WO2004019989A1 - Compose d'inclusion a base de nateglinide - Google Patents

Compose d'inclusion a base de nateglinide Download PDF

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Publication number
WO2004019989A1
WO2004019989A1 PCT/CN2003/000707 CN0300707W WO2004019989A1 WO 2004019989 A1 WO2004019989 A1 WO 2004019989A1 CN 0300707 W CN0300707 W CN 0300707W WO 2004019989 A1 WO2004019989 A1 WO 2004019989A1
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Prior art keywords
nateglinide
cyclodextrin
inclusion
inclusion compound
derivative
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PCT/CN2003/000707
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English (en)
French (fr)
Inventor
Zhanqi Niu
Lifang Wang
Yujie Chen
Dongmin Shen
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Zhongqi Pharmaceutical Technology (Shijiazhuang) Co., Ltd.
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Priority to AU2003255130A priority Critical patent/AU2003255130A1/en
Publication of WO2004019989A1 publication Critical patent/WO2004019989A1/zh

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    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B82—NANOTECHNOLOGY
    • B82Y—SPECIFIC USES OR APPLICATIONS OF NANOSTRUCTURES; MEASUREMENT OR ANALYSIS OF NANOSTRUCTURES; MANUFACTURE OR TREATMENT OF NANOSTRUCTURES
    • B82Y5/00—Nanobiotechnology or nanomedicine, e.g. protein engineering or drug delivery
    • 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
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
    • A61K31/197—Carboxylic acids, e.g. valproic acid having an amino group the amino and the carboxyl groups being attached to the same acyclic carbon chain, e.g. gamma-aminobutyric acid [GABA], beta-alanine, epsilon-aminocaproic acid or pantothenic acid
    • A61K31/198—Alpha-amino acids, e.g. alanine or edetic acid [EDTA]
    • 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
    • A61K47/50—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/69—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit
    • A61K47/6949—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit inclusion complexes, e.g. clathrates, cavitates or fullerenes
    • A61K47/6951—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit inclusion complexes, e.g. clathrates, cavitates or fullerenes using cyclodextrin
    • 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
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics

Definitions

  • the invention relates to a novel inclusion compound of nateglinide with P-cyclodextrin or a derivative molecule thereof, a preparation method of the inclusion compound, and a pharmaceutical composition containing the inclusion compound.
  • Naglinide ((-)-N- (trans-4-isopropylcyclohexylformyl) -D-phenylalanine) is a phenylalanine derivative, which is a novel oral drug Sugar medicine.
  • glucose-lowering drugs such as sulfonylureas, biguanides, ⁇ -glucosidase inhibitors, and insulin sensitizers
  • this drug causes calcium influx and increases calcium flow by closing potassium channels on insulin ⁇ -cell membranes. The concentration of calcium in the cells stimulates the secretion of insulin and achieves the purpose of reducing glucose.
  • nateglinide Due to the physical properties of Naglinetna in the following aspects: (1) Very poor fluidity and high static electricity. (2) There are three crystalline forms of nateglinide, B, H, and S. The stability of the three is very different. The type of nateglinide of type B is unstable and easily crystallized. At present, there is only the crystalline form of H type. Lienide is used in preparations, and the recently discovered S-type nateglinide has not been reported in the literature. In addition, nateglinide is insoluble in water and has a bad odor, which places higher requirements on the formulation process. For the reasons mentioned above, nateglinide not only brings great difficulties to the production of preparations, but also the production of raw materials is quite difficult.
  • Naglinide ordinary tablet (30mg) prepared according to European Patent 0965339 has a low dissolution rate, 900 ml of phosphate buffer solution (pH 7.4) is used as a solvent, and the rotation speed is 75 rpm, and the dissolution rate is measured in 10 minutes, and the dissolution amount About 75% ⁇ 85% of the indicated amount. If water is used as the solvent, the dissolution amount is only 10% ⁇ 30% of the labeled amount, which does not meet the quality requirements and cannot be applied to the production of preparations.
