WO2021097650A1 - 奥利司他与氨基酸的共晶体及包含该共晶体的药物组合物 - Google Patents

奥利司他与氨基酸的共晶体及包含该共晶体的药物组合物 Download PDF

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WO2021097650A1
WO2021097650A1 PCT/CN2019/119381 CN2019119381W WO2021097650A1 WO 2021097650 A1 WO2021097650 A1 WO 2021097650A1 CN 2019119381 W CN2019119381 W CN 2019119381W WO 2021097650 A1 WO2021097650 A1 WO 2021097650A1
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orlistat
crystal
capsules
leucine
proline
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PCT/CN2019/119381
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English (en)
French (fr)
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向飞
杜志博
彭韪
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中山万汉制药有限公司
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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
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/365—Lactones
    • 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
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/401—Proline; Derivatives thereof, e.g. captopril
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/04—Anorexiants; Antiobesity agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C227/00—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton
    • C07C227/38—Separation; Purification; Stabilisation; Use of additives
    • C07C227/40—Separation; Purification
    • C07C227/42—Crystallisation
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C229/00—Compounds containing amino and carboxyl groups bound to the same carbon skeleton
    • C07C229/02—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton
    • C07C229/04—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated
    • C07C229/06—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having only one amino and one carboxyl group bound to the carbon skeleton
    • C07C229/08—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having only one amino and one carboxyl group bound to the carbon skeleton the nitrogen atom of the amino group being further bound to hydrogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D207/10—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D207/16—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D305/00—Heterocyclic compounds containing four-membered rings having one oxygen atom as the only ring hetero atoms
    • C07D305/02—Heterocyclic compounds containing four-membered rings having one oxygen atom as the only ring hetero atoms not condensed with other rings
    • C07D305/10—Heterocyclic compounds containing four-membered rings having one oxygen atom as the only ring hetero atoms not condensed with other rings having one or more double bonds between ring members or between ring members and non-ring members
    • C07D305/12—Beta-lactones

Definitions

  • the invention belongs to the field of medical technology, and specifically relates to a co-crystal of orlistat and amino acids and a pharmaceutical composition containing the co-crystal.
  • Orlistat is a lipase inhibitor weight-loss drug developed by Roche Pharmaceuticals under the trade name Xenical. It was the first to be marketed in Europe and the United States in the late 1990s. It was listed in China in 2001 and was approved by China Food in 2005. The Drug Administration approved the conversion to over-the-counter drugs.
  • Its chemical name is N-formyl-L-leucine(s)-1[(2s,3s)3-hexyl-4oxy-2-epoxypropylmethyl]dodecyl ester, also known as tetrahydro Tetrahydrolipstatin (THL) is a semi-synthetic lipostatin derivative, its chemical structure is shown in the figure below:
  • Orlistat is used for medicinal purposes with its II crystal form capsules and tablets. It is also the only chemical weight loss drug at home and abroad that does not affect appetite and does not act on the central nervous system. It has superior safety characteristics.
  • the type II orlistat crystals in the commercially available preparations are white to off-white crystalline powders, which are basically insoluble in water, easily soluble in chloroform, extremely soluble in methanol and ethanol, and have no pKa value in the physiological pH range.
  • orlistat there are two methods for the production of orlistat in China: one is chemical total synthesis, with many reaction steps, low yield and poor environmental compatibility; the other is to obtain orlistat intermediates by microbial fermentation, and then the intermediates are processed Orlistat is synthesized by one-step hydrogenation, and orlistat produced by the second method is dominant. Regardless of the method, the orlistat obtained in the last step of the chemical reaction needs to be dried to remove the moisture and organic solvents in the product. The melting point of crystalline form II orlistat is only 43°C, which requires strict control of temperature and time during the drying process of the raw materials and finished preparations.
  • Orlistat's low melting point and poor solubility directly limit its application, and the melting point and solubility are often related to the crystal form of the substance.
  • the researches on the crystal form of orlistat in the prior art include: International patent WO2005026140 discloses the preparation methods of type I and type II orlistat, and the characteristic parameter maps of the two crystal forms, such as X-ray diffraction (XRD) Spectra, differential scanning calorimetry (DSC) spectra and infrared analysis (IR) spectra.
  • XRD X-ray diffraction
  • DSC differential scanning calorimetry
  • IR infrared analysis
  • the international patent WO2010084502 discloses a crystal form of orlistat and its XRD and IR characteristic parameters.
  • the crystallization is obtained by recrystallizing solid orlistat in a mixed system of polar solvent and non-polar organic solvent. Therefore, the solvent mixing system is preferably the acetone-heptane system, but the patent does not disclose the proportion of various solvents in the mixing system, nor does it disclose other structural characteristics of the obtained orlistat crystal form (whether it is a solvent or not). Compound) and pharmacological activity parameters.
