WO2019007441A1 - 一种包含地佐辛类似物酯的缓释混悬液及其制备方法 - Google Patents

一种包含地佐辛类似物酯的缓释混悬液及其制备方法 Download PDF

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WO2019007441A1
WO2019007441A1 PCT/CN2018/099232 CN2018099232W WO2019007441A1 WO 2019007441 A1 WO2019007441 A1 WO 2019007441A1 CN 2018099232 W CN2018099232 W CN 2018099232W WO 2019007441 A1 WO2019007441 A1 WO 2019007441A1
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oil
sustained release
suspension
release suspension
formula
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PCT/CN2018/099232
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English (en)
French (fr)
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张杨
邓冰
吴家虎
伍文韬
李志祥
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山东丹红制药有限公司
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Priority to JP2019572161A priority Critical patent/JP6850371B2/ja
Priority to US16/607,685 priority patent/US10744109B2/en
Publication of WO2019007441A1 publication Critical patent/WO2019007441A1/zh

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    • 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
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
    • 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
    • A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
    • A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
    • 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
    • A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
    • A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
    • A61K31/22—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acyclic acids, e.g. pravastatin
    • A61K31/23—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acyclic acids, e.g. pravastatin of acids having a carboxyl group bound to a chain of seven or more carbon atoms
    • 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
    • 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
    • A61K47/12—Carboxylic acids; Salts or anhydrides thereof
    • 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
    • A61K47/14—Esters of carboxylic acids, e.g. fatty acid monoglycerides, medium-chain triglycerides, parabens or PEG fatty acid esters
    • 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
    • A61K47/26—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
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/32—Macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. carbomers, poly(meth)acrylates, or polyvinyl pyrrolidone
    • 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
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
    • 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
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
    • A61K47/38—Cellulose; Derivatives thereof
    • 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
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/42—Proteins; Polypeptides; Degradation products thereof; Derivatives thereof, e.g. albumin, gelatin or zein
    • 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

Definitions

  • the invention relates to the technical field of medicine, in particular to an analgesic oily sustained release suspension comprising the compound of the formula (I) and a preparation method thereof.
  • the compound of the formula (I) is a sebacic acid diester prodrug of the compound represented by the formula (II), which is unstable in plasma and can release the active compound of the formula (II) after hydrolysis in vivo. .
  • the compound of the formula (I) has a low solubility in water and an oil solution, and is a drug which is slightly soluble in water and hardly soluble or insoluble in an oil solution. Further, the compound of the formula (I) has a short half-life, and the clearance rate of the aqueous solution in the body is too fast to achieve a sustained release effect.
  • the suspension injection preparation of the invention has simple composition, stable preparation performance, simple preparation process, and is suitable for large-scale production research and development. Moreover, the suspension has the advantages of low viscosity, sedimentation ratio, redispersibility, and excellent needle-passing properties.
  • the invention provides a sustained release suspension comprising a compound of formula (I), an injectable oil, and an excipient,
  • the compound of formula (I) is present in the sustained release suspension in an amount of from 5 to 20% by weight.
  • the amount of excipient in the sustained release suspension is from 0.25 to 2 wt.%.
  • the injectable oil is present in the sustained release suspension in an amount of from 80 to 95 wt.%.
  • the above injectable oil is selected from the group consisting of medium chain triglycerides, soybean oil, olive oil, sesame oil, corn oil, cottonseed oil, isopropyl myristate, and mixtures thereof.
  • the above excipients are selected from the group consisting of: wetting agents and suspending agents.
  • the wetting agent is selected from the group consisting of: Tween 80, RH40, PEG 400, poloxamer 188, HS-15, ethanol, propylene glycol, Span 80, polyoxyethylene hydrogenated stearate, Polyoxyethylene castor oil and its derivatives.
  • suspending agent is selected from the group consisting of methylcellulose, PVP, gelatin, sodium alginate, aluminum stearate, and aluminum tristearate.
  • the present invention provides a process for the preparation of the above sustained release suspension, characterized in that the method employs a highly dispersed process.
  • the above highly dispersed method is selected from the group consisting of micronization, antisolvent, high pressure homogenization, and pre-suspension.
