JPWO2019194095A1 - Solifenacin-containing pharmaceutical composition - Google Patents
Solifenacin-containing pharmaceutical composition Download PDFInfo
- Publication number
- JPWO2019194095A1 JPWO2019194095A1 JP2020512218A JP2020512218A JPWO2019194095A1 JP WO2019194095 A1 JPWO2019194095 A1 JP WO2019194095A1 JP 2020512218 A JP2020512218 A JP 2020512218A JP 2020512218 A JP2020512218 A JP 2020512218A JP WO2019194095 A1 JPWO2019194095 A1 JP WO2019194095A1
- Authority
- JP
- Japan
- Prior art keywords
- pharmaceutical composition
- solifenacin
- drug layer
- present
- particles
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
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- 229960003855 solifenacin Drugs 0.000 title claims abstract description 33
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- JEIPFZHSYJVQDO-UHFFFAOYSA-N iron(III) oxide Inorganic materials O=[Fe]O[Fe]=O JEIPFZHSYJVQDO-UHFFFAOYSA-N 0.000 description 1
- YOBAEOGBNPPUQV-UHFFFAOYSA-N iron;trihydrate Chemical compound O.O.O.[Fe].[Fe] YOBAEOGBNPPUQV-UHFFFAOYSA-N 0.000 description 1
- 229960001375 lactose Drugs 0.000 description 1
- 229910003002 lithium salt Inorganic materials 0.000 description 1
- 159000000002 lithium salts Chemical class 0.000 description 1
- 229960003511 macrogol Drugs 0.000 description 1
- 159000000003 magnesium salts Chemical class 0.000 description 1
- 229940049920 malate Drugs 0.000 description 1
- 150000002688 maleic acid derivatives Chemical class 0.000 description 1
- BJEPYKJPYRNKOW-UHFFFAOYSA-N malic acid Chemical compound OC(=O)C(O)CC(O)=O BJEPYKJPYRNKOW-UHFFFAOYSA-N 0.000 description 1
- 239000000845 maltitol Substances 0.000 description 1
- VQHSOMBJVWLPSR-WUJBLJFYSA-N maltitol Chemical compound OC[C@H](O)[C@@H](O)[C@@H]([C@H](O)CO)O[C@H]1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O VQHSOMBJVWLPSR-WUJBLJFYSA-N 0.000 description 1
- 235000010449 maltitol Nutrition 0.000 description 1
- 229940035436 maltitol Drugs 0.000 description 1
- 229960001855 mannitol Drugs 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- HEBKCHPVOIAQTA-UHFFFAOYSA-N meso ribitol Natural products OCC(O)C(O)C(O)CO HEBKCHPVOIAQTA-UHFFFAOYSA-N 0.000 description 1
- 229920000609 methyl cellulose Polymers 0.000 description 1
- 239000001923 methylcellulose Substances 0.000 description 1
- 235000010981 methylcellulose Nutrition 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- GOQYKNQRPGWPLP-UHFFFAOYSA-N n-heptadecyl alcohol Natural products CCCCCCCCCCCCCCCCCO GOQYKNQRPGWPLP-UHFFFAOYSA-N 0.000 description 1
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 1
- OQCDKBAXFALNLD-UHFFFAOYSA-N octadecanoic acid Natural products CCCCCCCC(C)CCCCCCCCC(O)=O OQCDKBAXFALNLD-UHFFFAOYSA-N 0.000 description 1
- 239000003921 oil Substances 0.000 description 1
- 239000006186 oral dosage form Substances 0.000 description 1
- 235000005985 organic acids Nutrition 0.000 description 1
- 150000007530 organic bases Chemical class 0.000 description 1
- 150000003891 oxalate salts Chemical class 0.000 description 1
- 239000003002 pH adjusting agent Substances 0.000 description 1
- 239000012188 paraffin wax Substances 0.000 description 1
- 230000000704 physical effect Effects 0.000 description 1
- 239000004014 plasticizer Substances 0.000 description 1
- 229920001223 polyethylene glycol Polymers 0.000 description 1
- 229920002503 polyoxyethylene-polyoxypropylene Polymers 0.000 description 1
- XAEFZNCEHLXOMS-UHFFFAOYSA-M potassium benzoate Chemical compound [K+].[O-]C(=O)C1=CC=CC=C1 XAEFZNCEHLXOMS-UHFFFAOYSA-M 0.000 description 1
- 239000000473 propyl gallate Substances 0.000 description 1
- 229940075579 propyl gallate Drugs 0.000 description 1
- 235000010388 propyl gallate Nutrition 0.000 description 1
- 239000008213 purified water Substances 0.000 description 1
- 238000012216 screening Methods 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229940080237 sodium caseinate Drugs 0.000 description 1
- HRZFUMHJMZEROT-UHFFFAOYSA-L sodium disulfite Chemical compound [Na+].[Na+].[O-]S(=O)S([O-])(=O)=O HRZFUMHJMZEROT-UHFFFAOYSA-L 0.000 description 1
- 235000010262 sodium metabisulphite Nutrition 0.000 description 1
- 159000000000 sodium salts Chemical class 0.000 description 1
- 239000012453 solvate Substances 0.000 description 1
- 239000006076 specific stabilizer Substances 0.000 description 1
- 239000007921 spray Substances 0.000 description 1
- 238000005507 spraying Methods 0.000 description 1
- 230000000087 stabilizing effect Effects 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 239000008117 stearic acid Substances 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 150000003890 succinate salts Chemical class 0.000 description 1
- 239000001384 succinic acid Substances 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- 150000003892 tartrate salts Chemical class 0.000 description 1
- 230000002123 temporal effect Effects 0.000 description 1
- 230000036962 time dependent Effects 0.000 description 1
- 239000001993 wax Substances 0.000 description 1
- 239000000811 xylitol Substances 0.000 description 1
- 235000010447 xylitol Nutrition 0.000 description 1
- HEBKCHPVOIAQTA-SCDXWVJYSA-N xylitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)CO HEBKCHPVOIAQTA-SCDXWVJYSA-N 0.000 description 1
- 229960002675 xylitol Drugs 0.000 description 1
- 239000005019 zein Substances 0.000 description 1
- 229940093612 zein Drugs 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/47—Quinolines; Isoquinolines
- A61K31/472—Non-condensed isoquinolines, e.g. papaverine
- A61K31/4725—Non-condensed isoquinolines, e.g. papaverine containing further heterocyclic rings
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/02—Inorganic compounds
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P13/00—Drugs for disorders of the urinary system
- A61P13/10—Drugs for disorders of the urinary system of the bladder
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- General Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- Animal Behavior & Ethology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Epidemiology (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Engineering & Computer Science (AREA)
- Organic Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Inorganic Chemistry (AREA)
- Urology & Nephrology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicinal Preparation (AREA)
Abstract
安定かつ経時的な着色のないソリフェナシン含有医薬組成物を提供する。医薬組成物は、（Ａ）非晶質体のソリフェナシンまたはその薬学的に許容される塩と、（Ｂ）亜硫酸ナトリウムまたは亜硫酸水素ナトリウムとを含有する薬物層を有する。Provided is a solifenacin-containing pharmaceutical composition that is stable and does not stain over time. The pharmaceutical composition has a drug layer containing (A) an amorphous solifenacin or a pharmaceutically acceptable salt thereof and (B) sodium sulfite or sodium hydrogen sulfite.