  • the international patent WO2003047531 also discloses the type I and type II crystalline forms of orlistat, as well as the XRD patterns, thermogravimetric analysis (TGA) patterns and DSC patterns of these two crystalline forms, the preparation method of the crystals, and the preparation methods containing these two crystalline forms. It is a solid preparation in a crystalline form, but no activity data is disclosed, nor is it disclosed what advantages these two crystalline forms have compared to the orlistat type I and type II disclosed in the international patent WO2005026140.
  • Co-crystal refers to the crystal formed by the combination of active pharmaceutical ingredient (API) and cocrystal former (CCF) under the action of hydrogen bonds or other non-covalent bonds.
  • API and CCF are in a pure state. All are solid at room temperature, and there is a fixed stoichiometric ratio between the components. After API forms a eutectic, it can be improved in many aspects such as melting point, moisture absorption, stability, solubility and dissolution, bioavailability, bioavailability, release, and mechanical properties. Therefore, the eutectic theory is in the field of new drug research. Has broad application prospects.
  • the purpose of the present invention is to provide a co-crystal of orlistat and amino acid and a pharmaceutical composition containing the co-crystal.
  • the co-crystal has a higher melting point, can reduce the requirements for drying conditions in the preparation process of the raw material drug and the preparation, has a higher dissolution rate, and accelerates the onset of the drug.
  • the present invention uses the melting point and melting range as indicators to investigate the possibility of preparing co-crystals from a variety of common amino acids and orlistat by conventional co-crystal preparation methods.
  • the co-crystal preparation method is a drug Methods known in the chemical field, such as the method for preparing drug co-crystals disclosed by Gao Yuan et al. in "Research Progress of Drug Co-crystals" (Progress in Chemistry, 2010, 05:829-836), are incorporated herein by reference . It was found that among the potential co-crystal formations of amino acids under investigation, only L-leucine, L-valine, and L-proline can be used in different solvents by cooling crystallization method and orlistat. The formation of a crystal-like substance with a narrow melting range ( ⁇ 1°C) indicates that a single pure substance is formed.
  • the present invention uses nuclear magnetic resonance (1H-NMR), powder X-ray diffraction (XRPD), differential scanning calorimetry (DSC), and thermogravimetric analysis (TGA) to analyze the formation of orlistat and the above-mentioned eutectic.
  • the structure of the eutectic formed by the material was characterized, which further confirmed the formation of eutectic.
  • the present invention provides a co-crystal of orlistat and an amino acid, wherein the amino acid is selected from one of L-proline, L-leucine or L-valine.
  • the orlistat and L-proline form a co-crystal at a molar ratio of 1:1.
  • the orlistat and L-leucine form a co-crystal at a molar ratio of 1:1.
  • the orlistat and L-valine form a co-crystal at a molar ratio of 3:2.
  • the X-ray powder diffraction pattern of the co-crystal of orlistat and L-proline has characteristic absorption peaks at angles of 19.2°, 22.6°, 25.0° and 27.1°2 ⁇ 0.2°2 ⁇ .
  • the X-ray powder diffraction pattern of the co-crystal of orlistat and L-leucine has characteristics at 9.4°, 18.5°, 19.3°, 24.9° and 27.0°2 ⁇ 0.2°2 ⁇ angles. Absorption peak.
  • the X-ray powder diffraction pattern of the co-crystal of orlistat and L-valine is at 19.0°, 19.3°, 22.4°, 24.9°, 27.1° and 27.8°2 ⁇ 0.2°2 ⁇ angle There are characteristic absorption peaks.
  • the present invention also relates to a pharmaceutical composition containing the co-crystal.
  • the pharmaceutical composition is an oral solid preparation containing orlistat L-proline co-crystal and orlistat L-leucine co-crystal. At least one of the crystal and orlistat L-valine co-crystal is used as an active ingredient and is prepared with pharmaceutically acceptable additives.
  • the additive basically does not change the co-crystal formed by orlistat and amino acid, nor does it have any effect with any component in the pharmaceutical composition and is incompatible with the used orlistat amino acid co-crystal.
  • the oral solid preparation is prepared by a method known in the field of pharmaceutical preparations, for example, see Cui Fude, editor in chief, "Pharmacy” (7th edition) (Published by People's Medical Publishing House). Specifically, 1:1 orlistat L-proline co-crystal, 1:1 orlistat L-leucine co-crystal, or 3:2 orlistat L-valine co-crystal can be combined with At least one pharmaceutically acceptable excipient is mixed.
