JP5874545B2 - Pharmaceutical composition for oral administration - Google Patents
Pharmaceutical composition for oral administration Download PDFInfo
- Publication number
- JP5874545B2 JP5874545B2 JP2012138410A JP2012138410A JP5874545B2 JP 5874545 B2 JP5874545 B2 JP 5874545B2 JP 2012138410 A JP2012138410 A JP 2012138410A JP 2012138410 A JP2012138410 A JP 2012138410A JP 5874545 B2 JP5874545 B2 JP 5874545B2
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- Japan
- Prior art keywords
- parts
- pharmaceutical composition
- tablet
- hydrate
- weight
- Prior art date
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- 239000008194 pharmaceutical composition Substances 0.000 title description 81
- 229950011129 minodronic acid Drugs 0.000 claims description 50
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- 239000003814 drug Substances 0.000 claims description 16
- 238000004090 dissolution Methods 0.000 claims description 15
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- 235000002639 sodium chloride Nutrition 0.000 description 30
- GPAPAOGRNKUFGH-UHFFFAOYSA-N (1-hydroxy-2-imidazo[1,2-a]pyridin-3-yl-1-phosphonoethyl)phosphonic acid;hydrate Chemical compound O.C1=CC=CN2C(CC(O)(P(O)(O)=O)P(O)(O)=O)=CN=C21 GPAPAOGRNKUFGH-UHFFFAOYSA-N 0.000 description 28
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- 210000000936 intestine Anatomy 0.000 description 1
- 229910052742 iron Inorganic materials 0.000 description 1
- WTFXARWRTYJXII-UHFFFAOYSA-N iron(2+);iron(3+);oxygen(2-) Chemical compound [O-2].[O-2].[O-2].[O-2].[Fe+2].[Fe+3].[Fe+3] WTFXARWRTYJXII-UHFFFAOYSA-N 0.000 description 1
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Landscapes
- Medicinal Preparation (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Description
本発明は、ミノドロン酸もしくは製薬学的に許容されるその塩又はその水和物を含有してなる高用量経口投与用医薬組成物に関する。 The present invention relates to a pharmaceutical composition for high-dose oral administration comprising minodronic acid or a pharmaceutically acceptable salt or hydrate thereof.
特許文献１には、一般式：
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:
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.
特許文献１によれば、ヘテロ環ビスフォスフォン酸誘導体またはその塩は、すぐれた血清カルシウム量の低下作用を示し、骨吸収を抑制することが知られている。また、骨吸収の亢進が病態に重要な関与をしていると考えられている疾患である、Paget病、高カルシウム血症、癌の骨転移、骨粗鬆症、及び慢性関節リウマチ等の炎症性関節疾患に伴う骨吸収の亢進（骨粗鬆化）に対して、骨吸収を抑制し、骨量の減少を防止あるいは骨吸収の亢進に伴う血清カルシウム値の上昇等を防止または低下させる薬剤として有用であることが報告されている。また、その改善された製造方法が、特許文献２に開示されている。 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.
骨粗鬆症治療剤として、前記ヘテロ環ビスフォスフォン酸誘導体の１つである下記式：
ビスフォスフォン酸誘導体を有効成分としてなる骨吸収抑制剤としては、特許文献３に、経口投与による食道、胃および腸への悪影響を最小限に抑え、簡便に投与可能なビスフォスフォン酸誘導体、殊にミノドロン酸、その塩またはその水和物を有効成分としてなる骨吸収抑制剤を提供するため、月または４週に４日投与するスケジュールで経口投与される骨吸収抑制剤が開示されている。 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. .
ビスフォスフォン酸誘導体を含有する製剤としては、特許文献４に、ビスフォスフォン酸誘導体を含有する安定な高用量製剤を提供するためとして、活性物質30.0〜36.0重量%、結合剤4.0〜6.0重量%、賦形剤39.6〜59.4重量%、崩壊剤4.5〜5.5重量%、滑沢剤1.8〜2.2重量%、及び流動性調製剤0.9〜1.1重量%からなる医薬組成物が開示されている。
また、特許文献５には、ビスフォスフォン酸誘導体の安定性を改善した、ビスフォスフォン酸、糖アルコール、水溶性結合剤を造粒物相に含有する経口製剤が開示されている。
一方、特許文献６には、打錠障害を誘引しやすい医薬活性成分の錠剤として、(A)打錠障害を誘引しやすい薬物及び結晶セルロースを含む顆粒及び（B)Mg-St及び結晶セルロースを含む打錠助剤からなる、成形性や薬物の溶出性が優れる錠剤が開示されている。
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.
ビスフォスフォン酸誘導体を含有する製剤は、服用方法が厳しく設定されており、より服用間隔を長くした製剤が求められているため、１日１回型製剤に加えて、週１回、さらには4週に１回という服用間隔が長い製剤の開発が切望されている。 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.
