JP6361925B2 - Solid preparation - Google Patents

Description

  The present invention relates to the field of solid preparations, and in particular, to a solid preparation containing ibuprofen and etenzamide as active ingredients.

  Ibuprofen, which is widely used as an active ingredient in headache and general cold medicine, is a low-melting drug with a melting point of 75-77 ° C, but when it is mixed with etenzaamide, which is also known as an active ingredient in headache and general cold medicine, it causes a melting point drop It was known (see Non-Patent Document 1). The melting point drop of ibuprofen, which has a large content among the active ingredients, makes handling of the powder extremely difficult, causing adhesion and aggregation, and may cause problems such as discoloration after commercialization.

  Therefore, in a solid preparation containing ibuprofen and etenzamide as active ingredients, if they are mixed in different granules, etc., and provided as a double tablet or multilayer tablet, even if ibuprofen and etenzamide are combined in the same preparation, It was possible to avoid the direct contact and prevent the melting point drop of ibuprofen (see Non-Patent Document 2).

  However, when providing powders, granules, etc. containing ibuprofen and etenzamide, contact with these ingredients alone is not enough to avoid contact and sufficiently suppress the melting point drop of ibuprofen. I couldn't.

JP-A-7-277962 Japanese Patent No. 4835818

Aoki S. Et al., Drug Development and Industrial Pharmacy, 1997, 23, 6, 561-565. Japan Society for Powder Technology, Formulation and Particle Design Subcommittee, “Useful Particle Design / Processing Technology”, Jiho, September 30, 2003, pages 288-291

  Thus, as a conventional means, it is conceivable to mix ibuprofen and etenzamide into different granules and then coat at least one of them (see Patent Documents 1 and 2), but the most popular hypromellose (hydroxyl) as a film base. When the ibuprofen-containing granule was coated with a film layer mainly composed of propylmethylcellulose and mixed with the ethenamide-containing granule, the melting point drop of ibuprofen could not be sufficiently suppressed (see Comparative Example 1 described later).

  The object of the present invention is to combine the active ingredients ibuprofen and etenzamide into separate granules, etc., and to select and preserve the most effective film base to suppress the melting point drop when coating ibuprofen-containing granules etc. It is to provide a solid preparation containing ibuprofen and etezamide such as powders and granules excellent in stability and administration.

  As a result of intensive studies to solve the above-mentioned problems, the present inventors have found that polyvinyl alcohol (hereinafter, abbreviated as “PVA” as appropriate) or polyvinyl alcohol / acrylic acid / methyl methacrylate copolymer ( In the following, it has been found that the drop in melting point of ibuprofen due to the mixture with the ethenamide-containing granule can be effectively suppressed only when it is appropriately abbreviated as “PVA copolymer”.

The embodiments of the present invention obtained from such findings are as follows.
(1) Ibuprofen and etenzaamide are blended in different preparation particles, and the preparation particles containing ibuprofen are coated with a film layer containing polyvinyl alcohol or polyvinyl alcohol / acrylic acid / methyl methacrylate copolymer. A solid preparation containing ibuprofen and etezamide.
(2) Said (1) whose content of polyvinyl alcohol or polyvinyl alcohol-acrylic acid-methyl methacrylate copolymer in a film layer is 0.04-0.4 mass part with respect to 1 mass part of ibuprofen. A solid preparation containing ibuprofen and etezamide as described in 1. above.
(3) The ibuprofen and ethenzamide-containing solid preparation according to (1) or (2) above, wherein the solid preparation is a powder, granule, fine granule or capsule.

  According to the present invention, it has become possible to provide solid preparations such as powders and granules containing ibuprofen and etezamide as active ingredients. Further, by coating ibuprofen-containing granules and the like with PVA or PVA copolymer, sublimation and bitterness of ibuprofen are suppressed, and it has become possible to provide a solid preparation excellent in storage stability and ingestion.

  The ibuprofen and etenzamide-containing solid preparation of the present invention is a film layer in which ibuprofen and etezamide are blended in different preparation particles, and the preparation particles containing ibuprofen contain polyvinyl alcohol or polyvinyl alcohol / acrylic acid / methyl methacrylate copolymer. It is characterized by being covered with.

  When the active ingredients ibuprofen and etenzamide are mixed, the melting point is lowered. Therefore, in the present invention, these active ingredients are blended in separate preparation particles.

