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Publication numberCN105641686 A
Publication typeApplication
Application numberCN 201610060265
Publication date8 Jun 2016
Filing date18 Sep 2006
Priority date19 Sep 2005
Also published asCA2619673A1, CN101627011A, EP1937627A2, EP1937627A4, US8026392, US8431736, US9238074, US20080269108, US20120065128, US20130303444, WO2007035718A2, WO2007035718A3
Publication number201610060265.X, CN 105641686 A, CN 105641686A, CN 201610060265, CN-A-105641686, CN105641686 A, CN105641686A, CN201610060265, CN201610060265.X
InventorsN多霍特, WE拜伊, S丁, S马尤鲁, JP科文诺, DC奥图勒
Applicant爱密斯菲尔科技公司
Export CitationBiBTeX, EndNote, RefMan
External Links: SIPO, Espacenet
Crystalline forms of the di-sodium salt of N-(5-chlorosalicyloyl)-8-aminocaprylic acid
CN 105641686 A
Abstract
The present invention relates to crystalline polymorphic forms of the di-sodium salt of N-(5-chlorosalicyloyl)-8-aminocaprylic acid, pharmaceutical compositions containing the same, methods of preparing the same, and methods for facilitating the delivery of active agents with the same.
Claims(5)  translated from Chinese
1. 药物组合物,其包含形式IV的N-(5-氯水杨酰基)-8-氨基辛酸的二钠盐以及生物活性剂,其中所述形式IV的N-(5-氯水杨酰基)-8-氨基辛酸的二钠盐为N-(5-氯水杨酰基)-8-氨基辛酸的二钠盐的结晶一水合物,其展现出的X射线粉末衍射图具有与图5中示出的峰基本相同的峰。 A pharmaceutical composition comprising Form IV of N- (5- chlorosalicyloyl) -8-aminocaprylic acid disodium salt and a biologically active agent, wherein the Form IV of N- (5- chlorosalicyloyl ) 8-amino-octanoic acid as the disodium salt of N- (5- chlorosalicyloyl) -8-aminocaprylic acid disodium salt monohydrate crystals, which exhibits an X-ray powder diffraction pattern with Figure 5 It shows a peak substantially the same peak.
2. 权利要求1的药物组合物,其中所述生物活性剂是降钙素。 The pharmaceutical composition of claim 1, wherein said biologically active agent is calcitonin.
3. 权利要求2的药物组合物,其还包含甲状旁腺激素。 The pharmaceutical composition of claim 2, further comprising parathyroid hormone.
4. 权利要求1的药物组合物,其中所述生物活性剂是胰岛素。 The pharmaceutical composition of claim 1, wherein said bioactive agent is insulin.
5. 权利要求1的药物组合物,其中所述生物活性剂是生长激素。 The pharmaceutical composition of claim 1, wherein said bioactive agent is growth hormone.
Description  translated from Chinese
N-(5-氯水杨酰基)-8-氨基辛酸的二钠盐的晶形 N- (5- chlorosalicyloyl) 8-amino octanoic acid disodium salt crystalline form

[0001 ]本申请为2006年9月18日提交的、发明名称为"N-(5-氯水杨酰基)-8-氨基辛酸的二钠盐的晶形"的PCT申请PCT/US2006/036455的分案申请,所述PCT申请进入中国国家阶段的日期为2008年3月19日,申请号为200680034457.8。 [0001] for the September 18, 2006 filed the present application, an invention entitled "N- (5- chlorosalicyloyl) 8-amino octanoic acid disodium salt crystalline form" PCT Application PCT / US2006 / 036455 of divisional application, the PCT application to enter the national phase in China dated March 19, 2008, application No. 200680034457.8.

技术领域 TECHNICAL FIELD

[0002] 本发明涉及N-(5-氯水杨酰基)-8-氨基辛酸(以下称为"5-CNAC")的二钠盐的晶形、含有其的药物组合物、制备其的方法,以及利用其来促进活性剂的递送的方法。 [0002] The present invention relates to N- (5- chlorosalicyloyl) -8-amino acid (hereinafter referred to as "5-CNAC") disodium salt crystalline form, pharmaceutical compositions containing them, methods of making, delivery method and the use of it to promote the active agent.

背景技术 Background technique

[0003] 美国专利第5,773,647号公开了193种递送剂化合物,包含^(5-氯水杨酰基)-8-氨基辛酸("5-CNAC")。 [0003] U.S. Patent No. 5,773,647 discloses a delivery agent 193 kinds of compounds contain ^ (5 chlorosalicyloyl) 8-amino octanoic acid ( "5-CNAC"). 这些递送剂化合物增加了大范围的生物活性剂(特别是通常不适用于口服施用的生物活性剂)的生物可利用性。 The delivery agent compound increases the wide range of biologically active agents (in particular generally not suitable for oral administration of a biologically active agent) in bioavailability. 美国公开申请号No. 2006/0078622以及2006/ 0078623公开了递送剂化合物(包括5-CNAC)的微颗粒或纳米颗粒。 U.S. Published Application No. 2006/0078622 and No. 2006/0078623 discloses a delivery agent compound (including 5-CNAC) microparticles or nanoparticles. 美国公开专利申请号No. 2005/0054557公开了包含甲状旁腺激素、降钙素与5-CNAC的药物组合物。 U.S. Patent Application Publication No. 2005/0054557 discloses No. comprising parathyroid hormone, calcitonin pharmaceutical composition of 5-CNAC. 国际公开号No.WO 00/59863公开了N-(5-氯水杨酰基)-8-氨基辛酸的二钠盐。 International Publication No. No.WO 00/59863 discloses N- (5- chlorosalicyloyl) -8-aminocaprylic acid disodium salt.

[0004] 国际公开申请号No.WO 2005/01403公开了使用降钙素与5-CNAC来治疗骨关节炎的用途。 [0004] International Application Publication No. No.WO 2005/01403 discloses use of calcitonin and 5-CNAC to treat osteoarthritis purposes. 美国公开申请号2006/0106110公开了一种用以抑制哺乳动物中的血小板聚集的方法,其包括施用经修饰的氨基酸,包括5-CNAC。 U.S. Application Publication No. 2006/0106110 discloses a method for inhibiting platelet aggregation in a mammal comprising administering a modified amino acid, including 5-CNAC. 国际公开申请号No. 03/015822公开了使用5-CNAC作为用于甲状旁腺激素片段的口服递送剂的用途。 International Publication No. Application No. 03/015822 discloses the use of 5-CNAC as an oral delivery agent for parathyroid hormone fragment uses. 国际公开申请号WO 02/45754公开了包含有药理活性剂、交聚维酮(crospovidone)或聚维酮(povidone)以及递送剂(例如,5-CNAC)的药物组合物。 International Application Publication No. WO 02/45754 discloses compositions comprising pharmacologically active agents, cross-povidone (crospovidone) or povidone (povidone) as well as the delivery agent (for example, 5-CNAC) in pharmaceutical compositions. 发明概要 SUMMARY OF THE INVENTION

[0005] 本发明涉及N-(5_氯水杨酰基)-8_氨基辛酸("5-CNAC")的二钠盐的四种晶形(以下称为形式I至IV),包括5-CNAC的八水合物(OCtahydrate)。 [0005] The present invention relates to N- (5_ chlorosalicyloyl) -8_ four kinds of crystalline amino octanoic acid ( "5-CNAC") disodium salt (hereinafter referred to as form I to IV), including 5-CNAC eight hydrate (oCtahydrate).

[0006] 本发明一个实施方案是药物组合物,其包含(A)5_CNAC的形式I至IV的一种或多种,以及(B)活性剂,例如,降钙素(例如,鲑鱼降钙素)或人生长激素(例如,重组人生长激素)。 [0006] An embodiment of the present invention is a pharmaceutical composition, which comprises (A) 5_CNAC form I to IV with one or more, and (B) an active agent, e.g., calcitonin (e.g., salmon calcitonin ) or human growth hormone (for example, recombinant human growth hormone). 根据优选实施方案,该药物组合物包含有,基于5-CNAC在该药物组合物中的100 %总重量,以重量计至少大约20、30、40、50、60、70、80、90、95、96、97、98、99、99.1、99.2、99.3、 99.4、99.5、99.6、99.7、99.8或99.9 %的5-CNAC的形式I至IV之一。 According to a preferred embodiment, the pharmaceutical composition comprises, based on the 5-CNAC 100% of the total weight of the pharmaceutical composition, by weight of at least about 20,30,40,50,60,70,80,90,95 , 96,97,98,99,99.1,99.2,99.3, 99.4,99.5,99.6,99.7,99.8 or 99.9% of 5-CNAC I to form one IV. 根据另一个优选实施方案,该药物组合物包含有,基于结晶5-CNAC在该药物组合物中的100 %总重量,以重量计至少大约20、30、40、50、60、70、80、90、95、96、97、98、99、991、992、993、994、995、996、 99 7、99 8或99 9% 的5-CNAC 的形式I至IV 之一。 According to another preferred embodiment, the pharmaceutical composition comprises, based on the crystalline 5-CNAC 100% of the total weight of the pharmaceutical composition, by weight of at least about 20,30,40,50,60,70,80, 90,95,96,97,98,99,99 1,99 2,99 3,99 4,99 5,99 6, 8 or 99 7,99 99 9% 5 -CNAC I to form one IV.

[0007] 另一个实施方案是药物组合物(例如片剂),其包含至少一种5-CNAC的形式I至IV, 以及至少一种活性剂和/或可药用的添加剂(例如那些被描述于下面者)。 [0007] Another embodiment is a pharmaceutical composition (e.g., tablets) comprising at least one 5-CNAC I to IV of the form, and at least one active agent and / or pharmaceutically acceptable additives (e.g., those described in those below). 优选的活性剂是降钙素。 A preferred active agent is calcitonin. 又另一优选的活性剂是降钙素与甲状旁腺激素(例如ΡΤΗ[1-34])的治疗混合物。 Yet another preferred active agent is calcitonin and parathyroid hormone (e.g. ΡΤΗ [1-34]) of the treatment mixture. 又另一优选的活性剂是胰岛素。 Yet another preferred active agent is insulin. 又另一优选的活性剂是生长激素(例如重组人生长激素)。 Yet another preferred active agent is growth hormone (e.g., recombinant human growth hormone).

[0008] 本发明的又另一个实施方案是通过施用本发明的药物组合物来施用或促进动物(例如人)中活性剂的递送的方法。 [0008] Yet another embodiment of the present invention is obtained by administering a pharmaceutical composition of the present invention is administered to an animal or promote (e.g., a human) an active agent delivery methods.