骨粗鬆症治療剤「ボノテオ（登録商標）錠1mg」医薬品インタビューフォーム（アステラス製薬株式会社）によると、ミノドロン酸水和物は、第十六改正日本薬局方の通則に記載されている「溶解性」の規定では、水に極めて溶けにくい。更に、pHによって溶解性が変化し、特にpH3以下において極めて溶けにくいことが知られている。
かかる状況下、発明者らは、ミノドロン酸水和物の４週に１回型高用量製剤を提供すべく鋭意検討した結果、従来技術では溶出性に改善の余地があることを知った。また、圧縮成形したところ、杵や臼への付着といった打錠障害が生じることを知った。
本発明は、速やかな溶出性と適度な硬度を有する高用量のミノドロン酸もしくは製薬学的に許容されるその塩又はその水和物を含有する医薬組成物を提供することを課題とする。
また、本発明は、打錠障害等がなく、製造可能である高用量のミノドロン酸もしくは製薬学的に許容されるその塩又はその水和物を含有する医薬組成物を提供することを課題とする。
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.
本発明者らは上記課題を解決すべく鋭意検討した結果、特定の粒子径を有するミノドロン酸水和物を選択・使用することにより、錠剤の良好な溶出性を保持できることを知見して、本発明を完成させるに至った。
すなわち、本発明は、特定の粒子径を有する原薬の使用並びにその含有量の選択、更には結晶セルロースの使用並びにその含有量の選択により、薬物の溶出性の改善、錠剤硬度の改善、及び杵付着性の改善等、所望の効果を得られる高用量の医薬組成物を提供するものである。
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.
ここに、本発明は、
［１］ミノドロン酸もしくは製薬学的に許容されるその塩又はその水和物を含有し、溶出試験開始後15分後の薬物溶出率が80％以上である、高用量経口投与用医薬組成物、
［２］ミノドロン酸もしくは製薬学的に許容されるその塩又はその水和物の平均粒子径が1μm以上20μm以下である、［１］の高用量経口投与用医薬組成物、
［３］ミノドロン酸もしくは製薬学的に許容されるその塩又はその水和物を医薬組成物中に0.1重量％以上50重量％以下含有する、［１］または［２］の高用量経口投与用医薬組成物、
［４］ミノドロン酸もしくは製薬学的に許容されるその塩又はその水和物を医薬組成物中に10mg以上1g以下含有する、［１］〜［３］のいずれかの高用量経口投与用医薬組成物、
［５］更に結晶セルロースを含有する、［１］〜［４］のいずれかの高用量経口投与用医薬組成物、
［６］結晶セルロースの量が、ミノドロン酸もしくは製薬学的に許容されるその塩又はその水和物の重量に対して10重量％以上150重量％以下である、［５］の高用量経口投与用医薬組成物、
［７］結晶セルロースの量が、医薬組成物の重量に対して3重量％以上30重量％以下である、［５］または［６］の高用量経口投与用医薬組成物、
［８］結晶セルロースの平均粒子径が50μm以下である、［５］〜［７］のいずれかの高用量経口投与用医薬組成物、
［９］更に、クロスカルメロースナトリウム、クロスポビドン、カルボキシメチルスターチナトリウムからなる群より選択される１、または２以上の物質を含有する、［１］〜［８］のいずれかの高用量経口投与用医薬組成物、
［１０］前記物質の量が、医薬組成物の重量に対して5重量％以上50重量％以下である、［９］の高用量経口投与用医薬組成物、
［１１］経口投与用医薬組成物が、錠剤である、［１］〜［１０］のいずれかの高用量経口投与用医薬組成物、
［１２］ミノドロン酸もしくは製薬学的に許容されるその塩又はその水和物を造粒する工程、及び該造粒物に各種添加剤を含み圧縮成型する工程、を含む、［１］の高用量経口投与用医薬組成物の製造方法、
に関する。
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.
本発明は、（１）薬物溶出性を改善し、（２）流通過程で破損しない程度の錠剤硬度を有し、（３）圧縮成型時における杵付着性を改善する等、の効果を有する。 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.
以下、本発明の実施の形態について、詳細に説明する。 Hereinafter, embodiments of the present invention will be described in detail.
本明細書において「高用量」とは、例えば、医薬組成物中に含有する薬物量がミノドロン酸水和物として10mg以上1g以下、他の態様として10mg以上500mg以下、更なる態様として20mg以上100mg以下である。別の態様として、40mg、50mg、又は60mgである。更に別の態様として50mgである。 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.
本明細書において「速やかな溶出性」とは、例えば、第十六改正日本薬局方に記載されている溶出試験法で測定した際の薬物の溶出率が、溶出試験開始後15分で80％以上溶出であると規定する。 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.
