritional components that are not contraindicated.

The bulk density of the granulated raw granule is not particularly limited, but is preferably 0.35 to 0.75 g / mL, more preferably 0.40 to 0.65 g / mL, and 0.5 to 0.63 g / mL. mL is particularly preferred. When the bulk density is less than 0.35 g / mL, the bulk becomes high, and the amount of packaging may increase. On the other hand, when the bulk density exceeds 0.75 g / mL, the bulk is reduced, and a heavy granule is obtained, and the amount of packaging is also reduced. However, it is relatively difficult to prepare granules of 0.75 g / mL or more in consideration of raw material powder properties other than mineral raw materials having a large specific gravity as raw materials. Under such circumstances, when a granule with a large bulk density is added, the bulk density difference between various granules becomes large, causing segregation, which may make it difficult to ensure mixing uniformity of the one-piece granule. .
The 50% particle size of the original granule is not particularly limited, but is preferably 400 to 700 μm, more preferably 450 to 650 μm, and particularly preferably 500 to 600 μm. If the 50% particle diameter is larger than 700 μm, it becomes difficult to drink, and if it is smaller than 400 μm, the granules may aggregate in the coating.

When the additive is coated on the original granule, the bulk density difference and 50% particle size difference of the original granule to be blended are important factors. The difference in bulk density of the original granules is preferably 0 to 30 (w / w)%, more preferably 0 to 15 (w / w)%, and 0 to 10 (w / w). % Is particularly preferable. If the bulk density difference is greater than 30 (w / w)%), it is difficult to ensure mixing uniformity.
Further, the difference in 50% particle size is preferably 0 to 30%, more preferably 0 to 20%, and particularly preferably 0 to 15%. If the 50% particle size difference exceeds 30%, it becomes difficult to ensure mixing uniformity.
Therefore, before coating the additive on the original granule, granulation, sizing, classification, etc. of the original granule so that the bulk density difference and 50% particle size difference of the original granule are within the above ranges. It is preferable to perform grain processing.

Next, the obtained raw granules are dried.
The drying process needs to be dried until the moisture content of the original granule becomes 2% or less.
The drying method is not particularly limited, and any method can be adopted as long as it is a drying method used for ordinary granule drying, but the vacuum drying method and the air drying method are preferable. The vacuum drying method and the blast drying method may be carried out independently or in combination. However, it is particularly preferable to use a vacuum drying method because the moisture of the granules can be removed as much as possible.
In addition, when the water content exceeds 2%, there are inconveniences such as various decomposition changes such as acceleration of decomposition of contraindicated drugs or granules of nutritional components, lowering of melting point of drugs, color change of preparation, generation of off-flavor, and the like.

Next, the surface of each dried original granule is coated with an additive. The additive for coating is not limited, but polyglycerin fatty acid ester is preferably used. In addition, the coating not only suppresses the mixing change of the contraindicated drug or nutritional ingredient granule, but also has the effect of suppressing the bitter taste of the drug contained in the granule.
The amount of the additive for coating is preferably 1 to 1000 parts by weight, more preferably 10 to 100 parts by weight, and more preferably 10 wt. Considering it, it is particularly preferable to set it to about 20 parts by mass.

As a method for coating the original granules with additives, it is preferable to use the above-described triaxial kneading granulator manufactured by Shinagawa Kogyo. In this case, the apparatus in which the raw granules are prepared can subsequently be used in the coating.
That is, the apparatus for preparing the raw granules can be coated with an additive for coating, preferably a required amount of polyglycerin fatty acid ester. In coating, the temperature in the container is preferably set to a temperature in the vicinity of the melting point of the coating agent. When polyglycerin fatty acid ester is used, the temperature in the vicinity of the melting point is preferably about 55 ° C.

  The bulk density of the mixed granule coated with the additive is preferably from 0.55 to 0.75 g / mL, and the 50% particle size is preferably from 450 to 650 μm. Further, the standard deviation of the content of the drug or nutritional component in the mixed granule is preferably within 5%, more preferably within 4%, and particularly preferably within 3%.

  The target granule may be prepared by mixing the original granules thus obtained, but the moisture content of the original granules after being coated as described above will be 2% or more. In this case, the raw granule mixed with incompatible drugs and nutritional components reacts quickly, and browning and coagulation proceed. For this reason, it is preferable to perform a drying process again about an original granule after coating. The drying of the granule is not particularly limited, but is preferably vacuum drying. When a vacuum drying apparatus is used, it is preferable that the moisture content is 2% or less by performing a drying treatment for 2 to 8 hours.

Next, the original granule is mixed and hermetically packaged with a packaging material having no water permeability, whereby the mixed granule of the present invention can be produced.
The mixing is not particularly limited as long as it is a commonly used mixing apparatus, and any of them can be used. However, when a V-type rotary mixing apparatus is used, a uniform granular preparation can be efficiently prepared. It is possible and preferable.

  Even when the mixed granule of the present invention is stored over time, the composition does not change, the appearance hardly changes, and no off-flavor is generated. Specifically, even when stored for a period of 2 months or longer, preferably 4 months or longer, more preferably 6 months or longer, at 40 ° C. and a relative humidity of 75% or higher, there is no change in composition and no change in appearance. .

  Hereinafter, the present invention will be described more specifically with reference to Examples and Comparative Examples, but these are merely examples and do not limit the present invention.

