WO2020000831A1 - 一种酮咯酸氨丁三醇片剂 - Google Patents

一种酮咯酸氨丁三醇片剂 Download PDF

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Publication number
WO2020000831A1
WO2020000831A1 PCT/CN2018/113331 CN2018113331W WO2020000831A1 WO 2020000831 A1 WO2020000831 A1 WO 2020000831A1 CN 2018113331 W CN2018113331 W CN 2018113331W WO 2020000831 A1 WO2020000831 A1 WO 2020000831A1
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Prior art keywords
ketorolac tromethamine
solid dispersion
povidone
ketorolac
tablet
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PCT/CN2018/113331
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English (en)
French (fr)
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孙建合
王昭钦
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山东新时代药业有限公司
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Publication of WO2020000831A1 publication Critical patent/WO2020000831A1/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
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/141—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers
    • A61K9/146—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers with organic macromolecular compounds
    • 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
    • A61K31/407—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 condensed with other heterocyclic ring systems, e.g. ketorolac, physostigmine
    • 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
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/2027—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
    • 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
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/2031—Organic macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyethylene glycol, polyethylene oxide, poloxamers
    • 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
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/28—Dragees; Coated pills or tablets, e.g. with film or compression coating
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]

Definitions

  • the invention belongs to the technical field of pharmaceutical preparations, and particularly relates to a ketorolac tromethamine tablet.
  • Ketorolac tromethamine is a non-steroidal antipyretic and analgesic, which inhibits the synthesis of prostaglandin (PG) to achieve analgesic, anti-inflammatory and antipyretic effects, rather than acting on opioid receptors or stimulating Opioid peptide release in vivo.
  • Ketorolac tromethamine can be converted into ketorolac in the human body to play a therapeutic effect.
  • Ketorolac can inhibit arachidonic acid or collagen-induced platelet aggregation, but it has no effect on ADP-induced platelet aggregation.
  • the mechanism of action of steroid drugs is similar, the action site is PG, arachidonic acid.
  • Ketorolac tromethamine can relieve toxic pain of various muscles, soft tissues and joints. It is suitable for short-term treatment of acute and severe pain that requires opioid analgesics. It is usually used for postoperative pain, but not for mild or severe pain. For the treatment of chronic pain, the drug is not addictive. In a standard animal model of analgesic activity, the analgesic activity of ketorolac tromethamine is 800 times that of aspirin, which is much stronger than indomethacin and naproxen, which is better than that of baotaisong.
  • ketorolac tromethamine is mainly used in oral and injection preparations, such as capsules and injections.
  • injection preparations such as capsules and injections.
  • Oral administration is welcomed by the majority of patients due to its convenience.
  • the solid oral administration method is slow in drug absorption, and for patients with acute and severe pain, a rapid analgesic method is most needed.
  • the main reason for the slow onset of action of solid oral drugs is the slow dissolution of ketorolac tromethamine; and ketorolac tromethamine is unstable to light, heat, acid and alkali, and it is prone to decarboxylation oxidation and produce impurities. , To a certain extent affect the safety of clinical medication. Therefore, there is an urgent need to provide a stable, fast-dissolving ketorolac tromethamine tablet.
  • ketorolac tromethamine solid oral preparations in the prior art, which are unstable to light, heat, acid, and alkali, and are prone to decarboxylation oxidation and produce impurities
  • the present invention provides a ketorolac tromethamine Triol tablets, said tablets have high dissolution and good stability.
  • ketorolac tromethamine is poorly water-soluble, so preparing it as a solid dispersion can effectively improve its dissolution; the inventor unexpectedly found in the test that poloxamer was mixed with other water-soluble carriers
  • the use of the prepared solid dispersion can not only improve the dissolution of the drug, but also effectively improve the stability of the drug, avoid the oxidation reaction of ketorolac tromethamine to generate impurities, and thereby improve the safety of clinical medication.