  • ⁇ -Cyclodextrin is an excellent inclusion material.
  • this special structure of cyclic hollow In the molecular cavity there is a CH group and an oxygen atom on a glycosidic bond, which is hydrophobic.
  • One end of the hole has C 2 and C 3 linked hydroxyl groups on the glucose molecule, and the other end has C 6 linked hydroxyl groups.
  • the two ends of the tubular structure are hydrophilic, so ⁇ -cyclodextrin and its derivatives
  • it can improve the solubility of poorly soluble drugs, mask bad taste, and improve bioavailability. Therefore, it is widely used in formulation research and production. Summary of the invention
  • the purpose of the present invention is to improve the above-mentioned defects of nateglinide by inclusion technology. It is because of the special structure of ⁇ -cyclodextrin that we germinated the idea of including nateglinide with P-cyclodextrin. Experiment The result is satisfactory. Inclusion of nateglinide by ⁇ -cyclodextrin not only improves the dissolution rate and dissolution rate of nateglinide, but also ensures the stability of the crystalline form, which produces the pharmacological effect of nateglinide. Unexpected effect.
  • ⁇ -cyclodextrin derivatives have a similar molecular structure to ⁇ -cyclodextrin, and they also produce the same inclusion effect for nateglinide.
  • nalglinide is embedded in the molecular cavity that is hydrophobic in the inner cavity and hydrophilic at the upper and lower ends, the nalglinide and ⁇ -cyclodextrin or Its derivatives are included without affecting the molecular skeleton structure of ⁇ -cyclodextrin and its derivatives, which cuts off the connection between the active molecule and the surrounding environment and plays a protective and stable role. It masks the odor of nateglinide, improves the solubility, and overcomes the shortcomings of the poor fluidity of the drug substance and the large static electricity, thereby simplifying the preparation process and facilitating industrial production.
  • the nateglinide inclusion compound according to the present invention contains the active ingredient nateglinide and the inclusion agent ⁇ -cyclodextrin or a derivative thereof.
  • the molar ratio of nateglinide to ⁇ -cyclodextrin or its derivative molecule is 1: ⁇ ⁇ ⁇ .
  • Derivatives of inclusion agents ⁇ -cyclodextrin are: hydroxyethyl ⁇ -cyclodextrin, hydroxypropyl ⁇ -cyclodextrin,
  • the inclusion agent is preferably ⁇ -cyclodextrin to obtain a nateglinide- ⁇ -cyclodextrin inclusion compound.
  • the molecular inclusion compound of the present invention can be prepared by the following three methods:
  • Saturated solution method ⁇ -cyclodextrin or a derivative thereof is prepared into a saturated aqueous solution, and an appropriate amount of a lower alcohol is used in accordance with a molar ratio of nateglinide to ⁇ -cyclodextrin or a derivative thereof of 1: 1 to 10 Dissolve nateglinide, add to the above saturated solution, stir to form a precipitate, wash with the same lower alcohol, and dry to obtain nateglinide inclusion compound.
  • Ultrasound method ⁇ -cyclodextrin or its derivative is prepared into a saturated aqueous solution, and the molecular weight of nateglinide and ⁇ -cyclodextrin or its derivative is 1: 1 to 10, and dissolved with an appropriate amount of a lower alcohol. Naglinide is added to the saturated solution, placed in an ultrasonic bath, shaken, filtered, washed, and dried to obtain the nateglinide inclusion compound.
  • the lower alcohol used for dissolving and washing nateglinide is an alcohol having 1 to 6 carbon atoms.
  • it may be methanol, ethanol, n-propanol, or isopropanol, and ethanol is preferred.
  • the nateglinide inclusion compound can be used as a starting material or an ingredient in pharmaceutical compositions for the preparation of tablets, capsules, granules and all adaptable pharmaceutical preparations. Therefore, the present invention also relates to a pharmaceutical composition comprising a nateglinide inclusion compound and a pharmaceutically acceptable carrier or excipient.