  • the 90% particle size obtained by the above preparation method is ⁇ 15 ⁇ m.
  • intermediate compounds of the present invention can be prepared by a variety of synthetic methods well known to those skilled in the art, including the specific embodiments listed below, combinations thereof with other chemical synthesis methods, and those skilled in the art.
  • Well-known equivalents, preferred embodiments include, but are not limited to, embodiments of the invention.
  • the solvent used in the present invention is commercially available.
  • the present invention uses the following abbreviations:
  • RH40 Polyoxyethylene 40 hydrogenated castor oil
  • PEG400 Polyethylene glycol 400
  • HS-15 polyethylene glycol 15 hydroxystearic acid
  • PVP polyvinylpyrrolidone
  • Test conditions Take an appropriate amount of the test substance into the sample bottle, add the dispersion medium (isoparaffin solvent containing 0.25% lecithin), mix it by hand and add it to the sample cell to test the sample.
  • the detailed PSD parameters are shown in Table 2 below (wet method):
  • Test method The sample was placed on a glass slide, and the silicone oil was dispersed and observed. Eyepiece: 10 times, objective lens: 20/50 times.
  • Mobile phase A 0.05% aqueous solution of trifluoroacetic acid
  • mobile phase B 0.05% trifluoroacetic acid in acetonitrile
  • column temperature 35 ° C
  • flow rate 1 mL / min
  • Detection wavelength 215 nm; sample solution concentration: 0.08 mg/mL, injection amount: 50 ⁇ L;
  • the gradient program is shown in Table 3 below:
  • Mobile phase A 0.05% aqueous solution of trifluoroacetic acid
  • mobile phase B 0.05% trifluoroacetic acid in acetonitrile
  • column temperature 35 ° C
  • flow rate 1 mL / min
  • Detection wavelength 215 nm; sample solution concentration: 0.08 mg/mL, injection amount: 10 ⁇ L;
  • the gradient program is shown in Table 4 below:
  • time Mobile phase B (%) 0.01 20 10.00 45 40.00 100 50.01 100 50.00 20 60.00 20
  • the preparation method of the test solution and the reference solution is the same as the preparation method of the test solution and the reference solution of 5.3 and 5.4.
  • Figure 1 is a graph showing the particle size distribution of the suspension obtained in Example 4.
  • Figure 2 is a PLM micrograph of the suspension obtained in Example 4.
  • an embodiment of the present invention is as follows:
  • injection oil is one or more of medium chain triglyceride, soybean oil, olive oil, sesame oil, corn oil, cottonseed oil, and isopropyl myristate.
  • medium chain triglycerides and soybean oil are preferred.
  • the above suspending agents are one or more of aluminum stearate, aluminum tristearate, methylcellulose, PVP, gelatin, and sodium alginate.
  • Aluminum stearate and aluminum tristearate are preferred.
  • the above wetting agent is one of Tween 80, RH40, PEG400, poloxamer 188, HS-15, ethanol, propylene glycol, Span 80, polyoxyethylene hydrogenated stearate, polyoxyethylene castor oil. Or several. Tween 80, RH40 are preferred.
  • step 2 Weigh accurately the oil solution obtained in step 1, and add a wetting agent at 60 ° C, stir at high speed (2500 rpm) for 5 minutes, accurately weigh the compound of formula (I), and slowly add a small amount of high-speed stirring oil. The suspension was obtained by maintaining the solution for 1 hour.
  • the powder of the compound represented by the formula (I) is pulverized in a pulverizer to 90% particle diameter ⁇ 7 ⁇ m;
  • the compound of formula (I) is aseptically treated and micronized, and 0.05 g of a vial in a 2 mL vial is dispensed under sterile conditions;
  • the preparation method of the oily suspension injection of the compound of the above formula (I) can be prepared by a high pressure homogenization method, and the specific steps are as follows:
  • the powder of the compound represented by the formula (I) is pulverized in a pulverizer to 90% particle diameter ⁇ 7 ⁇ m;
  • the oil obtained in the step 2 is added, and stirred at 10,000 rpm for 1 minute using a high-speed homogenizer to completely disperse into a suspension;
  • step 3 The suspension obtained in step 3 is ultra-fineized in a high-pressure homogenizer to obtain the suspension injection;
  • step 4 The suspension injection obtained in step 4 is dispensed into a coated vial, sealed with a coated rubber stopper and an aluminum cap, and placed in a moist heat sterilizer for terminal sterilization.