  • a ketorolac tromethamine solid dispersion contains a water-soluble carrier material, and the water-soluble carrier material is a mixture of poloxamer and a polyethylene glycol-based carrier or a povidone-based carrier.
  • the mass ratio of ketorolac tromethamine to the water-soluble carrier material is 1: 5 ⁇ 8
  • poloxamer is selected from poloxamer 188.
  • the polyethylene glycol-based carrier is PEG4000 or PEG6000.
  • the degree of polymerization of the povidone-based carrier is K15, K25, K30 or K90.
  • the mass ratio of the poloxamer to the polyethylene glycol-based carrier or the povidone-based carrier is 1: 2 to 4.
  • a method for preparing ketorolac tromethamine solid dispersion dissolving ketorolac tromethamine and a water-soluble carrier material in an organic solvent, removing the organic solvent, and obtaining a ketorolac tromethamine solid dispersion .
  • the organic solvent is selected from one or more of ethanol, acetone, dichloromethane, and chloroform.
  • a ketorolac tromethamine tablet prepared from the ketorolac tromethamine solid dispersion.
  • the ketorolac tromethamine tablet also contains excipients, disintegrants and lubricants.
  • the ketorolac tromethamine tablet further contains an excipient, and the excipient is selected from one or more of lactose, microcrystalline cellulose, pregelatinized starch, and mannitol.
  • the ketorolac tromethamine tablet further contains a disintegrant, the disintegrant being selected from the group consisting of crospovidone, low-substituted hydroxypropyl cellulose, croscarmellose sodium, and carboxymethyl One or more of sodium starch.
  • the ketorolac tromethamine tablet also contains a lubricant, and the lubricant is magnesium stearate or talc.
  • the ketorolac tromethamine tablet contains the following components by weight:
  • Ketorolac tromethamine solid dispersion 1 serving excipient 1 ⁇ 1.2 servings Disintegrant 0.2 copies Lubricant 0.02 copies
  • the invention also provides a method for preparing ketorolac tromethamine tablets, which specifically includes the following steps:
  • ketorolac tromethamine solid dispersion is mechanically pulverized; a prescribed amount of the pulverized ketorolac tromethamine solid dispersion is mixed with the additional excipients, uniformly compressed, and tableted to obtain ketorolac Butytriol tablets.
  • the ketorolac tromethamine tablet of the present invention improves the dissolution rate of the drug by dispersing it in a water-soluble carrier, thereby shortening its onset time.
  • the drug and the water-soluble carrier material are dispersed in an organic reagent, thereby Makes the drug more evenly dispersed.
  • a ketorolac solid dispersion is prepared by mixing poloxamer with a polyethylene glycol-based or povidone-based carrier material, and the drug can also be effectively improved on the basis of improving the dissolution rate of ketorolac tromethamine.
  • the stability Therefore, the influence of light on the drug is avoided, the generation of impurities is reduced, and the drug is more stable.
  • the ketorolac tromethamine tablet provided by the present invention has a simple preparation process and is suitable for industrial production.
  • Preparation method mechanically pulverize the ketorolac tromethamine solid dispersion; weigh a prescribed amount of the pulverized ketorolac tromethamine solid dispersion and add the auxiliary materials to uniformly mix, tablet, and film coat to obtain Ketorolac tromethamine tablets.
  • Preparation method mechanically pulverize the ketorolac tromethamine solid dispersion; weigh a prescribed amount of the pulverized ketorolac tromethamine solid dispersion and add the auxiliary materials to uniformly mix, tablet, and film coat to obtain Ketorolac tromethamine tablets.
  • Zh Preparation method Dissolve ketorolac tromethamine in chloroform; dissolve povidone K15 and poloxamer 188 in chloroform by stirring; add the above while stirring The solutions were mixed; chloroform was removed by spray drying to obtain a solid dispersion.
  • Ketorolac tromethamine solid dispersion 90g Pregelatinized starch 99g Crospovidone 18g Magnesium stearate 1.8g Silica 0.7g
  • Preparation method mechanically pulverize the ketorolac tromethamine solid dispersion; weigh a prescribed amount of the pulverized ketorolac tromethamine solid dispersion and add the auxiliary materials to uniformly mix, tablet, and film coat to obtain Ketorolac tromethamine tablets.
  • Zh Preparation method dissolving ketorolac tromethamine in ethanol; dissolving or dispersing povidone K30 and poloxamer 188 in ethanol; mixing the above solution by adding while stirring; spraying The ethanol was removed by drying to obtain a solid dispersion.
