JP6142892B2 - Pharmaceutical composition for oral administration - Google Patents

Description

  The present invention relates to a pharmaceutical composition for high-dose oral administration comprising minodronic acid or a pharmaceutically acceptable salt or hydrate thereof.

（式中、R¹,R²,R³,R⁴は、同一又は異なって、水素原子又は低級アルキル基であり、R⁵,R⁶は水素原子又は低級アルキル基であり、nは0又は１である）
で示されるヘテロ環ビスフォスフォン酸誘導体またはその塩並びに該化合物を有効成分とする骨吸収抑制剤に関する発明が開示されている。 Patent Document 1 includes a general formula:

Wherein R ¹ , R ² , R ³ and R ⁴ are the same or different and are a hydrogen atom or a lower alkyl group, R ⁵ and R ⁶ are a hydrogen atom or a lower alkyl group, and n is 0 or 1)
The invention relates to a heterocyclic bisphosphonic acid derivative represented by the formula (1) or a salt thereof and a bone resorption inhibitor comprising the compound as an active ingredient.

  According to Patent Document 1, it is known that a heterocyclic bisphosphonic acid derivative or a salt thereof has an excellent effect of lowering the amount of serum calcium and suppresses bone resorption. Inflammatory joint diseases such as Paget's disease, hypercalcemia, bone metastasis of cancer, osteoporosis, and rheumatoid arthritis are diseases in which increased bone resorption is thought to have an important role in the pathological condition. It is useful as a drug that suppresses bone resorption and prevents bone loss or prevents or lowers serum calcium levels associated with increased bone resorption against bone resorption (osteoporosis) associated with It has been reported. Moreover, the improved manufacturing method is disclosed in Patent Document 2.

で表されるミノドロン酸水和物（化学名：[1-Hydroxy-2-(imidazo[1,2-a]pyridin-3-yl)ethylidene] bisphosphonic acid monohydrate）が「ボノテオ（登録商標）錠1mg」として販売されている。ボノテオ錠1mgは、ミノドロン酸水和物の１日１回型製剤であり、乳糖水和物、トウモロコシデンプン、ヒドロキシプロピルセルロース、ステアリン酸マグネシウム、ヒプロメロース、マクロゴール、タルク、及び酸化チタンを含有する（非特許文献１）。 As a therapeutic agent for osteoporosis, the following formula, which is one of the heterocyclic bisphosphonic acid derivatives:

The minodronic acid hydrate represented by the formula (chemical name: [1-Hydroxy-2- (imidazo [1,2-a] pyridin-3-yl) ethylidene] bisphosphonic acid monohydrate) is “Bonoteo® Tablets 1 mg Is sold as. Bonoteo Tablets 1 mg is a once-daily formulation of minodronic acid hydrate containing lactose hydrate, corn starch, hydroxypropyl cellulose, magnesium stearate, hypromellose, macrogol, talc, and titanium oxide ( Non-patent document 1).

  As a bone resorption inhibitor comprising a bisphosphonic acid derivative as an active ingredient, Patent Document 3 discloses a bisphosphonic acid derivative that can be easily administered with minimal adverse effects on the esophagus, stomach, and intestines by oral administration, In particular, in order to provide a bone resorption inhibitor comprising minodronic acid, a salt thereof or a hydrate thereof as an active ingredient, a bone resorption inhibitor which is orally administered on a schedule of four days a month or four weeks is disclosed. .

As a preparation containing a bisphosphonic acid derivative, Patent Document 4 discloses that a stable high-dose preparation containing a bisphosphonic acid derivative is provided in an amount of 30.0 to 36.0% by weight of an active substance and 4.0 to 6.0% by weight of a binder. A pharmaceutical composition is disclosed, comprising 3% to 59.4% by weight excipient, 4.5 to 5.5% by weight disintegrant, 1.8 to 2.2% by weight lubricant, and 0.9 to 1.1% by weight fluidity modifier.
Patent Document 5 discloses an oral preparation containing bisphosphonic acid, a sugar alcohol, and a water-soluble binder in the granulated phase, which has improved stability of the bisphosphonic acid derivative.
On the other hand, in Patent Document 6, as a tablet of a pharmaceutically active ingredient that easily induces a tableting trouble, (A) a granule containing a drug that easily induces a tableting trouble and crystalline cellulose, and (B) Mg-St and crystalline cellulose are included. A tablet having excellent moldability and drug elution is disclosed, which comprises a tableting aid.

  In the preparation containing a bisphosphonic acid derivative, the method of taking is strictly set, and a preparation with a longer dosing interval is required. Therefore, in addition to the once-daily preparation, once a week, The development of a product with a long dosing interval of once every four weeks is eagerly desired.