  • the excipient can be citric acid or dicalcium phosphate, or (a) a filler or bulking agent, for example, starch, lactose, sucrose, glucose, Mannitol and silicic acid; (b) binders, such as cellulose derivatives, starch, alginate, gelatin, polyvinylpyrrolidone, sucrose and acacia gum; (c) disintegrants, such as agar, carbonic acid Calcium, potato or tapioca starch, alginic acid, croscarmellose sodium, complex silicate and sodium carbonate; (d) solution retarders, such as paraffin wax; (e) absorption enhancers, such as quaternary ammonium compounds; (f) Wetting agents, such as cetyl alcohol and glyceryl monostearate, magnesium stearate, etc.; (g) adsorbents, such as kaolin and bentonite; and (h) lubricants, such as talc, hard Calcium fatty
  • oral solid preparations are commonly used preparations in the field, such as granules, capsules, tablets or pills.
  • the pharmaceutical composition is made into a capsule.
  • the melting points of the eutectic are 95.3°C, 130.3°C and 103.5°C, which are significantly higher than the melting point of orlistat type II in the commercially available orlistat capsules, which makes the drying process in the preparation of raw materials and preparations It can be carried out at a higher temperature, which shortens the drying time, improves the drying efficiency, and reduces the drying energy consumption.
  • Figure 1 is the solution proton NMR spectrum of commercially available medicinal type II orlistat.
  • Figure 2 shows the solution proton NMR spectrum of the 1:1 orlistat L-proline co-crystal.
  • Figure 3 shows the solution proton NMR spectrum of the 1:1 orlistat L-leucine co-crystal.
  • Figure 4 shows the solution proton NMR spectrum of the 3:2 orlistat L-valine co-crystal.
  • Figure 5 shows the XRPD pattern of the 1:1 orlistat L-proline co-crystal.
  • Figure 6 shows the XRPD pattern of the 1:1 orlistat L-leucine co-crystal.
  • Figure 7 is the XRPD pattern of the 3:2 orlistat L-valine co-crystal.
  • Figure 8 shows the DSC spectrum of the 1:1 orlistat L-proline co-crystal.
  • Figure 9 is the DSC spectrum of the 1:1 orlistat L-leucine co-crystal.
  • Figure 10 is the DSC spectrum of the 3:2 orlistat L-valine co-crystal.
  • Figure 11 shows the TGA spectrum of the 1:1 orlistat L-proline co-crystal.
  • Figure 12 shows the TGA spectrum of the 1:1 orlistat L-leucine co-crystal.
  • Figure 13 is the TGA spectrum of the 3:2 orlistat L-valine co-crystal.
  • Figure 14 is a dissolution profile of commercially available orlistat capsules.
  • Figure 15 shows the dissolution profile of 1:1 orlistat L-proline co-crystal capsules.
  • Figure 16 shows the dissolution profile of 1:1 orlistat L-leucine co-crystal capsules.
  • Figure 17 shows the dissolution profile of 3:2 orlistat L-valine co-crystal capsules.
  • Example 1 The 1:1 orlistat L-proline co-crystal and 1:1 orlistat L-leucine prepared in Example 1 according to the automatic melting point tester method included in the 2015 edition of the Chinese Pharmacopoeia The melting point and melting range of the eutectic and the 3:2 orlistat L-valine eutectic were determined. The results are shown in Table 1 below.
  • DSC Thermal analysis-Differential Scanning Calorimetry
  • TGA Thermogravimetric analysis
  • the co-crystal is 1:1 orlistat L-proline co-crystal, 1:1 orlistat L-leucine co-crystal or 3:2 orlistat L-valine co-crystal .
  • Determination of particle content According to the content determination method in the quality standard, determine the content of orlistat in the dry particles and calculate the theoretical loading.
  • 4Filling capsules According to the calculated theoretical filling quantity, fill the dry particles into No. 0 capsules (mainly composed of gelatin, titanium dioxide, lemon yellow, and bright blue).
  • Example 5 Determination of dissolution of co-crystal capsules containing orlistat and amino acid
  • the dissolution rate ( Use 3.5% sodium lauryl sulfate aqueous solution as the dissolution medium).
  • the average dissolution rate of various capsules at each time point is shown in Table 5 below.
  • Commercially available orlistat capsules, 1:1 orlistat L-proline capsules prepared in Example 4, 1:1 orlistat L-leucine capsules and 3:2 orlistat The dissolution curves of L-valine capsules are shown in Figure 14, Figure 15, Figure 16, and Figure 17, respectively.