  • Preparation method mechanically pulverize the ketorolac tromethamine solid dispersion; weigh a prescribed amount of the pulverized ketorolac tromethamine solid dispersion and add the auxiliary materials to uniformly mix, tablet, and film coat to obtain Ketorolac tromethamine tablets.
  • Zh Preparation method Dissolving ketorolac tromethamine in ethanol; dissolving or dispersing povidone K90 and poloxamer 188 in ethanol; mixing the above solutions by adding while stirring; flow The ethanol was removed by a chemical bed drying method to obtain a solid dispersion.
  • Preparation method mechanically pulverize the ketorolac tromethamine solid dispersion; weigh a prescribed amount of the pulverized ketorolac tromethamine solid dispersion and add the auxiliary materials to uniformly mix, tablet, and film coat to obtain Ketorolac tromethamine tablets.
  • ketorolac tromethamine is dissolved in acetone; povidone K25 and poloxamer 188 are dissolved or dispersed in acetone by stirring; the above solution is mixed by adding while stirring; rotating The acetone was removed in an evaporator to obtain a solid dispersion.
  • Preparation method mechanically pulverize the ketorolac tromethamine solid dispersion; weigh a prescribed amount of the pulverized ketorolac tromethamine solid dispersion and add the auxiliary materials to uniformly mix, tablet, and film coat to obtain Ketorolac tromethamine tablets.
  • Preparation method mechanically pulverize the ketorolac tromethamine solid dispersion; weigh a prescribed amount of the pulverized ketorolac tromethamine solid dispersion and add the auxiliary materials to uniformly mix, tablet, and film coat to obtain Ketorolac tromethamine tablets.
  • Zh Preparation method Dissolve ketorolac tromethamine in ethanol; dissolve or disperse PEG4000 and poloxamer 188 in ethanol; mix the above solution by adding while stirring; remove by spray drying Ethanol to obtain a solid dispersion.
  • Preparation method mechanically pulverize the ketorolac tromethamine solid dispersion; weigh a prescribed amount of the pulverized ketorolac tromethamine solid dispersion and add the auxiliary materials to uniformly mix, tablet, and film coat to obtain Ketorolac tromethamine tablets.
  • Zh Preparation method Dissolve ketorolac tromethamine in ethanol; dissolve or disperse PEG4000 and poloxamer 188 in ethanol; mix the above solution by adding while stirring; remove by spray drying Ethanol to obtain a solid dispersion.
  • Preparation method mechanically pulverize the ketorolac tromethamine solid dispersion; weigh a prescribed amount of the pulverized ketorolac tromethamine solid dispersion and add the auxiliary materials to uniformly mix, tablet, and film coat to obtain Ketorolac tromethamine tablets.
  • Preparation method mechanically pulverize the ketorolac tromethamine solid dispersion; weigh a prescribed amount of the pulverized ketorolac tromethamine solid dispersion and add the auxiliary materials to uniformly mix, tablet, and film coat to obtain Ketorolac tromethamine tablets.
  • Zh Preparation method Dissolve ketorolac tromethamine in ethanol; dissolve or disperse PEG4000 in ethanol; mix the above solution by adding while stirring; remove ethanol from the rotary evaporator to obtain a solid Dispersions.
  • Preparation method mechanically pulverize the ketorolac tromethamine solid dispersion; weigh a prescribed amount of the pulverized ketorolac tromethamine solid dispersion and add the auxiliary materials to uniformly mix, tablet, and film coat to obtain Ketorolac tromethamine tablets.
  • Preparation method mechanically pulverize the ketorolac tromethamine solid dispersion; weigh a prescribed amount of the pulverized ketorolac tromethamine solid dispersion and add the auxiliary materials to uniformly mix, tablet, and film coat to obtain Ketorolac tromethamine tablets.
  • Preparation method mechanically pulverize the ketorolac tromethamine solid dispersion; weigh a prescribed amount of the pulverized ketorolac tromethamine solid dispersion and add the auxiliary materials to uniformly mix, tablet, and film coat to obtain Ketorolac tromethamine tablets.
  • ketorolac tromethamine is mixed with other auxiliary materials through an 80-mesh sieve, compressed, and film-coated to obtain ketorolac tromethamine tablets.
  • the tablets in Examples 1-10 and Comparative Examples 1-4 were taken and tested in accordance with the relevant substance determination method (2015 edition Part 4 General Principle 0512 High Performance Liquid Chromatography).
  • the column was Alltima-C18 (250mm ⁇ 4.6 mm, 5 ⁇ m); mobile phase: 0.02mol / L ammonium dihydrogen phosphate solution (pH adjusted to 3.0 with phosphoric acid) -acetonitrile (65:35), flow rate: 1.2ml / min, column temperature: 40 ° C, injection volume: 20 ⁇ l, detection wavelength: 313 nm; sample concentration: 3 mg / ml.
  • Table 2 The test results of related substances in the ketorolac tromethamine tablet examples and comparative examples are shown in Table 2.