[0009] 又另一个实施方案是在需要治疗的哺乳动物(例如人)中治疗佩吉特病或高钙血症,或治疗或预防骨质疏松症的方法,其通过口服地施用有效量的本发明的药物组合物(例如,所述药物组合物包含有形式I、π、III和/或IV的5-CNAC以及(i)降钙素(例如,鲑鱼降钙素)或(ii)降钙素与甲状旁腺激素或其片段(例如ΡΤΗ[1-34])的组合)。 [0009] Yet another embodiment is a mammal in need of treatment (e.g., human) a method of treating Paget's disease or hypercalcemia, or treating or preventing osteoporosis, which by orally administering an effective amount of the pharmaceutical compositions of the present invention (e.g., the form of pharmaceutical compositions comprising I, π, III and / or IV of 5-CNAC and (i) calcitonin (e.g. salmon calcitonin) or (ii) reducing calcium and parathyroid hormone or fragments thereof (such as ΡΤΗ [1-34]) in combination). 其它可被治疗的疾病或病症,或通过口服地施用有效量的本发明的药物组合物(例如,所述药物组合物包含有形式Ι、ΙΙ、ΙΙΙ和/或IV的5-CNAC以及⑴降钙素(例如,鲑鱼降钙素)或(ii)降钙素与甲状旁腺激素或其片段(例如ΡΤΗ[1-34])的组合)而实现的生理效用包含:骨的疾病、骨疼痛(包含与骨质疏松症或癌症有关的疼痛)、骨关节炎、软骨下骨(sub-chondral bone)的不正常再吸收(>68?01'1:;[011)与转换(1:111'11061')、保存和/或刺激软骨、抑制磷脂酶42和/或胶原酶活性、刺激糖胺聚糖和/或蛋白聚糖合成、刺激新骨形成、对软骨下骨的密度或劲度的不均一性产生作用、对发炎过程产生作用、导致运动疼痛以及相关症状的减弱、减低患者关节内退化变化(degenerative change) 0 Other diseases which may be treated or disorder, or pharmaceutical compositions by orally administering an effective amount of the present invention (e.g., a pharmaceutical composition comprising the form Ι, ΙΙ, ΙΙΙ and / or IV of 5-CNAC and drop ⑴ calcium (e.g., salmon calcitonin) or (ii) calcitonin parathyroid hormone or fragments thereof (e.g. ΡΤΗ [1-34]) of the combination) to achieve the physiological effects and comprising: bone disease, bone pain (including osteoporosis or cancer-related pain), osteoarthritis, subchondral bone (sub-chondral bone) is not normal resorption (> 68 01'1:;? [011) and conversion (1: 111 '110 61'), preservation and / or stimulating cartilage, inhibition of phospholipase 42 and / or collagenase activity, stimulation of glycosaminoglycan and / or proteoglycan synthesis, stimulating new bone formation of subchondral bone density or a uniform stiffness of an effect, an effect on the inflammatory process, resulting in pain and reduced movement-related symptoms, reduce patient degenerative joint changes (degenerative change) 0

[0010] 又另一个实施方案是制备形式I的5-CNAC的方法,其包括通过:(a)将5-CNAC的单乙醇溶剂合物溶解于乙腈与水的混合物中,以及(b)将步骤(a)中所制得的溶液冷却至有效温度(例如,从大约5C至大约15C),以产生形式I的5-CNAC。 [0010] Yet another embodiment is the preparation of Form I of 5-CNAC, comprising by: (a) the 5-CNAC monoethanol solvate was dissolved in a mixture of acetonitrile and water, and (b) the step (a), the obtained solution was cooled to an effective temperature (for example, from about 5 C to about 15 C), to produce form I 5-CNAC.

[0011] 又另一个实施方案是用以制备形式I的5-CNAC的方法,其通过:(a)将5-CNAC的水溶液加热(例如,从大约4 0 C至大约7 0 C ),以及(b)从该溶液中移除水以产生形式I的5 -CNAC(例如,用旋转蒸发器和/或真空干燥箱)。 [0011] Yet another embodiment is for the preparation of Form I of 5-CNAC method, by which: (a) heating an aqueous solution of 5-CNAC (e.g., from about 4 0 C to about 7 0 C) and (b) removing water from the solution to produce the form I of 5 -CNAC (for example, using a rotary evaporator and / or vacuum oven).

[0012] 又另一个实施方案是用以制备5-CNAC的单乙醇溶剂合物(例如形式II)的方法,其系通过:(a)将氢氧化钠加入至N-(5-氯水杨酰基)-8-氨基辛酸与乙醇的溶液中,以及(b)将形式Π的5-CNAC从该溶液中沉淀出来。 Method [0012] Yet another embodiment is for the preparation of 5-CNAC monoethanol solvate (e.g., in the form of II), which is based by: (a) Sodium hydroxide was added to N- (5- chlorosalicyloyl acyl) -8-amino bitterness and a solution of ethanol, and (b) will be in the form of 5-CNAC Π precipitated from the solution. 优选地,氢氧化钠与N- (5-氯水杨酰基)-8-氨基辛酸的摩尔比是大约2:1。 Preferably, sodium hydroxide and N- (5- chlorosalicyloyl) -8-amino-octanoic acid molar ratio of about 2: 1.

[0013] 又另一个实施方案是用以制备5-CNAC的八水合物(OCtahydrate)(例如形式III) 的方法,其系通过将(i )5-CNAC的一水合物(例如形式I、IV或它们的混合物)、(ii )5-CNAC的单乙醇溶剂合物(例如形式II)或(iii)其混合物在至少大约75%的相对湿度下维持足够时间,以形成该八水合物。 [0013] Yet another embodiment is a method for the preparation of 5-CNAC octahydrate (octahydrate) (e.g., form III), which is based by (i) 5-CNAC monohydrate (e.g. in the form of I, IV or a mixture thereof), (ii) 5-CNAC monoethanol solvate (e.g., in the form of II) or (iii) mixtures thereof in sufficient time to maintain at least about 75% relative humidity, to form the octahydrate. 根据一个实施方案,该八水合物在环境温度或范围在大约22C至大约40C或大约50C的温度下制备。 According to one embodiment, the octahydrate at ambient temperature or in the range of from about 22 C to a temperature of about 40 C to 50 C or about preparation.

[0014] 又另一个实施方案是用以制备形式IV的5-CNAC的方法,其系通过:(a)在升高的温度(例如,从大约30C至大约70C)下,将5-CNAC溶解于甲基•乙基酮中,以及(b)将步骤(a) 的甲基•乙基酮溶液冷却,以产生形式IV的5-CNAC。 [0014] Yet another embodiment is a method for the preparation of 5-CNAC form IV, which by the Department: (a) at elevated temperature (for example, from about 30 C to about 70 C), a solution 5-CNAC • dissolved in methyl ethyl ketone, and (b) to step (a) • a methyl ethyl ketone solution was cooled to yield form IV of 5-CNAC.

[0015] 又另一个实施方案是用以制备形式I与IV的5-CNAC的混合物的方法,其系通过将5-CNAC与丙酮的溶液冷却足够时间,以产生形式I与IV的混合物。 [0015] Yet another embodiment is a method for a mixture of 5-CNAC for the preparation of Form I and IV, which by the Department of 5-CNAC solution with acetone cooling time sufficient to produce a mixture of forms I and IV. 任选地,该溶液也可以含有水。 Optionally, the solution may contain water.

[0016] 通过上述任何方法所制备的晶体可以通过本领域中已知的任何方法来回收。 [0016] The crystals prepared by any of the above methods may be recovered by any method known in the art.

[0017] 附图简述 [0017] BRIEF DESCRIPTION

[0018]图1、3、4与5分别是如实施例1至4所制备的形式I至IV的5-CNAC的X射线粉末衍射图(XRPD)(图3的上方光谱是形式II的光谱);以及 [0018] FIG 1,3,4 and 5 are in the form as prepared in Example 1-4 embodiments I to IV of 5-CNAC powder X-ray diffraction pattern (the XRPD) spectra of the top (FIG. 3 is a spectrum of Form II );as well as

[0019] 第2与6图分别是如在实施例1与4中所制备的形式I与IV的5-CNAC的差示扫描量热法(DSC)分析。 [0019] FIG. 2 and 6 are in the form of Example 1 as prepared in the embodiment 4 I and IV of 5-CNAC of differential scanning calorimetry (DSC) analysis.

[0020] 发明详述 [0020] DETAILED DESCRIPTION OF INVENTION

[0021] 定义 [0021] defined

[0022] 术语"多晶型物"意指物质的结晶学上的不同形式。 [0022] The term "polymorph" refers to different forms of crystalline material on the school.

[0023] 如本文所用的,术语"水合物"包括但不限于:以确定比例包含一个或多个水分子作为晶体的组成部分的结晶物质或包含游离水的结晶材料。 [0023] As used herein, the term "hydrate" includes but is not limited to: to determine the ratio of one or more water molecules as part of a crystalline material containing free water crystals or crystalline material.

[0024] 如本文所用的,术语"5-CNAC"意指N-(5_氯水杨酰基)-8_氨基辛酸的二钠盐。 [0024] As used herein, the term "5-CNAC" means N- (5_-chlorosalicyloyl) -8_ amino caprylic acid disodium salt. 除非另有指明,如本文所用的,术语"5-CNACT'意指5-CNAC的所有多晶型物。 Unless otherwise indicated, as used herein, the term "5-CNACT '5-CNAC refers to all polymorphs.

[0025]如本文所用的,术语"5-CNAC-水合物"意指5-CNAC的一种晶形,其中每个5-CNAC 的分子与一个水分子缔合。 [0025] As used herein, the term "5-CNAC- hydrate" means a crystalline form of 5-CNAC, wherein each molecule of 5-CNAC associated with a water molecule.

[0026]如本文所用的,术语"5-CNAC八水合物"意指5-CNAC的一种晶形,其中每个5-CNAC 的分子与八个水分子缔合。 [0026] As used herein, the term "5-CNAC octahydrate" means a crystalline form of 5-CNAC, wherein each molecule of 5-CNAC and eight water molecules associated.

[0027] 如本文所用的,术语"溶剂合物"包括但不限于:溶剂的分子或离子与5-CNAC的分子或离子的分子或离子复合物。 [0027] As used herein, the term "solvate" includes, but is not limited to: the molecular or ionic complex of molecules or ions of solvent with 5-CNAC of molecules or ions. 如本文所用的,术语"共-溶剂合物"包括但不限于:两个或多个溶剂的分子或离子与5-CNAC的分子或离子的分子或离子复合物。 As used herein, the term "co - solvate" includes, but is not limited to: two or more molecular or ionic complex of molecules or ions of solvent with 5-CNAC of molecules or ions.

[0028] 如本文所用的,术语"递送剂"意指5-CNAC(包含它的晶形)。 [0028] As used herein, the term "delivery agent" means a 5-CNAC (crystal form containing it).

[0029] "药物的有效量"是活性剂(例如,肝素、降钙素、甲状旁腺激素或重组人生长激素) 的量,其能有效治疗或预防存活生物中的病症(所述存活生物被施用了一段时间的所述活性剂),例如,在所需的给药间隔期间提供了治疗效果。 [0029] "Effective amount of drug" are active agents (e.g., heparin, calcitonin, parathyroid hormone, or recombinant human growth hormone) in an amount which is effective in the treatment or prevention of a disorder surviving organisms (viable organisms of the the active agent is administered for a period of time), e.g., during a dosing interval it provides the desired therapeutic effect. 如本领域的技术人员所认知的,有效剂量根据下列而变化:施用的途径,存在的赋形剂,以及该活性剂是否是使用其它用于治疗病症的药剂的共同疗法的一部分。 As those skilled in the art that cognition, the effective dose varies according to the following: the route of administration, excipient is present, and if a portion of the active agent is a medicament for the treatment of other disorders of common therapy.

[0030] 术语"治疗(treat)"、"治疗(treating)"或"治疗的(treated)"意指施用活性剂以达到下列目的:治愈(cure)、愈合(heal)、减轻(alleviate)、缓和(relieve)、改变(alter)、 矫治(remedy )、改进(ameliorate)、改善(improve)或影响病症(例如,疾病)、该病症的症状或易患该病症的倾向。 [0030] The term "treatment (treat)", "treatment (treating)" or "treatment (treated)" means the administration of the active agent to achieve the following purposes: to cure (cure), healing (heal), mitigate (alleviate), relaxation (relieve), change (alter), treatment (remedy), improve (ameliorate), improve (improve) or affect disorders (such as disease), the symptoms of the disorder or susceptible to the tendency of the disorder.

[0031] "递送剂的有效量"是递送剂的量,其促进所需量的活性剂经由任何施用途径(例如在本申请中所讨论的,包括但不限于:口服的(例如,穿越胃肠道内的生物膜)、鼻的、肺的、皮肤的、阴道的和/或眼睛的途径)的吸收。 [0031] An "effective amount of delivery agent" is the amount of the delivery agent which promotes the desired amount of the active agent via any route of administration (e.g., as discussed in this application, including but not limited to: oral (e.g., through the stomach biofilm intestine), nasal, pulmonary, skin, vaginal and / or ocular route) absorption.