Abstract

本发明属于医药技术领域，具体涉及一种奥利司他与氨基酸的共晶体及包含该共晶体的药物组合物。所述的奥利司他与L-脯氨酸、L-亮氨酸或L-缬氨酸以适当的摩尔比形成的共晶具有较高的熔点，分别为95.3℃、130.3℃与103.5℃，均显著高于市售奥利司他胶囊剂中的II型奥利司他，使得原料药制备与制剂制备过程中的干燥程序可以在较高的温度下进行，缩短了干燥时间，提高了干燥效率，降低了干燥能耗。此外，以所得的共晶作为原料制备胶囊剂，所得胶囊剂中奥利司他的溶出度均高于市售奥利司他胶囊中所用的II型奥利司他，其起效快于后者。

Description

奥利司他与氨基酸的共晶体及包含该共晶体的药物组合物 技术领域
本发明属于医药技术领域，具体涉及奥利司他与氨基酸的共晶体及包含该共晶体的药物组合物。
背景技术
奥利司他(orlistat)为由罗氏制药公司研发脂肪酶抑制剂类减肥药，商品名Xenical，上个世纪九十年代末率先在欧美上市，2001年在中国上市，并于2005年被中国食品药品监督管理局批准转为非处方药。其化学名为N-甲酰-L-亮氨酸(s)-1[(2s，3s)3-己基-4氧基-2-环氧丙基甲基]十二酯，也称四氢脂抑素(Tetrahydrolipstatin，THL)，是一种半合成的脂抑素衍生物，其化学结构式如下图所示：
Figure PCTCN2019119381-appb-000001
奥利司他以其Ⅱ晶型的胶囊剂与片剂供药用，也是目前国内外唯一一种不影响食欲、不作用于中枢神经系统的化学减肥药，安全性特征优越。市售制剂中的Ⅱ型奥利司他结晶为白色至灰白色结晶性粉末，基本不溶于水，易溶于氯仿，极易溶于甲醇与乙醇，且在生理pH值范围内无pKa值。目前，国内生产奥利司他有两种方法：一种是化学全合成，反应步骤多，收率低，环境兼容性差；另一种是微生物发酵得到奥利司他中间体，然后中间体经一步氢化合成奥利司他，第二种方法生产的奥利司他占主导地位。无论何种方法，都需要对最后一步化学反应所得的奥利司他进行干燥，以除去产品中水分与有机溶剂。而Ⅱ晶型奥利司他的熔点仅为43℃，从而需要对原料药及制剂成品干燥过程中对温度与时间予以严格的控制。
奥利司他的低熔点以及溶解性差直接限制其应用，而熔点与溶解性往往与物质的晶型有关。现有技术中关于奥利司他晶型的研究有：国际专利WO2005026140公开了Ⅰ型与Ⅱ型奥利司他的制备方法，以及两种晶型的特征参数图谱，如X射线衍射(XRD) 图谱、差示扫描量热(DSC)图谱与红外分析(IR)图谱。另有，国际专利WO2010084502公开了一种奥利司他结晶形式及其XRD与IR特征参数，该结晶是将固体奥利司他在极性溶剂与非极性有机溶剂的混合体系中重结晶而得，所述的溶剂混合体系优选了丙酮-庚烷体系，但该专利中未公开混合体系中各种溶剂所占比例，亦未公开所得奥利司他结晶形式的其他结构特征(是否为溶剂合物)与药理活性参数。此外，国际专利WO2003047531同样公开了奥利司他的Ⅰ型与Ⅱ型结晶形式，以及这两种结晶形式的XRD图谱、热重分析(TGA)图谱与DSC图谱、结晶的制备方法和含有此两种结晶形式的固体制剂，但未公开活性资料，未披露此两种结晶形式与国际专利WO2005026140公开的奥利司他Ⅰ型及Ⅱ型相比有何优势。
共晶是指药物活性成分(Active pharmaceutical ingredient，API)和共晶形成物(cocrystal former，CCF)在氢键或其他非共价键的作用下结合而成的晶体，其中API与CCF在纯态在室温下均为固体，并且各组分间存在固定的化学计量比。API形成共晶后，可以熔点、引湿性、稳定性、溶解度和溶出度、生物利用度、生物利用度、释放度、机械性能等诸多方面均会有所改善，因此共晶理论在新药研究领域有着广阔的应用前景。
目前没有关于利用奥利司他与氨基酸制备共晶形成物，以克服奥利司他存在熔点低、溶解性差的缺陷的相关报道。
发明内容
为解决现有技术中存在的技术问题，本发明的目的在于提供一种奥利司他与氨基酸的共晶体及包含该共晶体的药物组合物。所述的共晶体具有较高的熔点，可降低原料药与制剂的制备过程中对干燥条件的要求，并具有较高的溶出度，加快药物起效。
本发明通过如下技术方案以实现上述目的：
