WO2019218953A1 - 一种mor受体激动剂药物组合物 - Google Patents

一种mor受体激动剂药物组合物 Download PDF

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WO2019218953A1
WO2019218953A1 PCT/CN2019/086544 CN2019086544W WO2019218953A1 WO 2019218953 A1 WO2019218953 A1 WO 2019218953A1 CN 2019086544 W CN2019086544 W CN 2019086544W WO 2019218953 A1 WO2019218953 A1 WO 2019218953A1
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pharmaceutical composition
pharmaceutically acceptable
composition according
acceptable salt
active ingredient
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PCT/CN2019/086544
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French (fr)
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杨晓容
蒋艳霞
陈昊
贺峰
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江苏恒瑞医药股份有限公司
成都盛迪医药有限公司
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Priority to CN201980004491.8A priority Critical patent/CN111163778B/zh
Publication of WO2019218953A1 publication Critical patent/WO2019218953A1/zh

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/4433—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a six-membered ring with oxygen as a ring hetero atom
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]

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  • the present disclosure belongs to the field of pharmaceutical preparations and relates to a MOR receptor agonist (1S, 4S)-4-methoxy-N-(2-((R)-9-(pyridin-2-yl)-6-)
  • Opioid receptors are an important class of G protein-coupled receptors (GPCRs), which are targets for the binding of endogenous opioid peptides and opioids.
  • GPCRs G protein-coupled receptors
  • the opioid receptors activate the nervous system and the endocrine system. It has a regulating effect, and opioids are the strongest and commonly used central analgesics.
  • the ⁇ -opioid receptor is a target for endogenous enkephalins and opioid analgesics such as morphine.
  • endogenous enkephalin and a class of drugs etomorphine can agonize G protein and trigger receptor endocytosis, but morphine does not induce endocytosis of the receptor at all, because morphine is agonistic of MOR phosphorylation.
  • the ability is too weak to recruit only a small amount of beta-arrestin on the membrane (Zhang et al, Proc Natl Acad Sci USA, 1998, 95(12): 7157-7162).
  • Such ligands exert their physiological functions entirely through the G protein signaling pathway rather than the beta-arrestin pathway.
  • WO2014022733 discloses a class of oxa-spira MOR receptor agonists whose structures are as follows:
  • the present disclosure provides a pharmaceutical composition
  • a pharmaceutical composition comprising the active ingredient (1S,4S)-4-methoxy-N-(2-((R)-9-(pyridin-2-yl)-6-oxa) Spiro[4.5]decane-9-yl)ethyl)-1,2,3,4-tetrahydronaphthalen-1-amine or a pharmaceutically acceptable salt thereof, and a phosphate buffer.
  • the pharmaceutical composition has a pH of about 5.5 to 8.0, and may be about 5.50, 5.60, 5.70, 5.80, 5.90, 6.00, 6.10, 6.20, 6.30, 6.40, 6.50, 6.60, 6.70, 6.80. 6.90, 7.00, 7.10, 7.20, 7.30, 7.40, 7.50, 7.60, 7.70, 7.80, 7.90 or 8.00, preferably about 6.0 to 7.5, most preferably about 6.0 to 7.0.
  • the concentration of the buffer in the pharmaceutical composition is from about 1 to 100 mM, and may be about 1, 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60. 65, 70, 75, 80, 85, 90, 95 or 100 mM, preferably about 5 to 80 mM, and most preferably about 10 to 50 mM.
  • the active ingredient or a pharmaceutically acceptable salt thereof in the pharmaceutical composition of the present disclosure has a concentration of about 0.1 to 5.0 mg/ml, and may be about 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1.0, 1.2, 1.4, 1.6, 1.8, 2.0, 2.2, 2.4, 2.6, 2.8, 3.0, 3.2, 3.4, 3.6, 3.8, 4.0, 4.2, 4.4, 4.6, 4.8, 5.0 mg/ml .