  • the inclusion compound of the present invention can be used within the range that does not impair the effects of the present invention by adding additives used in conventional formulation compositions.
  • additives include excipients such as microcrystalline cellulose, compressible starch, lactose, mannitol, and polyethylene glycol; sodium carboxymethyl starch, cross-linking Disintegrants such as polyvinylpyrrolidone and croscarmellose sodium; Binders such as sodium hydroxypropylmethylcellulose and polyvinylpyrrolidone; flavoring agents such as citric acid and flavor; stearin Lubricants such as magnesium acid and talc.
  • the preparation composition of the present invention can be prepared according to a general wet granulation method. That is, the above components are thoroughly mixed, granulated with water, and dried, and then prepared into different dosage forms by means of formulation.
  • the clathrate product according to the present invention is a loose powder, has good fluidity, and has almost no odor of nateglinide.
  • nateglinide and ⁇ -cyclodextrin When the clathrate formed by nateglinide and ⁇ -cyclodextrin is dissolved in water, it is It exists in the form of clathrate and does not separate, thereby ensuring the stability of the crystal form. Therefore, when the inclusion compound is used as a starting material or an ingredient to prepare an oral preparation, the bioavailability is high and the stability is good.
  • Figure 1 is the infrared spectrum of nateglinide- ⁇ -cyclodextrin inclusion complex
  • Figure 2 is the X-ray diffraction pattern of nateglinide- ⁇ -cyclodextrin inclusion complex
  • FIG. 3 is a differential thermal scan pattern of nateglinide- ⁇ -cyclodextrin inclusion complex.
  • the inclusion agent is preferably -cyclodextrin to give nateglinide- ⁇ -cyclodextrin inclusion compound.
  • Naglinide- ⁇ -cyclodextrin inclusion compound is prepared by a saturated solvent method, an ultrasonic method, and a grinding method. In the preparation, ethanol is preferably used as a dissolving agent of nateglinide.
  • Example 1 Preparation of Naglip ⁇ " ⁇ ⁇ -cyclodextrin inclusion compound by saturated solution method
  • the nateglinide content was determined by HPLC at 11.34%.
  • Infrared spectrum After nateglinide raw material, ⁇ -cyclodextrin, nateglinide- ⁇ -cyclodextrin inclusion compound, nateglinide and ⁇ -cyclodextrin mixture were tabletted with potassium bromide, Scanning the infrared absorption spectrum in the range of 4000cm- 1 AOOcm- 1 , the nateglinide raw material has strong absorption peaks at 1714 cm 1650 cm " 1 , 1542 cm-1212 cm- 1 , and there is no lattice in the inclusion compound These four characteristic absorption peaks of Nai raw material prove that nateglinide and ⁇ -cyclodextrin have formed a stable new phase of inclusion complex, as shown in FIG. 1.
  • X-Ray Diffraction Powder X-ray diffraction tests were performed on nateglinide raw materials, ⁇ -cyclodextrin, nateglinide- ⁇ -cyclodextrin inclusion compounds, nateglinide and -cyclodextrin mixture
  • the specific conditions are: a graphite monochromator, 40kV, 150mA, a scanning speed of 8 ° / min, and a step size of 0.02. .
  • Differential thermal scanning Differential calorimetry was used to separate nateglinide raw materials, ⁇ -cyclodextrin, nateglinide- ⁇ -cyclodextrin molecular inclusion compounds, and mixtures of nateglinide and ⁇ -cyclodextrin molecules
  • the analyzer performs scanning. The measurement conditions are based on a crucible. The sampling volume is about 2 ⁇ 3mg, the scanning speed is 5 ° C / min, and the scanning range is from room temperature to 400 ° C.
  • the ingredients shown in the tablet formulation were weighed and, except for magnesium stearate, the ingredients were mixed in a speed mixer for 10 minutes.
  • a polyvinylpyrrolidone-containing binder (15 to 75 parts by weight) containing particles having a particle size of about 100 to 500 ⁇ m was added, and the mixture was granulated by stirring for 10 minutes. Granulate all soft materials into granules and dry.
