WO2021104253A1 - 布洛芬药物组合物、制备方法及应用 - Google Patents

布洛芬药物组合物、制备方法及应用 Download PDF

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WO2021104253A1
WO2021104253A1 PCT/CN2020/131100 CN2020131100W WO2021104253A1 WO 2021104253 A1 WO2021104253 A1 WO 2021104253A1 CN 2020131100 W CN2020131100 W CN 2020131100W WO 2021104253 A1 WO2021104253 A1 WO 2021104253A1
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ibuprofen
pharmaceutical composition
ibuprofen pharmaceutical
mesh
hot melt
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French (fr)
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应述欢
郭桢
王爱慧
王婷婷
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上海博志研新药物技术有限公司
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • 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
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1605—Excipients; Inactive ingredients
    • A61K9/1629—Organic macromolecular compounds
    • A61K9/1652—Polysaccharides, e.g. alginate, cellulose derivatives; Cyclodextrin
    • 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
    • A61K31/192—Carboxylic acids, e.g. valproic acid having aromatic groups, e.g. sulindac, 2-aryl-propionic acids, ethacrynic acid 
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—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
    • A61K47/30—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
    • 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
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • 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
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1605—Excipients; Inactive ingredients
    • A61K9/1617—Organic compounds, e.g. phospholipids, fats
    • 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]
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
    • Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
    • Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Definitions

  • the invention belongs to the field of medicine, and specifically relates to an ibuprofen pharmaceutical composition, a preparation method and an application.
  • Ibuprofen has anti-inflammatory, analgesic and antipyretic effects. It is suitable for the treatment of rheumatoid arthritis, rheumatoid arthritis, osteoarthritis, ankylosing spondylitis and neuritis, etc. It is the mainstay product for antipyretic and analgesic. However, due to the low solubility of ibuprofen in water, its bioavailability is low.
  • an improved oral solid preparation of ibuprofen is proposed. At least 20% of ibuprofen is released within 2 hours, and then ibuprofen is released at a relatively constant rate within at least 8 hours.
  • the preparation process mostly adopts direct compression of powder and compressed into single tablets. The fluidity of ibuprofen is poor, and it is difficult to control the rapid release and slow sustained release of the single tablets, the release effect is not ideal, and the industrial production is difficult.
  • CN201910438690.1 there is provided an ibuprofen immediate-release sustained-release double-layer tablet and a preparation method thereof.
  • the dosage form is composed of an ibuprofen immediate-release layer and an ibuprofen sustained-release layer, and the ibuprofen is in a certain proportion Dispersed in the immediate release layer and the sustained release layer, it can provide rapid release and slow release for the following 12 hours, so as to achieve the effect of rapid onset of action and continuous maintenance of effective blood concentration.
  • the auxiliary materials used in the two-layer tablets are different, and the two-layer wet granulation is required to be compressed, and the process is more complicated and complicated. Therefore, finding a technology with simple process and easy operation to prepare an appropriate dosage form of ibuprofen so as to improve the bioavailability and achieve a sustained release effect is a technical problem that needs to be solved urgently.
  • the technical problem to be solved by the present invention is to provide an ibuprofen pharmaceutical composition, preparation method and application in order to overcome the disadvantages of poor slow-release effect of ibuprofen suspension and unsatisfactory dissolution effect in the prior art.
  • the ibuprofen pharmaceutical composition of the present invention can release part of the medicine quickly and partly continuously, and is convenient to carry, convenient to transport, good stability, convenient to take, and its slow-release effect reaches 12 hours, which reduces the number of times the patient takes the medicine and reduces
  • the peak-to-valley phenomenon of blood drug concentration exhibited by common dosage form administration keeps the blood drug concentration within a relatively stable and long-lasting effective range, and improves the safety of the drug.
  • the present invention provides an ibuprofen pharmaceutical composition, which comprises the following components: ibuprofen, a sustained-release matrix material, a suspending agent, a flavoring agent and a pH regulator; the sustained-release matrix material is beech Acid glycerides and ethyl cellulose.
  • the ibuprofen can be a conventional commercially available ibuprofen bulk drug, or an ibuprofen bulk drug prepared with reference to corresponding literature.
  • the particle size of the ibuprofen is preferably 10 mesh to 60 mesh, more preferably 16 mesh to 50 mesh, such as 16 mesh to 45 mesh, 16 mesh to 30 mesh or 20 mesh to 50 mesh. Item.
  • the suspending agent can be a conventional suspending agent in the art, preferably selected from hydroxypropyl cellulose (HPC), xanthan gum and hydroxypropyl methyl cellulose (HPMC) One or more of them is more preferably xanthan gum.