Japanese Patent Publication No. 6-99457 Patent No. 3385208 Specification International Publication WO2005 / 072747 Pamphlet Patent No.4427453 International Publication WO2005 / 030177 Pamphlet Special Table 2010-517936

Package for Osteoporosis Treatment “Bonoteo (registered trademark) 1 mg”, Astellas Pharma Inc.

According to the osteoporosis treatment “Bonoteo (registered trademark) tablets 1 mg” pharmaceutical interview form (Astellas Pharma Inc.), minodronic acid hydrate has “solubility” as described in the 16th revised Japanese Pharmacopoeia General Rules. By convention, it is extremely insoluble in water. Furthermore, it is known that the solubility changes depending on pH, and it is extremely difficult to dissolve particularly at pH 3 or lower.
Under such circumstances, the inventors have intensively studied to provide a once-in-a-time high-dose formulation of minodronic acid hydrate, and as a result, have found that there is room for improvement in dissolution in the prior art. In addition, when compression molding, I knew that tableting troubles such as sticking to a punch or mortar would occur.
An object of the present invention is to provide a pharmaceutical composition containing a high dose of minodronic acid or a pharmaceutically acceptable salt thereof or a hydrate thereof having rapid dissolution and moderate hardness.
Another object of the present invention is to provide a pharmaceutical composition containing a high dose of minodronic acid or a pharmaceutically acceptable salt or hydrate thereof that can be produced without any tableting troubles. To do.

As a result of intensive studies to solve the above-mentioned problems, the present inventors have found that a good dissolution property of a tablet can be maintained by selecting and using minodronic acid hydrate having a specific particle size. The invention has been completed.
That is, the present invention improves drug dissolution, improves tablet hardness by using a drug substance having a specific particle size and selecting its content, further using crystalline cellulose and selecting its content, and The present invention provides a high-dose pharmaceutical composition capable of obtaining a desired effect such as improvement of wrinkle adhesion.

Here, the present invention
[1] A pharmaceutical composition for high-dose oral administration containing minodronic acid or a pharmaceutically acceptable salt thereof or a hydrate thereof, and having a drug dissolution rate of 15% or more 15 minutes after the start of dissolution test ,
[2] The pharmaceutical composition for high-dose oral administration according to [1], wherein the average particle size of minodronic acid or a pharmaceutically acceptable salt or hydrate thereof is 1 μm or more and 20 μm or less,
[3] For high-dose oral administration according to [1] or [2], wherein minodronic acid or a pharmaceutically acceptable salt thereof or a hydrate thereof is contained in a pharmaceutical composition in an amount of 0.1% by weight to 50% by weight. Pharmaceutical composition,
[4] A pharmaceutical for high-dose oral administration according to any one of [1] to [3], wherein minodronic acid or a pharmaceutically acceptable salt thereof or a hydrate thereof is contained in a pharmaceutical composition in an amount of 10 mg to 1 g. Composition,
[5] The high-dose pharmaceutical composition for oral administration according to any one of [1] to [4], further comprising crystalline cellulose,
[6] The high dose oral administration of [5], wherein the amount of crystalline cellulose is 10% by weight or more and 150% by weight or less based on the weight of minodronic acid or a pharmaceutically acceptable salt or hydrate thereof. Pharmaceutical composition for
[7] The pharmaceutical composition for high-dose oral administration according to [5] or [6], wherein the amount of crystalline cellulose is 3% by weight or more and 30% by weight or less based on the weight of the pharmaceutical composition;
[8] The high-dose pharmaceutical composition for oral administration according to any one of [5] to [7], wherein the average particle size of the crystalline cellulose is 50 μm or less,
[9] The high-dose oral administration according to any one of [1] to [8], further comprising one or more substances selected from the group consisting of croscarmellose sodium, crospovidone, and sodium carboxymethyl starch Pharmaceutical composition for
[10] The pharmaceutical composition for high-dose oral administration according to [9], wherein the amount of the substance is 5% by weight or more and 50% by weight or less based on the weight of the pharmaceutical composition,
[11] The high-dose pharmaceutical composition for oral administration according to any one of [1] to [10], wherein the pharmaceutical composition for oral administration is a tablet,
[12] The method according to [1], comprising granulating minodronic acid or a pharmaceutically acceptable salt thereof or a hydrate thereof, and compressing and molding the granulated product with various additives. A method for producing a pharmaceutical composition for oral administration of a dose;
About.

  The present invention has effects such as (1) improvement of drug dissolution, (2) tablet hardness to such an extent that it does not break during distribution, and (3) improvement of wrinkle adhesion during compression molding.

  Hereinafter, embodiments of the present invention will be described in detail.

  In the present specification, the term “high dose” means, for example, that the amount of drug contained in the pharmaceutical composition is 10 mg to 1 g as minodronic acid hydrate, 10 mg to 500 mg as another embodiment, and 20 mg to 100 mg as a further embodiment. It is as follows. In another embodiment, it is 40 mg, 50 mg, or 60 mg. Yet another embodiment is 50 mg.

