TWI819756B - Pharmaceutical composition containing dinalbuphine sebacate - Google Patents

Pharmaceutical composition containing dinalbuphine sebacate Download PDF

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TWI819756B
TWI819756B TW111131408A TW111131408A TWI819756B TW I819756 B TWI819756 B TW I819756B TW 111131408 A TW111131408 A TW 111131408A TW 111131408 A TW111131408 A TW 111131408A TW I819756 B TWI819756 B TW I819756B
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senabuphine
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TW202308628A (en
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李雄
施能靜
董達文
儲開慧
陳晶
赫俠平
鈺 蔣
卜淼淼
周珺
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大陸商蘇州恩華生物醫藥科技有限公司
大陸商江蘇恩華藥業股份有限公司
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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
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/485—Morphinan derivatives, e.g. morphine, codeine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
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    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/26—Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/28—Steroids, e.g. cholesterol, bile acids or glycyrrhetinic acid
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/44—Oils, fats or waxes according to two or more groups of A61K47/02-A61K47/42; Natural or modified natural oils, fats or waxes, e.g. castor oil, polyethoxylated castor oil, montan wax, lignite, shellac, rosin, beeswax or lanolin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/10—Dispersions; Emulsions
    • A61K9/107—Emulsions ; Emulsion preconcentrates; Micelles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/04—Centrally acting analgesics, e.g. opioids

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Abstract

The present invention relates to the field of medicine, particularly relates to a pharmaceutical composition containing dinalbuphine sebacate, and producing method and usage thereof. The pharmaceutical composition comprises acylglycerol, phosphatidylcholine, at least one oxygen-containing organic solvent, at least one acid and dinalbuphine sebacate. The pharmaceutical composition has higher stability, faster onset, longer action time, and can reduce injection pain and hemolysis.

Description

包含塞納布啡的藥物組合物Pharmaceutical compositions containing senabuphine

本專利申請要求2021年8月20日向中國國家知識產權局提交的申請號為202110957327.8，發明名稱為「一種包含塞納布啡的藥物組合物」的在先發明專利申請的優先權。該在先申請的全文通過引用方式納入本申請中。This patent application claims the priority of the prior invention patent application with the application number 202110957327.8 submitted to the State Intellectual Property Office of China on August 20, 2021, and the invention name is "A pharmaceutical composition containing senabuphine". The entire text of this prior application is incorporated by reference into this application.

本發明屬於醫藥技術領域，具體涉及一種包含塞納布啡的藥物組合物，其製備方法以及在製藥工業中的應用。The invention belongs to the field of medical technology, and specifically relates to a pharmaceutical composition containing senabuphine, its preparation method and its application in the pharmaceutical industry.

納布啡癸二酸酯 (dinalbuphine sebacate, DNS)又叫塞納布啡，是納布啡的二聚體，其化學結構如下所示， 。 Nalbuphine sebacate (DNS), also called senabuphine, is a dimer of nalbuphine. Its chemical structure is as follows: .

塞納布啡是通過癸二酸連接基連接的納布啡 (Nalbuphine)的二酯，為納布啡的前藥，主要用於治療中度至重度術後疼痛。因納布啡必須每4至6小時注射一次，而DNS作為納布啡前藥能夠緩慢降解，具備製備成緩釋製劑的潛力。Senabuphine is the diester of Nalbuphine linked through a sebacic acid linker. It is a prodrug of Nalbuphine and is mainly used to treat moderate to severe postoperative pain. Because nalbuphine must be injected every 4 to 6 hours, DNS, as a nalbuphine prodrug, can slowly degrade and has the potential to be prepared into a sustained-release preparation.

阿片藥物因存在依賴和成癮風險，因此施用的阿片藥物的藥物濃度需要恰到好處的達到鎮痛效果但儘量避免帶來藥物依賴風險。此外，因術後痛、癌痛或其他較為劇烈的慢性或急性疼痛往往需要在較長的時間應用，為避免反覆注射，減少疼痛管理負擔，具有平穩血藥濃度的長效緩釋阿片藥物注射製劑一直是開發的熱點。目前納布啡癸二酸酯的長效緩釋製劑已在臺灣上市，使劇烈或長期疼痛的患者無需頻繁施用納布啡製劑，其處方工藝在WO2016189393A中公開，為一種注射用油混溶性製劑，該製劑通過將DNS溶於比例為0.8~1.2:1的苯甲酸苄酯與芝麻油、蓖麻油等植物溶劑的混合溶劑中製備得到，該注射用油溶液存在容易氧化，易污染，不易保存等缺點，並且芝麻油、蓖麻油等植物性溶劑易導致過敏反應，在臨床肌肉注射時病人痛苦感比較強、易導致肌肉結塊。此外，患者在手術後仍然需要口服酮咯酸來緩解疼痛；另外苯甲酸苄酯還具有包括皮膚刺激和過敏反應等不良反應。Opioids carry risks of dependence and addiction, so the concentration of opioids administered needs to be just right to achieve the analgesic effect but try to avoid the risk of drug dependence. In addition, since postoperative pain, cancer pain or other severe chronic or acute pain often requires long-term application, in order to avoid repeated injections and reduce the burden of pain management, long-acting sustained-release opioid injections with stable blood concentrations are needed. Formulation has always been a hot topic in development. Currently, the long-acting sustained-release preparation of nalbuphine sebacate has been launched in Taiwan, which allows patients with severe or long-term pain to avoid frequent administration of nalbuphine preparations. Its prescription process is disclosed in WO2016189393A, which is an oil-miscible preparation for injection. , this preparation is prepared by dissolving DNS in a mixed solvent of benzyl benzoate and sesame oil, castor oil and other plant solvents with a ratio of 0.8 to 1.2:1. This injection oil solution is easy to oxidize, easy to contaminate, and difficult to preserve. Disadvantages, and plant-based solvents such as sesame oil and castor oil can easily cause allergic reactions. Patients feel more pain during clinical intramuscular injection and can easily lead to muscle agglomeration. In addition, patients still need to take oral ketorolac to relieve pain after surgery; in addition, benzyl benzoate also has adverse reactions including skin irritation and allergic reactions.

專利CN104968338A公開了一種長效止痛藥癸二醯二納布啡酯-PLGA控釋劑型，採用聚乳酸、聚乳酸-聚乙二醇共聚物等作為載體，製備成微球。但微球製備過程複雜，有機溶劑殘留及無菌保障等均是工業化面臨的一大挑戰。Patent CN104968338A discloses a long-acting analgesic nalbuphine-PLGA controlled-release dosage form, which uses polylactic acid, polylactic acid-polyethylene glycol copolymer, etc. as carriers to prepare microspheres. However, the microsphere preparation process is complex, organic solvent residues and sterility assurance are all major challenges facing industrialization.

專利CN101014319A公開了一種包含一種醯基甘油和/或至少一種生育酚，至少一種磷脂醯甘油，至少一種生物相容溶劑的通用低黏度非液晶混合物的預製劑，適用於多種給藥途徑，但其載藥量不高，說明書中記載奧曲肽藥物負載量約為0.5~3%(w/w)，氯己定的藥物負載量約為5%(w/w)，抗炎/鎮痛藥物苄達明的藥物負載量約為3.2~4.5%(w/w)，維思通的藥物負載量約為5%(w/w)，因此對於緩釋長期給藥和/或需要藥物負載量較大的製劑並不適用。Patent CN101014319A discloses a preformulation of a universal low-viscosity non-liquid crystal mixture containing one acylglycerol and/or at least one tocopherol, at least one phospholipid acylglycerol, and at least one biocompatible solvent. It is suitable for a variety of administration routes, but its The drug loading capacity is not high. The instructions state that the drug loading capacity of octreotide is about 0.5~3% (w/w), that of chlorhexidine is about 5% (w/w), and that of the anti-inflammatory/analgesic drug benzydamine. The drug loading capacity of Risperdal is about 3.2~4.5% (w/w), and the drug loading capacity of Risperdal is about 5% (w/w). Therefore, for sustained-release long-term administration and/or preparations requiring larger drug loading capacity does not apply.

專利CN101123949A公開了一種包含10~40%的至少一種磷脂醯膽鹼，30~75%的至少一種醯基甘油、至少一種生育酚或其混合物，5~30%的至少一種分子量低於8000道爾頓的表面活性劑的離子組合物。但是該組合物最多只能引入20wt%的活性劑。此外為了增加載藥量和降低注射組合物的黏度，其所用表面活性劑含量較高，對於長效緩釋的注射製劑而言存在著一定的溶血風險。Patent CN101123949A discloses a product containing 10 to 40% of at least one phosphatidyl choline, 30 to 75% of at least one acylglycerol, at least one tocopherol or a mixture thereof, and 5 to 30% of at least one molecular weight lower than 8000 Dal. Dayton's ionic composition of surfactants. However, this composition can only incorporate up to 20% by weight of active agent. In addition, in order to increase the drug loading capacity and reduce the viscosity of the injection composition, the surfactant content used is relatively high, and there is a certain risk of hemolysis for long-acting and sustained-release injection preparations.

綜上所述，目前塞納布啡長效注射劑尚不能滿足臨床需求，對於具有合適載藥量，同時能夠降低藥物組合物黏度，提高穩定性，減少患者注射痛，避免產生溶血及過敏反應、提高藥物起效速度等一個或多個方面仍極需改善。To sum up, the current long-acting injection of senabuphine cannot meet the clinical needs. It has a suitable drug loading capacity and can simultaneously reduce the viscosity of the pharmaceutical composition, improve stability, reduce injection pain for patients, avoid hemolysis and allergic reactions, and improve One or more aspects, including the speed of drug onset of action, still need improvement.

本發明提供一種包含塞納布啡的藥物組合物，與目前現有技術中的塞納布啡的注射組合物相比，本發明採用非油性製劑配方，具有提高藥物起效速度、延長藥物作用時間，減少血管刺激性和溶血風險的發生，提高疼痛管理中患者用藥順應性，解決塞納布啡析晶等導致的混懸穩定性問題等一個或多個方面的有益效果。The present invention provides a pharmaceutical composition containing senabuphine. Compared with the injection composition of senabuphine in the current prior art, the present invention adopts a non-oily preparation formula, which has the advantages of improving the drug onset speed, prolonging the drug action time, and reducing It has beneficial effects in one or more aspects, such as reducing the risk of vascular irritation and hemolysis, improving patient medication compliance in pain management, and solving suspension stability problems caused by senabuphine crystallization.

首先，第一方面，本發明提供了一種藥物組合物，其包含下列組分： (a)醯基甘油； (b)磷脂醯膽鹼； (c)至少一種含氧有機溶劑； (d)至少一種酸； (e)塞納布啡； 其中，所述組分(e)塞納布啡含量為5~20重量%，組分(a)和組分(b)的含量之和為40~79重量%，例如60~79重量%或40重量%~低於60重量%；組分(e)塞納布啡與組分(d)酸的重量比為5~15:1；組分(c)的含量為15~42重量%，例如15~34重量%或34重量%以上~42重量%； 所述重量百分比為相對於(a)、(b)、(c)、(d)和(e)的總重量而言。 較佳地，所述組分(e)塞納布啡含量為5~20重量%；組分(a)和組分(b)的含量之和為60~79重量%；組分(e)塞納布啡與組分(d)酸的重量比為5~15:1；組分(c)的含量為15~34重量%； 所述重量百分比為相對於(a)、(b)、(c)、(d)和(e)的總重量而言。 進一步較佳的，在本發明的一些實施方式中，上述組合物中，所述塞納布啡含量為7.5~10重量%；組分(a)和組分(b)的含量之和為65~75重量%；組分(e)塞納布啡與組分(d)酸的重量比為6~10:1；組分(c)含氧有機溶劑的含量為20~25重量%，所述重量百分比為相對於(a)、(b)、(c)、(d)和(e)的總重量而言。 進一步較佳的，在本發明的另一些實施方式中，上述組合物中，所述塞納布啡含量為7~15重量%，較佳為7.5~10重量%；組分(a)和組分(b)的含量之和為50~75重量%；組分(e)塞納布啡與組分(d)酸的重量比為6~15:1；組分(c)含氧有機溶劑的含量為15~35重量%，所述重量百分比為相對於(a)、(b)、(c)、(d)和(e)的總重量而言。 First, in a first aspect, the present invention provides a pharmaceutical composition comprising the following components: (a) acylglycerol; (b) Phosphatidylcholine; (c) At least one oxygen-containing organic solvent; (d) at least one acid; (e) Senabuphine; Wherein, the content of component (e) senabuphine is 5~20% by weight, and the sum of the contents of component (a) and component (b) is 40~79% by weight, such as 60~79% by weight or 40% by weight. Weight%~less than 60% by weight; the weight ratio of component (e) senabuphine to component (d) acid is 5~15:1; the content of component (c) is 15~42% by weight, for example 15 ~34% by weight or above 34% by weight ~42% by weight; The weight percentages are relative to the total weight of (a), (b), (c), (d) and (e). Preferably, the content of component (e) sennabuphine is 5~20% by weight; the sum of the contents of component (a) and component (b) is 60~79% by weight; component (e) senna The weight ratio of buphine to component (d) acid is 5~15:1; the content of component (c) is 15~34% by weight; The weight percentages are relative to the total weight of (a), (b), (c), (d) and (e). Further preferably, in some embodiments of the present invention, in the above composition, the content of senabuphine is 7.5~10% by weight; the sum of the contents of component (a) and component (b) is 65~ 75% by weight; the weight ratio of component (e) senabuphine to component (d) acid is 6~10:1; the content of component (c) oxygenated organic solvent is 20~25% by weight, the weight Percentages are relative to the total weight of (a), (b), (c), (d) and (e). Further preferably, in other embodiments of the present invention, in the above composition, the senabuphine content is 7 to 15% by weight, preferably 7.5 to 10% by weight; component (a) and component The sum of the contents of (b) is 50~75% by weight; the weight ratio of component (e) senabuphine to component (d) acid is 6~15:1; the content of component (c) oxygen-containing organic solvent is 15 to 35% by weight, and the weight percentage is relative to the total weight of (a), (b), (c), (d) and (e).

本發明的一個實施方案中，所述藥物組合物在20 ℃具有100~1000 cps的黏度，較佳具有100~500 cps的黏度，更佳具有200~400 cps的黏度。In one embodiment of the present invention, the pharmaceutical composition has a viscosity of 100~1000 cps at 20°C, preferably a viscosity of 100~500 cps, and more preferably a viscosity of 200~400 cps.

本發明的一個實施方案中，所述藥物組合物在25 ℃具有30~1000 cps的黏度，例如，30~500 cps的黏度、30~400 cps的黏度、30~300 cps的黏度、30~200 cps的黏度、50~200 cps的黏度、50~300 cps的黏度、50~400 cps的黏度、100~500 cps的黏度、或200~400 cps的黏度及其之間的任意範圍，優選具有30~500 cps的黏度，例如50~300 cps的黏度或200~400 cps的黏度等。In one embodiment of the present invention, the pharmaceutical composition has a viscosity of 30~1000 cps at 25°C, for example, a viscosity of 30~500 cps, a viscosity of 30~400 cps, a viscosity of 30~300 cps, a viscosity of 30~200 cps, cps, 50~200 cps, 50~300 cps, 50~400 cps, 100~500 cps, or 200~400 cps and any range therebetween, preferably 30 ~500 cps viscosity, such as 50~300 cps viscosity or 200~400 cps viscosity, etc.

本發明的一個實施方案中，所述組分(a)和組分(b)的含量之和為40~79重量%，例如45~79重量%、50~79重量%、55~79重量%、60~79重量%、65~79重量%、70~79重量%、40~75重量%、45~75重量%、50~75重量%、55~75重量%、60~75重量%、65~75重量%、70~75重量%、40~70重量%、45~70重量%、50~70重量%、55~70重量%、60~70重量%、65~70重量%、40~65重量%、45~65重量%、50~65重量%、55~65重量%、60~65重量%、40~60重量%、45~60重量%、50~60重量%、55~60重量%、40~55重量%、45~55重量%、50~55重量%、48~72重量%、49~72重量%、48~71重量%、60~68重量%、40重量%~低於60重量%、53重量%、50重量%等，以及包含其中的所有範圍；進一步舉例說明，所述組分(a)和組分(b)的含量之和可以以下列量存在於組合物中：約75重量%、74重量%、約72重量%、約71重量%、約70重量%、約69重量%、約68重量%、約67重量%、約66重量%、約65重量%、約64重量%、約60重量%、約59重量%、約54重量%、約52重量%、約50重量%、約49重量%及其任意兩個數值之間的範圍。In one embodiment of the present invention, the sum of the contents of component (a) and component (b) is 40 to 79 wt%, such as 45 to 79 wt%, 50 to 79 wt%, 55 to 79 wt% , 60~79% by weight, 65~79% by weight, 70~79% by weight, 40~75% by weight, 45~75% by weight, 50~75% by weight, 55~75% by weight, 60~75% by weight, 65 ~75% by weight, 70~75% by weight, 40~70% by weight, 45~70% by weight, 50~70% by weight, 55~70% by weight, 60~70% by weight, 65~70% by weight, 40~65 Weight%, 45~65% by weight, 50~65% by weight, 55~65% by weight, 60~65% by weight, 40~60% by weight, 45~60% by weight, 50~60% by weight, 55~60% by weight , 40~55% by weight, 45~55% by weight, 50~55% by weight, 48~72% by weight, 49~72% by weight, 48~71% by weight, 60~68% by weight, 40% by weight~less than 60 Weight %, 53 weight %, 50 weight %, etc., and all ranges inclusive therein; to further illustrate, the sum of the contents of component (a) and component (b) can be present in the composition in the following amounts: About 75% by weight, 74% by weight, about 72% by weight, about 71% by weight, about 70% by weight, about 69% by weight, about 68% by weight, about 67% by weight, about 66% by weight, about 65% by weight, about 64% by weight, about 60% by weight, about 59% by weight, about 54% by weight, about 52% by weight, about 50% by weight, about 49% by weight, and the range between any two values thereof.

