JP2010502584A - リファキサミンの安定多形型を得るためのポリオールの使用 - Google Patents
リファキサミンの安定多形型を得るためのポリオールの使用 Download PDFInfo
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- JP2010502584A JP2010502584A JP2009526185A JP2009526185A JP2010502584A JP 2010502584 A JP2010502584 A JP 2010502584A JP 2009526185 A JP2009526185 A JP 2009526185A JP 2009526185 A JP2009526185 A JP 2009526185A JP 2010502584 A JP2010502584 A JP 2010502584A
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- Prior art keywords
- rifaximin
- polyols
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- polymorph
- residual moisture
- 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.)
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Images
Classifications
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- C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
- C07D491/22—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains four or more hetero rings
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- A—HUMAN NECESSITIES
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- 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
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D498/22—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains four or more hetero rings
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- 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
- A61K31/4353—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 ortho- or peri-condensed with heterocyclic ring systems
- A61K31/437—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 ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline
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- 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
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
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Abstract
Description
医薬製品に含まれる活性成分は、例えば溶解性および化学的安定性などの化学的・物理的性質の異なる多形型として得られることがある。
H−[O−CH−(X)−CH2]n−OH
(I)
(ここでXは水素または低級アルキルで、nは1から20の範囲を取り得る)
または1,2,3−プロパントリオールおよび1,2−プロパンジオールが好ましい。
上述のように、本発明の目的は、上述のポリオールを用いてリファキシミンの多形型、特にViscomi G. C.らによってUS7045620B1 (2003)で開示されたβ型を安定化することにより、活性成分リファキシミンの残存水分率が4.5%(w/w)未満であるβ型のリファキシミンを含む医薬製剤を得て、直接的または間接的にリファキシミンの乾燥につながり得る製造工程の間に多形βを変化させずに維持することである。この製造工程は、ポリオールを用いなければβ型を保持することができず、適用される乾燥条件の厳しさによってはβ型がまさにリファキシミンの他の多形型に転移すると思われる条件下にある。
残存水分率4.5%未満のリファキシミンβ型の調製
リファキシミンβ型199gとAerosil(登録商標)1gとを、入口温度80℃の流動床装置中で5分間、混合する。
本比較例は、ポリオールの非存在下においては、残存水分率が4.5%未満のリファキシミンが多形β型を取らないこと、およびポリオールの添加により残存水分率が4.5%未満でも固相でβ型のリファキシミンが得られることを示す(操作は実施例1に記載したものと同じであるが、噴霧溶液は1,2−プロパンジオールを含まない)。
本比較例は、残存水分率4.5%未満のリファキシミン多形β型を得るためにポリオール中の水酸基の存在が重要であることを示す。操作は実施例1記載のものと同じであるが、1,2−プロパンジオールをエステル化水酸基を有するポリオール、例えば1,2,3−プロパントリオールトリアセテートに置き換えたものである。