[0032] 如本文所用的,术语"降钙素"意指所有形式的降钙素,包括但不限于:人、鲑鱼、猪以及鳗鱼降钙素(包括其天然的、合成的或重组的来源),以及降钙素衍生物(例如1,7-Asu-鳗鱼降钙素)。 [0032] As used herein, the term "calcitonin" means all forms of calcitonin, including, but not limited to: human, salmon, pig and eel calcitonin (including natural, synthetic or recombinant sources ), as well as calcitonin derivatives (for example, 1,7-Asu- eel calcitonin). 优选的降钙素是合成的鲑鱼降钙素。 The preferred calcitonin is synthetic salmon calcitonin.

[0033] 术语"甲状旁腺激素"意指所有形式的甲状旁腺激素(天然的与合成的)、其片段以及激动剂。 [0033] The term "parathyroid hormone" refers to all forms of parathyroid hormone (natural and synthetic), and fragments thereof agonists. 例如,它可以包括但不限于:人甲状旁腺激素[1-36]与人甲状旁腺激素[1-34]。 For example, it may include, but are not limited to: human parathyroid hormone [1-36] and human parathyroid hormone [1-34].

[0034] 术语"胰岛素"意指所有形式的胰岛素(天然的与合成的),包括但不限于:重组人膜岛素。 [0034] The term "insulin" refers to all forms of insulin (natural and synthetic), including but not limited to: recombinant human insulin film.

[0035] 术语"生长激素"意指所有形式的生长激素(天然的与合成的),包括但不限于:人生长激素(例如,重组人生长激素)。 [0035] The term "growth hormone" means all forms of growth hormone (natural and synthetic), including but not limited to: human growth hormone (for example, recombinant human growth hormone).

[0036] 如本文所用的,术语活性剂的"片段"意指活性剂的截短形式,当施用至受试者时, 所述活性剂的截短形式提供与未截短的活性剂类似的生理效用。 [0036] As used herein, the term active agent "fragment" refers to a truncated form of the active agent, when administered to a subject, the truncated forms of the active agent to provide the active agent and not truncated similar physiological effects. 如本文所用的,术语活性剂的"类似物"意指活性剂的经轻微修饰的形式,当施用至受试者时,它提供与该类似物所基于的活性剂类似的生理效用。 As used herein, "analogs" is meant an active agent an active agent by a slight modification of the terms of the form, when administered to a subject, which provides the active agent is based on the analog similar physiological effects. 已知,活性剂的类似物(例如,公开于美国专利第5,474,978 号中的胰岛素类似物)与活性剂的片段(例如,公开于本文的PTH片段)可以与形式I至IV的5-CNAC-起施用,其具有与施用该活性剂(例如,胰岛素与PTH)本身与形式I至IV的5-CNAC 类似的效力。 Known analogs of active agents (e.g., as disclosed in U.S. Patent No. 5,474,978, the insulin analogues) and fragments of active agents (e.g., PTH fragments disclosed herein) can be in the form of I to IV 5-CNAC- from the administration, which has administered the active agent (eg insulin and PTH) itself in the form of 5-CNAC I to IV of similar effect.

[0037] 如本文所用的,术语"大约"意指落在给定值的10%内,优选为落在5%内,且更优选为落在给定值的1%内。 [0037] As used herein, the term "about" means to fall within 10% of a given value, preferably falls within 5%, and more preferably falls to 1% of the set value. 备选地,术语"大约"意指数值可以落在就该数值的类型而言是科学上可接受的误差范围内,这取决于可利用的工具给出的测量的性质如何。 Alternatively, the term "about" means a value in relation to the type of value may fall within the terms of a scientifically acceptable error range, depending on how the nature of the measurement tools available given.

[0038] 5-CNAC-水合物形式I [0038] 5-CNAC- hydrate form I

[0039] 形式I的5-CNAC是一水合物。 [0039] Form I of 5-CNAC monohydrate. 在室温下,形式I是形式I至IV当中最稳定的。 At room temperature, form I in the form of I to IV among the most stable. 根据差示扫描量热法(DSC),形式I具有第一个吸热转变(具有大约69C (69.3C)的起始温度并在大约76C (75.2C)达到峰),随后有第二宽的吸热事件(具有大约98C的起始温度并在大约140〇(141.2(:)达到峰)(参见图2)。形式1的5-0熟(:具有与图1中显示的父1^0图基本上相同的XRPD图。例如,形式I展现特征峰在15.52Θ0.2或0.12Θ处。形式I的特征XRTO峰位(以度2Θ02、0 1、0.05或0.01 2Θ表示)与d-间距(d-spacing)提供于下面表1中。 According to differential scanning calorimetry (the DSC), Form I has a first endothermic transition (onset temperature of about 69 C (69.3 C) and at about 76 C (75.2 C) to peak), followed by a second broad endothermic event (having a starting temperature of about 98 C and about 140 billion (141.2 (:) to peak) (see FIG. 2) in the form of a cooked 5-0 (: having FIG 1 shows a parent ^ 0 by substantially the same XRPD pattern. for example, form I shows a characteristic peak at 15.5 2Θ 0.2 or at 0.1 2Θ. XRTO form I characteristic peaks (in degrees 2Θ 0 2,0 1,0.05, or 0.01 2Θ shown) and d- spacing (d-spacing) is provided in table 1 below.

[0040]藍 [0040] Blue

[0041 ] 形式I的5-CNAC的特征XRH)峰(以度2Θ表示) [0041] Form I of 5-CNAC characteristic XRH) peaks (expressed in degrees 2Θ)

Figure CN105641686AD00071

[0043]形式I可以通过在上面与在下面的实施例1中所描述的方法制备。 [0043] Form I can be prepared by the above method and in the following examples as described in 1.

[0044] 本发明还提供含有形式I的5-CNAC的药物组合物,其中小于90、80、70或60 %的5-CNAC是结晶的(以5-CNAC的100 %总重量为基础)。 [0044] The present invention further provides Form I comprising 5-CNAC pharmaceutical composition, wherein less than 90,80,70 or 60% of the 5-CNAC is crystalline (5-CNAC to the total weight of 100%).

[0045] 本发明还提供药物组合物(例如片剂),其包含形式I的5-CNAC以及至少一种活性剂和/或可药用的添加剂(例如那些被描述于下面的)的经研磨的(例如,球磨的)或直接压制(compre ssed)的混合物。 [0045] The present invention also provides pharmaceutical compositions (e.g. tablets), comprising 5-CNAC Form I and at least one active agent and / or pharmaceutically acceptable additives (e.g., those described below) of the milled (for example, ball milling) or a mixture of direct compression (compre ssed) of. 优选地,该药物组合物(或经研磨的或直接压制的混合物)包含, 基于5-CNAC在该药物组合物(或经研磨的或直接压制的混合物)中的总重量,以重量计至少50、60、70、80、90、95、96、97、98或99%的形式1。 Preferably, the pharmaceutical composition (or or direct compression of a mixture of milled) contains, based on 5-CNAC total weight of the pharmaceutical composition (or or direct compression of a mixture of milled) in order to weight, at least 50 , 60,70,80,90,95,96,97,98, or 99% of form 1.

[0046] 5-CNAC 形式II [0046] 5-CNAC form II

[0047] 形式II是5-CNAC的单乙醇溶剂合物。 [0047] Form II is 5-CNAC monoethanol solvate. 形式II的5-CNAC具有与图3中显示的XRPD图基本上相同的XRro图。 Form II of 5-CNAC has an XRPD Figure 3 shows substantially the same as FIG XRro FIG. 例如,形式II展现特征峰在16.5 2Θ ο. 2或0.1 2Θ处。 For example, Form II exhibit characteristic peaks 16.5 2Θ ο. 2 or at 0.1 2Θ. 形式II的特征XRPD峰位置(以度20〇.2、〇.1、〇.〇5或〇.〇120表示)与(1-间距提供于下面表2中。 Form II Characteristic XRPD peak positions (in degrees 20 〇.2, 〇.1, 〇.〇5 or 〇.〇1 20) versus the (1-spacing is provided in Table 2 below.

[0048] ^2 [0048] ^ 2

[0049] 形式II的5-CNAC的特征XRI3D峰(以度2 Θ表示) 5-CNAC is characterized [0049] Form II XRI3D peaks (expressed in degrees 2 Θ)

Figure CN105641686AD00081

[0051] 形式II的5-CNAC可以如上述以及于实施例2中所述的来制备。 [0051] Form II of 5-CNAC may be prepared as described above and as described in Example 2.

[0052] 5_0熟(:八水合物形式111 [0052] 5_0 cooked (: octahydrate form 111

[0053] 形式III是5-CNAC的八水合物。 [0053] in the form of III is 5-CNAC octahydrate. 形式III在低于大约50%的相对湿度下是不稳定的。 Form III at a temperature below about 50% relative humidity is not stable. 形式III的5-CNAC具有与图4中显示的XRPD图基本上相同的XRPD图。 Form III of 5-CNAC has an XRPD pattern shown in FIG. 4 is substantially the same XRPD pattern. 例如,形式III展现特征峰在4.8 2Θ 〇. 2或0.1 2Θ处。 For example, Form III show characteristic peaks at 4.8 2Θ billion. 2 or 0.1 2Θ place. 形式ΠI的特征XRPD峰位(以度2Θ 〇. 2、0.1、0.05或0.01 2Θ表示)与d-间距提供于下面表3中。 ΠI form characteristic XRPD peaks (in degrees 2Θ square. 2,0.1,0.05 or 0.01 2Θ shown) and d- spacing provided in Table 3 below.

[0054] ^3 [0054] ^ 3

[0055] 形式III的5-CNAC的特征XRI3D峰(以度2 Θ表示) 5-CNAC is characterized [0055] form III XRI3D peaks (expressed in degrees 2 Θ)

Figure CN105641686AD00082

[0057] 形式III可以如上述以及于实施例3中所述的来制备。 [0057] Form III may be as described above and in Example 3 was prepared as described. 例如,形式III可以通过将二钠5-CNAC(例如它的乙醇溶剂合物)贮存在75% (或更高)的相对湿度下至少6天来制备。 For example, Form III can be prepared by disodium 5-CNAC (such as its ethanol solvate) is stored in at least six days to prepare a 75% (or more) relative humidity. [0058]本发明还提供药物组合物(例如片剂),其包含形式III的5-CNAC以及至少一种活性剂和/或可药用的添加剂(例如那些被描述于下面的)的直接压制的混合物。 Direct compression [0058] The present invention also provides pharmaceutical compositions (e.g. tablets), containing form III of 5-CNAC and at least one active agent and / or pharmaceutically acceptable additives (e.g., those described below) of mixture. 优选地,该药物组合物(或直接压制的混合物)包含,基于5-CNAC在该药物组合物(或直接压制的混合物) 中的总重量,以重量计至少50、60、70、80、90、95、96、97、98或99%的形式111。 Preferably, the pharmaceutical composition (or directly compressed mixture) contains 5-CNAC based on the total weight of the pharmaceutical composition (or directly compressed mixture) in order to weight, at least 50,60,70,80,90 , 95,96,97,98 or 99% of the 111 form.

