JP6983139B2 - Compositions for solid formulations, solid formulations and methods for producing them - Google Patents

Description

The present invention relates to a composition for a solid preparation, a solid preparation, and a method for producing the same.

The solid preparation is widely used because it is easy to take. Among them, the sustained release preparation is a useful preparation because the concentration of the active ingredient dissolved in the blood can be controlled to a certain value or less, or the number of doses can be reduced. Sustained release preparations are broadly classified into single unit type and multiple unit type.
The single unit type exhibits sustained release by gradually releasing the active ingredient while maintaining the dosage form in the gastrointestinal tract, and is manufactured by mixing with a water-soluble polymer or wax and tableting. Ru. Examples of the single unit type include a matrix type and the like. On the other hand, in the multiple unit type, the administered tablet or capsule rapidly disintegrates and releases granules coated with the active ingredient with a polymer film, exhibiting sustained release.

The matrix-type sustained release preparation is one of the most widely used sustained release preparations because of its simple production method and easy elution control. Among the matrix-type sustained-release preparations, for example, hydroxypropylmethyl cellulose (hereinafter, also referred to as “HPMC”), which is a nonionic water-soluble polymer, is used for the gel matrix-type sustained-release preparation.

In a matrix-type sustained release preparation containing HPMC, reproducibility in the dissolution test of the preparation is extremely important, and it is required to design a preparation having high reproducibility of the dissolution test, that is, a preparation having a small dissolution variation. Generally, it is known that increasing the content of HPMC in the pharmaceutical product reduces the variation in elution, but the tablet size becomes large and the dosage is inferior. Therefore, it is better that the content of HPMC is small. .. However, if the content of HPMC is low, it is conceivable that when the tablets are subjected to the dissolution test, the matrix is not stably formed and the dissolution variation becomes large.
As the sustained-release preparation using HPMC, the sustained-release preparation containing HPMC particles having a specific degree of substitution and powder physical properties (Patent Document 1) and the zero-order release including high-viscosity HPMC and low-viscosity HPMC. Examples thereof include a sustained-release preparation (Patent Document 2).

Japanese Unexamined Patent Publication No. 6-305982 Japanese Unexamined Patent Publication No. 7-53364

However, although the sustained release preparation containing HPMC described in Patent Document 1 has been shown to control the dissolution rate, no elution variation has been suggested. On the other hand, although it is suggested that the sustained release preparation containing the high-viscosity HPMC and the low-viscosity HPMC described in Patent Document 2 in a predetermined ratio shows a zero-order release state, the elution variation is I haven't suggested anything. Further, since the HPMC mixture obtained by mixing the HPMC having a high viscosity and the HPMC having a low viscosity at the ratio shown in Patent Document 2 has a low viscosity, the content of HPMC in the tablet is increased in order to obtain a preferable elution behavior. However, it is not preferable because the tablet size becomes large and the ingestibility is inferior.
The present invention provides a composition for a solid preparation containing at least hydroxypropylmethylcellulose and an active ingredient, which can produce a solid preparation having a small elution variation even at a low content of HPMC, and a solid preparation and a method for producing the same. With the goal.

As a result of diligent studies, the present inventors have found that the polydispersity by absolute molecular weight measurement is 4.0 or more, and the viscosity of the 2 mass% aqueous solution at 20 ° C. is 1,500 to 150,000 mPa · s. We have found that a composition for a solid preparation containing at least hydroxypropylmethylcellulose and an active ingredient can solve the above-mentioned problems, and have completed the present invention.
According to one aspect of the present invention, hydroxypropylmethylcellulose has a polydispersity of 4.0 or more as measured by absolute molecular weight and a viscosity of a 2% by mass aqueous solution at 20 ° C. of 1,500 to 15,000 mPa · s. And a composition for a solid preparation containing at least the active ingredient.
Further, according to another aspect of the present invention, there is provided a solid preparation containing at least this composition for a solid preparation.
According to still another aspect of the present invention, hydroxypropyl having a polydispersity of 4.0 or more as measured by absolute molecular weight and a viscosity of a 2% by mass aqueous solution at 20 ° C. of 1,500 to 150,000 mPa · s. Provided is a method for producing a tablet, which comprises at least a step of dry mixing methylcellulose and an active ingredient to obtain a mixture and a step of tableting the mixture to obtain a tablet.
Further, according to another aspect of the present invention, hydroxy has a polydispersity of 4.0 or more as measured by absolute molecular weight and a viscosity of a 2% by mass aqueous solution at 20 ° C. of 1,500 to 150,000 mPa · s. Provided is a method for producing a tablet, which comprises at least a step of granulating propylmethylcellulose and an active ingredient to obtain a granulated product and a step of tableting the granulated product to obtain a tablet.

According to the present invention, it is possible to obtain a solid preparation in which the amount of HPMC added is reduced and the elution variation of the active ingredient is small.

First, HPMC used in the composition for a solid preparation will be described.
The polydispersity of HPMC used in the composition for solid preparation by absolute molecular weight measurement is 4.0 or more, preferably 4.0 to 20.0, more preferably 5.0 to 17.0, still more preferably 7.0. ~ 17.0. If the degree of polydispersity is less than 4.0, the elution variation becomes large.
The degree of polydispersity is defined by the ratio (Mw / Mn) of the weight average molecular weight (Mw) to the number average molecular weight (Mn), and represents the spread of the molecular weight (molecular weight distribution). The smaller the Mw / Mn value, the narrower the molecular weight distribution, and the larger the Mw / Mn value, the wider the molecular weight distribution.
Weight average molecular weight (Mw) and number average molecular weight (Mn) are absolute molecular weight measurement methods using a combination of size exclusion chromatography (SEC) and multi-angle light scattering (MALLS) (Tavelts & Capsules, 14-20, July, 2007). Can be measured by.