Description
本発明は、ソリフェナシンまたはその薬学的に許容される塩を含有する医薬組成物に関する。 The present invention relates to pharmaceutical compositions containing solifenacin or a pharmaceutically acceptable salt thereof.
ソリフェナシンまたはその薬学的に許容される塩（以下、ソリフェナシンまたはその薬学的に許容される塩を「ソリフェナシン」と呼ぶ場合もある。）の非晶質体は非常に不安定であり、保存中に分解することが知られている。また、非晶質体のソリフェナシンは、経時的に変色することが知られている。 Amorphous forms of solifenacin or its pharmaceutically acceptable salt (hereinafter, solifenacin or its pharmaceutically acceptable salt may be referred to as "solifenacin") are very unstable and during storage. It is known to decompose. In addition, amorphous solifenacin is known to discolor over time.
そのため、従来、非晶質体のソリフェナシン含有製剤の安定性を高めるために様々な工夫がされている。例えば、国際公開ＷＯ２０１０／１１３８４０号（特許文献１）には、ソリフェナシンの非晶質体の安定化と、着色の防止を目的として、特定の安定化剤を用いることが記載されている。 Therefore, conventionally, various measures have been taken to improve the stability of the amorphous solifenacin-containing preparation. For example, International Publication WO2010 / 113840 (Patent Document 1) describes the use of a specific stabilizer for the purpose of stabilizing the amorphous form of solifenacin and preventing coloring.
具体的には、特許文献１には、コハク酸ソリフェナシン、クエン酸と、ヒドロキシプロピルメチルセルロースを水に撹拌溶解させ薬物溶液を調製し、凍結乾燥させて得た医薬組成物について、所定の条件下で、安定性がよく、着色が防止されたことが記載されている。 Specifically, Patent Document 1 describes a pharmaceutical composition obtained by stirring and dissolving solifenacin succinate, citric acid, and hydroxypropylmethyl cellulose in water to prepare a drug solution, and then freeze-drying the pharmaceutical composition under predetermined conditions. It is described that the stability is good and the coloring is prevented.
しかしながら、特許文献１に記載の医薬組成物の原料を用いると、製造上適さない場合があり、例えば流動層造粒によって医薬組成物を製造することができない。 However, if the raw material of the pharmaceutical composition described in Patent Document 1 is used, it may not be suitable for production, and the pharmaceutical composition cannot be produced by, for example, fluidized bed granulation.
そこで、本発明の目的は、安定かつ経時的な着色のないソリフェナシン含有医薬組成物を提供することであり、特に、流動層造粒によって製造することが可能な、安定かつ経時的な着色のないソリフェナシン含有医薬組成物を提供することである。 Therefore, an object of the present invention is to provide a solifenacin-containing pharmaceutical composition that is stable and does not color over time, and in particular, it can be produced by fluidized bed granulation and does not have coloration over time. To provide a solifenacin-containing pharmaceutical composition.
特許文献１に記載の医薬組成物の原料（クエン酸、ピロ亜硫酸ナトリウム）を用いると、流動層造粒によって医薬組成物を製造することができない場合がある。本発明者らは、原因について鋭意検討した。その結果、これは、クエン酸等をスプレーする際に、配合成分（例えばヒドロキシプロピルメチルセルロース）のｐＨが局所的に低下し、配合成分（ヒドロキシプロピルメチルセルロース）が不溶化し、硬化することによって、ソリフェナシンの非晶質体がヒドロキシプロピルメチルセルロースから分離して非常に高い粘度をもち、急激に凝集してしまうためであると考えられた。 When the raw materials (citric acid, sodium pyrosulfite) of the pharmaceutical composition described in Patent Document 1 are used, the pharmaceutical composition may not be produced by fluidized bed granulation. The present inventors diligently investigated the cause. As a result, this is because when citric acid or the like is sprayed, the pH of the compounding component (for example, hydroxypropylmethylcellulose) is locally lowered, and the compounding component (hydroxypropylmethylcellulose) is insolubilized and hardened, whereby soriphenacin is used. It was considered that this is because the amorphous substance separates from hydroxypropyl methylcellulose, has a very high viscosity, and rapidly aggregates.
そこで、本発明者らは、鋭意検討を重ねた結果、意外にも本発明のソリフェナシン含有医薬組成物を次のように構成することによって、流動層造粒が可能な、安定かつ経時的な着色のないソリフェナシン含有医薬組成物を提供することができることを見出した。 Therefore, as a result of diligent studies, the present inventors surprisingly constructed the solifenacin-containing pharmaceutical composition of the present invention as follows, whereby a fluidized bed granulation is possible, and stable and temporal coloring is possible. It has been found that a solifenacin-containing pharmaceutical composition without solifenacin can be provided.
すなわち、本発明に従った医薬組成物は、（Ａ）非晶質体のソリフェナシンまたはその薬学的に許容される塩と、（Ｂ）亜硫酸ナトリウムまたは亜硫酸水素ナトリウムとを含有する薬物層を有する。 That is, the pharmaceutical composition according to the present invention has a drug layer containing (A) amorphous solifenacin or a pharmaceutically acceptable salt thereof, and (B) sodium sulfite or sodium hydrogen sulfite.
また、本発明に従った医薬組成物においては、薬物層に含まれる（Ｂ）の含量は、薬物層の１０質量％以下であることが好ましい。 Further, in the pharmaceutical composition according to the present invention, the content of (B) contained in the drug layer is preferably 10% by mass or less of the drug layer.
また、本発明に従った医薬組成物においては、薬物層に含まれる（Ｂ）の含量は、薬物層の１質量％以下であることが好ましい。 Further, in the pharmaceutical composition according to the present invention, the content of (B) contained in the drug layer is preferably 1% by mass or less of the drug layer.
また、本発明に従った医薬組成物においては、薬物層に含まれる（Ａ）の含量に対する（Ｂ）の含量の比は、（Ａ）の含量：（Ｂ）の含量が１：１以下であることが好ましい。 Further, in the pharmaceutical composition according to the present invention, the ratio of the content of (B) to the content of (A) contained in the drug layer is such that the content of (A): the content of (B) is 1: 1 or less. It is preferable to have.
また、本発明に従った医薬組成物は、造粒された粒子状であることが好ましい。 Further, the pharmaceutical composition according to the present invention is preferably in the form of granulated particles.
また、本発明に従った錠剤は、上記のいずれかの医薬組成物を含む。 In addition, the tablet according to the present invention contains any of the above-mentioned pharmaceutical compositions.