本發明的一個實施方案中，組分(a)醯基甘油和組分(b)磷脂醯膽鹼的重量比例可在較寬的範圍內配製前體組合物，組分(a)醯基甘油含量為20~60重量%，例如20~50重量%、25~50重量%、30~50重量%、35~50重量%、40~50重量%、45~50重量%、20~40重量%、25~40重量%、35~40重量%、20~30重量%、25~30重量%、20~45重量%、25~45重量%、30~45重量%、31~40重量%、37~41重量%、35~45重量%、或20重量%~低於30重量%等，以及包含其中的所有範圍；進一步作為舉例說明，組分(a)醯基甘油可以以下列量存在於組合物中：約20重量%、約26重量%、約29重量%、約30重量%、約31重量%、約33重量%、約34重量%、約35重量%、約37重量%、約38重量%、約39重量%、約40重量%、約41重量%、約44重量%、約46重量%或約50重量%等，以及其中任意兩個數值之間的範圍；較佳組分(a)醯基甘油含量為30~50重量%，更佳為30~45重量%；組分(b)磷脂醯膽鹼的含量為15~40重量%，例如20~40重量%，25~40重量%、30~40重量%、20~35重量%、25~35重量%、30~35重量%、20~30重量%、20~31重量%、20~25重量%、26~31重量%、31~35重量%、25~30重量%或35~40重量%等，以及包含其中的所有範圍；進一步作為舉例說明，組分(b)磷脂醯膽鹼可以以下列量存在於組合物中：約20重量%、約22重量%、約23重量%、約24重量%、約25重量%、約26重量%、約27重量%、約28重量%、約29重量%、約30重量%、約31重量%、約33重量%、約35重量%、約40重量%等，以及其中任意兩個數值之間的範圍；較佳組分(b)磷脂醯膽鹼的含量為20~35重量%，進一步較佳25~35重量%或20~30重量%。In one embodiment of the present invention, the weight ratio of component (a) acylglycerol and component (b) phosphatidylcholine can be used to prepare the precursor composition within a wide range. Component (a) acylglycerol The content is 20~60% by weight, such as 20~50% by weight, 25~50% by weight, 30~50% by weight, 35~50% by weight, 40~50% by weight, 45~50% by weight, 20~40% by weight , 25~40% by weight, 35~40% by weight, 20~30% by weight, 25~30% by weight, 20~45% by weight, 25~45% by weight, 30~45% by weight, 31~40% by weight, 37 ~41% by weight, 35~45% by weight, or 20% by weight~less than 30% by weight, etc., and all ranges including them; further as an example, component (a) acylglycerol can be present in the combination in the following amounts Material: about 20% by weight, about 26% by weight, about 29% by weight, about 30% by weight, about 31% by weight, about 33% by weight, about 34% by weight, about 35% by weight, about 37% by weight, about 38% by weight Weight %, about 39 weight %, about 40 weight %, about 41 weight %, about 44 weight %, about 46 weight % or about 50 weight %, etc., and the range between any two values therein; the preferred component ( a) The content of acylglycerol is 30~50% by weight, more preferably 30~45% by weight; the content of component (b) phosphatidylcholine is 15~40% by weight, for example, 20~40% by weight, 25~40% Weight%, 30~40% by weight, 20~35% by weight, 25~35% by weight, 30~35% by weight, 20~30% by weight, 20~31% by weight, 20~25% by weight, 26~31% by weight , 31~35% by weight, 25~30% by weight or 35~40% by weight, etc., and all ranges included therein; further as an example, component (b) phosphatidylcholine can be present in the composition in the following amounts : About 20% by weight, about 22% by weight, about 23% by weight, about 24% by weight, about 25% by weight, about 26% by weight, about 27% by weight, about 28% by weight, about 29% by weight, about 30% by weight , about 31% by weight, about 33% by weight, about 35% by weight, about 40% by weight, etc., and the range between any two of them; the content of the preferred component (b) phosphatidylcholine is 20 to 35 % by weight, more preferably 25 to 35% by weight or 20 to 30% by weight.

本發明的一個實施方案中，組分(a)醯基甘油包括「頭部基團」甘油部分和獨立地2~3個「尾部基團」醯基基團部分，在本發明中，所述醯基甘油為二醯基甘油、三醯基甘油或二者的混合物；特別地，較佳二醯基甘油。In one embodiment of the present invention, component (a) acylglycerol includes a "head group" glycerol moiety and independently 2 to 3 "tail group" acylyl group moieties. In the present invention, said Glycerol is diacylglycerol, triacylglycerol or a mixture of the two; in particular, diacylglycerol is preferred.

本發明的一個實施方案中，組分(a)醯基甘油可以包括至少50重量%的具有這樣的醯基基團的部分。In one embodiment of the invention, component (a) acylglycerol may comprise at least 50% by weight of moieties having such acyl groups.

進一步較佳的，所述醯基甘油包括至少50重量%的具有C 12-C 24醯基基團部分，所述醯基基團具有0~9個不飽和度。 Further preferably, the acylglycerol includes at least 50% by weight of a portion having a C 12 -C 24 acyl group, and the acyl group has 0 to 9 degrees of unsaturation.

更佳的，所述醯基甘油包括至少50重量%的具有C 12-C 18醯基基團部分，所述醯基基團具有0~2個不飽和度。 More preferably, the acylglycerol includes at least 50% by weight of a portion having a C 12 -C 18 acyl group, and the acyl group has 0 to 2 degrees of unsaturation.

進一步的，所述醯基甘油包括至少50重量%的具有C 16-C 18醯基基團部分，所述醯基基團具有0~2個不飽和度。 Further, the acylglycerol includes at least 50% by weight of a portion having a C 16 -C 18 acyl group, and the acyl group has 0 to 2 degrees of unsaturation.

本發明的一個實施方案中，所述「尾部基團」的選擇是獨立的，即醯基基團可具有相同或不同的碳原子，且各自獨立地是飽和或不飽和的，在本發明中，所述醯基甘油的醯基基團選自月桂醯基 (C12:0)、肉豆蔻醯基 (C14:0)、棕櫚醯基 (C16:0)、植烷醯基 (phytanoly)(C16:0)、棕櫚油醯基 (C16:1)、硬脂醯基 (C18:0)、油醯基 (C18:1)、反油酸醯基 (elaidoyl)(C18:1)、亞油醯基 (linoleoyl)(C18:2)、亞麻醯基 (linolenoyl)(C18:3)、花生四烯醯基 (C20:4)、山崳醯基 (C22:0)和二十四碳醯基(C24:9)，較佳為油醯基。In one embodiment of the present invention, the selection of the "tail group" is independent, that is, the acyl group can have the same or different carbon atoms, and each is independently saturated or unsaturated. In the present invention , the acyl group of the acylglycerol is selected from lauryl group (C12:0), myristyl group (C14:0), palmityl group (C16:0), phytanolyl (C16 :0), palm oil acyl (C16:1), stearyl (C18:0), oleyl (C18:1), elaidoyl (C18:1), linoleyl Linoleoyl (C18:2), linoleoyl (C18:3), arachidonic acid (C20:4), behenyl (C22:0) and icosinoyl ( C24:9), preferably oleyl group.

本發明的一個實施方案中，所述醯基基團基於天然脂肪酸，包括但不限於月桂酸、肉豆蔻酸、棕櫚酸、植烷酸、棕櫚炔酸、硬脂酸、油酸、反油酸、亞油酸、亞麻酸、花生四烯酸、山崳酸或二十四碳酸。較佳的醯基基團的來源是棕櫚酸、硬脂酸、油酸和亞麻酸，特別地，較佳為油酸。In one embodiment of the present invention, the acyl group is based on natural fatty acids, including but not limited to lauric acid, myristic acid, palmitic acid, phytanic acid, palmitinoic acid, stearic acid, oleic acid, and elaidic acid. , linoleic acid, linolenic acid, arachidonic acid, behenic acid or behenic acid. Preferred sources of acyl groups are palmitic acid, stearic acid, oleic acid and linolenic acid, in particular oleic acid is preferred.

本發明的一個實施方案中，所述醯基甘油至少包括一部分二醯基甘油，也可以是單一的二醯基甘油；其中二醯基甘油包含至少50重量%的二油酸甘油酯 (GDO)，較佳包含至少80重量%的GDO，更佳的基本上全部都為GDO的二醯基甘油。In one embodiment of the present invention, the diacylglycerol includes at least a portion of diacylglycerol, and can also be a single diacylglycerol; wherein the diacylglycerol includes at least 50% by weight of glyceryl digylglyceride (GDO) , preferably contains at least 80% by weight of GDO, and more preferably is substantially all diylglycerol of GDO.

通常GDO和其他二醯基甘油存在一定比例的具有其他鏈長的「雜質」脂等。因此，在一個方面中，本文所用的GDO用於表示含有伴隨雜質的任何商品級的GDO（即商品純度的GDO）。這些雜質可通過純化來分離和除去，但是如果級別相符，則所述純化很少有必要。如果必要，「GDO」可以基本上為化學純的GDO，例如至少80%純度，較佳至少85%純度，更佳為至少90%純度的GDO。Usually GDO and other diacylglycerols contain a certain proportion of "impurity" lipids with other chain lengths, etc. Thus, in one aspect, GDO as used herein is used to mean any commercial grade GDO that contains concomitant impurities (i.e., commercial purity GDO). These impurities can be isolated and removed by purification, but if the grades are consistent, such purification is rarely necessary. If necessary, "GDO" can be substantially chemically pure GDO, such as at least 80% pure, preferably at least 85% pure, more preferably at least 90% pure GDO.

在一個較佳實施方案中，組分(b)所述磷脂醯膽鹼（磷脂，PC）可源自天然來源。磷脂 (PC)的合適來源包括卵、心臟（例如牛的）、腦、肝臟（例如牛的）和包括大豆的植物來源。此類來源可提供組分(b)的一種或多種成分，其可包含磷脂的任意混合物。可使用來自這些或其他來源的任何單一PC或PC的混合物，但是含大豆PC或卵PC的混合物是非常合適的，由此，本發明組分(b)所述的磷脂醯膽鹼選自卵PC、心PC、腦PC、肝PC、蛋黃PC或大豆PC中的至少一種，較佳為卵PC、蛋黃PC或大豆PC中的至少一種，更佳為大豆PC。In a preferred embodiment, the phosphatidylcholine (phospholipid, PC) of component (b) can be derived from natural sources. Suitable sources of phospholipids (PC) include eggs, heart (eg bovine), brain, liver (eg bovine) and plant sources including soybeans. Such sources may provide one or more components of component (b), which may comprise any mixture of phospholipids. Any single PC or mixture of PCs from these or other sources may be used, but mixtures containing soybean PC or egg PC are very suitable, whereby the phosphatidylcholine of component (b) of the invention is selected from egg At least one of PC, heart PC, brain PC, liver PC, egg yolk PC or soybean PC, preferably at least one of egg PC, egg yolk PC or soybean PC, more preferably soybean PC.

在一個較佳實施方案中，組分(a)和(b)的特別有利的組合是GDO和PC，特別是GDO與大豆PC。In a preferred embodiment, a particularly advantageous combination of components (a) and (b) is GDO and PC, in particular GDO and soybean PC.

含氧有機溶劑可顯著降低組合物的黏度，在一個具體實施方案中，組分(c)所述含氧有機溶劑選自醯胺類，C 1-C 3的醇類中的至少一種，所述醯胺類選自N-甲基吡咯烷酮 (NMP)、二甲基甲醯胺、2-吡咯烷酮和二甲基乙醯胺（DMAC，又稱為N,N-二甲基乙醯胺）中的至少一種，所述C 1-C 3的醇類例如甲醇，乙醇，異丙醇或丙醇。發明人通過研究發現，納布啡癸二酸酯在NMP和DMAC中穩定性優於其他含氧有機溶劑，較佳組分(c)所述有機溶劑為N-甲基吡咯烷酮和/或二甲基乙醯胺。 Oxygen-containing organic solvents can significantly reduce the viscosity of the composition. In a specific embodiment, the oxygen-containing organic solvent of component (c) is selected from at least one of amide and C 1 -C 3 alcohols, so The amides are selected from N-methylpyrrolidone (NMP), dimethylformamide, 2-pyrrolidone and dimethylacetamide (DMAC, also known as N,N-dimethylacetamide) At least one of the C 1 -C 3 alcohols such as methanol, ethanol, isopropyl alcohol or propanol. The inventor found through research that the stability of nalbuphine sebacate is better than other oxygen-containing organic solvents in NMP and DMAC, and the organic solvent of the preferred component (c) is N-methylpyrrolidone and/or dimethyl Acetamide.

所述含氧有機溶劑可以以下列量存在於組合物中：約15~42重量%，例如15~40重量%、16~40重量%、20~40重量%、25~40重量%、30~40重量%、35~40重量%、15~35重量%、15~34重量%、34重量%以上~42重量%、20~35重量%、25~35重量%、30~35重量%、15~30重量%、20~30重量%、25~30重量%、15~25重量%、20~25重量%、15~20重量%、15~34重量%等，以及包含其中的所有範圍；進一步作為舉例說明，所述組分(c)含氧有機溶劑可以以下列量存在於組合物中：例如約16重量%、約17重量%、約18重量%、約19重量%、約20重量%、約21重量%、約22重量%、約23重量%、約24重量%、約25重量%、約26重量%、約27重量%、約28重量%、約29重量%、約30重量%、約33重量%、約34重量%、約35重量%、約40重量%及其任意兩個數值之間的範圍。The oxygen-containing organic solvent may be present in the composition in the following amounts: about 15~42% by weight, such as 15~40% by weight, 16~40% by weight, 20~40% by weight, 25~40% by weight, 30~ 40% by weight, 35~40% by weight, 15~35% by weight, 15~34% by weight, more than 34% by weight~42% by weight, 20~35% by weight, 25~35% by weight, 30~35% by weight, 15 ~30 wt%, 20~30 wt%, 25~30 wt%, 15~25 wt%, 20~25 wt%, 15~20 wt%, 15~34 wt%, etc., and all ranges inclusive therein; further As an example, the oxygen-containing organic solvent of component (c) may be present in the composition in the following amounts: for example, about 16% by weight, about 17% by weight, about 18% by weight, about 19% by weight, about 20% by weight. , about 21% by weight, about 22% by weight, about 23% by weight, about 24% by weight, about 25% by weight, about 26% by weight, about 27% by weight, about 28% by weight, about 29% by weight, about 30% by weight , about 33% by weight, about 34% by weight, about 35% by weight, about 40% by weight and the range between any two values thereof.

在一個具體實施方案中，上述組合物中所述塞納布啡含量為5~20重量%，例如：7~15重量%、7.5 ~15重量%、7.5~12.5重量%、7.5 ~10重量%、約7.5重量%、約7.9重量%、8重量%、約8.2重量%、約9.2重量%、約9.5重量%、約10重量%、約10.5重量%、約10.6重量%、約11重量%、約11.5重量%、約12重量%、約14重量%、約11.5重量%及其任意兩個數值之間的範圍。In a specific embodiment, the senabuphine content in the above composition is 5~20% by weight, for example: 7~15% by weight, 7.5~15% by weight, 7.5~12.5% by weight, 7.5~10% by weight, About 7.5% by weight, about 7.9% by weight, 8% by weight, about 8.2% by weight, about 9.2% by weight, about 9.5% by weight, about 10% by weight, about 10.5% by weight, about 10.6% by weight, about 11% by weight, about 11.5% by weight, about 12% by weight, about 14% by weight, about 11.5% by weight and the range between any two values thereof.

在一個具體實施方案中，組分(d)所述酸為甲磺酸、馬來酸、對甲苯磺酸、乙酸、富馬酸、檸檬酸或鹽酸中至少一種，酸的加入對提高藥物組合物的穩定性是有益的，穩定性的增加可以通過以下得以證明：在存在本發明所述酸（特別是甲磺酸）的情形下比不存在酸的情形下通過穩定性實驗（40 ℃±5 ℃/RH75%±10%穩定性試驗箱中15天，25 ℃±5 ℃/RH60%±10%穩定性試驗箱中1個月，2~8 ℃冷藏箱中1個月），藥物組合物的化學穩定性顯著改善，體現在雜質降解少，從HPLC檢測的純度結果可以看出；同樣穩定性的增加還體現在物理穩定性增加，具體體現在酸的加入可以減少藥物組合物中賽納布啡析晶問題，在研究過程中發現甲磺酸的加入可以顯著的解決藥物組合物中塞納布啡析晶導致混懸的問題，因此，較佳組分(d)為甲磺酸。進一步的研究發現，馬來酸的加入對於改善藥物組合物的化學穩定性是有利的，因此，在更較佳的實施方式中，所述組分(d)還包括馬來酸。塞納布啡與甲磺酸的重量比為5~15:1是有利的，較佳的塞納布啡與甲磺酸的重量比為6~15:1，更佳為6~10:1；當塞納布啡與甲磺酸的重量比為6~15:1，較佳為6~10:1，馬來酸為0~0.2重量%，較佳為0~0.01重量%，效果是最佳的。In a specific embodiment, the acid in component (d) is at least one of methanesulfonic acid, maleic acid, p-toluenesulfonic acid, acetic acid, fumaric acid, citric acid or hydrochloric acid. The addition of the acid can improve the pharmaceutical composition. The stability of the substance is beneficial, and the increase in stability can be demonstrated by the following: in the presence of the acid of the invention (especially methanesulfonic acid) than in the absence of the acid, the stability test (40 ℃ ± 15 days in 5 ℃/RH75%±10% stability test chamber, 1 month in 25 ℃±5 ℃/RH60%±10% stability test chamber, 1 month in 2~8 ℃ refrigerator), drug combination The chemical stability of the drug is significantly improved, which is reflected in the less degradation of impurities, as can be seen from the purity results of HPLC testing; the same increase in stability is also reflected in the increase in physical stability, specifically reflected in the addition of acid which can reduce the amount of salts in the pharmaceutical composition. Regarding the crystallization problem of nalbuphine, during the research process, it was found that the addition of methanesulfonic acid can significantly solve the problem of suspension caused by the crystallization of nalbuphine in the pharmaceutical composition. Therefore, the preferred component (d) is methanesulfonic acid. Further research found that the addition of maleic acid is beneficial to improving the chemical stability of the pharmaceutical composition. Therefore, in a more preferred embodiment, the component (d) also includes maleic acid. The weight ratio of senabuphine to methanesulfonic acid is advantageous to be 5~15:1, and the preferred weight ratio of senabuphine to methanesulfonic acid is 6~15:1, and more preferably 6~10:1; when The weight ratio of senabuphine to methanesulfonic acid is 6~15:1, preferably 6~10:1, and the maleic acid is 0~0.2% by weight, preferably 0~0.01% by weight. The effect is the best .