  • step 4 specifically includes the following steps:
  • the present invention provides three methods of preparing an oily suspension of the compound of formula (I). Since the oily suspension generally has the characteristics of easy sedimentation, the present invention adopts three preparation methods, and according to the sedimentation property of the suspension, the viscosity of the suspension is increased, the particle diameter of the drug is reduced, and the method of premixing and dispensing is respectively adopted. Increase the stability of the suspension.
  • the preparation method of the three methods is simple, the auxiliary materials are cheap and easy to obtain, the obtained preparation has stable performance, meets the requirements of the pharmacopoeia, can be industrialized, and has a broad application prospect.
  • Example 1 The stability of the suspension in Example 1 under the conditions of strong light, high temperature and high pressure and the influence of the relevant substances were measured. The results are shown in Table 5. The influencing factors showed that there was no significant increase in the relevant substances, and there was no significant change in the particle size distribution. The sedimentation ratio was in accordance with the requirements of the pharmacopoeia and was stable.
  • Step 3 Measure 10 mL of the oil phase obtained in Step 1, place in a 60 ° C water bath, stir at high speed (2400 rpm), slowly add dropwise the ethanol solution of the compound of the formula (I) obtained in Step 2, and open for 1 hour. Suspending injection;
  • Bottle 1 Compound of formula (I)
  • Bottle 2 diluent
  • the powder of the compound represented by the formula (I) is pulverized in a pulverizer to 90% particle diameter ⁇ 7 ⁇ m;
  • step 3 The suspension obtained in step 3 is ultra-fineized in a high-pressure homogenizer to obtain the suspension injection;
  • step 4 specifically includes the following steps:
  • step 4 The suspension injection obtained in step 4 is dispensed into a coated vial, sealed with a coated rubber stopper and an aluminum lid, and placed in a moist heat sterilizer for terminal sterilization.
  • Example 4 The suspension obtained in Example 4 was characterized, including particle size detection, polarized light microscopy (PLM), settling ratio, viscosity, redispersibility, and through-needle properties.
  • PLM polarized light microscopy
  • the particle size distribution and PLM micrographs of the suspension obtained in Example 4 are shown in Figures 1 and 2.
  • Example 4 The stability of the suspension obtained in Example 4 under different accelerated conditions and the influence of related substances were measured, as shown in Table 9.
  • the stability of the suspension of Example 4 for 2 months showed that the particle size under the three conditions did not change significantly after being placed for two months, and the sedimentation ratio showed that the stability of the suspension material was very good, and at the same time
  • the results of the relevant substances showed that there was no significant increase in the relevant substances in the two months.
  • the above results show that the overall stability of the suspension in Example 4 is good.
  • the compound of formula (I) was administered by intramuscular injection.
  • Whole blood samples were collected at 0.25, 0.50, 1.0, 2.0, 4.0, 8.0, 12.0, 24.0, and 48.0 hours after administration of the aqueous suspension group.
  • Whole blood samples were taken at 0.25, 0.50, 2.0, 4.0, 8.0, 10.0, 24.0, 48.0, 72.0, 96.0, 120.0 and 144.0 hours after administration of the oil suspension group.
  • Rat pharmacokinetic studies of the compounds of formula (I) showed that the oil suspensions significantly reduced the highest blood concentration after intramuscular administration (Table 11) compared to the aqueous suspension (Table 10). And prolonging the half-life of the drug in vivo, thereby achieving the purpose of reducing the frequency of administration, reducing side effects, and prolonging the action time of the drug in vivo.
  • ND indicates uncertainty (since the blood concentration is below the detection limit, the end elimination phase cannot be determined and the parameter is uncertain).
  • ND indicates uncertainty (since the blood concentration is below the detection limit, the end elimination phase cannot be determined and the parameter is uncertain).