また、本発明に従った口腔内崩壊錠は、上記のいずれかの医薬組成物を含む。 In addition, the orally disintegrating tablet according to the present invention contains any of the above-mentioned pharmaceutical compositions.
本発明に従えば、安定かつ経時的な着色のないソリフェナシン含有医薬組成物を提供することであり、特に、流動層造粒によって製造することが可能な、安定かつ経時的な着色のないソリフェナシン含有医薬組成物を提供することができる。 According to the present invention, it is an object of the present invention to provide a stable and aging-free solifenacin-containing pharmaceutical composition, and in particular, a stable and aging-free solifenacin-containing composition that can be produced by fluidized bed granulation. Pharmaceutical compositions can be provided.
以下、本発明の実施形態を説明する。 Hereinafter, embodiments of the present invention will be described.
本発明に従った医薬組成物は、（Ａ）非晶質体のソリフェナシンまたはその薬学的に許容される塩と、（Ｂ）亜硫酸ナトリウムまたは亜硫酸水素ナトリウムとを含有する薬物層を有する。 A pharmaceutical composition according to the present invention has a drug layer containing (A) an amorphous solifenacin or a pharmaceutically acceptable salt thereof, and (B) sodium sulfite or sodium hydrogen sulfite.
本発明における「医薬組成物」とは、種々の経口投与剤形に供しうるソリフェナシン又はその塩を含有する組成物を意味する。 The "pharmaceutical composition" in the present invention means a composition containing solifenacin or a salt thereof that can be used in various oral dosage forms.
本発明の医薬組成物において、ソリフェナシンの塩は、薬学的に許容される塩であれば特に限定されず、例えば、塩酸塩、ヨウ化水素酸塩、臭化水素酸塩、硝酸塩、硫酸塩等の無機酸との塩、コハク酸塩、クエン酸塩、シュウ酸塩、酢酸塩、リンゴ酸塩、酒石酸塩、マレイン酸塩、フマル酸塩、ベンゼンスルホン酸塩等の有機酸との塩、カルシウム塩、マグネシウム塩等のアルカリ土類金属との塩、リチウム塩、カリウム塩、ナトリウム塩等のアルカリ金属との塩、エチレンジアミン塩、ジエタノールアミン塩、Ｎ−メチルグルカミン塩等の有機塩基との塩等が挙げられる。これらは単独で用いてもよく、２種以上を併用してもよい。薬学的に許容される塩は、有機酸との塩であることが好ましく、有機酸との塩のうち、コハク酸を用いることがより好ましい。また、ソリフェナシン又はその塩は、これらの無水物であってもよく。水和物等の溶媒和物であってもよい。 In the pharmaceutical composition of the present invention, the salt of soliphenacin is not particularly limited as long as it is a pharmaceutically acceptable salt, and for example, hydrochloride, hydroiodide, hydrobromide, nitrate, sulfate and the like. Salts with inorganic acids, succinates, citrates, oxalates, acetates, malate, tartrates, maleates, fumarates, salts with organic acids such as benzenesulfonates, calcium Salts with alkaline earth metals such as salts and magnesium salts, salts with alkali metals such as lithium salt, potassium salt and sodium salt, salts with organic bases such as ethylenediamine salt, diethanolamine salt and N-methylglucamine salt, etc. Can be mentioned. These may be used alone or in combination of two or more. The pharmaceutically acceptable salt is preferably a salt with an organic acid, and among the salts with an organic acid, it is more preferable to use succinic acid. Further, solifenacin or a salt thereof may be an anhydride thereof. It may be a solvate such as a hydrate.
本発明の医薬組成物において、「薬物層」とは、（Ａ）非晶質体のソリフェナシンまたはその薬学的に許容される塩と、（Ｂ）亜硫酸ナトリウムまたは亜硫酸水素ナトリウムとを含有するものである。言い換えれば、薬物層においては、（Ａ）成分および（Ｂ）成分が同じ層に配合されているもので、（Ａ）成分と（Ｂ）成分とが接する状態にある。また、薬物層は、好ましくは、不活性な成分を含み、（Ａ）成分と（Ｂ）成分とが、不活性な成分のマトリクス中に分散された状態で存在するもの、すなわち、（Ａ）成分と（Ｂ）成分とが固体分散体を構成しているものが好適である。薬物層が不活性な成分を含む場合には、該不活性な成分は、ヒドロキシプロピルメチルセルロースであることがより好ましい。 In the pharmaceutical composition of the present invention, the "drug layer" contains (A) amorphous solifenacin or a pharmaceutically acceptable salt thereof, and (B) sodium sulfite or sodium hydrogen sulfite. is there. In other words, in the drug layer, the component (A) and the component (B) are blended in the same layer, and the component (A) and the component (B) are in contact with each other. Further, the drug layer preferably contains an inert component, and the component (A) and the component (B) are present in a dispersed state in the matrix of the inert component, that is, (A). It is preferable that the component and the component (B) form a solid dispersion. When the drug layer contains an inert component, the inactive component is more preferably hydroxypropylmethylcellulose.
薬物層には、その他、必要に応じて、タルクなどを含有させてもよい。本発明の医薬組成物は、慣用される添加物として使用される各種医薬添加剤を使用して製造することができることは言うまでもない。医薬添加剤としては、例えば、矯味剤、甘味剤、香料、着色剤、安定（化）剤、抗酸化剤、ｐＨ調節剤、可溶化剤、溶解補助剤、流動化剤、緩衝剤などが挙げられるが、これらに限定されるものではない。添加剤は、典型的には、薬物の粒子の結合性を高めるために配合される結合剤であり、必要に応じて、糖類や崩壊剤等の溶解速度改善剤等を含有させることは自由である。結合剤としては、ヒドロキシプロピルセルロース、ヒドロキシプロピルメチルセルロース、ポリビニルピロリドン、コポリビドン、エチルセルロース等が挙げられるが、これらに限定されるものではない。 The drug layer may also contain talc or the like, if necessary. It goes without saying that the pharmaceutical composition of the present invention can be produced using various pharmaceutical additives used as commonly used additives. Examples of the pharmaceutical additive include a flavoring agent, a sweetening agent, a fragrance, a coloring agent, a stabilizing agent, an antioxidant, a pH adjusting agent, a solubilizing agent, a solubilizing agent, a fluidizing agent, a buffering agent, and the like. However, it is not limited to these. The additive is typically a binder that is added to enhance the binding of the drug particles, and is free to contain a dissolution rate improving agent such as a saccharide or a disintegrant, if necessary. is there. Examples of the binder include, but are not limited to, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, polyvinylpyrrolidone, copolyvidone, ethyl cellulose and the like.
本発明におけるソリフェナシン又はその塩が「非晶質体」であるかどうかは、Ｘ線回折により評価できる。ソリフェナシンに特異的なピークが確認された場合を、一部結晶体に変化したものと評価し、ハローピークの場合、非晶質状態を維持したものと評価することができる。 Whether or not solifenacin or a salt thereof in the present invention is an "amorphous substance" can be evaluated by X-ray diffraction. When a peak specific to solifenacin is confirmed, it can be evaluated as having partially changed to a crystal, and in the case of a halo peak, it can be evaluated as maintaining an amorphous state.