在一個具體實施方案中，本發明提供了一種藥物組合物，其包含： (a)二油酸甘油酯； (b)大豆PC； (c)N-甲基吡咯烷酮； (d)甲磺酸和馬來酸； (e)塞納布啡； 其中，塞納布啡含量為5~20重量%； 二油酸甘油酯和大豆PC的含量之和為40~79重量%，較佳為60~79重量%； 塞納布啡與甲磺酸的重量比為5~15:1，N-甲基吡咯烷酮的含量為15~35重量%，較佳為15~34重量%；馬來酸的含量為0~0.2重量%，較佳為0~0.02重量%； 所述重量百分比為相對於(a)、(b)、(c)、(d)和(e)的總重量而言。 In a specific embodiment, the invention provides a pharmaceutical composition comprising: (a) Diolein; (b) Soybean PC; (c) N-methylpyrrolidone; (d) methanesulfonic acid and maleic acid; (e) Senabuphine; Among them, the content of senabuphine is 5~20% by weight; The sum of the contents of diolein and soybean PC is 40 to 79% by weight, preferably 60 to 79% by weight; The weight ratio of senabuphine to methanesulfonic acid is 5~15:1, the content of N-methylpyrrolidone is 15~35% by weight, preferably 15~34% by weight; the content of maleic acid is 0~0.2% by weight. %, preferably 0~0.02% by weight; The weight percentages are relative to the total weight of (a), (b), (c), (d) and (e).

在一個具體實施方案中，本發明提供了一種藥物組合物，其包含： (a)二油酸甘油酯； (b)大豆PC； (c)N-甲基吡咯烷酮； (d)甲磺酸和馬來酸； (e)塞納布啡； 其中，塞納布啡含量為7~10重量%，較佳為7.5~10重量%； 二油酸甘油酯和大豆PC的含量之和為65~75重量%； 塞納布啡與甲磺酸的重量比為6~10:1，N-甲基吡咯烷酮的含量為15~35重量%，較佳為15~34重量%；馬來酸的含量為0~0.2重量%，較佳為0~0.02重量%，更佳為0~0.01重量%； 所述重量百分比為相對於(a)、(b)、(c)、(d)和(e)的總重量而言。 在本發明的一個具體實施方案中，上述藥物組合物，其中二油酸甘油酯的含量為20~60重量%，較佳為25~55重量%，例如30~50重量%、35~50重量%、40~50重量%、45~50重量%、35~45重量%、40~45重量%、30~40重量%、35~40重量%、37~41重量%、約30重量%、約35重量%、約37重量%、約38重量%、約39重量%、約40重量%、約41重量%、約44重量%、約50重量%及任意兩個數值之間的範圍； 其中所述大豆PC的含量為20~40重量%，例如25~40重量%、30~40重量%、35~40重量%、20~35重量%、25~35重量%、30~35重量%、20~30重量%、25~30重量%、約25重量%、約26重量%、約27重量%、約28重量%、約29重量%、約30重量%、約31重量%、約33重量%、及任意兩個數值之間的範圍； 進一步較佳的，二油酸甘油酯的含量為35~45重量%，大豆PC的含量為25~35重量%。 所述N-甲基吡咯烷酮的含量為15~34重量%，例如15~30重量%、20~30重量%、25~30重量%、15~25重量%、20~25重量%、約17重量%、約21重量%、約23重量%、約24重量%、約25重量%、約26重量%、約27重量%及任意兩個數值之間的範圍，較佳為20~25重量%。 In a specific embodiment, the invention provides a pharmaceutical composition comprising: (a) Diolein; (b) Soybean PC; (c) N-methylpyrrolidone; (d) methanesulfonic acid and maleic acid; (e) Senabuphine; Among them, the content of senabuphine is 7~10% by weight, preferably 7.5~10% by weight; The sum of the contents of diolein and soybean PC is 65~75% by weight; The weight ratio of senabuphine to methanesulfonic acid is 6~10:1, the content of N-methylpyrrolidone is 15~35% by weight, preferably 15~34% by weight; the content of maleic acid is 0~0.2% by weight. %, preferably 0~0.02% by weight, more preferably 0~0.01% by weight; The weight percentages are relative to the total weight of (a), (b), (c), (d) and (e). In a specific embodiment of the present invention, the above-mentioned pharmaceutical composition has a content of glyceryl dioleate of 20 to 60% by weight, preferably 25 to 55% by weight, such as 30 to 50% by weight, 35 to 50% by weight. %, 40~50% by weight, 45~50% by weight, 35~45% by weight, 40~45% by weight, 30~40% by weight, 35~40% by weight, 37~41% by weight, about 30% by weight, about 35% by weight, about 37% by weight, about 38% by weight, about 39% by weight, about 40% by weight, about 41% by weight, about 44% by weight, about 50% by weight, and the range between any two values; The content of soybean PC is 20~40% by weight, such as 25~40% by weight, 30~40% by weight, 35~40% by weight, 20~35% by weight, 25~35% by weight, 30~35% by weight. , 20~30% by weight, 25~30% by weight, about 25% by weight, about 26% by weight, about 27% by weight, about 28% by weight, about 29% by weight, about 30% by weight, about 31% by weight, about 33 Weight %, and the range between any two values; More preferably, the content of glycerol dioleate is 35 to 45% by weight, and the content of soybean PC is 25 to 35% by weight. The content of the N-methylpyrrolidone is 15~34% by weight, such as 15~30% by weight, 20~30% by weight, 25~30% by weight, 15~25% by weight, 20~25% by weight, about 17% by weight %, about 21 wt%, about 23 wt%, about 24 wt%, about 25 wt%, about 26 wt%, about 27 wt% and the range between any two values, preferably 20 to 25 wt%.

在一個具體實施方案中，本發明提供了一種藥物組合物，其包含： (a)二油酸甘油酯； (b)大豆PC； (c)二甲基乙醯胺； (d)甲磺酸和任選含有的馬來酸； (e)塞納布啡； 其中，二油酸甘油酯和大豆PC的含量之和為40~79重量%； 塞納布啡的含量為5~20重量%；塞納布啡與甲磺酸的重量比為5~15:1；馬來酸的含量為0~0.2重量%； 二甲基乙醯胺的含量為15~42重量%，較佳為16~40重量%； 所述重量百分比為相對於(a)、(b)、(c)、(d)和(e)的總重量而言。 In a specific embodiment, the invention provides a pharmaceutical composition comprising: (a) Diolein; (b) Soybean PC; (c) Dimethylacetamide; (d) methanesulfonic acid and optionally maleic acid; (e) Senabuphine; Among them, the sum of the contents of diolein and soybean PC is 40~79% by weight; The content of senabuphine is 5~20% by weight; the weight ratio of senabuphine to methanesulfonic acid is 5~15:1; the content of maleic acid is 0~0.2% by weight; The content of dimethylacetamide is 15~42% by weight, preferably 16~40% by weight; The weight percentages are relative to the total weight of (a), (b), (c), (d) and (e).

在一個具體實施方案中，本發明提供了一種藥物組合物，其包含： (a)二油酸甘油酯； (b)大豆PC； (c)二甲基乙醯胺； (d)甲磺酸和任選含有的馬來酸； (e)塞納布啡； 其中，二油酸甘油酯和大豆PC的含量之和為45~75重量%，較佳為50~75重量%； 塞納布啡的含量為7.5~15重量%；塞納布啡與甲磺酸的重量比為6~15：1；馬來酸的含量為0~0.01%； 二甲基乙醯胺的含量為15~40重量%，較佳為15~35重量%； 所述重量百分比為相對於(a)、(b)、(c)、(d)和(e)的總重量而言。 較佳地，所述藥物組合物，其中二油酸甘油酯的含量為20~50重量%，例如25~50重量%、30~50重量%、35~50重量%、40~50重量%、45~50重量%、25~45重量%、30~45重量%、35~45重量%、40~45重量%、25~40重量%、30~40重量%、35~40重量%、40~45重量%、26~47重量%、29~40重量%、約26重量%、約29重量%、約31重量%、約32重量%、約33重量%、約34重量%、約40重量%、約46重量%、約47重量%及任意兩個數值之間的範圍； 其中，大豆PC的含量為20~40重量%，例如25~40重量%、30~40重量%、35~40重量%、20~35重量%、25~35重量%、30~35重量%、20~30重量%、25~30重量%、約22重量%、約23重量%、約24重量%、約25重量%、約27重量%、約28重量%、約29重量%、約30重量%、約31重量%及任意兩個數值之間的範圍； 其中，二甲基乙醯胺的含量為15~42重量%，例如15~40重量%、15~35重量%、15~30重量%、16~40重量%、16~35重量%、16~30重量%、16~25重量%、16~20重量%、20~40重量%、25~40重量%、30~40重量%、35~40重量%、20~35重量%、20~30重量%、20~25重量%及其範圍內的任意值，例如約16重量%、約17重量%、約20重量%、約21重量%、約24重量%、約25重量%、約29重量%、約30重量%、約34重量%、約35重量%、約40重量%及任意兩個數值之間的範圍。 其中，塞納布啡的含量為7.5~15重量%，例如7.5 ~12.5重量%、7.5 ~10重量%、9 ~10重量%、10 ~11重量%、9 ~11重量%、8 ~11重量%、8 ~12重量%、約8重量%、約9重量%、約10重量%、約10.3重量%、約10.5重量%、約10.6重量%、約11重量%、約12重量%、約13重量%、約14重量%及其任意兩個數值之間的範圍。 在本發明的另一方面，發明人研究發現當藥物組合物中，組分(b)的含量比組分(a)的含量低，有利於塞納布啡的藥物釋放，因而是有益的。因此，對於包含組分(a)，組分(b)，組分(c)，組分(d)和組分(e)的藥物組合物，組分(a)和組分(b)的比率可變化。在一個實施方案中，組分(b)與組分(a)的比值按照重量計約0.1~1，較佳為0.4~1，更佳為0.5~0.9，例如0.6~0.8，0.65~0.75等。在又一個實施方案中，所述組合物包含(a)二油酸甘油酯，(b)大豆PC，(c)N-甲基吡咯烷酮，(d)甲磺酸，任選的包括馬來酸，(e)塞納布啡，其中(b)大豆PC與(a)二油酸甘油酯的比值按照重量計約為0.1~1，較佳為0.4~1，更佳為0.6~0.8，例如0.65~0.75。在又一個實施方案中，所述組合物包含(a)二油酸甘油酯，(b)大豆PC，(c)二甲基乙醯胺，(d)甲磺酸，任選的包括馬來酸，(e)塞納布啡，其中(b)大豆PC與(a)二油酸甘油酯的比值按照重量計約為0.1~1，較佳為0.4~1，更佳為0.5~0.9，例如0.7~0.9。 In a specific embodiment, the invention provides a pharmaceutical composition comprising: (a) Diolein; (b) Soybean PC; (c) Dimethylacetamide; (d) methanesulfonic acid and optionally maleic acid; (e) Senabuphine; Among them, the sum of the contents of diolein and soybean PC is 45~75% by weight, preferably 50~75% by weight; The content of senabuphine is 7.5~15% by weight; the weight ratio of senabuphine to methanesulfonic acid is 6~15:1; the content of maleic acid is 0~0.01%; The content of dimethylacetamide is 15~40% by weight, preferably 15~35% by weight; The weight percentages are relative to the total weight of (a), (b), (c), (d) and (e). Preferably, in the pharmaceutical composition, the content of glyceryl dioleate is 20~50% by weight, such as 25~50% by weight, 30~50% by weight, 35~50% by weight, 40~50% by weight, 45~50% by weight, 25~45% by weight, 30~45% by weight, 35~45% by weight, 40~45% by weight, 25~40% by weight, 30~40% by weight, 35~40% by weight, 40~ 45% by weight, 26~47% by weight, 29~40% by weight, about 26% by weight, about 29% by weight, about 31% by weight, about 32% by weight, about 33% by weight, about 34% by weight, about 40% by weight , about 46% by weight, about 47% by weight, and the range between any two values; Among them, the content of soybean PC is 20~40% by weight, such as 25~40% by weight, 30~40% by weight, 35~40% by weight, 20~35% by weight, 25~35% by weight, 30~35% by weight, 20~30% by weight, 25~30% by weight, about 22% by weight, about 23% by weight, about 24% by weight, about 25% by weight, about 27% by weight, about 28% by weight, about 29% by weight, about 30% by weight %, about 31% by weight and the range between any two values; Among them, the content of dimethylacetamide is 15~42% by weight, such as 15~40% by weight, 15~35% by weight, 15~30% by weight, 16~40% by weight, 16~35% by weight, 16~ 30% by weight, 16~25% by weight, 16~20% by weight, 20~40% by weight, 25~40% by weight, 30~40% by weight, 35~40% by weight, 20~35% by weight, 20~30% by weight %, 20~25% by weight and any value within the range, such as about 16% by weight, about 17% by weight, about 20% by weight, about 21% by weight, about 24% by weight, about 25% by weight, about 29% by weight , about 30% by weight, about 34% by weight, about 35% by weight, about 40% by weight and the range between any two values. Among them, the content of senabuphine is 7.5~15% by weight, such as 7.5~12.5% by weight, 7.5~10% by weight, 9~10% by weight, 10~11% by weight, 9~11% by weight, 8~11% by weight , 8~12% by weight, about 8% by weight, about 9% by weight, about 10% by weight, about 10.3% by weight, about 10.5% by weight, about 10.6% by weight, about 11% by weight, about 12% by weight, about 13% by weight %, about 14% by weight, and the range between any two values. In another aspect of the present invention, the inventor found that when the content of component (b) is lower than the content of component (a) in the pharmaceutical composition, it is beneficial to the drug release of senabuphine, and is therefore beneficial. Therefore, for a pharmaceutical composition comprising component (a), component (b), component (c), component (d) and component (e), the The ratio can vary. In one embodiment, the ratio of component (b) to component (a) is about 0.1~1 by weight, preferably 0.4~1, more preferably 0.5~0.9, such as 0.6~0.8, 0.65~0.75, etc. . In yet another embodiment, the composition comprises (a) glyceryl diolein, (b) soybean PC, (c) N-methylpyrrolidone, (d) methanesulfonic acid, optionally including maleic acid , (e) senabuphine, wherein the ratio of (b) soybean PC to (a) diolein is about 0.1~1 by weight, preferably 0.4~1, more preferably 0.6~0.8, such as 0.65 ~0.75. In yet another embodiment, the composition comprises (a) glyceryl diolein, (b) soybean PC, (c) dimethylacetamide, (d) methanesulfonic acid, optionally including maleic acid Acid, (e) senabuphine, wherein the ratio of (b) soybean PC to (a) glyceryl dioleate is about 0.1~1 by weight, preferably 0.4~1, more preferably 0.5~0.9, for example 0.7~0.9.

因此，在本發明的另一個實施方案中，所述組合物包含(a)二油酸甘油酯，(b)大豆PC，(c)N-甲基吡咯烷酮，(d)甲磺酸和馬來酸，(e)塞納布啡，其中(b)大豆PC與(a)二油酸甘油酯的比值按照重量計約為0.1~1，較佳為0.4~1，更佳為0.6~0.8，例如0.65~0.75。在本發明的另一個實施方案中，所述組合物包含(a)二油酸甘油酯，(b)大豆PC，(c)二甲基乙醯胺，(d)甲磺酸和馬來酸，(e)塞納布啡，其中(b)大豆PC與(a)二油酸甘油酯的比值按照重量計約為0.1~1，較佳為0.4~1，更佳為0.5~0.9，例如0.7~0.9。Accordingly, in another embodiment of the invention, the composition comprises (a) glyceryl diolein, (b) soybean PC, (c) N-methylpyrrolidone, (d) methanesulfonic acid and maleic acid Acid, (e) senabuphine, wherein the ratio of (b) soybean PC to (a) glyceryl dioleate is about 0.1~1 by weight, preferably 0.4~1, more preferably 0.6~0.8, for example 0.65~0.75. In another embodiment of the invention, the composition comprises (a) glyceryl diolein, (b) soybean PC, (c) dimethylacetamide, (d) methanesulfonic acid and maleic acid , (e) senabuphine, wherein the ratio of (b) soybean PC to (a) glyceryl dioleate is about 0.1~1 by weight, preferably 0.4~1, more preferably 0.5~0.9, such as 0.7 ~0.9.

進一步較佳的，上述組合物中所述塞納布啡含量為5~20重量%，較佳為7.5重量%~15重量%，例如7.5重量%~12.5重量%，例如7.5重量%~10重量%，例如約7.5重量%、約7.9重量%、約8.0重量%、約8.2重量%、約9.2重量%、約10重量%、約10.5重量%、約10.6重量%、約11重量%、約11.5重量%、約12重量%，從而呈現例如7.5重量%~15重量%，或者7.5重量%~12.5重量%，或者7.5重量%~10重量%的範圍。More preferably, the content of senabuphine in the above composition is 5 to 20% by weight, preferably 7.5% to 15% by weight, such as 7.5% to 12.5% by weight, such as 7.5% to 10% by weight. , for example, about 7.5% by weight, about 7.9% by weight, about 8.0% by weight, about 8.2% by weight, about 9.2% by weight, about 10% by weight, about 10.5% by weight, about 10.6% by weight, about 11% by weight, about 11.5% by weight %, about 12% by weight, thus showing a range of, for example, 7.5% to 15% by weight, or 7.5% to 12.5% by weight, or 7.5% to 10% by weight.

所述二油酸甘油酯和大豆PC的含量之和為40~79重量%，例如50~75重量%、50~70重量%、60~79重量%、60~70重量%、或65~75重量%等，例如約70重量%、約71重量%、約72重量%、約75重量%、約68重量%、約64重量%、約60重量%、約59重量%、約53重量%、約50重量%等。The total content of the diolein and soybean PC is 40~79% by weight, such as 50~75% by weight, 50~70% by weight, 60~79% by weight, 60~70% by weight, or 65~75% by weight. Weight %, etc., such as about 70% by weight, about 71% by weight, about 72% by weight, about 75% by weight, about 68% by weight, about 64% by weight, about 60% by weight, about 59% by weight, about 53% by weight, About 50% by weight, etc.

所述塞納布啡與甲磺酸的重量比為5~15:1，例如6:1，7.5:1，8:1，9:1，9.3:1， 9.5:1，10:1，11:1，12:1，或15:1等，較佳重量比為6~10:1，例如6.5:1，7.5:1，8.3:1，9.3:1，9.4:1，9.5:1或10:1等。The weight ratio of senabuphine and methanesulfonic acid is 5~15:1, such as 6:1, 7.5:1, 8:1, 9:1, 9.3:1, 9.5:1, 10:1, 11: 1, 12:1, or 15:1, etc., the best weight ratio is 6~10:1, such as 6.5:1, 7.5:1, 8.3:1, 9.3:1, 9.4:1, 9.5:1 or 10: 1 etc.