[0059] 5-CNAC-水合物形式IV [0059] 5-CNAC- hydrate form IV

[0060] 形式IV的5-CNAC是一水合物。 [0060] Form IV of 5-CNAC monohydrate. 形式IV的5-CNAC具有与图5中所示的XRH)图基本上相同的XRro图。 Form IV of 5-CNAC has XRH shown in FIG. 5) is substantially the same as FIG XRro FIG. 例如,形式IV展现特征峰在7.2和/或18.2 2Θ 〇. 2或0.1 2Θ处。 For example, Form IV show characteristic peaks at 7.2 and / or 18.2 2Θ billion. 2 or 0.1 2Θ place. 形式IV的特征XRro峰位(以度2Θ 0.2、0.1、0.05或0.01 2Θ表示)与d-间距提供于下面表4中。 Form IV XRro characteristic peaks (in degrees 2Θ 0.2,0.1,0.05 or 0.01 2Θ shown) and d- spacing provided in Table 4 below.

[0061] 產I [0061] I yield

[0062] 形式IV的5-CNAC的特征XRPD峰(以度2Θ表示) 5-CNAC is characterized [0062] Form IV of XRPD peaks (expressed in degrees 2Θ)

Figure CN105641686AD00091

[0064]形式IV可以如上述以及于实施例4中所述的来制备。 [0064] Form IV may be as well to the embodiments described above are prepared as described in 4 cases.

[0065]本发明还提供含有形式IV的5-CNAC的药物组合物,其中基于5-CNAC的100%重量, 至少50、60、70、80或90 %的5-CNAC是结晶的。 [0065] The present invention further provides a pharmaceutical composition comprising 5-CNAC form IV, wherein 5-CNAC is based on 100% by weight, at least 50,60, 70,80 or 90% of the 5-CNAC is crystalline.

[0066] 5-CNAC形式I与IV的混合物 [0066] a mixture of 5-CNAC form I and IV of

[0067] 形式I与IV的5-CNAC是一水合物。 [0067] Form I and IV of 5-CNAC monohydrate. 该混合物的特征XRPD峰位(以度2Θ 〇. 2、0.1、 0.05或0.01 2Θ表示)与d-间距提供于下面表5中。 XRPD peaks characteristic of the mixture (in degrees 2Θ billion. 2,0.1, 0.05 or 0.01 2Θ showing) and d- spacing is provided in Table 5 below.

[0068] ^5 [0068] ^ 5

[0069] 形式I与IV的5-CNAC的混合物的特征XRH)峰(以度2Θ表示) [0069] Form I of 5-CNAC mixture XRH IV characteristic) peaks (expressed in degrees 2Θ)

Figure CN105641686AD00092

Figure CN105641686AD00101

[0072]该混合物可以如上述以及于实施例5中所述的来制备。 [0072] The mixture may be as described above and in Example 5 was prepared as described.

[0073]通过上述任何方法制备的晶体可以经由本领域中已知的任一种方法来回收。 [0073] Any crystal prepared by the above method can be recovered in any method known in the art via.

[0074] 活性剂 [0074] agents

[0075] 适合用于本发明的活性剂包含生物活性剂与化学活性剂,包括但不限于:杀虫剂、 药物活性剂(pharmacological agents)以及治疗剂。 [0075] Suitable active agents used in the present invention comprises a biologically active agent and chemically active agents, including, but not limited to: insecticides, pharmaceutically active agent (pharmacological agents), and therapeutic agents. 适合的活性剂包含在胃肠道内通过酸水解、酶等使之效用较低的、无效的或被破坏的那些。 Suitable active agents contained in the gastrointestinal tract by acid hydrolysis, enzymes so that the effectiveness of low, invalid or damaged ones. 还被包括作为适合的活性剂的是那些大分子剂,当口服给药时,它们的生理化学特性(例如,大小、结构或电荷)会阻止或妨碍吸收。 Is also included as suitable active agents are those macromolecular agents, when administered orally, their physical and chemical properties (for example, size, structure or charge) may prevent or hinder the absorption.

[0076] 例如,适合用于本发明的生物或化学活性剂包括但不限于:蛋白质;多肽;肽;激素;多糖,以及特别是黏多糖的混合物;糖类;脂类;极性有机小分子(即,具有500道尔顿或更低的分子量的极性有机分子);其它的有机化合物;以及,特别地,本身不会通过(或仅施用剂量的部分通过)胃肠粘膜和/或对胃肠道中的酸与酶的化学裂解易感的化合物;或其任何组合。 [0076] For example, suitable for biological or chemical agents of the invention include, but are not limited to: proteins; polypeptides; peptides; hormones; polysaccharides, and particularly mixtures of mucopolysaccharides; carbohydrates; lipids; polar organic molecules (i.e., having 500 or less daltons molecular weight polar organic molecules); other organic compounds; and, in particular, by itself does not (or only partially through the administered dose) gastrointestinal mucosa and / or chemical gastrointestinal tract acid and enzymatic cleavage compound susceptible; or any combination thereof.

[0077] 其它实例包括但不限于下列,包括它们的合成、天然或重组来源:生长激素,包括人生长激素(hGH)、重组人生长激素(rhGH)、牛生长激素以及猪生长激素;生长激素释放激素;生长激素释放因子、干扰素,包括α(例如,干扰素alfacon-i (可以作为丨nfergen而从CA布里斯班英姆有限公司(InterMune, Inc.of Brisbane ,CA)得到))、β以及γ ;白细胞介素-1;白细胞介素-2;胰岛素,包括猪的、牛的、人的以及人重组的胰岛素,任选地带有包括锌、钠、钙以及铵的平衡离子;胰岛素样生长因子,包括IGF-I;肝素,包含未分级分离的(unfractionated)肝素、类肝素(heparinoid)、皮肤素、软骨素、低分子量肝素、极低分子量肝素以及超低分子量肝素;降钙素,包含鲑鱼的、鳗鱼的、猪的以及人的降钙素;促红细胞生成素;心房利尿钠因子(atrial natriuretic factor);抗原;单克隆抗体;促生长素抑制素;蛋白酶抑制剂;促皮质素、促性腺素释放素;催产素;黄体化激素释放激素(leutinizing-hormone-releasing-hormone);促卵泡激素;葡糖脑苷脂酶;血小板生成素; 非格司亭(filgrastim);前列腺素;环孢霉素;加压素;色甘酸钠(cromolyn sodium)(色甘酸钠或色甘酸二钠;万古霉素;去铁胺(DFO);二膦酸盐,包括阿仑膦酸盐、替鲁膦酸盐、依替膦酸、氯膦酸盐、帕米膦酸盐、奥帕膦酸盐和伊卡膦酸盐;甲状旁腺激素(PTH),包括其片段; 抗偏头痛剂,例如BIBN-4096BS以及其它降钙素基因相关蛋白拮抗剂;胰高血糖素样肽1 (GLP-1);阿加曲班(Argatroban);抗微生物剂,包括抗生素、抗细菌剂以及抗真菌剂;维生素;这些化合物的类似物、片段、模拟物或经聚乙二醇(PEG)修饰的衍生物;或它们任意的组合。抗生素的非限制性实例包括革兰氏阳性作用的的、杀细菌的、脂肽以及环肽抗生素,例如潜霉素及其类似物。 [0077] Other examples include, but are not limited to, the following, including their synthetic, natural or recombinant sources: growth hormone, including human growth hormone (of hGH), recombinant human growth hormone (of rhGH), bovine growth hormone and porcine growth hormone; growth hormone releasing hormone; growth hormone releasing factor, interferons, including α (for example, interferon alfacon-i (as Shu nfergen obtained from CA Brisbane British Farm Limited (InterMune, Inc.of Brisbane, CA))) , β and γ; interleukin-1; interleukin-2; insulin, including porcine, bovine, and human recombinant human insulin, optionally with include zinc, sodium, calcium and ammonium counterions; insulin-like growth factor, including IGF-I; heparin, including unfractionated (unfractionated) heparin, heparan (heparinoid), dermatan sulfate, chondroitin sulfate, low molecular weight heparin, very low molecular weight heparin and ultra low molecular weight heparin; calcitonin factors, including salmon, eel, porcine and human calcitonin; erythropoietin; atrial natriuretic factor (atrial natriuretic factor); antigen; monoclonal antibodies; somatostatin; protease inhibitors; promoting corticotropin, gonadotropin releasing hormone; oxytocin; luteinizing hormone-releasing hormone (leutinizing-hormone-releasing-hormone); follicle stimulating hormone; glucocerebrosidase; thrombopoietin; filgrastim (filgrastim); prostaglandins; cyclosporine; vasopressin; cromolyn sodium (cromolyn sodium) (cromolyn sodium or sodium cromoglycate; vancomycin; deferoxamine (DFO); bisphosphonates, including alendronate salt, tiludronate, etidronate, clodronate, pamidronate, Opatija phosphonate and phosphonate Ica; parathyroid hormone (PTH), including its fragments; antimigraine headache agents such BIBN-4096BS and other calcitonin gene-related protein antagonists; glucagon-like peptide-1 (GLP-1); argatroban (argatroban); antimicrobials, including antibiotics, anti-bacterial agents and antifungal agents; vitamins; analogs of these compounds, a fragment, mimetic or poly-glycol (PEG) modified derivatives;., or any combination thereof non-limiting examples of antibiotics include gram-positive acting of , bactericidal lipopeptide and cyclic peptide antibiotics such as neomycin latent and the like.

[0078]根据一个实施方案,该活性剂是一种有药理活性的肽,例如骨活性剂(例如,降钙素)。 [0078] According to one embodiment, the active agent is a pharmacologically active peptide, e.g., bone-active agents (e.g., calcitonin). 骨活性剂包括在动物中展现出体内药理活性(例如骨的稳定、愈合或生长;骨转变(bone turnover)的减缓或抑制;骨再吸收的减缓或抑制;破骨细胞活性的抑制;以及成骨细胞活性的刺激)的药剂种类。 Bone active agents include demonstrated in animals in vivo pharmacological activity (such as bone stability, healing or growth; bone change (bone turnover) mitigation or inhibition; bone resorption to slow or inhibit; inhibit osteoclast activity; and to stimulation of bone cell activity) of the type of chemicals. 这些药剂之中的某些可以是肽类(peptidic),例如,降钙素、 甲状旁腺激素(PTH)、PTH片段(例如,PTH[ 1-34])、转化生长因子(TGF),以及上面任一者的类似物与片段。 Some of these agents may be peptidic among (- peptidic), e.g., calcitonin, parathyroid hormone (PTH), PTH fragments (e.g., PTH [1-34]), transforming growth factor (of TGF), and analogs and fragments of any one of the above. 骨活性剂还可以是小分子的非肽结构,它们显示出如在这个段落的前面所描述的体内药理骨活性。 Bone active agent may also be a non-peptide small molecule structure, they exhibit bone in vivo pharmacological activity as previously described in this paragraph.

[0079]此等药理活性剂的已知类,降钙素,具有多样化的药学利用并且一般地被使用于治疗,例如,佩吉特病、高钙血症以及骨质疏松症(包括但不限于:经绝后骨质疏松症)。 [0079] Such known class of pharmacologically active agent, calcitonin, has the advantage of a variety of pharmaceutical and generally used in the treatment of, e.g., Paget's disease, hypercalcemia and osteoporosis (including, but not limited to: post-menopausal osteoporosis). 多种降钙素(包含鲑鱼、猪以及鳗鱼降钙素)是商业上可得的,并且一般地被使用于治疗,例如, 佩吉特病、恶性高钙血症以及骨质疏松症。 A variety of calcitonin (including salmon, pig and eel calcitonin) are commercially available, and is generally used in the treatment of, for example, Paget's disease, hypercalcemia of malignancy and osteoporosis. 降钙素可以是任何降钙素(例如,人、鲑鱼、猪或鳗鱼),包括其天然的、合成的或重组的来源,以及降钙素衍生物(例如1,7-Asu-鳗鱼降钙素)。 Calcitonin can be any calcitonin (for example, human, salmon, pig or eel), including its natural, synthetic or recombinant sources, as well as calcitonin derivatives (for example, 1,7-Asu- eel calcitonin Su). 该组合物可以包含单一的降钙素或两种或多种降钙素的任何组合。 The composition may comprise a single calcitonin or any combination of two or more of calcitonin. 优选的降钙素是合成的鲑鱼降钙素。 The preferred calcitonin is synthetic salmon calcitonin.