本発明に従った医薬組成物は、薬物層の外側を被覆する外層をさらに備えてもよい。外層は、例えば、ゲル化膨潤層と、ゲル化膨潤層をさらに被覆する１種または２種以上の水不溶性物質からなる被覆層であり、１種または２種以上の導水性調整物質を含んでもよい。 The pharmaceutical composition according to the present invention may further include an outer layer covering the outside of the drug layer. The outer layer is, for example, a coating layer composed of a gelled swelling layer and one or more water-insoluble substances that further coat the gelled swelling layer, and may contain one or more water-conducting substances. Good.
水不溶性物質からなる外層を形成させる場合、例えば、水に溶けにくい、極めて溶けにくい、ほとんど溶けないとされる溶解性を有することが好ましい。具体的には、エチルセルロース、アセチルセルロース、セルロースアセテートフタレート、カルボキシメチルエチルセルロース、ヒドロキシプロピルメチルセルロースアセテートサクシネート、ヒドロキシプロピルメチルセルロースフタレート、ジメチルアミノエチルメタアクリレート・メチルメタアクリレートコポリマー、メチルアクリレート・メタクリル酸コポリマー、アクリル酸エチル・メタクリル酸メチルコポリマー分散液、アミノアルキルメタクリレートコポリマーＲＳ、乾燥メタクリル酸コポリマーＬＤ、アミノアルキルメタクリレートコポリマーＥ、メタクリル酸コポリマーＬ、メタクリル酸コポリマーＬＤ（水分散液）、メタクリル酸コポリマーＳ、ポリビニルアセタールジエチルアミノアセテート、乾燥乳状白ラック、セラック、ゼイン、ステアリン酸などの高級脂肪酸、セタノールやステアリルアルコールなどの高級アルコール、カルナウバロウやミツロウやパラフィンなどの融点が３０〜１２０℃の低融点物質、ショ糖脂肪酸エステルなどの高級脂肪酸と多価アルコールのエステル、カスターワックスなどの油に水素を添加して得た脂肪、合成ワックス、タルク、ステアリン酸マグネシウムなどの滑沢剤などが挙げられるが、これらに限定されるものではない。水不溶性物質はその１種または２種以上を適宜組み合わせて使用することもできる。また、ヒマシ油、フタル酸ジブチル、クエン酸トリエチルなどの可塑剤を混合して用いることも自由である。 When forming an outer layer made of a water-insoluble substance, for example, it is preferable to have solubility that is difficult to dissolve in water, extremely difficult to dissolve, or almost insoluble. Specifically, ethyl cellulose, acetyl cellulose, cellulose acetate phthalate, carboxymethyl ethyl cellulose, hydroxypropyl methyl cellulose acetate succinate, hydroxypropyl methyl cellulose phthalate, dimethylaminoethyl methacrylate / methyl methacrylate copolymer, methyl acrylate / methacrylate copolymer, acrylic acid. Ethyl / methyl methacrylate copolymer dispersion, aminoalkyl methacrylate copolymer RS, dry methacrylate copolymer LD, aminoalkyl methacrylate copolymer E, methacrylate copolymer L, methacrylate copolymer LD (aqueous dispersion), methacrylate copolymer S, polyvinyl acetal diethylamino Higher fatty acids such as acetate, dried milky white rack, cellac, zein, stearic acid, higher alcohols such as cetanol and stearyl alcohol, low melting point substances such as carnauba wax, honeydew and paraffin with a melting point of 30 to 120 ° C, sucrose fatty acid esters, etc. Higher fatty acids and polyhydric alcohol esters, fats obtained by adding hydrogen to oils such as castor wax, synthetic waxes, talc, lubricants such as magnesium stearate, etc., but are limited to these. is not it. As the water-insoluble substance, one kind or a combination of two or more kinds thereof can be used as appropriate. It is also free to mix and use plasticizers such as castor oil, dibutyl phthalate, and triethyl citrate.
また、外層を形成する際、水不溶性物質に導水性調整物質として水溶性物質、親水性物質などを配合することができる。ここでいう導水性調整物質とは、水の浸入速度と浸入量を調節するために、水不溶性物質と共に外層に配合する成分であり、水に溶けやすい成分や、崩壊剤等の親水性で水を通過させやすい成分である。具体的に本発明の外層における導水性調整物質を例示すると、アルファー化デンプン、カゼインナトリウム、カルボキシビニルポリマー、カルボキシメチルスターチナトリウム、ショ糖脂肪酸エステル、ヒドロキシプロピルセルロース、ヒドロキシプロピルメチルセルロース、メチルセルロース、ヒドロキシエチルセルロース、プルラン、ポリビニルピロリドン、コポリビドン、ポリオキシエチレン−ポリオキシプロピレングリコール、ポリビニルアルコール−ポリエチレングリコール移植片コポリマー、ポリビニルアルコール、マクロゴール、ポリエチレンオキサイド、グリシンやアラニンなどのアミノ酸、グリチルリチン酸などの甘味剤、デキストリンや乳糖などの糖類、マンニトールやキシリトールなどの糖アルコール、結晶セルロース、クロスポビドン、クエン酸トリエチルなどが挙げられるが、これらに限定されるものではなく、また、導水性調整物質はその１種または２種以上を適宜組み合わせて使用することもできる。 Further, when forming the outer layer, a water-soluble substance, a hydrophilic substance, or the like can be blended with the water-insoluble substance as a water-conducting adjusting substance. The water-conducting substance referred to here is a component to be blended in the outer layer together with a water-insoluble substance in order to adjust the infiltration rate and the amount of infiltration of water. It is a component that easily passes through. Specific examples of the water-conducting substance in the outer layer of the present invention include pregelatinized starch, sodium caseinate, carboxyvinyl polymer, sodium carboxymethyl starch, sucrose fatty acid ester, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, methyl cellulose, hydroxyethyl cellulose, and the like. Purulan, polyvinylpyrrolidone, copolyvidone, polyoxyethylene-polyoxypropylene glycol, polyvinyl alcohol-polyethylene glycol implant copolymer, polyvinyl alcohol, macrogol, polyethylene oxide, amino acids such as glycine and alanine, sweeteners such as glycyrrhizinic acid, dextrin and Examples include, but are not limited to, sugars such as lactose, sugar alcohols such as mannitol and xylitol, crystalline cellulose, crospovidone, and triethyl citrate, and one or two water-conducting regulators thereof. The above can be used in combination as appropriate.
本発明の外層における水不溶性物質と導水性調整物質の組成比は、薬物の物性や吸収部位、製剤の種類などの目的に応じ、目的達成のために適した比率が選択される。 As for the composition ratio of the water-insoluble substance and the water-conducting substance in the outer layer of the present invention, a ratio suitable for achieving the object is selected according to the purpose such as the physical properties of the drug, the absorption site, and the type of the preparation.