Various methods have been reported for measuring the molecular weight of HPMC, for example, Journal of Pharmacology and Pharmacology, Vol. 32,116-119 (1980), SEC-based relative molecular weight measurement method, Polymer Proceedings, Vol. 39, No. The absolute molecular weight measurement method by the combination of SEC and low angle light scattering (LALLS) described in 4,293-298 (1982), and the absolute molecular weight measurement method by the combination of SEC and MALLS described in Tablets & Capsules, 14-20, July, 2007. Molecular weight measurement methods and the like are known.
It has been pointed out that the relative molecular weight measurement method by SEC has a higher value than the actual polydispersity (Mw / Mn) because the influence of the molecular association of HPMC is not sufficiently removed. On the other hand, the absolute molecular weight measurement method using the combination of SEC and LALLS and the absolute molecular weight measurement method using the combination of SEC and MALLS are preferable in that the above-mentioned problems are few, the measuring method is simpler, and the molecular weight can be measured with high accuracy. Therefore, an absolute molecular weight measurement method using a combination of SEC and MALLS is more preferable. Therefore, in the present invention, an absolute molecular weight measurement method using a combination of SEC and MALLS is adopted.

The weight average molecular weight (Mw) of HPMC used in the composition for solid preparation by absolute molecular weight measurement is preferably 200,000 to 800,000, more preferably 250,000 to 700, from the viewpoint of controlling the elution of the active ingredient. It is 000.
The number average molecular weight (Mn) of HPMC used in the composition for solid preparation by absolute molecular weight measurement is preferably 10,000 to 200,000, more preferably 15,000 to 150, from the viewpoint of controlling the elution of the active ingredient. It is 000.

The viscosity of a 2% by mass aqueous solution of HPMC used in the composition for a solid preparation at 20 ° C. is 1,500 to 150,000 mPa · s, preferably 2,000 to 100,000 mPa · s, and more preferably 3,500 to 80. It is 000 mPa · s. When the viscosity is less than 1,500 mPa · s, for example, when the HPMC content in the tablet in the sustained release preparation is small, the effect of suppressing the elution of the active ingredient is inferior. On the other hand, when it exceeds 150,000 mPa · s, the effect of suppressing elution is excellent, but the elution of the active ingredient is inferior.
When the viscosity of the 2 mass% aqueous solution at 20 ° C is less than 600 mPa · s, the viscosity of the aqueous solution is according to the capillary viscometer method of the general test method viscosity measuring method described in the 17th revised Japanese Pharmacy. It can be measured using a mold viscometer. On the other hand, when the viscosity of the aqueous solution measured by the Ubbelohde viscometer is 600 mPa · s or more, it can be measured using MCR301, which is a rheometer manufactured by Antonio Par.

The degree of substitution of the methoxy group of HPMC used in the composition for a solid preparation is not particularly limited, but is preferably 14.0 to 32.0% by mass, more preferably 16.5 from the viewpoint of controlling the elution of the active ingredient. It is ~ 30.0% by mass, more preferably 19.0 to 30.0% by mass, and particularly preferably 19.0 to 24.0% by mass.
The degree of substitution of the hydroxypropoxy group of HPMC used in the composition for a solid preparation is not particularly limited, but is preferably 3.0 to 32.0% by mass, more preferably 3. It is 0 to 12.0% by mass, more preferably 4.0 to 12.0% by mass, and particularly preferably 8.5 to 10.5% by mass.
The degree of substitution of the methoxy group and the hydroxypropoxy group can be measured by a method based on the method for measuring the degree of substitution of hydroxypropylmethylcellulose (hypromellose) described in the 17th revised Japanese Pharmacopoeia.

As the degree of substitution type of HPMC, 1828 (degree of substitution of methoxy group: 16.5 to 20.0% by mass, degree of substitution of hydroxypropoxy group: 23. 0 to 32.0% by mass), 2208 (degree of substitution of methoxy group: 19.0 to 24.0% by mass, degree of substitution of hydroxypropoxy group 4.0 to 12.0% by mass), 2906 (degree of substitution of methoxy group) Degree: 27.0 to 30.0% by mass, degree of substitution of hydroxypropoxy group 4.0 to 7.5% by mass), and 2910 (degree of substitution of methoxy group: 28.0 to 30.0% by mass, hydroxypropoxy) The degree of substitution of the group is 7.0 to 12.0% by mass), but 2208 or 2910 is preferable from the viewpoint of controlling the elution of the active ingredient.

The volume-based average particle size of HPMC used in the composition for a solid preparation by the dry laser diffraction method is preferably 20 to 200 μm, more preferably 40 to 150 μm from the viewpoint of controlling the elution of the active ingredient in the sustained release preparation. It is more preferably 50 to 100 μm, and particularly preferably 60 to 90 μm.
The average particle size is calculated by irradiating a powder sample ejected with compressed air with a laser beam using a master sizer 3000 manufactured by Malvern in the UK or a HELOS device manufactured by Symbolec in Germany, and converting the volume by the diffraction intensity thereof. It can be measured by a dry laser diffraction method that measures the average particle size.

HPMCs used in solid formulation compositions are obtained from single HPMCs from the same batch or HPMC mixtures from two or more batches, eg, low viscosity HPMCs from one batch and other batches. It may be an HPMC mixture containing at least high-viscosity HPMC (hereinafter, "single HPMC", "low-viscosity HPMC" and "high-viscosity HPMC" are also referred to as "raw material HPMC").