PEG400の存在下における、残存水分率4.5%未満のリファキシミンβの調製
リファキシミン199gと、Aerosil(登録商標)1gとを、入口温度80℃の流動床装置中で5分間混合する。
1,2−プロパンジオールの存在下における、残存水分率4.5%未満の胃抵抗性リファキシミンβ細粒の調製
本実施例は、残存水分率4.5%未満のリファキシミンβを得るためにリファキシミンに添加したポリオール1,2−プロパンジオールが同時に、顆粒をカバーするためのフィルムの調製において、可塑化機能を有する他の化合物の添加なしに可塑剤としても作用することを示す。
熱シールバッグ中で調製したリファキシミンβの医薬製剤
実施例5に従って調製した胃抵抗性リファキシミン細粒9.12kg、ソルビトール19.58kg、アスパルテーム0.49kg、無水クエン酸0.21kg、ペクチン2.10kg、マンニトール2.10kg、ネオヘスペリジンDC0.21kg、チェリー香料1.12kg、およびシリカゲル0.07kgを0.5mmメッシュの篩で篩い、次いでVミキサー中で20分間混合する。得られた混合物を、リファキシミン800mgに対応する製品5gを含む熱シールバッグに分配して入れる。熱シールバッグに含まれる特製医薬の組成を下記の表3に示す。
実施例5に従って調製したリファキシミンβを含有する錠剤形の医薬製剤
実施例1に従って調製した胃抵抗性リファキシミン細粒9.3kg、デンプングリコール酸ナトリウム(Sodium Starch Glicolate)593g、およびステアリン酸マグネシウム100gを0.5mmメッシュの篩で篩い、次いでVミキサー中で20分間混合する。得られた混合物を、刻み目を有する楕円形の19×9mmのパンチを備えた回転式打錠機(Fette 1200)を用いて打錠し、リファキシミン400mgに対応する最終重量718mgを得る。
Claims (15)
- リファキシミンの多形型を安定化するための、少なくとも2個の水酸基を有する1種または複数の化合物(以下、「ポリオール」と定義する)の使用。
- 2個から7個の炭素原子および2個から7個の水酸基を含むポリオール、単糖類、二糖類、デンプン、セルロースおよびそれらの誘導体等の多糖類、デキストリンおよびマルトデキストリン、キサンタンガム、ジヒドロキシ酸、およびポリヒドロキシ酸からなる群から選択される1種または複数のポリオールの請求項1に記載の使用。
- 式I:
H−[O−CH−(X)−CH2]n−OH
(I)
(ここで、Xは水素または低級アルキルを表し、nは1から20の範囲を取り得る)
で表される1種または複数のポリオールの請求項1に記載の使用。 - 1,2,3−プロパントリオールの請求項1に記載の使用。
- 一般式H−[O−CH2−CH2]n−OH(ここで、nは2から14の範囲を取り得る)を有するポリオールの請求項2に記載の使用。
- 1,2−プロパンジオールの請求項2に記載の使用。
- 残存水分率が4.5%未満である多形型βのリファキシミンを固体状態で得るためのポリオールの請求項1に記載の使用。
- 残存水分率にかかわらず、請求項1から6に記載の1種または複数のポリオールの使用によって安定化された固体状態のリファキシミンの多形型。
- 残存水分率にかかわらず、請求項1から6に記載の1種または複数のポリオールの使用によって安定化された固体状態のリファキシミン多形型β。
- 残存水分率にかかわらず、請求項1から6に記載の1種または複数のポリオールによって安定化されたリファキシミン多形型βを希釈剤、リガンド、滑剤、崩壊剤、染料、香味料、および甘味料等の当業界でよく知られた賦形剤とともに含む、抗生物質治療を必要とする病態の治療のための経口用および局所用医薬製剤。
- 残存水分率にかかわらず、多形βが請求項1から6に記載の1種または複数のポリオールによって安定化された、胃抵抗性リファキシミンβの細粒。
- 残存水分率にかかわらず、多形βが請求項1から6に記載の1種または複数のポリオールの使用によって安定化された、熱シールされたバッグに入れられたリファキシミンβ。
- 残存水分率にかかわらず、多形βが請求項1から6に記載の1種または複数のポリオールの使用によって安定化された、錠剤の形態のリファキシミンβ。
- 固体状態のリファキシミンを、請求項1から6に記載の1種または複数のポリオールの濃度5%から59%(w/w)の水溶液と、30℃から90℃の温度で、1から24時間、接触させ、固体残留物を分離した後に、該固体残留物を30℃から80℃の温度で周囲圧力または真空下で2から72時間、乾燥させることを特徴とする、請求項9に記載の多形型βのリファキシミンの調製方法。
- 請求項1から6に記載の1種または複数のポリオールの濃度5から50%(w/w)の水溶液を入口温度40℃から90℃で流動床装置中で固体状態のリファキシミンβに噴霧し、このようにして得られた混合物を40℃から90℃の温度の気流下で乾燥させることを特徴とする、請求項9に記載の多形型βのリファキシミンの調製方法。
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JP2013537900A (ja) * | 2010-09-22 | 2013-10-07 | アルファ ワッセルマン ソシエタ ペル アチオニ | リファキシミンを含む医薬処方物、それを得るための方法及び腸疾患を治療する方法 |
JP2016520556A (ja) * | 2013-04-12 | 2016-07-14 | アルファ ワッセルマン ソシエタ ペル アチオニAlfa Wassermann S.P.A. | Nsaid投与並びに関連する組成物、方法及びシステム |
JP2017515821A (ja) * | 2014-05-12 | 2017-06-15 | アルファ ワッセルマン ソシエタ ペル アチオニAlfa Wassermann S.P.A. | リファキシミンの新規溶媒和物結晶形、生成物、組成物及びそれらの使用 |