  • the osmotic pressure of the pharmaceutical composition in the present disclosure is about 280-320 mOsmol/kg, and the non-limiting examples include 280, 281, 282, 283, 284, 285, 286, 287, 288, 289, 290, 291, 292, 293, 294, 295, 296, 297, 298, 299, 300, 301, 302, 303, 304, 305, 306, 307, 308, 309, 310, 311, 312, 313, 314, 315, 316, 317, 318, 319 or 320 mOsmol/kg.
  • the pharmaceutical composition further comprises an osmotic pressure adjusting agent selected from the group consisting of, but not limited to, mannitol, xylitol, sorbitol, sodium chloride, glucose, preferably sodium chloride. .
  • the concentration of the osmotic pressure adjusting agent in the pharmaceutical composition is from about 1 to 40 mM, and the non-limiting examples include 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40 mM, preferably about 5-20 mM, most preferably about 9.0 mM.
  • the pharmaceutical composition of the present disclosure has a dissolved oxygen content of less than about 1.0 mg/L, preferably less than about 0.5 mg/L.
  • composition of the present disclosure comprises:
  • composition of the present disclosure comprises:
  • composition of the present disclosure comprises:
  • composition of the present disclosure comprises:
  • composition of the present disclosure comprises:
  • an osmotic pressure adjusting agent of 1 to 40 mg/ml, wherein the pharmaceutical composition has an dissolved oxygen amount of less than about 100 ug/ml, preferably the pH of the pharmaceutical composition is about 6.0 to 7.5.
  • composition of the present disclosure comprises:
  • the present disclosure provides a pharmaceutical composition
  • a pharmaceutical composition comprising the active ingredient (1S,4S)-4-methoxy-N-(2-((R)-9-(pyridin-2-yl)-6-oxyl) Heterospiro[4.5]decane-9-yl)ethyl)-1,2,3,4-tetrahydronaphthalen-1-amine or a pharmaceutically acceptable salt thereof, wherein the pharmaceutical composition has a dissolved oxygen content of less than about 1.0 mg/L, preferably less than about 0.5 mg/L.
  • the low dissolved oxygen amount of the pharmaceutical composition has better stability and clarity for long-term stable placement.
  • the pharmaceutically acceptable salt of the active ingredient in the present disclosure is a pharmaceutically acceptable salt selected from, but not limited to, fumaric acid.
  • a method of preparing the aforementioned pharmaceutical composition which comprises: (1S, 4S)-4-methoxy-N-(2-((R)-9-(pyridin-2-yl)) a step of mixing -6-oxaspiro[4.5]nonane-9-yl)ethyl)-1,2,3,4-tetrahydronaphthalen-1-amine or a pharmaceutically acceptable salt thereof, and a buffer, further Also included is the step of adding a osmotic adjusting agent.
  • the foregoing preparation method further comprises the step of deoxidizing the pharmaceutical composition, wherein the oxygen removal method is a bubble deaeration method, that is, using an inert gas such as nitrogen, argon, carbon dioxide and a mixture thereof.
  • the oxygen removal method is a bubble deaeration method, that is, using an inert gas such as nitrogen, argon, carbon dioxide and a mixture thereof.
  • the pharmaceutical composition is stable for at least 3 months, at least 6 months, at least 12 months, at least 18 months, or at least 24 months at 25 ⁇ 2 °C. In some embodiments, the pharmaceutical composition is stable at 60 ⁇ 2 ° C, 40 ⁇ 2 ° C, light stable for at least 7 days, at least 14 days or at least 28 days, and after low temperature cycling, freeze-thaw cycles.
  • the pharmaceutical composition is placed at 40 ° C ⁇ 2 ° C, humidity of 75% ⁇ 5% for 1 month, 2 months, 3 months or 6 months, the total impurity content growth rate is not more than 20 % can be 20, 18, 16, 14, 12, 10, 9, 8, 7, 6, 5, 4, 3, 2, 1% or lower.
  • the pharmaceutical composition is placed at 25 ⁇ 2 ° C, 40 ⁇ 5% RH for 3 months, 6 months, 9 months, 12 months or 18 months, and the total impurity content growth rate is not greater than 20%, which may be 20, 18, 16, 14, 12, 10, 9, 8, 7, 6, 5, 4, 3, 2, 1% or lower.