The single HPMC can be produced by the same production method as the known method for producing hydroxypropylmethylcellulose by using a pulp mixture containing at least a low degree of polymerization pulp and a high degree of polymerization pulp. That is, a single HPMC having a polydispersity of 4.0 or more as measured by absolute molecular weight and a viscosity of a 2% by mass aqueous solution at 20 ° C. of 1,500 to 150,000 mPa · s has a high degree of polymerization and a high degree of polymerization. Degree of Polymerization It can be produced by contacting a pulp mixture containing at least a pulp with an alkali metal hydroxide solution and reacting an etherifying agent with the alkali cellulose obtained. Preferably, a pulp mixture consisting of a low degree of polymerization pulp and a high degree of polymerization pulp can be used.
The intrinsic viscosity of the low-polymerization pulp is preferably 300 to 700 ml / g, more preferably 330 to 630 ml / g, still more preferably 330 to 510 ml / g, and particularly preferably 330, from the viewpoint of reducing the elution variation of the active ingredient. ~ 410 ml / g. The intrinsic viscosity of the high degree of polymerization pulp is preferably 750 to 2,500 ml / g, more preferably 850 to 2,000 ml / g, and further preferably 1,200 to 2, from the viewpoint of reducing the elution variation of the active ingredient. It is 000 ml / g, particularly preferably 1,400 to 2,000 ml / g. The intrinsic viscosity of low-polymerization pulp and high-polymerization pulp is determined by using a Uberode viscous meter in accordance with the viscosity measurement method according to JIS P8215: 1998 "7. B Method-Measurement of Extreme Viscosity Number at Constant Shear Rate". Can be measured.

The ratio of the intrinsic viscosity of the high polymerization degree pulp to the intrinsic viscosity of the low polymerization degree pulp (intrinsic viscosity of the high polymerization degree pulp / intrinsic viscosity of the low polymerization degree pulp) is preferably 3 from the viewpoint of reducing the elution variation of the active ingredient. It is 9.0 or more, more preferably 3.5 to 9.0, and even more preferably 4.0 to 8.5.
The mass ratio of the low degree of polymerization pulp to the high degree of polymerization pulp is preferably 1:99 to 99: 1, more preferably 10:90 to 70:30, from the viewpoint of reducing the elution variation of the active component.

A step of contacting a pulp mixture consisting of a low-polymerization degree pulp and a high-polymerization degree pulp, for example, a pulp mixture consisting of a low-polymerization degree pulp and a high-polymerization degree pulp with an alkali metal hydroxide solution to obtain alkali cellulose, and the above-mentioned alkali cellulose and ether. A single HPMC, ie HPMC in one batch, can be produced by a method comprising at least a step of reacting the agent.
Examples of the form of the low-polymerization degree pulp and the high-polymerization degree pulp include sheet-like pulp, chip-like pulp and powdered pulp.
Examples of the alkali metal hydroxide solution include a sodium hydroxide solution and a potassium hydroxide solution, but a sodium hydroxide solution is preferable from an economical point of view, and an aqueous solution such as a sodium hydroxide aqueous solution and a potassium hydroxide aqueous solution is more preferable. Preferably, an alcohol solution such as ethanol or a mixed solution of a water-soluble alcohol and water may be used.
Examples of the etherifying agent include methyl halides such as methyl chloride, methyl bromide and methyl iodide, and alkylene oxides such as propylene oxide, but from an economical point of view, methyl chloride and propylene oxide are preferable.

Next, as the HPMC used in the composition for a solid preparation, an HPMC mixture containing at least a low-viscosity HPMC and a high-viscosity HPMC will be described. As the HPMC mixture, an HPMC mixture containing 90 to 100% by mass of low-viscosity HPMC and high-viscosity HPMC is preferable from the viewpoint of reducing the elution variation of the active ingredient.

The viscosity of the 2% by mass aqueous solution of low-viscosity HPMC at 20 ° C. is preferably 2.0 to 150 mPa · s, more preferably 2.5 to 125 mPa · s, from the viewpoint of reducing the elution variation of the active ingredient.
The degree of polydispersity of low-viscosity HPMC measured by absolute molecular weight is preferably 1.5 to 3.9, more preferably 1.8 to 3.5, and even more preferably 2. It is 0 to 3.0. The weight average molecular weight (Mw) of the low-viscosity HPMC measured by absolute molecular weight is preferably 10,000 to 200,000 from the viewpoint of controlling the elution of the active ingredient. The number average molecular weight (Mn) of the low-viscosity HPMC measured by absolute molecular weight is preferably 5,000 to 60,000 from the viewpoint of controlling the elution of the active ingredient.

The viscosity of a 2% by mass aqueous solution of high-viscosity HPMC at 20 ° C. is preferably 3,500 to 200,000 mPa · s, more preferably 4,000 to 130,000 mPa · s, from the viewpoint of reducing the elution variation of the active ingredient. Is.
The degree of polydispersity of high-viscosity HPMC measured by absolute molecular weight is preferably 1.5 to 3.9, more preferably 1.8 to 3.7, and even more preferably 2. It is 0 to 3.7. The weight average molecular weight (Mw) of the high-viscosity HPMC measured by absolute molecular weight is preferably 240,000 to 1,000,000 from the viewpoint of controlling the elution of the active ingredient. The number average molecular weight (Mn) measured by absolute molecular weight measurement of high-viscosity HPMC is preferably 70,000 to 300,000 from the viewpoint of controlling the elution of the active ingredient.

The viscosity and polydispersity of a 2% by mass aqueous solution of low-viscosity HPMC and high-viscosity HPMC at 20 ° C. can be measured by the same method as HPMC used for the composition for a solid pharmaceutical product.