A. Manufacture of raw granules 1) Raw carrot extract raw granules Add 0.07kg of ethanol to 0.8kg of ginseng extract and use a triaxial kneading granulator (Triple Master TMGV-5: Shinagawa Kogyo Co., Ltd.). Mixed granulated.
Next, 0.012 Kg of purified water was added to 0.1499 kg of crystalline cellulose (Theolas UF-F702: manufactured by Asahi Kasei Chemicals Co., Ltd.) prepared in advance, and the same triaxial kneading granulator (Triple Master TMGV-5: Shinagawa Industry) 0.081 Kg was added, and further granulated, followed by primary drying at 50 ° C. Next, after the particles were crushed, the particles were taken out from the apparatus and dried at 50 ° C. for 12 hours using a blower drying apparatus to reduce the moisture of the granules to 2% or less. The dried granules were sized with a JIS 16 mesh sieve to obtain a uniform particle size, and 1 kg of the original granule was obtained.

2) γ-aminobutyric acid (GABA) raw granules GABA extract (manufactured by Oriza Oil Chemical Co., Ltd.) 0.8 kg and crystalline cellulose (Ceolus FD-F20: manufactured by Asahi Kasei Chemicals Co., Ltd.) 0.2 kg are added with 0.1 kg of ethanol, and Primary granulation was performed using Triple Master TMGV-5. Next, 100 g of 50% ethanol was added to perform secondary granulation, and 0.05 kg of water was further added to perform tertiary granulation, followed by primary drying. Thereafter, the raw granule was taken out from the apparatus, and dried at 50 ° C. for 12 hours using a blowing low-temperature dryer, so that the moisture content of the granules was 2% or less. After the completion of drying, the mixture was sieved with a 16 mesh sieve in the same manner as described above, and the size was adjusted to obtain 1 kg of the original granule.

3) Vitamin C granules Vitamin C (manufactured by BASF) 0.73939 kg and water-soluble cellulose powder (Metroses SE-60: Shin-Etsu Chemical Co., Ltd.) 0.0316 Kg were mixed using the triple master TMGV-5. As a granulation liquid, kneading granulation was performed using a liquid obtained by dissolving 0.0045 kg of the above water-soluble cellulose in 0.0405 kg of purified water. After granulation, the original granule was dried at 50 ° C. for 12 hours using an air dryer to obtain 0.8 kg of the original granule having a moisture content of 2% or less.

4) Seamless Encapsulating Agent Encapsulating Eicosapentaenoic Acid (EPA) According to the description of WO2009 / 004999, 10 kg of gelatin seamless encapsulating agent encapsulating eicosapentaenoic acid having the composition of Example 1 of the publication was obtained.

B. Coating of original granules 1) Coating method 2 parts by mass of polyglycerin fatty acid ester (Poem TR-FB: manufactured by Riken Vitamin Co., Ltd.) is added to 8 parts by mass of the original granules prepared in 1) to 3) above. Coating was performed using Triple Master TMGV-5, which was used when the granules were prepared. In the coating, the temperature in the container was set to a temperature setting (55 ° C.) near the softening point of the polyglycerol fatty acid ester. After cooling, the mixture was sieved using a 16 mesh sieve and sized.
2) Properties of the original granule The thus obtained original granule has a moisture content of 2% or less and is coated, and its reactivity with other particles is suppressed.

C. Mixing and packaging GABA granules and vitamin C granules (Example 1), ginseng granules and eicosapentaenoic acid (EPA) -containing seamless capsules (Example 2), EPA-containing seamless capsules and vitamin C granules In the combination of (Example 3), each was used in an equal amount, mixed by a V-type mixer, and each 1 g was packaged with a GX film (Toppan Co.), which is a high barrier film, to obtain a mixed granule.

D. Preparation of comparative product (Comparative Example 1)
The original granules obtained in the above “A.1) to 3)” were used and mixed in the same manner as in the above C without coating to obtain mixed granules.
(Comparative Example 2)
In addition, using the raw granule before drying in “A” with a moisture content of 2% or less, coating is performed in the same manner as in “B.1)” with the high moisture content (5% or more) as in C above. A mixed preparation was obtained by mixing.

E. Storage test and evaluation The products of Examples 1 to 3, Comparative Example 1 and Comparative Example 2 prepared in C and D above were placed in an environment of 40 ° C. and 75% humidity for 2 weeks to change the composition, change the appearance, and change the odor. Occurrence etc. were observed. The observation results are shown in Table 1 below.

As is clear from the results shown in Table 1, in Examples, no change in formulation, change in appearance, generation of off-flavor, etc. occurred even after 2 weeks. In Comparative Example 2 in which the drying for reducing the water content to 2% was not performed, the composition change and the appearance change occurred from an early stage, and even a strange odor was generated.
From these facts, it was found that, after granulation, it is essential to prevent the change in the blending after the moisture content is reduced to 2% or less.

  According to the present invention, it is possible to produce a mixed granule that does not cause coagulation or browning despite the combination of two or more incompatible drugs or nutritional components. As a result, the number of drugs and supplements that need to be administered and ingested can be reduced, which can contribute to reducing the burden on patients and supplement users.

Claims (1)

A mixture of a plurality of types of granules containing a contraindicated drug or nutritional component, wherein one or more or all of the plurality of types of granules have a moisture content of 2% or less, and the surface of the granules There are coated with polyglycerin fatty acid ester, a combination of drugs or nutrients is the incompatible is mixed-granule you being a γ-aminobutyric acid and vitamin C.