WO2021253681A1 - Favipiravir composition and preparation method thereof - Google Patents

Favipiravir composition and preparation method thereof Download PDF

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Publication number
WO2021253681A1
WO2021253681A1 PCT/CN2020/118723 CN2020118723W WO2021253681A1 WO 2021253681 A1 WO2021253681 A1 WO 2021253681A1 CN 2020118723 W CN2020118723 W CN 2020118723W WO 2021253681 A1 WO2021253681 A1 WO 2021253681A1
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Prior art keywords
favipiravir
composition
povidone
composition according
disintegrant
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PCT/CN2020/118723
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French (fr)
Chinese (zh)
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章正赞
徐彪
娄贵川
张津州
赵周明
郭晓迪
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浙江华海药业股份有限公司
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Priority to CN202080100612.1A priority Critical patent/CN115551484A/en
Publication of WO2021253681A1 publication Critical patent/WO2021253681A1/en

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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
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/4965—Non-condensed pyrazines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
    • A61K47/38—Cellulose; Derivatives thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • 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
    • 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
    • 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 technical field of medicine, and specifically relates to a favipiravir composition and a preparation method thereof.
  • Favipiravir was developed by Fujifilm Toyama Chemical Co., Ltd., and its chemical name is 6-fluoro-3-hydroxypyrazine-2-carboxamide.
  • the drug has broad-spectrum antiviral activity, and has antiviral effects against RNA viruses such as influenza virus, Ebola virus, yellow fever virus, arena virus, bunya virus, and West Nile virus.
  • Fapilavir was sold under the trade name in Japan in 2014 Conditionally approved and marketed for the treatment of new or recurrent influenza in adults (only used when other anti-influenza drugs are ineffective or ineffective).
  • the marketed dosage form is a tablet, each with a specification of 200 mg favipiravir.
  • the usual course of treatment for adults is 5 days. On day 1, 1600 mg of favipiravir is taken once, twice a day; from day 2 to day 5, 600 mg of favipiravir is taken once, twice a day. Each administration requires multiple oral tablets.
  • the plasma concentration reaches its peak in about 30 minutes and exerts its efficacy. Therefore, the developed formulation requires rapid dissolution capability, that is, it can dissolve ⁇ 85% of the drug in 15 minutes in an in vitro dissolution test.
  • the content of favipiravir in the developed tablets must be as high as possible, so that the weight of each tablet is reduced, thereby reducing the size and making it easier to take.
  • the reduction in the weight of each tablet means that fewer excipients need to be used, which will slow down the release of the drug. Therefore, the difficulty in the development of the drug is to achieve rapid dissolution under the condition of lower tablet weight (15 minutes dissolution ⁇ 85% Drug).
  • the patent CN201080011876.6 of the original research Toyama Chemical Co., Ltd. discloses a favipiravir tablet and a preparation method thereof, by using low-substituted hydroxypropyl cellulose or croscarmellose sodium to achieve the effect of improving the dissolution rate , And maintain a low film weight.
  • sodium carboxymethyl starch was used as a disintegrant.
  • the weight of sodium carboxymethyl starch in the preparation of Comparative Example 5 was 5.6 mg, the total mass of the preparation was 260.0 mg, and the sodium carboxymethyl starch accounted for 2.15% by weight of the total mass of the preparation.
  • the dissolution rate of Comparative Example 5 using sodium carboxymethyl starch as the disintegrant was only 63.6%. It can be seen that the patent actually teaches that the use of sodium carboxymethyl starch as a disintegrant cannot achieve the rapid dissolution of favipiravir (ie, the dissolution of ⁇ 85% of the drug in 15 minutes), that is, the avoidance of the use of carboxymethyl
  • the opposite teaching of sodium starch as a disintegrant is 5.6 mg, the total mass of the preparation was 260.0 mg, and the sodium carboxymethyl starch accounted for 2.15% by weight of the total mass of the preparation.
  • the dissolution rate of Comparative Example 5 using sodium carboxymethyl starch as the disintegrant was only 63.6%. It can be seen that the patent actually teaches that the
  • Patent 201510755106.7 describes the effect of increasing the dissolution rate by adding silicified microcrystalline cellulose 50.
  • the content of favipiravir in a single tablet formulation is 55-70%, and the total weight of a single tablet is even as high as 400 mg, which is too high. .
  • the patent requires that the particle size distribution D90 of favipiravir must be between 40 ⁇ m and 160 ⁇ m, otherwise the rapid dissolution of favipiravir cannot be achieved.
  • the patent also pointed out that in the case of using silicified microcrystalline cellulose 50 as a disintegrant, the amount of binder must be controlled so that the weight percentage relative to the tablet is 4% to 7%.
  • Patent 201610163419.8 achieves the effect of increasing the dissolution rate by adding a large amount of microcrystalline cellulose PH-102 and a solubilizer, and the content of favipiravir in a single tablet preparation is less than 67%.
  • the amount of microcrystalline cellulose PH-102 relative to the amount of favipiravir is 0.5-1:1, that is, 200 mg of favipiravir needs to add 100-200 mg of microcrystalline cellulose PH-102,
  • the total weight of the prepared single favipiravir tablet is greatly increased. Therefore, although these two methods can improve the dissolution rate, they need to add more excipients, and the content of favipiravir is less than 74%.
  • each administration of favipiravir requires multiple oral tablets. Therefore, the content of favipiravir in the developed tablets needs to be as high as possible, so that the weight of each tablet is reduced and the size is reduced. Easy to take. However, the reduction in the weight of each tablet means that fewer excipients need to be used, which will slow down the release of the drug. Therefore, the difficulty in the development of the drug is that it can achieve rapid drug dissolution under the condition of lower tablet weight.
  • the present invention provides a favipiravir composition, which contains:
  • the favipiravir composition can dissolve more than 85% in 15 minutes in an in vitro dissolution test.
  • the present invention also provides a favipiravir composition, which contains:
  • a disintegrant of 2.5%-15% by weight of the composition is selected from one or a combination of sodium carboxymethyl starch or calcium carboxymethyl cellulose;
  • the favipiravir composition can also achieve rapid release, wherein the favipiravir composition can dissolve ⁇ 85% in 15 minutes in an in vitro dissolution test.
  • the dissolution method can be determined according to the second method of the Chinese Pharmacopoeia (paddle method). The specific conditions of the method are: the rotating speed of the stirring blade is 50 rpm, the dissolution medium is pH 4.5 acetate buffer, the medium volume is 900 ml, and the medium temperature is 37°C ⁇ 0.5°C.
  • the weight ratio of favipiravir to the composition is more than 60%, preferably more than 70%, more preferably 70%-85%, even more preferably 75%-82%.
  • the disintegrant is selected from one or a combination of two of sodium carboxymethyl starch or calcium carboxymethyl cellulose, and the disintegrant accounts for a weight percentage of the composition 2.5%-15%, more preferably 3-12%.
  • the favipiravir composition provided by the present invention may further contain a filler.
  • Fillers suitable for the composition of the present invention include but are not limited to: mannitol, xylitol, lactose, microcrystalline cellulose, silicified microcrystalline cellulose, starch, sucrose, glucose, maltitol, calcium hydrogen phosphate, dihydrogen phosphate One of calcium and calcium silicate or any combination thereof, preferably mannitol and/or microcrystalline cellulose, more preferably microcrystalline cellulose.
  • the weight percentage of the filler in the composition is ⁇ 15%, preferably ⁇ 12%.
  • Binders suitable for the composition of the present invention include but are not limited to: hypromellose, hydroxypropyl cellulose, methyl cellulose, copovidone, povidone, etc., preferably copovidone and/or povidone , More preferably povidone, povidone is preferably selected from povidone K30, povidone K25, povidone K17, povidone K90 and the like.
  • the weight percentage of the binder in the composition is 0.5-5%, preferably 2-5%.
  • the favipiravir composition provided by the present invention may further contain an anti-sticking agent.
  • Anti-sticking agents suitable for the composition of the present invention include, but are not limited to, silicon dioxide, diatomaceous earth, etc., preferably silicon dioxide.
  • the weight percentage of the anti-sticking agent in the composition is 0.5-5%, preferably 2-5%.