本明細書において「杵付着性の改善」とは、例えば、圧縮成型した際に、杵に曇りが目視にて見られない態様と規定する。他の態様として、マイクロスコープによって観察し、杵表面に曇りがないことと規定する。 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.
本発明では、薬物としてミノドロン酸もしくは製薬学的に許容されるその塩又はその水和物を使用する。 In the present invention, minodronic acid or a pharmaceutically acceptable salt or hydrate thereof is used as a drug.
ここに、ミノドロン酸の製薬学的に許容される塩としては具体的には、ナトリウム、カリウムなどのアルカリ金属との塩、カルシウム、マグネシウムなどのアルカリ土類金属との塩など無機塩基との塩、アンモニウム塩、メチルアミン、エチルアミン、ジメチルアミン、ジエチルアミン、トリメチルアミン、トリエチルアミン、シクロヘキシルアミン、エタノールアミン、ジエタノールアミンなどの有機塩基との塩、リジン、オルニチンなどの塩基性アミノ酸との塩等が挙げられる。
更に、ミノドロン酸もしくは製薬学的に許容されるその塩は水和物を形成していてもよい。好適には、下記式（Ｉ）で示されるフリー体の水和物であるミノドロン酸水和物である。
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).
薬物の投与量は投与対象、投与ルート、症状等によって異なるが、例えば成人１日当たり経口投与で0.1mg以上10mg以下、又は、0.5mg以上5mg以下である。他の態様として成人4週間当たり経口投与で3mg以上1g以下、10mg以上500mg以下、又は20mg以上100mg以下である。ある態様としては、成人4週間当たり経口投与で20mg、30mg、40mg、50mg、60mg、70mg又は80mgである。別の態様としては、成人4週間当たり経口投与で50mgである。本発明の医薬組成物中に0.1重量％以上50重量％以下、他の態様として1重量%以上20重量％以下が適当である。 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.
薬物の平均粒子径は、溶出性が改善されれば特に制限されない。例えば、平均粒子径が1μm以上20μm以下である。他の態様として、日本薬局方に記載されているレーザー回折法による粒子径測定法（分散溶媒はエタノール(99.5)、相対屈折率1.18）で測定した際のD50が1μm以上20μm以下である。平均粒子径の測定方法は、例えば、レーザー回折法等が挙げられる。 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.
本発明で所望により用いることのできる結晶セルロースは、本発明の効果が得られる限り、特に限定されるものではないが、例えば、繊維性植物からパルプとして得たα−セルロースを酸で部分的に解重合し精製することによって得られるもの（第十六改正日本薬局方）を挙げることができる。
結晶セルロースは、製薬学的に許容され、ミノドロン酸もしくは製薬学的に許容されるその塩又はその水和物の良好な溶出性を保持し、ミノドロン酸もしくは製薬学的に許容されるその塩又はその水和物を含む医薬組成物を圧縮成型した際に杵付着等の打錠障害が生じないものであれば、その嵩密度及び平均重合度等に特に制限なく用いることができる。
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.
具体的な結晶セルロースの例としては、セオラスPH101（平均粒子径50μm）、セオラスPH102（平均粒子径90μm）、セオラスPH101D（平均粒子径50μm）、セオラスKG802（平均粒子径50μm）、セオラスKG801（平均粒子径50μm）、セオラスUF711（平均粒子径50μm）、セオラスUF702（平均粒子径90μm）、セオラスKG1000（平均粒子径50μm）、セオラスPH301（平均粒子径50μm）、セオラスPH301D（平均粒子径50μm）、セオラスPH301Z（平均粒子径50μm）、セオラスPH302（平均粒子径90μm）、セオラスPH F20JP（平均粒子径20μm）（何れも旭化成）、Avicel PH101、Avicel PH112、Avicel Ph113、Avicel PH200、Avicel PH301、Avicel PH302、Avicel HFE−102、Avicel DG、Avicel PH−105（何れもFMC Biopolymer）、Celex 101（International Specialty Products）、Emcocel 90M、Emcocel LM50M 、Emcocel 50M、Vivacel 12、VIVAPUR（登録商標）101 Premium、VIVAPUR 105、VIVAPUR 301（J．Rettenmaier & Sohne）、Pharmacel 101（DMV-Fonterra Excipients）セルフィア（三栄源エフ・エフ・アイ）が挙げられる。 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 50 μm), Theolas PH302 (average particle size 90 μm), Theolas PH F20JP (average particle size 20 μm) (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).
結晶セルロースの形状は、粒状、針状等、特に制限されない。針状のものを粉砕して使用することもできる。
また、他の添加剤（カラギーナン、カルボキシメチルセルロースナトリウム、グァーガムなど）と複合化された混合物として市販されているものを用いることもできる。
結晶セルロースの平均粒子径は、特に制限されない。例えば、50μm以下、他の態様として1μm以上50μm以下である。結晶セルロースの形状が粒状の場合、平均粒子径の測定方法として、例えば、日本薬局方に記載されている粉体粒度測定法の第２法（ふるい分け法）による測定が挙げられる。
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, 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.