Further, the degree of substitution and the average particle size of the methoxy group and the hydroxypropoxy group of the low-viscosity HPMC and the high-viscosity HPMC are the same as the degree of substitution and the average particle size of the methoxy group and the hydroxypropoxy group of HPMC used in the composition for solid preparation. be.
The degree of substitution type of the low-viscosity HPMC and the high-viscosity HPMC may be the same degree of substitution type or a different degree of substitution type, but from the viewpoint of suppressing the elution of the active ingredient in the sustained-release preparation, the same degree of substitution is used. It is preferably a type.

The low-viscosity HPMC and the high-viscosity HPMC can be produced by known methods for producing HPMC, respectively. For example, a step of contacting pulp having an arbitrary intrinsic viscosity with an alkali metal hydroxide solution to obtain alkali cellulose, a step of reacting the alkali cellulose with an etherifying agent to obtain a reaction product, and a step of obtaining the reaction product. A powdered HPMC is obtained by a production method including at least a step of washing and drying and a step of pulverizing if necessary. Here, as the pulp having an arbitrary intrinsic viscosity, for example, when producing low-viscosity HPMC, a low-polymerization degree pulp can be used in the production of a single HPMC, and when producing a high-viscosity HPMC, a single HPMC can be used. High degree of polymerization pulp can be used in the production of HPMC. The low-viscosity HPMC can also be produced by depolymerizing the high-viscosity HPMC by a known HPMC depolymerization method.

The mixing ratio (mass ratio) of the low-viscosity HPMC and the high-viscosity HPMC is not particularly limited, but is preferably 5:95 to 95: from the viewpoint of suppressing elution in the sustained release preparation or reducing the elution variation of the active ingredient. 5, more preferably 10:90 to 80:20, still more preferably 10:90 to 65:35.

The content of HPMC in the composition for a solid preparation is preferably 2 or more and 99.99% by mass or less, more preferably 2 or more and 40% by mass or less, from the viewpoint of controlling the elution of the active ingredient in the sustained release preparation. Even more preferably, it is 10 or more and 40% by mass or less, particularly preferably 10 or more and 30% by mass or less, and particularly preferably 10 or more and less than 20% by mass.
Usually, the content of HPMC in the solid preparation (the content of HPMC in the composition for the solid preparation) is 20 mass from the viewpoint of controlling the elution of the active ingredient in the sustained release preparation and reducing the elution variation. % Is recommended. However, according to the present invention, the HPMC content can be reduced to less than 20% by mass because the elution property can be controlled and the elution variation can be reduced even if the HPMC content is low, and the tablet can be miniaturized. You can expect it.

The active ingredient in the composition for a solid preparation is not particularly limited as long as it is an active ingredient that can be orally administered, but it is not particularly limited as long as it is an active ingredient that can be orally administered. Examples thereof include active ingredients used in health foods of.
Drugs used in pharmaceutical products include, for example, central nervous system drugs, cardiovascular drugs, respiratory drugs, digestive system drugs, antibiotics, antitussives / expectorants, antihistamines, antipyretic analgesic and anti-inflammatory agents, diuretics, and autonomy. Examples thereof include neuroactive agents, antimalaria agents, expectorants, antipyretics, vitamins and derivatives thereof.

Examples of the central nervous system drug include diazepam, idebenone, naproxen, piroxicam, indomethacin, slindac, lorazepam, nitrazepam, phenitoin, acetaminophen, ethenzamide, ketoprofen and chlordiazepoxide.
Cardiovascular drugs include, for example, morsidemin, vinposetin, propranolol, methyldopa, dipyridamole, furosemide, triamterene, nifedibin, atenolol, spironolactone, metoprolol, pindolol, captopril, isosorbit nitrate, derapril hydrochloride, meclophenoxate hydrochloride, diltiazem hydrochloride. Examples thereof include etilefrine hydrochloride, digitoxin and alprenolol hydrochloride.

Respiratory drugs include, for example, amlexanox, dextromethorphan, theophylline, pseudoephedrine, salbutamol, guaifenesin and the like.
Examples of digestive drugs include 2-[[3-methyl-4- (2,2,2-trifluoroethoxy) -2-pyridyl] methylsulfinyl] benzimidazole and 5-methoxy-2-[(4). -Methoxy-3,5-dimethyl-2-pyridyl) methylsulfinyl] benzimidazole drugs having anti-ulcer activity such as benzimidazole, cimetidine, ranitidine, pirenzepine hydrochloride, pancreatin, bisacodyl, 5-aminosalicylic acid and the like can be mentioned. ..

Examples of the antibiotic include talampicillin hydrochloride, bacampicillin hydrochloride, cefaclor and erythromycin.
Examples of the antitussive / expectorant include noscapine hydrochloride, carbetapentane citrate, isoaminile citrate, dimemorfan phosphate and the like.
Examples of the antihistamine include chlorpheniramine maleate, diphenhydramine hydrochloride, promethazine hydrochloride and the like.
Examples of the antipyretic analgesic and anti-inflammatory agent include ibuprofen, diclofenac sodium, flufenamic acid, metamizole, aspirin and ketoprofen.

Examples of the diuretic include caffeine and the like.
Examples of the autonomic nerve agonist include dihydrocodeine phosphate and dl-methylephedrine hydrochloride, atropine sulfate, acetylcholine chloride, neostigmine and the like.
Examples of the antimalarial agent include quinine hydrochloride and the like.
Examples of the antidiarrheal agent include loperamide hydrochloride and the like.
Examples of the psychotropic agent include chlorpromazine and the like.
Examples of vitamins and their derivatives include vitamin A, vitamin B1, flusultiamine, vitamin B2, vitamin B6, vitamin B12, vitamin C, vitamin D, vitamin E, vitamin K, calcium pantothenate, and tranexamic acid. Be done.