  In this specification, “rapid dissolution” means, for example, the dissolution rate of a drug measured by the dissolution test method described in the 16th revised Japanese Pharmacopoeia is 80% 15 minutes after the start of dissolution test. This is defined as elution.

  In this specification, “improvement of wrinkle adhesion” is defined, for example, as an aspect in which fogging is not visually observed in a wrinkle when compression molding. In another embodiment, the surface is observed with a microscope and is defined as having no haze on the surface.

  In the present invention, minodronic acid or a pharmaceutically acceptable salt or hydrate thereof is used as a drug.

Specific examples of the pharmaceutically acceptable salt of minodronic acid include a salt with an inorganic base such as a salt with an alkali metal such as sodium or potassium, or a salt with an alkaline earth metal such as calcium or magnesium. And ammonium salts, salts with organic bases such as methylamine, ethylamine, dimethylamine, diethylamine, trimethylamine, triethylamine, cyclohexylamine, ethanolamine and diethanolamine, and salts with basic amino acids such as lysine and ornithine.
Furthermore, minodronic acid or a pharmaceutically acceptable salt thereof may form a hydrate. Preferable is minodronic acid hydrate which is a free hydrate represented by the following formula (I).

  The dose of the drug varies depending on the administration subject, administration route, symptom, and the like, and is, for example, 0.1 mg to 10 mg or 0.5 mg to 5 mg by oral administration per day for an adult. In other embodiments, the dose is 3 mg to 1 g, 10 mg to 500 mg, or 20 mg to 100 mg orally administered every 4 weeks for adults. In one embodiment, 20 mg, 30 mg, 40 mg, 50 mg, 60 mg, 70 mg or 80 mg is administered orally per 4 weeks for an adult. In another embodiment, the dose is 50 mg orally per 4 weeks for an adult. In the pharmaceutical composition of the present invention, 0.1 wt% or more and 50 wt% or less is suitable, and in another embodiment, 1 wt% or more and 20 wt% or less is suitable.

  The average particle size of the drug is not particularly limited as long as the dissolution property is improved. For example, the average particle size is 1 μm or more and 20 μm or less. In another embodiment, D50 is 1 μm or more and 20 μm or less as measured by a particle size measurement method (dispersion solvent is ethanol (99.5), relative refractive index 1.18) by laser diffraction method described in Japanese Pharmacopoeia. Examples of the method for measuring the average particle diameter include a laser diffraction method.

The crystalline cellulose that can be optionally used in the present invention is not particularly limited as long as the effects of the present invention can be obtained. For example, α-cellulose obtained as a pulp from a fibrous plant is partially used with an acid. What can be obtained by depolymerizing and purifying (16th revision Japanese Pharmacopoeia) can be mentioned.
Crystalline cellulose is pharmaceutically acceptable and retains good dissolution properties of minodronic acid or pharmaceutically acceptable salts or hydrates thereof, and minodronic acid or pharmaceutically acceptable salts thereof or If the tablet composition such as wrinkle adhesion does not occur when the pharmaceutical composition containing the hydrate is compression-molded, the bulk density and the average degree of polymerization can be used without particular limitation.

  Specific examples of crystalline cellulose include Theola PH101 (average particle diameter 50 μm), Theola PH102 (average particle diameter 90 μm), Theola PH101D (average particle diameter 50 μm), Theola KG802 (average particle diameter 50 μm), Theola KG801 (average Particle size 50μm), Theolas UF711 (average particle size 50μm), Theolas UF702 (average particle size 90μm), Theolas KG1000 (average particle size 50μm), Theolas PH301 (average particle size 50μm), Theolas PH301D (average particle size 50μm), Theolas PH301Z (average particle size 50μm), Theolas PH302 (average particle size 90μm), Theolas PH F20JP (average particle size 20μm) (all Asahi Kasei), Avicel PH101, Avicel PH112, Avicel Ph113, Avicel PH200, Avicel PH301, Avicel PH302 , Avicel HFE-102, Avicel DG, Avicel PH-105 (all FMC Biopolymer), Celex 101 (International Specialty Products), Emcocel 90M, Emcocel LM50M, Emcocel 50M, Vivacel 12, VIVAPUR (registered trademark) 101 Premium, VI Examples include VAPUR 105, VIVAPUR 301 (J. Rettenmaier & Sohne), and Pharmacel 101 (DMV-Fonterra Excipients) Selfia (San-Eigen FFI).

The shape of the crystalline cellulose is not particularly limited, such as granular or acicular. Needle-shaped ones can also be crushed and used.
Moreover, what is marketed as a mixture compounded with other additives (carrageenan, sodium carboxymethylcellulose, guar gum, etc.) can also be used.
The average particle diameter of the crystalline cellulose is not particularly limited. For example, it is 50 μm or less, and in another embodiment, it is 1 μm or more and 50 μm or less. When the crystalline cellulose has a granular shape, examples of the method for measuring the average particle size include measurement by the second method (sieving method) of the powder particle size measurement method described in the Japanese Pharmacopoeia.