  • a pharmaceutical composition as described above for the manufacture of a medicament for the treatment or prevention of a MOR receptor-associated disease or condition in a mammal selected from the group consisting of pain, immune dysfunction, inflammation , esophageal reflux, neurological and psychiatric disorders, urinary and reproductive diseases, cardiovascular and respiratory diseases.
  • the pain described in the present disclosure may be postoperative pain, pain caused by cancer, neuropathic pain, traumatic pain, and pain caused by inflammation, etc.; wherein the cancer may be selected from breast cancer, uterus Endometrial cancer, cervical cancer, skin cancer, prostate cancer, ovarian cancer, fallopian tube tumor, ovarian tumor, hemophilia and leukemia.
  • a pharmaceutical composition as described above for the manufacture of a medicament for the treatment or prevention of a disease or condition associated with a MOR receptor selected from the group consisting of pain, immune dysfunction, inflammation, esophageal reflux , neurological and psychiatric disorders, urinary and reproductive diseases, cardiovascular diseases and respiratory diseases.
  • the pain described in the present disclosure may be postoperative pain, pain caused by cancer, neuropathic pain, traumatic pain, and pain caused by inflammation, etc.; wherein the cancer may be selected from breast cancer, uterus Endometrial cancer, cervical cancer, skin cancer, prostate cancer, ovarian cancer, fallopian tube tumor, ovarian tumor, hemophilia and leukemia.
  • Buffer refers to a buffer that is resistant to changes in pH by the action of its acid-base conjugate component.
  • Examples of the buffer which controls the pH in an appropriate range include acetate, succinate, gluconate, histidine, oxalate, lactate, phosphate, citrate, tartrate, fumarate, Glycyl glycine and other organic acid buffers.
  • “Pharmaceutical composition” means a mixture comprising one or more compounds described herein, or a physiologically/pharmaceutically acceptable salt or prodrug thereof, with other chemical components, such as physiological/pharmaceutically acceptable Carrier and excipients.
  • the purpose of the pharmaceutical composition is to maintain the stability of the active ingredient of the antibody, promote the administration to the organism, and facilitate the absorption of the active ingredient to exert biological activity.
  • “pharmaceutical composition” and “formulation” are not mutually exclusive.
  • Phosphate buffer is a buffer that includes phosphate ions.
  • examples of the phosphate buffer solution include disodium hydrogen phosphate-sodium dihydrogen phosphate, disodium hydrogen phosphate-potassium dihydrogen phosphate, and the like, and a preferred phosphate buffer solution is disodium hydrogen phosphate-sodium dihydrogen phosphate.
  • the "about” error range described in this disclosure is from ⁇ 10% to 20%.
  • Typical acceptable criteria for stability in the present disclosure are as follows: typically no more than about 10%, preferably no more than about 5%, of the active ingredient is degraded by HPLC.
  • the amount of dissolved oxygen involved in the present disclosure is determined by using a dissolved oxygen meter.
  • the pharmaceutical excipients or reagents in the present disclosure may be derived from a commercial route, the active ingredient compound A: (1S, 4S)-4-methoxy-N-(2-((R)-9-(pyridin-2-yl)) -6-oxaspiro[4.5]decane-9-yl)ethyl)-1,2,3,4-tetrahydronaphthalen-1-amine can be prepared by reference to the examples of WO2017063509, pharmaceutically acceptable salts thereof (such as Fumarate) can be referred to PCT/CN2018/082935.
  • the high-pH pharmaceutical composition has poor stability for long-term placement.
  • the total amount of the pharmaceutical composition is as high as 1.05%.