Examples of the active ingredient used in health foods include the vitamins and derivatives thereof, minerals, carotenoids, amino acids and derivatives thereof, plant extracts, health food materials and the like.
Examples of minerals include calcium, magnesium, manganese, zinc, iron, copper, selenium, chromium, sulfur, iodine and the like.
Examples of carotenoids include β-carotene, α-carotene, lutein, cryptoxanthin, zeaxanthin, lycopene, astaxanthin, and multicarotene.

Examples of amino acids include acidic amino acids, basic amino acids, neutral amino acids, acidic amino acid amides and the like.
Examples of the acidic amino acid include aspartic acid and glutamic acid.
Examples of the basic amino acid include lysine, arginine and histidine.
Examples of the neutral amino acid include linear aliphatic amino acids such as alanine and glycine, branched aliphatic amino acids such as valine, leucine and isoleucine, hydroxy amino acids such as serine and threonine, and sulfurization such as cysteine and methionine. Examples thereof include amino acids, aromatic amino acids such as phenylalanine and tyrosine, heterocyclic amino acids such as tryptophan, and iminoic acid such as proline.
Examples of the acidic amino acid amide include asparagine and glutamine.
Examples of amino acid derivatives include acetylglutamine, acetylcysteine, carboxymethylcysteine, acetyltyrosine, acetylhydroxyproline, 5-hydroxyproline, glutathion, creatine, S-adenosylmethionine, glycylglycine, glycylglutamine, dopa, and alanyl. Glutamine, carnitine, γ-aminobutyric acid and the like can be mentioned.

Examples of the plant extract include aloe, propolis, agaricus, ginkgo biloba, ginkgo biloba, turmeric, curcumin, germinated brown rice, shiitake mycelium, sweet tea, sweet tea, mesimacob, sesame, garlic, maca, winter worm summer grass, chamomile and pearl oyster. ..
Examples of health food materials include royal jelly, dietary fiber, protein, bifidobacteria, lactic acid bacteria, chitosan, yeast, glucosamine, lecithin, polyphenols, animal seafood cartilage, sponge, lactoferrin, shijimi, eicosapentaenoic acid, germanium, enzymes, creatin, carnitine. , Citrate, raspberry ketone, coenzyme Q10, methylsulfonylmethane, phospholipid-bound soybean peptide and the like.

The content of the active ingredient in the composition for a solid preparation is not particularly limited, but is preferably 0.01% by mass to 98% by mass from the viewpoint of medicinal effect or efficacy.

In addition to HPMC and active ingredients, compositions for solid preparations are commonly used in this field, such as excipients, binders, disintegrants, sluiceants, antiaggregating agents and solubilizing agents of active ingredients, as required. Various additives that can be added can be added.

Examples of the excipient include sugars such as sucrose, lactose, glucose and maltose, sugar alcohols such as mannitol, sorbitol, erythritol and maltitol, starch, powdered cellulose, crystalline cellulose, calcium phosphate and calcium sulfate.
Binders include polyvinyl alcohol, polyacrylic acid, polymethacrylic acid, polyvinylpyrrolidone, glucose, sucrose, lactose, maltose, dextrin, sorbitol, mannitol, maltitol, macrogol, gum arabic, gelatin, agar, starch, and powder. Examples thereof include cellulose, crystalline cellulose and low-substituted hydroxypropyl cellulose.

Examples of the disintegrant include low-degree-of-substitution hydroxypropyl cellulose, carmellose or a salt thereof, croscarmellose sodium, carboxymethyl starch sodium, crospovidone, crystalline cellulose and crystalline cellulose / carmellose sodium.
Examples of the lubricant and the antiaggregating agent include talc, magnesium stearate, calcium stearate, colloidal silica, stearic acid, waxes, hydrogenated oils, polyethylene glycols and sodium benzoate.
Examples of the solubilizing agent for the active ingredient include organic acids such as fumaric acid, succinic acid, malic acid and adipic acid.
The content of these additives is not particularly limited, but is preferably 1 to 97.99% by mass from the viewpoint of controlling the elution of the active ingredient.

The composition for a solid preparation can be produced by mixing or granulating HPMC, an active ingredient and, if necessary, the above-mentioned additive.
The mixing method is not particularly limited, but can be carried out using a commonly used mixer. Examples of the mixer include a V-type mixer, a ribbon-type mixer, a container-type mixer, a tumbler-type mixer, and the like.
The granulation method is not particularly limited, and examples thereof include a dry granulation method and a wet granulation method, and the granulation method can be performed using a commonly used granulator. Examples of the granulator include a dry granulator such as a roller compactor, a high-speed stirring granulator, and a fluidized bed granulator.
The mixing time and granulation time are not particularly limited, but are usually 1 to 120 minutes.

Next, a solid preparation containing at least a composition for a solid preparation will be described. As the solid preparation, a solid preparation composed of a composition for a solid preparation is preferable from the viewpoint of reducing the elution variation of the active ingredient.
Examples of the dosage form of the solid preparation include tablets, granules, fine granules and the like, but tablets are preferable from the viewpoint of ingestibility. The granules and fine granules refer to granules obtained by granulating a composition for a solid preparation containing at least HPMC and an active ingredient, and can be used as capsules by filling them in capsules. You can also.
In addition, the solid preparation is preferably a sustained release preparation from the viewpoint of controlling the concentration of the active ingredient dissolved in the blood to a certain value or less or reducing the number of doses, and is easy to handle and most widely used. Matrix tablets, which are sustained release formulations, are more preferred.