The average particle diameter of the crystalline cellulose is, for example, obtained by sieving 10 g or 30 g of a sample for 10 minutes using a JIS standard sieve (Z8801-1987) using a low-tap sieve shaker (Sieve Shaker A type, manufactured by Hiraiko Seisakusho) A particle size of 50% by weight can be measured as an average particle size.
The average particle size of crystalline cellulose is determined from the particle size of 50% by weight using an air jet sheave particle size distribution analyzer (ALPINE air jet sheave A200LS type) when there are many fractions of 45 μm or less.
In addition, the crystalline cellulose may be used in a combination of one kind or two or more kinds having different grades, shapes, average particle diameters and the like as appropriate.

  The blending amount of crystalline cellulose is not particularly limited as long as minodronic acid or a pharmaceutically acceptable salt thereof or a hydrate thereof usually shows good dissolution properties and does not cause tableting trouble such as wrinkle adhesion. Is, for example, 3% by weight to 30% by weight in the pharmaceutical composition of the present invention, and in another embodiment 5% by weight to 20% by weight, or minodronic acid or a pharmaceutically acceptable salt thereof Or it is 10 weight% or more and 150 weight% or less with respect to the weight of the hydrate, and is 30 weight% or more and 100 weight% or less as another aspect.

  The pharmaceutical composition of the present invention may optionally contain one or more substances selected from the group consisting of croscarmellose sodium, crospovidone, and sodium carboxymethyl starch.

Croscarmellose sodium is a sodium salt of a crosslinked polyvalent carboxymethyl ether of cellulose (16th revised Japanese Pharmacopoeia).
Croscarmellose sodium is not particularly limited as long as it is pharmaceutically acceptable. Specific examples include Ac-Di-Sol (FMC Biopolymer) and Kiccolate (Asahi Kasei). An appropriate amount of these croscarmellose sodium can be added as appropriate, alone or in combination.

  Crospovidone is not particularly limited as long as it is pharmaceutically acceptable. Specific examples include Kollidon CL (BASF Japan), Kollidon CL-F (BASF Japan), Kollidon CL-M (BASF Japan), and Kollidon CL-SF (BASF Japan). These crospovidones can be appropriately added in an appropriate amount, alone or in combination.

  Sodium carboxymethyl starch is not particularly limited as long as it is pharmaceutically acceptable. Specifically, for example, Primojel (DMV-Fonterra Excipients) can be mentioned, and an appropriate amount can be appropriately added in combination of one or more.

  The amount of croscarmellose sodium, crospovidone, and sodium carboxymethyl starch is not particularly limited as long as minodronic acid or a pharmaceutically acceptable salt thereof or a hydrate thereof exhibits an excellent dissolution property. The total blending amount thereof is, for example, 5% by weight or more and 50% by weight or less in the pharmaceutical composition of the present invention. 5 wt% or more and 90 wt% or less with respect to the weight of the salt or hydrate thereof, and in another embodiment 30 wt% or more and 60 wt% or less.

  In the pharmaceutical composition of the present invention, various pharmaceutical additives are appropriately used and formulated as desired. Such a pharmaceutical additive is not particularly limited as long as it is pharmaceutically acceptable and pharmacologically acceptable. For example, excipients, binders, disintegrants, acidulants, foaming agents, artificial sweeteners, fragrances, lubricants, colorants, buffers, antioxidants, surfactants, and the like are used.

Examples of the excipient include D-mannitol and lactose hydrate.
Examples of the binder include gum arabic, hydroxypropylmethylcellulose, hydroxypropylcellulose, hydroxyethylcellulose and the like.
Examples of the disintegrant include corn starch, potato starch, carmellose calcium, carmellose sodium, low-substituted hydroxypropylcellulose, croscarmellose sodium, crospovidone, and carboxymethyl starch sodium.
Examples of the sour agent include citric acid, tartaric acid, malic acid and the like.
Examples of the foaming agent include baking soda.
Examples of the artificial sweetener include saccharin sodium, dipotassium glycyrrhizin, aspartame, stevia and thaumatin.
Examples of the fragrances include lemon, lemon lime, orange and menthol.
Examples of the lubricant include light anhydrous silicic acid, magnesium stearate, calcium stearate, sucrose fatty acid ester, polyethylene glycol, talc, stearic acid and the like.
Examples of the colorant include yellow ferric oxide, red ferric oxide, black iron oxide, edible yellow Nos. 4 and 5, edible red Nos. 3 and 102, and edible blue No. 3 and the like.
Buffers include citric acid, succinic acid, fumaric acid, tartaric acid, ascorbic acid or salts thereof, glutamic acid, glutamine, glycine, aspartic acid, alanine, arginine or salts thereof, magnesium oxide, zinc oxide, magnesium hydroxide, phosphoric acid Boric acid or a salt thereof.
Examples of the antioxidant include ascorbic acid, dibutylhydroxytoluene, propyl gallate and the like.
Examples of the surfactant include polysorbate 80, sodium lauryl sulfate, polyoxyethylene hydrogenated castor oil, and the like.