[0080] 该等降钙素是商业上可得到的,或可通过已知的方法来合成。 [0080] Such calcitonin are commercially available or can be synthesized by known methods.

[0081] 当该药理活性剂是鲑鱼降钙素时,适当的剂量当然地将根据,例如,宿主以及要被治疗的病症的性质与严重性,而变化。 [0081] When the pharmacologically active agent is salmon calcitonin, the appropriate dosage will of course be based on, for example, the host to be treated and the nature of the condition and the severity varies. 适合的剂量被提供于国际公开号WO 2004/012772、TO 2005/004900以及WO 2005/014031中,它们全部在此被引入本案以作为参考。 Suitable dosages are provided in International Publication No. WO 2004/012772, TO 2005/004900 and in WO 2005/014031, all of which are herein incorporated by reference in the present case. 当与口服递送剂(例如,5-CNAC)联合施用时,鲑鱼降钙素的口服人剂量通常在大约0.05mg至5mg的范围内,优选为大约〇. Img至2.5mg。 When the oral delivery agent (e.g., 5-CNAC) administered in combination, the oral human dose of salmon calcitonin is typically in the range of from about 0.05mg to 5mg, preferably about square. Img to 2.5mg. 根据一个实施方案,从大约0.4mg至大约2.5mg的鲑鱼降钙素被每日施用给患者(例如,人(例如为大约70kg的一般人))中。 According to one embodiment, from about 0.4mg to about 2.5mg of salmon calcitonin was administered daily to the patient (for example, people (for example, approximately 70kg for the average person)) in. 更优选地,从大约0.8至大约1.2mg(例如,大约Img)被每日施用。 More preferably, from about 0.8 to about 1.2mg (for example, about Img) is administered daily. 又优选的是低于Img,但高于0.4mg的剂量。 And preferably less than Img, but higher than 0.4mg dose.

[0082] 适合的甲状旁腺激素的剂量被提供于国际公开号WO 2005/002549、W0 03/015822 以及WO 02/098453中,它们全部在此被并入本案以作为参考。 [0082] Suitable doses of parathyroid hormone are provided in International Publication No. WO 2005/002549, W0 03/015822 and in WO 02/098453, all of which is hereby incorporated by reference in the present case. 要被施用的甲状旁腺激素的量是能有效达到所需的生理状况的量。 The amount of the amount of parathyroid hormone is to be administered is effective to achieve the desired physiological condition. 在一个实施方案中,甲状旁腺组份(例如,PTH、PTH [1-28]-ΡΤΗ[ 1-41 ])的量是会使得它会提供一个PTH组份的每日施用剂量是从大约0.001μ g/kg至大约10mg/kg的动物体重,或从大约lyg/kg至大约6yg/kg的动物体重。 In one embodiment, the amount of parathyroid component (e.g., PTH, PTH [1-28] -ΡΤΗ [1-41]) is such that it will provide a daily administration of PTH component dosage is from about 0.001μ g / kg to about 10mg / kg of animal body weight, or from about lyg / kg to about 6yg / kg of animal body weight. 单位剂量形式可以含有,例如,800yg的PTH组份。 The unit dosage forms may contain, for example, 800yg of PTH component. 用于具体应用的特定PTH数量将根据要被治疗的受试者的年龄、大小、性别以及病症而变化,并且可由本领域的技术人员来确定。 PTH particular number for a particular application will be treated according to the age, size, sex and condition changes, and within the skill of the art to determine.

[0083] HGH或HGH组份的量也可以由本领域的技术人员来确定。 [0083] HGH or HGH component amount may be determined by one skilled in the art. 在一个实施方案中,HGH (例如,191个氨基酸的天然种类(促生长素))或HGH组份(例如,192个氨基酸的N-端甲硫氨酸(met)种类(人蛋氨生长素(somatrem)))的量是会使得它提供大约IOmg至大约300mg的HGH或HGH组份(例如,IOOmg的HGH或HGH组份)的单位剂量形式。 In one embodiment, HGH (e.g., 191 amino acid native species (somatotropin)) or HGH component (e.g., 192 amino acid N- terminal methionine (Met) Type (methionyl human growth hormone (somatrem))) in an amount such that it would provide about IOmg to about 300mg of HGH or HGH component (for example, IOOmg of HGH or HGH component) unit dosage form. 用于具体应用的特定HGH数量将根据要被治疗的受试者的年龄、大小、性别以及病症而变化,并且可由本领域的技术人员来确定。 HGH specific number for a particular application to be treated according to the age, size, sex and condition changes, and within the skill of the art to determine.

[0084]药理活性剂通常包含有,相对于整个药物组合物的总重量,从大约0.05百分比至大约70百分比(以重量计),优选为从大约0.01百分比至大约50百分比(以重量计)的数量, 更优选为相对于整个药物组合物的总重量是大约〇. 3百分比至大约30百分比(以重量计)。 [0084] pharmacologically active agent generally comprises, relative to the total weight of the overall pharmaceutical composition, of from about 0.05 percent to about 70 percent (by weight), preferably from about 0.01 percent to about 50 percent (by weight) of number, more preferably the total weight of the pharmaceutical composition of the whole square is about 3 percent to about 30 percent (by weight). [0085] 药物组合物 [0085] The pharmaceutical compositions

[0086] 药物组合物优选地是呈固体形式并且可以呈剂型的形式(例如,固体剂型,例如固体口服剂型)。 [0086] The pharmaceutical compositions are preferably in solid form and may be in a dosage form (e.g., solid dosage forms, e.g., solid oral dosage forms). 固体剂型可以是胶囊剂、片剂或颗粒剂,例如散剂或囊剂(sachet)。 The solid dosage forms may be capsules, tablets or granules, powders, or sachets for example (sachet). 散剂可以是与液体混合并施用的囊剂的形式。 In the form of powder can be mixed with a liquid and administered in capsules. 同样,散剂还可被包装进胶囊剂中或被压制成片剂,或者散剂可以照原样直接施用给受试者。 Similarly, a powder may be packed into capsules or compressed into tablets, or powders as they are can be administered directly to the subject.

[0087] 备选地,固体剂型可以是局部递送系统,例如软膏剂、乳膏剂或半固体。 [0087] Alternatively, the solid dosage form can be a local delivery system, e.g., ointments, creams or semi-solid. 例如,散剂可以被加入至局部赋形剂(例如,聚乙二醇)并且作为软膏剂施用。 For example, powders may be added to the topical vehicle (e.g., polyethylene glycol) and administered as an ointment.

[0088] 药物组合物可以包含一持续释放或控制释放系统。 [0088] The pharmaceutical compositions may comprise a sustained release or controlled release system. 优选地,固体剂型用于口服施用。 Preferably, the solid dosage forms for oral administration.

[0089]递送剂在固体剂型中的量是递送有效量,并且可就任何特定的化合物或生物或化学活性剂通过本领域技术人员已知的方法来确定。 [0089] the amount of delivery agent in the solid dosage form is a delivery effective amount and in respect of any particular compound or biologically or chemically active agents known to persons skilled in the art are methods to determine.

[0090] 在施用之后,单位剂型中的活性剂被吸收到循环中。 [0090] After administration, the unit dosage form of the active agent is absorbed into the circulation. 活性剂的生物可利用性可通过测量血液中已知的药理活性而被容易地评估,所述药理活性例如,由肝素所引起的血液凝固时间的增加,或由降钙素所引起的循环钙水平的降低。 Biologically active agent can be controlled by use of known measuring pharmacological activity in blood and be easily evaluated the pharmacological activity, for example, by the heparin-induced increase in blood clotting time, or calcitonin loop caused by the calcium decreased levels. 备选地,可以直接地测量活性剂本身的循环水平。 Alternatively, it is possible to directly measure circulating levels of the active agent itself.

[0091] 固体剂型可以包含可药用的添加剂,例如:赋形剂、载体、稀释剂、稳定剂、增塑剂、 粘合剂、助流剂、崩解剂、膨胀剂、润滑剂、增塑剂、着色剂、成膜剂、矫味剂、防腐剂、给药载剂、表面活性剂,以及上述的任何的任意任何组合。 [0091] The solid dosage forms may contain pharmaceutically acceptable additives such as: excipients, carriers, diluents, stabilizers, plasticizers, binders, glidants, disintegrants, bulking agents, lubricants, plasticizers, coloring agents, film formers, flavoring agents, preservatives, dosing carriers, surfactants, and any combination of any of any of the above. 优选地,这些添加剂是可药用的添加剂, 例如那些被描述于Remington ' s,The Science and Practice of Pharmacy (Gennaro , AR,编,第19版,1995,马克帕博公司(Mack Pub. Co.))中的,该文献在此被引入本案以作为参考。 Preferably, these additives are pharmaceutically acceptable additives, such as those described in Remington 's, The Science and Practice of Pharmacy (Gennaro, AR, ed., 19th edition, 1995, Makepabo company (Mack Pub. Co. )) of which is hereby introduced as a reference case.

[0092] 适合的粘合剂包括但不限于:淀粉、明胶、糖类(例如蔗糖、糖蜜与乳糖)、磷酸二氢钙二水合物、天然的与合成的树胶(例如阿拉伯胶)、藻酸钠、羧甲基纤维素、甲基纤维素、聚乙烯吡咯烷酮、聚乙二醇、乙基纤维素以及蜡。 [0092] Suitable binders include, but are not limited to: starch, gelatin, sugars (such as sucrose, molasses and lactose), calcium dihydrogen phosphate dihydrate, natural and synthetic gums (e.g., acacia), alginate sodium carboxymethyl cellulose, methyl cellulose, polyvinylpyrrolidone, polyethylene glycol, ethylcellulose and waxes.

[0093] 适合的助流剂包括但不限于:滑石以及二氧化硅(硅石)(例如,烟雾硅胶与胶态二氧化硅)。 [0093] Suitable glidants include, but are not limited to: talc and silicon dioxide (silica) (for example, silica gel and colloidal silica smoke).

[0094] 适合的崩解剂包括但不限于:淀粉、羟基乙酸淀粉钠、交联羧甲基纤维素钠、交聚维酮、粘土、纤维素(例如纯化的纤维素、甲基纤维素、羧甲基纤维素钠)、藻酸盐、预胶化玉米淀粉和树胶(例如琼脂、瓜尔豆胶、刺槐豆胶、梧桐胶、果胶和黄蓍胶)。 [0094] Suitable disintegrants include, but are not limited to: starch, sodium starch glycolate, cross-linked sodium carboxymethyl cellulose, crospovidone, clays, celluloses (such as purified cellulose, methyl cellulose, sodium carboxymethyl cellulose), alginates, pregelatinized corn starch and gums (such as agar, guar gum, locust bean gum, karaya gum, pectin, and tragacanth). 优选的崩解剂是羟基乙酸淀粉钠。 A preferred disintegrant is sodium starch glycolate.

[0095] 适合的膨胀剂包括但不限于:淀粉(例如米淀粉)、微晶纤维素、乳糖(例如,乳糖一水合物)、蔗糖、葡萄糖(dextrose)、甘露糖醇、硫酸钙、硫酸二钙以及硫酸三钙。 [0095] Suitable bulking agents include, but are not limited to: starches (such as rice starch), microcrystalline cellulose, lactose (e.g., lactose monohydrate), sucrose, glucose (dextrose), mannitol, calcium sulfate, dimethyl sulfate calcium sulfate and tricalcium.