  “Formulation particles” means, for example, a dry granulation, spray-drying granulation, kneading granulation, extrusion granulation, stirring granulation after mixing powders containing additives described below in addition to active ingredients Solid particles having a geometric average particle diameter of 80 to 400 μm prepared by wet granulation such as fluidized bed granulation, stirred fluidized bed granulation, rolling fluidized bed granulation, and rolling granulation.

  Examples of the additive to be blended with the preparation particles containing ibuprofen and the preparation particles containing ethenamide (hereinafter also referred to as “ibuprofen-containing preparation particles” and “ethenzamid-containing preparation particles”) according to the present invention include, for example, Forms, binders, disintegrants and other medicinal ingredients can be mentioned.

  The excipient may be any component that gives a certain bulk in a solid preparation, such as light anhydrous silicic acid, crystalline cellulose, candy powder, talc, magnesium stearate, lactose, sucrose, D-mannitol, potato starch, Corn starch can be mentioned.

  The binder may be any component that provides a binding force between particles in a solid preparation, such as crystalline cellulose, sucrose, D-mannitol, dextrin, hydroxypropylcellulose, hydroxypropylmethylcellulose, polyvinylpyrrolidone, starch, sucrose, Examples include gelatin, methylcellulose, and sodium carboxymethylcellulose.

  The disintegrating agent may be any component that promotes the disintegration and dispersion of solid preparations. For example, low-substituted hydroxypropylcellulose, crospovidone, sodium carboxymethyl starch, croscarmellose sodium, carmellose calcium, potato starch, corn starch Is mentioned.

  There is no restriction | limiting in particular as another medicinal ingredient, For example, vitamins (riboflavin etc.), anhydrous caffeine which assists the analgesic effect by ibuprofen and ethenamide caffeine, etc. are mentioned.

  Moreover, the suitable content (blending) amount of ibuprofen in the ibuprofen-containing preparation particles according to the present invention is 30 to 60% by mass, and the suitable content (blending) amount of ethenamide in the ethenamide-containing preparation particles according to the present invention is It is 10 to 35% by mass in the ethenamide-containing preparation particles.

  Since the ibuprofen-containing preparation particles are always subjected to film coating, they are usually hard particles having a particle strength of 7 mass% or less in a friability test described below.

  The friability is such that 5 g of particles of 850 μm or less and two metal spheres having a diameter of 20 mm and a mass of 28 g are filled into a cylindrical metal container (for example, a ball mill grinder) having a diameter of 32 mm and a height of 88 mm, and an amplitude of 15 mm. The increase in the proportion (%) of fine powder of 75 μm or less generated when vibrating for 1 minute at a frequency of 1500 times / minute. Specifically, the sample is classified with a 850 μm sieve, the residue of the sieve is removed, the sample that has passed through the 850 μm sieve is mixed, and the ratio (%) of the fine powder of 75 μm is measured. Next, 5 g of the sample that passed through the 850 μm sieve was filled into a cylindrical stainless steel container (beta mill (trade name): manufactured by Mitsubishi Chemical Engineering Co., Ltd.) having a diameter of 32 mm and a height of 88 mm together with two stainless balls having a diameter of 20 mm and a mass of 28 g. To do. The container is vibrated for 1 minute at an amplitude of 15 mm and a frequency of 1500 times / minute, and then the ratio (%) of fine powder of 75 μm or less is measured. The “friability” is determined as an increase in the ratio (%) of fine powder of 75 μm or less before and after measurement.

  In the present invention, it is not always necessary to apply a film coating to the ethenamide-containing preparation particles. However, if a film coating is applied, it is preferable that the drug particles have a particle strength comparable to that of the ibuprofen-containing preparation particles.

  In the present invention, ibuprofen-containing preparation particles need to be coated with a film layer containing PVA or a PVA copolymer, but ethenamide-containing preparation particles do not necessarily have to be coated. This is because the drug particles containing ibuprofen having a low melting point are more effective in suppressing the melting point drop. In addition, since ibuprofen has a large content (formulation), it is easy to sublimate and has a bitter taste with a specific irritation, so that it has a large merit for coating ibuprofen-containing preparation particles from the viewpoint of sublimation prevention and bitterness masking. Because.

  “Polyvinyl alcohol (PVA)” is a polymer obtained by saponifying polyvinyl acetate, and is a white or slightly yellowish white powder. Here, the type of PVA used in the present invention is not particularly limited, but it is preferable to use a partially saponified material in consideration of adhesion and solubility, and a preferable degree of saponification is 85 to 90 mol%. It is a product.