進一步的，所述N-甲基吡咯烷酮的含量為15重量%~34重量%，例如15重量%~25重量%、20重量%~25重量%等，較佳為15重量%~30重量%，例如約17.5重量%、約18.5重量%、約21重量%、約25重量%、約27重量%等，從而呈現15重量%~30重量%的範圍；更佳為所述N-甲基吡咯烷酮的含量為20重量%~25重量%。Further, the content of N-methylpyrrolidone is 15% to 34% by weight, such as 15% to 25% by weight, 20% to 25% by weight, etc., preferably 15% to 30% by weight, For example, about 17.5% by weight, about 18.5% by weight, about 21% by weight, about 25% by weight, about 27% by weight, etc., thus showing a range of 15% by weight to 30% by weight; more preferably, the N-methylpyrrolidone is The content is 20% to 25% by weight.

進一步的，所述二甲基乙醯胺的含量為15~42重量%，例如16~40重量%，較佳為15~35重量%，例如約17重量%、約20重量%、約21重量%、約25重量%、約29重量%或約35重量%等。Further, the content of dimethylacetamide is 15~42% by weight, such as 16~40% by weight, preferably 15~35% by weight, such as about 17% by weight, about 20% by weight, or about 21% by weight. %, about 25% by weight, about 29% by weight, or about 35% by weight, etc.

任選的馬來酸的含量為0~0.2重量%。The optional maleic acid content is 0 to 0.2% by weight.

其中所述重量百分比為相對於(a)、(b)、(c)、(d)和(e)的總重量而言。The weight percentages are relative to the total weight of (a), (b), (c), (d) and (e).

在本發明的另一個實施方式中，本發明所述的藥物組合物是由以下組分組成： (a)醯基甘油； (b)磷脂醯膽鹼； (c)至少一種含氧有機溶劑； (d)至少一種酸； (e)塞納布啡； 其中組分(a)、(b)、(c)、(d)和(e)的含量如前所述。 In another embodiment of the present invention, the pharmaceutical composition of the present invention consists of the following components: (a) acylglycerol; (b) Phosphatidylcholine; (c) At least one oxygen-containing organic solvent; (d) at least one acid; (e) Senabuphine; The contents of components (a), (b), (c), (d) and (e) are as described above.

在本發明的另一個實施方案中，所述的藥物組合物是由以下組分組成： (a)二油酸甘油酯； (b)大豆PC； (c)N-甲基吡咯烷酮； (d)甲磺酸和馬來酸； (e)塞納布啡； 其中，組分(b)與組分(a)的比值按照重量計約0.1~1，較佳為0.4~1，更佳為0.6~0.8，最佳為0.65~0.75。 In another embodiment of the invention, the pharmaceutical composition consists of the following components: (a) Diolein; (b) Soybean PC; (c) N-methylpyrrolidone; (d) methanesulfonic acid and maleic acid; (e) Senabuphine; Among them, the ratio of component (b) to component (a) is about 0.1~1 by weight, preferably 0.4~1, more preferably 0.6~0.8, and most preferably 0.65~0.75.

在本發明的一個實施方式中，二油酸甘油酯和大豆PC的含量之和為45~79重量%，較佳地，60~79重量%，更佳為65~75重量%；In one embodiment of the present invention, the sum of the contents of diolein and soybean PC is 45~79% by weight, preferably 60~79% by weight, more preferably 65~75% by weight;

在本發明的一個實施方式中，塞納布啡與甲磺酸的重量比為5~15:1，較佳為6~10：1；In one embodiment of the present invention, the weight ratio of senabuphine to methanesulfonic acid is 5~15:1, preferably 6~10:1;

在本發明的一個實施方式中，N-甲基吡咯烷酮的含量為15~35重量%，較佳為15~34重量%，更佳為20~25重量%；In one embodiment of the present invention, the content of N-methylpyrrolidone is 15~35% by weight, preferably 15~34% by weight, and more preferably 20~25% by weight;

在本發明的一個實施方式中，馬來酸的含量為0~0.2重量%，較佳為0~0.02重量%，更佳為0~0.01重量%。In one embodiment of the present invention, the content of maleic acid is 0~0.2% by weight, preferably 0~0.02% by weight, and more preferably 0~0.01% by weight.

在本發明的另一個實施方式中，本發明所述的藥物組合物是由以下組分組成： (a)二油酸甘油酯； (b)大豆PC； (c)N-甲基吡咯烷酮； (d)甲磺酸和馬來酸； (e)塞納布啡； 其中，塞納布啡含量為7.5~10重量%； 二油酸甘油酯和大豆PC的含量之和為65~75重量%； 塞納布啡與甲磺酸的重量比為6~10:1，N-甲基吡咯烷酮的含量為20~25重量%；馬來酸的含量為0~0.01重量%； 所述重量百分比為相對於(a)、(b)、(c)、(d)和(e)的總重量而言。 進一步較佳的，組分(b)與組分(a)的比值按照重量計約0.1~1，較佳為0.4~1，更佳為0.6~0.8，最佳為0.65~0.75。 In another embodiment of the present invention, the pharmaceutical composition of the present invention consists of the following components: (a) Diolein; (b) Soybean PC; (c) N-methylpyrrolidone; (d) methanesulfonic acid and maleic acid; (e) Senabuphine; Among them, the content of senabuphine is 7.5~10% by weight; The sum of the contents of diolein and soybean PC is 65~75% by weight; The weight ratio of senabuphine to methanesulfonic acid is 6~10:1, the content of N-methylpyrrolidone is 20~25% by weight; the content of maleic acid is 0~0.01% by weight; The weight percentages are relative to the total weight of (a), (b), (c), (d) and (e). Further preferably, the ratio of component (b) to component (a) is about 0.1~1 by weight, preferably 0.4~1, more preferably 0.6~0.8, and most preferably 0.65~0.75.

在本發明的另一個實施方案中，所述的藥物組合物是由以下組分組成： (a)二油酸甘油酯； (b)大豆PC； (c)二甲基乙醯胺； (d)甲磺酸和任選含有的馬來酸； (e)塞納布啡； 其中，組分(b)與組分(a)的比值按照重量計約0.1~1，較佳為0.4~1，更佳為0.5~0.9。 In another embodiment of the invention, the pharmaceutical composition consists of the following components: (a) Diolein; (b) Soybean PC; (c) Dimethylacetamide; (d) methanesulfonic acid and optionally maleic acid; (e) Senabuphine; Among them, the ratio of component (b) to component (a) is about 0.1~1 by weight, preferably 0.4~1, more preferably 0.5~0.9.

在本發明的一個實施方式中，二油酸甘油酯和大豆PC的含量之和為40~79重量%，較佳為50~75重量%。In one embodiment of the present invention, the sum of the contents of diolein and soybean PC is 40 to 79% by weight, preferably 50 to 75% by weight.

在本發明的一個實施方式中，塞納布啡與甲磺酸的重量比為5~15:1，例如6~15:1，7.5~15:1，9~15: 1，6~10:1或6~15:1等；更具體地，例如6:1，7.5:1，8:1，9:1，9.3:1，9.4:1，9.5:1，10:1，11:1，12:1，或15:1等。In one embodiment of the invention, the weight ratio of senabuphine to methanesulfonic acid is 5~15:1, such as 6~15:1, 7.5~15:1, 9~15:1, 6~10:1 Or 6~15:1, etc.; more specifically, such as 6:1, 7.5:1, 8:1, 9:1, 9.3:1, 9.4:1, 9.5:1, 10:1, 11:1, 12 :1, or 15:1, etc.

在本發明的一個實施方式中，二甲基乙醯胺的含量為15~42重量%，較佳為15~35重量%。In one embodiment of the present invention, the content of dimethylacetamide is 15 to 42% by weight, preferably 15 to 35% by weight.

在本發明的一個實施方式中，馬來酸的含量為0~0.2重量%，較佳為0~0.02重量%，較佳為0~0.01重量%。In one embodiment of the present invention, the content of maleic acid is 0~0.2% by weight, preferably 0~0.02% by weight, preferably 0~0.01% by weight.

在本發明的另一個實施方案中，所述的藥物組合物是由以下組分組成： (a)二油酸甘油酯； (b)大豆PC； (c)二甲基乙醯胺； (d)甲磺酸和任選含有的馬來酸； (e)塞納布啡； 其中，二油酸甘油酯和大豆PC的含量之和為40~79重量%，較佳為50~75重量%； 塞納布啡的含量為5~20重量%；較佳為7.5~15重量%，例如10~11重量%； 塞納布啡與甲磺酸的重量比為5~15:1，例如6~15:1，7.5~15:1，9:15~1，6~10:1或6~15:1等；更具體地，例如6:1，7.5:1，8:1，9:1，9.3:1，9.4:1，9.5:1，10:1，11:1，12:1，或15:1等； 二甲基乙醯胺的含量為15~42重量%，較佳為15~35重量%； 馬來酸的含量為0~0.2重量%，較佳為0~0.01重量%； 所述重量百分比為相對於(a)、(b)、(c)、(d)和(e)的總重量而言； 進一步較佳的，組分(b)與組分(a)的比值按照重量計約0.1~1，較佳為0.4~1，更佳為0.5~0.9。 在一個實施方案中，組分(b)與組分(a)的重量比是使得所述藥物組合物可以順利通過國際通用標準注射器針頭，也可通過各種細針孔，例如18G或更小的針孔，23G或更小的針孔，27G或更小的針孔。 進一步的，所述藥物組合物，在20 ℃具有100~1000 cps的黏度，較佳具有100~500 cps的黏度，更佳具有200~400 cps的黏度。 In another embodiment of the invention, the pharmaceutical composition consists of the following components: (a) Diolein; (b) Soybean PC; (c) Dimethylacetamide; (d) methanesulfonic acid and optionally maleic acid; (e) Senabuphine; Among them, the sum of the contents of diolein and soybean PC is 40 to 79% by weight, preferably 50 to 75% by weight; The content of senabuphine is 5~20% by weight; preferably, it is 7.5~15% by weight, such as 10~11% by weight; The weight ratio of senabuphine to methanesulfonic acid is 5~15:1, such as 6~15:1, 7.5~15:1, 9:15~1, 6~10:1 or 6~15:1, etc.; more Specifically, for example, 6:1, 7.5:1, 8:1, 9:1, 9.3:1, 9.4:1, 9.5:1, 10:1, 11:1, 12:1, or 15:1, etc.; The content of dimethylacetamide is 15~42% by weight, preferably 15~35% by weight; The content of maleic acid is 0~0.2% by weight, preferably 0~0.01% by weight; The weight percentages are relative to the total weight of (a), (b), (c), (d) and (e); Further preferably, the ratio of component (b) to component (a) is about 0.1~1 by weight, preferably 0.4~1, more preferably 0.5~0.9. In one embodiment, the weight ratio of component (b) to component (a) is such that the pharmaceutical composition can smoothly pass through an international standard syringe needle, and can also pass through various fine needle holes, such as 18G or smaller. Pinhole, 23G or smaller pinhole, 27G or smaller pinhole. Further, the pharmaceutical composition has a viscosity of 100~1000 cps at 20°C, preferably a viscosity of 100~500 cps, and more preferably a viscosity of 200~400 cps.

進一步的，所述藥物組合物，在25 ℃具有30~1000 cps的黏度，例如，30~500 cps的黏度、30~400 cps的黏度、30~300 cps的黏度、30~200 cps的黏度、50~200 cps的黏度、50~300 cps的黏度、50~400 cps的黏度、100~500 cps的黏度、或200~400 cps的黏度及其之間的任意範圍，優選具有30~500 cps的黏度，例如50~300 cps的黏度或200~400 cps的黏度等。Further, the pharmaceutical composition has a viscosity of 30~1000 cps at 25°C, for example, a viscosity of 30~500 cps, a viscosity of 30~400 cps, a viscosity of 30~300 cps, a viscosity of 30~200 cps, A viscosity of 50~200 cps, a viscosity of 50~300 cps, a viscosity of 50~400 cps, a viscosity of 100~500 cps, or a viscosity of 200~400 cps and any range therebetween, preferably 30~500 cps Viscosity, such as 50~300 cps viscosity or 200~400 cps viscosity, etc.

在本發明中，所述的參數範圍選擇包括端點值，例如5~20重量%包括端點值「5%」和「20%」；比值範圍6~10:1包括「6:1」和「10:1」。特別是在提到給定的數值時，術語「約」指包括加或減5%的偏差，較佳為包括加或減3%的偏差，加或減2%的偏差，加或減1%的偏差，加或減0.5%的偏差。In the present invention, the parameter range selection includes endpoint values, for example, 5~20% by weight includes the endpoint values "5%" and "20%"; the ratio range 6~10:1 includes "6:1" and "10:1". In particular when referring to a given numerical value, the term "about" is meant to include a deviation of plus or minus 5%, preferably plus or minus 3%, plus or minus 2%, plus or minus 1% Deviation, plus or minus 0.5% deviation.

「任選的」、「任選」或「任選地」是指隨後描述的事件或情形可以但不一定出現，並且該描述包括其中所述事件或情形出現的情況和不出現的情況。"Optional," "optionally," or "optionally" means that the subsequently described event or circumstance may but need not occur, and that the description includes instances where the stated event or circumstance occurs and instances where it does not occur.

術語「包含」為開放式表達，即包括本發明所指明的內容，但並不排除其他方面的內容。應當理解，術語「包含」可以涵蓋封閉式的含義，即「由…組成」。The term "comprising" is an open expression, which includes the contents specified in the present invention, but does not exclude other aspects. It should be understood that the term "comprising" can encompass a closed meaning, i.e. "consisting of."

本發明所提供藥物組合物較佳為通過胃腸外施用。在某些實施例中，該組合物被配製以便通過針頭遞送到宿主中，該施用通常通過皮下注射或肌肉注射進行施用。The pharmaceutical composition provided by the present invention is preferably administered parenterally. In certain embodiments, the compositions are formulated for delivery to the host via a needle, with administration typically by subcutaneous or intramuscular injection.

本發明所提供的藥物組合物，關鍵在於提供塞納布啡可注射用的藥物組合物，所述組合物穩定性好，黏度低，特別是所述組合物可使用18G至23G規格的針頭進行注射。另一方面，與目前現有技術中的塞納布啡的注射組合物相比，採用非油性製劑配方，能夠減少注射部位疼痛，減少過敏反應的發生，提高疼痛管理中患者用藥順應性。The key point of the pharmaceutical composition provided by the present invention is to provide an injectable pharmaceutical composition of senabuphine. The composition has good stability and low viscosity. In particular, the composition can be injected using a needle of 18G to 23G specifications. . On the other hand, compared with the injection composition of senabuphine in the current prior art, the non-oily formulation can reduce pain at the injection site, reduce the occurrence of allergic reactions, and improve patient medication compliance in pain management.

此外，本發明提供的藥物組合物避免了表面活性劑的使用，減少了血管刺激性和溶血風險。而在更佳的實施方案中通過酸特別是甲磺酸的加入，解決了製劑組合物中塞納布啡析晶混懸的問題，從而顯著提高了塞納布啡藥物組合物的穩定性和可通針性。In addition, the pharmaceutical composition provided by the present invention avoids the use of surfactants and reduces the risk of vascular irritation and hemolysis. In a better embodiment, the addition of acid, especially methanesulfonic acid, solves the problem of crystallization and suspension of senabuphine in the preparation composition, thereby significantly improving the stability and accessibility of the senabuphine pharmaceutical composition. Targeted.

本發明所提供的藥物組合物，還因為獨特的高載藥量的特性，注射體積較佳為不超過3 mL/每次施用，更佳為不超過2 mL/每次施用。在一個實施例方案中，在單位制劑中，所述的藥物組合物至少包括100~180 mg，例如100 mg、120 mg、150 mg、180 mg等，較佳為150 mg的塞納布啡。Due to the unique high drug loading characteristics of the pharmaceutical composition provided by the present invention, the injection volume is preferably no more than 3 mL/each administration, and more preferably no more than 2 mL/each administration. In one embodiment, in a unit preparation, the pharmaceutical composition includes at least 100 to 180 mg, such as 100 mg, 120 mg, 150 mg, 180 mg, etc., preferably 150 mg of senabuphine.

進一步，較佳的本發明所述藥物組合物的單位制劑體積為1.0~2.0 ml，例如1.0 ml~1.5 ml、1.5~2.0 ml或1.8~2.0 ml，更佳為1.0 ml~1.5 ml，其中至少塞納布啡含量為150 mg的塞納布啡。其中本發明所述的單位制劑具有本領域常規的含義，是指藥品中能夠拆分的最小給藥單位或最小給付單位或最小包裝單位，例如片劑的單位制劑為一片，膠囊劑的單位制劑為一粒，散劑的單位制劑為一瓶，袋的單位制劑為一盒，注射劑的單位制劑為一支。Further, the preferred unit preparation volume of the pharmaceutical composition of the present invention is 1.0~2.0 ml, such as 1.0 ml~1.5 ml, 1.5~2.0 ml or 1.8~2.0 ml, more preferably 1.0 ml~1.5 ml, wherein at least Senabuphine content is 150 mg of Senabuphine. The unit preparation described in the present invention has the conventional meaning in this field, and refers to the smallest dosing unit or the smallest delivery unit or the smallest packaging unit that can be divided into medicines. For example, the unit preparation of a tablet is one piece, and the unit preparation of a capsule is one piece. The unit preparation of powder is one bottle, the unit preparation of bag is one box, and the unit preparation of injection is one tube.

本發明的一個顯著優點還在於，所述藥物組合物中，塞納布啡起效快，並且能夠經過較長時間釋放，持續起效；與現有技術相比，解決了納疼解需要術前提前一天給藥的問題；並且本發明提供的藥物組合物還能解決藥物濫用的問題。A significant advantage of the present invention is that in the pharmaceutical composition, senabuphine has a quick onset of action, can be released over a long period of time, and has sustained onset of action; compared with the prior art, it solves the need for preoperative treatment of narcotic pain relief. The problem of daily administration; and the pharmaceutical composition provided by the invention can also solve the problem of drug abuse.