As a pharmaceutical additive, one or a combination of two or more can be appropriately added in an appropriate amount.
As for the blending amount, any pharmaceutical additive is used in an amount within the range in which the desired effect of the present invention is achieved.

  As a pharmaceutical composition of this invention, the formulation manufactured by compression molding processes, such as an orally disintegrating tablet, is included other than a normal tablet.

The method for producing the pharmaceutical composition of the present invention will be described below.
The method for producing a pharmaceutical composition of the present invention includes at least a granulation step and a compression molding step (tablet step). If desired, for example, a pulverization step, a granulation step and a compression step that can be performed before the granulation step. It can include a mixing step that can be performed during the molding step and / or a film coating step that can be performed after the compression molding step.

The pulverization step is not particularly limited to any device or means as long as it is a method that can pharmaceutically pulverize drugs and appropriate additives. Examples of the pulverizer include an impact pulverizer, a hammer mill, a ball mill, a jet pulverizer, and a colloid mill. The grinding conditions are not particularly limited as long as they are appropriately selected.
The mixing step of each component continuous with the pulverization is not particularly limited to any device or means as long as it is a method that can generally uniformly mix each component pharmaceutically.

In the granulation step, the pulverized product obtained in the pulverization step and various additives are put into a granulator and sprayed with a binder solution. You may dry during a granulation process. Examples of the granulator include a fluidized bed granulator.
As granulation methods, for example, fluidized bed granulation method, melt granulation method, high speed stirring granulation method, crushing (pulverization) granulation method, extrusion granulation method, rolling granulation method, spray granulation method, dry method Examples thereof include a granulation method and an apparatus used by those methods. Another embodiment is a fluidized bed granulation method.
The preparation conditions of the spray liquid are not particularly limited as long as they are appropriately selected.
It can also be dried after granulation. The drying method is not particularly limited as long as it is a pharmaceutically drying method.

  In the mixing step, the granulated product and various additives are mixed.

In the compression molding process (tabletting process), the mixed product is tableted using a rotary tableting machine to obtain a tableted product.
The process is not particularly limited to any device or means as long as it is a method for molding the pharmaceutical composition of the present invention. For example, a method of granulating and further mixing a lubricant and then compression molding to produce a tablet can be mentioned.
Examples of the tableting device include a rotary tableting machine, a single tableting machine, and an oil press.
Tableting conditions such as tableting pressure are not particularly limited as long as the tablet can be molded and the tableting pressure does not damage the tablet during the production process. For example, compression molding can be performed at about 3 kN or more and about 20 kN or less, and as another embodiment, about 5 kN or more and about 20 kN.
In addition, the tablet hardness is not particularly limited as long as the hardness is such that it does not break in the distribution process or the like. For example, 80N or more and 200N or less, and other modes include 90N or more and 170N or less.

As the film coating step, the tablet surface may be appropriately coated after tableting.
The method is not particularly limited as long as it is usually a pharmaceutically coating method. Examples thereof include pan coating and dip coating.
The film coating agent can be appropriately added in an appropriate amount by combining one or more kinds. A coating rate will not be restrict | limited especially if it is a rate which forms a film in a tablet. For example, it is 1 to 5% by weight with respect to the tablet weight.
You may dry after film coating. The method is not particularly limited as long as it can be usually pharmaceutically dried.

EXAMPLES Hereinafter, although an Example, a comparative example, and a test example are given and this invention is demonstrated further in detail, this invention is not limitedly interpreted by these.
Minodronic acid hydrate was prepared by the method described in Japanese Patent No. 3385208.

Example 1
A 7% by weight hydroxypropylcellulose solution was prepared and used as a binder solution. Next, until 50 parts of minodronic acid hydrate pulverized product (average particle diameter D50: 15 μm, the same unless otherwise stated), 158 parts of D-mannitol, and 9 parts of croscarmellose sodium until 13.5 parts of hydroxypropylcellulose It was granulated with a fluid bed granulator by spraying the binder solution. After spraying the binder solution, the granulated product was dried to obtain the pharmaceutical composition (granulated product) of the present invention. 230.5 parts of the above pharmaceutical composition (granulated product), 45 parts of crystalline cellulose (PH-101, average particle size 50 μm, Asahi Kasei Chemicals), 20 parts of croscarmellose sodium and 4.5 parts of magnesium stearate using a container rotary mixer After mixing, the mixture was compressed with a rotary tableting machine to obtain the pharmaceutical composition (tablet) of the present invention (tablet mass 300 mg).