一方面，本发明以熔点与熔程为指标，考察了采用常规的共晶制备方法将多种常见的氨基酸与奥利司他制备成共晶体的可能性，所述的共晶制备方法是药物化学领域所已知的方法，比如高缘等人在“药物共晶研究进展”中披露的关于药物共晶的制备方法(化学进展，2010，05:829-836)，通过引用被并入本文。结果发现，在接受考察的氨基酸类潜在共晶形成物中，仅L-亮氨酸、L-缬氨酸、L-脯氨酸可在不同的溶剂中采用降温析晶法与奥利司他形成熔程窄(<1℃)的晶体状物质，说明形成了单一的纯净物。
另一方面，本发明分别采用核磁共振(1H-NMR)、粉末X-射线衍射(XRPD)、示差扫描量热法(DSC)、热重分析(TGA)对奥利司他与上述共晶形成物所形成的共晶进行了结构表征，从而进一步证实了共晶的形成。
基于此，本发明提供一种奥利司他与氨基酸共晶体，所述的氨基酸选自：L-脯氨酸、L-亮氨酸或L-缬氨酸中的一种。
进一步地，所述的奥利司他与L-脯氨酸以1:1的摩尔比形成共晶。
进一步地，所述的奥利司他与L-亮氨酸以1:1的摩尔比形成共晶。
进一步地，所述的奥利司他与L-缬氨酸以3:2的摩尔比形成共晶。
更进一步地，所述的奥利司他与L-脯氨酸共晶体的X-射线粉末衍射图在19.2°、22.6°、25.0°与27.1°2θ±0.2°2θ角处有特征吸收峰。
更进一步地，所述的奥利司他与L-亮氨酸共晶体的X-射线粉末衍射图在9.4°、18.5°、19.3°、24.9°与27.0°2θ±0.2°2θ角处有特征吸收峰。
更进一步地，所述的奥利司他与L-缬氨酸共晶体的X-射线粉末衍射图在19.0°、19.3°、22.4°、24.9°、27.1°与27.8°2θ±0.2°2θ角处有特征吸收峰。
此外，本发明还涉及一种含有所述共晶体的药物组合物，该药物组合物为口服固体制剂，以奥利司他L-脯氨酸共晶体、奥利司他L-亮氨酸共晶体、奥利司他L-缬氨酸共晶体中的至少一种作为有效成分，配以药学可接受的添加剂制备而成。所述的添加剂基本不改变奥利司他与氨基酸形成的共晶体，也不会与药物组合物中的任何成分发生任何作用而与所用的奥利司他氨基酸共晶体不相容。
所述的口服固体制剂通过药物制剂领域中已知的方法来制备，例如，参见崔福德主编，《药剂学》(第7版)(人民卫生出版社出版)。具体地，可以将1:1奥利司他L-脯氨酸共晶、1:1奥利司他L-亮氨酸共晶或3:2奥利司他L-缬氨酸共晶与至少一种药学上可接受的赋形剂相混合，所述赋形剂可以为柠檬酸或磷酸二钙，或者为(a)填充剂或增量剂，例如，淀粉、乳糖、蔗糖、葡萄糖、甘露醇和硅酸；(b)粘合剂，例如，纤维素衍生物、淀粉、海藻酸盐、明胶、聚乙烯基吡咯烷酮、蔗糖和金合欢树胶；(c)崩解剂，例如，琼脂、碳酸钙、马铃薯或木薯淀粉、海藻酸、交联羧甲纤维素钠、复合硅酸盐和碳酸钠；(d)溶液缓凝剂，例如，石蜡；(e)吸收促进剂，例如季铵化合物；(f)润湿剂，例如，鲸蜡醇和单硬脂酸甘油酯、硬脂酸镁等；(g)吸附剂，例如高岭土和皂粘土；和(h)润滑剂，例如，滑石粉，硬脂酸钙、硬脂酸镁、固体聚二醇、月桂基硫酸钠或它们的混合物。
进一步地，所述的口服固体制剂为本领域常用的制剂，如颗粒剂、胶囊剂、片剂或丸剂等。
优选地，所述的药物组合物被制成胶囊剂。
与现有技术相比，本发明的优势在于：
(1)本发明所提供的1:1奥利司他L-脯氨酸共晶体、1:1奥利司他L-亮氨酸共晶体与3:2奥利司他L-缬氨酸共晶体的熔点分别为95.3℃、130.3℃与103.5℃，均显著高于市售奥利司他胶囊剂中的Ⅱ型奥利司他的熔点，使得原料药制备与制剂制备过程中的干燥程序可以在较高的温度下进行，缩短了干燥时间，提高了干燥效率，降低了干燥能耗。
(2)溶出度试验发现，分别以本发明所提供的1:1奥利司他L-脯氨酸共晶体、1:1奥利司他L-亮氨酸共晶体或3:2奥利司他L-缬氨酸共晶体为原料药，按照常规药剂学方法所制备得到的三种胶囊剂在10分钟及以后的溶出度均高于市售奥利司他胶囊中所用的Ⅱ型奥利司他的溶出度，改性奥利司他的溶解性能，加快药物起效。
附图说明
图1为市售药用Ⅱ型奥利司他的溶液质子NMR图谱。
图2为1:1奥利司他L-脯氨酸共晶的溶液质子NMR图谱。
图3为1:1奥利司他L-亮氨酸共晶的溶液质子NMR图谱。
图4为3:2奥利司他L-缬氨酸共晶的溶液质子NMR图谱。
图5为1:1奥利司他L-脯氨酸共晶的XRPD图谱。
图6为1:1奥利司他L-亮氨酸共晶的XRPD图谱。
图7为3:2奥利司他L-缬氨酸共晶的XRPD图谱。