本發明所提供的藥物組合物，一般充填於預填充裝置進行臨床應用，例如預灌封注射器，或者採用西林瓶罐裝。在一個實施例方案中，因本發明所提供的藥物組合物具有較低的黏度，因而具有良好的通針性。本發明的藥物組合物可以順利通過國際通用標準注射器針頭，也可通過各種細針孔，例如18G或更小的針孔，23G或更小的針孔，27G或更小的針孔。The pharmaceutical composition provided by the present invention is generally filled in a pre-filled device for clinical application, such as a pre-filled syringe, or canned in a vial. In one embodiment, the pharmaceutical composition provided by the present invention has low viscosity and therefore has good needle penetration. The pharmaceutical composition of the present invention can pass through the international standard syringe needle smoothly, and can also pass through various fine needle holes, such as 18G or smaller needle holes, 23G or smaller needle holes, and 27G or smaller needle holes.

在本發明中，國際通用標準注射器針頭18G、23G、27G尺寸如下所示：    內徑 外徑 27G 約0.2 mm 約0.41 mm 23G 約0.33 mm 約0.63 mm 18G 約0.81 mm 約1.27mm In the present invention, the sizes of internationally accepted standard syringe needles 18G, 23G, and 27G are as follows: inner diameter outer diameter 27G About 0.2 mm About 0.41 mm 23G About 0.33 mm About 0.63 mm 18G About 0.81mm About 1.27mm

本文中組分(d)所用的「酸」通常是在水性介質(即水)中形成酸性溶液的低分子量化合物。這些酸通常具有小於6的pKa，或小於5的pKa，較佳為小於4.7，最佳為小於4.5。由於所述酸是作為胃腸外藥物釋放系統的一部分施用的，所以在相關量中的生物相容性也是必需的。合適的酸在本文中較佳為甲磺酸、馬來酸、對甲苯磺酸、乙酸、富馬酸、檸檬酸、磷酸二氫鈉或鹽酸。特別較佳的為有機酸，選自甲磺酸、馬來酸、乙酸、富馬酸、檸檬酸。最佳的酸為甲磺酸和馬來酸中的至少一種。"Acid" as used herein for component (d) is generally a low molecular weight compound that forms an acidic solution in an aqueous medium (ie, water). These acids generally have a pKa of less than 6, or less than 5, preferably less than 4.7, most preferably less than 4.5. Since the acid is administered as part of a parenteral drug delivery system, biocompatibility in relevant amounts is also necessary. Suitable acids here are preferably methanesulfonic acid, maleic acid, p-toluenesulfonic acid, acetic acid, fumaric acid, citric acid, sodium dihydrogen phosphate or hydrochloric acid. Particularly preferred are organic acids, selected from methanesulfonic acid, maleic acid, acetic acid, fumaric acid, and citric acid. The most preferred acid is at least one of methanesulfonic acid and maleic acid.

本發明第二方面還提供了所述的藥物組合物的製備方法，包括以下步驟： 方法一、將處方比例的塞納布啡、酸溶解於含氧有機溶劑中，然後加入醯基甘油，最後加入磷脂醯膽鹼，溶解即得；或者， 方法二、先將處方比例的酸加入到有機溶劑中，然後依次加入醯基甘油、磷脂醯膽鹼攪拌溶解，最後加入塞納布啡，攪拌溶解即得。 A second aspect of the present invention also provides a preparation method of the pharmaceutical composition, which includes the following steps: Method 1: Dissolve the prescribed proportion of senabuphine and acid in an oxygen-containing organic solvent, then add acylglycerol, and finally add phosphatidylcholine and dissolve; or, Method 2: First add the acid in the prescribed proportion to the organic solvent, then add acylglycerol and phosphatidylcholine in sequence, stir and dissolve, and finally add senabuphine, stir and dissolve.

在本發明所述的製備方法一和方法二中，所述酸、含氧有機溶劑、醯基甘油和磷脂醯膽鹼定義如前述。In the preparation method one and method two of the present invention, the acid, oxygen-containing organic solvent, acylglycerol and phosphatidylcholine are as defined above.

在一個具體實施方案中，所述的藥物組合物的製備方法，包括以下步驟： 將處方比例的塞納布啡、甲磺酸和馬來酸溶於N-甲基吡咯烷酮中，然後加入二油酸甘油酯攪拌，最後加入大豆PC，溶解即得；或者， 按照處方比例，先將甲磺酸和馬來酸溶於N-甲基吡咯烷酮中，然後加入二油酸甘油酯攪拌、再加入大豆PC攪拌溶解，最後加入塞納布啡，攪拌溶解即得。 In a specific embodiment, the preparation method of the pharmaceutical composition includes the following steps: Dissolve the prescribed ratio of senabuphine, methanesulfonic acid and maleic acid in N-methylpyrrolidone, then add glyceryl diolein and stir, finally add soybean PC and dissolve; or, According to the prescription proportion, first dissolve methanesulfonic acid and maleic acid in N-methylpyrrolidone, then add glyceryl diolein and stir, then add soybean PC and stir to dissolve, and finally add senabuphine, stir and dissolve to get it.

在另一個具體實施方案中，所述的藥物組合物的製備方法，包括以下步驟： 將處方比例的塞納布啡、甲磺酸和任選進一步含有的馬來酸溶於二甲基乙醯胺中，然後加入二油酸甘油酯攪拌，最後加入大豆PC，溶解即得；或者， 按照處方比例，先將甲磺酸和任選進一步含有的馬來酸溶於二甲基乙醯胺中，然後加入二油酸甘油酯攪拌、再加入大豆PC攪拌溶解，最後加入塞納布啡，攪拌溶解即得。 較佳的，上述方法在加入磷脂醯膽鹼溶解時，先將混合物加熱至不超過45 ℃，較佳的加熱至40 ℃，可顯著加快溶解速度。 In another specific embodiment, the preparation method of the pharmaceutical composition includes the following steps: Dissolve the prescription ratio of senabuphine, methanesulfonic acid and optionally further maleic acid in dimethylacetamide, then add glyceryl diolein and stir, finally add soybean PC and dissolve; or, According to the prescription proportion, first dissolve methanesulfonic acid and optionally further maleic acid in dimethylacetamide, then add glyceryl diolein and stir, then add soybean PC and stir to dissolve, and finally add senabuphine, Stir to dissolve. Preferably, when adding phosphatidylcholine to dissolve in the above method, the mixture is first heated to no more than 45°C, preferably to 40°C, which can significantly speed up the dissolution rate.

本發明的一些實施方案中，本發明的製備方法還包含將所述製備得到的組合物以通過0.22 μm無菌過濾膜的方式進行過濾除菌。In some embodiments of the present invention, the preparation method of the present invention further includes filtering and sterilizing the prepared composition through a 0.22 μm sterile filter membrane.

在本發明第三方面還提供了所述的藥物組合物在製備治療疼痛藥物中的用途。In the third aspect of the present invention, the use of the pharmaceutical composition in preparing pain treatment drugs is also provided.

本發明還提供一種治療疼痛的方法，其包括向有需要的個體(例如哺乳動物個體，如人)給藥本發明所述的藥物組合物。The present invention also provides a method of treating pain, comprising administering a pharmaceutical composition of the present invention to an individual in need thereof (eg, a mammalian individual, such as a human).

本發明所述疼痛選自外科手術疼痛或長期慢性疼痛。所述外科手術包括但不限於常見類型的普通外科手術，如疝氣手術、痔瘡手術、腹部手術、整形科手術、骨科手術、耳鼻喉科手術等；所述長期慢性疼痛包括但不限於癌痛、慢性後背疼痛和慢性關節疼痛等。除非有其他說明，否則本文中所有的百分數均為重量比。所述藥物組合物可基本上僅由這些組分組成，並且在一個方面中完全由這些組分組成。The pain described in the present invention is selected from surgical pain or long-term chronic pain. The surgical operations include but are not limited to common types of general surgical operations, such as hernia surgery, hemorrhoid surgery, abdominal surgery, plastic surgery, orthopedic surgery, otolaryngology surgery, etc.; the long-term chronic pain includes but is not limited to cancer pain, Chronic back pain and chronic joint pain, etc. Unless otherwise stated, all percentages herein are by weight. The pharmaceutical composition may consist essentially only of, and in one aspect entirely of, these components.

下面詳細描述本發明的實施例。下面描述的實施例是示例性的，僅用於解釋本發明，而不能理解為對本發明的限制。除非另外指明，本文所指的比例、百分比等均以重量計。Embodiments of the present invention are described in detail below. The embodiments described below are illustrative and are only used to explain the present invention and are not to be construed as limitations of the present invention. Unless otherwise specified, proportions, percentages, etc. referred to herein are by weight.

試劑 塞納布啡（來源：自製）；納布啡（來源：賽諾菲）；大豆PC（來源：瀋陽天峰生物製藥有限公司）；二油酸甘油酯（來源：英國Croda公司）；納疼解（來源：順天醫藥生技股份有限公司）； 設備 黏度計：SNB-1，上海天美； 溶出儀：Logan 850DL 全自動溶出取樣系統； 高效液相管柱層析：Agilent 1260 Infinity 液相管柱層析儀； pH計：Mettler Toledo FiveEasy Plus； Reagents Senabuphine (source: self-made); Nalbuphine (source: Sanofi); Soybean PC (Source: Shenyang Tianfeng Biopharmaceutical Co., Ltd.); Glyceryl dioleate (Source: British Croda Company); Natongjie (Source: Shuntian Pharmaceutical Biotechnology Co., Ltd.); equipment Viscometer: SNB-1, Shanghai Tianmei; Dissolution apparatus: Logan 850DL fully automatic dissolution sampling system; High performance liquid phase column chromatography: Agilent 1260 Infinity liquid phase column chromatography; pH meter: Mettler Toledo FiveEasy Plus;

實施例1 溶解度測試 在本發明中，經過研究發現（參照中國藥典2015版四部＜凡例＞溶解度測定方法），所述的藥物組合物中的活性成分塞納布啡與其代謝物納布啡差異較大，塞納布啡與納布啡在不同緩衝液中的溶解度不同，具體溶解度差異如下表1所示。 表1：塞納布啡與納布啡溶解度差異 介質 納布啡 塞納布啡 所用介質體積 近似溶解度 所用介質體積 近似溶解度 pH1.2鹽酸溶液 0.2 mL 易溶 3 mL 溶解 pH3.8醋酸鹽溶液 0.2 mL 易溶 25 mL 微溶 pH6.0磷酸鹽溶液 0.3 mL 易溶 130 mL 極微溶解 水 0.3 mL 易溶 340 mL 極微溶解 pH7.4磷酸鹽溶液 0.3 mL 易溶 ＞1000 mL 幾乎不溶 結果 從上述表1內容可知，納布啡和塞納布啡在模擬人體緩衝液中，溶解度差異較大，而活性成分的溶解度對於製劑處方研究中具有重要意義，因此在研究賽納布啡處方時參考納布啡的意義不大。 Example 1 Solubility Test In the present invention, it was found through research (referring to the Chinese Pharmacopoeia 2015 Edition Part 4 <General Examples> Solubility Determination Method) that the active ingredient senabuphine in the pharmaceutical composition is significantly different from its metabolite nalbuphine. The solubility of senabuphine and nalbuphine in different buffers is different. The specific solubility differences are shown in Table 1 below. Table 1: Differences in solubility between senabuphine and nalbuphine medium Nalbuphine sennabuphine Volume of media used Approximate solubility Volume of media used Approximate solubility pH1.2 hydrochloric acid solution 0.2mL Soluble 3mL Dissolve pH3.8 acetate solution 0.2mL Soluble 25mL Slightly soluble pH6.0 phosphate solution 0.3mL Soluble 130mL Very slightly soluble water 0.3mL Soluble 340mL Very slightly soluble pH7.4 phosphate solution 0.3mL Soluble >1000mL Almost insoluble Results From the above table 1, it can be seen that the solubility difference between nalbuphine and senabuphine in simulated human body buffer is large, and the solubility of active ingredients is of great significance in the preparation formulation research. Therefore, when studying the senabuphine prescription Reference to nalbuphine makes little sense.

實施例2 溶劑對塞納布啡穩定性的影響 稱量適量塞納布啡，用pH3.8的醋酸鹽緩衝液配置成約3 μg/mL，加入2%(v/v)乙醇或NMP，分別在0 min、10 min、30 min、60 min進行HPLC檢測，HPLC方法如下所述。 液相管柱層析檢測（安捷倫1260），色譜柱ZORBAX SB-Aq，4.6×150，5 μm。管柱層析條件：A相（稱取3.85 g乙酸銨加入到1000 mL超純水中，超音波溶解，加入3 mL乙酸，過0.45 μm濾膜，超音波15 min後待用）：B相（乙腈）=40%：60%(v/v)；柱溫箱：40 ℃；進樣器：25 ℃；流速：1.5 mL/min；波長：278 nm。進樣量10 μL，按外標法，以不同取樣時間點的峰面積相對於0 min的峰面積百分比，通過峰面積計算塞納布啡在不同時間點的含量。結果如下表2和表3所示。 表2：塞納布啡在NMP中的含量變化 時間 塞納布啡峰面積(NMP) 峰面積百分比 0 min 917.312 100.0% 10 min 910.237 99.2% 30 min 923.139 100.6% 60 min 915.091 99.8% 表3：塞納布啡在乙醇中的含量變化 時間 塞納布啡峰面積（乙醇） 峰面積百分比 0 min 919.367 100.0% 10 min 910.123 99.0% 30 min 891.659 97.0% 60 min 844.870 91.9% 結果 通過上述表2和表3的結果可知，塞納布啡在乙醇中不穩定，第60分鐘後含量下降顯著，僅為91.9%，說明塞納布啡在乙醇中容易降解產生雜質；而塞納布啡在NMP中的含量穩定，第60分鐘的測定值幾乎與最初測定值（第0分鐘）無任何變化，說明塞納布啡在NMP中穩定，NMP為適宜塞納布啡的溶劑。 Example 2 Effect of solvents on the stability of senabuphine. Weigh an appropriate amount of senabuphine, use acetate buffer with pH 3.8 to prepare it to about 3 μg/mL, add 2% (v/v) ethanol or NMP, respectively, at 0 min, 10 min, 30 min, and 60 min for HPLC detection. The HPLC method is as follows. Liquid phase column chromatography detection (Agilent 1260), chromatographic column ZORBAX SB-Aq, 4.6×150, 5 μm. Column chromatography conditions: Phase A (weigh 3.85 g of ammonium acetate and add it to 1000 mL of ultrapure water, dissolve it with ultrasonic waves, add 3 mL of acetic acid, pass through a 0.45 μm filter, and ultrasonic for 15 minutes before use): Phase B (acetonitrile) = 40%: 60% (v/v); column oven: 40 ℃; injector: 25 ℃; flow rate: 1.5 mL/min; wavelength: 278 nm. The injection volume was 10 μL. According to the external standard method, the peak area at different sampling time points was compared to the peak area percentage at 0 min. The content of senabuphine at different time points was calculated based on the peak area. The results are shown in Tables 2 and 3 below. Table 2: Content changes of senabuphine in NMP time Sennabuphine peak area (NMP) Peak area percentage 0 min 917.312 100.0% 10 minutes 910.237 99.2% 30 minutes 923.139 100.6% 60 minutes 915.091 99.8% Table 3: Content changes of senabuphine in ethanol time Senabuphine peak area (ethanol) Peak area percentage 0 min 919.367 100.0% 10 minutes 910.123 99.0% 30 minutes 891.659 97.0% 60 minutes 844.870 91.9% Results From the results in Table 2 and Table 3 above, it can be seen that senabuphine is unstable in ethanol, and the content dropped significantly after 60 minutes, only 91.9%, indicating that senabuphine is easily degraded in ethanol to produce impurities; while senabuphine The content in NMP is stable, and the measured value at 60 minutes has almost no change from the initial measured value (at 0 minutes), indicating that senabuphine is stable in NMP, and NMP is a suitable solvent for senabuphine.