  • HPC hydroxypropyl cellulose
  • HPMC hydroxypropyl methyl cellulose
  • the flavoring agent may be a conventional flavoring agent in the art, preferably one or more of flavor, sucrose, sucralose and aspartame, and more preferably flavor and / Or sucrose.
  • the pH adjusting agent is an organic acid capable of adjusting the pH of the suspension solution of the ibuprofen pharmaceutical composition in water to 3.0-4.0, preferably malic acid and/or citric acid.
  • the ibuprofen pharmaceutical composition preferably includes the following components: each component is calculated by mass fraction, 9.0% to 12.0% ibuprofen, 20.0% to 25.0% behenic acid glycerin Ester, 1.0% ⁇ 2.0% ethyl cellulose, 2.0% ⁇ 3.0% suspending agent, 60% ⁇ 68% flavoring agent and 0.5% ⁇ 1.0% pH regulator, the mass fraction refers to the single component The mass accounts for the percentage of the total mass of the ibuprofen pharmaceutical composition.
  • the ibuprofen pharmaceutical composition preferably includes the following components: each component is calculated by mass fraction, 9.5% to 11.5% ibuprofen, 21.0% to 23.0% behenic acid glycerin Ester, 1.3% to 1.8% ethyl cellulose, 2.3% to 2.8% suspending agent, 62% to 66% flavoring agent and 0.6% to 0.9% pH regulator, the mass fraction refers to the single component The mass accounts for the percentage of the total mass of the ibuprofen pharmaceutical composition.
  • the ibuprofen pharmaceutical composition is further preferably composed of the following components: each component is calculated by mass fraction, 10.72% ibuprofen, 21.44% glyceryl behenate, 1.69 % Ethyl cellulose, 2.14% suspending agent, 63.29% flavoring agent, 0.72% pH regulator, the mass fraction refers to the percentage of the mass of a single component to the total mass of the ibuprofen pharmaceutical composition.
  • the ibuprofen pharmaceutical composition is further preferably composed of the following components: each component is calculated by mass fraction, 10.67% ibuprofen, 21.34% glyceryl behenate, 1.68 % Ethyl cellulose, 2.56% suspending agent, 63.03% flavoring agent, 0.72% pH regulator, the mass fraction refers to the percentage of the mass of a single component to the total mass of the ibuprofen pharmaceutical composition.
  • the invention also provides a preparation method of the ibuprofen pharmaceutical composition, which comprises the following steps:
  • Step 1 Mix ibuprofen and the sustained-release matrix material to obtain a mixture
  • Step 2 Hot-melt extrude the mixture obtained in Step 1 to obtain a hot-melt extrudate
  • Step 3 pulverize the hot melt extrudate obtained in step 2 to obtain a pulverized product
  • Step 4 The pulverized product obtained in Step 3 is mixed with a suspending agent, a flavoring agent and a pH adjusting agent to obtain an ibuprofen pharmaceutical composition.
  • the temperature of the hot melt extrusion is preferably 55°C to 70°C, more preferably 60°C to 70°C.
  • the hot melt extrusion is preferably carried out in a hot melt extruder.
  • the particle size of the pulverized product is preferably 16 mesh to 45 mesh, more preferably 16 mesh to 30 mesh.
  • the pulverized product in a certain particle size range obtained in step 3 can be mixed uniformly with suspending agent, flavoring agent and pH regulator, wet granulated, sieved, dried, and then mixed with The pulverized products of 16 mesh to 30 mesh are mixed uniformly to obtain an ibuprofen pharmaceutical composition.
  • the particle size range of the pulverized product with a certain particle size range may be 30 mesh to 60 mesh or less than 30 mesh.
  • the sieving is an 18-mesh sieve.
  • the drying temperature is 30°C-40°C, for example 35°C.
  • the drying time is 1 to 4 hours, for example 2 hours.
  • the invention also provides an ibuprofen pharmaceutical composition prepared by the preparation method of the ibuprofen pharmaceutical composition.
  • the invention also provides the application of the ibuprofen pharmaceutical composition in the preparation of medicines for treating and/or relieving mild to moderate painful diseases.
  • the reagents and raw materials used in the present invention are all commercially available.
  • the beneficial effects of the present invention include: the ibuprofen pharmaceutical composition prepared by the present invention not only has the characteristics of a solid preparation, such as convenient carrying, convenient transportation, good stability, etc., but also has the advantages of a liquid preparation, is convenient to take, and is suitable for Patients who have difficulty swallowing, such as children and the elderly, and its sustained-release effect greatly reduces the number of patients taking it. After taking this product, the drug can quickly reach the therapeutic concentration in the body, and then slowly release to keep the blood concentration within a relatively stable and long-lasting effective range, reducing the peak and valley phenomenon of the blood concentration of the common dosage form administration, and improving the drug Security.