  • composition of the present invention based on the weight percentage of the composition, includes the following components:
  • Favipiravir or its salt is more than 60%, preferably more than 70%, more preferably 70%-85%;
  • Disintegrant selected from one or a combination of sodium carboxymethyl starch or calcium carboxymethyl cellulose 2.5%-15%, more preferably 3-12%;
  • Anti-sticking agent 0.5-5%, preferably 2-5%;
  • the composition is powdered granules.
  • the invention provides a method for preparing a favipiravir composition in the form of powdered granules, which comprises: obtaining powdered granules by wet granulation.
  • the method for preparing favipiravir in the form of powdered particles includes: dissolving a binder (such as povidone) in water, and then adding an anti-sticking agent (such as silicon dioxide) to obtain a binder solution ; Then Favipiravir or its salt, filler (such as microcrystalline cellulose) and one or a combination of disintegrant sodium carboxymethyl starch or calcium carboxymethyl cellulose, add the above binder solution Wet granulation, selective drying, and sieving to obtain favipiravir powder granules.
  • a binder such as povidone
  • an anti-sticking agent such as silicon dioxide
  • the present invention also provides a favipiravir tablet, which contains the following components based on the weight percentage of the tablet:
  • Favipiravir or its salt is more than 60%, preferably more than 70%, more preferably 70%-85%;
  • Anti-sticking agent 0.5-5%, preferably 2-5%;
  • Lubricant and optional other additives 0.1-5%, preferably 0.5%-2%;
  • an external disintegrant is added by 1-4%, preferably 1.5-3%.
  • the external disintegrant suitable for the tablet of the present invention includes but is not limited to: crospovidone, sodium carboxymethyl starch, calcium carboxymethyl cellulose, etc., preferably crospovidone.
  • the weight percentage of the external disintegrant in the preparation is 1-4%, preferably 1.5-3%.
  • the external lubricant includes but is not limited to: stearic acid, magnesium stearate, sodium stearyl fumarate, talc, etc., preferably sodium stearyl fumarate.
  • additives include coloring agents, coating agents, flavoring agents, surfactants, plasticizers or fragrances and the like.
  • the favipiravir tablet of the present invention can be optionally film-coated.
  • the coating film is usually about 1.5-5% of the total weight of the tablet, and the coating film is composed of film-forming agents, plasticizers, pigments, and the like.
  • the present invention also provides a method for preparing favipiravir tablets, which includes: dissolving a binder (such as povidone) in water, and then adding an anti-sticking agent (such as silicon dioxide) to obtain a binder solution ; Then Favipiravir or its salt, filler (such as microcrystalline cellulose) and one or a combination of disintegrant sodium carboxymethyl starch or calcium carboxymethyl cellulose are mixed, and the binder solution is added Wet granulation, selective drying, sieving and sieving to obtain favipiravir powdered granules; then adding lubricants such as sodium stearyl fumarate and optionally disintegrating agents such as crospovidone, Perform total mixing and compression to prepare favipiravir tablets.
  • a binder such as povidone
  • an anti-sticking agent such as silicon dioxide
  • the favipiravir composition provided by the present invention is prepared by adding one or both of the disintegrating agent sodium carboxymethyl starch or calcium carboxymethyl cellulose, which accounts for 2.5%-15% of the weight percentage of the preparation, Unexpected technical effects are obtained. In the in vitro dissolution test, it can dissolve ⁇ 85% in 15 minutes.
  • the favipiravir composition provided by the present invention has moderate hardness of the tablet, smooth tablet surface, good appearance, and no scratches or spots.
  • the preparation method of the favipiravir composition provided by the present invention has simple operation and good reproducibility, and the obtained favipiravir composition product has stable quality and is suitable for large-scale industrial production.
  • Favipiravir tablet composition :
  • Dissolve povidone K30 in purified water then add silicon dioxide and stir evenly to obtain a binder solution; mix favipiravir, microcrystalline cellulose and sodium carboxymethyl starch evenly, add the binder solution to wet Method of granulation and drying, the dry granules are sieved and granulated, and then sodium stearyl fumarate is added for total mixing and tableting.
  • Favipiravir tablet composition :
  • Dissolve povidone K30 in purified water then add silicon dioxide and stir evenly to obtain a binder solution; mix favipiravir and sodium carboxymethyl starch evenly, add the binder solution for wet granulation and drying, The dry granules are sieved and granulated, then crospovidone and sodium stearyl fumarate are added for total mixing and then compressed.
  • Favipiravir tablet composition :
  • Dissolve copovidone VA64 in purified water then add silicon dioxide and stir evenly to obtain a binder solution; mix favipiravir and sodium carboxymethyl starch evenly, add the binder solution for wet granulation and drying, The dry granules are sieved and granulated, then crospovidone and sodium stearyl fumarate are added for total mixing and then compressed.
  • Favipiravir tablet composition :
  • Dissolve povidone K30 in purified water then add silicon dioxide and stir evenly to obtain a binder solution; mix favipiravir, microcrystalline cellulose and sodium carboxymethyl starch evenly, add the binder solution to wet Method of granulation and drying, the dry granules are sieved and granulated, then cross-linked povidone and sodium stearyl fumarate are added for total mixing and then compressed.
  • Favipiravir tablet composition :
  • Favipiravir tablet composition :
  • Dissolve 2/3 povidone K30 in purified water then add silicon dioxide and stir evenly to obtain a binder solution; mix favipiravir, mannitol, sodium carboxymethyl starch and 1/3 povidone K30 Evenly, the binder solution is added for wet granulation and drying, the dry granules are sieved and granulated, and crospovidone and sodium stearyl fumarate are added for total mixing and tableting.
  • Favipiravir tablet composition :
  • Dissolve povidone K30 in purified water then add silicon dioxide and stir evenly to obtain a binder solution; mix favipiravir and carboxymethyl cellulose calcium evenly, add the binder solution for wet granulation and drying , The dry granules are sieved and granulated, then cross-linked povidone and sodium stearyl fumarate are added for total mixing and then compressed.
  • Favipiravir tablet composition :
  • Dissolve povidone K30 in purified water then add silicon dioxide and stir to obtain a binder solution; mix favipiravir, silicified microcrystalline cellulose and carboxymethyl cellulose calcium, and add the binder solution
  • Wet granulation and drying are carried out, the dry granules are sieved and granulated, and crospovidone and sodium stearyl fumarate are added for total mixing and then compressed.
  • Favipiravir tablet composition :
  • Dissolve povidone K30 in purified water then add silicon dioxide and stir evenly to obtain a binder solution; mix favipiravir and corn starch uniformly, add the binder solution for wet granulation and drying, and dry granules for After sieving and granulating, add cross-linked povidone and sodium stearyl fumarate for total mixing and then press tablets.
  • Favipiravir tablet composition :
  • Dissolve povidone K30 in purified water then add silicon dioxide and stir evenly to obtain a binder solution; mix favipiravir, microcrystalline cellulose and the internally added crospovidone evenly, and add the adhesive
  • the agent solution is subjected to wet granulation and drying, and the dry granules are sieved and granulated, and then an additional part of cross-linked povidone and sodium stearyl fumarate are added for total mixing and tableting.
  • Favipiravir tablet composition :
  • the comparative example 3 is the comparative example 4 of the patent CN201080011876.6. As shown in Comparative Example 4 of Patent CN201080011876.6, the favipiravir tablet only dissolves 76.3% in 15 minutes in the in vitro dissolution test.
  • Favipiravir tablet composition :
  • the comparative example 4 is the comparative example 5 of the patent CN201080011876.6. As shown in Comparative Example 5 of Patent CN201080011876.6, the favipiravir tablet only dissolves 63.6% in 15 minutes in the in vitro dissolution test.
  • the favipiravir tablets prepared in Examples 1-7 and the favipiravir tablets in Comparative Examples 1-3 were subjected to the determination of the dissolution profile according to the second method of the Chinese Pharmacopoeia (paddle method).
  • the rotating speed of the stirring blade is 50rpm
  • the dissolution medium is pH4.5 acetate buffer
  • the volume of the medium is 900ml
  • the temperature of the medium is 37°C ⁇ 0.5°C.