  Examples of suitable commercial products of the PVA of the present invention include Gohsenol (registered trademark) EG-05P (manufactured by Nippon Synthetic Chemical Co., Ltd., degree of saponification: 86.5-89.0 mol%, viscosity: 4.8-5.8 mPa). S (measured by a Heppler viscometer for a 4% aqueous solution at 20 ° C.)).

  “Polyvinyl alcohol / acrylic acid / methyl methacrylate copolymer (PVA copolymer)” is a polymer obtained by copolymerizing partially saponified polyvinyl alcohol with acrylic acid and methyl methacrylate. It is.

  A suitable average degree of polymerization in the “PVA copolymer” according to the present invention is 450 to 550. The preferred weight average molecular weight of the “PVA copolymer” according to the present invention is about 40,000.

  Examples of suitable commercial products of the PVA copolymer according to the present invention include POVACOAT (registered trademark) Type: F (manufactured by Daido Kasei Kogyo, weight average molecular weight: about 40,000, average degree of polymerization: 450 to 550, polymerization ratio: 80% by mass of partially saponified polyvinyl alcohol, 17.5% by mass of acrylic acid, and 2.5% by mass of methyl methacrylate).

  The content (formulation) of the PVA or PVA copolymer is 0.04 mass relative to 1 mass part of ibuprofen from the viewpoint of sufficiently suppressing the melting point drop of ibuprofen in consideration of the specific surface area of the ibuprofen-containing preparation particles. Part or more is preferable, and unnecessary coating is not preferable from the viewpoint of economy and the like, so 0.4 mass part is the upper limit.

  The ibuprofen-containing preparation particles can be coated with a film layer containing PVA or a PVA copolymer by a technique generally used in the field of solid preparations. Examples of the technique include a method in which the preparation particles are charged in a fluidized bed granulation dryer (fluidized bed coating machine) and dried while spraying a film coating solution containing PVA or PVA copolymer.

  In the film coating solution, in addition to PVA or PVA copolymer, other coating agents, plasticizers, suspending agents, fluidizing agents, coloring agents and the like may be dissolved and suspended in purified water or the like.

  Examples of other coating agents include hydroxypropylmethylcellulose, hydroxypropylcellulose, ethylcellulose, hydroxypropylmethylcellulose phthalate, carboxymethylethylcellulose, carmellose sodium, carmellose potassium, cellulose acetate, cellulose acetate, cellulose acetate phthalate and the like, polyvinyl acetal Polymeric materials such as diethylaminoacetate, aminoalkyl methacrylate copolymer E, aminoalkyl methacrylate copolymer RS, methacrylic acid copolymer L, methacrylic acid copolymer LD, methacrylic acid copolymer S, natural such as carnauba wax, gelatin, succinylated gelatin, gum arabic, shellac And polysaccharides such as pulling polymers, pullulan and chitosan.

  Examples of the plasticizer include sucrose fatty acid ester, paraffin, dioctyl adipate, triethyl citrate, triacetin, glycerin, concentrated glycerin, and propylene glycol.

  Examples of the suspending agent include sucrose fatty acid ester, polysorbate (polysorbate-80, etc.), polyglycerin fatty acid ester, lecithin, polyoxyethylene hydrogenated castor oil, and polyoxyethylene / polyoxypropylene copolymer.

  Examples of the fluidizing agent include talc, magnesium aluminate metasilicate, hydrous silicon dioxide, light anhydrous silicic acid, titanium oxide, magnesium stearate, and calcium stearate.

  Examples of the colorant include titanium oxide, zinc oxide, talc, turmeric extract, caramel, carotene solution, β-carotene, copper chlorophyll, copper chlorophyllin sodium, riboflavin, carbon black, medicinal charcoal, edible yellow No. 4, edible yellow Tar-type pigments such as No. 5, Edible Red No. 2, Edible Red No. 102, Edible Blue No. 1, Edible Blue No. 2, Edible Yellow No. 4 Aluminum Lake, and the like.

  In addition to ibuprofen-containing preparation particles and etenzamide-containing preparation particles, the solid preparation of the present invention contains, as necessary, preparation particles containing ibuprofen or etezamide and a contraindicated active ingredient, a medicinal ingredient that assists the analgesic effect of ibuprofen or ethenamide. Preparation particles containing, for example, bromovaleryl urea, fluidizing agents, and the like may be added and mixed to provide powders, granules, fine granules, capsules, and the like. The fluidizing agent to be added to and mixed with ibuprofen-containing preparation particles and ethenamide-containing preparation particles may be any component that improves the fluidity of the preparation particles, and examples thereof include magnesium aluminate metasilicate described above. .