Tablets can be produced by any of the production methods such as dry direct tableting method, wet stirring granulation tableting method, fluidized layer granulation tableting method, dry granulation tableting method, etc., and in particular, dry direct tableting method. The tableting method is suitable because the manufacturing process is simple, the manufacturing process can be simplified as compared with other tableting methods, and the manufacturing cost can be significantly reduced.
The dry direct tableting method is a method for tableting a composition for a solid preparation obtained by dry mixing, and is a highly productive method because there is no granulation step and the manufacturing process can be simplified.
In the wet stirring granulation and tableting method, a binder solution is sprayed on a composition for a solid pharmaceutical product, and a fluid motion is applied by a blade or the like installed in the container to granulate the composition to produce granulated products, and then the product is dried. It is a method of tableting and has the advantage of being able to granulate in a short time.
Examples of the apparatus used for wet stirring granulation include a vertical granulator, a high speed mixer and the like.
In the fluidized bed granulation and tableting method, the powders of the solid pharmaceutical composition are agglomerated and granulated by spraying the binder liquid while flowing the powder of the solid pharmaceutical composition in the fluidized bed. This is a method of tableting after the granulated product is manufactured, and has the advantage that it can be dried at the same time.
Examples of the apparatus used for fluidized bed granulation include multiplexes and flow coaters.
The dry granulation and tableting method is a method of tableting a compressed granulated product of a solid pharmaceutical composition obtained by compression granulation as a tableting powder, and when an active ingredient that is easily affected by water or a solvent is used. This is an effective method.
The compression granulation product can be produced, for example, by roller compression using a consolidation granulation machine such as a roller compactor.
Locking by any of the locking methods can be performed by a conventional method.
As described above, the hydroxypropylmethylcellulose and the active ingredient having a polydispersity of 4.0 or more as measured by absolute molecular weight and a viscosity of a 2% by mass aqueous solution at 20 ° C. of 1,500 to 150,000 mPa · s. A composition for a solid preparation and a solid preparation containing at least the same can be obtained.

Hereinafter, the present invention will be specifically described with reference to synthetic examples, examples and comparative examples, but the present invention is not limited to these examples.
<Ingredient HPMC used for preparation of composition for solid preparation>
Viscosity of 2% by mass aqueous solution of raw material HPMC-1 to 9 used for preparing the solid pharmaceutical composition of Examples 1 to 11 and Comparative Examples 1 to 5 at 20 ° C., degree of methoxy group substitution, hydroxypropoxy group substitution. Table 1 shows the degree, average particle size, molecular weight and polydispersity. The raw material HPMC-8 used in Example 11 and the raw material HPMC-9 used in Comparative Example 5 were produced by the methods shown in Synthesis Examples 1 and 2, respectively.

Synthesis example 1
In a pressure vessel with an internal stirrer, wood-derived powdered pulp (low polymerization degree pulp) having an intrinsic viscosity of 380 mL / g is weighed 5.2 kg in terms of anhydrous, and linter-derived having an intrinsic viscosity of 1,880 mL / g. Alkaline cellulose was produced by adding 11.5 kg of 49% by mass sodium hydroxide aqueous solution to 2.8 kg of powdered pulp (highly polymerized pulp) in terms of anhydrous value. To the obtained alkaline cellulose, 9.2 kg of methyl chloride and 2.3 kg of propylene oxide were added and reacted to obtain crude HPMC.
Then, the crude HPMC was dispersed in hot water having a temperature of 90 ° C., dehydrated and washed, and then dried in a dryer using both jacket heating and hot air heating until the residual water content became 2% by mass or less. The dried product was pulverized by compaction pulverization and then sieved with a sieve having an opening of 355 μm to obtain a raw material HPMC-8.

Synthesis example 2
The raw material HPMC-9 was obtained by the same method as in Synthesis Example 1 except that 8.0 kg of wood-derived powdered pulp having an intrinsic viscosity of 820 mL / g was used in terms of anhydrous water.

Various physical properties of the raw material HPMC were measured by the following methods.
<Viscosity of 2% by mass aqueous solution at 20 ° C>
A 2% by mass aqueous solution of HPMC was prepared by the method of the first method described in the 17th revised Japanese Pharmacy method for measuring the viscosity of hypromellose, and the general test method described in the 17th revised Japanese Pharmacy method was used for the viscosity measuring method. It was measured using a Uberode type viscometer according to the capillary viscometer method.
When the viscosity of the aqueous solution was less than 600 mPa · s, the value measured using a Uberode type viscometer was taken as the viscosity of the 2% by mass aqueous solution at 20 ° C.
On the other hand, when the viscosity of the aqueous solution was 600 mPa · s or more, the viscosity of the aqueous solution was measured again using MCR301, which is a rheometer manufactured by Antonio Par. That is, the temperature of the sample measurement part of the leometer was adjusted to 20 ° C. in advance, and the prepared 2% by mass aqueous solution was used as a CC27 measurement cup (CC27 / T200 / AL, diameter 29 mm and height 68 mm) made of aluminum. Pour up to the marked line (25 ml) of the container), set the bob cylinder (CC27, diameter 26.7 mm and height 40.0 mm) to the measurement position in the CC27 measurement cup and at a shear rate of ^{0.01 sec -1.} After holding for 2 minutes, the ^{measurement was started at a shear rate of 0.4 sec -1} , and the value 5 minutes after the start of the measurement was taken as the viscosity of the 2 mass% aqueous solution at 20 ° C.

<Degree of substitution of methoxy group and hydroxypropoxy group>
The degree of substitution of the methoxy group and the hydroxypropoxy group was measured by a method based on the method for measuring the degree of substitution of hypromellose in the 17th revised Japanese Pharmacopoeia.