  • Magnesium stearate was added to the obtained dry granules, mixed with a type mixer for 2 minutes, and compressed into tablets having a diameter of 12 mm, a thickness of 3 mm, and a weight of 400 mg.
  • Measurement of dissolution Water was used as the solvent, the rotation speed was 75 rpm, and the dissolution was measured after 10 minutes. The dissolution amount was about 90% or more of the indicated amount.
  • Flavor 20g polyethylene glycol 6000 5g The ingredients shown in the formula were weighed, except for polyethylene glycol 6000, and the ingredients were placed in a fast mixer and mixed for 10 minutes. Next, a polyvinylpyrrolidone-containing binder (15 to 35 parts by weight) capable of producing particles having a particle size of about 800 m was added, and the mixture was granulated by stirring for 10 minutes. All the granules were granulated with granules and dried. Polyethylene glycol 6000 was added to the obtained dry granules, and mixed with a V-type mixer for 2 minutes, and divided into granules each having a minimum package of about 1.1 grams.

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Description

00707
一种那格列奈包合物 技术领域
本发明涉及一种新的那格列奈与 P -环糊精或者其衍生物分子的包 合物、 该包合物的制备方法以及包含该包合物的药物组合物。 背景技术
那格列奈（ (-) -N- (反式 -4-异丙基环己基甲酰基） -D-苯丙氨酸） 为 苯丙氨酸衍生物， 是一种具有新型结构的口服降糖药物。 与现有的磺酰 脲类、 双胍类、 α -糖甙酶抑制剂、 胰岛素增敏剂等降糖药相比， 该药 物通过关闭胰岛素 β -细胞膜上的钾通道， 造成钙内流， 增加细胞内钙 的浓度， 从而剌激胰岛素的分泌， 达到降糖目的。
由于那格列奈在以下几个方面的物理特性： （1 ) 流动性极差， 静电 大。 （2)那格列奈存在 B、 H、 S三种晶型， 三者的稳定性差异很大， B 型的那格列奈不稳定， 易发生转晶， 目前仅有 H型的那格列奈用于制 剂， 最近发现的 S型的那格列奈， 是否有药理活性未见文献报道。此外， 那格列奈在水中不溶， 且有不良气味， 对制剂工艺提出了更高的要求。 因上述几个方面的原因， 那格列奈不仅给制剂生产带来了很大困难， 而 且原料生产也相当困难。