實施例3 塞納布啡藥物組合物的製備方法 方法一：將處方比例的塞納布啡，酸攪拌溶於NMP，再加入GDO攪勻，最後加入大豆PC溶解，製備得到塞納布啡藥物組合物。 方法二：將處方比例的酸攪拌溶於NMP，再加入GDO攪勻，接著加入大豆PC攪拌溶解，最後加入塞納布啡攪拌溶解，製備得到塞納布啡藥物組合物。 上述步驟中大豆PC溶解時可適當加熱至40 ℃，可顯著加快溶解速度。 處方如下表4.1和4.2所示。 表4.1：按方法一配製的塞納布啡藥物組合物單劑量處方 物料名稱 處方1 處方2 處方3 處方4 處方5 處方6 塞納布啡/mg 150 150 150 150 150 150 NMP/mg 450 350 400 400 400 400 GDO/mg 840 300 964 844 750 675 大豆PC/mg 560 200 385 506 600 675 大豆PC/GDO 0.7 0.7 0.4 0.6 0.8 1 甲磺酸/mg 15 15 20 20 20 20 馬來酸/mg 0.3 0.2 / / / / 載藥量 7.4% 14.8% 7.8% 7.8% 7.8% 7.8% 總計/mg 2015.3 1015.2 1919 1920 1920 1920 表4.2：按方法二配製的塞納布啡藥物組合物單劑量處方 物料名稱 處方12 處方13 處方18 處方19 處方26 處方42 處方46 處方51 塞納布啡/mg 150 150 150 150 150 150 150 150 NMP/mg 350 350 350 400 350 450 400 450 GDO/mg 600 571 833 750 571 710 780 701 大豆 PC/mg 400 428 666 525 428 565 546 574 大豆PC/GDO 0.67 0.75 0.8 0.7 0.75 0.8 0.7 0.82 甲磺酸/mg 15 15 18 15 20 20 20 20 載藥量 9.9% 9.9% 7.4% 8.2% 9.9% 7.9% 7.9% 7.9% 總計 1515 1514 2017 1840 1519 1895 1896 1895    加0.01%馬來酸 Example 3 Preparation method of senabuphine pharmaceutical composition Method 1: Stir and dissolve the senabuphine and acid in the prescribed proportion in NMP, then add GDO and stir evenly, finally add soybean PC to dissolve, and prepare a senabuphine pharmaceutical composition. Method 2: Stir and dissolve the acid in the prescribed proportion into NMP, then add GDO and stir evenly, then add soybean PC and stir to dissolve, and finally add senabuphine and stir to dissolve, to prepare a senabuphine pharmaceutical composition. In the above steps, when soybean PC is dissolved, it can be appropriately heated to 40°C, which can significantly speed up the dissolution rate. The prescriptions are shown in Tables 4.1 and 4.2 below. Table 4.1: Single-dose prescription of senabuphine pharmaceutical composition prepared according to method 1 Material name Prescription 1 Prescription 2 Prescription 3 Prescription 4 Prescription 5 Prescription 6 Senabuphine/mg 150 150 150 150 150 150 NMP/mg 450 350 400 400 400 400 GDO/mg 840 300 964 844 750 675 Soybean PC/mg 560 200 385 506 600 675 Soybean PC/GDO 0.7 0.7 0.4 0.6 0.8 1 Methanesulfonic acid/mg 15 15 20 20 20 20 Maleic acid/mg 0.3 0.2 / / / / drug loading 7.4% 14.8% 7.8% 7.8% 7.8% 7.8% Total/mg 2015.3 1015.2 1919 1920 1920 1920 Table 4.2: Single-dose prescription of senabuphine pharmaceutical composition prepared according to method 2 Material name Prescription 12 Prescription 13 Prescription 18 Prescription 19 Prescription 26 Prescription 42 Prescription 46 Prescription 51 Senabuphine/mg 150 150 150 150 150 150 150 150 NMP/mg 350 350 350 400 350 450 400 450 GDO/mg 600 571 833 750 571 710 780 701 Soybean PC/mg 400 428 666 525 428 565 546 574 Soybean PC/GDO 0.67 0.75 0.8 0.7 0.75 0.8 0.7 0.82 Methanesulfonic acid/mg 15 15 18 15 20 20 20 20 drug loading 9.9% 9.9% 7.4% 8.2% 9.9% 7.9% 7.9% 7.9% total 1515 1514 2017 1840 1519 1895 1896 1895 Add 0.01% maleic acid

實施例4 通針性及黏度測試 將實施例3中製備的部分處方在常溫(25 ℃)下採用數位黏度計測定其黏度，其中轉子選擇4號轉子，轉速選擇60 rpm。並測定每個處方通過國際通用標準注射器針頭18G、23G、27G的情況。測試結果如下表5所示。 表5 通針性及黏度測試結果 處方 處方12 處方13 處方18 處方19 處方26 處方42 處方46 處方51 黏度/cps 220 315 348 245 293 298 268 317 通針性 27G √ × × √ × × × × 23G √ √ √ √ √ √ √ √ 18G √ √ √ √ √ √ √ √ √表示該處方能通過對應注射器針頭，×表示難以通過針頭。 結果表明：實施例3中的製備的塞納布啡藥物組合物黏度範圍在200~400 cps之間，且都能通過18G與23G的國際標準通用注射器針頭，部分處方可以通過27G針頭。 Example 4 Needle penetration and viscosity test The viscosity of some of the formulas prepared in Example 3 was measured using a digital viscometer at normal temperature (25°C). The rotor was No. 4 and the rotation speed was 60 rpm. And the performance of each prescription through the internationally accepted standard syringe needles 18G, 23G, and 27G was measured. The test results are shown in Table 5 below. Table 5 Test results of needle penetration and viscosity prescription Prescription 12 Prescription 13 Prescription 18 Prescription 19 Prescription 26 Prescription 42 Prescription 46 Prescription 51 Viscosity/cps 220 315 348 245 293 298 268 317 Acupuncture properties 27G √ × × √ × × × × 23G √ √ √ √ √ √ √ √ 18G √ √ √ √ √ √ √ √ √ indicates that the prescription can pass through the corresponding syringe needle, and × indicates that it is difficult to pass through the needle. The results show that the viscosity range of the senabuphine pharmaceutical composition prepared in Example 3 is between 200 and 400 cps, and it can pass through 18G and 23G international standard universal syringe needles, and some prescriptions can pass through 27G needles.

實施例5 不同處方的溶出度測試 將納疼解、本發明提供的處方1和處方2進行溶出度考察，溶出方法採用USP 2法即槳法，轉速為200 rpm，溶出介質為pH3.8的醋酸鹽緩衝溶液（溶出介質為900 mL），分別於5 min、30 min、60 min、120 min、240 min和360 min取樣5 mL，過濾後取續濾液進HPLC檢測，並計算其溶出度。試驗結果如圖1所示，說明本發明提供的藥物組合物具有與納疼解相當或者類似的溶出曲線。 將實施例3中製備的處方3、處方4、處方5、處方6進行溶出度實驗考察，溶出方法採用USP 1法即轉籃法，轉速為50 rpm，溶出介質中加入0.5%的SDS，分別於5 min、10 min、30 min、60 min、120 min、180 min、240 min和360 min取樣5 mL，過濾後取續濾液進HPLC檢測並計算其溶出度。 HPLC檢測條件：液相管柱層析檢測（安捷倫1260），管柱：島津ODS-3，4.6×250，5 μm。管柱層析條件：A相（稱取3.85 g乙酸銨加入到1000 mL超純水中，超音波溶解，加入3 mL乙酸，過0.45 μm濾膜，超音波15 min後待用）：B相（乙腈）=40%：60%(v/v)；柱溫箱：40 ℃；進樣器：25 ℃；流速：1.5 mL/min；波長：278 nm。進樣量60 μL，按外標法通過峰面積計算塞納布啡在不同時間點的含量。 結果（如圖2所示）表明，處方中磷脂醯膽鹼與油酸甘油酯的比例在0.4~1之間時溶出釋放效果較好，當比例為0.6~0.8之間時，溶出釋放效果最佳。 Example 5 Dissolution testing of different prescriptions The dissolution of Natongjie, Prescription 1 and Prescription 2 provided by the present invention is investigated. The dissolution method adopts USP 2 method, that is, the paddle method, the rotation speed is 200 rpm, and the dissolution medium is an acetate buffer solution with pH 3.8 (the dissolution medium is 900 mL), sample 5 mL at 5 min, 30 min, 60 min, 120 min, 240 min and 360 min respectively. After filtration, take the filtrate for HPLC detection and calculate its dissolution. The test results are shown in Figure 1, indicating that the pharmaceutical composition provided by the present invention has a dissolution profile that is equivalent to or similar to that of nanoalgesia. The dissolution experiments of Prescription 3, Prescription 4, Prescription 5 and Prescription 6 prepared in Example 3 were carried out. The dissolution method was USP 1 method, that is, the rotating basket method. The rotation speed was 50 rpm. 0.5% SDS was added to the dissolution medium. Sample 5 mL at 5 min, 10 min, 30 min, 60 min, 120 min, 180 min, 240 min and 360 min. After filtration, take the filtrate for HPLC testing and calculate its dissolution. HPLC detection conditions: liquid phase column chromatography detection (Agilent 1260), column: Shimadzu ODS-3, 4.6×250, 5 μm. Column chromatography conditions: Phase A (weigh 3.85 g of ammonium acetate and add it to 1000 mL of ultrapure water, dissolve it with ultrasonic waves, add 3 mL of acetic acid, pass through a 0.45 μm filter, and ultrasonic for 15 minutes before use): Phase B (acetonitrile) = 40%: 60% (v/v); column oven: 40 ℃; injector: 25 ℃; flow rate: 1.5 mL/min; wavelength: 278 nm. The injection volume was 60 μL, and the content of senabuphine at different time points was calculated through the peak area according to the external standard method. The results (shown in Figure 2) show that the dissolution and release effect is better when the ratio of phosphatidylcholine to glyceryl oleate in the prescription is between 0.4 and 1, and the best dissolution and release effect is when the ratio is between 0.6 and 0.8. good.

實施例6 單因素控制試驗 本實施例通過設計單因素控制實驗，採用方法二製備了含有不同酸的塞納布啡藥物組合物（處方如表6所示），靜置48 h，檢查其外觀與通針性。通針性測試具體方法為將注射器放置於注射器支撐裝置上，通過與力量感應元連接的柱型探頭對注射器活塞施加壓力，推動溶液通過注射器和針頭，直到將溶液推出針頭，計算溶液流出針頭的平均力。可順利通過者標記為「√」，不能通過者標記為「×」。 表6：4批塞納布啡藥物組合物處方及外觀和通針性 物料名稱 處方A01 處方A02 處方A03 處方A04 塞納布啡/mg 150 150 150 150 NMP/mg 450 450 450 450 大豆PC+GDO/mg 1000（400+600） 1000（400+600） 1000（400+600） 1000（400+600） 檸檬酸/mg 20 / / / 甲磺酸/mg / 20 / / 富馬酸/mg / / 20 / 乙酸/mg / / / 20 外觀 部分混懸 澄清 部分混懸 部分混懸 通針性 23G × √ × 差 18G √ √ √ √ 從以上結果可以看出，本發明所述的塞納布啡藥物組合物中，所述酸為檸檬酸、甲磺酸、富馬酸、或乙酸時，均能不同程度的抑制塞納布啡從製劑中結晶析出，均能夠通過18G針孔；並且與乙酸、檸檬酸、富馬酸相比，甲磺酸在抑制塞納布啡從製劑中結晶析出的效果更好，同時因能夠更好的抑制塞納布啡析出，製劑外觀為澄清，通針性更佳，能夠通過18G和23G針孔。富馬酸和檸檬酸組對組合物中塞納布啡析晶抑制效果相對較弱，製劑中含有部分粒徑較大的結晶顆粒，導致通針性相對甲磺酸組差一些。 進一步研究處方A01、處方A02、處方A04樣品的高溫60 ℃穩定性；將上述3批樣品同時放置在高溫60 ℃的穩定性試驗箱中，分別於0 W、1 W、2 W和4 W取樣檢測樣品外觀與純度。其中純度採用HPLC法測定，液相管柱層析檢測（安捷倫1260），管柱：Shim-pack CIST C8 ，4.6×250，3 μm。管柱層析條件：A相（量取1 L超純水，導入燒杯中，稱取辛烷磺酸鈉1.0795 g左右，攪拌均勻，用磷酸調節pH到2，過濾超音波後使用）；B相（乙腈），梯度洗脫 (MPA：90%→10%v/v)；柱溫箱：40 ℃；進樣器：25 ℃；流速：1.5 mL/min；波長：220 nm。進樣量3 μL。檢測結果如下表7所示。 表7：3批樣品穩定性研究結果 時間 / 0W 1W 2W 4W 批號 酸種類 純度 外觀 純度 外觀 純度 外觀 純度 外觀 處方A01 檸檬酸 97.3% 淡黃色 94.6% 黃色 87.2% 黃色 75.3% 黃色 處方A02 甲磺酸 97.3% 淡黃色 95.6% 黃色 87.7% 黃色 81.0% 黃色 處方A04 乙酸 97.5% 淡黃色 83.0% 黃色 72.3% 黃色 50.9% 深黃色 從表7的試驗結果可以看出，與檸檬酸組和乙酸組相比，甲磺酸組樣品在高溫60 ℃時的穩定性更好。 Example 6 Single-factor control experiment In this example, a single-factor control experiment was designed and method 2 was used to prepare senabuphine pharmaceutical compositions containing different acids (prescriptions are shown in Table 6). The compositions were left to stand for 48 hours and their appearance and composition were checked. Acupuncture properties. The specific method of the needle penetration test is to place the syringe on the syringe support device, apply pressure to the syringe piston through the cylindrical probe connected to the force sensing element, push the solution through the syringe and needle until the solution is pushed out of the needle, and calculate the flow rate of the solution out of the needle. average force. Those who can successfully pass are marked as "√", and those who cannot pass are marked as "×". Table 6: Prescriptions, appearance and needle penetration of 4 batches of senabuphine pharmaceutical compositions Material name Prescription A01 Prescription A02 Prescription A03 Prescription A04 Senabuphine/mg 150 150 150 150 NMP/mg 450 450 450 450 Soybean PC+GDO/mg 1000(400+600) 1000(400+600) 1000(400+600) 1000(400+600) Citric acid/mg 20 / / / Methanesulfonic acid/mg / 20 / / fumaric acid/mg / / 20 / Acetic acid/mg / / / 20 Appearance partially suspended clarify partially suspended partially suspended Acupuncture properties 23G × √ × Difference 18G √ √ √ √ It can be seen from the above results that in the senabuphine pharmaceutical composition of the present invention, when the acid is citric acid, methanesulfonic acid, fumaric acid, or acetic acid, it can inhibit senabuphine from the preparation to varying degrees. can pass through the 18G pinhole; and compared with acetic acid, citric acid, and fumaric acid, methanesulfonic acid has a better effect in inhibiting the crystallization and precipitation of senabuphine from the preparation. Buphine precipitates, the appearance of the preparation is clear, and the needle penetration is better, and it can pass through 18G and 23G pinholes. The fumaric acid and citric acid groups have a relatively weak inhibitory effect on the crystallization of senabuphine in the composition, and the preparation contains some crystal particles with larger particle sizes, resulting in poorer needle penetration than the methanesulfonic acid group. Further study the stability of prescription A01, prescription A02, and prescription A04 samples at high temperature 60 ℃; place the above three batches of samples in a high temperature 60 ℃ stability test chamber at the same time, and take samples at 0 W, 1 W, 2 W, and 4 W respectively. Test the sample appearance and purity. The purity was determined by HPLC method, liquid phase column chromatography detection (Agilent 1260), column: Shim-pack CIST C8, 4.6×250, 3 μm. Column chromatography conditions: Phase A (measure 1 L of ultrapure water, introduce it into a beaker, weigh about 1.0795 g of sodium octane sulfonate, stir evenly, adjust the pH to 2 with phosphoric acid, filter and use after ultrasonic wave); B Phase (acetonitrile), gradient elution (MPA: 90% → 10% v/v); column oven: 40 ℃; injector: 25 ℃; flow rate: 1.5 mL/min; wavelength: 220 nm. The injection volume is 3 μL. The test results are shown in Table 7 below. Table 7: Stability study results of 3 batches of samples time / 0W 1W 2W 4W Batch number Acid type Purity Appearance Purity Appearance Purity Appearance Purity Appearance Prescription A01 citric acid 97.3% light yellow 94.6% yellow 87.2% yellow 75.3% yellow Prescription A02 methanesulfonic acid 97.3% light yellow 95.6% yellow 87.7% yellow 81.0% yellow Prescription A04 Acetic acid 97.5% light yellow 83.0% yellow 72.3% yellow 50.9% dark yellow From the test results in Table 7, it can be seen that compared with the citric acid group and the acetic acid group, the methanesulfonic acid group samples have better stability at a high temperature of 60°C.

實施例7 穩定性試驗 本實施例配製了兩批樣品，處方如下表8所示；製備方法採用前述方法一。 表8：處方B01和處方B02樣品處方 物料名稱 處方B01 處方B02 塞納布啡/mg 150 150 NMP/mg 400 400 GDO/mg 600 600 大豆PC/mg 400 400 甲磺酸/mg 15 15 馬來酸/mg 0.3 0 將上述兩批樣品同時放置在高溫60 ℃的穩定性試驗箱中，分別於1周 (1 W)、2周 (2 W)和4周 (4 W)取樣檢測其外觀與純度，其中純度採用HPLC法測定，管柱層析條件同實施例6。 結果如下表9所示： 表9：處方B01和處方B02樣品穩定性試驗結果 時間 0 W 1 W 2 W 4 W 批號 純度 外觀 純度 外觀 純度 外觀 純度 外觀 處方B01 97.4% 淡黃色 93.7% 淡黃色 91.0% 黃色 84.8% 黃色 處方B02 97.5% 淡黃色 91.2% 黃色 88.3% 黃色 81.1% 深黃色 上述結果表明，在高溫60 ℃條件下，處方中加入少量的馬來酸在一定程度上可以提高塞納布啡的穩定性，減慢有關雜質的產生。 Example 7 Stability test In this example, two batches of samples were prepared. The prescriptions are shown in Table 8 below; the preparation method adopted the aforementioned method one. Table 8: Prescription B01 and Prescription B02 sample prescriptions Material name Prescription B01 Prescription B02 Senabuphine/mg 150 150 NMP/mg 400 400 GDO/mg 600 600 Soybean PC/mg 400 400 Methanesulfonic acid/mg 15 15 Maleic acid/mg 0.3 0 The above two batches of samples were placed in a stability test chamber at a high temperature of 60°C at the same time. Samples were taken at 1 week (1 W), 2 weeks (2 W) and 4 weeks (4 W) to test their appearance and purity. The purity was measured using Measured by HPLC method, column chromatography conditions were the same as Example 6. The results are shown in Table 9 below: Table 9: Stability test results of prescription B01 and prescription B02 samples time 0W 1 W 2W 4 W Batch number Purity Appearance Purity Appearance Purity Appearance Purity Appearance Prescription B01 97.4% light yellow 93.7% light yellow 91.0% yellow 84.8% yellow Prescription B02 97.5% light yellow 91.2% yellow 88.3% yellow 81.1% dark yellow The above results show that under high temperature conditions of 60°C, adding a small amount of maleic acid to the prescription can improve the stability of senabuphine to a certain extent and slow down the production of related impurities.

實施例8 以DMAC（二甲基乙醯胺）為溶劑的藥物組合物研究 8.1：本實施例配製了6個處方的藥物組合物，處方如下表8.1所示；製備方法採用前述方法一。黏度及通針性測試方法同實施例4。 表8.1：處方C01~處方C06藥物組合物處方及黏度、穩定性、通針性檢測結果 處方組成 物料名稱（單位：mg） 處方C01 處方C02 處方C03 處方C04 處方C05 處方C06 大豆PC/GDO 0.5 0.7 0.9 0.9 0.8 0.9 塞納布啡 150 150 150 150 150 150 N,N-二甲基乙醯胺（DMAC） 250 310 370 440 500 565 二油酸甘油酯（GDO） 700 604 507 470 420 370 大豆PC 370 420 457 425 350 320 甲磺酸 25 20 16 10 10 10 總量 1495 1504 1500 1495 1430 1415 檢測項 性狀 淡黃色 淡黃色 淡黃色 淡黃色 淡黃色 淡黃色 黏度/cps 262.71 174.37 147.50 70.00 50.41 39.45 2~8 ℃放置3天是否析晶 否 否 否 否 否 否 通針性 18G √ √ √ √ √ √ 23G √ √ √ √ √ √ 上述藥物組合物在2~8 ℃下放置3天無析晶現象，且具有18G和23G注射針頭的良好通針性。 Example 8 Research 8.1 on pharmaceutical compositions using DMAC (dimethylacetamide) as solvent: In this example, six prescriptions of pharmaceutical compositions were prepared. The prescriptions are shown in Table 8.1 below; the preparation method adopted the aforementioned method one. The viscosity and needle penetration test methods are the same as in Example 4. Table 8.1: Prescription C01 ~ Prescription C06 pharmaceutical composition prescription and viscosity, stability, and needle penetration test results Prescription composition Material name (unit: mg) Prescription C01 Prescription C02 Prescription C03 Prescription C04 Prescription C05 Prescription C06 Soybean PC/GDO 0.5 0.7 0.9 0.9 0.8 0.9 sennabuphine 150 150 150 150 150 150 N,N-dimethylacetamide (DMAC) 250 310 370 440 500 565 Glyceryl diolein (GDO) 700 604 507 470 420 370 Soy PC 370 420 457 425 350 320 methanesulfonic acid 25 20 16 10 10 10 total amount 1495 1504 1500 1495 1430 1415 Detection items Traits light yellow light yellow light yellow light yellow light yellow light yellow Viscosity/cps 262.71 174.37 147.50 70.00 50.41 39.45 Leave it at 2~8℃ for 3 days to see if crystallization occurs. no no no no no no Acupuncture properties 18G √ √ √ √ √ √ 23G √ √ √ √ √ √ The above pharmaceutical composition has no crystallization phenomenon when placed at 2-8°C for 3 days, and has good needle penetration properties of 18G and 23G injection needles.