医薬組成物中のソリフェナシン又はその塩の配合量は特に制限されないが、医薬組成物粒子全体の０．５重量％以上であることが好ましい。ただし、ここに示したソリフェナシン又はその塩の配合量は本発明に適用できうる一例であり、限定的に解釈されるべきではない。 The blending amount of solifenacin or a salt thereof in the pharmaceutical composition is not particularly limited, but is preferably 0.5% by weight or more of the total particles of the pharmaceutical composition. However, the blending amount of solifenacin or a salt thereof shown here is an example applicable to the present invention and should not be construed in a limited manner.
また、医薬組成物においては、薬物層に含まれる（Ｂ）の含量は、薬物層の１０質量％以下であることが好ましく、１質量％以下であることが特に好ましい。 Further, in the pharmaceutical composition, the content of (B) contained in the drug layer is preferably 10% by mass or less, and particularly preferably 1% by mass or less of the drug layer.
また、本医薬組成物においては、薬物層に含まれる（Ａ）の含量に対する（Ｂ）の含量の比は、（Ａ）の含量：（Ｂ）の含量が１：１以下であることが好ましい。 Further, in the present pharmaceutical composition, the ratio of the content of (B) to the content of (A) contained in the drug layer is preferably the content of (A): the content of (B) of 1: 1 or less. ..
本発明の医薬組成物は、そのまま必要量を配合して種々の経口投与医薬組成物の形態に製することができる。ここでいう製剤とは、散剤、顆粒剤、錠剤、トローチ剤、ドライシロップ剤などである。散剤や顆粒は、該製剤化用微粒子をそのまま配合して混合するだけでも製剤化が可能な場合もある。最近注目されている口腔内崩壊錠にする場合、該製剤化用微粒子を配合して製剤化法を工夫することが必要である。 The pharmaceutical composition of the present invention can be produced in various forms of orally administered pharmaceutical compositions by blending a required amount as it is. The preparation referred to here is a powder, a granule, a tablet, a troche, a dry syrup, or the like. In some cases, powders and granules can be formulated simply by blending and mixing the formulation fine particles as they are. In the case of an orally disintegrating tablet, which has been attracting attention recently, it is necessary to devise a formulation method by blending the formulation fine particles.
次に、本発明の医薬組成物粒子の製造方法を説明する。 Next, a method for producing the pharmaceutical composition particles of the present invention will be described.
本発明の医薬組成物粒子は、例えば、結晶セルロースのような核微粒子上に、（Ａ）成分と（Ｂ）成分と、ヒドロキシプロピルメチルセルロースのようなマトリクスを形成するための成分と、他の添加剤とを同時にスプレーし、核粒子上に薬物層を形成する。このようにして形成された薬物層においては、ソリフェナシンまたはその薬学的に許容される塩と、亜硫酸ナトリウムまたは亜硫酸水素ナトリウムとが固体分散体を形成している。 The pharmaceutical composition particles of the present invention include, for example, components (A) and (B), components for forming a matrix such as hydroxypropylmethylcellulose, and other additions on nuclear fine particles such as crystalline cellulose. The agent is sprayed simultaneously to form a drug layer on the nuclear particles. In the drug layer thus formed, solifenacin or a pharmaceutically acceptable salt thereof and sodium sulfite or sodium hydrogen sulfite form a solid dispersion.
核粒子は、例えば流動層コーティング装置などにより、適当な核となる添加物粒子（例えば結晶セルロース（粒）、精製白糖球状粒子、マンニトール球状粒子等）に、結合剤などを溶解または分散した液を噴霧して製してもよい。 The nuclear particles are prepared by dissolving or dispersing a binder or the like in appropriate core additive particles (for example, crystalline cellulose (grains), purified sucrose spherical particles, mannitol spherical particles, etc.) using a fluidized layer coating device or the like. It may be manufactured by spraying.
核粒子上に薬物層を形成する方法としては、流動層コーティング装置、転動コーティング装置、遠心転動コーティング装置など、粒子状組成物の被覆操作に汎用されている機械によって被覆する方法を採用することが好ましい。 As a method for forming the drug layer on the nuclear particles, a method of coating with a machine generally used for coating operations of particulate compositions such as a fluidized bed coating device, a rolling coating device, and a centrifugal rolling coating device is adopted. Is preferable.
（Ａ）成分と（Ｂ）成分と、ヒドロキシプロピルメチルセルロースのようなマトリクスを形成するための成分と、他の添加剤とが含まれる液体は、必須成分などを水、エタノール、メタノール等の溶媒に溶解または分散して調製されるが、これらの溶媒は適宜混合して用いることも可能である。なお、これらの層の被覆方法については、湿式法に限定されるものではないことは言うまでもない。 For the liquid containing the component (A), the component (B), the component for forming a matrix such as hydroxypropylmethylcellulose, and other additives, the essential component or the like is used as a solvent such as water, ethanol, or methanol. Although it is prepared by dissolving or dispersing, these solvents can be appropriately mixed and used. Needless to say, the coating method for these layers is not limited to the wet method.
仮に、安定化剤が酸性であれば、ヒドロキシプロピルメチルセルロースのようなマトリクス成分が不溶化し、硬化することによって、ソリフェナシンの非晶質体がヒドロキシプロピルメチルセルロースから分離して非常に高い粘度をもち、急激に凝集してしまう。しかし、本願発明の医薬組成物では、安定化剤として亜硫酸ナトリウムまたは亜硫酸水素ナトリウムを用いることによって、薬物と安定化剤（亜硫酸ナトリウムまたは亜硫酸水素ナトリウム）とを同時にスプレーすることが可能であるので、製造工程数と製造時間を低減することが可能である。 If the stabilizer is acidic, the matrix component such as hydroxypropylmethylcellulose is insolubilized and hardened, so that the amorphous form of solifenacin separates from hydroxypropylmethylcellulose and has a very high viscosity, which is abrupt. Aggregates into. However, in the pharmaceutical composition of the present invention, the drug and the stabilizer (sodium sulfite or sodium hydrogen sulfite) can be sprayed at the same time by using sodium sulfite or sodium hydrogen sulfite as the stabilizer. It is possible to reduce the number of manufacturing processes and the manufacturing time.
次に、必要に応じて、例えばゲル化膨潤層や苦味マスキング層、水浸入量制御層、表面改質層等を薬物層の上に形成させて、医薬組成物が得られる。 Next, if necessary, for example, a gelled swelling layer, a bitterness masking layer, a water infiltration amount control layer, a surface modification layer and the like are formed on the drug layer to obtain a pharmaceutical composition.