Example 2
A 7% by weight hydroxypropylcellulose solution was prepared and used as a binder solution. Next, the fluidized bed granulator was sprayed with 60 parts of minodronic acid hydrate product, 184.8 parts of D-mannitol, and 10.8 parts of croscarmellose sodium until the hydroxypropylcellulose was 16.2 parts. Granulated with. After spraying the binder solution, the granulated product was dried to obtain the pharmaceutical composition (granulated product) of the present invention. 271.8 parts of the above pharmaceutical composition (granulated product), 54 parts of crystalline cellulose (KG-802, average particle size 50 μm, Asahi Kasei Chemicals), 25.2 parts of croscarmellose sodium and 5.4 parts of magnesium stearate are charged into a container rotary mixer. After mixing, the pharmaceutical composition (tablet) of the present invention was obtained using a rotary tableting machine (tablet mass 356.4 mg).

Example 3
A 7% by weight hydroxypropylcellulose solution was prepared and used as a binder solution. Next, the fluidized bed granulator was sprayed with 60 parts of minodronic acid hydrate product, 184.8 parts of D-mannitol, and 10.8 parts of croscarmellose sodium until the hydroxypropylcellulose was 16.2 parts. Granulated with. After spraying the binder solution, the granulated product was dried to obtain the pharmaceutical composition (granulated product) of the present invention. After mixing 271.8 parts of the pharmaceutical composition (granulated product), 54 parts of crystalline cellulose (PH-101), 25.2 parts of croscarmellose sodium and 5.4 parts of magnesium stearate using a container rotary mixer, rotary tableting machine To obtain a pharmaceutical composition (tablet) of the present invention (tablet mass 356.4 mg).

Example 4
A 7% by weight hydroxypropylcellulose solution was prepared and used as a binder solution. Next, the fluidized bed granulator was sprayed with 50 parts of minodronic acid hydrate product, 158 parts of D-mannitol, and 9 parts of croscarmellose sodium until the hydroxypropyl cellulose was 13.5 parts. Granulated with. After spraying the binder solution, the granulated product was dried to obtain the pharmaceutical composition (granulated product) of the present invention. After mixing 230.5 parts of the pharmaceutical composition (granulated product), 45 parts of crystalline cellulose (PH-101), 20 parts of croscarmellose sodium and 4.5 parts of magnesium stearate using a container rotary mixer, rotary tableting machine To obtain a pharmaceutical composition (tablet) of the present invention (tablet mass 300 mg).

Example 5
A 7% by weight hydroxypropylcellulose solution was prepared and used as a binder solution. Next, spray the binder solution on 50 parts of minodronic acid hydrate (average particle size D50: 10 μm), 158 parts of D-mannitol and 9 parts of croscarmellose sodium until 13.5 parts of hydroxypropylcellulose is obtained. Was granulated with a fluid bed granulator. After spraying the binder solution, the granulated product was dried to obtain the pharmaceutical composition (granulated product) of the present invention. After mixing 230.5 parts of the pharmaceutical composition (granulated product), 45 parts of crystalline cellulose (PH-101), 20 parts of croscarmellose sodium and 4.5 parts of magnesium stearate using a container rotary mixer, rotary tableting machine To obtain a pharmaceutical composition (tablet) of the present invention (tablet mass 300 mg).

Example 6
A 7% by weight hydroxypropylcellulose solution was prepared and used as a binder solution. Next, 40 parts of minodronic acid hydrate pulverized product and 178.4 parts of lactose hydrate were charged into a fluidized bed granulator, and the binder solution was sprayed and granulated until 7.2 parts of hydroxypropylcellulose was formed. After spraying the binder solution, the granulated product was dried to obtain the pharmaceutical composition (granulated product) of the present invention. 225.6 parts of the above pharmaceutical composition (granulated product), 12 parts of croscarmellose sodium and 2.4 parts of magnesium stearate are charged into a container rotary mixer and mixed, then autograph (Shimadzu Corporation, AGS-20KNG, the same applies below) Was used to obtain the pharmaceutical composition (tablet) of the present invention (tablet mass 240 mg).

Example 7
A 7% by weight hydroxypropylcellulose solution was prepared and used as a binder solution. Next, 40 parts of minodronic acid hydrate pulverized product and 178.4 parts of lactose hydrate were charged into a fluidized bed granulator, and the binder solution was sprayed and granulated until 7.2 parts of hydroxypropylcellulose was formed. After spraying the binder solution, the granulated product was dried to obtain the pharmaceutical composition (granulated product) of the present invention. Charge 225.6 parts of the pharmaceutical composition (granulated product), 12 parts of crospovidone and 2.4 parts of magnesium stearate into a container rotary mixer, and after mixing, use the autograph to obtain the pharmaceutical composition (tablet) of the present invention. Obtained (tablet weight 240 mg).