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Abstract

本发明公开了一种包含地佐辛类似物酯的缓释混悬液及其制备方法。本发明选择药学上作为缓释储库的可注射的油性辅料和赋形剂，采用微粉化技术并联合高压均质技术、反溶剂法成功制备了供注射用的长效混悬液。它主要成分为式（Ⅰ）所示化合物、可注射用油等。

Description

一种包含地佐辛类似物酯的缓释混悬液及其制备方法
相关申请的交叉引用
本申请主张2017年07月04日提交的中国专利申请CN201710539419.8的优先权，其内容在此并入本申请。
技术领域
本发明涉及医药技术领域，具体涉及一种包含式(Ⅰ)所示化合物的止痛油性缓释混悬液及其制备方法。
背景技术
式(Ⅰ)所示化合物是地佐辛类似物式(Ⅱ)所示化合物的癸二酸二酯前药，在血浆中不稳定，体内水解后可释放出活性成分式(Ⅱ)所示化合物。
式(Ⅰ)所示化合物在水和油溶液中的溶解度都较低，属于在水中微溶，在油溶液中几乎不溶或不溶的药物。而且式(Ⅰ)所示化合物的半衰期较短，配置成水溶液在体内的清除率过快，无法达到缓释效果。
Figure PCTCN2018099232-appb-000001
技术效果
本发明的混悬注射液制剂组成简单，制剂性能稳定，制备工艺简单，适合大规模生产研发。而且该混悬液具有粘度低，可沉降比、可重分散性以及通针性优良等优点。
发明内容
一方面，本发明提供了一种包含式(Ⅰ)所示化合物、可注射用油以及赋形剂的缓释混悬液，
Figure PCTCN2018099232-appb-000002
在本发明的一些方案中，上述缓释混悬液中式(Ⅰ)所示化合物的含量为5-20wt.％。
在本发明的一些方案中，上述缓释混悬液中赋形剂的含量为0.25-2wt.％。
在本发明的一些方案中，上述缓释混悬液中可注射用油的含量为80-95wt.％。
在本发明的一些方案中，上述可注射用油选自：中链甘油三酸酯、大豆油、橄榄油、芝麻油、玉米油、棉籽油、肉豆蔻酸异丙酯，以及它们的混合物。
在本发明的一些方案中，上述赋形剂选自：润湿剂和助悬剂。
在本发明的一些方案中，上述润湿剂选自：吐温80、RH40、PEG400、泊洛沙姆188、HS-15、乙醇、丙二醇、司盘80、聚氧乙烯氢化硬脂酸酯、聚氧乙烯蓖麻油及其衍生物。
在本发明的一些方案中，其中助悬剂选自：甲基纤维素、PVP、明胶、海藻酸钠、硬脂酸铝和三硬脂酸铝。
另一方面，本发明提供了一种上述缓释混悬液的制备方法，其特征在于，该方法采用高度分散法。
在本发明的一些方案中，上述高度分散法选自：微粉化法、反溶剂法、高压均质法和预混悬法。
在本发明的一些方案中，上述制备方法得到的90％颗粒粒径≤15μm。
定义和说明
除非另有说明，本文所用的下列术语和短语旨在含有下列含义。一个特定的短语或术语在没有特别定义的情况下不应该被认为是不确定的或不清楚的，而应该按照普通的含义去理解。当本文出现商品名时，旨在指代其对应的商品或其活性成分。
本发明的中间体化合物可以通过本领域技术人员所熟知的多种合成方法来制备，包括下面列举的具体实施方式、其与其他化学合成方法的结合所形成的实施方式以及本领域技术上人员所熟知的等同替换方式，优选的实施方式包括但不限于本发明的实施例。
本发明具体实施方式的化学反应是在合适的溶剂中完成的，所述的溶剂须适合于本发明的化学变化及其所需的试剂和物料。为了获得本发明的化合物，有时需要本领域技术人员在已有实施方式的基础上对合成步骤或者反应流程进行修改或选择。
下面会通过实施例具体描述本发明，这些实施例并不意味着对本发明的任何限制。
本发明所使用的所有溶剂是市售的，无需进一步纯化即可使用。
本发明所使用的溶剂可经市售获得。