根据欧洲专利 0965339制备的那格列奈普通片剂 （30mg)， 溶出度 低， 以磷酸盐缓冲液 （ pH 7.4) 900ml为溶剂， 转速 75转 /分， 经 10 分钟， 测定溶出度， 溶出量约为标示量的 75 %~85 %。 若改用水为溶剂， 则溶出量仅为标示量的 10%〜30%， 不符合质量要求， 无法应用于制剂 生产。
β -环糊精是一种优良的包合材料， 在这种环状中空的特殊结构 中， 分子空穴内有一 CH基和糖甙键上的氧原子， 呈疏水性。 空穴的一 端开口处有葡萄糖分子上 C2、 C3连结的羟基， 另一端开口有 C6连结的 羟基存在， 筒状结构的两端为亲水性， 因此 β -环糊精及其衍生物作为 一种优良的包合材料， 可以改善难溶药物的溶解性， 掩盖不良味道， 提 高生物利用度等， 因此被广泛地应用于制剂研究及生产。 发明内容
本发明的目的是通过包合技术改善那格列奈的上述缺陷， 正是由于 β -环糊精的特殊结构， 使我们萌发了用 Ρ -环糊精包合那格列奈的设 想， 实验结果达到了令人满意的效果。 通过 β -环糊精对那格列奈的包 合， 不仅提高了那格列奈的溶解速度和溶出度， 还保证了晶型的稳定， 对正常发挥那格列奈的药效作用产生了意想不到的作用。
β -环糊精衍生物有着与 β -环糊精相似的分子结构， 同样对那格列 奈产生相同的包合作用。
这种包合作用主要来源于范德华力， 当那格列奈分子嵌入这种内腔 疏水而上下两端开口处亲水的分子空穴中时， 那格列奈分子与 β -环糊 精或者其衍生物包合， 且不影响 β -环糊精及其衍生物的分子骨架结构， 这就切断了活性分子与周围环境的联系， 起到保护和稳定的作用。 掩盖 了那格列奈臭味， 提高了溶解度， 克服了原料药流动性极差， 静电大等 不足之处， 从而使制剂工艺简化， 便于工业化生产。
在本发明所述的那格列奈包合物中， 含有活性成分那格列奈和包合 剂 β -环糊精或者其衍生物。 优选的是， 那格列奈与 β -环糊精或者其衍 生物分子的摩尔比为 1 : ι〜ιο。
包合剂 β -环糊精的衍生物是：羟乙基 β -环糊精、羟丙基 β -环糊精、
2、 6-二甲基 β -环糊精、 2、 3、 6-三甲基 β -环糊精、 2、 6-二乙基 β -环 糊精、 2、 3、 6-三乙基 -环糊精或麦芽糖基 3 -环糊精。 包合剂优选 β -环糊精， 得到那格列奈一 β -环糊精包合物。
通过对该包合物进行红外光谱、 差式热分析、 X-射线衍射实验， 发 现以上特征数据既不同于那格列奈， 也不同于 β -环糊精， 证明生成了 新物相。
本发明所述分子包合物可以通过以下三种方法制备：
饱和溶液法： 将 β -环糊精或者其衍生物配制成饱和水溶液， 按照 那格列奈与 β -环糊精或者其衍生物分子摩尔比为 1 : 1~10 的用量， 用 适量低级醇溶解那格列奈， 加至上述饱和溶液， 搅拌， 形成沉淀， 用同 样低级醇洗涤， 干燥， 即得那格列奈包合物。
超声波法： 将 β -环糊精或者其衍生物配制成饱和水溶液， 按照那 格列奈与 β -环糊精或者其衍生物分子摩尔比为 1 : 1~10 的用量， 用适 量低级醇溶解那格列奈， 加至上述饱和溶液， 置于超声波池内， 震荡、 抽滤、 洗涤、 干燥， 即得那格列奈包合物。
研磨法： 将 β -环糊精或者其衍生物加少许水润湿， 按照那格列奈 与 β -环糊精或者其衍生物分子摩尔比为 1 : 1-10 的用量， 用适量低级 醇溶解那格列奈， 研磨至逐渐粘稠呈糊状， 干燥、 洗涤， 即得那格列奈 包合物。
用于溶解、 洗涤那格列奈的低级醇是具有 1一 6个碳原子的醇， 例 如可以是甲醇、 乙醇、 正丙醇或异丙醇， 其中优选乙醇。
那格列奈包合物可以作为药物组合物中的一种起始原料或一种成 分， 用来制备片剂、胶囊剂、颗粒剂以及一切可适应的药物制剂。 因此， 本发明还涉及包含那格列奈包合物以及药物学上可接受的载体或赋形剂 的药物组合物。
在本发明的包合物中， 加入通常制剂组合物中所使用的添加剂， 可 在不损害本发明效果的范围内使用。 此类添加剂可列举微晶纤维素， 可 压性淀粉， 乳糖， 甘露醇， 聚乙二醇等的赋形剂； 羧甲基淀粉钠， 交联 聚乙烯吡咯烷酮， 交联羧甲基纤维素钠等的崩解剂； 羟丙基甲基纤维素 钠， 聚乙烯吡咯垸酮等的粘合剂； 柠檬酸， 香精等的矫味剂； 硬脂酸镁， 滑石粉等的润滑剂。