  • Figure 1 is the dissolution profile of the ibuprofen pharmaceutical composition of Example 1.
  • Figure 2 is the dissolution profile of the ibuprofen pharmaceutical composition of Example 2.
  • Figure 3 is the dissolution profile of the ibuprofen pharmaceutical composition of Example 3.
  • Figure 4 is the dissolution profile of the ibuprofen pharmaceutical composition of Example 4.
  • Figure 5 is the dissolution profile of the ibuprofen pharmaceutical composition of Example 5.
  • Figure 6 is the dissolution profile of the ibuprofen pharmaceutical composition of Example 6.
  • Figure 7 is the dissolution profile of the ibuprofen pharmaceutical composition of Example 7.
  • Figure 8 is the dissolution profile of the ibuprofen pharmaceutical composition of Example 8.
  • Figure 9 is the dissolution profile of the ibuprofen pharmaceutical composition of Example 9.
  • the obtained hot-melt extrudate is crushed into granules, a suitable particle size range (16 mesh to 45 mesh) is taken, and other auxiliary materials (suspending agent, flavoring agent and pH adjuster) in the above formula are added and mixed. After the mixing is uniform, the unit prescription quantity is sampled.
  • the dissolution data of the prepared ibuprofen pharmaceutical composition is shown in Table 1, and the dissolution curve is shown in Figure 1.
  • Ibuprofen 100 10.67 Glyceryl behenate 200 21.34 Ethyl cellulose 15.78 1.68 Xanthan gum twenty four 2.56 essence 40.53 4.33 Sucrose (granules) 550 58.70 Citric acid 6.69 0.72 total 937 100.00
  • the hot-melt extrudate is crushed into particles, a suitable particle size range (16 mesh to 30 mesh) is taken, and other auxiliary materials (suspending agent, flavoring agent and pH adjuster) are added and mixed. After the mixing is uniform, the unit prescription quantity is sampled.
  • the dissolution data of the prepared ibuprofen pharmaceutical composition is shown in Table 2, and the dissolution curve is shown in Figure 2.
  • Ibuprofen 100 10.67 Glyceryl behenate 200 21.34 Ethyl cellulose 15.78 1.68 Xanthan gum twenty four 2.56 essence 40.53 4.33 sucrose 550 58.70 Citric acid 6.69 0.72 total 937 100.00
  • the hot-melt extrudate is crushed into particles, a suitable particle size range (20 mesh to 50 mesh) is taken, and other auxiliary materials (suspending agent, flavoring agent and pH adjuster) are added and mixed. After the mixing is uniform, the unit prescription quantity is sampled.
  • the dissolution data of the prepared ibuprofen pharmaceutical composition is shown in Table 3, and the dissolution curve is shown in Figure 3.
  • Ibuprofen 100 10.67 Glyceryl behenate 200 21.34 Ethyl cellulose 15.78 1.68 Xanthan gum twenty four 2.56 essence 40.53 4.33 sucrose 550 58.70 Citric acid 6.69 0.72 total 937 100.00
  • Ibuprofen 100 10.67 Glyceryl behenate 200 21.34 Ethyl cellulose 15.78 1.68 Xanthan gum twenty four 2.56 essence 40.53 4.33 sucrose 550 58.70 Citric acid 6.69 0.72 total 937 100.00
  • the dissolution data of the prepared ibuprofen pharmaceutical composition is shown in Table 5, and the dissolution curve is shown in Figure 5.
  • Ibuprofen 100 10.67 Glyceryl behenate 200 21.34 Ethyl cellulose 15.78 1.68 Xanthan gum twenty four 2.56 essence 40.53 4.33 sucrose 550 58.70 Citric acid 6.69 0.72 total 937 100.00
  • the hot melt extrudate is collected.
  • the dissolution data of the prepared ibuprofen pharmaceutical composition is shown in Table 6, and the dissolution curve is shown in Fig. 6.
  • Ibuprofen 100 10.67 Glyceryl behenate 200 21.34 Ethyl cellulose 15.78 1.68 Xanthan gum twenty four 2.56 essence 40.53 4.33 sucrose 550 58.70 Citric acid 6.69 0.72 total 937 100
  • the hot melt extrudate is collected.
  • the dissolution data of the prepared ibuprofen pharmaceutical composition is shown in Table 7, and the dissolution curve is shown in Fig. 7.
  • Ibuprofen suspension (commercially available) (Shanghai Johnson Pharmaceutical Co., Ltd., batch number: 190603296), its dissolution data are shown in Table 8, and the dissolution curve is shown in Figure 8.