本发明采用下述缩略词：
RH40:聚氧乙烯40氢化蓖麻油
PEG400:聚乙二醇400
HS-15:聚乙二醇15羟基硬脂酸
PVP:聚乙烯吡咯烷酮
RH:相对湿度
wt.％:重量百分比
仪器及分析方法
1.制剂过程所用主要仪器及参数如表1所示
表1
Figure PCTCN2018099232-appb-000003
Figure PCTCN2018099232-appb-000004
2.混悬液沉降比的测试：
将混悬液分装于50mL的量筒中并振摇1分钟混匀，室温下静置，记录沉降前原始高度H0，同时记录静置1h、2h、3h后沉降高度H，按照公式F＝H/H0计算可沉降比。
仪器：量筒，直尺
3.混悬液粒径和粒度分布的测试：
仪器型号：Microtrac-X100麦奇克激光粒度仪(Particle Size Distribution Analyzer,PSD)
测试条件：取适量的待测物到样品瓶中，加入分散介质(含有0.25％卵磷脂的异构烷烃溶剂)，手动混合均匀后加入到样品池，测试样品。详细的PSD参数如下表2(湿法)所示：
表2
Figure PCTCN2018099232-appb-000005
4.偏光显微镜(PLM)实验方案
偏光显微镜(Polarized Light Microscope,PLM)
仪器型号：Nikon LV100偏光显微镜
测试方法：样品置于载玻片上，硅油分散后观察。目镜：10倍，物镜：20/50倍。
5.混悬液含量检测试验方案：
5.1设备型号：
高效液相检测仪(安捷伦1260配制PDA检测器)
色谱柱：Kromasil C18(4.6×250mm,5μm)
5.2色谱条件
流动相A：0.05％的三氟乙酸的水溶液，流动相B：0.05％的三氟乙酸的乙腈溶液；柱温：35℃；流速：1mL/min；
检测波长：215nm；样品溶液浓度：0.08mg/mL，进样量：50μL；
梯度程序如下表3所示：
表3
时间 流动相B(％)
0.01 20
30.00 98
40.00 98
40.01 20
60.00 停止
5.3供试品溶液的制备
取制剂样品(规格：1mL，50mg)一份，充分振摇后转移至5mL离心管，精密量取3mL乙腈-水(2:1)溶液分次冲洗制剂瓶内壁，合并冲洗液倒入离心管中；摇匀后超声20min(强度50％)，使用漩涡仪强力振摇1min(强度4)，将样品置于转速为12000rpm的离心机中，离心15min，用注射器吸取上清液至西林瓶中；精密量取1.5mL上清液置于25mL容量瓶中，加乙腈-水(2:1)稀释并定容至刻度；精密量取2mL置于25mL容量瓶中，加乙腈-水(2:1)稀释并定容至刻度，即得浓度约为0.08mg/mL的供试品溶液。
5.4对照品溶液的制备
精密称取对照品10mg，置于25mL容量瓶中，加乙腈-水(2:1)溶液溶解、稀释并定容至刻度；精密量取2mL置10mL容量瓶中，加乙腈-水(2:1)稀释并定容至刻度，即得浓度约为0.08mg/mL的对照品溶液。
6.混悬液有关物质含量的检测试验方案：
6.1设备型号：
高效液相检测仪(安捷伦1260配制PDA检测器)
色谱柱：Kromasil C18(4.6×250mm,5μm)；
6.2色谱条件
流动相A：0.05％的三氟乙酸的水溶液，流动相B：0.05％的三氟乙酸的乙腈溶液；柱温：35℃；流速：1mL/min；
检测波长：215nm；样品溶液浓度：0.08mg/mL，进样量：10μL；
梯度程序如下表4所示：
表4
时间 流动相B(％)
0.01 20
10.00 45
40.00 100
50.01 100
50.00 20
60.00 20
6.3供试品溶液和对照品溶液的制备方法同5.3、5.4供试品溶液和对照品溶液的制备方法。