图8为1:1奥利司他L-脯氨酸共晶的DSC图谱。
图9为1:1奥利司他L-亮氨酸共晶的DSC图谱。
图10为3:2奥利司他L-缬氨酸共晶的DSC图谱。
图11为1:1奥利司他L-脯氨酸共晶的TGA图谱。
图12为1:1奥利司他L-亮氨酸共晶的TGA图谱。
图13为3:2奥利司他L-缬氨酸共晶的TGA图谱。
图14为市售奥利司他胶囊的溶出曲线图。
图15为1:1奥利司他L-脯氨酸共晶胶囊的溶出曲线图。
图16为1:1奥利司他L-亮氨酸共晶胶囊的溶出曲线图。
图17为3:2奥利司他L-缬氨酸共晶胶囊的溶出曲线图。
具体实施方式
以下通过具体实施方式进一步描述本发明，但本发明不仅仅限于以下实施例。
实施例1奥利司他与氨基酸共晶的制备
(1)1:1奥利司他L-脯氨酸共晶的制备研究
取0.496gⅡ型奥利司他(0.001mol)，置于100mL三颈烧瓶中，35℃水浴轻轻搅拌下缓慢滴加丙酮-正庚烷1:1(v/v)混合溶液，直至固体完全溶解；然后置于35℃下搅拌过夜后冷却至室温，缓慢滴加0.173mg/L-脯氨酸(0.0015mol)的饱和丙酮-正庚烷(1:1，v/v)溶液；再置于35℃下于振荡器中成熟3天；最后在冰浴条件下静置2天，真空过滤析出的固体，将析出的固体于真空箱中70℃下干燥4小时，得白色针状结晶型固体0.589g，总收率96.4％。
(2)1:1奥利司他L-亮氨酸共晶的制备研究
取0.496gⅡ型奥利司他(0.001mol)，置于100mL三颈烧瓶中，40℃水浴轻轻搅拌下缓慢滴加正辛醇，直至固体完全溶解；然后置于40℃下搅拌过夜后冷却至室温，缓慢滴加0.197mg/L-亮氨酸(0.0015mol)的饱和正辛醇溶液；再置于40℃下于振荡器中成熟3天；最后在冰浴条件下静置2天后真空过滤析出的固体，将析出的固体置于真空箱中70℃下干燥4小时，得白色片状结晶0.617g，总收率为98.4％。
(3)3:2奥利司他L-缬氨酸共晶的制备研究
取0.496gⅡ型奥利司他(0.001mol)，置于100mL三颈烧瓶中，35℃水浴轻轻搅拌下缓慢滴加异丙醇-氯仿(1:1)混合溶剂，直至固体完全溶解；然后置于35℃下搅拌过夜后冷却至室温，缓慢滴加0.176mg/L-缬氨酸(0.0015mol)的饱和异丙醇-氯仿(1:1)饱和溶液；再置于35℃下于振荡器中成熟3天；最后在冰浴条件下静置2天后真空过滤析出的固体，将析出的固体置于真空干燥箱中70℃下干燥4小时，得灰白色片状结晶0.547g，总收率54.7％。
实施例2奥利司他与氨基酸共晶熔点的测定
根据《中国药典》2015年版收载的熔点自动测定仪法对实施例1分别制得的1:1奥利司他L-脯氨酸共晶、1:1奥利司他L-亮氨酸共晶和3:2奥利司他L-缬氨酸共晶进行熔点和熔程测定，结果见下表1。
表1奥利司他与氨基酸共晶体的熔点测定结果
结果显示，本发明制得的1:1奥利司他L-脯氨酸共晶、1:1奥利司他L-亮氨酸共晶和3:2奥利司他L-缬氨酸共晶的熔程窄(<1℃)，表明制得的共晶体纯度高，为单一的纯净物。并且制得的共晶体的熔点均显著高于市售奥利司他胶囊剂中的Ⅱ型奥利司他的熔点(43℃)。
实施例3奥利司他与氨基酸共晶的表征
分别采用核磁共振(1H-NMR)、粉末X-射线衍射(XRPD)、示差扫描量热法(DSC)、热重分析(TGA)对实施例1分别制得的1:1奥利司他L-脯氨酸共晶、1:1奥利司他L-亮氨酸共晶和3:2奥利司他L-缬氨酸共晶进行结构表征，从而进一步证实共晶的形成，各项表征的仪器与条件如下表所示。
Figure PCTCN2019119381-appb-000002
具体地：
(1)溶液质子NMR：在装备有自动取样器并由DRX400控制台控制的Bruker-400MHz波长谱仪上记录1H-NMR谱。将样品溶解在d6-DMSO中用于分析。使用标准的Bruker负载实验，利用以Topsin v1.3(补丁级别8)运行的ICON-NMR v4.0.4(构造1)来获取数据。
结果：奥利司他的溶液质子NMR图谱如图1所示；
实施例1中所制备得到的1:1奥利司他L-脯氨酸共晶的溶液质子NMR图谱如图2所示，所有峰的积分面积是0.88～0.94ppm范围内峰积分面积的4.3倍，从而说明奥利司他与L-脯氨酸系以1:1的摩尔比形成共晶；