  • Ibuprofen sustained-release suspension (commercially available) (Sichuan Zhongfang Pharmaceutical Co., Ltd., batch number: 180404), the dissolution data is shown in Table 9, and the dissolution curve is shown in Figure 9.
  • the ibuprofen pharmaceutical composition of the present invention can achieve rapid release and slow sustained release, the drug has a fast onset of action in the body, and maintains the effective drug concentration for a long time, thereby reducing the drug dose and improving the drug effect. , Prolong the action time of the drug and reduce the effect of adverse drug reactions.

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Abstract

一种布洛芬药物组合物，包括以下组分：布洛芬、缓释骨架材料、助悬剂、矫味剂和pH调节剂；所述缓释骨架材料为山嵛酸甘油酯和乙基纤维素。所述组合物可使部分药物迅速释放、部分药物持续释放，使血药浓度保持在比较平稳持久的有效范围内，提高了药物的安全性。且稳定性好，方便携带和运输。

Description

布洛芬药物组合物、制备方法及应用
本申请要求以下在先申请的优先权：2019年11月25日向中国国家知识产权局提交的专利申请号为201911165219.6，发明名称为“布洛芬药物组合物、制备方法及应用”的在先申请。所述在先申请的全文通过引用的方式结合于本申请中。
技术领域
本发明属于医药领域，具体涉及布洛芬药物组合物、制备方法及应用。
背景技术
布洛芬具有抗炎、镇痛、解热作用，适用于治疗风湿性关节炎、类风湿性关节炎、骨关节炎、强直性脊椎炎和神经炎等，是解热镇痛的支柱产品。但由于布洛芬在水中溶解度较低，导致其生物利用度较低。
CN101068532的专利文献中，提出了一种经改进的布洛芬口服固体制剂，至少20％的布洛芬在2小时内释放出来，随后以相对恒定的速率在至少8小时内释放布洛芬，但其制备工艺多采用粉末直压且压制成单片，布洛芬流动性较差，单片控制快速释放与缓慢持续释放的难度大，释放效果并不理想，工业化生产难度大。CN201910438690.1的专利文献中，提供了一种布洛芬速释缓释双层片及其制备方法，该剂型由布洛芬速释层与布洛芬缓释层组成，布洛芬按一定比例分散在速释层与缓释层，可提供快速释放，以及后续12小时的缓慢释放作用，从而达到快速起效和持续维持有效血药浓度的效果。但其两层片剂所使用的辅料不同，需两次湿法制粒后压片，工艺比较复杂繁琐。因此，寻找工艺简单、操作简便的技术，制备布洛芬的适当剂型，从而提高生物利用度并达到 缓释效果是目前急需解决的技术问题。
发明内容
本发明所要解决的技术问题是为了克服现有技术中布洛芬混悬剂缓释效果不佳、溶出效果不理想等缺陷而提供了一种布洛芬药物组合物、制备方法及应用。本发明的布洛芬药物组合物可使药物部分迅速释放，部分持续释放，方便携带、运输方便、稳定性好、方便服用且其缓释效果达12小时，减少了患者的服药次数、减少了普通剂型给药所呈现血药浓度的峰谷现象，使血药浓度保持在比较平稳持久的有效范围内，提高了药物的安全性。
本发明提供了一种布洛芬药物组合物，其包括以下组分：布洛芬、缓释骨架材料、助悬剂、矫味剂和pH调节剂；所述的缓释骨架材料为山嵛酸甘油酯和乙基纤维素。
根据本发明的实施方案，所述的布洛芬可以为常规市售布洛芬原料药，或者参照相应文献制备的布洛芬原料药。
根据本发明的实施方案，所述的布洛芬的粒径优选为10目～60目，进一步优选为16目～50目，例如16目～45目、16目～30目或者20目～50目。
