CN103330694A - 口服制剂 - Google Patents

口服制剂 Download PDF

Info

Publication number
CN103330694A
CN103330694A CN2013102920051A CN201310292005A CN103330694A CN 103330694 A CN103330694 A CN 103330694A CN 2013102920051 A CN2013102920051 A CN 2013102920051A CN 201310292005 A CN201310292005 A CN 201310292005A CN 103330694 A CN103330694 A CN 103330694A
Authority
CN
China
Prior art keywords
solid composite
excipient
tablet
antioxidant
solution
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.)
Pending
Application number
CN2013102920051A
Other languages
English (en)
Inventor
小罗纳德.S.弗拉迪卡
戴维.C.达尔加诺
约翰.D.尤利厄希
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Ariad Gene Therapeutics Inc
Original Assignee
Ariad Gene Therapeutics Inc
Priority date (The priority date 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 date listed.)
Filing date
Publication date
Application filed by Ariad Gene Therapeutics Inc filed Critical Ariad Gene Therapeutics Inc
Publication of CN103330694A publication Critical patent/CN103330694A/zh
Pending legal-status Critical Current

Links

Classifications

    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/33Heterocyclic compounds
    • A61K31/395Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435Heterocyclic 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
    • A61K31/439Heterocyclic 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 the ring forming part of a bridged ring system, e.g. quinuclidine
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00Medicinal preparations characterised by special physical form
    • A61K9/20Pills, tablets, discs, rods
    • A61K9/2004Excipients; Inactive ingredients
    • A61K9/2013Organic compounds, e.g. phospholipids, fats
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/33Heterocyclic compounds
    • A61K31/395Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435Heterocyclic 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
    • A61K31/4353Heterocyclic 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
    • A61K31/436Heterocyclic 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 six-membered ring having oxygen as a ring hetero atom, e.g. rapamycin
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00Medicinal preparations characterised by special physical form
    • A61K9/20Pills, tablets, discs, rods
    • A61K9/2004Excipients; Inactive ingredients
    • A61K9/2013Organic compounds, e.g. phospholipids, fats
    • A61K9/2018Sugars, or sugar alcohols, e.g. lactose, mannitol; Derivatives thereof, e.g. polysorbates
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00Medicinal preparations characterised by special physical form
    • A61K9/20Pills, tablets, discs, rods
    • A61K9/2004Excipients; Inactive ingredients
    • A61K9/2022Organic macromolecular compounds
    • A61K9/205Polysaccharides, e.g. alginate, gums; Cyclodextrin
    • A61K9/2054Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00Medicinal preparations characterised by special physical form
    • A61K9/20Pills, tablets, discs, rods
    • A61K9/28Dragees; Coated pills or tablets, e.g. with film or compression coating
    • A61K9/2806Coating materials
    • A61K9/2833Organic macromolecular compounds
    • A61K9/284Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00Medicinal preparations characterised by special physical form
    • A61K9/20Pills, tablets, discs, rods
    • A61K9/28Dragees; Coated pills or tablets, e.g. with film or compression coating
    • A61K9/2806Coating materials
    • A61K9/2833Organic macromolecular compounds
    • A61K9/284Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone
    • A61K9/2846Poly(meth)acrylates
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00Medicinal preparations characterised by special physical form
    • A61K9/20Pills, tablets, discs, rods
    • A61K9/28Dragees; Coated pills or tablets, e.g. with film or compression coating
    • A61K9/2886Dragees; Coated pills or tablets, e.g. with film or compression coating having two or more different drug-free coatings; Tablets of the type inert core-drug layer-inactive layer
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/10Laxatives
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00Drugs for disorders of the respiratory system
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00Drugs for disorders of the urinary system
    • A61P13/08Drugs for disorders of the urinary system of the prostate
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P15/00Drugs for genital or sexual disorders; Contraceptives
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00Drugs for dermatological disorders
    • A61P17/06Antipsoriatics
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00Drugs for skeletal disorders
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00Drugs for disorders of the nervous system
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00Drugs for disorders of the senses
    • A61P27/02Ophthalmic agents
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00Drugs for disorders of the metabolism
    • A61P3/08Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/10Antimycotics
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00Antineoplastic agents
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00Antineoplastic agents
    • A61P35/02Antineoplastic agents specific for leukemia
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00Drugs for immunological or allergic disorders
    • A61P37/02Immunomodulators
    • A61P37/06Immunosuppressants, e.g. drugs for graft rejection
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00Drugs for disorders of the blood or the extracellular fluid
    • A61P7/06Antianaemics
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00Drugs for disorders of the cardiovascular system
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00Drugs for disorders of the cardiovascular system
    • A61P9/10Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis

Abstract

本发明公开了适于口服给药的含有AP23573的固体药物组合物。

Description

口服制剂
本申请是中国发明申请(发明名称:口服制剂;申请号:200780042435.0;申请日:2007年11月14日)的分案申请。
发明背景
本发明涉及雷帕霉素-43-二甲基次膦酸酯(AP23573)的固体制剂:
Figure BDA00003501317200011
体外和体内异种移植模型中,AP23573强效地抑制多种人肿瘤细胞系(包括前列腺、子宫内膜、软组织和骨肉瘤、白血病、淋巴瘤和成胶质细胞瘤细胞系)的增殖。
AP23573的人类临床研究已经表现出对于患有不同癌症的患者具有积极的结果,包括可能延迟肿瘤进展和复发的时间。
AP23573也用于开发AP23573-涂层支架(eluting stents)的研究中。在该内容中AP23573的作用为在支架引入后抑制再狭窄。
部分基于对其它mTOR抑制剂的已知的生物学活性,AP23573也可以用于一系列对于用mTOR抑制剂治疗敏感的适应症,包括但不限于,治疗和预防器官移植排斥和自身免疫性疾病、真菌感染、多发性硬化;类风湿性关节炎、全身性红斑狼疮[参见,例如美国专利5,078,999]、肺炎[美国专利5,080,899]、胰岛素依赖型糖尿病[美国专利5,321,009]、皮肤病,如牛皮癣[美国专利5,286,730]、肠病[美国专利5,286,731]、血管损伤后的平滑肌细胞增殖和内膜增厚[美国专利5,288,711和5,516,781]、成人T-细胞白血病/淋巴瘤[欧洲专利申请525,960A1]、眼炎[美国专利5,387,589]、恶性肿瘤[美国专利5,206,018]、心脏炎性疾病[美国专利5,496,832],和贫血[美国专利5,561,138]。
研发和使用AP23573的一个重要的挑战为开发用于口服给药的存储稳定的固体剂型。更具体地,我们已经发现AP23573片剂(通过直接压制未微粉化的AP23573与标准赋形剂和填充剂制备得到,含有或不含有抗氧化剂)迄今提供了欠佳的片剂,其不能呈现所需的高均匀性(homogeneity)和稳定性。
发明概述
我们已经对AP23573的降解进行了详细的研究,且已经确定的重要的降解途径涉及化合物的三烯部分的氧化。而且,我们已经发现AP23573也通过内酯键的断裂发生水解降解,导致形成开环的seco-AP23573。
因为AP23573为无定形的固体,而不是如雷帕霉素或西罗莫司(temsirolimus)的结晶物质,所以我们不能直接利用在配制那些化合物中所报导的知识,而是基于根据AP23573本身的经验研究。
源自那些研究的本发明克服了上述的问题,且提供了合理储存稳定性、生物利用度的AP23573的口服制剂,其适合用于药用,且不需要微粉化。
适于口服给药的药物组合物包含2-35%的AP23573,0.01-3%的抗氧化剂和70-97%的载体物质(该载体物质包含至少一种纤维素聚合物),任选含有一种或多种其它的可药用赋形剂。除非另有说明,本文中所有百分比均基于重量/重量。合适的载体物质包括微晶纤维素、羟丙基纤维素和乳糖单水合物,其通常分别以20-55%,2-15%和15-70%的量使用。当前用于本发明组合物的优选的抗氧化剂为丁羟甲苯(butylated hydroxytoluene,"BHT")。其它的赋形剂可包括物质如交联羧甲基纤维素钠和硬脂酸镁。
该组合物可制备为多种物理形式(胶囊、片剂、小胶囊(caplets)等),且最关注那些含有10-60mg,一般为10-40mg的AP23573的组合物。含有10mg的AP23573的压制片剂是当前最感兴趣的。该片剂可任选含有可药用的膜包衣或肠溶包衣。
该组合物可使用其它常规混合技术和设备制备,使用高切应力型制粒机湿法制粒,然后使用流化床干燥的方法是当前最感兴趣的。
在该方法中,提供AP23573在选择的溶剂中的溶液,如含水乙醇溶液或水溶液(且可用其它醇代替乙醇)。该溶液(其也可以含有抗氧化剂)与载体混合,形成湿块。该过程通常在制粒机或其它混合设备(如高切应力型制粒机)中进行。然后将该湿块混合(如通过制粒),得到湿颗粒。然后将该湿颗粒干燥(例如在流化床干燥器中),得到干颗粒,将其压制成片剂,且视需要包衣。
如上所述,AP23573的溶液也可以含有抗氧化剂。替代性地,或进一步地,抗氧化剂可在加入AP23573溶液之前或之后单独与载体物质混合,在任一情形下,掺入至所得的湿块中。其它的赋形剂也可以在掺入至湿块的步骤中加入。也可以将赋形剂加入至湿或干颗粒中。
已发现通过该方法制备的固体药物组合物具有合适的存储稳定性和生物利用度(适于用于人类临床研究)。
发明详述
本发明提供了储存稳定的单一剂型(unit dosage form)的固体药物组合物,其包含AP23573,抗氧化剂和纤维素聚合物。该组合物也可含有一种或多种其它的可药用赋形剂,如螯合剂、填充剂、粘合剂、表面活性剂、崩解剂、润滑剂、pH调节剂等。该组合物通过上述湿法制粒方法制备。
用于制备AP23573溶液且在制粒步骤中可能使用的合适的溶剂包括但不限于水和有机溶剂(如,甲醇、乙醇、异丙醇、丙酮),每种溶剂单独使用或组合使用。优选该湿法制粒用醇溶剂体系进行,其中乙醇是当前最感兴趣的醇。含水乙醇是组合制粒溶剂体系的实例,其包括水和乙醇。