結晶セルロースの平均粒子径は、例えば、ロータップ式篩振盪機（平工製作所製シーブシェーカーA型）によりJIS標準篩（Z8801-1987）を用いて試料10ｇまたは30ｇを10分間篩分し、その累積50重量％の粒度を平均粒子径として測定できる。
結晶セルロースの平均粒子径は、45μm以下の留分が多い場合はエアジェットシーブ粒度分布測定機（ALPINE製エアジェットシーブA200LS型）を用いて累積50重量％の粒度から求められる。
また、結晶セルロースは、グレード、形状、平均粒子径等の異なるものを１種または２種以上適宜組合せて使用することができる。
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.
結晶セルロースの配合量は、通常ミノドロン酸もしくは製薬学的に許容されるその塩又はその水和物が良好な溶出性を示し、杵付着等の打錠障害が発生しない量であれば特に制限されないが、例えば、本発明の医薬組成物中に3重量％以上30重量％以下、他の態様として5重量％以上20重量％以下であるか、あるいはミノドロン酸もしくは製薬学的に許容されるその塩又はその水和物の重量に対して10重量％以上150重量％以下、他の態様として30重量％以上100重量％以下である。 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.
本発明の医薬組成物は、所望により、クロスカルメロースナトリウム、クロスポビドン、カルボキシメチルスターチナトリウムからなる群から選択される１、または２以上の物質を含有することができる。 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.
クロスカルメロースナトリウムは、セルロースの多価カルボキシメチルエーテル架橋物のナトリウム塩である（第16改正日本薬局方）。
クロスカルメロースナトリウムは、製薬学的に許容されるものであれば特に制限されない。具体的には、例えば、Ac-Di-Sol（ＦＭＣバイオポリマー社）、及びKiccolate（旭化成）等を挙げることができる。これらのクロスカルメロースナトリウムを、1種または2種以上組合せて適宜適量添加することができる。
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.
クロスポビドンは、製薬学的に許容されるものであれば特に制限されない。具体的には、例えば、コリドンCL（BASFジャパン）、コリドンCL-F（BASFジャパン）、コリドンCL-M（BASFジャパン）、コリドンCL-SF（BASFジャパン）を挙げることができる。これらのクロスポビドンを、1種または2種以上組合せて適宜適量添加することができる。 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.
カルボキシメチルスターチナトリウムは、製薬学的に許容されるものであれば特に制限されない。具体的には、例えば、Primojel（DMV−Fonterra Excipients）を挙げることができ、1種または2種以上組合せて適宜適量添加することができる。 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.
クロスカルメロースナトリウム、クロスポビドン、カルボキシメチルスターチナトリウムの配合量は、通常ミノドロン酸もしくは製薬学的に許容されるその塩又はその水和物が良好な溶出性を示す量であれば特に制限されないが、それらの合計配合量として、例えば、本発明の医薬組成物中に5重量％以上50重量％以下、他の態様として5重量％以上20重量％以下、ミノドロン酸もしくは製薬学的に許容されるその塩又はその水和物の重量に対して5重量％以上90重量％以下、他の態様として30重量％以上60重量％以下である。 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, and in another embodiment, 5% by weight or more and 20% by weight or less, minodronic acid or pharmaceutically acceptable 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.
本発明の医薬組成物には、所望によりさらに各種医薬添加剤が適宜使用され、製剤化される。かかる医薬添加剤としては、製薬的に許容され、かつ薬理的に許容されるものであれば特に制限されない。例えば、賦形剤、結合剤、崩壊剤、酸味料、発泡剤、人工甘味料、香料、滑沢剤、着色剤、緩衝剤、抗酸化剤、界面活性剤などが使用される。 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.