附图说明
图1为实施例4所得混悬液的粒径分布图。
图2为实施例4所得混悬液的PLM显微图。
为了实现上述技术效果，本发明的实施方案如下：
方案1
式(Ⅰ)所示化合物的油性混悬注射液的制备，每10mL该注射液组成如下：
式(Ⅰ)所示化合物：0.5g
注射用油：8g
助悬剂：0.5-4％
润湿剂：0.2-0.6％
上述的注射用油为中链甘油三酸酯、大豆油、橄榄油、芝麻油、玉米油、棉籽油、肉豆蔻酸异丙酯的一种或几种。优选的为中链甘油三酸酯、大豆油。
上述的助悬剂为硬脂酸铝、三硬脂酸铝、甲基纤维素、PVP、明胶、海藻酸钠的一种或几种。优选硬脂酸铝、三硬脂酸铝。
上述的润湿剂为吐温80、RH40、PEG400、泊洛沙姆188、HS-15、乙醇、丙二醇、司盘80、聚氧乙烯氢化硬脂酸酯、聚氧乙烯蓖麻油中的一种或几种。优选吐温80，RH40。
上述式(Ⅰ)所示化合物的油性混悬注射液制备方法，其可以由分散法制备，具体步骤如下：
1.精密称取注射用油，加入助悬剂，于常温搅拌1小时，加热至120℃后搅拌3小时，关闭加热，持续搅拌至室温，备用。
2.精密称取步骤1所得油溶液，并加入润湿剂于60℃条件下，高速搅拌(2500rpm)5分钟，精密称取处方量式(Ⅰ)所示化合物，缓慢少量加入高速搅拌的油溶液中，维持1小时即得所述混悬注射液。
方案2
式(Ⅰ)所示化合物油性混悬注射液的制备，每1mL该注射液组成如下：
式(Ⅰ)所示化合物：0.05g
注射用油：0.947g
上述式(Ⅰ)所示化合物的长效油性混悬注射液，其可以由预混法制备，具体步骤如下：
1.取式(Ⅰ)所示化合物粉末置粉碎机内粉碎至90％颗粒粒径≤7μm；
2.称量注射用油0.947g于2mL西林瓶，密封并灭菌；
3.对式(Ⅰ)所示化合物进行无菌处理并微粉化，并在无菌环境下分装0.05g于2mL西林瓶；
4.待用时将灭菌后的油注入步骤3的西林瓶中，并手动混匀即得所述混悬注射液。
方案3
式(Ⅰ)所示化合物的油性混悬注射液，每10mL该注射液组成如下：
式(Ⅰ)所示化合物：0.5g
注射用油：9.47g
润湿剂：0.2-0.6％
上述的式(Ⅰ)所示化合物的油性混悬注射液的制备方法，其可以由高压均质法制备，具体步骤如下：
1.取式(Ⅰ)所示化合物粉末置粉碎机内粉碎至90％颗粒粒径≤7μm；
2.取适量的表面活性剂加入注射用油中，于60℃加热搅拌30分钟；
3.在步骤1所得的式(Ⅰ)所示化合物粉末中加入步骤2所得油中，使用高速均质机以10000rpm转速搅拌1分钟，使完全分散成混悬液；
4.将步骤3所得混悬液于高压均质机进行超细化，即得所述混悬注射液；
5.将步骤4所得混悬注射液分装镀膜西林瓶，使用镀膜胶塞和铝盖密封，置于湿热灭菌器内进行终 端灭菌。
步骤4中所述的高压均质过程，具体包括如下步骤：
a)6000psi压力均质5个循环；
b)3000psi压力均质5个循环；其中均质过程中管道温度控制在0至-20℃。
本发明提供了三种制备式(Ⅰ)所示化合物油性混悬注射液的方法。由于油性混悬剂普遍存在易沉降的特点，本发明采用三种制备方法，根据混悬液的沉降性质，分别从增加混悬液的粘度、降低药物的粒径以及通过预混分装的方法增加混悬液的稳定性。三种方法制备工艺简单，辅料廉价易得，所得的制剂性能稳定，符合药典要求，能够工业化生产，应用前景十分广阔。
具体实施方式
下面通过实施例对本发明进行详细描述，但并不意味着对本发明任何不利限制。本文已经详细地描述了本发明，其中也公开了其具体实施例方式，对本领域的技术人员而言，在不脱离本发明精神和范围的情况下针对本发明具体实施方式进行各种变化和改进将是显而易见的。
实施例1
1.精密称取中链甘油三酸酯50g，再加入三硬脂酸铝0.4g，于常温搅拌1小时，加热至120℃后搅拌3小时，关闭加热，持续搅拌至室温，备用。