本发明的制剂组合物可依据一般的湿式造粒法制备。 即， 将上述成 分充分混合后， 使用水进行造粒， 干燥后， 通过制剂手段制备成不同的 剂型。
本发明所述包合物产品呈疏松状粉末， 流动性好， 几乎没有了那格 列奈原料的臭味， 那格列奈与 β -环糊精形成的包合物在水中溶解时， 是以包合物的形式存在， 并不分离， 从而保证晶型的稳定。 因此该包合 物作为起始原料或成分制备口服制剂时， 生物利用度高， 稳定性好。 附图说明
图 1是那格列奈一 β -环糊精包合物红外图谱
图 2是那格列奈一 β -环糊精包合物 X-射线衍射图谱
图 3是那格列奈一 β -环糊精包合物差示热扫描图谱 具体实施方式
包合剂优选 -环糊精得到那格列奈一 β -环糊精包合物。
使用饱和溶媒法、 超声波法、 研磨法制备那格列奈一 β -环糊精包 合物， 制备中优选乙醇作为那格列奈的溶解剂。 实施例 1: 饱和溶液法制备那格列^" ·β -环糊精包合物
称取 β -环糊精 10.5克（0.0093mol)，置于附有电动搅拌装置的 500ml 三颈瓶中， 加水 200ml，至 50°C水浴使熔化。那格列奈 1克（0.0031mol) 以 10ml无水乙醇溶解， 并将其滴入 β -环糊精溶液中， 恒温搅拌 6小时， 析出大量白色沉淀。 反应液静置沉淀， 抽滤， 沉淀物以适量的无水乙醇 洗漆。 置于真空干燥， 即得那格列奈一 -环糊精包合物 8.08克。
用 HPLC测定那格列奈含量 11.34%。
为确定那格列奈一 β -环 f胡精分子包合物不同于那格列奈原料、 3 - 环糊精、 那格列奈与 β-环糊精分子的简单混合物， 分别进行红外光谱、 X-射线衍射、 差示热扫描， 结果如下：
红外光谱： 将那格列奈原料、 β-环糊精、 那格列奈一 β-环糊精包 合物、 那格列奈与 β-环糊精混合物分别用溴化钾压片后， 在 4000cm-1 AOOcm-1范围内扫描红外吸收光谱图， 那格列奈原料在 1714 cm 1650 cm"1, 1542 cm- 1214 cm-1处有强吸收峰， 而该包合物中没有格列奈原 料这四个特征吸收峰， 由此证明那格列奈与 β -环糊精已经形成稳定包 合物新物相， 如附图 1所示。
X-射线衍射： 将那格列奈原料、 β-环糊精、 那格列奈一 β-环糊精 包合物、 那格列奈与 -环糊精混合物分别进行粉末 X-射线衍射试验， 具体条件为： 石墨单色器， 40kV， 150mA, 扫描速度为 8° /分钟， 步 长为 0.02。 。 那格列奈一 β -环糊精包合物的 X-射线衍射图谱均不同于 将那格列奈原料、 β-环糊精、 那格列奈与 β-环糊精混合物的 X-射线衍 射图谱， 特别是在 2 Θ =17.4° 位置， 出现一个新的强吸收峰， 由此可证 明该包合物为一新物相， 如附图 2所示。
差示热扫描： 将那格列奈原料、 β-环糊精、 那格列奈一 β-环糊精 分子包合物、 那格列奈与 β -环糊精分子混合物分别用差示热分析仪进 行扫描，测定条件以坩埚为参比，取样量约 2〜3mg，扫描速度为 5°C/min， 扫描范围为室温〜 400°C， 那格列奈原料的特征峰相当与它的熔化峰 (136.7 ), β-环糊精的特征峰为它的水分蒸发峰 （50〜90°C) 和它的 分解峰 （300~370°C)， 那格列奈与 β-环糊精分子混合物同时出现那格 列奈、 β-环糊精的特征峰， 而那格列奈一 β-环糊精分子包合物中， 那 格列奈的特征峰消失。 因此差示热扫描显示： 那格列奈一 β-环糊精分 子包合物为一新物相， 而非物理混合， 如附图 3所示。 实施例 2: 饱和溶液法制备那格列奈一羟丙基 β -环糊精包合物