賦形剤としては、例えば、D-マンニトール、乳糖水和物などが挙げられる。
結合剤としては、例えば、アラビアゴム、ヒドロキシプロピルメチルセルロース、ヒドロキシプロピルセルロース、ヒドロキシエチルセルロースなどが挙げられる。
崩壊剤としては、例えばトウモロコシデンプン、バレイショデンプン、カルメロースカルシウム、カルメロースナトリウム、低置換度ヒドロキシプロピルセルロース、クロスカルメロースナトリウム、クロスポビドン、カルボキシメチルスターチナトリウムなどが挙げられる。
酸味料としては、例えばクエン酸、酒石酸、リンゴ酸などが挙げられる。
発泡剤としては、例えば重曹などが挙げられる。
人工甘味料としては、例えばサッカリンナトリウム、グリチルリチン二カリウム、アスパルテーム、ステビア、ソーマチンなどが挙げられる。
香料としては、例えばレモン、レモンライム、オレンジ、メントールなどが挙げられる。
滑沢剤としては、例えば軽質無水ケイ酸、ステアリン酸マグネシウム、ステアリン酸カルシウム、ショ糖脂肪酸エステル、ポリエチレングリコール、タルク、ステアリン酸などが挙げられる。
着色剤としては、例えば黄色三二酸化鉄、赤色三二酸化鉄、黒色酸化鉄、食用黄色4号、5号、食用赤色3号、102号、食用青色3号などが挙げられる。
緩衝剤としては、クエン酸、コハク酸、フマル酸、酒石酸、アスコルビン酸またはその塩類、グルタミン酸、グルタミン、グリシン、アスパラギン酸、アラニン、アルギニンまたはその塩類、酸化マグネシウム、酸化亜鉛、水酸化マグネシウム、リン酸、ホウ酸またはその塩類などが挙げられる。
抗酸化剤としては、例えばアスコルビン酸、ジブチルヒドロキシトルエン、没食子酸プロピルなどが挙げられる。
界面活性剤としては、例えばポリソルベート80、ラウリル硫酸ナトリウム、ポリオキシエチレン硬化ヒマシ油などが挙げられる。
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.
医薬添加剤としては、1種または2種以上組合せて適宜適量添加することができる。
配合量については、いずれの医薬添加剤についても、本発明の所望の効果が達成される範囲内の量で使用される。
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.
本発明の医薬組成物としては、通常の錠剤の他、例えば、口腔内崩壊錠等の圧縮成型工程により製造される製剤を包含する。 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.
以下に本発明の医薬組成物の製造方法に関して説明する。
本発明の医薬組成物の製造方法は、少なくとも、造粒工程および圧縮成型工程（打錠工程）を含み、所望により、例えば、造粒工程の前に実施可能な粉砕工程、造粒工程と圧縮成型工程との間に実施可能な混合工程、および／または、圧縮成型工程の後に実施可能なフィルムコーティング工程を含むことができる。
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.
粉砕工程は、薬物、及び適当な添加剤を通常製薬学的に粉砕できる方法であれば、装置、手段とも特に制限されない。粉砕装置としては、例えば衝撃式粉砕機、ハンマーミル、ボールミル、ジェット粉砕機、コロイドミルなどが挙げられる。粉砕条件は適宜選択されれば特に制限されない。
粉砕に連続した各成分の混合工程は、通常製薬学的に各成分を均一に混合できる方法であれば、装置、手段とも特に制限されない。
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.
造粒工程では、粉砕工程で得られた粉砕品、及び各種添加剤を造粒機に入れ、結合剤液で噴霧する。造粒工程中に乾燥してもよい。造粒機として、例えば流動層造粒機等が挙げられる。
造粒方法として、たとえば、流動層造粒法、溶融造粒法、高速攪拌造粒法、解砕（粉砕）造粒法、押出造粒法、転動造粒法、噴霧造粒法、乾式造粒法あるいはそれらの方法により用いられる装置などが挙げられる。他の態様として流動層造粒法である。
噴霧液の調製条件は適宜選択されれば特に制限されない。
造粒後に乾燥することもできる。乾燥方法は、通常製薬学的に乾燥する方法であれば特に制限されない。
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.
混合工程では、造粒品と各種添加剤を混合する。 In the mixing step, the granulated product and various additives are mixed.
圧縮成型工程（打錠工程）では、混合品を、回転式打錠機を用いて打錠し、打錠品とする。
該工程としては、本発明の医薬組成物を成形する方法であれば装置、手段とも特に制限されない。例えば、造粒し更に滑沢剤を混合した後に圧縮成形し錠剤を製する方法が挙げられる。
打錠装置としては、例えば回転式打錠機、単発打錠機、オイルプレスなどが挙げられる。
打錠圧などの打錠条件としては、錠剤を成型でき、製造工程中に錠剤が破損しない打錠圧であれば特に制限されない。例えば約3kN以上約20kN以下で、他の態様として、約5kN以上約20kNで圧縮成型できる。
また、錠剤硬度としては、流通過程等で破損しない程度の硬度であれば特に制限されない。例えば、80N以上200N以下、他の様態として90N以上170N以下が挙げられる。
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.
フィルムコーティング工程として、適宜打錠後に錠剤表面にフィルムコーティングを施してもよい。
方法としては、通常製薬学的にコーティングする方法であれば特に制限されない。例えば、パンコーティング、ディップコーティングなどが挙げられる。
フィルムコーティング剤は、１種または２種以上組合せて適宜適量添加することができる。コーティング率は、錠剤にフィルムを形成する率であれば特に制限されない。例えば、錠剤重量に対して1重量％以上5重量％以下等である。
フィルムコーティング後に乾燥してもよい。方法としては、通常製薬学的に乾燥できる方法であれば特に制限されない。
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 type or two or more types. 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.