2.精密称取步骤1所得油溶液8.0g，RH40 0.25g，于60℃条件下，高速搅拌(2500rpm)5分钟。精密称取式(Ⅰ)所示化合物3.125g，缓慢少量加入高速搅拌的油溶液中，维持1小时即得所述混悬注射液。
测量强光、高温、高压条件下实施例1中的混悬液稳定性情况以及有关物质的影响。结果如表5，影响因素结果显示，有关物质无明显增加，粒径分布无明显改变，可沉降比符合药典要求，稳定较好。
表5：实施例1所得混悬液稳定性以及有关物质含量的情况
Figure PCTCN2018099232-appb-000006
实施例2
1.称取中链甘油三酸酯50g，三硬脂酸铝0.15g，常温搅拌30分钟，油浴加热至120℃，搅拌2小时，油溶解澄清透明，放冷备用；
2.称取式(Ⅰ)所示化合物0.5g，溶于4mL无水乙醇中，超声10秒即溶，备用；
3.量取步骤1所得油相10mL，置于60℃水浴中，高速搅拌(2400rpm)，缓慢滴加步骤2的所得式(Ⅰ)所示化合物的乙醇溶液，敞口搅拌1小时即得所述混悬注射液；
表6：实施例2所得混悬液的表征数据
沉降比 粘度 粒径D90(μm) 分散性能
0.95 易流动 13.1 易分散
结果显示，该混悬液3小时测定沉降比大于药典要求的0.9，其粒径也符合药典中混悬剂项下粒径的相关要求。
实施例3
1.瓶1：式(Ⅰ)所示化合物
将式(Ⅰ)所示化合物过微粉化后，按50mg/mL分装至2mL西林瓶中。
2.瓶2：稀释液
精密量取100mL中链甘油三酸酯，加入针用活性炭100mg，于60℃搅拌15分钟后，通过0.8μm滤膜，再通过0.22μm微孔滤膜，按1.1mL/瓶分装。
表7:实施例3所得混悬液三个月稳定性考察数据
条件 复溶 化合物含量(％) 有关物质含量(％) 粒度分布D90(μm) 水分含量(％)
常温 可分散混匀 97.12 2.16 11.32 3.28
60℃ 可分散均匀 92.43 5.91 11.86 4.12
由表7结果得出：在室温下放置三个月，化合物含量无明显下降且有关物质无明显增加，粉末能够在中链甘油三酸酯分散均匀且粒径D90(μm)为11.32μm，仍符合药典要求；但在60℃条件下，含量有所下降以及有关物质明显增加，但药物粉末仍可以很好分散，以上结果表明，在控制储存温度情况下，预混装制备混悬液可行性较高。
实施例4
1.取式(Ⅰ)所示化合物粉末置粉碎机内粉碎至90％颗粒粒径≤7μm；
2.取6.7g的吐温80加入可注射用油中，于60℃加热搅拌30分钟；
3.在步骤1所得的式(Ⅰ)所示化合物的粉末150.8g加入步骤2所得油中，使用高速均质机以10000rpm转速搅拌1分钟，使其完全分散成混悬液；
4.将步骤3所得混悬液于高压均质机进行超细化，即得所述混悬注射液；
步骤4中所述的高压均质过程，具体包括如下步骤：
1)6000psi压力均质5个循环；
2)3000psi压力均质5个循环；其中均质过程中管道温度控制在0至-20℃。
5.将步骤4所得混悬注射液分装在镀膜西林瓶，使用镀膜胶塞和铝盖密封，置于湿热灭菌器内进行终端灭菌。
对实施例4所得混悬液进行表征，包括粒径检测、偏光显微镜(PLM)、可沉降比、粘度、重分散性能以及通针性。实施例4所得混悬液的粒径分布图和PLM显微图如图1和图2所示。
表8:实施例4所得混悬液的表征数据
沉降比 粘度 粒度分布D90(μm) 分散性能 通针性
1 易流动 14.1 易分散 可过27规格
测量不同加速条件下实施例4所得混悬液稳定性情况以及有关物质的影响，具体见表9。实施例4混悬液2个月稳定性结果显示，三个条件下的粒径放置两个月后，无明显变化，同时通过沉降比结果可以看出混悬液的物料稳定性非常良好，同时通过有关物质的结果显示，两个月的有关物质亦无明显增加。以上结果显示实施例4中混悬液整体稳定性较好。