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Abstract

本披露中涉及一种MOR受体激动剂药物组合物。具体而言，本披露涉及的MOR受体激动剂药物组合物其包含(1S,4S)-4-甲氧基-N-(2-((R)-9-(吡啶-2-基)-6-氧杂螺[4.5]癸烷-9-基)乙基)-1,2,3,4-四氢萘-1-胺或其可药用盐，和磷酸盐缓冲液。本披露中之药物组合物在储存数月之后展现了良好的稳定性。

Description

一种MOR受体激动剂药物组合物 技术领域
本披露中属于药物制剂领域，涉及一种MOR受体激动剂(1S,4S)-4-甲氧基-N-(2-((R)-9-(吡啶-2-基)-6-氧杂螺[4.5]癸烷-9-基)乙基)-1,2,3,4-四氢萘-1-胺或其可药用盐的药物组合物及其制备方法。
背景技术
阿片受体是一类重要的G蛋白偶联受体(G protein coupled receptor,GPCR)，是内源性阿片肽及阿片类药物结合的靶点，阿片受体激活后对神经系统免疫及内分泌系统具有调节作用，阿片类药物是目前最强且常用的中枢镇痛药。
μ-阿片受体(μ-opioid receptor，MOR)是内源性脑啡肽和吗啡等阿片类镇痛药物的作用靶点。早期研究显示，内源性脑啡肽和阿类药物埃托啡可以激动G蛋白并引发受体内吞，但是吗啡却完全不会引发受体的内吞，这是因为吗啡激动MOR磷酸化的能力太弱，仅能募集微量的β-arrestin于膜上(Zhang等，Proc Natl Acad Sci USA,1998,95(12):7157-7162)。此类配体完全通过G蛋白信号通路而不是β-arrestin途径来发挥其生理功能。研究发现给β-arrestin2基因敲除小鼠注射吗啡后，由G蛋白信号介导的镇痛效果更强且维持时间更长(Bohn等，Science，1999年)。可以预见，如果此类配体的负性β-arrestin偏爱性更强，甚至可以逃脱β-arrestin介导的受体脱敏，则可导致G蛋白信号传递时间延长，产生更强大的镇痛作用。
目前公开的MOR激动剂专利申请包括WO2014022733、WO2008009415、WO2009018169、WO2012129495、WO2001049650、WO2002020481、WO2010051476和WO2013087589等。同时WO2017063509也公开了一类氧杂螺环类的MOR受体激动剂，其结构如下：
Figure PCTCN2019086544-appb-000001
但对于新的MOR受体激动剂，即，(1S,4S)-4-甲氧基-N-(2-((R)-9-(吡啶-2-基)-6-氧杂螺[4.5]癸烷-9-基)乙基)-1,2,3,4-四氢萘-1-胺或其可药用盐，使其适合于给药， 并且在储存及随后使用过程中能保持稳定性，发挥更好的效果，需要研制更适于给药的MOR受体激动剂的药物(制剂)组合物。
发明内容
本披露中提供一种药物组合物，其包含活性成分(1S,4S)-4-甲氧基-N-(2-((R)-9-(吡啶-2-基)-6-氧杂螺[4.5]癸烷-9-基)乙基)-1,2,3,4-四氢萘-1-胺或其可药用盐，和磷酸盐缓冲液。
在可选实施方案中，所述药物组合物的pH约为5.5～8.0，可约为5.50、5.60、5.70、5.80、5.90、6.00、6.10、6.20、6.30、6.40、6.50、6.60、6.70、6.80、6.90、7.00、7.10、7.20、7.30、7.40、7.50、7.60、7.70、7.80、7.90或8.00，优选约为6.0～7.5，最优选约为6.0～7.0。