8.2：穩定性 將上述6個處方的樣品分別置於40 ℃±5 ℃/RH75%±10%穩定性試驗箱中15天，25 ℃±5 ℃/RH60%±10%穩定性試驗箱中1個月，2~8 ℃冷藏箱中1個月，檢測性狀和純度。其中純度採用HPLC法檢測。檢測結果如下表8.2所示： 表8.2：處方C01~處方C06樣品穩定性檢測結果 批號 0天 40 ℃-15天 25 ℃-1M 2~8 ℃-1M 性狀 純度 性狀 純度 性狀 純度 性狀 純度 處方C01 淡黃色 99.32% 黃色略微加深 98.36% 淡黃色 99.04% 淡黃色 99.35% 處方C02 淡黃色 99.28% 黃色略微加深 98.52% 淡黃色 99.11% 淡黃色 99.35% 處方C03 淡黃色 99.31% 黃色略微加深 98.69% 淡黃色 99.16% 淡黃色 99.36% 處方C04 淡黃色 99.33% 黃色略微加深 98.84% 淡黃色 99.21% 淡黃色 99.43% 處方C05 淡黃色 99.38% 黃色略微加深 98.86% 淡黃色 99.24% 淡黃色 99.41% 處方C06 淡黃色 99.34% 黃色略微加深 98.90% 淡黃色 99.29% 淡黃色 99.41% 上述樣品在40 ℃下放置15天，純度未發生明顯改變；在25 ℃，以及2~8 ℃下放置1個月，純度未發生變化，說明樣品穩定性好。 本發明藥物組合物的常規存儲溫度為2~8 ℃，上述實施例6、7和8中的穩定性試驗（尤其是高溫穩定性試驗）充分證明本發明的藥物組合物（尤其是以NMP和/或DMAC為溶劑，含有甲磺酸並任選進一步含有馬來酸）穩定性好，能夠滿足常規存儲溫度條件下的長期穩定性要求。 8.2: Stability Place the samples of the above six prescriptions in a stability test chamber at 40 ℃±5 ℃/RH75%±10% for 15 days and a stability test chamber at 25 ℃±5 ℃/RH60%±10% for 1 Month, 1 month in a refrigerator at 2~8 ℃, and check the properties and purity. The purity is tested by HPLC method. The test results are shown in Table 8.2 below: Table 8.2: Stability test results of prescription C01~prescription C06 samples Batch number 0 days 40℃-15 days 25℃-1M 2~8℃-1M Traits Purity Traits Purity Traits Purity Traits Purity Prescription C01 light yellow 99.32% slightly darker yellow 98.36% light yellow 99.04% light yellow 99.35% Prescription C02 light yellow 99.28% slightly darker yellow 98.52% light yellow 99.11% light yellow 99.35% Prescription C03 light yellow 99.31% slightly darker yellow 98.69% light yellow 99.16% light yellow 99.36% Prescription C04 light yellow 99.33% slightly darker yellow 98.84% light yellow 99.21% light yellow 99.43% Prescription C05 light yellow 99.38% slightly darker yellow 98.86% light yellow 99.24% light yellow 99.41% Prescription C06 light yellow 99.34% slightly darker yellow 98.90% light yellow 99.29% light yellow 99.41% The purity of the above sample did not change significantly when it was placed at 40 ℃ for 15 days; when it was placed at 25 ℃ and 2~8 ℃ for 1 month, the purity did not change, indicating that the sample has good stability. The conventional storage temperature of the pharmaceutical composition of the present invention is 2~8°C. The stability tests (especially high temperature stability tests) in the above Examples 6, 7 and 8 fully prove that the pharmaceutical composition of the present invention (especially based on NMP and /or DMAC as a solvent, containing methanesulfonic acid and optionally further containing maleic acid) has good stability and can meet the long-term stability requirements under normal storage temperature conditions.

8.3 溶出度檢測： 將實施例8.1中製備的處方C01、處方C02、處方C04、處方C05共4個處方的樣品進行溶出度實驗考察，溶出方法採用USP 1法（同實施例5中記載的USP1法）；結果（如圖7所示）表明以DMAC為溶劑，PC與GDO重量比為0.5~0.9，塞納布啡與酸的重量比在5~15:1時的藥物組合物均具有良好的溶出釋放度，均具有緩釋效果。 8.3 Dissolution testing: Samples of four prescriptions including prescription C01, prescription C02, prescription C04, and prescription C05 prepared in Example 8.1 were subjected to a dissolution experiment. The dissolution method was the USP 1 method (same as the USP 1 method described in Example 5); the results were ( As shown in Figure 7), it shows that when DMAC is used as the solvent, the weight ratio of PC to GDO is 0.5~0.9, and the weight ratio of senabuphine to acid is 5~15:1, the pharmaceutical compositions all have good dissolution release. Has a sustained release effect.

生物測試例1：鎮痛強度試驗 方法及步驟： 動物：取體重合格的雄性SPF級SD雄性大鼠70隻，體重180-220，適應性飼養4天。 基礎值檢測：大鼠初篩，測試基礎值（至少測兩次，如果兩次結果差異太大，測試第三次，取平均值），剔除敏感型動物； 手術造模：除空白對照組外，其餘各組進行手術操作，7%水合氯醛作為麻醉劑，灌胃給藥體積6.3 ml/kg，碘伏對大鼠腳底手術部位進行表面消毒，從足跟部邊緣0.5 cm處向前作一1 cm縱向切口，包括皮膚、筋膜及蹠肌，縫合皮膚兩針，按壓止血及清潔傷口。 術後分組：術後24 h再次測試基礎值，平均分組，使得每組基礎值盡可能保持一致；大鼠分為7組，每組8隻：空白組、模型組、處方1組合物 (100 mpk)、處方1組合物 (75 mpk)、處方1組合物 (50 mpk)，以及納疼解 (100 mpk)、納疼解 (75 mpk)組。 給藥：造模後第二天，根據各組不同劑量，分別配製不同濃度溶液進行給藥，空白組、模型組、處方1各劑量組為背部皮下給藥，納疼解為右側大腿肌肉給藥。空白組和模型組溶媒為生理鹽水。 機械觸痛縮足閾值 (MWT)測試：軟體自動記錄造模後第30 min、4 h、28 h、76 h、124 h時間機械觸痛縮足閾值 (MWT)，使用Mann-whitney test進行統計學分析。MWT提高率(%)的計算公式為： MWT提高率(%)=(給藥組MWT值-模型組MWT值)/模型組MWT值×100 試驗結果如表10所示。 表10：處方1及納疼解鎮痛強度試驗結果 實驗組 處方1的組合物 納疼解 給藥劑量（mg/kg） 100 75 50 100 75 30min 各檢測時間點MWT提高率(%) 126.7 80.6 49.5 19.6 33.8 4h 90.5 28.9 3.3 30.0 40.8 28h 115.5 29.6 21.1 69.0 78.6 76h 28.0 -23.5 -2.4 24.1 16.3 124h 77.3 11.4 23.8 31.4 41.7 如圖3和表10所示，塞納布啡組合物組100 mpk在30 min、4 h、28 h (1 d)均顯示出顯著的鎮痛作用，納疼解100 mpk、75 mpk在28 h (1 d)顯示出顯著的鎮痛作用，說明與納疼解組相比，本發明提供的塞納布啡藥物組合物組起效時間快，劑量小，鎮痛作用顯著。並且塞納布啡組合物100 mpk組鎮痛作用時間顯著優於納疼解100 mpk組。 76 h和124 h測量的處方1的組合物與納疼解組在疼痛緩解方面並沒有明顯區別，這可能是由於76小時後，模型中大鼠疼痛開始消失導致。根據實驗過程中觀察到的大鼠傷口癒合情況以及文獻報導 (Pain, 64 (1996) 493-501)可知，76小時後，模型中大鼠疼痛開始消失。 Biological test example 1: Analgesic intensity test method and steps: Animals: 70 male SPF grade SD male rats with qualified body weight, weighing 180-220, were adaptively raised for 4 days. Basic value detection: Preliminary screening of rats, test the basic value (at least twice, if the two results are too different, test a third time, take the average), and eliminate sensitive animals; Surgical modeling: Except for the blank control group , the remaining groups performed surgical operations, 7% chloral hydrate was used as an anesthetic, and the intragastric administration volume was 6.3 ml/kg. The surface of the surgical site on the sole of the rat's foot was disinfected with iodophor, and a 1-inch incision was made forward from 0.5 cm from the edge of the heel. cm longitudinal incision, including skin, fascia and plantaris muscle, suture the skin with two stitches, apply pressure to stop bleeding and clean the wound. Postoperative grouping: The basal values were tested again 24 hours after the operation, and the groups were averaged to keep the basal values of each group as consistent as possible; the rats were divided into 7 groups, 8 rats in each group: blank group, model group, prescription 1 composition (100 mpk), Prescription 1 composition (75 mpk), Prescription 1 composition (50 mpk), and Natongjie (100 mpk), Natongjie (75 mpk) groups. Administration: On the second day after modeling, solutions of different concentrations were prepared according to different dosages in each group for administration. The blank group, model group, and prescription 1 dosage groups were administered subcutaneously on the back, and Natongjie was administered subcutaneously on the right thigh muscle. Medicine. The vehicle of the blank group and model group was physiological saline. Mechanical tenderness and withdrawal threshold (MWT) test: The software automatically records the mechanical tenderness and withdrawal threshold (MWT) at 30 minutes, 4 hours, 28 hours, 76 hours, and 124 hours after modeling, and the Mann-whitney test is used for statistics. Study analysis. The calculation formula for the MWT increase rate (%) is: MWT increase rate (%) = (MWT value of the drug group - MWT value of the model group)/MWT value of the model group × 100. The test results are shown in Table 10. Table 10: Prescription 1 and analgesic strength test results experimental group Composition of Recipe 1 pain relief Dosage (mg/kg) 100 75 50 100 75 30min MWT improvement rate at each testing time point (%) 126.7 80.6 49.5 19.6 33.8 4h 90.5 28.9 3.3 30.0 40.8 28h 115.5 29.6 21.1 69.0 78.6 76h 28.0 -23.5 -2.4 24.1 16.3 124h 77.3 11.4 23.8 31.4 41.7 As shown in Figure 3 and Table 10, the senabuphine composition group 100 mpk showed significant analgesic effects at 30 min, 4 h, and 28 h (1 d). 1 d) showed a significant analgesic effect, indicating that compared with the naralgeon group, the senabuphine pharmaceutical composition group provided by the invention has a faster onset of action, a smaller dose, and a significant analgesic effect. Moreover, the analgesic effect time of the senabuphine composition 100 mpk group was significantly better than that of the natongjie 100 mpk group. There was no significant difference in pain relief between the composition of Prescription 1 and the nalnoide group measured at 76 hours and 124 hours, which may be due to the fact that after 76 hours, the pain in the rats in the model began to disappear. According to the wound healing conditions of rats observed during the experiment and literature reports (Pain, 64 (1996) 493-501), it can be seen that after 76 hours, the pain in the rats in the model began to disappear.

生物測試例2：藥代動力學研究 動物及分組：取體重合格的雄性SPF級SD雄性大鼠20隻，體重180-220 g，適應性飼養4天后，隨機分為5組，塞納布啡組（處方13給藥組、處方18給藥組、處方42給藥組、處方46給藥組）、納疼解組，每組4隻。 給藥：塞納布啡組合物組每隻大鼠皮下給藥（按納布啡計75 mpk），納疼解組每隻大鼠右側大腿肌肉給藥（按納布啡計75 mpk）。 採樣及檢測：分別於給藥後0 min、30 min、2 h、4 h、6 h、8 h、12 h、24 h、48 h、72 h、96 h、120 h、144 h、168 h大鼠眼眶採血，血液樣品應在採集後20 min內離心取血漿，離心前血液樣品置於碎冰上。離心取得的血漿樣品儲存在-80 ℃冷凍冰箱內直至檢測分析。離心條件：4-10 ℃，6000 rpm，5分鐘。用LCMSMS檢測血樣中納布啡濃度，計算PK參數。 納布啡在小鼠體內的有效血藥濃度約為25 ng/mL，如圖4所示，試驗結果表明，本發明方案提供的塞納布啡藥物組合物的起效時間小於30 min，可術後及時給藥，而納疼解起效時間為12~24 h，需要術前1天給藥。 採用同樣的方法，測試前述處方C03的藥物組合物，測試結果如圖5所示。納布啡在小鼠體內的有效血藥濃度約為25 ng/mL，藥代動力學研究表明，處方C03能在30 min內達到高於200 ng/mL的血藥濃度，且在給藥後168 h內保持高於25 ng/mL的血藥濃度，說明以DMAC為溶劑的處方可在給藥後的30 min內起效，可術後及時給藥，且藥效持續時間長，可降低給藥頻次。 Biological test example 2: pharmacokinetic study Animals and groupings: 20 male SPF grade SD male rats with qualified body weight, weighing 180-220 g, were adaptively raised for 4 days and randomly divided into 5 groups: senabuphine group (prescription 13-administration group, prescription 18-administration group). medicine group, prescription 42 administration group, prescription 46 administration group), natongjie group, each group has 4 animals. Administration: Each rat in the senabuphine composition group was administered subcutaneously (75 mpk based on nalbuphine), and each rat in the nalbuphine group was administered to the right thigh muscle (75 mpk based on nalbuphine). Sampling and detection: 0 min, 30 min, 2 h, 4 h, 6 h, 8 h, 12 h, 24 h, 48 h, 72 h, 96 h, 120 h, 144 h, 168 h after administration Blood is collected from the rat orbit. The blood sample should be centrifuged within 20 minutes after collection to obtain plasma. The blood sample should be placed on crushed ice before centrifugation. Plasma samples obtained by centrifugation were stored in a -80°C freezer until analysis. Centrifugation conditions: 4-10°C, 6000 rpm, 5 minutes. LCMSMS was used to detect the concentration of nalbuphine in blood samples and calculate the PK parameters. The effective blood concentration of nalbuphine in mice is about 25 ng/mL, as shown in Figure 4. The test results show that the onset time of the nalbuphine pharmaceutical composition provided by the scheme of the present invention is less than 30 minutes and can be used for surgery. The drug should be administered in time after surgery, while the onset time of Natongjie is 12 to 24 hours, and it needs to be administered 1 day before surgery. Using the same method, the pharmaceutical composition of the aforementioned prescription C03 was tested, and the test results are shown in Figure 5. The effective blood concentration of nalbuphine in mice is about 25 ng/mL. Pharmacokinetic studies show that prescription C03 can reach a blood concentration higher than 200 ng/mL within 30 minutes, and after administration The blood concentration remained higher than 25 ng/mL within 168 hours, indicating that the prescription using DMAC as a solvent can take effect within 30 minutes after administration, can be administered promptly after surgery, and has a long duration of drug effect, which can reduce Frequency of dosing.

測試例3、給藥刺激性檢測 採用2.5 ml注射器給大鼠大腿外側皮下給與本發明製備的藥物組合物，給藥劑量75 mpk，觀察給藥部位皮膚狀態。給藥後藥物在給藥部位形成塊狀凝膠，給藥部位無潰爛、發炎現象，隨著給藥時間的延長，給藥部位的塊狀物緩慢減小。結果如圖6所示。 Test example 3. Administration irritation test Use a 2.5 ml syringe to subcutaneously administer the pharmaceutical composition prepared in the present invention to the outer thigh of the rat at a dosage of 75 mpk, and observe the skin condition of the administration site. After administration, the drug formed a lumpy gel at the administration site, and there was no ulceration or inflammation at the administration site. As the administration time increased, the lumps at the administration site slowly decreased. The results are shown in Figure 6.

所屬技術領域中具有通常知識者會清楚，可以進行本發明的許多修改和變化而不背離其精神和範圍。本文所述的具體實施方案僅通過實例的方式提供，並不意味著以任何方式限制。本發明的真正範圍和精神通過所附請求項示出，說明書和實施例僅是示例性的。It will be apparent to those of ordinary skill in the art that many modifications and variations of the present invention can be made without departing from its spirit and scope. The specific embodiments described herein are provided by way of example only and are not meant to be limiting in any way. The true scope and spirit of the invention is indicated by the appended claims and the specification and examples are exemplary only.