  • Example 1 63 81 89 94 98
  • Example 2 70 82 89 93 97
  • Example 3 72 84 90 94 97
  • Example 4 66 80 88 93 97
  • Example 5 73 84 90 94 98
  • Example 6 69 78 85 89 95
  • Example 7 73 83 88 92 96
  • Example 8 60 77 87 93 99 Comparative Example 1 63 72 79 83 89 Comparative Example 2 51 68 78 86 94

Abstract

A Favipiravir composition, a Favipiravir tablet, and a preparation method thereof. The composition contains Favipiravir or a salt thereof, one or a combination of two of a disintegrant carboxymethyl starch sodium (CMS) or a carboxymethylcellulose calcium, making up 2.5%–15% of the composition weight, and an adhesive. The drug content of the Favipiravir composition is high, and quick release of Favipiravir may be achieved; in in vitro dissolution tests, ≥ 85% was dissolved in 15 minutes.

Description

一种法匹拉韦组合物及其制备方法Favipiravir composition and preparation method thereof
本申请要求于2020年6月19日提交中国专利局、申请号为202010565808.X发明名称为“一种法匹拉韦组合物及其制备方法”的中国专利申请的优先权，其全部内容通过引用并入到本申请中。This application claims the priority of a Chinese patent application filed with the Chinese Patent Office with an application number of 202010565808.X on June 19, 2020, with the title of “a fapilavir composition and its preparation method”, and the entire content of which is passed The reference is incorporated into this application.
技术领域Technical field
本发明属于医药技术领域，具体地涉及一种法匹拉韦组合物及其制备方法。The invention belongs to the technical field of medicine, and specifically relates to a favipiravir composition and a preparation method thereof.
背景技术Background technique
法匹拉韦(favipiravir)是由日本富士胶片富山化学株式会社开发的，化学名称为6-氟-3-羟基吡嗪-2-甲酰胺。该药具有广谱抗病毒活性，对流感病毒、埃博拉病毒、黄热病毒、沙粒病毒、布尼亚病毒、西尼罗病毒等RNA病毒均具有抗病毒作用。Favipiravir was developed by Fujifilm Toyama Chemical Co., Ltd., and its chemical name is 6-fluoro-3-hydroxypyrazine-2-carboxamide. The drug has broad-spectrum antiviral activity, and has antiviral effects against RNA viruses such as influenza virus, Ebola virus, yellow fever virus, arena virus, bunya virus, and West Nile virus.
法匹拉韦于2014年在日本以商品名
Figure PCTCN2020118723-appb-000001
有条件批准上市，用于成人新型或复发流感的治疗(仅限于其他抗流感病毒药物治疗无效或效果不佳时使用)。上市剂型为片剂，每片规格为200mg法匹拉韦。通常成人疗程为5天，第1天，1次服用1600mg法匹拉韦，1日2次；第2天到第5天，1次服用600mg法匹拉韦，1日2次。每次给药需要口服多片。 Fapilavir was sold under the trade name in Japan in 2014
Figure PCTCN2020118723-appb-000001
Conditionally approved and marketed for the treatment of new or recurrent influenza in adults (only used when other anti-influenza drugs are ineffective or ineffective). The marketed dosage form is a tablet, each with a specification of 200 mg favipiravir. The usual course of treatment for adults is 5 days. On day 1, 1600 mg of favipiravir is taken once, twice a day; from day 2 to day 5, 600 mg of favipiravir is taken once, twice a day. Each administration requires multiple oral tablets.
法匹拉韦口服给药后血药浓度在30分钟左右达到峰值而发挥药效，因此研发的制剂需要快速的溶出能力，即在体外溶出试验中能够在15分钟溶出≥85％的药物。After oral administration of favipiravir, the plasma concentration reaches its peak in about 30 minutes and exerts its efficacy. Therefore, the developed formulation requires rapid dissolution capability, that is, it can dissolve ≥85% of the drug in 15 minutes in an in vitro dissolution test.
同时，由于每次给药需要口服多片法匹拉韦，因此研发的片剂中法匹拉韦的含量需尽量较高，这样每片片重减小，从而降低尺寸，易于服用。但每片重量的减小意味着需要使用较少的辅料，这将导致药物释放的减慢，因此该药的研发难点是在较低片重的情况下实现快速溶出(15分钟溶出≥85％的药物)。At the same time, since multiple favipiravir tablets need to be taken orally for each administration, the content of favipiravir in the developed tablets must be as high as possible, so that the weight of each tablet is reduced, thereby reducing the size and making it easier to take. However, the reduction in the weight of each tablet means that fewer excipients need to be used, which will slow down the release of the drug. Therefore, the difficulty in the development of the drug is to achieve rapid dissolution under the condition of lower tablet weight (15 minutes dissolution ≥ 85% Drug).
原研富山化学株式会社的专利CN201080011876.6公开了一种法匹拉韦片 及其制备方法，通过使用低取代羟丙基纤维素或交联羧甲基纤维素钠，以达到提高溶出度的效果，并且维持较低的片重。该专利实施例中片重为250-263mg，法匹拉韦含量可达76％(200/263*100％＝76％)。另外，在该专利的比较例5中使用了羧甲基淀粉钠作为崩解剂。该比较例5的制剂中羧甲基淀粉钠的重量为5.6mg，制剂总质量为260.0mg，羧甲基淀粉钠占制剂总质量的2.15重量％。然而，该使用羧甲基淀粉钠作为崩解剂的比较例5的溶出率仅为63.6％。由此可见，该专利实际上教导了使用羧甲基淀粉钠作为崩解剂不能实现法匹拉韦的快速溶出(即15分钟溶出≥85％的药物)，即给出了避免使用羧甲基淀粉钠作为崩解剂的相反教导。The patent CN201080011876.6 of the original research Toyama Chemical Co., Ltd. discloses a favipiravir tablet and a preparation method thereof, by using low-substituted hydroxypropyl cellulose or croscarmellose sodium to achieve the effect of improving the dissolution rate , And maintain a low film weight. In the examples of the patent, the tablet weight is 250-263 mg, and the favipiravir content can reach 76% (200/263*100%=76%). In addition, in Comparative Example 5 of the patent, sodium carboxymethyl starch was used as a disintegrant. The weight of sodium carboxymethyl starch in the preparation of Comparative Example 5 was 5.6 mg, the total mass of the preparation was 260.0 mg, and the sodium carboxymethyl starch accounted for 2.15% by weight of the total mass of the preparation. However, the dissolution rate of Comparative Example 5 using sodium carboxymethyl starch as the disintegrant was only 63.6%. It can be seen that the patent actually teaches that the use of sodium carboxymethyl starch as a disintegrant cannot achieve the rapid dissolution of favipiravir (ie, the dissolution of ≥85% of the drug in 15 minutes), that is, the avoidance of the use of carboxymethyl The opposite teaching of sodium starch as a disintegrant.
专利201510755106.7记载了通过加入硅化微晶纤维素50以达到提高溶出度的效果，单片制剂中法匹拉韦含量为55-70％，单片片剂的总重量甚至高达400mg，片重过高。在使用硅化微晶纤维素50作为崩解剂的情况下，该专利要求法匹拉韦的粒径分布D90必须在40μm-160μm之间，否则不能实现法匹拉韦的快速溶出。另外，该专利还指出，在使用硅化微晶纤维素50作为崩解剂的情况下，必须控制粘合剂的用量使其相对于片剂的重量百分比为4％-7％。如果粘合剂用量低于4％，则片剂的脆碎度过高，外观检测有磕痕的片剂大大增加，次品较多；如果粘合剂的用量高于7％，则溶出效果不理想。因此，必须控制粘合剂的用量。综上，该专利的申请人并没有认识到在实现法匹拉韦快速溶出的同时要去控制单片片剂的总重量。专利201610163419.8通过加入大量的微晶纤维素PH-102和增溶剂以达到提高溶出度的效果，单片制剂中法匹拉韦含量低于67％。在该专利中，微晶纤维素PH-102的量相对于法匹拉韦的量为0.5-1:1，即200mg的法匹拉韦需加入100-200mg的微晶纤维素PH-102，使得制得的法匹拉韦单片片剂的总重量大大增加。因此，虽然这两种方法都能提高溶出度，但均需要加入较多的辅料，法匹拉韦含量均低于74％。Patent 201510755106.7 describes the effect of increasing the dissolution rate by adding silicified microcrystalline cellulose 50. The content of favipiravir in a single tablet formulation is 55-70%, and the total weight of a single tablet is even as high as 400 mg, which is too high. . In the case of using silicified microcrystalline cellulose 50 as a disintegrant, the patent requires that the particle size distribution D90 of favipiravir must be between 40 μm and 160 μm, otherwise the rapid dissolution of favipiravir cannot be achieved. In addition, the patent also pointed out that in the case of using silicified microcrystalline cellulose 50 as a disintegrant, the amount of binder must be controlled so that the weight percentage relative to the tablet is 4% to 7%. If the amount of binder is less than 4%, the friability of the tablet will be too high, and the number of tablets with scratches in appearance detection will increase greatly, and there will be more defective products; if the amount of binder is higher than 7%, the dissolution effect will be achieved. not ideal. Therefore, the amount of adhesive must be controlled. In summary, the applicant of the patent did not realize that the total weight of a single tablet must be controlled while achieving fast dissolution of favipiravir. Patent 201610163419.8 achieves the effect of increasing the dissolution rate by adding a large amount of microcrystalline cellulose PH-102 and a solubilizer, and the content of favipiravir in a single tablet preparation is less than 67%. In this patent, the amount of microcrystalline cellulose PH-102 relative to the amount of favipiravir is 0.5-1:1, that is, 200 mg of favipiravir needs to add 100-200 mg of microcrystalline cellulose PH-102, The total weight of the prepared single favipiravir tablet is greatly increased. Therefore, although these two methods can improve the dissolution rate, they need to add more excipients, and the content of favipiravir is less than 74%.