称取羟丙基 β—环糊精 34 (0.0252mol) 克， 溶于 200ml水中， 另 称取 4克那格列奈 （0.0126mol)， 用 13ml无水乙醇溶解， 搅拌下将那 格列奈溶液加入羟丙基 β—环糊精溶液中， 待溶解完全， 置于 70Ό旋 转蒸发仪中除去水， 3 小时后得到白色固体粉末， 置于真空干燥， 即得 那格列奈环一羟丙基 β -环糊精包合物 38克。
用 HPLC测定含量： 9.98 % 实施例 3: 超声波法制备那格列 环糊精包合物
称取 lg那格列奈溶于 15毫升的无水乙醇中， 待用。 称取 β -环糊 精 7g加入盛有 200ml蒸馏水的烧杯中， 待全溶后烧杯放在超声波池中， 水温为 40°C左右。 将那格列奈醇溶液加入 —环糊精溶液中， 超声波 振荡 30分钟， 取出， 抽滤， 洗涤， 干燥， 即得包合物 5.5 克。 测得含 量为 10.25 %。
实施例 4: 研磨法制备那格列 环糊精包合物
将 Ί克 β—环糊精置于研钵中， 加 2~5倍的水润湿后， 再加入 lg 那格列奈溶于 10毫升的无水乙醇溶液， 充分研磨混合 30分钟， 研磨至 逐渐粘稠呈糊状， 干燥后用无水乙醇洗净， 即得包合物 6.2克。 测得含 实施例 5: 那格列奈包合物片剂的制备
配方：
那格列奈一 β -环糊精包合物 244g
可压性淀粉 100g
交联羧甲基纤维素钠 50g
硬脂酸镁 6g 制成 1000片 压片工艺：
称量片剂配方中所示的各成分， 除了硬脂酸镁以外， 将各成分放入 快速搅拌机混合 10分钟。 其次添加可制得粒径 100〜500 μ ηι颗粒左右 的含聚乙烯吡咯烷酮的粘合剂 （15〜75 重量份）， 并进行搅拌制粒 10 分钟。 将所有软材用颗粒机制粒， 干燥。 与所得的干颗粒中加入硬脂酸 镁， 并以型混合机混合 2 分钟， 并压片做成直径 12mm， 厚度 3mm， 重量 400mg的片剂。
测定溶出度： 以水为溶剂， 转速 75转 /分， 经 10分钟， 测定溶出 度， 溶出量约为标示量的 90%以上。
实施例 6： 那格列奈包合物胶囊剂的制备
配方：
那格列奈一 β -环糊精包合物 244g 乳糖 15g 微晶纤维素 20g 羧甲基淀粉钠 12g 滑石粉 3g
制成 1000粒 制备工艺：
称量配方中所示的各成分， 除了滑石粉以外， 将各成分放入快速搅 拌机混合 10 分钟。 充分搅拌混合后， 加入适量纯水， 并进行搅拌制粒 10 分钟。 将所有的颗粒用颗粒机制粒， 干燥。 于所得的干颗粒中加入 滑石粉， 并以 V型混合机混合 2分钟， 充填至 1 #胶囊中， 得平均粒重 294mg的胶囊剂。 实施例 7： 那格列奈包合物颗粒剂的制备
配方：
那格列奈一 β -环糊精包合物 244g 乳糖 150g 淀粉 100g 甘露醇 250g 麦芽糖糊精 300g 梓檬酸 8g
香精 20g 聚乙二醇 6000 5g 称量配方中所示的各成分， 除了聚乙二醇 6000 以外， 将各成分放 入快速搅拌机混合 10分钟。 其次添加可制得粒径 800 m颗粒左右的 含聚乙烯吡咯垸酮的粘合剂（15〜35 重量份）， 并进行搅拌制粒 10分 钟。 将所有的颗粒用颗粒机制粒， 干燥。 于所得的干颗粒中加入聚乙二 醇 6000， 并以 V型混合机混合 2分钟， 分装得每一个最小包装为 1.1 克左右的颗粒剂。

Claims

权利要求:
1、 一种那格列奈包合物， 其含有活性成分那格列奈和包合剂 β -环 糊精或者其衍生物。
2、 根据权利要求 1所述的那格列奈包合物， 其中所述包合剂 β -环 糊精的衍生物是： 羟乙基 -环糊精、 羟丙基 - β -环糊精、 2、 6-二甲基 β -环糊精、 2、 3、 6-三甲基 β -环糊精、 2、 6-二乙基 β -环糊精、 2、 3、 6-三乙基 β -环糊精或麦芽糖基 β -环糊精。
3、 一种那格列奈包合物的制备方法， 其包括以下步骤： 将 β -环糊 精或者其衍生物配制成饱和水溶液， 按照那格列奈与 β -环糊精或者其 衍生物分子摩尔比为 1 : 1~10的用量， 用适量低级醇溶解那格列奈， 加 至上述饱和溶液， 搅拌， 形成沉淀， 用同样低级醇洗涤， 干燥， 即得那 格列奈包合物。