医薬組成物を口腔内崩壊錠の製造に用いる場合には、医薬組成物の平均粒子径は、通常１００〜２００μｍ程度であることが望まれる。実質上球形の核粒子が球形状を保ったままで核粒子被覆層と外層が被覆されて１００〜２００μｍ程度にされるためには、被覆に用いる溶液中に懸濁して使用する物質の平均粒子径は被被覆粒子の１０分の１以下の粒子径であることが必要である。 When the pharmaceutical composition is used for producing an orally disintegrating tablet, it is desirable that the average particle size of the pharmaceutical composition is usually about 100 to 200 μm. In order to cover the nuclear particle coating layer and the outer layer to a size of about 100 to 200 μm while maintaining the spherical shape of the substantially spherical nuclear particles, the average particle size of the substance suspended in the solution used for coating is used. Must have a particle size of 1/10 or less of the coated particles.
薬物層が被覆された粒子に外層を被覆する方法としては、流動層コーティング装置、転動コーティング装置、遠心転動コーティング装置など、粒子状組成物の被覆操作に汎用されている機械によって被覆する方法を採用することが好ましい。例えば、転動流動層コーティング装置中で、核粒子を流動させながら、スプレーガンにて被覆成分を含有する液を必要量噴霧すればよい。この被覆成分を含有する液は、必須成分などを水、エタノール、メタノール等の溶媒に溶解または分散して調製されるが、これらの溶媒は適宜混合して用いることも可能であり、例えば溶媒として水のみを用いてもかまわない。なお、これらの層の被覆方法については、湿式法に限定されるものではないことは言うまでもない。 As a method of coating the outer layer on the particles coated with the drug layer, a method of coating with a machine commonly used for coating operation of a particulate composition such as a fluidized layer coating device, a rolling coating device, and a centrifugal rolling coating device. It is preferable to adopt. For example, in a rolling fluidized bed coating apparatus, a required amount of a liquid containing a coating component may be sprayed with a spray gun while flowing nuclear particles. The liquid containing this coating component is prepared by dissolving or dispersing essential components in a solvent such as water, ethanol, methanol, etc., but these solvents can be appropriately mixed and used, for example, as a solvent. Only water may be used. Needless to say, the coating method for these layers is not limited to the wet method.
以下に本発明の医薬組成物粒子を含有する口腔内崩壊錠に関して説明する。 The orally disintegrating tablet containing the pharmaceutical composition particles of the present invention will be described below.
本発明で言う口腔内崩壊錠とは、口腔内において、錠剤が一定時間内、好ましくは１分以内、より好ましくは４５秒以内に崩壊する錠剤に類する製剤を意味する。例えば特開２０１２−２４０９１７号公報、特許第４０１９３７４号公報、特許第３７４６１６７号公報などに開示される医薬組成物粒子を含有させた口腔内崩壊錠が挙げられる。それらと同じように、本発明の医薬組成物粒子を、適切な賦形剤、崩壊剤、結合剤、滑沢剤などとともに口腔内崩壊錠にすることができる。 The orally disintegrating tablet referred to in the present invention means a preparation similar to a tablet in which the tablet disintegrates within a certain period of time, preferably within 1 minute, more preferably within 45 seconds. Examples thereof include orally disintegrating tablets containing pharmaceutical composition particles disclosed in Japanese Patent Application Laid-Open No. 2012-240917, Japanese Patent No. 4019374, Japanese Patent No. 3746167, and the like. Similarly, the pharmaceutical composition particles of the present invention can be made into orally disintegrating tablets with suitable excipients, disintegrants, binders, lubricants and the like.
具体的に製法を例示すれば、（１）医薬組成物粒子をそのまま糖又は糖アルコール類や選択された崩壊剤とともに混合して加圧圧縮することにより錠剤に製する方法、（２）医薬組成物粒子を糖又は糖アルコール類や選抜した崩壊剤などと混合し結合剤溶液で造粒して製した粒子に、適切なその他の錠剤用添加剤を混合して加圧圧縮することにより錠剤に製する方法、（３）医薬組成物粒子に成形性の低い糖類を混合し、かかる混合物を成形性の高い糖類を結合剤として噴霧し被覆及び／または造粒したものを低圧圧縮成形した後、加湿、乾燥して錠剤に製する方法など、いろいろな製法がある。なお、医薬組成物粒子を配合した口腔内崩壊錠の場合、粒子の破壊、錠剤の硬度、崩壊性、含量均一性などへの特別な配慮が必要で、口腔内崩壊錠の製造方法については、ここで述べた方法に限定するべきではなく、鋳型法、湿式成形乾燥法など、錠剤化に際していかなる方法が採用されても差し支えはない。 Specific examples of the production method include (1) a method of mixing pharmaceutical composition particles as they are with sugars or sugar alcohols or a selected disintegrant and pressurizing and compressing them to form tablets, and (2) pharmaceutical composition. Tablets are made by mixing physical particles with sugar or sugar alcohols, selected disintegrants, etc., granulating them with a binder solution, mixing them with other appropriate tablet additives, and pressurizing and compressing them. Method for producing, (3) Pharmaceutical composition A saccharide having low moldability is mixed with particles, and the mixture is sprayed with a saccharide having high moldability as a binder, coated and / or granulated, and then subjected to low-pressure compression molding. There are various manufacturing methods such as humidification, drying and manufacturing into tablets. In the case of an orally disintegrating tablet containing pharmaceutical composition particles, special consideration must be given to particle destruction, tablet hardness, disintegration, content uniformity, etc., and the method for producing an orally disintegrating tablet is described. The method should not be limited to the method described here, and any method may be adopted for tableting, such as a molding method and a wet molding / drying method.
製剤化用微粒子、すなわち、医薬組成物粒子の錠剤中の配合量は、錠剤重量に対して５重量％以上８５重量％以下が好ましく、より好ましくは５重量％以上７０重量％以下、さらに好ましくは１０重量％以上７０重量％以下、より好ましくは２０重量％以上４０重量％以下であるが、これに限定されるべきものではない。医薬組成物粒子の配合量が８５重量％より多い場合、錠剤、特に口腔内崩壊錠としての強度や溶解特性が達成されないことが懸念される場合がある。 The amount of the fine particles for formulation, that is, the pharmaceutical composition particles in the tablet is preferably 5% by weight or more and 85% by weight or less, more preferably 5% by weight or more and 70% by weight or less, still more preferably. It is 10% by weight or more and 70% by weight or less, more preferably 20% by weight or more and 40% by weight or less, but is not limited to this. If the blending amount of the pharmaceutical composition particles is more than 85% by weight, there may be a concern that the strength and dissolving characteristics of tablets, particularly orally disintegrating tablets, may not be achieved.