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Abstract

本发明属于医药制剂领域，具体涉及一种酮咯酸氨丁三醇片剂，本发明将酮咯酸氨丁三醇制备成固体分散体再制备成片剂，不仅大大提高了酮咯酸氨丁三醇的溶出度还有效提高了其稳定性。有效避免了酮咯酸氨丁三醇因光热等因素产生的杂质，提高了临床用药的安全性。

Description

一种酮咯酸氨丁三醇片剂 技术领域
本发明属于医药制剂技术领域，具体涉及一种酮咯酸氨丁三醇片剂。
 背景技术
酮咯酸氨丁三醇是一种非甾体类解热镇痛药，通过抑制前列腺素(PG)的合成而达到止痛、抗炎和退热的作用，而非作用于阿片受体或激发体内阿片肽的释放。酮咯酸氨丁三醇在人体内能转化为酮咯酸发挥疗效，酮咯酸能抑制花生四烯酸或胶原诱发的血小板聚集作用，而对ADP诱发的血小板聚集无效，它与其他的非甾体药物作用机制相似，作用位点是PG、花生四烯酸。酮咯酸氨丁三醇可以缓解各种肌肉、软组织和关节的中毒疼痛，适用于需要阿片镇痛药的急性较严重疼痛的短期治疗，通常用于手术后阵痛，而不适用于轻度或慢性疼痛的治疗，该药无成瘾性。在标准的阵痛活性动物模型中，酮咯酸氨丁三醇的镇痛活性是阿司匹林的800倍，比消炎痛和萘普生强的多，优于保泰松。
目前临床上所用的酮咯酸氨丁三醇主要有口服给药和注射给药制剂，如胶囊、注射液等。注射液主要有国外的品种，价格较高，使用不方便。口服给药以其方便服用的优点，受到广大患者的欢迎。然而固体口服给药方式在药物吸收上较慢，而对于急性、严重疼痛的患者最需要快速的镇痛方式。固体口服给药药物起效慢的主要原因在于酮咯酸氨丁三醇溶出较慢；并且酮咯酸氨丁三醇对光、热、酸、碱均不稳定，易发生脱羧氧化反应产生杂质，在一定程度上影响了临床用药安全。因此亟需提供一种稳定、快速溶出的酮咯酸氨丁三醇片剂。
 技术问题
针对现有技术中酮咯酸氨丁三醇固体口服制剂的溶出较慢，对光、热、酸、碱不稳定易发生脱羧氧化反应产生杂质的缺陷，本发明提供一种酮咯酸氨丁三醇片剂，所述的片剂溶出度高且稳定性好。
 技术解决方案
发明人考虑，由于酮咯酸氨丁三醇水溶性较差，将其制备成固体分散体可有效提高其溶出度；发明人在试验中意外发现，采用泊洛沙姆与其他水溶性载体混合使用制备固体分散体，不仅可以提高药物的溶出度，还可以有效提高药物的稳定性，避免酮咯酸氨丁三醇发生氧化反应生成杂质，进而提高临床用药的安全性。
本发明的技术方案如下：
一种酮咯酸氨丁三醇固体分散体，它含有水溶性载体材料，所述的水溶性载体材料为泊洛沙姆和聚乙二醇类载体或聚维酮类载体的混合物。
优选地，酮咯酸氨丁三醇与水溶性载体材料的质量比为1：5~8
优选地，泊洛沙姆选自泊洛沙姆188。
优选地，聚乙二醇类载体为PEG4000或PEG6000。
优选地，聚维酮类载体的聚合度为K15，K25，K30或K90 。
优选地，泊洛沙姆与聚乙二醇类载体或聚维酮类载体的质量比为1：2~4 。
一种酮咯酸氨丁三醇固体分散体的制备方法，将酮咯酸氨丁三醇与水溶性载体材料溶解在有机溶剂中，除去有机溶剂，得到酮咯酸氨丁三醇固体分散体。
其中，所述的有机溶剂选自乙醇、丙酮、二氯甲烷、三氯甲烷中的一种或几种。
一种由所述酮咯酸氨丁三醇固体分散体制备而成的酮咯酸氨丁三醇片剂。
所述的酮咯酸氨丁三醇片剂还含有赋形剂，崩解剂和润滑剂。
所述的酮咯酸氨丁三醇片剂还含有赋形剂，所述赋形剂选自乳糖、微晶纤维素、预胶化淀粉、甘露醇中的一种或几种。
所述的酮咯酸氨丁三醇片剂还含有崩解剂，所述的崩解剂选自交联聚维酮、低取代羟丙纤维素、交联羧甲基纤维素钠，羧甲基淀粉钠中的一种或几种。