Example 8
A 7% by weight hydroxypropylcellulose solution was prepared and used as a binder solution. Next, 40 parts of minodronic acid hydrate pulverized product and 178.4 parts of lactose hydrate were charged into a fluidized bed granulator, and the binder solution was sprayed and granulated until 7.2 parts of hydroxypropylcellulose was formed. After spraying the binder solution, the granulated product was dried to obtain the pharmaceutical composition (granulated product) of the present invention. 225.6 parts of the pharmaceutical composition (granulated product), 12 parts of sodium carboxymethyl starch and 2.4 parts of magnesium stearate are charged in a container rotary mixer, and after mixing, the pharmaceutical composition (tablet of the present invention is used using an autograph. (Tablet weight 240 mg).

Example 9
A 7% by weight hydroxypropylcellulose solution was prepared and used as a binder solution. Next, 40 parts of minodronic acid hydrate pulverized product and 178.4 parts of lactose hydrate were charged into a fluidized bed granulator, and the binder solution was sprayed and granulated until 7.2 parts of hydroxypropylcellulose was formed. After spraying the binder solution, the granulated product was dried to obtain the pharmaceutical composition (granulated product) of the present invention. 225.6 parts of the pharmaceutical composition (granulated product), 24 parts of croscarmellose sodium and 2.4 parts of magnesium stearate are charged in a container rotary mixer, and after mixing, the pharmaceutical composition (tablet of the present invention using an autograph) (Tablet weight 252 mg).

Example 10
A 7% by weight hydroxypropylcellulose solution was prepared and used as a binder solution. Next, 40 parts of minodronic acid hydrate pulverized product and 178.4 parts of lactose hydrate were charged into a fluidized bed granulator, and the binder solution was sprayed and granulated until 7.2 parts of hydroxypropylcellulose was formed. After spraying the binder solution, the granulated product was dried to obtain the pharmaceutical composition (granulated product) of the present invention. Charge 225.6 parts of the pharmaceutical composition (granulated product), 24 parts of crospovidone and 2.4 parts of magnesium stearate into a container rotary mixer, and after mixing, use the autograph to obtain the pharmaceutical composition (tablet) of the present invention. Obtained (tablet weight 252 mg).

Example 11
A 7% by weight hydroxypropylcellulose solution was prepared and used as a binder solution. Next, 40 parts of minodronic acid hydrate pulverized product and 178.4 parts of lactose hydrate were charged into a fluidized bed granulator, and the binder solution was sprayed and granulated until 7.2 parts of hydroxypropylcellulose was formed. After spraying the binder solution, the granulated product was dried to obtain the pharmaceutical composition (granulated product) of the present invention. 225.6 parts of the pharmaceutical composition (granulated product), 24 parts of sodium carboxymethyl starch and 2.4 parts of magnesium stearate are charged into a container rotary mixer, and after mixing, using the autograph, the pharmaceutical composition (tablet of the present invention (Tablet weight 252 mg).

<< Comparative Example 1 >>
A 7% by weight hydroxypropylcellulose solution was prepared and used as a binder solution. Next, spray the binder solution onto 50 parts of minodronic acid hydrate (average particle size D50: 35 μm), 158 parts of D-mannitol, and 9 parts of croscarmellose sodium until hydroxypropylcellulose is 13.5 parts. This was granulated with a fluidized bed granulator. After spraying the binder solution, the granulated product was dried to obtain a comparative pharmaceutical composition (granulated product). After mixing 230.5 parts of the pharmaceutical composition (granulated product), 45 parts of crystalline cellulose (PH-101), 20 parts of croscarmellose sodium and 4.5 parts of magnesium stearate using a container rotary mixer, rotary tableting machine The pharmaceutical composition (tablet) for comparison was obtained (tablet mass 300 mg).

Example 12
A 7% by weight hydroxypropylcellulose solution was prepared and used as a binder solution. Next, the fluidized bed granulator was sprayed with 60 parts of minodronic acid hydrate product, 204.6 parts of D-mannitol, and 10.8 parts of croscarmellose sodium until the hydroxypropylcellulose was 16.2 parts. Granulated with. After spraying the binder solution, the granulated product was dried to obtain the pharmaceutical composition (granulated product) of the present invention. After mixing 291.6 parts of the pharmaceutical composition (granulated product), 54 parts of crystalline cellulose (KG-802), 25.2 parts of croscarmellose sodium and 7.3 parts of magnesium stearate using a container rotary mixer, rotary tableting machine To obtain a pharmaceutical composition (tablet) of the present invention (tablet mass 378 mg).