本発明による口腔内崩壊錠は、本発明の医薬組成物粒子を配合するほか、錠剤の製造に通常用いられる一般的な添加剤を配合して製造することができる。賦形剤としては、マンニトール、エリスリトール、マルチトール、乳糖などの糖又は糖アルコール、結晶セルロース、リン酸水素カルシウムなどを用いることができる。結合剤としては、トウモロコシデンプン、ポリビニルピロリドン、コポリビドン、ヒドロキシプロピルセルロース、ポリビニルアルコールなど通常の結合剤であれば制限されない。崩壊剤としては、通常用いられる、例えばカルメロース、クロスポビドン、コーンスターチ、部分アルファー化デンプン、カルメロースカルシウム、クロス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などを用いることができる。また、製剤中に、アスパルテーム等の甘味剤、矯味剤などを配合して、服用感を向上させることも自由であり、黄色三二酸化鉄等の着色剤を配合することもできる。 The orally disintegrating tablet according to the present invention can be produced by blending the pharmaceutical composition particles of the present invention and also blending a general additive usually used in the manufacture of tablets. As the excipient, sugars such as mannitol, erythritol, maltitol, lactose or sugar alcohols, crystalline cellulose, calcium hydrogen phosphate and the like can be used. The binder is not limited as long as it is an ordinary binder such as corn starch, polyvinylpyrrolidone, copolyvidone, hydroxypropyl cellulose, and polyvinyl alcohol. As the disintegrant, commonly used, for example, carmellose, crospovidone, cornstarch, partially pregelatinized starch, carmellose calcium, croscarmellose sodium, low degree of substitution hydroxypropyl cellulose and the like can be used. In addition, a sweetener such as aspartame, a flavoring agent, or the like can be freely added to the preparation to improve the feeling of ingestion, and a coloring agent such as yellow iron sesquioxide can also be added.
以下、実施例により本発明をより具体的に説明するが、本発明はこれらの実施例により限定されるものではない。 Hereinafter, the present invention will be described in more detail with reference to Examples, but the present invention is not limited to these Examples.
＜スクリーニング検討＞
＜実施例１＞
コハク酸ソリフェナシンとヒプロメロース（ヒドロキシプロピルメチルセルロース）を１：１で水に溶かし、そこに、コハク酸ソリフェナシンに対し亜硫酸ナトリウム１質量％となるように亜硫酸ナトリウムを溶解した後、−８０℃にて凍結し、凍結乾燥を行い、医薬組成物を作成した。<Screening examination>
<Example 1>
Solifenacin succinate and hypromellose (hydroxypropylmethylcellulose) are dissolved in water at a ratio of 1: 1, and sodium sulfite is dissolved therein so as to be 1% by mass of sodium sulfite with respect to solifenacin succinate, and then freezed at -80 ° C. , Freeze-dried to prepare a pharmaceutical composition.
＜実施例２＞
コハク酸ソリフェナシンに対し亜硫酸ナトリウム１０質量％となるように調製した以外は、実施例１に従い医薬組成物を製造した。<Example 2>
A pharmaceutical composition was produced according to Example 1 except that the sodium sulfite was adjusted to 10% by mass based on solifenacin succinate.
＜比較例１＞
亜硫酸ナトリウムを配合しない以外は、実施例１に従い医薬組成物を製造した。<Comparative example 1>
A pharmaceutical composition was produced according to Example 1 except that sodium sulfite was not added.
得られた実施例１〜２と比較例１の医薬組成物のＸ線回析プロファイルを次のように測定して、ソリフェナシンが非晶質体であることを確認した。 The X-ray diffraction profiles of the obtained pharmaceutical compositions of Examples 1 and 2 and Comparative Example 1 were measured as follows, and it was confirmed that solifenacin was an amorphous substance.
Ｘ線回折プロファイルの測定条件は次の通りであった。
Ｘ線出力：４０ｋＶ,４０ｍＡ、ゴニオメーター：ＳｍａｒｔＬａｂ、アタッチメント：ＡＳＣ６-反射、フィルター：Ｃｕ＿Ｋ−ｂｅｔａ、ＣＢＯ選択スリット：ＢＢ、検出器：Ｄ／ｔｅＸ Ｕｌｔｒａ、スキャンモード：ＣＯＮＴＩＮＵＯＵＳ、スキャンスピード１０ｄｅｇ／ｍｉｎ、ステップ幅：０．０２ｄｅｇ、スキャン軸：２θ／θ、スキャン範囲：５―４０ｄｅｇ、入射スリット１／２ｄｅｇ、長手制限スリット：１０ｍｍ、受光スリット１：８ｍｍ、受光スリット２:１３ｍｍThe measurement conditions of the X-ray diffraction profile were as follows.
X-ray output: 40kV, 40mA, goniometer: SmartLab, attachment: ASC6-reflection, filter: Cu_K-beta, CBO selection slit: BB, detector: D / teX Ultra, scan mode: CONTINUOUS, scan speed 10deg / min, Step width: 0.02 deg, scan axis: 2θ / θ, scan range: 5-40 deg, incident slit 1/2 deg, longitudinal limiting slit: 10 mm, light receiving slit 1: 8 mm, light receiving slit 2:13 mm
実施例１，２および比較例１の医薬組成物では、結晶構造を有する結晶性ソリフェナシン特有のピークが観察されず、ハローパターンが観察された。このことは、実施例１，２および比較例１で得られた医薬組成物中のソリフェナシンが非晶質であることを意味する。 In the pharmaceutical compositions of Examples 1 and 2 and Comparative Example 1, no peak peculiar to crystalline solifenacin having a crystal structure was observed, and a halo pattern was observed. This means that the solifenacin in the pharmaceutical compositions obtained in Examples 1 and 2 and Comparative Example 1 is amorphous.
得られた実施例１〜２、比較例１の医薬組成物を６０℃で５日または１０日間保存経過後の類縁物質量を測定した。結果を表１に示す。 The obtained pharmaceutical compositions of Examples 1 and 2 and Comparative Example 1 were stored at 60 ° C. for 5 or 10 days, and the amount of related substances was measured. The results are shown in Table 1.
表１に示すように、実施例１，２の医薬組成物では、主類縁物質量が５日後にも１０日後にも０％に抑えられた。 As shown in Table 1, in the pharmaceutical compositions of Examples 1 and 2, the amount of the main related substance was suppressed to 0% after 5 days and 10 days.
＜着色試験＞
得られた実施例１〜２、比較例１の医薬組成物を６０℃で１週間保存した時の色度を、ＪＩＳ Ｚ ８７３０記載の色表示方法により測定し、下記式に従って初期値との差（ΔＥ）を求めた。
ΔＥ＝√［（ΔＬ（初期値との差）２＋Δａ（初期値との差）２＋Δｂ（初期値との差）２］
結果を表２に示す。<Coloring test>
The chromaticity of the obtained pharmaceutical compositions of Examples 1 and 2 and Comparative Example 1 stored at 60 ° C. for 1 week was measured by the color display method described in JIS Z 8730, and the difference from the initial value was measured according to the following formula. (ΔE) was calculated.
ΔE = √ [(ΔL (difference from initial value) 2 + Δa (difference from initial value) 2 + Δb (difference from initial value) 2 ]
The results are shown in Table 2.