发明内容Summary of the invention
目前存在的技术问题是：法匹拉韦每次给药需要口服多片，因此研发的片剂中法匹拉韦的含量需尽可能地高，这样每片片重减小，从而降低尺寸，易于服用。但每片重量的减小意味着需要使用较少的辅料，这将导致药物释 放的减慢，因此该药的研发难点是在较低片重的情况下又能实现药物的快速溶出。The current technical problem is: each administration of favipiravir requires multiple oral tablets. Therefore, the content of favipiravir in the developed tablets needs to be as high as possible, so that the weight of each tablet is reduced and the size is reduced. Easy to take. However, the reduction in the weight of each tablet means that fewer excipients need to be used, which will slow down the release of the drug. Therefore, the difficulty in the development of the drug is that it can achieve rapid drug dissolution under the condition of lower tablet weight.
为了实现组合物中法匹拉韦含量高，尺寸便于服用，稳定性好，制备方法简便以及达到快速溶出等效果，本发明人进行了大量尝试，在研发的过程中出人意料地发现，通过加入特定量的崩解剂羧甲基淀粉钠或羧甲基纤维素钙中的一种或两种的组合，可在每片中法匹拉韦的含量较高时，即片重较低时，实现法匹拉韦的快速释放，在体外溶出试验中能够在15分钟溶出≥85％。In order to achieve the high content of favipiravir in the composition, the size is convenient to take, the stability is good, the preparation method is simple and the rapid dissolution and other effects, the inventors have made a lot of attempts, and unexpectedly discovered in the process of research and development that by adding specific The amount of disintegrant of sodium carboxymethyl starch or calcium carboxymethyl cellulose or a combination of both can be achieved when the content of favipiravir in each tablet is high, that is, when the tablet weight is low. The rapid release of favipiravir can dissolve ≥85% in 15 minutes in an in vitro dissolution test.
本发明提供一种法匹拉韦组合物，含有：The present invention provides a favipiravir composition, which contains:
a.法匹拉韦或其盐；a. Favipiravir or its salt;
b.羧甲基淀粉钠或羧甲基纤维素钙崩解剂中的一种或两种的组合；和b. Sodium carboxymethyl starch or calcium carboxymethyl cellulose disintegrant or a combination of two; and
c.粘合剂；c. Adhesive;
其中法匹拉韦组合物在体外溶出试验中能够在15分钟溶出≥85％。Among them, the favipiravir composition can dissolve more than 85% in 15 minutes in an in vitro dissolution test.
本发明还提供一种法匹拉韦组合物，含有：The present invention also provides a favipiravir composition, which contains:
a.法匹拉韦或其盐；a. Favipiravir or its salt;
b.占组合物重量百分比为2.5％-15％的崩解剂，所述崩解剂选自羧甲基淀粉钠或羧甲基纤维素钙中的一种或两种的组合；和b. a disintegrant of 2.5%-15% by weight of the composition, the disintegrant is selected from one or a combination of sodium carboxymethyl starch or calcium carboxymethyl cellulose; and
c.粘合剂。c. Adhesives.
该法匹拉韦组合物同样能实现快速释放，其中法匹拉韦组合物在体外溶出试验中能够在15分钟溶出≥85％。溶出方法可按中国药典第二法(桨法)进行溶出曲线测定。该方法的具体条件为：搅拌桨转速为50rpm，溶出介质为pH4.5醋酸盐缓冲液，介质体积为900ml，介质温度37℃±0.5℃。The favipiravir composition can also achieve rapid release, wherein the favipiravir composition can dissolve ≥85% in 15 minutes in an in vitro dissolution test. The dissolution method can be determined according to the second method of the Chinese Pharmacopoeia (paddle method). The specific conditions of the method are: the rotating speed of the stirring blade is 50 rpm, the dissolution medium is pH 4.5 acetate buffer, the medium volume is 900 ml, and the medium temperature is 37°C ± 0.5°C.
根据本发明提供的法匹拉韦组合物，所述法匹拉韦占组合物重量比为60％以上，优选70％以上，进一步优选70％-85％，甚至更优选75％-82％。According to the favipiravir composition provided by the present invention, the weight ratio of favipiravir to the composition is more than 60%, preferably more than 70%, more preferably 70%-85%, even more preferably 75%-82%.
根据本发明提供的法匹拉韦组合物，所述崩解剂选自羧甲基淀粉钠或羧甲基纤维素钙中的一种或两种的组合，崩解剂占组合物重量百分比为2.5％-15％，进一步优选3-12％。According to the favipiravir composition provided by the present invention, the disintegrant is selected from one or a combination of two of sodium carboxymethyl starch or calcium carboxymethyl cellulose, and the disintegrant accounts for a weight percentage of the composition 2.5%-15%, more preferably 3-12%.
本发明提供的法匹拉韦组合物可进一步含有填充剂。适合本发明的组合物的填充剂包括但不限于：甘露醇、木糖醇、乳糖、微晶纤维素、硅化微晶 纤维素、淀粉、蔗糖、葡萄糖、麦芽糖醇、磷酸氢钙、磷酸二氢钙、硅酸钙中的一种或其任意组合，优选甘露醇和/或微晶纤维素，更优选微晶纤维素。The favipiravir composition provided by the present invention may further contain a filler. Fillers suitable for the composition of the present invention include but are not limited to: mannitol, xylitol, lactose, microcrystalline cellulose, silicified microcrystalline cellulose, starch, sucrose, glucose, maltitol, calcium hydrogen phosphate, dihydrogen phosphate One of calcium and calcium silicate or any combination thereof, preferably mannitol and/or microcrystalline cellulose, more preferably microcrystalline cellulose.
进一步地，填充剂占组合物的重量百分比为≤15％，优选≤12％。Further, the weight percentage of the filler in the composition is ≤15%, preferably ≤12%.
适合本发明的组合物的粘合剂包括但不限于：羟丙甲纤维素、羟丙纤维素、甲基纤维素、共聚维酮、聚维酮等，优选共聚维酮和/或聚维酮，更优选聚维酮，聚维酮优选地选自聚维酮K30、聚维酮K25、聚维酮K17和聚维酮K90等。Binders suitable for the composition of the present invention include but are not limited to: hypromellose, hydroxypropyl cellulose, methyl cellulose, copovidone, povidone, etc., preferably copovidone and/or povidone , More preferably povidone, povidone is preferably selected from povidone K30, povidone K25, povidone K17, povidone K90 and the like.
进一步地，粘合剂占组合物的重量百分比为0.5-5％，优选2-5％。Further, the weight percentage of the binder in the composition is 0.5-5%, preferably 2-5%.
本发明提供的法匹拉韦组合物还可进一步含有抗粘剂。The favipiravir composition provided by the present invention may further contain an anti-sticking agent.
适合本发明的组合物的抗粘剂包括但不限于二氧化硅、硅藻土等，优选二氧化硅。Anti-sticking agents suitable for the composition of the present invention include, but are not limited to, silicon dioxide, diatomaceous earth, etc., preferably silicon dioxide.