所述的酮咯酸氨丁三醇片剂还含有润滑剂，所述的润滑剂为硬脂酸镁或滑石粉。
所述的酮咯酸氨丁三醇片剂含有如下重量份的组分：
酮咯酸氨丁三醇固体分散体 1份
赋形剂 1~1.2份
崩解剂 0.2份
润滑剂 0.02份
本发明还提供一种酮咯酸氨丁三醇片的制备方法：具体包括如下步骤：
将酮咯酸氨丁三醇固体分散体进行机械粉碎；称取处方量的粉碎的酮咯酸氨丁三醇固体分散体与外加辅料混合均匀，压片，包衣，即得酮咯酸氨丁三醇片。
 有益效果
本发明的酮咯酸氨丁三醇片，通过将药物分散在水溶性载体中从而提高了其溶出速率，进而缩短了其起效时间，另外药物与水溶性载体材料分散在有机试剂中，从而使药物分散更均匀。本发明采用泊洛沙姆与聚乙二醇类或聚维酮类载体材料混合制备酮咯酸固体分散体，在提高了酮咯酸氨丁三醇的溶出度的基础上还可以有效提高药物的稳定性。从而避免了光照对药物的影响，减少了杂质的产生，使得药物更加稳定。另外，本发明提供的酮咯酸氨丁三醇片的制备工艺简单，适合工业化生产。
 本发明的实施方式
以下内容通过一些实施例具体阐述本发明，应该理解的是这些实施例仅用于例证的目的，并不用来限制本发明。
实施例1
固体分散体配方：
酮咯酸氨丁三醇 10g
泊洛沙姆188 10g
PEG4000 40g
    制备方法：将酮咯酸氨丁三醇溶解在乙醇中；将PEG4000和泊洛沙姆188以搅拌的方式溶解或分散在乙醇中；以边搅拌边加入的方式将上述溶液混合；旋转蒸发仪中除去乙醇，得到固体分散体。
酮咯酸氨丁三醇片剂的制备：
处方：
酮咯酸氨丁三醇固体分散体 60g
乳糖 72g
羧甲基淀粉钠 12g
硬脂酸镁 1.2g
制备方法：将酮咯酸氨丁三醇固体分散体进行机械粉碎；称取处方量的粉碎的酮咯酸氨丁三醇固体分散体与外加辅料混合均匀，压片，薄膜包衣，即得酮咯酸氨丁三醇片。
实施例2
固体分散体配方：
酮咯酸氨丁三醇 10g
泊洛沙姆188 20g
PEG6000 40g
    制备方法：将酮咯酸氨丁三醇溶解在二氯甲烷中；将PEG6000和泊洛沙姆188以搅拌的方式溶解或分散在二氯甲烷中；以边搅拌边加入的方式将上述溶液混合；流化床干燥法除去二氯甲烷，得到固体分散体。
酮咯酸氨丁三醇片剂的制备：
处方： 
酮咯酸氨丁三醇固体分散体 70g
甘露醇 70g
交联羧甲基纤维素钠 14g
滑石粉 1.4g
制备方法：将酮咯酸氨丁三醇固体分散体进行机械粉碎；称取处方量的粉碎的酮咯酸氨丁三醇固体分散体与外加辅料混合均匀，压片，薄膜包衣，即得酮咯酸氨丁三醇片。
实施例3
固体分散体配方：
酮咯酸氨丁三醇 10g
泊洛沙姆188 20g
聚维酮K15 60g
    制备方法：将酮咯酸氨丁三醇溶解在三氯甲烷中；将聚维酮K15和泊洛沙姆188以搅拌的方式溶解或分散在三氯甲烷中；以边搅拌边加入的方式将上述溶液混合；喷雾干燥法除去三氯甲烷，得到固体分散体。
酮咯酸氨丁三醇片剂的制备：
处方： 
酮咯酸氨丁三醇固体分散体 90g
预胶化淀粉 99g
交联聚维酮 18g
硬脂酸镁 1.8g
二氧化硅 0.7g
制备方法：将酮咯酸氨丁三醇固体分散体进行机械粉碎；称取处方量的粉碎的酮咯酸氨丁三醇固体分散体与外加辅料混合均匀，压片，薄膜包衣，即得酮咯酸氨丁三醇片。
实施例4
固体分散体配方：
酮咯酸氨丁三醇 10g
泊洛沙姆188 20g
聚维酮K30 40g
    制备方法：将酮咯酸氨丁三醇溶解在乙醇中；将聚维酮K30和泊洛沙姆188以搅拌的方式溶解或分散在乙醇中；以边搅拌边加入的方式将上述溶液混合；喷雾干燥法除去乙醇，得到固体分散体。