[0096] 适合的润滑剂包括但不限于:硬脂酸、硬脂酸盐(例如硬脂酸钙与硬脂酸镁)、滑石、硼酸、苯甲酸钠、乙酸钠、富马酸钠、氯化钠、聚乙二醇、氢化棉籽油(hydrogenated cottonseed)与蓖麻油(castor oils)。 [0096] Suitable lubricants include, but are not limited to: stearic acid, stearates (such as calcium stearate and magnesium stearate), talc, boric acid, sodium benzoate, sodium acetate, sodium fumarate, chloride sodium, polyethylene glycol, hydrogenated cottonseed oil (hydrogenated cottonseed) and castor oil (castor oils).

[0097] 适合的表面活性剂包括但不限于:十二烷基硫酸钠、羟基化大豆卵磷脂、聚山梨醇酯类以及环氧丙烷与环氧乙烷的嵌段共聚物。 [0097] Suitable surfactants include, but are not limited to: sodium lauryl sulfate, hydroxylated soy lecithin, polysorbates and block copolymers of propylene oxide with ethylene oxide.

[0098] 可药用的非活性赋形剂可以包括聚合物与非活性化合物,它们,例如,辅助本发明所预期的固体口服剂型的配制或制备,或者它们可以辅助固体口服组合物在胃肠环境中的释放。 [0098] The pharmaceutically acceptable inactive excipients may include polymers and inactive compounds which are, for example, the preparation of secondary or contemplated by the invention for preparing solid oral dosage form, or they may assist in gastrointestinal solid oral compositions environment released.

[0099] 在本发明另一实施方案中,可药用的非活性赋形剂可以是聚合物交聚维酮或聚维酮之一或二者都是。 [0099] In another embodiment of the present invention, pharmaceutically acceptable inactive excipient may be a polymer of polyethylene cross povidone or povidone or both.

[0100] 于上所指的药物非活性成分,例如,任选地包括交聚维酮与聚维酮,它们可以是任何交聚维酮与聚维酮。 [0100] refers to the non-pharmaceutical active ingredients, for example, optionally include crospovidone and povidone, which may be any crospovidone and povidone. 交聚维酮是N-乙烯基-2-吡咯烷酮(还被称为1-乙烯基-2-吡咯烷酮(1-etheny 1-2-pyrrol idinone))的合成的交联均聚物,具有1,000,000或更高的分子量。 Crospovidone is N- vinyl-2-pyrrolidone (also known as 1-vinyl-2-pyrrolidone (1-etheny 1-2-pyrrol idinone)) synthetic crosslinked homopolymer having 1, or higher molecular weight of 000,000. 商业上可获得的交聚维酮包括Polyplasdone XL、Polyplasdone XL_10、Polyplasdone INF-10(可得自于ISP)、Kollidon CL(可得自于巴斯夫公司(BASF Corporation))。 Commercially available crospovidone include Polyplasdone XL, Polyplasdone XL_10, Polyplasdone INF-10 (available from within ISP), Kollidon CL (available from BASF Corporation in (BASF Corporation)). 优选的交聚维酮是Polyplasdone XL0 The preferred crospovidone is Polyplasdone XL0

[0101 ]聚维酮是由线性1-乙烯基-2-吡略烧酮(pyrrolidinone)基团所构成的合成的聚合物,具有通常是介于2,500与3,000,000之间的分子量。 [0101] Povidone is a linear 1-vinyl-2-one slightly burnt (pyrrolidinone) synthetic polymeric group constituted, usually have between 2,500 and 3,000,000 molecular weight. 商业上可获得的聚维酮包括Kollidon K_30、Kollidon K-90F(可得自于巴斯夫公司)以及Plasdone K-30与Plasdone K-29/32(可得自于ISP)。 Commercially available povidone include Kollidon K_30, Kollidon K-90F (available from BASF in) and Plasdone K-30 and Plasdone K-29/32 (available from within ISP).

[0102] 如在上面所提到的,该交聚维酮与聚维酮是商业上可获得的。 [0102] As mentioned above, the crospovidone and povidone are commercially available. 备选地,它们可通过已知的方法来合成。 Alternatively, they can be synthesized by known methods.

[0103] 交聚维酮、聚维酮或它们的组合通常是,相对于整个药物组合物的总重量,以重量计从大约0.5百分比至50百分比的量存在于组合物中,优选为从2百分比至25百分比,更优选以重量计为5百分比至20百分比的量(相对于药物组合物的总重量)。 [0103] crospovidone, povidone or combination thereof is usually, relative to the total weight of the entire pharmaceutical composition by weight from the amount of about 0.5 percent to 50 percent is present in the composition, preferably from 2 the percentage to 25 percentage, more preferably 5 weight percent to 20 volume percent (relative to the total weight of the pharmaceutical composition).

[0104] 递送系统 [0104] The delivery system

[0105]用于本发明药物组合物中的活性剂的量为实现用于靶适应证的活性剂目的的有效用量。 [0105] amount of a pharmaceutical composition of the present invention, the active agent used in an amount effective to achieve the target for the indication of the purpose of the active agent. 组合物中活性剂的用量一般为药理、生物、治疗或化学有效量。 The amount of active agent in the composition is typically a pharmacologically, biologically, therapeutically or chemically effective amount. 然而,该用量可以低于组合物用于单位剂型时的用量,因为单位剂型可以含有多种递送剂化合物/活性剂组合物或可以含有分次的药理、生物、治疗或活性有效量。 However, this amount may be less than the amount used in unit dosage form composition, as unit dosage forms may contain a variety of delivery agent compound / active agent compositions or may contain a pharmacologically, biologically, therapeutically or effective amount of the active fractionated. 可以以总计含有活性剂有效量的累积单位施用总有效量。 Total accumulation unit may contain the active agent administering an effective amount of the total effective amount.

[0106] 可以通过本领域技术人员公知的方法测定所用活性剂的总量。 [0106] The total amount can be determined by the active agent known to a person skilled in the art methods. 然而,因为本发明的组合物可以比其它组合物或含有单独的活性剂的组合物更有效地递送活性剂,所以可以对受试者施用比现有单位剂型或递送系统中使用的低的生物或化学活性剂用量,同时仍然可以达到相同的血液水平和/或治疗效用。 However, because the compositions of the invention may be other than composition or separate compositions comprising an active agent which more effectively deliver the active agent, can be administered to a subject is lower than the existing biological unit dosage form or delivery system used or the amount of chemical agents, while still achieving the same blood levels and / or therapeutic utility.

[0107] 一般而言,递送剂(例如,5-CNAC)相对于活性剂(例如,HGH或HGH组份,PTH或PTH片段)的重量比在从大约〇. 1:1至大约300:1或1000:1的范围内。 [0107] Generally, the delivery agent (e.g., 5-CNAC) with respect to the weight of active agent (e.g., HGH or HGH component, PTH or PTH fragment) in the ratio of from about 1 square: 1 to about 300: 1 or 1000: 1 range. 在一个实施方案中,递送剂(例如,5-CNAC)相对于活性剂(例如,HGH或HGH组份,PTH或PTH片段)的重量比在从大约50:1 或40:1至大约0.5:或0.2:1的范围内。 In one embodiment, a delivery agent (e.g., 5-CNAC) with respect to the weight of active agent (e.g., HGH or HGH component, PTH or PTH fragment) ratio from about 50: 1 or 40: 1 to about 0.5: or 0.2: 1 range. 在一个实施方案中,递送剂(例如,5-CNAC)相对于活性剂(例如,HGH或HGH组分,PTH或PTH片段)的重量比在从大约10:1至大约0 5:1 (例如,2:1) 的范围内。 In one embodiment, a delivery agent (e.g., 5-CNAC) with respect to the weight of active agent (e.g., HGH or HGH component, PTH or PTH fragment) in a ratio of from about 10: 1 to about 0.5: 1 ( within the range 1): e.g., 2. 递送剂(例如,5-CNAC)的重量比是根据该递送剂的游离酸形式来计算。 Weight delivery agent (for example, 5-CNAC) ratio is calculated based on the free acid form of the delivery agent. 重量比将根据活性剂以及该活性剂被施用的特定适应证而变化。 The weight ratio of the active agent in accordance with the indications and the specific active agent being administered varies.

[0108] 现在所公开的递送剂促进生物与化学活性剂的递送,特别是在口服的、舌下的、颊的、十二指肠内的、结肠内的、直肠的、阴道的、粘膜的、肺的、鼻内的以及眼部的系统中。 [0108] The disclosed delivery agent now promoting biological and chemical delivery of active agents, particularly in oral, sublingual, buccal, duodenum, colon, rectal, vaginal mucosa ,, intranasal, and ocular systems of the lung.

[0109] 本发明的化合物与组合物可应用于将生物或化学活性剂施用给任一种动物,包括但不限于:鸟类,例如鸡;哺乳动物,例如啮齿动物、牛、猪、狗、猫、灵长类,以及特别是人;以及昆虫。 [0109] compound and compositions of the invention may be applied to a biologically or chemically active agents to be administered to any animal, including but not limited to: the birds, such as chickens; mammals, such as rodents, cows, pigs, dogs, cats, primates, and particularly humans; and insects.

[0110] 这些化合物和组合物特别有利于递送如下化学或生物活性剂,所述的化学或生物活性剂否则可能因活性剂达到靶区(即递送组合物的活性剂待释放的区域)之前以及在它们所施用的动物体内被所遇到的情况所破坏或效用降低。 [0110] These compounds and compositions are particularly advantageous for delivering chemically or biologically active agents, the active chemical or biological agent. This can cause the active agent to reach the target area (i.e., delivery zone with an active agent of the composition to be delivered) and before in the case to which they are administered animals were encountered destroyed or less effective. 特别地,本发明的化合物和组合物用于口服施用活性剂,尤其是那些通常不可口服递送的或那些需要提高递送的活性剂。 Particularly, the compounds and compositions of the present invention for oral administration of the active agents, especially those not normally delivered orally or who need to improve delivery of the active agent.

[0111] 包括所述化合物和活性剂的组合物在将活性剂递送至所选择的生物系统,并且与不使用递送剂施用活性剂相比,增加或提高活性剂生物有效性上有用。 [0111] and a compound comprising the active agent in the composition of the active agent is delivered to selected biological systems and is not used as compared to administration of the active agent delivery agent, useful to increase or enhance the effectiveness of the biological agent. 可以通过在一段时间期限内递送更多的活性剂或在特定时间期限内(例如使得作用更快或延缓递送)或在一段时间期限内(例如持续递送)递送活性剂来改善递送。 It can be delivered more of the active agents over a time period or within a certain time period (e.g., so that the faster acting or delayed delivery) or over a period of period of time (e.g., sustained delivery) to improve the delivery of active agent delivery.

[0112] 本发明的另一个实施方案为通过在动物中施用本发明组合物来治疗或预防动物疾病或实现所需生理效用(例如下表中所列的那些)的方法。 [0112] Another embodiment of the present invention is by administering a composition of the invention in an animal to treat or prevent a disease or an animal to achieve the desired physiological effects (e.g., those listed in the following table) of. 活性剂的具体适应证可见于Physicians 'Desk Reference(第59版,2005,医学经济学有限公司(Medical Economics Company,Inc.),Montvale,NJ),将该文献引入本文作为参考。 Specific indications for active agents can be found in the Physicians' Desk Reference (59th Edition, 2005, Medical Economics Co., Ltd. (Medical Economics Company, Inc.), Montvale, NJ), which is incorporated herein by reference. 下表中的活性剂包括其类似物、片段、模拟物和聚乙二醇修饰的衍生物。 Active agents in the table below include their analogs, fragments, mimetics and polyethylene glycol-modified derivatives.