进一步地，抗粘剂占组合物的重量百分比为0.5-5％，优选2-5％。Further, the weight percentage of the anti-sticking agent in the composition is 0.5-5%, preferably 2-5%.
在一个实施方案中，本发明的组合物，以所述组合物的重量百分比计，包含以下组分：In one embodiment, the composition of the present invention, based on the weight percentage of the composition, includes the following components:
a.法匹拉韦或其盐60％以上，优选70％以上，进一步优选70％-85％；a. Favipiravir or its salt is more than 60%, preferably more than 70%, more preferably 70%-85%;
b.选自羧甲基淀粉钠或羧甲基纤维素钙中的一种或两种组合的崩解剂2.5％-15％，进一步优选3-12％；b. Disintegrant selected from one or a combination of sodium carboxymethyl starch or calcium carboxymethyl cellulose 2.5%-15%, more preferably 3-12%;
c.粘合剂0.5-5％；c. Adhesive 0.5-5%;
d.填充剂≤15％，优选≤12％；d. Filler≤15%, preferably≤12%;
e.抗粘剂0.5-5％，优选2-5％；e. Anti-sticking agent 0.5-5%, preferably 2-5%;
所述组合物为粉末状颗粒。The composition is powdered granules.
本发明提供一种用于制备粉末状颗粒形式的法匹拉韦组合物的方法，包括：通过湿法制粒得到粉末状颗粒。The invention provides a method for preparing a favipiravir composition in the form of powdered granules, which comprises: obtaining powdered granules by wet granulation.
在一个实施方案中，制备粉末状颗粒形式的法匹拉韦的方法包括：将粘合剂(例如聚维酮)溶于水中，再加入抗粘剂(例如二氧化硅)得到粘合剂溶液；再将法匹拉韦或其盐、填充剂(例如微晶纤维素)和崩解剂羧甲基淀粉钠或羧甲基纤维素钙的一种或其组合混合，加入以上粘合剂溶液进行湿法制粒、并选择性地干燥，过筛整粒，即得到法匹拉韦粉末状颗粒。In one embodiment, the method for preparing favipiravir in the form of powdered particles includes: dissolving a binder (such as povidone) in water, and then adding an anti-sticking agent (such as silicon dioxide) to obtain a binder solution ; Then Favipiravir or its salt, filler (such as microcrystalline cellulose) and one or a combination of disintegrant sodium carboxymethyl starch or calcium carboxymethyl cellulose, add the above binder solution Wet granulation, selective drying, and sieving to obtain favipiravir powder granules.
本发明还提供一种法匹拉韦片剂，以片剂的重量百分比计，包含以下组分：The present invention also provides a favipiravir tablet, which contains the following components based on the weight percentage of the tablet:
a.法匹拉韦或其盐60％以上，优选70％以上，进一步优选70％-85％；a. Favipiravir or its salt is more than 60%, preferably more than 70%, more preferably 70%-85%;
b.羧甲基淀粉钠或羧甲基纤维素钙中的一种或两种组合2.5％-15％，进一步优选3-12％；b. One or two combinations of sodium carboxymethyl starch or calcium carboxymethyl cellulose 2.5%-15%, more preferably 3-12%;
c.粘合剂0.5-5％；c. Adhesive 0.5-5%;
d.填充剂≤15％，优选≤12％；d. Filler≤15%, preferably≤12%;
e.抗粘剂0.5-5％，优选2-5％；e. Anti-sticking agent 0.5-5%, preferably 2-5%;
f.润滑剂和任选的其它添加剂0.1-5％，优选0.5％-2％；和f. Lubricant and optional other additives 0.1-5%, preferably 0.5%-2%; and
g.任选地，外加崩解剂1-4％，优选1.5-3％。g. Optionally, an external disintegrant is added by 1-4%, preferably 1.5-3%.
适合本发明的片剂的外加崩解剂包括但不局限于：交联聚维酮、羧甲基淀粉钠、羧甲基纤维素钙等，优选交联聚维酮。The external disintegrant suitable for the tablet of the present invention includes but is not limited to: crospovidone, sodium carboxymethyl starch, calcium carboxymethyl cellulose, etc., preferably crospovidone.
进一步地，外加崩解剂占制剂的重量百分比为1-4％，优选1.5-3％。Further, the weight percentage of the external disintegrant in the preparation is 1-4%, preferably 1.5-3%.
进一步地，外加润滑剂包括但不局限于：硬脂酸、硬脂酸镁，硬脂富马酸钠、滑石粉等，优选硬脂富马酸钠。Further, the external lubricant includes but is not limited to: stearic acid, magnesium stearate, sodium stearyl fumarate, talc, etc., preferably sodium stearyl fumarate.
进一步地，其它添加剂包括着色剂、包衣剂、矫味剂、表面活性剂、增塑剂或芳香剂等。Further, other additives include coloring agents, coating agents, flavoring agents, surfactants, plasticizers or fragrances and the like.
本发明的法匹拉韦片剂，可选择性的进行薄膜包衣。包衣膜通常为片剂总重量的约1.5-5％，包衣膜由成膜剂、增塑剂、色素等组成。The favipiravir tablet of the present invention can be optionally film-coated. The coating film is usually about 1.5-5% of the total weight of the tablet, and the coating film is composed of film-forming agents, plasticizers, pigments, and the like.
本发明还提供一种用于制备法匹拉韦片剂的方法，包括：将粘合剂(例如聚维酮)溶于水中，再加入抗粘剂(例如二氧化硅)得到粘合剂溶液；再将法匹拉韦或其盐、填充剂(例如微晶纤维素)和崩解剂羧甲基淀粉钠或羧甲基纤维素钙的一种或其组合混合，加入粘合剂溶液进行湿法制粒、选择性地干燥，过筛整粒，即得到法匹拉韦粉末状颗粒；再加入润滑剂例如硬脂富马酸钠和任选地外加崩解剂例如交联聚维酮，进行总混，压片，制备成法匹拉韦片剂。另外，本领域技术人员通过常规方法能够很容易地制备其他类型的固体制剂例如颗粒剂或胶囊等。The present invention also provides a method for preparing favipiravir tablets, which includes: dissolving a binder (such as povidone) in water, and then adding an anti-sticking agent (such as silicon dioxide) to obtain a binder solution ; Then Favipiravir or its salt, filler (such as microcrystalline cellulose) and one or a combination of disintegrant sodium carboxymethyl starch or calcium carboxymethyl cellulose are mixed, and the binder solution is added Wet granulation, selective drying, sieving and sieving to obtain favipiravir powdered granules; then adding lubricants such as sodium stearyl fumarate and optionally disintegrating agents such as crospovidone, Perform total mixing and compression to prepare favipiravir tablets. In addition, those skilled in the art can easily prepare other types of solid preparations such as granules or capsules by conventional methods.
本发明有益的技术效果：The beneficial technical effects of the present invention:
1、本发明提供的法匹拉韦组合物，通过加入占制剂重量百分比为2.5％-15％的崩解剂羧甲基淀粉钠或羧甲基纤维素钙中的一种或两种组合，得到意料不到的技术效果，体外溶出试验中能够在15分钟溶出≥85％。1. The favipiravir composition provided by the present invention is prepared by adding one or both of the disintegrating agent sodium carboxymethyl starch or calcium carboxymethyl cellulose, which accounts for 2.5%-15% of the weight percentage of the preparation, Unexpected technical effects are obtained. In the in vitro dissolution test, it can dissolve ≥85% in 15 minutes.
2、本发明提供的法匹拉韦组合物，片剂的硬度适中，压片表面光滑，外观良好，不会出现磕痕或斑点。2. The favipiravir composition provided by the present invention has moderate hardness of the tablet, smooth tablet surface, good appearance, and no scratches or spots.
3、本发明提供的法匹拉韦组合物制备方法，方法操作简便，重现性好，得到的法匹拉韦组合物产品质量稳定，适合工业化大生产。3. The preparation method of the favipiravir composition provided by the present invention has simple operation and good reproducibility, and the obtained favipiravir composition product has stable quality and is suitable for large-scale industrial production.
具体实施方式detailed description
下面结合实施例对本发明作进一步的详细说明，但并不限于下述实施例。The present invention will be further described in detail below in conjunction with embodiments, but it is not limited to the following embodiments.