当前尤其感兴趣的是,所述组合物含有1-45%,2-35%。5-25%,或8-15%重量的AP23573;1-50%,1-35%,1-15%,或2-15%重量的纤维素聚合物,和0.01%-3%,0.05%-1%,或0.05%-0.5%重量的抗氧化剂。然而,不同的实施方案可含有更多或更少的这些组分。
可接受的抗氧化剂包括,但不限于,柠檬酸、d,l-α-生育酚、BHA、BHT、单硫代甘油、抗坏血酸和没食子酸丙酯。本发明制剂的抗氧化剂的使用量为相对于片剂重量的0.01%-3%wt/wt。
螯合剂,或其它能够结合金属离子的物质,如乙二胺四乙酸(EDTA)及其盐,能够增强AP23573的稳定性,且可用作任选的赋形剂。
典型的纤维素聚合物包括,但不限于,羟丙基甲基纤维素(HPMC)、羟丙基甲基纤维素酞酸酯、甲基纤维素(MC)、羟乙基纤维素和羟丙基纤维素(HPC)。其它可药用的纤维素聚合物在本文不同地方提及,且许多其它纤维素聚合物是本领域公知的。
可药用赋形剂包括粘合剂、填充剂、崩解剂、pH调节剂、表面活性剂,和上述物质的任一组合。
可接受的pH调节剂包括,但不限于,柠檬酸、柠檬酸钠、稀HCl,和其它弱酸或碱,所述pH调节剂能够用于缓冲含AP23573的溶液,使pH范围为约4至约6。如果pH调节剂存在于组合物中,pH调节剂通常的量为相对于片剂重量的至多1%重量。
表面活性剂可存在于制剂中,且包括聚山梨酯80、月桂基硫酸钠、十二烷基硫酸钠、胆汁酸的盐(牛磺胆酸盐,甘氨胆酸盐,胆酸盐,脱氧胆酸盐等),其可与卵磷脂组合。或者,乙氧基化的植物油,如聚氧乙烯蓖麻油(Cremophor EL)、维生素E生育酚丙二醇琥珀酸酯(维生素E TGPS)、聚氧乙烯-聚氧丙烯嵌段共聚物,和泊洛沙姆。如果组合物中存在表面活性剂,其量通常为相对于片剂重量的至多20%,例如1-15%重量。
粘合剂、填充剂和崩解剂,如蔗糖、乳糖、微晶纤维素、交联羧甲基纤维素钠、硬脂酸镁、阿拉伯胶、胆固醇、西黄蓍胶、硬脂酸、明胶、酪蛋白、卵磷脂(磷脂)、羧甲基纤维素钙、羧甲基纤维素钠、甲基纤维素、羟乙基纤维素、羟丙基纤维素、羟丙基甲基纤维素酞酸酯、非晶态纤维素、聚乙烯基吡咯烷酮、十八/十六醇(cetostearyl alcohol)、鲸蜡醇、十六烷基酯蜡(cetyl esterswax)、葡聚糖结合剂(dextrates)、糊精、环糊精、乳糖、右旋糖、单油酸甘油酯、单硬脂酸甘油酯、棕榈酰硬脂酸甘油酯、聚氧乙烯烷基醚、聚乙二醇、聚氧乙烯蓖麻油衍生物、聚氧乙烯硬脂酸酯和聚乙烯醇等也可掺入到制剂中。
本发明得到的任一制剂可包含每类组分的多种成分。例如,包含抗氧化剂的制剂可包含一种或多种抗氧化剂作为抗氧化剂组分。
在一个示例性的实施方案中,湿法制粒方法包括下述步骤:混合、润湿、形成湿块、制粒、干燥和过筛。这些步骤在下面详述。
湿法制粒方法从制备包含AP23573和抗氧化剂的溶液开始。合适的溶剂包括水、甲醇、乙醇、异丙醇等,其中乙醇尤其感兴趣。下一步为将该溶液加入至含"基质形成物质"和一种或多种任选的粒内赋形剂的混合物中,同时搅拌混合物成分,得到湿块。该步骤也称为使粉末粒内共混物形成湿块。合适的基质形成物质的实例包括纤维素聚合物,且也包含粘合剂和填充剂以促进终产物的溶出增强。典型的粒内赋形剂可包括粘合剂、填充剂、崩解剂和上述成分的任何组合。纤维素聚合物/粒内赋形剂混合物的实例包括但不限于,微晶纤维素、乳糖单水合物、交联羧甲基纤维素钠和羟丙基纤维素的组合。然后湿块在混合器中制粒,得到湿颗粒形式的各种成分的混合物。继续制粒(即混合/搅拌)直到得到均匀颗粒(即直到颗粒的粒径达到希望的均匀度)。所述混合器可为配有增强棒(intensifying bar)、低切应力制粒机或高切应力制粒机。然后干燥湿颗粒,如在流化床干燥器中,温度为45-55℃。然后可使用合适的研磨设备(如Fitz研磨器)研磨干燥的颗粒状物质。湿法制粒和干燥可以在流化床制粒机/干燥器中进行。湿颗粒可使用盘式干燥烘箱(traydrying oven)干燥。它们被干燥后,颗粒可进一步过筛,即干燥过筛,单独进行,或与一种或多种其它的赋形剂一起进行。而且,视需要,经干燥的颗粒可进一步在混合器(如V-blender)中与颗粒外填充剂和粘合剂,如微晶纤维素、交联羧甲基纤维素钠和硬脂酸镁混合。这一般得到更均匀粒径的颗粒。然后将其压制成片剂。
在替代性的方法中,AP23573的溶液不含抗氧化剂。在该方法中,抗氧化剂而是存在于混合物的内容物中,该内容物也包括纤维素聚合物、粒内赋形剂等。
在其它实施方案中,抗氧化剂又存在于含纤维素聚合物和粒内赋形剂的混合物中,且将AP23573以固体形式加入,然后与粒内赋形剂混合。然后将溶剂加至混合物中,然后进行制粒步骤。其它的加入顺序在本发明种是可能的并且允许的。
口服片剂可进一步包含膜包衣以控制AP23573的释放。该片剂可使用不同包衣溶剂通过喷雾、浸渍或通过沉积而用膜包衣进行包衣。合适的包衣溶剂包括水、甲醇、乙醇、异丙醇等。膜包衣包括聚合物膜形成物质,如共聚维酮(即,聚乙烯基吡咯烷酮和乙酸乙烯酯的共聚物)、羟丙基甲基纤维素、羟丙基纤维素,和丙烯酸酯或甲基丙烯酸酯共聚物。而且,除膜形成聚合物外,膜包衣可进一步含有增塑剂,如聚乙二醇、柠檬酸三乙酯,表面活性剂,如Tween.RTM型,消泡剂,如二甲基硅油,和任选的色素,如二氧化钛或氧化铁。膜包衣也可包含滑石作为抗粘剂。膜包衣通常少于剂型的约5%重量。
在一个优选实施方案中,膜包衣物质包含共聚维酮,其使得AP23573快速释放。