Figure CN105641686AD00151

Figure CN105641686AD00161

Figure CN105641686AD00171

Figure CN105641686AD00181

Figure CN105641686AD00191

Figure CN105641686AD00201

Figure CN105641686AD00211

Figure CN105641686AD00221

[0121] 另一个实施方案是治疗有需要治疗的哺乳动物(例如,人)中响应降钙素作用的疾病(例如佩吉特病、高钙血症或骨质疏松症)的方法(例如,在停经后超过5年的、与健康的停经前女性相比具有较低的骨量(bone mass)的女性中治疗经绝后骨质疏松),这是通过口服地施用本发明的药物组合物(其包含有形式I、II、III和/或IV的5-CNAC和降钙素)。 [0121] Another embodiment is treating a mammal in need of such treatment (e.g., a human) in response to the action of calcitonin disease (e.g. Paget's disease, hypercalcemia and osteoporosis) methods (e.g., Women in menopause after more than five years, and healthy premenopausal women have lower bone mass compared to (bone mass) in the treatment of post-menopausal osteoporosis), which is administered by the oral pharmaceutical composition of the present invention ( which contains a form I, II, III and / or IV of 5-CNAC and calcitonin). 优选地, 药物组合物是在没有食物下被施用,有利地是在消耗食物之前的短间隔,例如饭前的短间隔,以提高降钙素的口服生物可利用性。 Preferably, the pharmaceutical composition is administered without food, the advantageously short intervals before the consumption of food, such as a short interval before meals to improve oral calcitonin bioavailability.

[0122] 另一个实施方案是治疗有需要治疗的哺乳动物(例如,人)中响应人生长激素作用的疾病(例如生长障碍(例如,身材矮小))的方法,这是通过口服地施用本发明的药物组合物(其包含形式Ι、Π、ΙΙΙ和/或IV的5-CNAC以及人生长激素)。 [0122] Another embodiment is treating a mammal in need of treatment (e.g., a human) method in response to human growth hormone diseases (such as growth disorders (for example, short stature)), which is administered orally by the present invention the pharmaceutical composition (comprising form Ι, Π, ΙΙΙ and / or IV of 5-CNAC and human growth hormone). 用本发明的药物组合物(其包括形式Ι、Π、ΙΙΙ和/或IV的5-CNAC以及人生长激素)所治疗的病症或达到的效用的其它实例包括:长期治疗由于内源生长激素的不充分分泌而具有生长不足的幼儿患者、长期治疗由于普-威综合征(PWS)而具有生长不足的幼儿患者、在骺没有被闭合的患者中与特纳综合征相关的身材矮小、特发性身材矮小(idiopathic short stature)、患有具幼年或成人发病病因学的生长激素缺乏(GHD)(例如,由于垂体疾病、下视丘病(hypothalamic disease)、 手术、放射疗法、慢性肾功能不全或创伤所造成的生长激素缺乏)的成人中的长期替补疗法,以及因为孕龄(gestational age)出生时体型小的、至两岁也无法表现出适龄成长(catch-up growth)的孩童的生长不足的长期治疗。 Disorders pharmaceutical composition of the present invention (including its form Ι, Π, ΙΙΙ and / or IV of 5-CNAC and human growth hormone), or treated to achieve the effectiveness of other examples include: long-term treatment due to the endogenous growth hormone inadequate secretion of growth failure in patients having children, long-term treatment due to the S & P - Willi syndrome (PWS) and has a growing shortage of pediatric patients, not in epiphyseal closure in patients with Turner syndrome associated with short stature, idiopathic short stature (idiopathic short stature), suffering from a juvenile or adult-onset growth hormone deficiency etiology (GHD) (for example, due to the pituitary disease, hypothalamic disease (hypothalamic disease), surgery, radiation therapy, chronic renal insufficiency or trauma caused by growth hormone deficiency) of long-term replacement therapy in adults, as well as gestational age (gestational age) of small size at birth to age two and can not exhibit growth (catch-up growth) the growth of children lack of long-term treatment.

[0123] 另一个实施方案是治疗有需要治疗的哺乳动物(例如,人)中响应甲状旁腺激素的作用的疾病(例如骨质疏松症(例如,具有骨质疏松症的停经后女性,她有骨折的高危险性))的方法,这是通过口服地施用本发明的药物组合物(其包含形式Ι、Π、ΙΙΙ和/或IV的5-CNAC以及甲状旁腺激素)。 [0123] Another embodiment is treating a mammal in need of treatment (e.g., a human) in response to the effects of parathyroid hormone disorders (such as osteoporosis (for example, having osteoporosis in postmenopausal women, she there is a high risk of fracture)) method, which is administered by the oral pharmaceutical composition of the present invention (which comprises the form Ι, Π, ΙΙΙ and / or IV of 5-CNAC and parathyroid hormone). 用本发明的药物组合物(其包括形式I、II、III和/或IV的5-CNAC 和甲状旁腺激素)所治疗的病症或达到的效用的其它实例包括:患有原发性骨质疏松或性腺功能减退(hy pogonada 1)骨质疏松症的人(有骨折的高危险性)的骨量的增加。 The pharmaceutical compositions of the present invention (including in the form of I, II, III and / or IV of 5-CNAC and parathyroid hormone) the condition being treated or other instances to achieve effectiveness include: with primary osteoporosis increase loose or hypogonadism (hy pogonada 1) osteoporosis people (there is a high risk of fracture) of the bone mass.

[0124] 另一个实施方案是治疗有需要治疗的哺乳动物(例如,人)中响应Imitinab的作用的疾病(例如慢性骨髓性白血病与胃肠道基质瘤)的方法,这是通过口服地施用本发明的药物组合物(其包含形式I、II、III和/或IV的5-CNAC以及Imitinab)。 [0124] Another embodiment is treating a mammal in need of treatment methods (for example, a human) in response Imitinab role of disease (such as chronic myelogenous leukemia and gastrointestinal stromal tumors), which is administered orally by this the pharmaceutical composition of the invention (which comprises the form I, II, III and / or IV of 5-CNAC and Imitinab).

[0125] 另一个实施方案是治疗有需要治疗的哺乳动物(例如,人)中响应流感病毒疫苗的作用的疾病(例如流感感染)的方法,这是通过口服地施用本发明的药物组合物(其包含形式I、II、III和/或IV的5-CNAC以及流感病毒疫苗)。 [0125] Another embodiment is treating a mammal in need of such treatment (e.g., a human) influenza virus vaccine action disease (e.g., influenza infection) response method, which is administered by the present invention is a pharmaceutical composition orally ( comprising form I, II, III and / or IV of 5-CNAC and influenza virus vaccine).

[0126] 另一个实施方案是治疗有需要治疗的哺乳动物(例如,人)中响应ranibizumab的作用的疾病(例如黄斑变性(例如,湿性黄斑变性以及年龄相关黄斑变性))的方法,这是通过口服地施用本发明的药物组合物(其包含形式I、II、III和/或IV的5-CNAC以及ranibizumab)〇 [0126] Another embodiment is treating a mammal in need of treatment methods (e.g., a human) in response to the action of ranibizumab diseases (e.g. macular degeneration (e.g., wet macular degeneration and age-related macular degeneration)), which is by orally administered pharmaceutical compositions of the present invention (which comprises the form I, II, III and / or IV of 5-CNAC and ranibizumab) billion

[0127] 下列实施例阐述而非限制本发明。 [0127] The following examples illustrate but not limit the invention. 除非有另外指明,所有的百分比是以重量计。 Unless otherwise indicated, all percentages are by weight.

[0128] DSC [0128] DSC

[0129] 引用的熔点是通过差示扫描热量法(DSC)来确定。 [0129] melting point of reference is determined by differential scanning calorimetry (DSC). 引用的数值是使用一种Perkin Elmer差示扫描量热器DSC-7来获得。 The reference value is the use of a Perkin Elmer differential scanning calorimeter, DSC-7 is obtained. DSC曲线是使用20K/分钟的加热速度与1至3mg的样品质量来记录。 DSC curve using 20K / min and a heating rate of 1 to 3mg of sample mass is recorded.

[0130] XRPD [0130] XRPD

[0131] 粉末X射线衍射分析使用一种Scintag Xl衍射计和铜Καί放射来进行。 [0131] Powder X-ray diffraction analysis using one Scintag Xl diffractometer and copper Καί to radiation.

[0132] 实施例1 [0132] Example 1

[0133] 形式I的5-CNAC的制备 Preparation [0133] Form I of 5-CNAC

[0134] 形式I的5-CNAC被制备如下。 [0134] Form I of 5-CNAC was prepared as follows. 200加仑的玻璃衬里的反应器被建立用于常压蒸馏。 200 gallons of a glass lined reactor is set up for atmospheric distillation. 应用冷却至冷凝器与接收器(receiver)上。 Application of cooling to the condenser and the receiver (receiver) on. 用氮净化该反应器。 The reactor was purged with nitrogen. 该反应器被充填以565L的乙腈。 The reactor is filled with 565L of acetonitrile. 搅拌器被设定在100转/分钟(rpm)。 The stirrer was set at 100 revolutions / minute (rpm). 该反应器被充填以13.7kg的纯水与43.25kg的5-CNAC单乙醇溶剂合物。 The reactor is filled with pure water and 5-CNAC monoethanol solvate of 43.25kg of 13.7kg. 该反应器内容物被加热至回流,使得馏出物(distil late)开始收集至该接收器中。 The reactor contents are heated to reflux, so that the distillate (distil late) to begin collecting in the receiver. 继续常压蒸馏,直至大约102L的馏出物被收集。 Atmospheric distillation continued until approximately 102L of distillate was collected. 终止加热反应器套(jacket),并且向反应器中添加102L的新鲜乙腈与2.5kg的纯水的混合物。 Termination heated reactor jacket (jacket), and add the mixture 102L fresh acetonitrile and 2.5kg of pure water to the reactor. 将该反应器内容物冷却至5至15C之间,并且搅拌1至2小时。 The reactor contents were cooled to between 5 and 15 C, and stirred for 1-2 hours. 所得到的淤浆通过离心被分离。 The resulting slurry was separated by centrifugation. 湿饼(wet cake)没有被清洗。 Wet cake (wet cake) has not been cleaned. 将该湿饼在完全真空、75至85 C之间在真空干燥箱内干燥48小时。 The wet cake was dried in a vacuum oven 48 hours at full vacuum between 75 Zhi 85 C. 二钠5-CNAC-水合物的产量大约是40kg,产率为约99.9%。 Disodium 5-CNAC- hydrate yield is about 40kg, a yield of about 99.9%.

[0135] 有关如上面所制备的形式I的XRH)与DSC光谱分别被显示在图1与图2中。 [0135] As related above form I prepared XRH) and DSC spectra, respectively, are shown in Figures 1 and 2.