在可选的实施方案中，药物组合物中缓冲液的浓度为约1～100mM，可约为1、5、10、15、20、25、30、35、40、45、50、55、60、65、70、75、80、85、90、95或100mM，优选约为5～80mM，最优选约为10～50mM。
在可选的实施方案中，本披露中所述药物组合物中活性成分或其可药用盐浓度约为0.1～5.0mg/ml，可约为0.1、0.2、0.3、0.4、0.5、0.6、0.7、0.8、0.9、1.0、1.2、1.4、1.6、1.8、2.0、2.2、2.4、2.6、2.8、3.0、3.2、3.4、3.6、3.8、4.0、4.2、4.4、4.6、4.8、5.0mg/ml。
进一步的，本披露中所述药物组合物的渗透压约为280～320mOsmol/kg，非限制性实施例包括280、281、282、283、284、285、286、287、288、289、290、291、292、293、294、295、296、297、298、299、300、301、302、303、304、305、306、307、308、309、310、311、312、313、314、315、316、317、318、319或320mOsmol/kg。
在可选的实施方案中，药物组合物还含有渗透压调节剂，所述渗透压调节剂选自但不限于甘露醇、木糖醇、山梨醇、氯化钠、葡萄糖，优选为氯化钠。
在可选的实施方案中，药物组合物中渗透压调节剂的浓度约为1～40mM，非限制性实施例包括1、2、3、4、5、6、7、8、9、10、11、12、13、14、15、16、17、18、19、20、21、22、23、24、25、26、27、28、29、30、31、32、33、34、35、36、37、38、39、40mM，优选约为5～20mM，最优选约为9.0mM。
在可选的实施方案中，本披露中药物组合物的溶氧量小于约1.0mg/L，优选小 于约0.5mg/L。
在可选的实施方案中，本披露中药物组合物包含：
(a)0.1-5.0mg/ml的活性成分(1S,4S)-4-甲氧基-N-(2-((R)-9-(吡啶-2-基)-6-氧杂螺[4.5]癸烷-9-基)乙基)-1,2,3,4-四氢萘-1-胺或其可药用盐，
(b)1～100mM的磷酸盐缓冲液。
在可选的实施方案中，本披露中药物组合物包含：
(a)0.1-5.0mg/ml的活性成分(1S,4S)-4-甲氧基-N-(2-((R)-9-(吡啶-2-基)-6-氧杂螺[4.5]癸烷-9-基)乙基)-1,2,3,4-四氢萘-1-胺或其可药用盐，
(b)1～100mM的磷酸盐缓冲液，
(c)1～40mg/ml的渗透压调节剂，优选所述药物组合物的pH约为6.0～7.5。
在可选的实施方案中，本披露中药物组合物包含：
(a)0.1-15.0mg/ml的活性成分(1S,4S)-4-甲氧基-N-(2-((R)-9-(吡啶-2-基)-6-氧杂螺[4.5]癸烷-9-基)乙基)-1,2,3,4-四氢萘-1-胺或其可药用盐，
(b)1～100mM的磷酸二氢钠-磷酸氢二钠缓冲液，
(c)1～40mg/ml的渗透压调节剂，优选所述药物组合物的pH约为6.0～7.5。
在可选的实施方案中，本披露中药物组合物包含：
(a)0.1-5.0mg/ml的活性成分(1S,4S)-4-甲氧基-N-(2-((R)-9-(吡啶-2-基)-6-氧杂螺[4.5]癸烷-9-基)乙基)-1,2,3,4-四氢萘-1-胺或其可药用盐，
(b)1～100mM的磷酸二氢钠-磷酸氢二钠缓冲液，
(c)1～9mg/ml的氯化钠，优选所述药物组合物的pH约为6.0～7.5。
在可选的实施方案中，本披露中药物组合物包含：