<Average particle size>
The average particle size is based on volume under the conditions of dispersion pressure 2 bar and scattering intensity 2 to 10% by Fraunhofer diffraction theory using a laser diffraction type particle size distribution measuring device Mastersizer 3000 (manufactured by Malvern) by a dry method. The diameter corresponding to the 50% cumulative value of the cumulative distribution curve of was measured.

<Molecular weight and polydispersity>
The molecular weight is measured by pump (LC-20AD, manufactured by Shimadzu Corporation), degasser (DGU-20A3R, manufactured by Shimadzu Corporation), auto sampler (SIL-20A, manufactured by Shimadzu Corporation), column oven (CTO-20A, manufactured by Shimadzu Corporation). Shimadzu), guard column (SB-G, Shoko Science), size exclusion column (OHpak SB-806M HQ, Shoko Science), 18-angle light scattering detector (DAWN Heleos 2, Wyatt Technologies) A GPC-MALLS system composed of a differential refractometer (Optilab rEx, manufactured by Wyatt Technologies) was used.
HPMC was weighed into a 50 mL volume screw bottle, _{then 20 mL of 0.1 M sodium nitrate (NaNO 3} ) buffer was added under stirring with a magnetic stirrer, and the mixture was dissolved by stirring at room temperature for 1 hour. The HPMC was then completely dissolved by stirring under ice cooling for 1 hour. Then, it was left at room temperature for 30 minutes to return the solution to room temperature. The concentration of the solution varies depending on the viscosity of the 2% by mass aqueous solution of HPMC at 20 ° C., 0.30% by mass when it is less than 6 mPa · s, 0.20% by mass when it is 6 or more and less than 50 mPa · s, and 50 or more and 400 mPa · s. Less than 0.15 mass%, 400 or more and less than 4000 mPa · s is 0.10 mass%, 4,000 or more and less than 8,000 mPa · s is 0.05 mass%, and 8,000 or more and less than 15,000 mPa · s is 0. It was adjusted to be 0.02% by mass when it was .04% by mass and 15,000 or more and less than 75,000 mPa · s, and 0.01% by mass when it was 75,000 mPa · s or more and 150,000 mPa · s or less. The prepared solution was filtered using a 0.45 μm membrane filter (DIMIC-13CP, manufactured by Advantec). _{As a standard product, 2 mL of 0.1 M sodium nitrate (NaNO 3} ) buffer was added to 5 mg of pullulan (P50, manufactured by Shoko Science Co., Ltd.) to dissolve it, and then a 0.20 μm membrane filter (DIMIC-13CP, Advantec) was added. Manufactured by).
The molecular weight of the standard Plulan solution and HPMC solution was 0.1 M sodium nitrate (NaNO ₃ ) buffer as the mobile phase, and the column temperature was 40 ° C. and the differential refractometer was at a flow rate of 1.0 mL / min. The measurement was performed under the measurement conditions of a measuring instrument temperature of 25 ° C., an injection amount of 200 μL, and a measurement time of 20 minutes.
After the measurement was completed, analysis was performed by the following method using ASTRA VI (version 6.14.25) as analysis software. The HPMC dn / dc value used was 0.139 mL / g. The peak range was selected from the obtained light scattering chromatogram, and the light scattering detector used was Detector No. 5 to 16. The molecular weight was calculated by AUTO Fitting using the extrapolation method (primary), and the weight average molecular weight (Mw), the number average molecular weight (Mn) and the polydispersity (Mw / Mn) were measured. The molecular weight measurement results of HPMC were standardized (Normalize) using the measurement results of pullulan measured as a standard product.

Example 1
The raw material HPMC-1 as the low-viscosity HPMC and the raw material HPMC-4 as the high-viscosity HPMC were weighed at the mixing ratios shown in Table 2 and then mixed to prepare an HPMC mixture to be used as a composition for a solid formulation. Table 2 shows the viscosity of the prepared 2% by mass aqueous solution of HPMC mixture at 20 ° C., the degree of substitution of methoxy group, the degree of substitution of hydroxypropoxy group, the average particle size, the molecular weight and the degree of polydispersity. Various physical properties were measured by the same method as the raw material HPMC.
Next, 85 parts by mass of theophylline (manufactured by Shiratori Pharmaceutical Co., Ltd.) and 15 parts by mass of the prepared HPMC mixture were mixed for 3 minutes to obtain a composition for a solid formulation. The obtained composition for solid preparation was tableted under the following tableting conditions using a single-shot tableting machine, and a sustained release tablet was produced by a dry direct tableting method.

<Locking conditions>
Locking machine HANDTAB-200 (manufactured by Ichihashi Seiki Co., Ltd.)
Tablet size 480 mg / tablet, diameter 12 mm, flat pestle only tablet pressure 10 kN

<Dissolution test>
The produced sustained release tablets were subjected to the dissolution test under the following dissolution test conditions in accordance with the dissolution test method (paddle method) of the 17th revised Japanese Pharmacopoeia.
The test solution was collected 1, 2, 4, 8, 12 and 16 hours after the start of the dissolution test, and the amount of theophylline in the collected test solution was measured using a UV detector (UV-1700, manufactured by Shimadzu Corporation). It was determined by measuring the absorbance at a wavelength of 271 nm. The dissolution test was carried out using 6 tablets, the dissolution rate at each time was calculated for each tablet, and the average dissolution rate at each time was calculated by the following formula. The results are shown in Table 3.
Further, the dissolution rate variation (RSD) at each time was calculated by the following formula, and based on this, the average dissolution rate variation was calculated by the following formula. The results are shown in Table 3.