酮咯酸氨丁三醇片剂的制备：
处方：
酮咯酸氨丁三醇固体分散体 70g
微晶纤维素 80g
低取代羟丙纤维素 14g
硬脂酸镁 1.4g
制备方法：将酮咯酸氨丁三醇固体分散体进行机械粉碎；称取处方量的粉碎的酮咯酸氨丁三醇固体分散体与外加辅料混合均匀，压片，薄膜包衣，即得酮咯酸氨丁三醇片。
实施例5
固体分散体配方：
酮咯酸氨丁三醇 10g
泊洛沙姆188 10g
聚维酮K90 40g
    制备方法：将酮咯酸氨丁三醇溶解在乙醇中；将聚维酮K90和泊洛沙姆188以搅拌的方式溶解或分散在乙醇中；以边搅拌边加入的方式将上述溶液混合；流化床干燥法除去乙醇，得到固体分散体。
酮咯酸氨丁三醇片剂的制备：
处方：
酮咯酸氨丁三醇固体分散体 60g
乳糖 72g
交联羧甲基纤维素钠 12g
滑石粉 1.2g
制备方法：将酮咯酸氨丁三醇固体分散体进行机械粉碎；称取处方量的粉碎的酮咯酸氨丁三醇固体分散体与外加辅料混合均匀，压片，薄膜包衣，即得酮咯酸氨丁三醇片。
实施例6
固体分散体配方：
酮咯酸氨丁三醇 10g
泊洛沙姆188 20g
聚维酮K25 60g
    制备方法：将酮咯酸氨丁三醇溶解在丙酮中；将聚维酮K25和泊洛沙姆188以搅拌的方式溶解或分散在丙酮中；以边搅拌边加入的方式将上述溶液混合；旋转蒸发仪中除去丙酮，得到固体分散体。
酮咯酸氨丁三醇片剂的制备：
处方： 
酮咯酸氨丁三醇固体分散体 90g
乳糖 90g
交联聚维酮 18g
硬脂酸镁 1.8g
二氧化硅 0.5g
制备方法：将酮咯酸氨丁三醇固体分散体进行机械粉碎；称取处方量的粉碎的酮咯酸氨丁三醇固体分散体与外加辅料混合均匀，压片，薄膜包衣，即得酮咯酸氨丁三醇片。
实施例7
固体分散体配方：
酮咯酸氨丁三醇 10g
泊洛沙姆188 15g
PEG4000 45g
    制备方法：将酮咯酸氨丁三醇溶解在乙醇中；将PEG4000和泊洛沙姆188以搅拌的方式溶解或分散在乙醇中；以边搅拌边加入的方式将上述溶液混合；旋转蒸发仪中除去乙醇，得到固体分散体。
酮咯酸氨丁三醇片剂的制备：
处方：   
酮咯酸氨丁三醇固体分散体 70g
微晶纤维素 72g
交联羧甲基纤维素钠 12g
硬脂酸镁 1.2g
制备方法：将酮咯酸氨丁三醇固体分散体进行机械粉碎；称取处方量的粉碎的酮咯酸氨丁三醇固体分散体与外加辅料混合均匀，压片，薄膜包衣，即得酮咯酸氨丁三醇片。
实施例8
固体分散体配方：
酮咯酸氨丁三醇 10g
泊洛沙姆188 10g
PEG4000 30g
    制备方法：将酮咯酸氨丁三醇溶解在乙醇中；将PEG4000和泊洛沙姆188以搅拌的方式溶解或分散在乙醇中；以边搅拌边加入的方式将上述溶液混合；喷雾干燥法除去乙醇，得到固体分散体。
酮咯酸氨丁三醇片剂的制备：
处方： 
酮咯酸氨丁三醇固体分散体 50g
乳糖 60g
羧甲基淀粉钠 10g
硬脂酸镁 1.0g
制备方法：将酮咯酸氨丁三醇固体分散体进行机械粉碎；称取处方量的粉碎的酮咯酸氨丁三醇固体分散体与外加辅料混合均匀，压片，薄膜包衣，即得酮咯酸氨丁三醇片。
实施例9
固体分散体配方：
酮咯酸氨丁三醇 10g
泊洛沙姆188 10g
PEG4000 50g
    制备方法：将酮咯酸氨丁三醇溶解在乙醇中；将PEG4000和泊洛沙姆188以搅拌的方式溶解或分散在乙醇中；以边搅拌边加入的方式将上述溶液混合；喷雾干燥法除去乙醇，得到固体分散体。
酮咯酸氨丁三醇片剂的制备：
处方：
酮咯酸氨丁三醇固体分散体 70g
乳糖 72g
羧甲基淀粉钠 12g