[0136] 实施例1A [0136] Example 1A

[0137] 形式I的5-CNAC的制备 Preparation [0137] Form I of 5-CNAC

[0138] 形式I的5-CNAC还可如下被制备。 [0138] Form I of 5-CNAC may also be prepared as follows. 22L、硬质玻璃、五颈、圆底烧瓶被配备以高架的揽摔器(overhead stirrer)、热电偶温度读出(thermocouple temperature read out)以及加热罩。 22L, hard glass, five-necked, round-bottom flask was equipped with an overhead throw Lan devices (overhead stirrer), thermocouple temperature read-out (thermocouple temperature read out), and heating mantle. 该烧瓶被充填以2602.3g的5-CNAC与4000mL的水。 The flask was filled with a 5-CNAC 2602.3g with 4000mL water. 将溶解在2000ml水中的660g的氢氧化钠溶液添加至此被搅拌的淤浆中。 Dissolved in 2000ml water, 660g of sodium hydroxide was added to this stirred slurry. 该混合物被加热至55C并且大部分的固体被溶解。 The mixture was heated to 55 C and most of the solids are dissolved. 将轻度混池的溶液经由Whatman#l滤纸(fi I ter paper)热过滤,以移除不可溶的颗粒。 The solution was mixed with mild thermal pool was filtered through a filter paper Whatman # l (fi I ter paper), to remove insoluble particles. 将滤液转移到大的实验室旋转式蒸发器的罐式烧瓶(pot flask)中。 The filtrate was transferred to a large laboratory rotary evaporator flask tank (pot flask) in. 该旋转式蒸发器在60 (:的浴温与60mmHg的压力下被操作。将水从二钠盐溶液中移除,直至在该旋转式蒸发器的罐式烧瓶中获得固体块(sol id mass)。真空被释放,并且从该旋转式蒸发器中移除该罐式烧瓶。该固体从该罐熔烧瓶被刮至盘子中。这些盘子继而被放置在真空干燥箱中,并且将该固体在60C下且完全真空下干燥48小时。使经干燥的固体穿过实验室研磨机(laboratory mi 11)直至所有的固体通过35筛目的筛网。经研磨与筛过的二钠5-CNAC-水合物被放进盘子中并且被放回至干燥箱中。干燥在45C和完全真空下被继续进行,产生2957. Ig的作为干燥粉末的所需产物。 The rotary evaporator at 60 (: bath temperature and at a pressure of 60mmHg is operated to remove water from the disodium salt solution until a solid block (sol id tank in the flask of the rotary evaporator. mass). vacuum is released and the flask was removed from the tank to the rotary evaporator. the solid from the melting pot flask was scraped to the plate. the plates were then placed in a vacuum oven, and the solid at 60 C under vacuum and completely dried for 48 hours. the dried solids so through laboratory mill (laboratory mi 11) until all the solids through a 35 mesh screen. milled and sieved disodium 5- CNAC- hydrate was placed in a dish and is back to the oven. and dried at 45 C under full vacuum to be continued, 2957. Ig produce the desired product as a dry powder.

[0139] 实施例2 [0139] Example 2

[0140] 形式II的5-CNAC的制备 Preparation [0140] Form II of 5-CNAC

[0141] 形式II的5-CNAC是如下被制备。 [0141] Form II is 5-CNAC is prepared as follows. 向200加仑的不锈钢反应器充填132L的乙醇与11.6kg的氢氧化钠颗粒。 Into a 200 gallon stainless steel reactor was filled with ethanol 132L 11.6kg of sodium hydroxide pellets. 将该反应器加热至大约55C并保持在此温度直至氢氧化钠被溶解。 The reactor was heated to about 55 C and is kept at this temperature until the sodium hydroxide dissolved. 将该氢氧化钠/乙醇溶液冷却并维持在至少25 C的温度下。 The sodium hydroxide / ethanol solution was cooled and maintained at a temperature of 25 C at least. 将该氢氧化钠/乙醇溶液取样以用于通过滴定的碱分析(base assay)。 The sodium hydroxide / ethanol solution was sampled for analysis by the alkali titration (base assay). 向另一个200加仑的玻璃衬里的反应器充填以135L的乙醇与44.691^的5-0祖(:。将淤浆加热至55(:,并伴随着搅拌。维持此温度与搅拌直至该固体溶解。将2摩尔当量(滴定测定所确定的)的乙醇/氢氧化钠溶液添加至搅拌的乙醇/5-CNAC溶液中。随着氢氧化钠溶液被加入时,二钠5-CNAC乙醇溶剂合物开始沉淀。此添加步骤是放热的并且必须被控制以避免过度回流。将该反应器建立用于常压蒸馏,并且大约146L的乙醇被蒸馏出来。将批次冷却至小于KTC并且保持在此温度大约4小时。固体产物经由离心过滤而被回收。将过滤饼(fi I ter cake)放置在干燥箱中并且在45 C与完全真空下干燥大约16至24小时之间。干燥的二钠5-CNAC单乙醇溶剂合物的产量是大约43.25kg。 Another 200 gallons of the glass lined 135L reactor was filled with ethanol and 44.691 ^ 5-0 progenitor (:.. The slurry was heated to 55 (:, and maintained at that temperature with stirring and stirred until the solid dissolved. Add the 2 molar equivalents (as determined by titration) in ethanol / sodium hydroxide solution was added to a stirred solution of ethanol / 5-CNAC solution. as when sodium hydroxide solution was added, disodium 5-CNAC ethanol co-solvent the precipitate was started. this addition step was exothermic and must be controlled to avoid excessive reflux. the reactor used for the establishment of the atmospheric distillation, and about 146L ethanol was distilled off. the batch was cooled to and kept at less than KTC this temperature for about 4 hours. the solid product was recovered by centrifugation and filtration. the filter cake (fi I ter cake) and placed in a drying oven at 45 C under full vacuum and dried between about 16 to 24 hours. the dried two sodium 5-CNAC monoethanol solvate yield is about 43.25kg.

[0142] 形式II的XRTO光谱显示在图3中。 XRTO spectrum [0142] Form II is shown in Figure 3.

[0143] 实施例3 [0143] Example 3

[0144] 形式III的5-CNAC的制备 Preparation [0144] in the form of 5-CNAC of III

[0145] 形式III是如下被制备。 [0145] Form III is prepared is as follows. 将一薄层的二钠5-CNAC单乙醇溶剂合物涂布在玻璃盘子中。 A thin layer of disodium 5-CNAC monoethanol solvate coated glass plate. 将该包含有材料的盘子放置在40C的被设定为75%RH的湿度室(humidity chamber) 中。 The plates containing material is placed in a 40 C or is set to 75% RH humidity chamber (humidity chamber) in. 将在玻璃盘中的固体定期地搅拌与秤重。 And stirred in a glass dish weighed periodically solid. 将该材料留在湿度室中直至该样品不再改变重量或含有乙醇(以气相色谱来测定的)。 The material was left in the humidity chamber until the sample does not change the weight or containing ethanol (to be determined by gas chromatography). 这需要大约6天。 It takes about six days.

[0146] 形式III的XRTO光谱被显示在图4中。 XRTO spectrum [0146] Form III is shown in Figure 4.

[0147] 实施例4 [0147] Example 4

[0148] 形式IV的5-CNAC的制备 Preparation [0148] Form IV of 5-CNAC of

[0149] 形式IV是如下被制备。 [0149] Form IV is being prepared as follows. 向配备有底部排水管(bottom drain)的1升反应器充填以375mL的2-丁酮、125mL的水,以及125g的二钠5-CNAC-水合物。 Equipped with a bottom drain (bottom drain) of one liter reactor was filled with 375mL of 2-butanone, 125mL of water and 125g of disodium 5-CNAC- hydrate. 将该反应器内容物搅拌并加热至50C。 The reactor contents were stirred and heated to 50 C. 固体溶解,形成双相溶液。 The solid dissolved to form a biphasic solution. 停止搅拌,并且使得该溶液分开成为两个不溶混的液体层。 Agitation is stopped so that the solution was separated into two immiscible liquid layers. 反应器上的底部排水管被用来移除并且丢弃较低的层。 The bottom drain on the reactor was used to remove and discard the lower layer. 将剩余的溶液冷却至环境温度。 The remaining solution was cooled to ambient temperature. 在此冷却循环期间,产物开始结晶。 During the cooling cycle, the product began to crystallize. 将250mL额外的2-丁酮添加至所得到的淤浆中。 Adding additional 250mL of 2-butanone to the obtained slurry. 固体产物通过经过一烧结玻璃板漏斗的真空过滤而被回收。 The solid product was recovered by passing through a sintered glass funnel by vacuum filtration. 将湿饼在55C的完全真空的真空干燥箱中干燥过夜。 The wet cake at 55 C in a complete vacuum dried overnight in a vacuum oven. 干燥的二钠5-CNAC-水合物具有54.35g的重量。 Dried disodium 5-CNAC- hydrate having a weight of 54.35g. 产率是43%。 The yield was 43%.

[0150] 形式IV的XRPD与DSC光谱分别被显示在图5与图6中。 [0150] XRPD and DSC of Form IV spectra are shown in Figures 5 and 6 in FIG.

[0151] 实施例5 [0151] Example 5

[0152] 形式I与IV的5-CNAC的混合物的制备 Preparation of 5-CNAC mixture of Form I and IV of the [0152]

[0153] 形式I与IV的5-CNAC的混合物被制备如下。 Mixture [0153] Form I and IV of 5-CNAC is prepared as follows. 将干净的200加仑的玻璃衬里的反应器充填以525的丙酮。 200 gallons of a clean glass-lined reactor was filled with 525 of acetone. 将该反应器以氮予以净化。 The reactor with nitrogen to be purified. 开始搅拌。 Stirring was started. 将35kg的5-CNAC充填至搅拌的反应器内容物中。 35kg of the 5-CNAC is filled to the stirred contents of the reactor. 将该反应器内容物加热至50至60C之间,并且保持在此温度下至少20分钟。 The reactor contents were heated to 50 to 60 C, and held at this temperature for at least 20 minutes. 在此时间期间,大多数的固体溶解。 During this time, most of the solids dissolved. 将该反应器内容物经由压滤器而被栗至邻近的200加仑的玻璃衬里的反应器中。 The contents of the reactor via a filter press which is adjacent to the Li 200 gallon glass lined reactor. 将最初的反应器与压滤器以20L的新鲜丙酮冲洗至所述另一个反应器中。 The initial reaction with the filter press to 20L of fresh water until the acetone another reactor. 在另一独立的罐中通过将8.92kg的氢氧化钠溶解在44.6L的纯水中来制备氢氧化钠水溶液。 In another separate tank by 8.92kg of sodium hydroxide dissolved in 44.6L of pure water to prepare an aqueous solution of sodium hydroxide. 将此碱性水溶液栗至含有丙酮/5-CNAC滤液的反应器中。 This alkaline aqueous solution containing acetone to Li / 5-CNAC filtrate reactor. 此水性碱添加引起该反应器内容物回流。 This aqueous base addition caused the reactor contents at reflux. 将该水性碱罐以8.9L的新鲜水冲洗至该回流的反应器中。 The aqueous base tank with fresh water rinse to 8.9L of refluxing the reaction vessel. 对该反应容器不施加加热或冷却,并且允许该反应器内容物允许缓慢地冷却至环境温度。 The reaction vessel without applying heating or cooling, and allows the reactor contents were allowed to slowly cool to ambient temperature. 将冷却施加至该反应器的套(jacket)上,并且将该反应内容物进一步冷却至(TC至5C之间。这一完整的冷却循环耗费16至24小时之间。在该反应混合物中已经形成的沉淀物通过离心过滤来回收。将过滤饼放置于干燥箱中,并且在60 C与完全真空下干燥至少16小时。经干燥的二钠5-CNAC-水合物的产量是大约39.9kg。发现这一5-CNAC-水合物形式I与IV的混合物。在贮存该材料的期间,发现形式IV会转化成形式I。 Applying cooling to the reactor jacket (Jacket) on, and the reaction contents were further cooled to between (TC to 5 C. This complete cooling cycle takes between 16 to 24 hours. The reaction mixture was already formed precipitate was recovered by centrifugal filtration. the filter cake is placed in the drybox, and 60 C and dried under full vacuum at least 16 hours. the dried disodium 5-CNAC- hydrate yield is about 39.9kg. found that the mixture of the 5-CNAC- the monohydrate form I and IV. during storage of the material found in the form of IV will be converted into the form I.

[0154] 在上面所提到的所有专利、专利申请、文献、出版物与测试方法在此引入本文作为参考。 [0154] All patents, patent applications, documents, publications and test methods mentioned above are hereby incorporated herein by reference.

Classifications
International ClassificationA61P19/08, A61P5/06, A61P19/10, A61K38/23, A61K38/28, A61K31/609, A61K38/27, A61K38/29
Cooperative ClassificationC07C235/52, A61K47/18, C07C235/60, C07C231/24, C07B2200/13
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