表9:实施例4所得混悬液2个月稳定性考察
Figure PCTCN2018099232-appb-000007
生物活性测试
药代动力学考察
每组3只雄性大鼠，通过肌肉注射给予式(Ⅰ)所示化合物。水混悬液组给药后0.25、0.50、1.0、2.0、4.0、8.0、12.0、24.0和48.0小时采集全血样品。油混悬液组给药后0.25、0.50、2.0、4.0、8.0、10.0、24.0、48.0、72.0、96.0、120.0和144.0小时采集全血样品。经乙腈/甲醇沉淀蛋白后，取上清进样，采用LC-MS/MS法测定血药浓度，使用WinNonlin TMVersion 6.3(Pharsight,Mountain View,CA)药动学软件，以非房室模型线性对数梯形法分别计算式(Ⅰ)和式(Ⅱ)所示化合物相关药代动力学参数。
式(Ⅰ)所示化合物的大鼠药代动力学研究显示，与水混悬液相比(表10)，油混悬液通过肌注给药后(表11)可以显著降低最高血药浓度和延长药物体内半衰期，从而达到降低给药频率，减少副作用，延长药物体内作用时间的目的。
表10:式(Ⅰ)所示化合物的水混悬液的大鼠药代动力学(肌肉注射，给药量：17.5μM/Kg)
Figure PCTCN2018099232-appb-000008
注：ND表示不确定(由于血药浓度低于检测限，不能确定末端消除相，该参数不确定)。
表11:式(Ⅰ)所示化合物的油混悬液的大鼠药代动力学(肌肉注射，给药量：51.4μM/Kg)
Figure PCTCN2018099232-appb-000009
注：ND表示不确定(由于血药浓度低于检测限，不能确定末端消除相，该参数不确定)。
以上对式(Ⅰ)所示化合物长效油性混悬注射液及其制备方法进行了详细介绍，所述的实施例只是为了能够更清楚的理解本发明的技术内容，而不应当视为是对本发明的限制，本领域的技术人员根据本发明做出的非本质的改进和调整均属于本发明范围。

Claims (11)

  1. 一种包含式(Ⅰ)所示化合物、可注射用油以及赋形剂的缓释混悬液，
    Figure PCTCN2018099232-appb-100001
  2. 根据权利要求1所述的缓释混悬液，其中式(Ⅰ)所示化合物的含量为5-20wt.％。
  3. 根据权利要求1所述的缓释混悬液，其中赋形剂的含量为0.25-2wt.％。
  4. 根据权利要求1所述的缓释混悬液，其中可注射用油的含量为80-95wt.％。
  5. 根据权利要求1所述的缓释混悬液，其中可注射用油选自：中链甘油三酸酯、大豆油、橄榄油、芝麻油、玉米油、棉籽油、肉豆蔻酸异丙酯，以及它们的混合物。
  6. 根据权利要求1所述的缓释混悬液，其中赋形剂选自：润湿剂和助悬剂。
  7. 根据权利要求6所述的缓释混悬液，其中润湿剂选自：吐温80、RH40、PEG400、泊洛沙姆188、HS-15、乙醇、丙二醇、司盘80、聚氧乙烯氢化硬脂酸酯、聚氧乙烯蓖麻油及其衍生物。
  8. 根据权利要求6所述的缓释混悬剂，其中助悬剂选自：甲基纤维素、PVP、明胶、海藻酸钠、硬脂酸铝和三硬脂酸铝。
  9. 一种如权利要求1所述的缓释混悬液的制备方法，其特征在于，该方法采用高度分散法。
  10. 根据权利要求9所述的制备方法，其中所述高度分散法选自：微粉化法、反溶剂法、高压均质法和预混悬法。
  11. 根据权利要求9或10所述的制备方法，其特征在于，该方法得到的90％颗粒粒径≤15μm。
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