硬脂酸镁 1.2g
制备方法：将酮咯酸氨丁三醇固体分散体进行机械粉碎；称取处方量的粉碎的酮咯酸氨丁三醇固体分散体与外加辅料混合均匀，压片，薄膜包衣，即得酮咯酸氨丁三醇片。
实施例10
固体分散体配方：
酮咯酸氨丁三醇 10g
泊洛沙姆188 25g
PEG4000 25g
    制备方法：将酮咯酸氨丁三醇溶解在乙醇中；将PEG4000和泊洛沙姆188以搅拌的方式溶解或分散在乙醇中；以边搅拌边加入的方式将上述溶液混合；旋转蒸发仪中除去乙醇，得到固体分散体。
酮咯酸氨丁三醇片剂的制备：
处方：
酮咯酸氨丁三醇固体分散体 60g
乳糖 72g
羧甲基淀粉钠 12g
硬脂酸镁 1.2g
制备方法：将酮咯酸氨丁三醇固体分散体进行机械粉碎；称取处方量的粉碎的酮咯酸氨丁三醇固体分散体与外加辅料混合均匀，压片，薄膜包衣，即得酮咯酸氨丁三醇片。
对比实施例1
固体分散体配方：
酮咯酸氨丁三醇 10g
PEG4000 50g
    制备方法：将酮咯酸氨丁三醇溶解在乙醇中；将PEG4000以搅拌的方式溶解或分散在乙醇中；以边搅拌边加入的方式将上述溶液混合；旋转蒸发仪中除去乙醇，得到固体分散体。
酮咯酸氨丁三醇片剂的制备：
处方： 
酮咯酸氨丁三醇固体分散体 60g
乳糖 72g
羧甲基淀粉钠 12g
硬脂酸镁 1.2g
制备方法：将酮咯酸氨丁三醇固体分散体进行机械粉碎；称取处方量的粉碎的酮咯酸氨丁三醇固体分散体与外加辅料混合均匀，压片，薄膜包衣，即得酮咯酸氨丁三醇片。
对比实施例2
固体分散体配方：
酮咯酸氨丁三醇 10g
泊洛沙姆188 50g
    制备方法：将酮咯酸氨丁三醇溶解在乙醇中；将泊洛沙姆188以搅拌的方式溶解或分散在乙醇中；以边搅拌边加入的方式将上述溶液混合；旋转蒸发仪中除去乙醇，得到固体分散体。
酮咯酸氨丁三醇片剂的制备：
处方：
酮咯酸氨丁三醇固体分散体 60g
乳糖 72g
羧甲基淀粉钠 12g
硬脂酸镁 1.2g
制备方法：将酮咯酸氨丁三醇固体分散体进行机械粉碎；称取处方量的粉碎的酮咯酸氨丁三醇固体分散体与外加辅料混合均匀，压片，薄膜包衣，即得酮咯酸氨丁三醇片。
对比实施例3
固体分散体配方：
酮咯酸氨丁三醇 10g
聚维酮K30 10g
PEG4000 40g
    制备方法：将酮咯酸氨丁三醇溶解在乙醇中；将PEG4000和聚维酮K30以搅拌的方式溶解或分散在乙醇中；以边搅拌边加入的方式将上述溶液混合；旋转蒸发仪中除去乙醇，得到固体分散体。
酮咯酸氨丁三醇片剂的制备：
处方：
酮咯酸氨丁三醇固体分散体 60g
乳糖 72g
羧甲基淀粉钠 12g
硬脂酸镁 1.2g
制备方法：将酮咯酸氨丁三醇固体分散体进行机械粉碎；称取处方量的粉碎的酮咯酸氨丁三醇固体分散体与外加辅料混合均匀，压片，薄膜包衣，即得酮咯酸氨丁三醇片。
对比实施例4
酮咯酸氨丁三醇片剂的制备：
处方：
酮咯酸氨丁三醇 10g
乳糖 90g
羧甲基淀粉钠 18g
硬脂酸镁 1.8g
二氧化硅 0.5g
制备方法：将酮咯酸氨丁三醇过80目筛与其他辅料混合均匀，压片，薄膜包衣，即得酮咯酸氨丁三醇片。
验证实施例
（1）溶出度测定试验
取实施例1-10和对比实施例1-4中的片剂，依照溶出度测定方法(2015年版第4部通则0931溶出度测定第二法)采用溶出度测定法进行检测，溶出介质600ml，转数50r/min，依法操作，并在5、10、15、20、30min时分别取样测定不同时间的酮咯酸氨丁三醇累积溶出度。
酮咯酸氨丁三醇片实施例及对比实施例平均累积溶出度结果见表1。
表1  酮咯酸氨丁三醇片实施例及平均累积溶出度
 