以下、実施例、比較例及び試験例を挙げて、本発明をさらに詳細に説明するが、本発明はこれらにより限定解釈されるものではない。
ミノドロン酸水和物は日本特許第3385208号公報に記載の方法により製造したものを使用した。
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.
《実施例１》
7重量%のヒドロキシプロピルセルロース溶液を調製し、結合剤液とした。次にミノドロン酸水和物粉砕品（平均粒子径D50：15μm、以下記載無い場合同じ）50部、D-マンニトール158部、及びクロスカルメロースナトリウム9部に、ヒドロキシプロピルセルロースが13.5部となるまで結合剤液を噴霧することにより、流動層造粒機で造粒した。結合剤液を噴霧後、造粒品を乾燥し、本発明の医薬品組成物（造粒品）を得た。前記医薬組成物（造粒品）230.5部、結晶セルロース（PH-101、平均粒子径50μm、旭化成ケミカルズ）45部、クロスカルメロースナトリウム20部とステアリン酸マグネシウム4.5部を容器回転式混合機を用いて混合後、ロータリー打錠機で圧縮成型することにより、本発明の医薬組成物（錠剤）を得た（錠剤質量300mg）。
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).
《実施例２》
7重量%のヒドロキシプロピルセルロース溶液を調製し、結合剤液とした。次にミノドロン酸水和物粉砕品60部、D-マンニトール184.8部、及びクロスカルメロースナトリウム10.8部に、ヒドロキシプロピルセルロースが16.2部となるまで結合剤液を噴霧することにより、流動層造粒機で造粒した。結合剤液を噴霧後、造粒品を乾燥し、本発明の医薬品組成物（造粒品）を得た。前記医薬組成物（造粒品）271.8部、結晶セルロース（KG-802、平均粒子径50μm、旭化成ケミカルズ）54部、クロスカルメロースナトリウム25.2部とステアリン酸マグネシウム5.4部を容器回転式混合機に仕込み、混合後、ロータリー打錠機を用いて、本発明の医薬組成物（錠剤）を得た（錠剤質量356.4mg）。
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).
《実施例３》
7重量%のヒドロキシプロピルセルロース溶液を調製し、結合剤液とした。次にミノドロン酸水和物粉砕品60部、D-マンニトール184.8部、及びクロスカルメロースナトリウム10.8部に、ヒドロキシプロピルセルロースが16.2部となるまで結合剤液を噴霧することにより、流動層造粒機で造粒した。結合剤液を噴霧後、造粒品を乾燥し、本発明の医薬品組成物（造粒品）を得た。前記医薬組成物（造粒品）271.8部、結晶セルロース（PH-101）54部、クロスカルメロースナトリウム25.2部とステアリン酸マグネシウム5.4部を容器回転式混合機を用いて混合後、ロータリー打錠機で圧縮成型することにより、本発明の医薬組成物（錠剤）を得た（錠剤質量356.4mg）。
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).
《実施例４》
7重量%のヒドロキシプロピルセルロース溶液を調製し、結合剤液とした。次にミノドロン酸水和物粉砕品50部、D-マンニトール158部、及びクロスカルメロースナトリウム9部に、ヒドロキシプロピルセルロースが13.5部となるまで結合剤液を噴霧することにより、流動層造粒機で造粒した。結合剤液を噴霧後、造粒品を乾燥し、本発明の医薬品組成物（造粒品）を得た。前記医薬組成物（造粒品）230.5部、結晶セルロース（PH-101）45部、クロスカルメロースナトリウム20部とステアリン酸マグネシウム4.5部を容器回転式混合機を用いて混合後、ロータリー打錠機で圧縮成型することにより、本発明の医薬組成物（錠剤）を得た（錠剤質量300mg）。
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).
《実施例５》
7重量%のヒドロキシプロピルセルロース溶液を調製し、結合剤液とした。次にミノドロン酸水和物粉砕品（平均粒子径D50：10μm）50部、D-マンニトール158部とクロスカルメロースナトリウム9部に、ヒドロキシプロピルセルロースが13.5部となるまで結合剤液を噴霧することにより、流動層造粒機で造粒した。結合剤液を噴霧後、造粒品を乾燥し、本発明の医薬品組成物（造粒品）を得た。前記医薬組成物（造粒品）230.5部、結晶セルロース（PH-101）45部、クロスカルメロースナトリウム20部とステアリン酸マグネシウム4.5部を容器回転式混合機を用いて混合後、ロータリー打錠機で圧縮成型することにより、本発明の医薬組成物（錠剤）を得た（錠剤質量300mg）。
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).