实施例1Example 1
法匹拉韦片剂组成：Favipiravir tablet composition:
辅料名称Accessory name 处方中单片用量/mgSingle tablet dosage/mg in prescription 百分比例％Percentage example%
法匹拉韦Favipiravir 200200 80.180.1
微晶纤维素Microcrystalline cellulose 18.5518.55 7.47.4
羧甲基淀粉钠Sodium Carboxymethyl Starch 7.657.65 3.13.1
聚维酮K30Povidone K30 11.511.5 4.64.6
二氧化硅Silica 11.511.5 4.64.6
硬脂富马酸钠Sodium Stearyl Fumarate 0.50.5 0.20.2
合计total 249.7249.7 100.0100.0
将聚维酮K30溶解在纯化水中，再加入二氧化硅搅拌均匀，得到粘合剂溶液；将法匹拉韦、微晶纤维素和羧甲基淀粉钠混合均匀，加入粘合剂溶液进行湿法制粒和干燥，干颗粒进行过筛整粒，再加入硬脂富马酸钠进行总混后压片。Dissolve povidone K30 in purified water, then add silicon dioxide and stir evenly to obtain a binder solution; mix favipiravir, microcrystalline cellulose and sodium carboxymethyl starch evenly, add the binder solution to wet Method of granulation and drying, the dry granules are sieved and granulated, and then sodium stearyl fumarate is added for total mixing and tableting.
实施例2Example 2
法匹拉韦片剂组成：Favipiravir tablet composition:
辅料名称Accessory name 处方中单片用量/mgSingle tablet dosage/mg in prescription 百分比例％Percentage example%
法匹拉韦Favipiravir 200200 78.4％78.4%
羧甲基淀粉钠Sodium Carboxymethyl Starch 26.226.2 10.3％10.3%
聚维酮K30Povidone K30 11.511.5 4.5％4.5%
二氧化硅Silica 11.511.5 4.5％4.5%
交联聚维酮Crospovidone 5.35.3 2.1％2.1%
硬脂富马酸钠Sodium Stearyl Fumarate 0.50.5 0.2％0.2%
合计total 255255 100％100%
将聚维酮K30溶解在纯化水中，再加入二氧化硅搅拌均匀，得到粘合剂溶液；将法匹拉韦和羧甲基淀粉钠混合均匀，加入粘合剂溶液进行湿法制粒和干燥，干颗粒进行过筛整粒，再加入交联聚维酮和硬脂富马酸钠进行总混后压片。Dissolve povidone K30 in purified water, then add silicon dioxide and stir evenly to obtain a binder solution; mix favipiravir and sodium carboxymethyl starch evenly, add the binder solution for wet granulation and drying, The dry granules are sieved and granulated, then crospovidone and sodium stearyl fumarate are added for total mixing and then compressed.
实施例3Example 3
法匹拉韦片剂组成：Favipiravir tablet composition:
辅料名称Accessory name 处方中单片用量/mgSingle tablet dosage/mg in prescription 百分比例％Percentage example%
法匹拉韦Favipiravir 200200 78.4％78.4%
羧甲基淀粉钠Sodium Carboxymethyl Starch 26.226.2 10.3％10.3%
共聚维酮VA64Copovidone VA64 11.511.5 4.5％4.5%
二氧化硅Silica 11.511.5 4.5％4.5%
交联聚维酮Crospovidone 5.35.3 2.1％2.1%
硬脂富马酸钠Sodium Stearyl Fumarate 0.50.5 0.2％0.2%
合计total 255255 100％100%
将共聚维酮VA64溶解在纯化水中，再加入二氧化硅搅拌均匀，得到粘合剂溶液；将法匹拉韦和羧甲基淀粉钠混合均匀，加入粘合剂溶液进行湿法制粒和干燥，干颗粒进行过筛整粒，再加入交联聚维酮和硬脂富马酸钠进行总混后压片。Dissolve copovidone VA64 in purified water, then add silicon dioxide and stir evenly to obtain a binder solution; mix favipiravir and sodium carboxymethyl starch evenly, add the binder solution for wet granulation and drying, The dry granules are sieved and granulated, then crospovidone and sodium stearyl fumarate are added for total mixing and then compressed.
实施例4Example 4
法匹拉韦片剂组成：Favipiravir tablet composition:
辅料名称Accessory name 处方中单片用量/mgSingle tablet dosage/mg in prescription 百分比例％Percentage example%
法匹拉韦Favipiravir 200200 78.4％78.4%
微晶纤维素Microcrystalline cellulose 18.5518.55 7.3％7.3%
羧甲基淀粉钠Sodium Carboxymethyl Starch 7.657.65 3.0％3.0%
聚维酮K30Povidone K30 11.511.5 4.5％4.5%
二氧化硅Silica 11.511.5 4.5％4.5%
交联聚维酮Crospovidone 5.35.3 2.1％2.1%
硬脂富马酸钠Sodium Stearyl Fumarate 0.50.5 0.2％0.2%
合计total 255255 100％100%
将聚维酮K30溶解在纯化水中，再加入二氧化硅搅拌均匀，得到粘合剂溶液；将法匹拉韦、微晶纤维素和羧甲基淀粉钠混合均匀，加入粘合剂溶液进行湿法制粒和干燥，干颗粒进行过筛整粒，再加入交联聚维酮和硬脂富马酸钠进行总混后压片。Dissolve povidone K30 in purified water, then add silicon dioxide and stir evenly to obtain a binder solution; mix favipiravir, microcrystalline cellulose and sodium carboxymethyl starch evenly, add the binder solution to wet Method of granulation and drying, the dry granules are sieved and granulated, then cross-linked povidone and sodium stearyl fumarate are added for total mixing and then compressed.
实施例5Example 5
法匹拉韦片剂组成：Favipiravir tablet composition:
辅料名称Accessory name 处方中单片用量/mgSingle tablet dosage/mg in prescription 百分比例％Percentage example%
法匹拉韦Favipiravir 200200 78.4％78.4%
微晶纤维素Microcrystalline cellulose 27.2527.25 10.7％10.7%
羧甲基淀粉钠Sodium Carboxymethyl Starch 7.657.65 3.0％3.0%
羟丙纤维素Hydroxypropyl cellulose 2.802.80 1.1％1.1%
二氧化硅Silica 11.511.5 4.5％4.5%
交联聚维酮Crospovidone 5.35.3 2.1％2.1%
硬脂富马酸钠Sodium Stearyl Fumarate 0.50.5 0.2％0.2%
合计total 255255 100％100%
将羟丙纤维素溶解在纯化水中，再加入二氧化硅搅拌均匀，得到粘合剂溶液；将法匹拉韦、微晶纤维素和羧甲基淀粉钠混合均匀，加入粘合剂溶液进行湿法制粒和干燥，干颗粒进行过筛整粒，再加入交联聚维酮和硬脂富马酸钠进行总混后压片。Dissolve the hydroxypropyl cellulose in purified water, then add silicon dioxide and stir evenly to obtain a binder solution; mix favipiravir, microcrystalline cellulose and sodium carboxymethyl starch evenly, and add the binder solution to wet Method of granulation and drying, the dry granules are sieved and granulated, then cross-linked povidone and sodium stearyl fumarate are added for total mixing and then compressed.
实施例6Example 6
法匹拉韦片剂组成：Favipiravir tablet composition:
辅料名称Accessory name 处方中单片用量/mgSingle tablet dosage/mg in prescription 百分比例％Percentage example%
法匹拉韦Favipiravir 200200 78.4％78.4%
甘露醇Mannitol 18.5518.55 7.3％7.3%
羧甲基淀粉钠Sodium Carboxymethyl Starch 7.657.65 3.0％3.0%
聚维酮K30Povidone K30 11.511.5 4.5％4.5%
二氧化硅Silica 11.511.5 4.5％4.5%
交联聚维酮Crospovidone 5.35.3 2.1％2.1%
硬脂富马酸钠Sodium Stearyl Fumarate 0.50.5 0.2％0.2%
合计total 255255 100％100%
将2/3聚维酮K30溶解在纯化水中，再加入二氧化硅搅拌均匀，得到粘合剂溶液；将法匹拉韦、甘露醇、羧甲基淀粉钠和1/3聚维酮K30混合均匀，加入粘合剂溶液进行湿法制粒和干燥，干颗粒进行过筛整粒，再加入交联聚维酮和硬脂富马酸钠进行总混后压片。Dissolve 2/3 povidone K30 in purified water, then add silicon dioxide and stir evenly to obtain a binder solution; mix favipiravir, mannitol, sodium carboxymethyl starch and 1/3 povidone K30 Evenly, the binder solution is added for wet granulation and drying, the dry granules are sieved and granulated, and crospovidone and sodium stearyl fumarate are added for total mixing and tableting.