实施例1中所制备得到的1:1奥利司他L-亮氨酸共晶的溶液质子NMR图谱如图3所示，所有峰的积分面积是0.88～0.94ppm范围内峰积分面积的5.2倍，从而说明奥利司他与L-亮氨酸系以1:1的摩尔比形成共晶；
实施例1中所制备得到的3:2奥利司他L-缬氨酸共晶的溶液质子NMR图谱如图4所示，所有峰的积分面积是0.88～0.94ppm范围内峰积分面积的4.9倍，从而说明奥利司他与L-缬氨酸系以3:2的摩尔比形成共晶。
(2)X-射线粉末衍射(XRPD)表征：使用CuKα辐射(40kV，40mA)、θ-2θ测角仪、V4接收狭缝、Ge单色仪和Lynxeye检测器，在Bruker D8衍射仪上获得样品的X-射线粉末衍射图样。使用经认证的Corundum标准(NIST1976)对仪器进行性能检查，使用0.05°2θ的步长和0.5秒的步进时间，在0°至50°2θ的角度范围内在环境温度收集数据。使用接收的未经研磨的粉末，将在环境条件下运行的样品制备为平板样本。将约35mg样品轻轻堆积到切成经抛光的、零背景(510)的硅片中的腔内。使用Diffrac Plus EVA v11.0.02或v13.0.0.2，对所有样品进行分析。
结果：实施例1中所制备得到的1∶1奥利司他L-脯氨酸共晶的XRPD图见图5，其主要吸收峰如下表2所示。
表2 1∶1奥利司他L-脯氨酸共晶的XRPD测定结果
角(°2θ±0.2°2θ) d值(埃) 强度(％)
9.2 9.5 vw
11.3 8.0 w
12.2 7.3 m
12.6 7.1 vw
13.3 6.7 w
14.6 5.99 vw
15.8 5.68 vw
16.5 5.31 m
17.1 5.22 w
17.6 5.08 m
18.2 4.86 vw
18.9 4.71 m
19.2 4.63 s
19.6 4.58 w
21.2 4.23 w
22.3 4.02 m
22.6 3.97 s
24.0 3.74 w
24.4 3.67 m
25.0 3.59 vs
25.4 3.40 w
26.4 3.40 m
27.1 3.31 s
27.9 3.22 m
28.7 3.13 w
29.3 3.06 w
34.8 2.59 w
实施例1中所制备得到的1:1奥利司他L-亮氨酸共晶的XRPD图见图6，其主要吸收峰如下表3所示。
表3 1:1奥利司他L-亮氨酸共晶的XRPD测定结果
实施例1中所制备得到的3:2奥利司他L-缬氨酸共晶的XRPD图见图7，其主要吸收峰如下表4所示。
表4 3:2奥利司他L-缬氨酸共晶的XRPD测定结果
(3)热分析-差示扫描量热(DSC)：在装备有50个位置自动取样器的TA仪器Q2000上收集DSC数据。使用蓝宝石进行热容量的校准，并使用经认证的铟进行能量和温度的校准。通常情况下，在针孔铝盘中，10℃/分钟将0.8～1.2mg的各个样品从25℃回执至350℃。在样品上倒挂50mL/分钟的干燥氮气流。仪器控制软件是Advantage(用于Q系列，v2.8.0.392)和Thermal Advantage v4.8.3。使用Universal Analysis v4.3A软件进行所有数据分析。
结果：实施例1中制备得到的1:1奥利司他L-脯氨酸共晶、1:1奥利司他L-亮氨酸共晶与3:2奥利司他L-缬氨酸共晶的DSC图分别见图8、图9与图10。
(3)热重分析(TGA)：在装备有16个位置自动取样器的TA仪器Q500TGA上收集TGA数据。使用经认证的铝镍合金(Alumel)对所述仪器进行温度校准。通常情况下，将5～30mg的各个样品装载到预先去除了皮重的铂坩埚的铝DSC盘上，并以10℃/分钟的速度从室温加热至350℃。在样品上面保持60mL/分钟的氮气。仪器控制软件是Advantage(用于Q系列，v2.8.0.392)和Thermal Advantage v4.8.3。
结果：实施例1中制备得到的1:1奥利司他L-脯氨酸共晶、1:1奥利司他L-亮氨酸共晶与3:2奥利司他L-缬氨酸共晶的TGA图分别见图11、图12与图13。
实施例4含奥利司他与氨基酸共晶胶囊的制备
(1)处方组成
Figure PCTCN2019119381-appb-000003
所述的共晶为1:1奥利司他L-脯氨酸共晶、1:1奥利司他L-亮氨酸共晶或3:2奥利司他L-缬氨酸共晶。
(2)胶囊制备