膜包衣也可为肠溶层,其包含肠溶聚合物以延迟AP23573的释放。肠溶层为在胃中的酸性介质不溶但在肠中所遇较高pH环境可溶的物质(即,聚合物)的包衣。该物质用作片剂的膜包衣,以改变药物的释放。合适的肠溶聚合物是本领域技术人员公知的(WO 01/051031),且包括,但不限于,甲基丙烯酸甲酯聚合物、甲基丙烯酸共聚物、乙酸酞酸纤维素、聚乙酸乙烯酯酞酸酯、羟丙基甲基酞酸酯(hydroxypropyl methyl phthalate)和羟丙基甲基纤维素酞酸酯。肠溶衣也可进一步包含前述的增塑剂、表面活性剂、消泡剂和任选的色素。
在一个优选的实施方案中,肠溶层包含甲基丙烯酸共聚物,如EudragitL100、Acryl-EZE等。
下述内容提供了本发明制剂的代表性实施例。AP23573的制备描述于美国专利7,091,213中,将其在此引入作为参考。这些实施例仅是示例性的,且不用于限制本文所述的本发明的范围。这些实施例仅用于说明本发明的实施方法。
实施例
实施例1:醇法制粒(alcoholic granulation)
片芯
使用下述步骤用于制备含10mg的AP23573,含下述列举的成分的片剂。该片剂为6mm直径,白色至灰白色,圆形,双凸面,包衣片剂。片芯的组成如下表所示。在该实施例中,片芯为膜包衣且可以如此使用,或可以为肠溶衣包衣以延迟释放。
Figure BDA00003501317200071
*加工时被移除
加工
将羟丙基纤维素、乳糖单水合物、微晶纤维素和一半的交联羧甲基纤维素钠在高切应力制粒机中混合。将AP23573和丁羟甲苯(BHT)溶于无水醇,USP中,混合不少于45分钟。将AP23573和BHT的溶液加入至制粒机中,并混合约3分钟以形成湿块。
将颗粒混合物在流化床干燥器(45-55℃)中干燥60-90分钟,然后使经干燥的颗粒物质通过配有0.045-英寸筛孔(screen opening)的研磨机以除去过大的物质。然后将经研磨的颗粒物质加入至V-混合器中,并与硬脂酸镁,NF和剩余的一半交联羧甲基纤维素钠,NF混合直到混合均匀。
使用具有6mm圆形凹面工具的压片机将颗粒物质压制成片剂。根据需要调节压力,使目标片重为125.0mg,硬度5.5kp,脆碎度不超过1%,且崩解时间小于10分钟。
膜包衣
根据下述方法使用下述组分制备膜包衣。
膜包衣                   溶液的百分比
共聚维酮                 20.00%
无水醇(乙醇)*            80.00%
*加工时被移除
将片剂加入至包衣锅中,并用共聚维酮的无水醇(USP)溶液包衣,保持产物温度为20-35℃,直到重量增加5%。然后将锅冷却,且将膜包衣的片剂进行干燥。膜包衣的片剂可以以本身封装,或可被肠溶包衣。
肠溶包衣
根据下述方法使用下述组分制备肠溶包衣。
Figure BDA00003501317200081
*加工时被移除
为了肠溶包衣,将片剂置于包衣锅中,并用甲基丙烯酸共聚物(NF)、柠檬酸三乙酯(NF)和滑石在无水醇(USP)中的混悬液包衣,保持产物温度为20-35℃,直到重量增加8%。然后将锅冷却,并将肠溶包衣片剂进行干燥。
实施例2:水法制粒(aqueous granulation)
片芯
使用下述步骤制备含有50mg的AP23573,含有下述成分的片剂。片芯的组成示于下表中。片芯为膜包衣且可以如此使用,或可为肠溶包衣。
Figure BDA00003501317200091
*加工时被移除
使丁羟甲苯(BHT)通过配有0.010筛的研磨机,并在高切应力制粒机中与羟丙基纤维素、一半微晶纤维素和1/3的交联羧甲基纤维素钠混合。然后将AP23573加入至制粒机中,并混合5分钟。然后开始制粒过程,同时经5分钟加入制粒流体(去离子水)。将AP23573、BHT和赋形剂混合约2分钟以形成湿块。
将颗粒物质在流化床干燥器(45-55℃)中干燥60-90分钟,之后使经干燥的颗粒物质通过配有0.065-英寸筛孔的研磨机以除去过大的物质。然后使经研磨的颗粒物质与硬脂酸镁、剩余的2/3交联羧甲基纤维素钠和剩余的一半微晶纤维素混合。
使用具有圆形凹面工具的压片机将颗粒物质压制成片剂。根据需要调节压力,使得目标片重为200.0mg,硬度为8.5kp,脆碎度不超过1%,且崩解时间小于10分钟。
膜包衣
根据下述方法使用下述组分制备膜包衣。
膜包衣                        溶液的百分比
共聚维酮                      7.00%
去离子水*                     93.00%
*加工时被移除
将片剂加入至包衣锅中,并用共聚维酮在去离子水中的溶液包衣,保持产物温度27-31℃,直到重量增加2%。将锅冷却,且将膜包衣的片剂进行干燥。膜包衣的片剂可以以其本身封装,或可被肠溶包衣。
肠溶包衣
根据下述方法使用下述组分制备肠溶包衣。
Figure BDA00003501317200101
*加工时被移除
为了肠溶包衣,将片剂置于包衣锅中。剧烈混合将二甲基硅油分散在去离子水中得到10%终包衣溶液。然后加入甲基丙烯酸共聚物,并与二甲基硅油/水混合物混合。温热包衣锅和片剂使产物温度为30-33℃。将包衣溶液喷雾至片剂上,直到重量增加10%。然后将锅冷却,并使肠溶包衣的片剂进行干燥。
本说明书中所引用的文献在此引入作为参考。对于上述详细描述和示例性实施例的方法和材料进行的较小的改变和更改对于本领域技术人员来说是明显的,且包含在本发明的范围内。