Figure dest_path_image002a
 
 （2）稳定性测定试验
取实施例1-10和对比实施例1-4中的片剂，依照有关物质测定方法(2015年版第4部通则0512高效液相色谱法)进行检测，色谱柱：Alltima-C18(250mm×4.6mm，5μm)；流动相：0.02mol/L磷酸二氢铵溶液（用磷酸调pH至3.0）-乙腈（65:35），流速：1.2ml/min，柱温：40℃，进样量：20μl，检测波长：313nm；样品浓度：3mg/ml。酮咯酸氨丁三醇片实施例及对比实施例有关物质检测结果见表2。
表2  酮咯酸氨丁三醇片实施例及对比实施例有关物质检测结果
 
Figure dest_path_image004
 

Claims (10)

  1. 一种酮咯酸氨丁三醇固体分散体，它含有水溶性载体材料，其特征在于，所述的水溶性载体材料为泊洛沙姆和聚乙二醇类载体或聚维酮类载体的混合物。
  2. 根据权利要求1所述的酮咯酸氨丁三醇固体分散体，其特征在于，酮咯酸氨丁三醇与水溶性载体材料的质量比为1:5~8。
  3. 根据权利要求1所述的酮咯酸氨丁三醇固体分散体，其特征在于，泊洛沙姆与聚乙二醇类载体或聚维酮类载体的质量比为1：2~4。
  4. 根据权利要求1所述的酮咯酸氨丁三醇固体分散体，其特征在于，所述的聚乙二醇类载体为PEG4000或PEG6000；聚维酮类载体为聚维酮K15，聚维酮K25，聚维酮K30或聚维酮K90；泊洛沙姆为泊洛沙姆188。
  5. 一种权利要求1所述的酮咯酸氨丁三醇固体分散体的制备方法，其特征在于，将酮咯酸氨丁三醇与水溶性载体材料溶解在有机溶剂中，除去有机溶剂，得到酮咯酸氨丁三醇固体分散体；其中所述的有机溶剂为乙醇、丙酮、二氯甲烷和三氯甲烷中的一种或几种。
  6. 一种由权利要求1所述的固体分散体制备的酮咯酸氨丁三醇片剂，其特征在于，它还含有赋形剂、崩解剂和润滑剂。
  7. 根据权利要求6所述的酮咯酸氨丁三醇片剂，其特征在于，所述的赋形剂选自乳糖、微晶纤维素、预胶化淀粉、甘露醇中的一种或几种。
  8. 根据权利要求6所述的酮咯酸氨丁三醇片剂，其特征在于，所述的崩解剂选自交联聚维酮、低取代羟丙纤维素、交联羧甲基纤维钠、羧甲基淀粉钠中的一种或几种。
  9. 根据权利要求6所述的酮咯酸氨丁三醇片剂，其特征在于，所述的润滑剂为硬脂酸镁或滑石粉。
  10. 根据权利要求6所述的酮咯酸氨丁三醇片剂，其特征在于，它含有如下重量份的组分：
    酮咯酸氨丁三醇固体分散体 1份 赋形剂 1~1.2份 崩解剂 0.2份 润滑剂 0.02份
    。
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CN102871952A (zh) * 2012-09-29 2013-01-16 中国科学院大连化学物理研究所 氟比洛芬对乙酰氨基酚酯固体分散体及其制备方法
CN106309354A (zh) * 2015-06-24 2017-01-11 复旦大学 一种含酮咯酸氨丁三醇的鼻腔给药温度敏感性原位凝胶缓释制剂
CN108451909A (zh) * 2018-06-29 2018-08-28 鲁南制药集团股份有限公司 一种酮咯酸氨丁三醇片剂

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CN102871952A (zh) * 2012-09-29 2013-01-16 中国科学院大连化学物理研究所 氟比洛芬对乙酰氨基酚酯固体分散体及其制备方法
CN106309354A (zh) * 2015-06-24 2017-01-11 复旦大学 一种含酮咯酸氨丁三醇的鼻腔给药温度敏感性原位凝胶缓释制剂
CN108451909A (zh) * 2018-06-29 2018-08-28 鲁南制药集团股份有限公司 一种酮咯酸氨丁三醇片剂

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