無without

[圖1]是實施例5中測試的納解疼、處方1和處方2的溶出曲線對比圖。 [圖2]是實施例5中對不同處方的藥物組合物進行溶出度測試，得到的溶出曲線圖。 [圖3]是納解疼、處方1的鎮痛強度對比圖；其中，縱坐標為機械觸痛縮足閾值 (MWT)；SC表示本發明處方1塞納布啡藥物組合物通過皮下注射給藥；IM是納疼解通過肌肉注射給藥；model是指模型組；control是指空白組；處方1塞納布啡藥物組合物為皮下 (SC)注射給藥，納疼解為肌肉 (IM)注射給藥，可以看出本發明提供的塞納布啡藥物組合物（處方1）的100 mpk鎮痛作用優於納疼解100 mpk；其中單位mpk是指毫克每公斤 (Milligrams Per Kilograms)。 [圖4]是納疼解以及本發明提供的塞納布啡藥物組合物在體內的藥代動力學研究曲線圖。 [圖5]是以DMAC為溶劑的處方C03的藥物組合物在體內的藥代動力學曲線圖。 [圖6]是本發明提供的塞納布啡藥物組合物在大鼠大腿外側皮下給藥後皮膚狀態的記錄照片。 [圖7]是實施例8中處方C01、處方C02、處方C04和處方C05的藥物組合物的溶出曲線圖。 [Fig. 1] is a comparison chart of the dissolution curves of the sodium chloride, prescription 1 and prescription 2 tested in Example 5. [Fig. 2] is a dissolution curve graph obtained by conducting a dissolution test on pharmaceutical compositions of different prescriptions in Example 5. [Figure 3] is a comparison chart of the analgesic intensity of narcotic and prescription 1; wherein, the ordinate is the mechanical tenderness and withdrawal threshold (MWT); SC indicates that the senabuphine pharmaceutical composition of prescription 1 of the present invention is administered by subcutaneous injection; IM is Natongjie administered by intramuscular injection; model refers to the model group; control refers to the blank group; Prescription 1: The senabuphine pharmaceutical composition is administered by subcutaneous (SC) injection, and Natongjie is administered by intramuscular (IM) injection. medicine, it can be seen that the analgesic effect of 100 mpk of the senabuphine pharmaceutical composition (prescription 1) provided by the present invention is better than that of 100 mpk of senabuphine; the unit mpk refers to milligrams per kilogram (Milligrams Per Kilograms). [Fig. 4] is a pharmacokinetic study curve in vivo of Natongjie and the senabuphine pharmaceutical composition provided by the present invention. [Fig. 5] is a pharmacokinetic curve in vivo of the pharmaceutical composition of prescription C03 using DMAC as a solvent. [Fig. 6] is a photograph showing the skin condition after subcutaneous administration of the senabuphine pharmaceutical composition provided by the present invention on the outer thigh of rats. [Fig. 7] is a dissolution curve diagram of the pharmaceutical composition of prescription C01, prescription C02, prescription C04, and prescription C05 in Example 8.

Claims (29)

一種藥物組合物，其包含下列組分：(a)醯基甘油；(b)磷脂醯膽鹼(PC)；(c)至少一種含氧有機溶劑，所述含氧有機溶劑選自N-甲基吡咯烷酮、二甲基甲醯胺、2-吡咯烷酮和二甲基乙醯胺中的至少一種；(d)至少一種酸，所述酸為甲磺酸和馬來酸；(e)塞納布啡；其中，所述組分(e)塞納布啡含量為5~20重量%；組分(a)醯基甘油和組分(b)磷脂醯膽鹼的含量之和為45~75重量%；組分(e)塞納布啡與組分(d)酸的重量比為5~15：1，馬來酸的含量為0~0.2重量%；組分(c)含氧有機溶劑的含量為15~42重量%；所述重量百分比為相對於(a)、(b)、(c)、(d)和(e)的總重量而言。 A pharmaceutical composition comprising the following components: (a) acylglycerol; (b) phosphatidylcholine (PC); (c) at least one oxygen-containing organic solvent, the oxygen-containing organic solvent is selected from N-methyl At least one of 2-pyrrolidone, dimethylformamide, 2-pyrrolidone and dimethylacetamide; (d) at least one acid, the acid is methanesulfonic acid and maleic acid; (e) senabuphine ; Wherein, the content of component (e) senabuphine is 5~20% by weight; the sum of the contents of component (a) acylglycerol and component (b) phosphatidylcholine is 45~75% by weight; The weight ratio of component (e) senabuphine to component (d) acid is 5~15:1, the content of maleic acid is 0~0.2% by weight; the content of component (c) oxygen-containing organic solvent is 15 ~42% by weight; the weight percentages are relative to the total weight of (a), (b), (c), (d) and (e). 如請求項1所述的藥物組合物，其中，組分(a)醯基甘油和組分(b)磷脂醯膽鹼的含量之和為50~75重量%。 The pharmaceutical composition according to claim 1, wherein the sum of the contents of component (a) acylglycerol and component (b) phosphatidylcholine is 50 to 75% by weight. 如請求項1所述的藥物組合物，其中，組分(c)含氧有機溶劑的含量為15~35重量%。 The pharmaceutical composition according to claim 1, wherein the content of the oxygen-containing organic solvent in component (c) is 15 to 35% by weight. 如請求項1所述的藥物組合物，其中，組分(e)塞納布啡與組分(d)的重量比為6~10：1。 The pharmaceutical composition according to claim 1, wherein the weight ratio of component (e) senabuphine to component (d) is 6 to 10:1. 如請求項1所述的藥物組合物，其中，塞納布啡含量為7~15重量%。 The pharmaceutical composition according to claim 1, wherein the content of senabuphine is 7 to 15% by weight. 如請求項1所述的藥物組合物，其中，組分(a)醯基甘油為二醯基甘油、三醯基甘油或二者的混合物。 The pharmaceutical composition according to claim 1, wherein component (a) acylglycerol is diacylglycerol, triacylglycerol or a mixture of the two. 如請求項1所述的藥物組合物，其中，所述醯基甘油的醯基基團各自獨立地選自月桂醯基、肉豆蔻醯基、棕櫚醯基、植烷醯基、棕櫚油醯基、硬脂醯基、油醯基、反油酸醯基、亞油醯基、亞麻醯基、花生四烯醯基、山崳醯基或二十四碳醯基。 The pharmaceutical composition according to claim 1, wherein the acyl groups of the acyl glycerol are each independently selected from the group consisting of lauryl group, myristyl group, palmityl group, phytanyl group, and palm oil acyl group. , stearyl, oleyl, elaidyl, linoleyl, linoleyl, arachidonic, behenyl or 24-carbon acyl. 如請求項1所述的藥物組合物，其中組分(b)所述磷脂醯膽鹼選自卵PC、心PC、腦PC、肝PC、蛋黃PC或大豆PC中的至少一種。 The pharmaceutical composition according to claim 1, wherein the phosphatidylcholine in component (b) is selected from at least one of egg PC, heart PC, brain PC, liver PC, egg yolk PC or soybean PC. 如請求項1所述的藥物組合物，其中，組分(a)醯基甘油含量為20~60重量%；組分(b)磷脂醯膽鹼的含量為15~40重量%。 The pharmaceutical composition according to claim 1, wherein the content of component (a) acylglycerol is 20~60% by weight; the content of component (b) phosphatidylcholine is 15~40% by weight. 如請求項1所述的藥物組合物，其中，組分(a)所述醯基甘油為二油酸甘油酯。 The pharmaceutical composition according to claim 1, wherein the acylglycerol in component (a) is glycerol dioleate. 如請求項1所述的藥物組合物，其中組分(d)為甲磺酸和馬來酸，並且塞納布啡與甲磺酸的重量比為6~15：1；馬來酸為0~0.2重量%。 The pharmaceutical composition as described in claim 1, wherein component (d) is methanesulfonic acid and maleic acid, and the weight ratio of senabuphine to methanesulfonic acid is 6~15:1; the maleic acid is 0~ 0.2% by weight. 如請求項1所述的藥物組合物，其包含：(a)二油酸甘油酯；(b)大豆PC；(c)N-甲基吡咯烷酮；(d)甲磺酸和馬來酸；(e)塞納布啡，其中，塞納布啡含量為5~20重量%； 二油酸甘油酯和大豆PC的含量之和為50~75重量%；塞納布啡與甲磺酸的重量比為5~15：1，N-甲基吡咯烷酮的含量為15~35重量%；馬來酸的含量為0~0.2重量%；所述重量百分比為相對於(a)、(b)、(c)、(d)和(e)的總重量而言。 The pharmaceutical composition according to claim 1, which includes: (a) glyceryl diolein; (b) soybean PC; (c) N-methylpyrrolidone; (d) methanesulfonic acid and maleic acid; ( e) Senabuphine, wherein the senabuphine content is 5~20% by weight; The sum of the contents of diolein and soybean PC is 50~75% by weight; the weight ratio of senabuphine and methanesulfonic acid is 5~15:1, and the content of N-methylpyrrolidone is 15~35% by weight; The content of maleic acid is 0~0.2% by weight; the weight percentage is relative to the total weight of (a), (b), (c), (d) and (e). 如請求項1所述的藥物組合物，其包含：(a)二油酸甘油酯；(b)大豆PC；(c)N-甲基吡咯烷酮；(d)甲磺酸和馬來酸；(e)塞納布啡；其中，塞納布啡含量為7~10重量%；二油酸甘油酯和大豆PC的含量之和為65~75重量%；塞納布啡與甲磺酸的重量比為6~10：1，N-甲基吡咯烷酮的含量為15~35重量%；馬來酸的含量為0~0.02重量%；所述重量百分比為相對於(a)、(b)、(c)、(d)和(e)的總重量而言。 The pharmaceutical composition according to claim 1, which includes: (a) glyceryl diolein; (b) soybean PC; (c) N-methylpyrrolidone; (d) methanesulfonic acid and maleic acid; ( e) Senabuphine; wherein, the content of Senabuphine is 7~10% by weight; the sum of the contents of diolein and soybean PC is 65~75% by weight; the weight ratio of Senabuphine to methanesulfonic acid is 6 ~10:1, the content of N-methylpyrrolidone is 15~35% by weight; the content of maleic acid is 0~0.02% by weight; the weight percentage is relative to (a), (b), (c), based on the total weight of (d) and (e). 如請求項12或13所述的藥物組合物，其中，二油酸甘油酯的含量為25~55重量%，大豆PC的含量為15~40重量%。 The pharmaceutical composition as described in claim 12 or 13, wherein the content of glyceryl diolein is 25 to 55% by weight, and the content of soybean PC is 15 to 40% by weight. 如請求項14所述的藥物組合物，其中，二油酸甘油酯的含量為35~45重量%，大豆PC的含量為20~35重量%。 The pharmaceutical composition according to claim 14, wherein the content of glycerol dioleate is 35 to 45% by weight, and the content of soybean PC is 20 to 35% by weight. 如請求項1所述的藥物組合物，其包含：(a)二油酸甘油酯；(b)大豆PC； (c)二甲基乙醯胺；(d)甲磺酸和馬來酸；(e)塞納布啡；其中，二油酸甘油酯和大豆PC的含量之和為50~75重量%；塞納布啡的含量為5~20重量%；塞納布啡與甲磺酸的重量比為5~15：1；馬來酸的含量為0~0.2重量%；二甲基乙醯胺的含量為15~42重量%；所述重量百分比為相對於(a)、(b)、(c)、(d)和(e)的總重量而言。 The pharmaceutical composition according to claim 1, which includes: (a) glyceryl diolein; (b) soybean PC; (c) Dimethylacetamide; (d) Methanesulfonic acid and maleic acid; (e) Senabuphine; wherein the sum of the contents of diolein and soybean PC is 50~75% by weight; Sena The content of buphine is 5~20% by weight; the weight ratio of senabuphine and methanesulfonic acid is 5~15:1; the content of maleic acid is 0~0.2% by weight; the content of dimethylacetamide is 15 ~42% by weight; the weight percentages are relative to the total weight of (a), (b), (c), (d) and (e). 如請求項1所述的藥物組合物，其包含：(a)二油酸甘油酯；(b)大豆PC；(c)二甲基乙醯胺；(d)甲磺酸和馬來酸；(e)塞納布啡；其中，二油酸甘油酯和大豆PC的含量之和為50~75重量%；塞納布啡的含量為7.5~15重量%；塞納布啡與甲磺酸的重量比為6~15：1；馬來酸的含量為0~0.01%；二甲基乙醯胺的含量為15~35重量%；所述重量百分比為相對於(a)、(b)、(c)、(d)和(e)的總重量而言。 The pharmaceutical composition according to claim 1, which contains: (a) glyceryl diolein; (b) soybean PC; (c) dimethylacetamide; (d) methanesulfonic acid and maleic acid; (e) Senabuphine; wherein, the sum of the contents of diolein and soybean PC is 50~75% by weight; the content of senabuphine is 7.5~15% by weight; the weight ratio of senabuphine to methanesulfonic acid is 6~15:1; the content of maleic acid is 0~0.01%; the content of dimethylacetamide is 15~35% by weight; the weight percentage is relative to (a), (b), (c) ), (d) and (e). 如請求項16或17所述的藥物組合物，其中，二油酸甘油酯的含量為20~50重量%，大豆PC的含量為20~40重量%。 The pharmaceutical composition as described in claim 16 or 17, wherein the content of glyceryl diolein is 20 to 50% by weight, and the content of soybean PC is 20 to 40% by weight. 如請求項18所述的藥物組合物，其中，二油酸甘油酯的含量為25~50重量%，大豆PC的含量為20~31重量%。 The pharmaceutical composition according to claim 18, wherein the content of glyceryl diolein is 25 to 50% by weight, and the content of soybean PC is 20 to 31% by weight. 如請求項1至13或16或17中任一項所述的藥物組合物，其中，組分(b)與組分(a)的比按照重量計為0.1~1。 The pharmaceutical composition according to any one of claims 1 to 13 or 16 or 17, wherein the ratio of component (b) to component (a) is 0.1 to 1 by weight. 如請求項20所述的藥物組合物，其中，組分(b)與組分(a)的比按照重量計為0.5~0.9。 The pharmaceutical composition according to claim 20, wherein the ratio of component (b) to component (a) is 0.5 to 0.9 by weight. 如請求項1所述的藥物組合物，其包含：(a)二油酸甘油酯；(b)大豆PC；(c)N-甲基吡咯烷酮；(d)甲磺酸和馬來酸；(e)塞納布啡；其中，(b)大豆PC與(a)二油酸甘油酯的比按照重量計為0.1~1，馬來酸的含量為0~0.2重量%；或者，所述的藥物組合物，其包含：(a)二油酸甘油酯；(b)大豆PC；(c)二甲基乙醯胺；(d)甲磺酸和馬來酸；(e)塞納布啡； 其中，(b)大豆PC與(a)二油酸甘油酯的比按照重量計為0.1~1，馬來酸的含量為0~0.2重量%。 The pharmaceutical composition according to claim 1, which includes: (a) glyceryl diolein; (b) soybean PC; (c) N-methylpyrrolidone; (d) methanesulfonic acid and maleic acid; ( e) Senabuphine; wherein the ratio of (b) soybean PC to (a) glyceryl diolein is 0.1~1 by weight, and the content of maleic acid is 0~0.2% by weight; or, the drug A composition comprising: (a) diolein; (b) soybean PC; (c) dimethylacetamide; (d) methanesulfonic acid and maleic acid; (e) senabuphine; Among them, the ratio of (b) soybean PC to (a) diolein glyceryl is 0.1~1 by weight, and the content of maleic acid is 0~0.2% by weight. 如請求項22所述的藥物組合物，對於含N-甲基吡咯烷酮的藥物組合物，其包含：塞納布啡含量為7.5%~10重量%；二油酸甘油酯和大豆PC的含量之和為65~75重量%；塞納布啡與甲磺酸的重量比為6~10：1，N-甲基吡咯烷酮的含量為15~25重量%；馬來酸的含量為0~0.02重量%；或者，對於含二甲基乙醯胺的藥物組合物，其包含：所述塞納布啡含量為7.5%~15重量%；二油酸甘油酯和大豆PC的含量之和為50~75重量%；塞納布啡與甲磺酸的重量比為6~15：1，二甲基乙醯胺的含量為15~35重量%；馬來酸的含量為0~0.02重量%；其中，所述重量百分比為相對於(a)、(b)、(c)、(d)和(e)的總重量而言。 The pharmaceutical composition as described in claim 22, for the pharmaceutical composition containing N-methylpyrrolidone, it contains: the content of senabuphine is 7.5%~10% by weight; the sum of the content of glyceryl diolein and soybean PC It is 65~75% by weight; the weight ratio of senabuphine and methanesulfonic acid is 6~10:1, the content of N-methylpyrrolidone is 15~25% by weight; the content of maleic acid is 0~0.02% by weight; Or, for the pharmaceutical composition containing dimethyl acetamide, it includes: the content of senabuphine is 7.5%~15% by weight; the sum of the contents of glyceryl diolein and soybean PC is 50~75% by weight. ; The weight ratio of senabuphine to methanesulfonic acid is 6~15:1, the content of dimethylacetamide is 15~35% by weight; the content of maleic acid is 0~0.02% by weight; wherein, the weight Percentages are relative to the total weight of (a), (b), (c), (d) and (e). 如請求項22或23所述的藥物組合物，其中，(b)大豆PC與(a)二油酸甘油酯的比按照重量計為0.5~0.9。 The pharmaceutical composition according to claim 22 or 23, wherein the ratio of (b) soybean PC to (a) glyceryl diolein is 0.5 to 0.9 by weight. 如請求項1所述的藥物組合物，其中所述組合物在25℃具有30~1000cps的黏度；或所述組合物可使用18G至23G規格的針頭進行注射。 The pharmaceutical composition according to claim 1, wherein the composition has a viscosity of 30 to 1000 cps at 25°C; or the composition can be injected using a needle of 18G to 23G specifications. 如請求項1所述的藥物組合物，其中單位製劑體積為1.0~2.0ml，其中單位製劑中含有塞納布啡150mg。 The pharmaceutical composition as described in claim 1, wherein the unit preparation volume is 1.0 to 2.0 ml, and the unit preparation contains 150 mg of senabuphine. 一種製備如請求項1至26中任一項所述的藥物組合物方法，包括以下步驟： 將塞納布啡、酸溶解於含氧有機溶劑中，然後加入醯基甘油，最後加入磷脂醯膽鹼，溶解即得；或者，先將酸加入到含氧有機溶劑中，然後依次加入醯基甘油、磷脂醯膽鹼攪拌溶解，最後加入塞納布啡，攪拌溶解即得。 A method for preparing a pharmaceutical composition as described in any one of claims 1 to 26, comprising the following steps: Dissolve senabuphine and acid in an oxygen-containing organic solvent, then add acylglycerol, and finally add phosphatidylcholine, and dissolve; or, first add acid to an oxygen-containing organic solvent, and then add acylglycerol in sequence. , phosphatidylcholine, stir and dissolve, and finally add senabuphine, stir and dissolve. 如請求項27所述的方法，其中，加入磷脂醯膽鹼時，先將混合物加熱至不超過45℃。 The method of claim 27, wherein when adding phosphatidylcholine, the mixture is first heated to no more than 45°C. 一種如請求項1至26中任一項所述的藥物組合物在製備治療疼痛藥物中的用途，所述疼痛選自外科手術疼痛或長期慢性疼痛。The use of a pharmaceutical composition as described in any one of claims 1 to 26 in the preparation of medicaments for treating pain, the pain being selected from surgical pain or long-term chronic pain.
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