Claims (12)

1.固体药物组合物,其适于口服给药,该固体药物组合物包含:
·2-35%重量的下式的雷帕霉素-43-二甲基次膦酸酯:
Figure FDA00003501317100011
·0.01-3%重量的抗氧化剂,和
·70-97%重量的载体物质,其包含至少一种纤维素聚合物,
任选含有一种或多种其它的可药用赋形剂。
2.权利要求1的固体组合物,其中所述载体物质包含微晶纤维素、羟丙基纤维素和乳糖单水合物。
3.权利要求1的固体组合物,其中所述抗氧化剂为丁羟甲苯。
4.权利要求1的固体组合物,其含有交联羧甲基纤维素钠和硬脂酸镁中的一种或两种作为任选的赋形剂。
5.权利要求1-4中任一项的固体组合物,其还包含可药用的膜包衣或肠溶包衣。
6.权利要求1-5中任一项的固体组合物,其含有10-40mg的雷帕霉素-43-二甲基次膦酸酯。
7.一种制备权利要求1的固体药物组合物的方法,该方法包括:
(a)制备雷帕霉素-43-二甲基次膦酸酯在选择的溶剂中的溶液;
(b)将该溶液与载体混合以形成湿块;
(c)制粒该湿块以得到湿颗粒;
(d)干燥该湿颗粒以得到经干燥的颗粒;
(e)压制所述经干燥的颗粒为片剂;以及
(f)任选用膜包衣聚合物包衣得到的片剂;
其中步骤(a)中的溶液还包含抗氧化剂,或步骤(b)中的载体先与抗氧化剂混合,然后再与雷帕霉素-43-二甲基次膦酸酯溶液混合。
8.权利要求7的方法,其中一种或多种其它的赋形剂在步骤(b)中混合并掺入到湿块中。
9.权利要求7和8的方法,其中在步骤(d)的干燥之前或之后,将一种或多种其它的赋形剂加入到颗粒中。
10.权利要求9的方法,其中一种或多种其它的赋形剂包含交联羧甲基纤维素钠和硬脂酸镁中的一种或两种。
11.固体药物组合物,其通过权利要求7-10中任一项的方法制备。
12.权利要求11的固体药物组合物,其包含10-40mg的雷帕霉素-43-二甲基次膦酸酯。
CN2013102920051A 2006-11-14 2007-11-14 口服制剂 Pending CN103330694A (zh)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US85887006P 2006-11-14 2006-11-14
US60/858,870 2006-11-14