实施例7Example 7
法匹拉韦片剂组成：Favipiravir tablet composition:
辅料名称Accessory name 处方中单片用量/mgSingle tablet dosage/mg in prescription 百分比例％Percentage example%
法匹拉韦Favipiravir 200200 78.4％78.4%
羧甲基纤维素钙Carboxymethyl Cellulose Calcium 26.226.2 10.3％10.3%
聚维酮K30Povidone K30 11.511.5 4.5％4.5%
二氧化硅Silica 11.511.5 4.5％4.5%
辅料名称Accessory name 处方中单片用量/mgSingle tablet dosage/mg in prescription 百分比例％Percentage example%
交联聚维酮Crospovidone 5.35.3 2.1％2.1%
硬脂富马酸钠Sodium Stearyl Fumarate 0.50.5 0.2％0.2%
合计total 255255 100％100%
将聚维酮K30溶解在纯化水中，再加入二氧化硅搅拌均匀，得到粘合剂溶液；将法匹拉韦、羧甲基纤维素钙混合均匀，加入粘合剂溶液进行湿法制粒和干燥，干颗粒进行过筛整粒，再加入交联聚维酮和硬脂富马酸钠进行总混后压片。Dissolve povidone K30 in purified water, then add silicon dioxide and stir evenly to obtain a binder solution; mix favipiravir and carboxymethyl cellulose calcium evenly, add the binder solution for wet granulation and drying , The dry granules are sieved and granulated, then cross-linked povidone and sodium stearyl fumarate are added for total mixing and then compressed.
实施例8Example 8
法匹拉韦片剂组成：Favipiravir tablet composition:
辅料名称Accessory name 处方中单片用量/mgSingle tablet dosage/mg in prescription 百分比例％Percentage example%
法匹拉韦Favipiravir 200200 78.4％78.4%
硅化微晶纤维素Silicified Microcrystalline Cellulose 18.5518.55 7.3％7.3%
羧甲基纤维素钙Carboxymethyl Cellulose Calcium 7.657.65 3.0％3.0%
聚维酮K30Povidone K30 11.511.5 4.5％4.5%
二氧化硅Silica 11.511.5 4.5％4.5%
交联聚维酮Crospovidone 5.35.3 2.1％2.1%
硬脂富马酸钠Sodium Stearyl Fumarate 0.50.5 0.2％0.2%
合计total 255255 100％100%
将聚维酮K30溶解在纯化水中，再加入二氧化硅搅拌均匀，得到粘合剂溶液；将法匹拉韦、硅化微晶纤维素和羧甲基纤维素钙混合均匀，加入粘合剂溶液进行湿法制粒和干燥，干颗粒进行过筛整粒，再加入交联聚维酮和硬脂富马酸钠进行总混后压片。Dissolve povidone K30 in purified water, then add silicon dioxide and stir to obtain a binder solution; mix favipiravir, silicified microcrystalline cellulose and carboxymethyl cellulose calcium, and add the binder solution Wet granulation and drying are carried out, the dry granules are sieved and granulated, and crospovidone and sodium stearyl fumarate are added for total mixing and then compressed.
对比实施例1：Comparative Example 1:
法匹拉韦片剂组成：Favipiravir tablet composition:
辅料名称Accessory name 处方中单片用量/mgSingle tablet dosage/mg in prescription 百分比例％Percentage example%
法匹拉韦Favipiravir 200200 78.4％78.4%
玉米淀粉corn starch 26.226.2 10.3％10.3%
聚维酮K30Povidone K30 11.511.5 4.5％4.5%
二氧化硅Silica 11.511.5 4.5％4.5%
交联聚维酮Crospovidone 5.35.3 2.1％2.1%
硬脂富马酸钠Sodium Stearyl Fumarate 0.50.5 0.2％0.2%
合计total 255255 100％100%
将聚维酮K30溶解在纯化水中，再加入二氧化硅搅拌均匀，得到粘合剂溶液；将法匹拉韦和玉米淀粉混合均匀，加入粘合剂溶液进行湿法制粒和干燥，干颗粒进行过筛整粒，再加入交联聚维酮和硬脂富马酸钠进行总混后压片。Dissolve povidone K30 in purified water, then add silicon dioxide and stir evenly to obtain a binder solution; mix favipiravir and corn starch uniformly, add the binder solution for wet granulation and drying, and dry granules for After sieving and granulating, add cross-linked povidone and sodium stearyl fumarate for total mixing and then press tablets.
对比实施例2：Comparative Example 2:
法匹拉韦片剂组成：Favipiravir tablet composition:
辅料名称Accessory name 处方中单片用量/mgSingle tablet dosage/mg in prescription 百分比例％Percentage example%
法匹拉韦Favipiravir 200200 78.4％78.4%
微晶纤维素Microcrystalline cellulose 18.5518.55 7.3％7.3%
交联聚维酮Crospovidone 7.657.65 3.0％3.0%
聚维酮K30Povidone K30 11.511.5 4.5％4.5%
二氧化硅Silica 11.511.5 4.5％4.5%
交联聚维酮Crospovidone 5.35.3 2.1％2.1%
硬脂富马酸钠Sodium Stearyl Fumarate 0.50.5 0.2％0.2%
合计total 255255 100％100%
将聚维酮K30溶解在纯化水中，再加入二氧化硅搅拌均匀，得到粘合剂溶液；将法匹拉韦、微晶纤维素和内加部分的交联聚维酮混合均匀，加入粘合剂溶液进行湿法制粒和干燥，干颗粒进行过筛整粒，再加入外加部分的交联聚维酮和硬脂富马酸钠进行总混后压片。Dissolve povidone K30 in purified water, then add silicon dioxide and stir evenly to obtain a binder solution; mix favipiravir, microcrystalline cellulose and the internally added crospovidone evenly, and add the adhesive The agent solution is subjected to wet granulation and drying, and the dry granules are sieved and granulated, and then an additional part of cross-linked povidone and sodium stearyl fumarate are added for total mixing and tableting.
对比实施例3：Comparative Example 3:
法匹拉韦片剂组成：Favipiravir tablet composition:
辅料名称Accessory name 处方中单片用量/mgSingle tablet dosage/mg in prescription 百分比例％Percentage example%
法匹拉韦Favipiravir 216.3216.3 86.52％86.52%
聚维酮K30Povidone K30 13.513.5 5.4％5.4%
二氧化硅Silica 5.45.4 2.16％2.16%
交联聚维酮Crospovidone 13.513.5 5.4％5.4%
硬脂富马酸钠Sodium Stearyl Fumarate 1.31.3 0.52％0.52%
合计total 250250 100％100%
该对比实施例3即为专利CN201080011876.6的比较例4。如专利CN201080011876.6的比较例4所示的，该法匹拉韦片剂在体外溶出试验中在15分钟仅溶出76.3％。The comparative example 3 is the comparative example 4 of the patent CN201080011876.6. As shown in Comparative Example 4 of Patent CN201080011876.6, the favipiravir tablet only dissolves 76.3% in 15 minutes in the in vitro dissolution test.
对比实施例4：Comparative Example 4:
法匹拉韦片剂组成：Favipiravir tablet composition:
辅料名称Accessory name 处方中单片用量/mgSingle tablet dosage/mg in prescription 百分比例％Percentage example%
法匹拉韦Favipiravir 223.5223.5 86.0％86.0%
羧甲基淀粉钠Sodium Carboxymethyl Starch 5.65.6 2.15％2.15%
聚维酮K30Povidone K30 14.014.0 5.4％5.4%
二氧化硅Silica 5.65.6 2.15％2.15%
硬脂酰醇富马酸钠Sodium stearyl fumarate 1.31.3 0.5％0.5%
欧巴代Opadry 10.010.0 3.8％3.8%
合计total 260.0260.0 100％100%
该对比实施例4即为专利CN201080011876.6的比较例5。如专利CN201080011876.6的比较例5所示的，该法匹拉韦片剂在体外溶出试验中在15分钟仅溶出63.6％。The comparative example 4 is the comparative example 5 of the patent CN201080011876.6. As shown in Comparative Example 5 of Patent CN201080011876.6, the favipiravir tablet only dissolves 63.6% in 15 minutes in the in vitro dissolution test.