根据本发明的实施方案，所述的助悬剂可以为本领域中的常规助悬剂，优选选自羟丙基纤维素(HPC)、黄原胶和羟丙基甲基纤维素(HPMC)中的一种或多种，进一步优选为黄原胶。
根据本发明的实施方案，所述的矫味剂可以为本领域中的常规矫味剂，优选为香精、蔗糖、三氯蔗糖和阿斯巴甜中的一种或多种，进一步优选香精和/或蔗糖。
根据本发明的实施方案，所述的pH调节剂为能调节布洛芬药物组合物在水中混悬溶液pH达到3.0-4.0的有机酸，优选为苹果酸和/或柠檬酸。
根据本发明的实施方案，所述的布洛芬药物组合物，优选其包括以下组分： 各组分采用质量分数计，9.0％～12.0％布洛芬、20.0％～25.0％山嵛酸甘油酯、1.0％～2.0％乙基纤维素、2.0％～3.0％助悬剂、60％～68％矫味剂和0.5％～1.0％pH调节剂，所述的质量分数是指单个组分的质量占布洛芬药物组合物总质量的百分比。
根据本发明的实施方案，所述的布洛芬药物组合物，优选其包括以下组分：各组分采用质量分数计，9.5％～11.5％布洛芬、21.0％～23.0％山嵛酸甘油酯、1.3％～1.8％乙基纤维素、2.3％～2.8％助悬剂、62％～66％矫味剂和0.6％～0.9％pH调节剂，所述的质量分数是指单个组分的质量占布洛芬药物组合物总质量的百分比。
根据本发明的实施方案，所述的布洛芬药物组合物，再进一步优选其由以下组分组成：各组分采用质量分数计，10.72％布洛芬、21.44％山嵛酸甘油酯、1.69％乙基纤维素、2.14％助悬剂、63.29％矫味剂、0.72％pH调节剂，所述的质量分数是指单个组分的质量占布洛芬药物组合物总质量的百分比。
根据本发明的实施方案，所述的布洛芬药物组合物，再进一步优选其由以下组分组成：各组分采用质量分数计，10.67％布洛芬、21.34％山嵛酸甘油酯、1.68％乙基纤维素、2.56％助悬剂、63.03％矫味剂、0.72％pH调节剂，所述的质量分数是指单个组分的质量占布洛芬药物组合物总质量的百分比。
本发明还提供了所述的布洛芬药物组合物的制备方法，其包括以下步骤：
步骤1：将布洛芬与缓释骨架材料混合得到混合物；
步骤2：将步骤1得到的混合物热熔挤出，得到热熔挤出物；
步骤3：将步骤2得到的热熔挤出物粉碎，得到粉碎物；
步骤4：将步骤3得到的粉碎物与助悬剂、矫味剂和pH调节剂混合，得到布洛芬药物组合物。
根据本发明的实施方案，步骤2中，所述的热熔挤出的温度优选为55℃～70℃，进一步优选为60℃～70℃。所述的热熔挤出优选在热熔挤出机中进行。
根据本发明的实施方案，步骤3中，所述的粉碎物的粒径优选为16目～45目，进一步优选为16目～30目。
根据本发明的实施方案，步骤4中，可以先将步骤3得到的一定粒径范围的粉碎物与助悬剂、矫味剂和pH调节剂混合均匀，湿法制粒过筛、干燥，再与16目～30目的粉碎物混合均匀，得到布洛芬药物组合物。
优选地，所述一定粒径范围的粉碎物的粒径范围可以为30目～60目或者小于30目。
优选地，所述过筛为过18目筛。
优选地，所述干燥的温度为30℃～40℃，例如35℃。
优选地，所述干燥的时间为1-4h，例如2h。
本发明还提供了所述的布洛芬药物组合物的制备方法制得的布洛芬药物组合物。
本发明还提供了所述的布洛芬药物组合物在制备治疗和/或缓解轻至中度疼痛疾病的药物中的应用。
在不违背本领域常识的基础上，上述各优选条件，可任意组合，即得本发明各较佳实例。
本发明所用试剂和原料均为市售可得。
本发明的有益效果包括：本发明制得的布洛芬药物组合物既具备了固体制剂的特点，如方便携带，运输方便，稳定性好等，又有液体制剂的优势，方便服用，适合于吞咽有困难的患者，如儿童、老人，且其缓释效果大大减少了患者的服用次数。服用本品后，药物在体内可迅速达到治疗浓度，然后缓慢释放使血药浓度保持在比较平稳持久的有效范围内，减少了普通剂型给药所呈现血药浓度的峰谷现象，提高了药物的安全性。
附图说明
图1为实施例1布洛芬药物组合物的溶出曲线。
图2为实施例2布洛芬药物组合物的溶出曲线。
图3为实施例3布洛芬药物组合物的溶出曲线。
图4为实施例4布洛芬药物组合物的溶出曲线。
图5为实施例5布洛芬药物组合物的溶出曲线。
图6为实施例6布洛芬药物组合物的溶出曲线。
图7为实施例7布洛芬药物组合物的溶出曲线。
图8为实施例8布洛芬药物组合物的溶出曲线。
图9为实施例9布洛芬药物组合物的溶出曲线。
具体实施方式