4、 根据权利要求 3 所述的那格列奈包合物的制备方法， 其中所述 低级醇可以是甲醇、 乙醇、 正丙醇、 异丙醇。
5、 一种那格列奈包合物的制备方法， 其包括以下步骤： 将 β -环糊 精或者其衍生物配制成饱和水溶液， 按照那格列奈与 β -环糊精或者其 衍生物分子摩尔比为 1 : 1~10的用量， 用适量低级醇溶解那格列奈， 加 至上述饱和溶液， 置于超声波池内， 震荡、 抽滤、 洗涤、 干燥， 即得那 格列奈包合物。
6、 根据权利要求 5所述的那格列奈包合物的制备方法， 其中所述 低级醇可以是甲醇、 乙醇、 正丙醇、 异丙醇。
7、 一种那格列奈包合物的制备方法， 其包括以下步骤： 将 β -环糊 精或者其衍生物加少许水润湿， 按照那格列奈与 β -环糊精或者其衍生 物分子摩尔比为 1 : 1〜10的用量， 用适量低级醇溶解那格列奈， 研磨至 逐渐粘稠呈糊状， 干燥、 洗涤， 即得那格列奈包合物。
8、 根据权利要求 7所述的那格列奈包合物的制备方法， 其中所述 低级醇可以是甲醇、 乙醇、 正丙醇或异丙醇。
9、 一种药物组合物， 其包括那格列奈包合物以及药物学上可接受 的载体或赋形剂。
PCT/CN2003/000707 2002-08-27 2003-08-22 Compose d'inclusion a base de nateglinide WO2004019989A1 (fr)

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
FR2912061A1 (fr) * 2007-02-01 2008-08-08 Aliscience Soc Par Actions Sim Complexes d'inclusion de cysteine, leur presparation et les compositions les contenant

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0965339A1 (en) * 1996-11-15 1999-12-22 Ajinomoto Co., Inc. Tabletted preparation
WO2001047557A1 (fr) * 1999-12-28 2001-07-05 Ajinomoto Co., Inc. Preparations orales pour diabetes

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0965339A1 (en) * 1996-11-15 1999-12-22 Ajinomoto Co., Inc. Tabletted preparation
WO2001047557A1 (fr) * 1999-12-28 2001-07-05 Ajinomoto Co., Inc. Preparations orales pour diabetes

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
FR2912061A1 (fr) * 2007-02-01 2008-08-08 Aliscience Soc Par Actions Sim Complexes d'inclusion de cysteine, leur presparation et les compositions les contenant
WO2008107569A3 (fr) * 2007-02-01 2008-11-06 Aliscience Complexes d'inclusion de cysteine, leur preparation et les compositions les contenant

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