Related Parent Applications (1)

Application Number Title Priority Date Filing Date
CNA2007800424350A Division CN101583347A (zh) 2006-11-14 2007-11-14 口服制剂

Publications (1)

Publication Number Publication Date
CN103330694A true CN103330694A (zh) 2013-10-02

Family

ID=39402236

Family Applications (2)

Application Number Title Priority Date Filing Date
CN2013102920051A Pending CN103330694A (zh) 2006-11-14 2007-11-14 口服制剂
CNA2007800424350A Pending CN101583347A (zh) 2006-11-14 2007-11-14 口服制剂

Family Applications After (1)

Application Number Title Priority Date Filing Date
CNA2007800424350A Pending CN101583347A (zh) 2006-11-14 2007-11-14 口服制剂

Country Status (8)

Country Link
US (3) US20080161335A1 (zh)
EP (1) EP2094241A4 (zh)
JP (2) JP2010509400A (zh)
CN (2) CN103330694A (zh)
AU (1) AU2007319825B2 (zh)
CA (1) CA2669415A1 (zh)
IL (1) IL198760A0 (zh)
WO (1) WO2008060546A2 (zh)

Families Citing this family (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8852590B2 (en) 2009-04-16 2014-10-07 Merck Sharp & Dohme Corp. Compositions and methods for treating cancer
CN102499929B (zh) * 2011-09-29 2014-10-08 福建省微生物研究所 42-(二甲基亚膦酰)雷帕霉素固体组合物及其包衣方法
CA3143529A1 (en) 2013-05-29 2014-12-04 Signal Pharmaceuticals, Llc Pharmaceutical compositions 0f 7-(6-(2-hydroxypropan-2-yl)pyridin-3-yl)-1-((trans)-4-methoxycyclohexyl)-3,4-dihydropyrazino [2,3-b]pyrazin-2(1h)-one, a solid form thereof and methods of their use
ES2959860T3 (es) 2017-06-22 2024-02-28 Celgene Corp Tratamiento del carcinoma hepatocelular caracterizado por la infección por el virus de la hepatitis B
CN110876730A (zh) * 2019-12-06 2020-03-13 怀化正好制药有限公司 妇康宁片及其制备方法

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20040077677A1 (en) * 2002-09-17 2004-04-22 Wyeth Oral formulations
US20040254210A1 (en) * 2001-09-28 2004-12-16 Barbara Haeberlin Pharmaceutical compositions comprising colloidal silicon dioxide
US20060094745A1 (en) * 2004-10-28 2006-05-04 Wyeth Use of an mTOR inhibitor in treatment of uterine leiomyoma