  Production of the solid preparation containing ibuprofen and ethenzamide of the present invention can be performed, for example, by the following method. First, they are blended into separate powders so that ibuprofen and etenzamide do not come into contact. That is, ibuprofen is mixed with the above-mentioned additive, and after rolling and fluidized bed granulation, it is dried to obtain ibuprofen-containing preparation particles. The obtained particles are charged into a Wurster column type fluidized bed coating machine, and PVA or PVA copolymer, the aforementioned plasticizer, suspending agent, coloring agent, etc. are dissolved and suspended in purified water, and the solid content concentration is about 15%. Is sprayed at 0.75 to 3.7 parts by mass with respect to 1 part by mass of the ibuprofen-containing preparation particles to obtain ibuprofen-containing preparation particles coated with a film layer containing PVA or PVA copolymer. Next, ethenzamide is mixed with the above-mentioned additives, and is dried after rolling-fluidized bed granulation to obtain ethenamide-containing preparation particles. The ibuprofen-containing preparation particles coated with the film layer and the ethenamide-containing preparation particles are mixed together with the fluidizing agent and the like to obtain the intended solid preparation containing ibuprofen and etenzamid.

  The solid preparation thus obtained is filled in a packaging container or a sachet according to the size of the particle and provided as a powder, granule, etc. It can also be provided as an agent.

  Hereinafter, the production examples, examples, comparative examples, and test examples will be given to explain the present description in more detail.

Production Example 1 Preparation of ibuprofen-containing preparation particles 27,000 g of ibuprofen, 240 g of riboflavin, 3,000 g of light anhydrous silicic acid, 12,000 g of crystalline cellulose, and 21,000 g of candy powder were weighed and mixed with hydroxypropyl cellulose (HPC). -L) Using a solution obtained by dissolving 5,400 g in purified water 54,600 g as a binding liquid, granulating using a rolling fluidized bed granulator (Multiplex (trade name): manufactured by POWREC), the average particle size 222 μm ibuprofen-containing formulation particles were produced.

Production Example 2 Preparation of ethenamide-containing preparation particles 126 g of ethenamide, 75 g of anhydrous caffeine, 60 g of crystalline cellulose, 300 g of D-mannitol, 30 g of hydroxypropylcellulose (HPC-L fine powder), and 6 g of light anhydrous silicic acid were weighed and mixed. Using purified water as a granulating solvent, granulation was carried out using a stirring granulator (vertical granulator (trade name): manufactured by POWREC). The resulting granulated product is dried using a fluidized bed dryer (Freund), and after drying, it is classified with a 30M (500 μm) sieve, and the sieve residue is crushed and ethenzamide-containing preparation particles having an average particle size of 164 μm. Got.

Production Example 3 Other Preparation Particles 300 g of bromovaleryl urea, 60 g of crystalline cellulose, 204 g of D-mannitol, 30 g of hydroxypropylcellulose (HPC-L fine powder), and 6 g of light anhydrous silicic acid were granulated in the same manner as in Production Example 2 and averaged particles Preparation particles having a diameter of 127 μm were obtained.

Example 1
570 g of the preparation particles obtained in Production Example 1 were charged into a fluidized bed granulator / dryer equipped with a draft tube (GPCG (trade name): manufactured by POWREC), and 36 g of hypromellose, PVA (GOHSENOL EG-05P (trade name): Nippon Synthetic Chemical Co., Ltd.) 36 g, paraffin 9.6 g, carnauba wax 9.6 g, sucrose fatty acid ester 2.4 g, polysorbate-80 2.4 g, and titanium oxide 24 g were dissolved and dispersed in purified water 720 g using a coating solution. According to the method, 630 g of formulation particles coated with a film layer (covering amount: 10% of formulation particles) was produced. 0.42 g of the preparation particles coated with the obtained film layer, 0.397 g of the preparation particles obtained in Production Example 2, 0.399 g of the preparation particles obtained in Production Example 3, 0.012 g of magnesium aluminate metasilicate, The powder obtained by adding the sweetener and the fragrance and mixing the mixture was filled in the packaging material to obtain the intended solid preparation containing ibuprofen and ethenzamide.