Example 13
A 7% by weight hydroxypropylcellulose solution was prepared and used as a binder solution. Next, the fluidized bed granulator was sprayed with 60 parts of minodronic acid hydrate product, 184.8 parts of D-mannitol, and 10.8 parts of croscarmellose sodium until the hydroxypropylcellulose was 16.2 parts. Granulated with. After spraying the binder solution, the granulated product was dried to obtain the pharmaceutical composition (granulated product) of the present invention. After mixing 230.5 parts of the pharmaceutical composition (granulated product), 54 parts of crystalline cellulose (PH-101), 25.2 parts of croscarmellose sodium and 5.4 parts of magnesium stearate using a container rotary mixer, rotary tableting machine To obtain a pharmaceutical composition (tablet) of the present invention (tablet mass 356.4 mg).

<< Test Example 1: Adhesion of wrinkles >>
The presence or absence of wrinkle adhesion of the pharmaceutical composition (tablet) of the present invention was evaluated. Evaluation was carried out using a rotary tableting machine (manufactured by Hata Iron Works Co., Ltd., HT-X-SS20, the same shall apply hereinafter) and the composition of the Examples and Comparative Examples were tableted under the conditions shown in Table 3, and the surface of the punch was visually observed. Or it observed with the microscope (KEYENCE, digital microscope). When the haze surface was cloudy, it was evaluated that there was haze adhesion, and when there was no haze, no haze adhesion was observed. The results are shown in Tables 4 and 5.
By using crystalline cellulose, it is considered that the adhesion between the powders is increased and the wrinkle adhesion is improved. When a composition containing minodronic acid hydrate (7 mg), lactose, corn starch, hydroxypropylcellulose, low-substituted hydroxypropylcellulose, and magnesium stearate is compression molded, there are tableting problems such as sticking to pestle and mortar. Although it occurred, the use of crystalline cellulose improved wrinkle adhesion.

<< Test Example 2: Dissolution Test >>
The dissolution test of the pharmaceutical composition (tablet) of the present invention and the comparative pharmaceutical composition (tablet) was conducted. The dissolution test was carried out according to the Japanese Pharmacopoeia dissolution test method using 6 tablets each of Examples and Comparative Examples. As a test solution, 900 mL of the first solution of the Japanese Pharmacopoeia dissolution test was used (apparatus 2 paddle method paddle rotation speed 50 rpm or apparatus 1 rotation basket method 100 rpm). The results (dissolution rate D _15min 15 minutes after the start of the test) are shown in Tables 4 and 5.

In Examples 1 to 11 in which the average particle diameter D50 of minodronic acid hydrate is 15 μm or 10 μm, respectively, D _15min is 80% or more, whereas the average particle diameter D50 of minodronic acid hydrate is 35 μm. In Comparative Example 1, D _15min was 56%. Therefore, elution was improved by using minodronic acid hydrate having a specific particle size.

<< Test Example 3: Hardness >>
The hardness of the pharmaceutical composition (tablet) of the present invention and the comparative pharmaceutical composition (tablet) was measured. The hardness was measured using 10 tablets each of the examples and comparative examples. The average values are shown in Tables 4 and 5.
As a result, the examples in which the average particle size of minodronic acid hydrate was small were higher in hardness than the comparative examples.

  The pharmaceutical composition of the present invention contains minodronic acid useful as a therapeutic agent for osteoporosis or a pharmaceutically acceptable salt or hydrate thereof, and has improved drug dissolution, tablet hardness, wrinkle adhesion, and the like. It can be used as a high dose formulation.

Claims (5)

The salt or a hydrate thereof is minodronic acid or pharmaceutically acceptable 50mg in the pharmaceutical tablet, or 60mg contain, Japanese Pharmacopoeia of minodronic acid or a pharmaceutically acceptable salt thereof or a hydrate thereof the average particle diameter D ₅₀ Ri der least 20μm or less 1 [mu] m, the drug dissolution rate of 15 minutes after the start of the dissolution test is 80% or more, der tablet hardness is more than 109N, measured by a laser diffraction method described in A high-dose pharmaceutical tablet for oral administration. The pharmaceutical tablet for high-dose oral administration according to claim 1, wherein minodronic acid or a pharmaceutically acceptable salt thereof or a hydrate thereof is contained in the pharmaceutical tablet in an amount of 0.1 wt% to 50 wt%. The pharmaceutical tablet for high-dose oral administration according to claim 1 or 2 , further comprising one or more substances selected from the group consisting of croscarmellose sodium, crospovidone, and sodium carboxymethyl starch. The amount of said substance is 50 wt% or less 5 wt% or more based on the weight of the pharmaceutical tablet, high-dose oral administration pharmaceutical tablet according to claim 3. High-dose oral administration pharmaceutical tablet is a once-type high-dose tablets 4 weeks, high dose oral pharmaceutical tablet according to any one of claims 1 to 4.