《実施例６》
7重量%のヒドロキシプロピルセルロース溶液を調製し、結合剤液とした。次にミノドロン酸水和物粉砕品40部と乳糖水和物178.4部を流動層造粒機に仕込み、ヒドロキシプロピルセルロースが7.2部となるまで結合剤液を噴霧し、造粒した。結合剤液を噴霧後、造粒品を乾燥し、本発明の医薬品組成物（造粒品）を得た。前記医薬組成物（造粒品）225.6部、クロスカルメロースナトリウム12部とステアリン酸マグネシウム2.4部を容器回転式混合機に仕込み、混合後、オートグラフ（島津製作所製、AGS-20KNG、以下同じ）を用いて、本発明の医薬組成物（錠剤）を得た（錠剤質量240mg）。
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).
《実施例７》
7重量%のヒドロキシプロピルセルロース溶液を調製し、結合剤液とした。次にミノドロン酸水和物粉砕品40部と乳糖水和物178.4部を流動層造粒機に仕込み、ヒドロキシプロピルセルロースが7.2部となるまで結合剤液を噴霧し、造粒した。結合剤液を噴霧後、造粒品を乾燥し、本発明の医薬品組成物（造粒品）を得た。前記医薬組成物（造粒品）225.6部、クロスポビドン12部とステアリン酸マグネシウム2.4部を容器回転式混合機に仕込み、混合後、オートグラフを用いて、本発明の医薬組成物（錠剤）を得た（錠剤質量240mg）。
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).
《実施例８》
7重量%のヒドロキシプロピルセルロース溶液を調製し、結合剤液とした。次にミノドロン酸水和物粉砕品40部と乳糖水和物178.4部を流動層造粒機に仕込み、ヒドロキシプロピルセルロースが7.2部となるまで結合剤液を噴霧し、造粒した。結合剤液を噴霧後、造粒品を乾燥し、本発明の医薬品組成物（造粒品）を得た。前記医薬組成物（造粒品）225.6部、カルボキシメチルスターチナトリウム12部とステアリン酸マグネシウム2.4部を容器回転式混合機に仕込み、混合後、オートグラフを用いて、本発明の医薬組成物（錠剤）を得た（錠剤質量240mg）。
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).
《実施例９》
7重量%のヒドロキシプロピルセルロース溶液を調製し、結合剤液とした。次にミノドロン酸水和物粉砕品40部と乳糖水和物178.4部を流動層造粒機に仕込み、ヒドロキシプロピルセルロースが7.2部となるまで結合剤液を噴霧し、造粒した。結合剤液を噴霧後、造粒品を乾燥し、本発明の医薬品組成物（造粒品）を得た。前記医薬組成物（造粒品）225.6部、クロスカルメロースナトリウム24部とステアリン酸マグネシウム2.4部を容器回転式混合機に仕込み、混合後、オートグラフを用いて、本発明の医薬組成物（錠剤）を得た（錠剤質量252mg）。
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).
《実施例１０》
7重量%のヒドロキシプロピルセルロース溶液を調製し、結合剤液とした。次にミノドロン酸水和物粉砕品40部と乳糖水和物178.4部を流動層造粒機に仕込み、ヒドロキシプロピルセルロースが7.2部となるまで結合剤液を噴霧し、造粒した。結合剤液を噴霧後、造粒品を乾燥し、本発明の医薬品組成物（造粒品）を得た。前記医薬組成物（造粒品）225.6部、クロスポビドン24部とステアリン酸マグネシウム2.4部を容器回転式混合機に仕込み、混合後、オートグラフを用いて、本発明の医薬組成物（錠剤）を得た（錠剤質量252mg）。
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).
《実施例１１》
7重量%のヒドロキシプロピルセルロース溶液を調製し、結合剤液とした。次にミノドロン酸水和物粉砕品40部と乳糖水和物178.4部を流動層造粒機に仕込み、ヒドロキシプロピルセルロースが7.2部となるまで結合剤液を噴霧し、造粒した。結合剤液を噴霧後、造粒品を乾燥し、本発明の医薬品組成物（造粒品）を得た。前記医薬組成物（造粒品）225.6部、カルボキシメチルスターチナトリウム24部とステアリン酸マグネシウム2.4部を容器回転式混合機に仕込み、混合後、オートグラフを用いて、本発明の医薬組成物（錠剤）を得た（錠剤質量252mg）。
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).