(a)0.1-5.0mg/ml的活性成分(1S,4S)-4-甲氧基-N-(2-((R)-9-(吡啶-2-基)-6-氧杂螺[4.5]癸烷-9-基)乙基)-1,2,3,4-四氢萘-1-胺或其可药用盐，
(b)1～100mM的磷酸盐缓冲液，
(c)1～40mg/ml的渗透压调节剂，其中所述药物组合物的溶氧量小于约100ug/ml，优选所述药物组合物的pH约为6.0～7.5。
在可选的实施方案中，本披露中药物组合物包含：
(a)0.1-5.0mg/ml的活性成分(1S,4S)-4-甲氧基-N-(2-((R)-9-(吡啶-2-基)-6-氧杂螺[4.5]癸烷-9-基)乙基)-1,2,3,4-四氢萘-1-胺或其可药用盐，
(b)1～100mM的磷酸二氢钠-磷酸氢二钠缓冲液，
(c)1～9mg/ml的氯化钠，其中所述药物组合物的溶氧量小于约100ug/ml，优选所述药物组合物的pH约为6.0～7.5。
本披露中提供了一种药物组合物，其包含活性成分(1S,4S)-4-甲氧基-N-(2-((R)-9-(吡啶-2-基)-6-氧杂螺[4.5]癸烷-9-基)乙基)-1,2,3,4-四氢萘-1-胺或其可药用盐，其中所述药物组合物的溶氧量小于约1.0mg/L，优选小于约0.5mg/L。
在可选实施方案中，低溶氧量的药物组合物具有更好的稳定性和澄清度，利于长期稳定放置。
本披露中所述活性成分的可药用盐为可药用盐选自但不限于富马酸。
本披露中还提供了制备前述药物组合物的方法，该方法包括：将(1S,4S)-4-甲氧基-N-(2-((R)-9-(吡啶-2-基)-6-氧杂螺[4.5]癸烷-9-基)乙基)-1,2,3,4-四氢萘-1-胺或其可药用盐，和缓冲液混合的步骤，进一步地，还包括加入渗透调节剂的步骤。
在可选实施方案中，前述制备方法中还包括药物组合物除氧的步骤，所述除氧的方式为鼓泡除氧法，即，利用惰性气体(如氮气、氩气、二氧化碳及其混合气体等)连续鼓泡处理(1S,4S)-4-甲氧基-N-(2-((R)-9-(吡啶-2-基)-6-氧杂螺[4.5]癸烷-9-基)乙基)-1,2,3,4-四氢萘-1-胺或其可药用盐，缓冲液和/或渗透调节剂混合所得液体，降低药物组合物中溶氧量，控制药物组合物的溶氧量小于约1.0mg/L，优选小于约0.5mg/L。
在一些实施方案中，该药物组合物于25±2℃稳定至少3个月，至少6个月，至少12个月，至少18个月或至少24个月。在一些实施方案中，该药物组合物于60±2℃、40±2℃、光照稳定至少7天，至少14天或至少28天，以及低温循环、冻融循环后稳定性良好。
在可选实施方案中，该药物组合物于40℃±2℃，湿度为75％±5％放置1个月，2个月，3个月或6个月，总杂含量增长率不大于20％，可以为20、18、16、14、12、10、9、8、7、6、5、4、3、2、1％或更低。
在可选实施方案中，该药物组合物于25±2℃，40±5％RH放置3个月，6个月，9个月、12个月或18个月，总杂含量增长率不大于20％，可以为20、18、16、14、12、10、9、8、7、6、5、4、3、2、1％或更低。
本披露中还提供前述的药物组合物用于制备治疗或预防哺乳动物的MOR受体相关的疾病或病况的药物中的用途，所述MOR受体相关的病况选自疼痛、免疫功能障碍、炎症、食管回流、神经和精神疾病、泌尿和生殖疾病、心血管疾病和 呼吸道疾病。
在可选实施方案中，本披露中所述疼痛可以是术后疼痛、癌症引起的疼痛、神经性疼痛、创伤性疼痛和炎症引起的疼痛等；其中所述的癌症可以选自乳腺癌、子宫内膜癌、宫颈癌、皮肤癌、前列腺癌、卵巢癌、输卵管肿瘤、卵巢瘤、血友病和白血病等。
本披露中还提供前述的药物组合物用于制备治疗或预防MOR受体相关的疾病或病况的药物中的用途，所述MOR受体相关的病况选自疼痛、免疫功能障碍、炎症、食管回流、神经和精神疾病、泌尿和生殖疾病、心血管疾病和呼吸道疾病。