Family Cites Families (66)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5206018A (en) 1978-11-03 1993-04-27 Ayerst, Mckenna & Harrison, Inc. Use of rapamycin in treatment of tumors
JPS6390534A (ja) 1986-10-06 1988-04-21 Hitachi Ltd アルカリ可溶性ラダ−シリコ−ン重合体
JPS63101427A (ja) 1986-10-17 1988-05-06 Hitachi Ltd アルカリ可溶性ラダ−シリコ−ン
US6146358A (en) 1989-03-14 2000-11-14 Cordis Corporation Method and apparatus for delivery of therapeutic agent
WO1990013332A1 (en) 1989-05-11 1990-11-15 Cedars-Sinai Medical Center Stent with sustained drug delivery
ATE120377T1 (de) 1990-02-08 1995-04-15 Howmedica Aufblasbarer dilatator.
US5545208A (en) 1990-02-28 1996-08-13 Medtronic, Inc. Intralumenal drug eluting prosthesis
US5378696A (en) 1990-09-19 1995-01-03 American Home Products Corporation Rapamycin esters
EP0552309A1 (en) 1990-10-09 1993-07-28 Merck & Co. Inc. New process for biophosphorylating organic compounds
US5604294A (en) 1991-09-05 1997-02-18 Luly; Jay R. Macrocyclic immunomodulators
US5252732A (en) 1991-09-09 1993-10-12 Merck & Co., Inc. D-heteroaryl, O-alkylheteroaryl, O-alkenylheteroaryl and O-alkynylheteroarylmacrolides having immunosuppressive activity
US5516781A (en) 1992-01-09 1996-05-14 American Home Products Corporation Method of treating restenosis with rapamycin
US5599352A (en) 1992-03-19 1997-02-04 Medtronic, Inc. Method of making a drug eluting stent
US5283257A (en) 1992-07-10 1994-02-01 The Board Of Trustees Of The Leland Stanford Junior University Method of treating hyperproliferative vascular disease
MX9304868A (es) 1992-08-13 1994-05-31 American Home Prod 27-hidroxirapamicina, derivados de la misma y composicion farmaceutica que la contiene.
US5434260A (en) 1992-10-13 1995-07-18 American Home Products Corporation Carbamates of rapamycin
US5489680A (en) 1992-10-13 1996-02-06 American Home Products Corporation Carbamates of rapamycin
US5310903A (en) 1993-03-05 1994-05-10 Merck & Co., Inc. Imidazolidyl rapamycin derivatives
CA2161101A1 (en) 1993-04-23 1994-11-10 Eduardo Gonzalez Rapamycin conjugates and antibodies
US5464650A (en) 1993-04-26 1995-11-07 Medtronic, Inc. Intravascular stent and method
US5387680A (en) 1993-08-10 1995-02-07 American Home Products Corporation C-22 ring stabilized rapamycin derivatives
US5391730A (en) 1993-10-08 1995-02-21 American Home Products Corporation Phosphorylcarbamates of rapamycin and oxime derivatives thereof
US5385910A (en) 1993-11-22 1995-01-31 American Home Products Corporation Gem-distributed esters of rapamycin
US6152141A (en) 1994-07-28 2000-11-28 Heartport, Inc. Method for delivery of therapeutic agents to the heart
US5660873A (en) 1994-09-09 1997-08-26 Bioseal, Limited Liability Corporaton Coating intraluminal stents
JP3942201B2 (ja) 1994-11-18 2007-07-11 株式会社カネカ フェニルポリシルセスキオキサンの製造方法
US5491231A (en) 1994-11-28 1996-02-13 American Home Products Corporation Hindered N-oxide esters of rapamycin
US5665591A (en) 1994-12-06 1997-09-09 Trustees Of Boston University Regulation of smooth muscle cell proliferation
JP3324360B2 (ja) 1995-09-25 2002-09-17 信越化学工業株式会社 ポリシロキサン化合物及びポジ型レジスト材料
CA2199890C (en) 1996-03-26 2002-02-05 Leonard Pinchuk Stents and stent-grafts having enhanced hoop strength and methods of making the same
US6273913B1 (en) 1997-04-18 2001-08-14 Cordis Corporation Modified stent useful for delivery of drugs along stent strut
US5780604A (en) 1997-09-26 1998-07-14 Abbott Laboratories 11,12-cyclic phosphite or phosphate derivatives of erythromycin and related macrolides
US6623521B2 (en) 1998-02-17 2003-09-23 Md3, Inc. Expandable stent with sliding and locking radial elements
US20010029351A1 (en) 1998-04-16 2001-10-11 Robert Falotico Drug combinations and delivery devices for the prevention and treatment of vascular disease
US6288234B1 (en) 1998-06-08 2001-09-11 Advanced Medicine, Inc. Multibinding inhibitors of microsomal triglyceride transferase protein
US6153252A (en) 1998-06-30 2000-11-28 Ethicon, Inc. Process for coating stents
US6087064A (en) 1998-09-03 2000-07-11 International Business Machines Corporation Silsesquioxane polymers, method of synthesis, photoresist composition, and multilayer lithographic method
US7125875B2 (en) 1999-04-15 2006-10-24 Bristol-Myers Squibb Company Cyclic protein tyrosine kinase inhibitors
WO2000077575A1 (en) 1999-06-10 2000-12-21 Alliedsignal Inc. Spin-on-glass anti-reflective coatings for photolithography
US6890448B2 (en) 1999-06-11 2005-05-10 Shipley Company, L.L.C. Antireflective hard mask compositions
JP4187879B2 (ja) 1999-08-06 2008-11-26 東京応化工業株式会社 感放射線レジスト組成物
AU2599501A (en) 1999-12-29 2001-07-09 Advanced Cardiovascular Systems Inc. Device and active component for inhibiting formation of thrombus-inflammatory cell matrix
GB0000482D0 (en) 2000-01-11 2000-03-01 Norton Healthcare Ltd Enteric coated pharmaceutical formulation
US6776796B2 (en) 2000-05-12 2004-08-17 Cordis Corportation Antiinflammatory drug and delivery device
CA2408754C (en) 2000-05-12 2011-01-04 Cordis Corporation Delivery devices for treatment of vascular disease
JP4622061B2 (ja) 2000-07-27 2011-02-02 Jsr株式会社 レジスト下層膜用組成物およびその製造方法
TW556047B (en) 2000-07-31 2003-10-01 Shipley Co Llc Coated substrate, method for forming photoresist relief image, and antireflective composition
JP4141625B2 (ja) 2000-08-09 2008-08-27 東京応化工業株式会社 ポジ型レジスト組成物およびそのレジスト層を設けた基材
US20030033007A1 (en) 2000-12-22 2003-02-13 Avantec Vascular Corporation Methods and devices for delivery of therapeutic capable agents with variable release profile
PT1385551E (pt) 2001-04-06 2008-11-03 Wyeth Corp Associações antineoplásicas compreendendo cci-779 (derivado de rapamicina) associado a gemcitabina ou fluorouracilo
TW594416B (en) 2001-05-08 2004-06-21 Shipley Co Llc Photoimageable composition
MXPA04006731A (es) * 2002-01-10 2004-10-04 Novartis Ag Sistema de administracion de farmacos que comprenden rapamicina y derivados de la misma para la prevencion y tratamiento de enfermedades vasculares.
IL162734A0 (en) 2002-02-01 2005-11-20 Ariad Gene Therapeutics Inc Phosphorus-containing compounds & uses thereof
US7432277B2 (en) 2002-02-01 2008-10-07 Araid Gene Therapeutics, Inc. Phosphorus-containing macrocycles
US20050026868A1 (en) 2003-07-11 2005-02-03 Metcalf Chester A. Phosphorus-containing macrocycles
JP4557497B2 (ja) 2002-03-03 2010-10-06 ローム・アンド・ハース・エレクトロニック・マテリアルズ,エル.エル.シー. シランモノマー及びポリマーを製造する方法及びそれを含むフォトレジスト組成物
KR20060037447A (ko) 2003-08-18 2006-05-03 화이자 프로덕츠 인크. erbB2 항암제에 대한 투약 스케쥴
AR045957A1 (es) * 2003-10-03 2005-11-16 Novartis Ag Composicion farmaceutica y combinacion
GB0327840D0 (en) 2003-12-01 2003-12-31 Novartis Ag Organic compounds
WO2006039414A2 (en) * 2004-09-30 2006-04-13 Ariad Gene Therapeutics, Inc. Treatment method
EP1838288A4 (en) 2004-12-20 2010-08-04 Ariad Pharma Inc THERAPEUTIC MATERIALS AND METHODS
WO2006071966A2 (en) * 2004-12-29 2006-07-06 The Brigham And Women's Hospital, Inc. Rapamycin compounds in the treatment of neurofibromatosis type 1
KR20070104908A (ko) 2005-02-15 2007-10-29 와이어쓰 경구적으로 생체이용가능한 cci-779 정제 제형물
US20070004767A1 (en) 2005-06-30 2007-01-04 Gutmann David H Methods for treating neurofibromatosis 1
WO2007056117A1 (en) 2005-11-04 2007-05-18 Wyeth Antineoplastic combinations of temsirolimus and sunitinib malate
CN101360495B (zh) * 2005-11-14 2012-03-14 阿里亚德医药股份有限公司 对癌症病人给药mTOR抑制剂