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ITBO20050123A1 (it) | 2005-03-07 | 2005-06-06 | Alfa Wassermann Spa | Formulazioni farmaceutiche gastroresistenti contenenti rifaximina |
ITMI20061692A1 (it) | 2006-09-05 | 2008-03-06 | Alfa Wassermann Spa | Uso di polioli per ottenere forme polimorfe stabili di rifaximina |
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IT1398550B1 (it) | 2010-03-05 | 2013-03-01 | Alfa Wassermann Spa | Formulazioni comprendenti rifaximina utili per ottenere un effetto prolungato nel tempo |
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CN103827122B (zh) | 2011-02-11 | 2016-08-31 | 萨利克斯药品有限公司 | 利福昔明的形式及其用途 |
ITBO20110461A1 (it) | 2011-07-29 | 2013-01-30 | Alfa Wassermann Spa | Composizioni farmaceutiche comprendenti rifaximina, processi per la loro preparazione e loro uso nel trattamento di infezioni vaginali. |
CA2876737A1 (en) | 2012-06-13 | 2013-12-19 | Apotex Pharmachem Inc. | Polymorphic forms of rifaximin |
ITBO20120368A1 (it) | 2012-07-06 | 2014-01-07 | Alfa Wassermann Spa | Composizioni comprendenti rifaximina e amminoacidi, cristalli di rifaximina derivanti da tali composizioni e loro uso. |
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AU2014229467A1 (en) | 2013-03-15 | 2015-08-06 | Alfa Wassermann S.P.A. | Rifaximin for use in the treating of vaginal infections. |
EP2971062A2 (en) | 2013-03-15 | 2016-01-20 | ALFA WASSERMANN S.p.A. | Method for diagnosing vaginal infections |
US9474699B2 (en) * | 2014-03-31 | 2016-10-25 | Johnson & Johnson Consumer Inc. | Compostions and methods for enhancing the topical application of a basic benefit agent |
ES2621557T3 (es) | 2014-03-31 | 2017-07-04 | Euticals S.P.A. | Mezcla polimórfica de rifaximina y su uso para la preparación de formulaciones sólidas |
WO2018197538A1 (en) * | 2017-04-26 | 2018-11-01 | Sandoz Ag | Oral dosage form comprising rifaximin in form beta |
KR101997341B1 (ko) * | 2017-09-05 | 2019-10-01 | 고려대학교 세종산학협력단 | 박막 트랜지스터 및 그 제조 방법 |
FR3123563A1 (fr) * | 2021-06-03 | 2022-12-09 | Algotherapeutix | Utilisation de l’amitriptyline et/ou l’un de ses sels pharmaceutiquement acceptable comme agent conservateur |
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JP2013537900A (ja) * | 2010-09-22 | 2013-10-07 | アルファ ワッセルマン ソシエタ ペル アチオニ | リファキシミンを含む医薬処方物、それを得るための方法及び腸疾患を治療する方法 |
JP2016520556A (ja) * | 2013-04-12 | 2016-07-14 | アルファ ワッセルマン ソシエタ ペル アチオニAlfa Wassermann S.P.A. | Nsaid投与並びに関連する組成物、方法及びシステム |
JP2017515821A (ja) * | 2014-05-12 | 2017-06-15 | アルファ ワッセルマン ソシエタ ペル アチオニAlfa Wassermann S.P.A. | リファキシミンの新規溶媒和物結晶形、生成物、組成物及びそれらの使用 |
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