在可选实施方案中，本披露中所述疼痛可以是术后疼痛、癌症引起的疼痛、神经性疼痛、创伤性疼痛和炎症引起的疼痛等；其中所述的癌症可以选自乳腺癌、子宫内膜癌、宫颈癌、皮肤癌、前列腺癌、卵巢癌、输卵管肿瘤、卵巢瘤、血友病和白血病等。
术语
“缓冲液”指通过其酸-碱共轭组分的作用而耐受pH变化的缓冲液。将pH控制在适当范围中的缓冲液的例子包括醋酸盐、琥珀酸盐、葡萄糖酸盐、组氨酸、草酸盐、乳酸盐、磷酸盐、柠檬酸盐、酒石酸盐、延胡索酸盐、甘氨酰甘氨酸和其它有机酸缓冲液。
“药物组合物”表示含有一种或多种本文所述化合物或其生理学上/可药用的盐或前体药物与其他化学组分的混合物，所述其他组分例如生理学/可药用的载体和赋形剂。药物组合物的目的是保持抗体活性成分的稳定性，促进对生物体的给药，利于活性成分的吸收进而发挥生物活性。本文中，“药物组合物”和“制剂”并不互相排斥。
“磷酸盐缓冲液”是包括磷酸离子的缓冲液。磷酸盐缓冲液的实例包括磷酸氢二钠酸-磷酸二氢钠、磷酸氢二钠酸-磷酸二氢钾等，优选的磷酸盐缓冲液是磷酸氢二钠酸-磷酸二氢钠。
本披露中所述的“约”的误差范围为±10％～20％。
本披露中稳定性的典型可接受的标准如下：通过HPLC测得，通常不超过约10％、优选不超过约5％的活性成分发生降解。
本披露中涉及溶氧量通过使用溶解氧测定仪检定。
本披露中涉及药物辅料或试剂均可来自商业途径，活性成分化合物A： (1S,4S)-4-甲氧基-N-(2-((R)-9-(吡啶-2-基)-6-氧杂螺[4.5]癸烷-9-基)乙基)-1,2,3,4-四氢萘-1-胺可参照WO2017063509实施例进行制备，其可药用盐(如富马酸盐)可参考PCT/CN2018/082935。
具体实施方式
以下为本披露中的具体实施方式，实施例是为进一步描述本披露而不是限制本披露，凡与本披露中等效的技术方案均属于本披露的保护范围。
实施例1
将(1S,4S)-4-甲氧基-N-(2-((R)-9-(吡啶-2-基)-6-氧杂螺[4.5]癸烷-9-基)乙基)-1,2,3,4-四氢萘-1-胺富马酸盐与缓冲液按表1中处方量配置，搅拌溶解、调节pH后，以备用，分别考察60℃条件下的稳定性，数据见表2：
表1
Figure PCTCN2019086544-appb-000002
表2
Figure PCTCN2019086544-appb-000003
由实验结果可知：即便体系pH值相同，但是不同缓冲液体系(如磷酸氢二钠-磷酸二氢钠、柠檬酸-磷酸二氢钠)对药物组合物的稳定性具有不同影响，尤其是药物组合物长期放置时(60℃，30天)。磷酸二氢钠-磷酸氢二钠缓冲体系更适用于制备稳定的药物组合物。
实施例2
将(1S,4S)-4-甲氧基-N-(2-((R)-9-(吡啶-2-基)-6-氧杂螺[4.5]癸烷-9-基)乙基)-1,2,3,4-四氢萘-1-胺富马酸盐与注射用水相混合，用磷酸氢二钠-磷酸二氢钠调节pH，搅拌溶解以备用，考察不同pH值下，60℃条件下的稳定性，数据见表3和4：
表3
Figure PCTCN2019086544-appb-000004
表4
Figure PCTCN2019086544-appb-000005
由实验结果可知：高pH的药物组合物长期放置稳定性较差，如pH＝7.0时，药物组合物的总杂量增长显著，放置14天后，药物组合物的总杂量高达1.05％，不能满足药典药品质量指导原则。
实施例3
化合物A富马酸盐       1.0mg/ml
缓冲盐浓度            50mM
pH值                  6.4