表２に示すように、実施例１，２の医薬組成物では、比較例１の医薬組成物と比較して、ΔＥを低く抑えることができた。一般的にΔＥが３以上であれば異なる色として識別可能である。実施例１，２は、ΔＥが３より小さいので、保存開始時と１週間保存後とで識別可能なほど色が変化しなかったことがわかる。一方、比較例１では、保存開始時と１週間保存後とで異なる色と識別されるほど変色したことがわかる。 As shown in Table 2, in the pharmaceutical compositions of Examples 1 and 2, ΔE could be suppressed lower than that of the pharmaceutical composition of Comparative Example 1. Generally, if ΔE is 3 or more, it can be identified as a different color. Since ΔE of Examples 1 and 2 is smaller than 3, it can be seen that the color did not change so as to be distinguishable between the start of storage and after storage for 1 week. On the other hand, in Comparative Example 1, it can be seen that the color changed to the extent that it could be identified as a different color at the start of storage and after storage for one week.
＜微粒子及び錠剤での試験＞
＜実施例３＞
水１５００．０ｇ、エタノール１５００．０ｇの混液に、ヒプロメロース（ＴＣ−５Ｅ）８０．０ｇ、コハク酸ソリフェナシンを８０．０ｇ、亜硫酸ナトリウム８．０ｇを溶解し、原薬溶解液を調製した。次に、水１００．０ｇ、エタノール１００．０ｇの混液に、タルク（ＦＬ１０８）３２．０ｇを分散し、原薬溶解液と混和した。転動流動型コーティング造粒機（株式会社パウレック製：ＭＰ−０１型）に結晶セルロース（粒）（セルフィアＣＰ１０２）２００．０ｇを投入し、撹拌流動させながら調製した液を噴霧・コーティングし乾燥して、薬物層を調製した。薬物層中のソリフェナシンが非晶質体であることをＸ線回折パターンを測定して確認した。<Test with fine particles and tablets>
<Example 3>
A drug substance solution was prepared by dissolving 80.0 g of hypromellose (TC-5E), 80.0 g of solifenacin succinate, and 8.0 g of sodium sulfite in a mixed solution of 1500.0 g of water and 1500.0 g of ethanol. Next, 32.0 g of talc (FL108) was dispersed in a mixed solution of 100.0 g of water and 100.0 g of ethanol, and mixed with the drug substance solution. 200.0 g of crystalline cellulose (grains) (Selfia CP102) is put into a rolling flow type coating granulator (manufactured by Paulek Co., Ltd .: MP-01 type), and the prepared liquid is sprayed, coated and dried while being stirred and flowed. To prepare a drug layer. It was confirmed by measuring the X-ray diffraction pattern that solifenacin in the drug layer was an amorphous substance.
次に、エタノール１５００．０ｇに、ヒドロキシプロピルセルロース（ＨＰＣ−ＳＬ）８０．０ｇ、を溶解し、カルメロースナトリウム（ブラノース７Ｍ１Ｆ−ＰＨ，Ａｓｈｌａｎｄ）１２０.０ｇを分散した。この液を薬物層に対して噴霧・コーティングし乾燥して、薬物層が外層によって被覆された医薬組成物を製した。 Next, 80.0 g of hydroxypropyl cellulose (HPC-SL) was dissolved in 1500.0 g of ethanol, and 12.0 g of carmellose sodium (Brannose 7M1F-PH, Ashland) was dispersed. This liquid was sprayed and coated on the drug layer and dried to prepare a pharmaceutical composition in which the drug layer was coated with an outer layer.
次いで、予め、エトセルＳＴＤ−７を５４.０ｇ、ＴＣ−５Ｅを６.０ｇとり、エタノール９６０.０ｇと精製水２４０.０ｇの混液に溶解させて調製した最外層溶液を噴霧・コーティングし乾燥させて、最外層が被覆された医薬組成物を得た。 Next, 54.0 g of Etocell STD-7 and 6.0 g of TC-5E were taken in advance, dissolved in a mixed solution of 960.0 g of ethanol and 240.0 g of purified water, and the outermost layer solution prepared was sprayed, coated and dried. A pharmaceutical composition coated with the outermost layer was obtained.
＜実施例４＞
実施例３の医薬組成物４２.０ｇとＤ−マンニトール（ペアリトール１６０Ｃ）７２.０ｇ、結晶セルロース（セオラスＵＦ７０２）３０.０ｇ、クロスポビドン（ＸＬ−１０）４．５ｇ、ステアリン酸マグネシウム１．５ｇを袋混合し、ロータリー打錠機（株式会社菊水製作所製：ＶＩＲＧＯ）にて打錠して、医薬組成物を含む１錠重量１５０ｍｇの錠剤を製造した。<Example 4>
42.0 g of the pharmaceutical composition of Example 3, 72.0 g of D-mannitol (Pearitol 160C), 30.0 g of crystalline cellulose (Theoras UF702), 4.5 g of crospovidone (XL-10), 1.5 g of magnesium stearate. The bags were mixed and tableted with a rotary tableting machine (manufactured by Kikusui Seisakusho Co., Ltd .: VIRGO) to produce tablets having a weight of 150 mg per tablet containing the pharmaceutical composition.
＜比較例２＞
亜硫酸ナトリウムの代わりに没食子酸プロピルを用いた以外は実施例３と同様に医薬組成物を調製した。<Comparative example 2>
A pharmaceutical composition was prepared in the same manner as in Example 3 except that propyl gallate was used instead of sodium sulfite.
得られた実施例３〜４、比較例２の医薬組成物の経時的着色を上述の＜着色試験＞において説明したように測定した。結果を表３に示す。 The time-dependent coloring of the obtained pharmaceutical compositions of Examples 3 to 4 and Comparative Example 2 was measured as described in the above-mentioned <coloring test>. The results are shown in Table 3.
表３に示すように、実施例３，４の医薬組成物または錠剤では、比較例２の医薬組成物と比較して、ΔＥを低く抑えることができた。実施例３，４は、ΔＥが３より小さいので、保存開始時から２週間後でも識別可能なほど色が変化しなかったことがわかる。一方、比較例２では、保存開始時と１週間保存後で異なる色と識別されるほど変色したことがわかる。 As shown in Table 3, the pharmaceutical compositions or tablets of Examples 3 and 4 were able to suppress ΔE lower than that of the pharmaceutical composition of Comparative Example 2. Since ΔE of Examples 3 and 4 is smaller than 3, it can be seen that the color did not change so as to be discernible even after 2 weeks from the start of storage. On the other hand, in Comparative Example 2, it can be seen that the color changed so as to be distinguished from the different colors at the start of storage and after storage for one week.
以上に開示された実施の形態と実施例はすべての点で例示であって制限的なものではないと考慮されるべきである。本発明の範囲は、以上の説明ではなく、請求の範囲によって示され、請求の範囲と均等の意味および範囲内でのすべての変形を含むものである。 It should be considered that the embodiments and examples disclosed above are exemplary in all respects and not restrictive. The scope of the present invention is shown by the claims, not the above description, and includes all modifications within the meaning and scope equivalent to the claims.
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