<Dissolution test conditions>
Dissolution tester NTR-6400A (manufactured by Toyama Sangyo Co., Ltd.)
Test solution Purified water 900 mL
Test temperature 37 ° C
Paddle rotation speed 50 rotations / minute Measurement number of tablets 6 tablets

<Calculation formula of average elution rate at each time>
Average elution rate (%) at each time
= Average value of elution rate of each tablet at each time

<Calculation formula for average elution rate variation>
Average elution rate variation (%)
= (Total elution rate variation (%) at each time) / 6
However, the variation in the elution rate at each time is based on the following formula.
Elution rate variation (%) at each time
= (Standard deviation of elution rate at each time / average elution rate at each time) × 100

Examples 2-11 and Comparative Examples 1-5
By the same method as in Example 1, the types and mixing ratios of the low-viscosity HPMC and the high-viscosity HPMC were changed to the formulations shown in Table 2 to produce a composition for a solid formulation. In Example 11, only the raw material HPMC-8 shown in Table 1, only the raw material HPMC-3 was used in Comparative Example 1, and only the raw material HPMC-9 was used in Comparative Example 5. Table 2 shows the viscosity, the degree of substitution of the methoxy group, the degree of substitution of the hydroxypropoxy group, the average particle size, the molecular weight and the degree of polydispersity of the 2% by mass aqueous solution of HPMC used in the obtained composition for solid preparation at 20 ° C.
In addition, a sustained release tablet was produced by the same method as in Example 1 and an dissolution test was carried out.
Table 3 shows the measurement results of the average elution rate and the variation in the average elution rate at each time.

As is clear from Table 3, the sustained release tablets produced using the solid pharmaceutical compositions of Examples 1 to 11 had drug elution suppressed for 16 hours. In addition, since the variation in the average elution rate was low, it was shown that the variation in elution was small and stable elution was ensured. Further, when comparing Examples having the same viscosity as Examples 1 and 2, Examples 4 and 5, and Examples 7 and 9, the larger the degree of polydispersity, the smaller the elution variation and the more stable. It was shown that elution can be ensured.
On the other hand, the sustained release tablets produced using the compositions for solid formulations of Comparative Examples 1, 2 and 5 had a large dissolution variation because the degree of polydispersity of HPMC used was less than 4.0.
Further, the sustained release tablets produced using the compositions for solid preparations of Comparative Examples 3 and 4 had a viscosity of a 2% by mass aqueous solution of HPMC used at 20 ° C. of less than 1,500 mPa · s, and thus 15 Regarding the amount of HPMC added by mass, the average elution rates after 8 hours were 95% and 86%, and most of the drugs were eluted in about 8 hours, which was inferior in the effect of suppressing elution as compared with the examples. Met.

Claims (11)

The polydispersity by absolute molecular weight measurement by the combination of size exclusion chromatography (SEC) and multi-angle light scattering (MALLS) is 4.0 or more, and the viscosity of the 2 mass% aqueous solution at 20 ° C. is 1,500 to 150. A composition for a solid preparation containing at least hydroxypropylmethyl cellulose having a molecular weight of 000 mPa · s and an active ingredient. The hydroxypropylmethyl cellulose has a low viscosity hydroxypropylmethyl cellulose having a viscosity of a 2% by mass aqueous solution at 20 ° C. of 2 to 150 mPa · s and a viscosity of a 2% by mass aqueous solution at 20 ° C. of 3,500 to 200,000 mPa · s. The composition for solid preparation according to claim 1, which comprises at least certain high-viscosity hydroxypropylmethyl cellulose. The composition for a solid preparation according to claim 2, wherein the mass ratio of the low-viscosity hydroxypropylmethyl cellulose to the high-viscosity hydroxypropylmethyl cellulose is 5:95 to 95: 5. A solid pharmaceutical product comprising at least the composition for a solid pharmaceutical product according to any one of claims 1 to 3. The solid preparation according to claim 4, wherein the solid preparation is a sustained release preparation. The solid preparation according to claim 4 or 5, which is a tablet. The polydispersity by absolute molecular weight measurement by the combination of size exclusion chromatography (SEC) and multi-angle light scattering (MALLS) is 4.0 or more, and the viscosity of the 2% by mass aqueous solution at 20 ° C. is 1,500 to 150. A step of dry mixing hydroxypropylmethyl cellulose at 000 mPa · s and an active ingredient to obtain a mixture, and
A method for producing a tablet, which comprises at least a step of tableting the mixture to obtain a tablet. The polydispersity by absolute molecular weight measurement by the combination of size exclusion chromatography (SEC) and multi-angle light scattering (MALLS) is 4.0 or more, and the viscosity of the 2% by mass aqueous solution at 20 ° C. is 1,500 to 150. A process of granulating hydroxypropylmethyl cellulose at 000 mPa · s and an active ingredient to obtain a granulated product,
A method for producing a tablet, which comprises at least a step of tableting the granulated product to obtain a tablet. A step of contacting a low polymerization degree pulp having an intrinsic viscosity of 300 to 700 ml / g and a high polymerization degree pulp having an intrinsic viscosity of 750 to 2,500 ml / g with an alkali metal hydroxide solution to obtain alkali cellulose. ,
The method for producing a tablet according to claim 7, further comprising a step of reacting the alkaline cellulose with an etherifying agent to obtain the hydroxypropylmethyl cellulose. The method for producing a tablet according to claim 9, wherein the mass ratio of the low degree of polymerization pulp to the degree of polymerization pulp is 1:99 to 99: 1. Claim 9 or claim that the ratio of the intrinsic viscosity of the high degree of polymerization pulp to the intrinsic viscosity of the low degree of polymerization pulp (the intrinsic viscosity of the high degree of polymerization pulp / the intrinsic viscosity of the low degree of polymerization pulp) is 3.0 or more. 10. The method for producing a tablet according to 10.