下文将结合具体实施例对本发明的技术方案做更进一步的详细说明。应当理解，下列实施例仅为示例性地说明和解释本发明，而不应被解释为对本发明保护范围的限制。凡基于本发明上述内容所实现的技术均涵盖在本发明旨在保护的范围内。
除非另有说明，以下实施例中使用的原料和试剂均为市售商品，或者可以通过已知方法制备。
实施例1
布洛芬药物组合物的处方
名称 质量(mg/瓶) 质量百分比(％)
布洛芬 100 10.67
山嵛酸甘油酯 200 21.34
乙基纤维素 15.78 1.68
黄原胶 24 2.56
香精 40.53 4.33
蔗糖(细粉) 550 58.70
柠檬酸 6.69 0.72
总计 937 100.00
制备过程：
根据各物料的性质，设置好热熔挤出机的温度等参数后(60℃～70℃)，将混好的布洛芬、山嵛酸甘油酯和乙基纤维素的混合物缓慢加入热熔挤出机中，得到热熔挤出物。
将得到的热熔挤出物粉碎成颗粒，取合适的粒径范围(16目～45目)，加入上述处方中其他辅料(助悬剂、矫味剂和pH调节剂)混合。混合均匀后，单位处方量取样。制得的布洛芬药物组合物的溶出度数据见表1，溶出曲线见图1。
表1 布洛芬药物组合物的溶出度数据表
时间(min) 累积溶出度(％) RSD(％)
5 24.90 4.9
15 32.20 4.1
30 41.00 4.2
60 51.40 4.4
120 62.20 5.4
240 67.40 5.9
360 82.70 12.2
480 86.00 10.6
600 83.40 9.5
720 84.10 10.5
实施例2
布洛芬药物组合物的处方
名称 mg/瓶 质量百分比(％)
布洛芬 100 10.67
山嵛酸甘油酯 200 21.34
乙基纤维素 15.78 1.68
黄原胶 24 2.56
香精 40.53 4.33
蔗糖(颗粒) 550 58.70
柠檬酸 6.69 0.72
总计 937 100.00
制备过程：
根据各物料的性质，设置好热熔挤出机的温度等参数后(60℃～70℃)，将混好的布洛芬、山嵛酸甘油酯、乙基纤维素的混合物缓慢加入热熔挤出机中，得到热熔挤出物。
将热熔挤出物粉碎成颗粒，取合适的粒径范围(16目～30目)，加入其他辅料(助悬剂、矫味剂和pH调节剂)混合。混合均匀后，单位处方量取样。制得的布洛芬药物组合物的溶出度数据见表2，溶出曲线见图2。
表2 布洛芬药物组合物的溶出度数据
时间(min) 累积溶出度(％) RSD(％)
5 17.40 10.4
15 26.30 10.6
30 34.00 10.4
60 43.50 10.3
120 53.90 10.7
240 64.20 11.0
360 69.60 11.2
480 72.70 11.5
600 74.70 11.7
720 76.10 11.7
实施例3
布洛芬药物组合物的处方
名称 mg/瓶 质量百分比(％)
布洛芬 100 10.67
山嵛酸甘油酯 200 21.34
乙基纤维素 15.78 1.68
黄原胶 24 2.56
香精 40.53 4.33
蔗糖 550 58.70
柠檬酸 6.69 0.72
总计 937 100.00
制备过程：
根据各物料的性质，设置好热熔挤出机的温度(60℃～70℃)等参数后，将混好的布洛芬、山嵛酸甘油酯和乙基纤维素的混合物缓慢加入热熔挤出机中，得到热熔挤出物。
将热熔挤出物粉碎成颗粒，取合适的粒径范围(20目～50目)，加入其他辅料(助悬剂、矫味剂和pH调节剂)混合。混合均匀后，单位处方量取样。制得的布洛芬药物组合物的溶出度数据见表3，溶出曲线见图3。
表3 布洛芬药物组合物的溶出度数据表
时间(min) 累积溶出度(％) RSD(％)
5 25.6 3.6
15 37.10 2.9
30 46.80 2.4
60 58.00 2.4
120 69.50 2.8
240 79.90 3.1
360 84.70 3.4
480 87.40 3.7
600 89.00 3.6
720 90.00 3.8
实施例4
布洛芬药物组合物的处方
名称 mg/瓶 质量百分比(％)
布洛芬 100 10.67
山嵛酸甘油酯 200 21.34
乙基纤维素 15.78 1.68
黄原胶 24 2.56
香精 40.53 4.33
蔗糖 550 58.70
柠檬酸 6.69 0.72
总计 937 100.00
制备过程：
根据各物料的性质，设置好热熔挤出机的温度(60℃～70℃)等参数后， 将混好的布洛芬、山嵛酸甘油酯和乙基纤维素的混合物缓慢加入热熔挤出机中，得到热熔挤出物。