(Example 2)
Coating in which 570 g of the preparation particles obtained in Production Example 1 were dissolved and dispersed in 96 g of PVA copolymer (POVACOAT type F (trade name): manufactured by Daido Kasei Kogyo), 9.6 g of talc and 14.4 g of titanium oxide in 586 g of purified water. Using the solution, 630 g of formulation particles coated with a film layer (coating amount: 10% of formulation particles) was produced in the same manner as in Example 1. 0.42 g of the preparation particles coated with the obtained film layer, 0.397 g of the preparation particles obtained in Production Example 2, 0.399 g of the preparation particles obtained in Production Example 3, 0.012 g of magnesium aluminate metasilicate, The powder obtained by adding the sweetener and the fragrance and mixing the mixture was filled in the packaging material to obtain the intended solid preparation containing ibuprofen and ethenzamide.

(Comparative Example 1)
630 g of formulation particles coated with a film layer in the same manner as in Example 1 using a coating solution obtained by dissolving and dispersing 570 g of the formulation particles obtained in Production Example 1 in 68 g of hypromellose and 46 g of talc in 1150 g of purified water Amount: 10% of formulation particles). Add 0.397 g of the granules obtained in Preparation Example 2, 0.399 g of the preparation particles obtained in Preparation Example 3, 0.012 g of magnesium aluminate metasilicate, sweeteners and flavors to 0.42 g of the resulting preparation particles and mix. The powder was filled into a packaging material to obtain a solid preparation containing ibuprofen and ethenzamide.

(Comparative Example 2)
0.38 g of preparation particles obtained in Production Example 1, 0.397 g of preparation particles obtained in Production Example 2, 0.399 g of preparation particles obtained in Production Example 3, 0.036 g of magnesium aluminate metasilicate, sweetener The powder mixed with the fragrance was filled in the packaging material to obtain a solid preparation containing ibuprofen and ethenzamide.

(Comparative Example 3)
0.38 g of the preparation particles obtained in Production Example 1, 0.397 g of the preparation particles obtained in Production Example 2, 0.399 g of the preparation particles obtained in Production Example 3, 0.036 g of light anhydrous silicic acid, The powder mixed with the fragrance was filled in the packaging material to obtain a solid preparation containing ibuprofen and ethenzamide.

(Test Example 1)
[Evaluation method]
The test preparation was stored for 3 months under conditions of 40 ° C. and 75% RH, and then sieved based on the Japanese Pharmacopoeia General Test Method Particle Size Test Method, and the state of solidification / aggregation of the preparation particles was observed.

[result]
The results are shown in Table 1.

  As apparent from Table 1, solid preparations (Comparative Examples 2 and 3) composed of preparation particles that were not subjected to film coating produced a large amount of coarse particles due to aggregation of the preparation particles, whereas film coating was performed to form a film layer. In the solid preparations containing ibuprofen-containing preparation particles coated with (Examples 1 and 2 and Comparative Example 1), the generation of coarse particles is suppressed, and in particular, a film containing PVA (Example 1) and PVA copolymer (Example 2) In the solid preparation containing ibuprofen-containing preparation particles coated with a layer, almost no aggregation was observed.

  According to the present invention, it has become possible to provide a solid preparation containing ibuprofen and etenzamide as a powder or granule, so that in addition to conventional double tablets and multilayer tablets, variations have been widened, and consumers (patients) Can now respond more accurately to the needs of

Claims (4)

A solid preparation containing ibuprofen and ethenzamide, ibuprofen and ethenzamide are formulated into different preparation particles, the formulation particles containing ibuprofen, a polyvinyl alcohol or a polyvinyl alcohol-acrylic acid-methyl methacrylate copolymer, oxidized A solid preparation which is coated with a film layer containing titanium and / or talc and whose dosage form is a powder, granule, fine granule or capsule. A solid formulation containing ibuprofen and etenzamid, comprising ibuprofen and etethamide Nzamid is formulated in different formulation particles, and the formulation particles containing ibuprofen are Covered with a film layer containing nyl alcohol, titanium oxide, carnauba wax and paraffin A solid preparation which is covered and whose dosage form is a powder, granule, fine granule or capsule. A solid formulation containing ibuprofen and etenzamid, comprising ibuprofen and etethamide Nzamid is formulated in different formulation particles, and the formulation particles containing ibuprofen are Nyl alcohol / acrylic acid / methyl methacrylate copolymer, titanium oxide and talc And the dosage form is powder, granule, fine granule or capsule A solid formulation. Film layer of the content of the polyvinyl alcohol or polyvinyl alcohol-acrylic acid-methyl methacrylate copolymer is a 0.04 to 0.4 parts by mass per 1 part by weight of ibuprofen, claims 1-3 in The ibuprofen and ethenzamide containing solid formulation as described in any one of them .