将(1S,4S)-4-甲氧基-N-(2-((R)-9-(吡啶-2-基)-6-氧杂螺[4.5]癸烷-9-基)乙基)-1,2,3,4-四氢萘-1-胺富马酸盐与注射用水相混合，用磷酸氢二钠-磷酸二氢钠调节pH至6.4后，进行充氮鼓泡除氧，控制溶氧量不大于0.5mg/L，灭菌，分装。放置于40±2℃，湿度为75±5％(加速)和25±2℃，40±5％RH条件下，考察稳定性，具体数据见表5。
表5
Figure PCTCN2019086544-appb-000006

Claims (15)

  1. 一种药物组合物，其包含活性成分(1S,4S)-4-甲氧基-N-(2-((R)-9-(吡啶-2-基)-6-氧杂螺[4.5]癸烷-9-基)乙基)-1,2,3,4-四氢萘-1-胺或其可药用盐，和磷酸盐缓冲液，所述磷酸盐缓冲液优选自磷酸二氢钠-磷酸氢二钠缓冲液。
  2. 权利要求1所述的药物组合物，其所述药物组合物的pH约为5.5～8.0，优选约为6.0～7.5，最优选约为6.0～7.0。
  3. 权利要求1或2所述的药物组合物，其中所述缓冲液浓度约为1～100mM，优选约为5～80mM，最优选约为10～50mM。
  4. 权利要求1至3任一项所述的药物组合物，其中所述活性成分或其可药用盐浓度约为0.1～5.0mg/ml。
  5. 权利要求1至4任一项所述的药物组合物，其中所述药物组合物的渗透压约为280～320mOsmol/kg。
  6. 权利要求1至5任一项所述的药物组合物，其中还含有渗透压调节剂，所述渗透压调节剂优选自甘露醇、木糖醇、山梨醇、氯化钠、葡萄糖，最优选为氯化钠。
  7. 权利要求1至6任一项所述的药物组合物，其中所述渗透压调节剂浓度约为1～40mg/ml，优选约为5～20mg/ml，最优选约为9.0mg/ml。
  8. 权利要求1至7任一项所述的药物组合物，其中所述药物组合物的溶氧量小于约1.0mg/L，优选小于约0.5mg/L。
  9. 权利要求1至8任一项所述的药物组合物，其中包含：
    (a)0.1-5.0mg/ml的活性成分(1S,4S)-4-甲氧基-N-(2-((R)-9-(吡啶-2-基)-6-氧杂螺[4.5]癸烷-9-基)乙基)-1,2,3,4-四氢萘-1-胺或其可药用盐，
    (b)1～100mM的磷酸盐缓冲液，
    (c)1～40mg/ml的渗透压调节剂，优选所述药物组合物的pH约为6.0～7.5。
  10. 一种药物组合物，其包含活性成分(1S,4S)-4-甲氧基-N-(2-((R)-9-(吡啶-2-基)-6-氧杂螺[4.5]癸烷-9-基)乙基)-1,2,3,4-四氢萘-1-胺或其可药用盐，其中所述药物组合物的溶氧量小于约1.0mg/L，优选小于约0.5mg/L。
  11. 权利要求1至10任一项所述的药物组合物，其中所述活性成分的可药用盐选自富马酸盐。
  12. 制备权利要求1至11任一项所述的药物组合物的方法，包括：将(1S,4S)-4-甲氧基-N-(2-((R)-9-(吡啶-2-基)-6-氧杂螺[4.5]癸烷-9-基)乙基)-1,2,3,4-四氢萘-1-胺或其可药用盐，和缓冲液混合的步骤。
  13. 权利要求12所述的方法，其还包括药物组合物除氧的步骤，所述除氧的方式优选为鼓泡除氧法。
  14. 权利要求1-11任一项所述的药物组合物或由权利要求12所述的方法制备的药物组合物在用于制备治疗或预防哺乳动物的MOR受体相关的疾病或病况的药物中的用途。
  15. 权利要求14所述的用途，其中所述MOR受体相关的病况选自疼痛、免疫功能障碍、炎症、食管回流、神经和精神病况、泌尿和生殖病况、心血管病况和呼吸道病况。
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