将热熔挤出物粉碎成颗粒，取合适的粒径范围(30目～60目)，加入其他辅料(助悬剂、矫味剂和pH调节剂)混合均匀后，湿法制粒过18目筛。35℃烘箱干燥2h后，加入16目～30目布洛芬颗粒，混合均匀，单位处方量取样。制得的布洛芬药物组合物的溶出度数据见表4，溶出曲线见图4。
表4 布洛药物组合物的溶出度数据表
时间(min) 累积溶出度(％) RSD(％)
5 18.4 2.8
15 28.9 1.8
30 37.8 1.7
60 48.3 1.6
120 60.9 1.6
240 74.6 1.9
360 82.2 2.1
480 87.6 2.3
600 90.8 2.6
720 93.1 2.6
实施例5
布洛芬药物组合物的处方
名称 mg/瓶 质量百分比(％)
布洛芬 100 10.67
山嵛酸甘油酯 200 21.34
乙基纤维素 15.78 1.68
黄原胶 24 2.56
香精 40.53 4.33
蔗糖 550 58.70
柠檬酸 6.69 0.72
总计 937 100.00
制备过程：
根据各物料的性质，设置好热熔挤出机的温度等参数后，将混好的布洛芬、 山嵛酸甘油酯和乙基纤维素的混合物缓慢加入热熔挤出机中，得到热熔挤出物。
将热熔挤出物粉碎成颗粒，颗粒粒径范围16目-30目:30-60目:＜60目＝2:1:1，＜30目颗粒加入其他辅料(助悬剂、矫味剂和pH调节剂)混合均匀后，湿法制粒过18目筛。35℃烘箱干燥2h后，加入16目～30目上述热熔挤出的布洛芬颗粒，混合均匀，单位处方量取样。制得的布洛芬药物组合物的溶出度数据见表5，溶出曲线见图5。
表5 布洛芬药物组合物的溶出度数据表
时间(min) 累积溶出度(％) RSD(％)
5 24.9 4.6
15 38.7 3.8
30 48.5 3.8
60 58.9 3.1
120 69.3 2.3
240 79.5 1.9
360 84.6 1.3
480 92.4 0.9
600 94.8 0.6
720 96.0 0.4
实施例6
布洛芬药物组合物的处方
名称 mg/瓶 质量百分比(％)
布洛芬 100 10.67
山嵛酸甘油酯 200 21.34
乙基纤维素 15.78 1.68
黄原胶 24 2.56
香精 40.53 4.33
蔗糖 550 58.70
柠檬酸 6.69 0.72
总计 937 100.00
制备过程：
根据各物料的性质，设置好热熔挤出机的温度(60℃～70℃)等参数后， 将混好的布洛芬、山嵛酸甘油酯和乙基纤维素的混合物缓慢加入热熔挤出机中，收集热熔挤出物。
将热熔挤出物粉碎成颗粒，颗粒粒径范围16目-30目:30目-60目:＜60目＝5:4:1，＜30目颗粒加入其他辅料混合均匀后，湿法制粒过18目筛。35℃烘箱干燥2h后，加入16-30目上述热熔挤出的布洛芬颗粒，混合均匀，单位处方量取样。制得的布洛芬药物组合物的溶出度数据见表6，溶出曲线见图6。
表6 布洛芬药物组合物的溶出度数据表
时间(min) 累积溶出度(％) RSD(％)
5 18.2 3.6
15 31.8 2.9
30 42.3 2.4
60 54.4 2.8
120 66.7 3.1
240 78.0 1.9
360 83.5 3.6
480 91.8 0.8
600 94.5 0.4
720 95.4 0.3
实施例7
布洛芬药物组合物的处方
名称 mg/瓶 质量百分比(％)
布洛芬 100 10.67
山嵛酸甘油酯 200 21.34
乙基纤维素 15.78 1.68
黄原胶 24 2.56
香精 40.53 4.33
蔗糖 550 58.70
柠檬酸 6.69 0.72
总计 937 100
制备过程：
根据各物料的性质，设置好热熔挤出机的温度(60℃～70℃)等参数后， 将混好的布洛芬、山嵛酸甘油酯和乙基纤维素的混合物缓慢加入热熔挤出机中，收集热熔挤出物。
将热熔挤出物粉碎成颗粒，颗粒粒径范围16-30目:30-60目:＜60目＝3:3:4，＜30目颗粒加入其他辅料混合均匀后，湿法制粒过18目筛。35℃烘箱干燥2h后，加入16-30目上述热熔挤出的布洛芬颗粒，混合均匀，单位处方量取样。制得的布洛芬药物组合物的溶出度数据见表7，溶出曲线见图7。
表7 布洛芬药物组合物的溶出度数据表
时间(min) 累积溶出度(％) RSD(％)
5 33.2 3.2
15 49.7 1.9
30 60.3 1.9
60 70.0 2.3