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20040254210A1 (en) * 2001-09-28 2004-12-16 Barbara Haeberlin Pharmaceutical compositions comprising colloidal silicon dioxide
US20040077677A1 (en) * 2002-09-17 2004-04-22 Wyeth Oral formulations
US20060094745A1 (en) * 2004-10-28 2006-05-04 Wyeth Use of an mTOR inhibitor in treatment of uterine leiomyoma

Also Published As

Publication number Publication date
WO2008060546A2 (en) 2008-05-22
US20080161335A1 (en) 2008-07-03
AU2007319825B2 (en) 2014-01-23
US8496967B2 (en) 2013-07-30
CN101583347A (zh) 2009-11-18
WO2008060546A3 (en) 2009-04-30
US20100247643A1 (en) 2010-09-30
AU2007319825A1 (en) 2008-05-22
JP2010509400A (ja) 2010-03-25
US20130202702A1 (en) 2013-08-08
IL198760A0 (en) 2010-02-17
CA2669415A1 (en) 2008-05-22
EP2094241A4 (en) 2013-04-17
JP2014040462A (ja) 2014-03-06
EP2094241A2 (en) 2009-09-02

Similar Documents

Publication Publication Date Title
AU2003272489B2 (en) Granulated formulation of the rapamycin ester CCI779
US11365197B2 (en) Dosage form compositions comprising an inhibitor of Bruton's tyrosine kinase
EP0514967A1 (en) Low solubility drug-coated bead compositions
KR20070115918A (ko) 멀티플 유닛형 경구 서방성 제제 및 그 제조방법
CN103330694A (zh) 口服制剂
CN115624525A (zh) 一种他克莫司缓释药物组合物及其制备方法
CN111565714B (zh) 包含依维莫司的实现稳定化的药剂学制剂
CN102499929B (zh) 42-(二甲基亚膦酰)雷帕霉素固体组合物及其包衣方法
CA3094115A1 (en) Pharmaceutical composition comprising meta arsenite and method of manufacture
CN103006605A (zh) 苄达赖氨酸缓释制剂和制备方法及其应用
AU2013203956A1 (en) Oral formulations
CN100448880C (zh) 2"氧代-voruscharin及其衍生物
CN112218626A (zh) 一种持续释放组合物及其制备方法
SI22571A (sl) Stabilen trden farmacevtski sestavek, ki obsega kandesartan ali njegove farmacevtsko sprejemljive oblike

Legal Events

Date Code Title Description
C06 Publication
PB01 Publication
C10 Entry into substantive examination
SE01 Entry into force of request for substantive examination
C12 Rejection of a patent application after its publication
RJ01 Rejection of invention patent application after publication

Application publication date: 20131002