《比較例１》
7重量%のヒドロキシプロピルセルロース溶液を調製し、結合剤液とした。次にミノドロン酸水和物粉砕品（平均粒子径D50：35μm）50部、D-マンニトール158部、及びクロスカルメロースナトリウム9部に、ヒドロキシプロピルセルロースが13.5部となるまで結合剤液を噴霧することにより、流動層造粒機で造粒した。結合剤液を噴霧後、造粒品を乾燥し、比較用の医薬品組成物（造粒品）を得た。前記医薬組成物（造粒品）230.5部、結晶セルロース（PH-101）45部、クロスカルメロースナトリウム20部とステアリン酸マグネシウム4.5部を容器回転式混合機を用いて混合後、ロータリー打錠機で圧縮成型することにより、比較用の医薬組成物（錠剤）を得た（錠剤質量300mg）。
<< 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).
《実施例１２》
7重量%のヒドロキシプロピルセルロース溶液を調製し、結合剤液とした。次にミノドロン酸水和物粉砕品60部、D-マンニトール204.6部、及びクロスカルメロースナトリウム10.8部に、ヒドロキシプロピルセルロースが16.2部となるまで結合剤液を噴霧することにより、流動層造粒機で造粒した。結合剤液を噴霧後、造粒品を乾燥し、本発明の医薬品組成物（造粒品）を得た。前記医薬組成物（造粒品）291.6部、結晶セルロース（KG-802）54部、クロスカルメロースナトリウム25.2部とステアリン酸マグネシウム7.3部を容器回転式混合機を用いて混合後、ロータリー打錠機で圧縮成型することにより、本発明の医薬組成物（錠剤）を得た（錠剤質量378mg）。
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).
《実施例１３》
7重量%のヒドロキシプロピルセルロース溶液を調製し、結合剤液とした。次にミノドロン酸水和物粉砕品60部、D-マンニトール184.8部、及びクロスカルメロースナトリウム10.8部に、ヒドロキシプロピルセルロースが16.2部となるまで結合剤液を噴霧することにより、流動層造粒機で造粒した。結合剤液を噴霧後、造粒品を乾燥し、本発明の医薬品組成物（造粒品）を得た。前記医薬組成物（造粒品）230.5部、結晶セルロース（PH-101）54部、クロスカルメロースナトリウム25.2部とステアリン酸マグネシウム5.4部を容器回転式混合機を用いて混合後、ロータリー打錠機で圧縮成型することにより、本発明の医薬組成物（錠剤）を得た（錠剤質量356.4mg）。
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).
《試験例１：杵付着性》
本発明の医薬組成物（錠剤）の杵付着の有無を評価した。評価は、ロータリー式打錠機（畑鉄工所製、HT-X-SS20、以下同じ）にて実施例、及び比較例の組成物を表３の条件にて打錠後、杵表面を目視観察またはマイクロスコープ（KEYENCE、デジタルマイクロスコープ）によって観察した。杵表面に曇りがある場合、杵付着はあり、曇りがない場合、杵付着はなしとして評価した。結果を表４、５に示す。
結晶セルロースを用いることにより、粉体間の付着力が大きくなり、杵付着性が改善されたと考えられる。ミノドロン酸水和物（7mg）、乳糖、トウモロコシデンプン、ヒドロキシプロピルセルロース、低置換度ヒドロキシプロピルセルロース、及びステアリン酸マグネシウムを含む組成物を圧縮成形したところ、杵や臼への付着といった打錠障害が生じたが、結晶セルロースを用いることにより、杵付着性が改善された。
<< 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.
《試験例２：溶出試験》
本発明の医薬組成物（錠剤）及び比較用の医薬品組成物（錠剤）の溶出試験を行った。溶出試験は実施例、及び比較例の錠剤をそれぞれ6錠ずつ用いて日本薬局方溶出試験法に従い行った。試験液として日本薬局方溶出試験第1液900mLを用いた（装置2パドル法パドル回転数50rpmまたは装置1回転バスケット法100rpm）。結果（試験開始後15分後の溶出率D15min）を表４、５に示す。
<< 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 Japanese Pharmacopoeia dissolution test first solution 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.
ミノドロン酸水和物の平均粒子径D50がそれぞれ15μm、または10μmである実施例１乃至１１はD15minが80％以上であるのに対し、ミノドロン酸水和物の平均粒子径D50が35μmである比較例１はD15minが56％であった。従って、特定の粒子径を有するミノドロン酸水和物を使用することで溶出性が改善した。 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.
《試験例３：硬度》
本発明の医薬組成物（錠剤）及び比較用の医薬品組成物（錠剤）の硬度測定を行った。硬度測定は実施例、及び比較例の錠剤をそれぞれ10錠ずつ用いて行った。その平均値を表４、５に示す。
その結果、ミノドロン酸水和物の平均粒子径が小さい実施例は、比較例よりも硬度は高くなった。
<< 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.
本発明の医薬組成物は、骨粗鬆症治療剤として有用なミノドロン酸もしくは製薬学的に許容されるその塩又はその水和物を含有する、薬物の溶出性、錠剤硬度、杵付着性等が改善された高用量製剤として使用することができる。 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.
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