120 78.6 2.8
240 86.0 3.8
360 89.4 1.7
480 94.6 0.6
600 96.4 0.6
720 96.9 0.9
实施例8
布洛芬混悬液(市售)(上海强生制药有限公司，批号：190603296)，其溶出度数据见表8，溶出曲线见图8。
表8 布洛芬混悬液的溶出度数据表
时间(min) 累积溶出度(％) RSD(％)
5 62.30 6.3
15 83.40 1.4
30 93.40 0.9
60 97.80 1.0
120 99.10 1.2
实施例9
布洛芬缓释混悬液(市售)(四川中方制药有限公司，批号：180404)， 其溶出度数据见表9，溶出曲线见图9。
表9 布洛芬混悬液的溶出度数据表
T(min) 累积溶出度(％) RSD(％)
15 19.7 8.1
30 30.4 8.6
60 43.2 7.6
120 57.3 7.7
240 64.7 6.7
360 67 6.2
480 67.4 7.3
极限 67.3 6.2
由上述实例可以看出，本发明布洛芬药物组合物，可以实现快速释放和缓慢持续释放，药物在体内起效快，且较长时间保持有效药物浓度，从而达到减少药物剂量，提高药效，延长药物作用时间和减少药物不良反应的效果。
以上，对本发明的实施方式进行了说明。但是，本发明不限定于上述实施方式。凡在本发明的精神和原则之内，所做的任何修改、等同替换、改进等，均应包含在本发明的保护范围之内。

Claims (10)

  1. 一种布洛芬药物组合物，其特征在于，所述布洛芬药物组合物包括以下组分：布洛芬、缓释骨架材料、助悬剂、矫味剂和pH调节剂；所述的缓释骨架材料为山嵛酸甘油酯和乙基纤维素。
  2. 如权利要求1所述的布洛芬药物组合物，其特征在于：所述的布洛芬的粒径为10目～60目。
  3. 如权利要求1或2所述的布洛芬药物组合物，其特征在于：所述的助悬剂为羟丙基纤维素、黄原胶和羟丙基甲基纤维素中的一种或多种。
  4. 如权利要求1-3任一项所述的布洛芬药物组合物，其特征在于：所述的矫味剂为香精、蔗糖、三氯蔗糖和阿斯巴甜中的一种或多种。
  5. 如权利要求1-4任一项所述的布洛芬药物组合物，其特征在于：所述的pH调节剂为能调节布洛芬药物组合物在水中混悬溶液pH达到3.0-4.0的有机酸。
  6. 如权利要求5所述的布洛芬药物组合物，其特征在于：所述的有机酸为苹果酸和/或柠檬酸。
  7. 如权利要求1-6任一项所述的布洛芬药物组合物，其特征在于：所述的布洛芬药物组合物包括以下组分：各组分采用质量分数计，9.0％～12.0％布洛芬、20.0％～25.0％山嵛酸甘油酯、1.0％～2.0％乙基纤维素、2.0％～3.0％助悬剂、60％～68％矫味剂和0.5％～1.0％pH调节剂，所述的质量分数是指单个组分的质量占布洛芬药物组合物总质量的百分比。
    优选地，所述的布洛芬药物组合物由以下组分组成：各组分采用质量分数计，10.72％布洛芬、21.44％山嵛酸甘油酯、1.69％乙基纤维素、2.14％助悬剂、63.29％矫味剂、0.72％pH调节剂，所述的质量分数是指单个组分的质量占布洛芬药物组合物总质量的百分比。
  8. 如权利要求1～7任一项所述的布洛芬药物组合物的制备方法，其特征在 于，所述制备方法包括以下步骤：
    步骤1：将布洛芬与缓释骨架材料混合得到混合物；
    步骤2：将步骤1得到的混合物热熔挤出，得到热熔挤出物；
    步骤3：将步骤2得到的热熔挤出物粉碎，得到粉碎物；
    步骤4：将步骤3得到的粉碎物与助悬剂、矫味剂和pH调节剂混合，得到布洛芬药物组合物。
    优选地，步骤2中，所述的热熔挤出的温度为55℃～70℃；
    和/或，
    步骤2中，所述的热熔挤出优选在热熔挤出机中进行；
    和/或，
    步骤3中，所述的粉碎的粒径为16目～45目。
  9. 如权利要求8所述的布洛芬药物组合物的制备方法，制得的布洛芬药物组合物。
  10. 如权利要求1～7和权利要求9任一项所述布洛芬药物组合物在制备治疗和/或缓解轻至中度疼痛疾病的药物中的应用。
PCT/CN2020/131100 2019-11-25 2020-11-24 布洛芬药物组合物、制备方法及应用 WO2021104253A1 (zh)

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