①混合：预先将十二烷基硫酸钠、交联聚维酮、羧甲淀粉钠、微晶纤维素过80目筛，得细粉备用；然后按处方量称取十二烷基硫酸钠、交联聚维酮、羧甲淀粉钠和微晶纤维素细粉以及共晶；先将十二烷基硫酸钠、交联聚维酮、羧甲淀粉钠混合均匀，再加入微晶纤维素和共晶混合均匀，过80目筛两遍，即得混匀的粉末。
②制粒与干燥：往混匀的粉末中缓慢加入含10％聚维酮K30的50％乙醇溶液，制软材，20目挤压过筛制湿颗粒，湿颗粒置60℃鼓风干燥箱中烘干6小时，取出过20目筛整粒。
③颗粒含量测定：按质量标准中含量测定方法进行，测定干燥颗粒中奥利司他含量，计算理论装量。
④灌装胶囊：按计算出的理论装量，将干燥颗粒灌装入0号胶囊(主要由明胶、钛白粉、柠檬黄、亮蓝构成)中。
实施例5含奥利司他与氨基酸共晶胶囊的溶出度测定
按照中国药典2015版二部附录XC浆法测定市售奥利司他胶囊(中山万汉医药科技有限公司提供，批号0015856)与实施4中制备得到的含有各种共晶的胶囊的溶出度(以3.5％十二烷基硫酸钠水溶液为溶出介质)。各种胶囊各时间点下的平均溶出度如下表5所示。市售奥利司他胶囊、实施例4中制备得到的1:1奥利司他L-脯氨酸胶囊、1:1奥利司他L-亮氨酸胶囊与3:2奥利司他L-缬氨酸胶囊的溶出曲线分别见图14、图15、图16和图17。
表5含奥利司他与氨基酸共晶胶囊的溶出度测定
Figure PCTCN2019119381-appb-000004
以上仅是本发明的优选实施方式，应当指出的是，上述优选实施方式不应视为对本发明的限制，本发明的保护范围应当以权利要求所限定的范围为准。对于本技术领域的普通技术人员来说，在不脱离本发明的精神和范围内，还可以做出若干改进和润饰，这些改进和润饰也应视为本发明的保护范围。

Claims (10)

  1. 一种奥利司他与氨基酸共晶体，其特征在于，所述的氨基酸选自：L-脯氨酸、L-亮氨酸或L-缬氨酸中的一种。
  2. 根据权利要求1所述的共晶体，其特征在于，所述的奥利司他与L-脯氨酸以1:1的摩尔比形成共晶。
  3. 根据权利要求2所述的共晶体，其特征在于，所述的奥利司他与L-脯氨酸共晶体的X-射线粉末衍射图在19.2°、22.6°、25.0°与27.1°2θ±0.2°2θ角处有特征吸收峰。
  4. 根据权利要求1所述的共晶体，其特征在于，所述的奥利司他与L-亮氨酸以1:1的摩尔比形成共晶。
  5. 根据权利要求4所述的共晶体，其特征在于，所述的奥利司他与L-亮氨酸共晶体的X-射线粉末衍射图在9.4°、18.5°、19.3°、24.9°与27.0°2θ±0.2°2θ角处有特征吸收峰。
  6. 根据权利要求1所述的共晶体，其特征在于，所述的奥利司他与L-缬氨酸以3:2的摩尔比形成共晶。
  7. 根据权利要求6所述的共晶体，其特征在于，所述的奥利司他与L-缬氨酸共晶体的X-射线粉末衍射图在19.0°、19.3°、22.4°、24.9°、27.1°与27.8°2θ±0.2°2θ角处有特征吸收峰。
  8. 一种药物组合物，其特征在于，所述的药物组合物包含如权利要求1-7任一所述的至少一种共晶体。
  9. 根据权利要求8所述的药物组合物，其特征在于，所述的药物组合物为口服固体制剂，所述的口服固体制剂以权利要求1-7任一所述的至少一种共晶体作为有效成分，配以药学可接受的添加剂制备而成。
  10. 根据权利要求9所述的药物组合物，其特征在于，所述口服固体制剂为胶囊剂。
PCT/CN2019/119381 2019-11-19 2019-11-19 奥利司他与氨基酸的共晶体及包含该共晶体的药物组合物 WO2021097650A1 (zh)

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CN106349192A (zh) * 2016-10-10 2017-01-25 中山万汉医药科技有限公司 奥利司他与氨基酸的共晶体及包含该共晶体的药物组合物

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CN106349192A (zh) * 2016-10-10 2017-01-25 中山万汉医药科技有限公司 奥利司他与氨基酸的共晶体及包含该共晶体的药物组合物

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