溶出结果：Dissolution results:
对实施例1～7制备的法匹拉韦片和对比实施例1-3中的法匹拉韦片按中国药典第二法(桨法)进行溶出曲线测定。搅拌桨转速为50rpm，溶出介质为pH4.5醋酸盐缓冲液，介质体积为900ml，介质温度37℃±0.5℃。溶出结果见下表：The favipiravir tablets prepared in Examples 1-7 and the favipiravir tablets in Comparative Examples 1-3 were subjected to the determination of the dissolution profile according to the second method of the Chinese Pharmacopoeia (paddle method). The rotating speed of the stirring blade is 50rpm, the dissolution medium is pH4.5 acetate buffer, the volume of the medium is 900ml, and the temperature of the medium is 37℃±0.5℃. The dissolution results are shown in the following table:
 To 5min5min 10min10min 15min15min 20min20min 30min30min
实施例1Example 1 6363 8181 8989 9494 9898
实施例2Example 2 7070 8282 8989 9393 9797
实施例3Example 3 7272 8484 9090 9494 9797
实施例4Example 4 6666 8080 8888 9393 9797
实施例5Example 5 7373 8484 9090 9494 9898
实施例6Example 6 6969 7878 8585 8989 9595
实施例7Example 7 7373 8383 8888 9292 9696
实施例8Example 8 6060 7777 8787 9393 9999
对比实施例1Comparative Example 1 6363 7272 7979 8383 8989
对比实施例2Comparative Example 2 5151 6868 7878 8686 9494
由实施例1-7与对比实施例1-4溶出结果可以看出，根据本发明的含有羧甲基淀粉钠或羧甲基纤维素钙的法匹拉韦组合物的溶出速度明显提升。在法匹拉韦每片的含量较高时，即片重较低时，可以实现法匹拉韦的快速释放，在体外溶出试验中能够在15分钟溶出≥85％。From the dissolution results of Examples 1-7 and Comparative Examples 1-4, it can be seen that the dissolution rate of the favipiravir composition containing sodium carboxymethyl starch or calcium carboxymethyl cellulose according to the present invention is significantly improved. When the content of each favipiravir tablet is high, that is, when the tablet weight is low, the rapid release of favipiravir can be realized, and the dissolution rate of favipiravir can be ≥85% in 15 minutes in the in vitro dissolution test.
以上所述仅为本发明的较佳实施例，并不用以限制本发明，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，均应包含在本发明保护的范围之内。The above are only the preferred embodiments of the present invention and are not intended to limit the present invention. Any modification, equivalent replacement, improvement, etc. made within the spirit and principle of the present invention shall be included in the protection of the present invention. Within the range.

Claims (13)

  1. 一种法匹拉韦组合物，含有：A favipiravir composition containing:
    a.法匹拉韦或其盐；a. Favipiravir or its salt;
    b.羧甲基淀粉钠或羧甲基纤维素钙崩解剂中的一种或两种的组合；和b. Sodium carboxymethyl starch or calcium carboxymethyl cellulose disintegrant or a combination of two; and
    c.粘合剂；c. Adhesive;
    其中法匹拉韦组合物在体外溶出试验中能够在15分钟溶出≥85％。Among them, the favipiravir composition can dissolve more than 85% in 15 minutes in an in vitro dissolution test.
  2. 一种法匹拉韦组合物，含有：A favipiravir composition containing:
    a.法匹拉韦或其盐；a. Favipiravir or its salt;
    b.占组合物重量百分比为2.5％-15％的崩解剂，崩解剂选自羧甲基淀粉钠或羧甲基纤维素钙中的一种或两种的组合；和b. A disintegrant of 2.5%-15% by weight of the composition, the disintegrant is selected from one or a combination of sodium carboxymethyl starch or calcium carboxymethyl cellulose; and
    c.粘合剂。c. Adhesives.
  3. 根据权利要求1或2所述的组合物，其特征在于：所述的法匹拉韦或其盐占组合物重量百分比为60％以上，优选70％以上，进一步优选70％-85％。The composition according to claim 1 or 2, wherein the weight percentage of the favipiravir or its salt in the composition is more than 60%, preferably more than 70%, and more preferably 70%-85%.
  4. 根据权利要求1或2所述的组合物，其特征在于：所述的崩解剂占组合物重量百分比为3-12％。The composition according to claim 1 or 2, wherein the disintegrant accounts for 3-12% by weight of the composition.
  5. 根据权利要求1至4中任一项所述的组合物，其特征在于：所述的组合物还含有填充剂，其中填充剂选自甘露醇、木糖醇、乳糖、微晶纤维素、硅化微晶纤维素、淀粉、蔗糖、葡萄糖、麦芽糖醇、磷酸氢钙、磷酸二氢钙和硅酸钙中的一种或其任意组合，优选甘露醇和/或微晶纤维素，更优选微晶纤维素。The composition according to any one of claims 1 to 4, wherein the composition further contains a filler, wherein the filler is selected from the group consisting of mannitol, xylitol, lactose, microcrystalline cellulose, silicified One or any combination of microcrystalline cellulose, starch, sucrose, glucose, maltitol, calcium hydrogen phosphate, calcium dihydrogen phosphate and calcium silicate, preferably mannitol and/or microcrystalline cellulose, more preferably microcrystalline fiber White.
  6. 根据权利要求5所述的组合物，其特征在于：所述填充剂占组合物的重量百分比为≤15％，优选≤12％。The composition according to claim 5, wherein the weight percentage of the filler in the composition is ≤15%, preferably ≤12%.
  7. 根据权利要求1至6中任一项所述的组合物，其特征在于：所述的粘合剂选自羟丙甲纤维素、羟丙纤维素、甲基纤维素、共聚维酮和聚维酮中的一种或其任意组合，优选共聚维酮和/或聚维酮，更优选聚维酮，聚维酮优选 选自聚维酮K30、聚维酮K25、聚维酮K17和聚维酮K90中的一种或其任意组合。The composition according to any one of claims 1 to 6, wherein the binder is selected from the group consisting of hypromellose, hypromellose, methyl cellulose, copovidone and povidone One or any combination of ketones, preferably copovidone and/or povidone, more preferably povidone, povidone is preferably selected from povidone K30, povidone K25, povidone K17 and povidone One of ketones K90 or any combination thereof.
  8. 根据权利要求1至7中任一项所述的组合物，其特征在于：所述粘合剂占组合物的重量百分比为0.5-5％。The composition according to any one of claims 1 to 7, wherein the binder accounts for 0.5-5% by weight of the composition.
  9. 根据权利要求1至8中任一项所述的组合物，其特征在于：所述的组合物还含有抗粘剂，其中抗粘剂为二氧化硅和/或硅藻土，优选二氧化硅；其中抗粘剂占组合物的重量百分比为0.5-5％，优选2-5％。The composition according to any one of claims 1 to 8, characterized in that: the composition further contains an anti-sticking agent, wherein the anti-sticking agent is silicon dioxide and/or diatomaceous earth, preferably silicon dioxide ; Wherein the weight percentage of the anti-sticking agent in the composition is 0.5-5%, preferably 2-5%.
  10. 根据权利要求1至9中任一项所述的组合物，按照组合物重量百分比计，其包含以下组分：The composition according to any one of claims 1 to 9, based on the weight percentage of the composition, comprising the following components:
    a.法匹拉韦或其盐60％以上，优选70％以上，进一步优选70％-85％；a. Favipiravir or its salt is more than 60%, preferably more than 70%, more preferably 70%-85%;
    b.羧甲基淀粉钠或羧甲基纤维素钙中的一种或两种组合2.5％-15％，进一步优选3-12％；b. One or two combinations of sodium carboxymethyl starch or calcium carboxymethyl cellulose 2.5%-15%, more preferably 3-12%;
    c.粘合剂0.5-5％；c. Adhesive 0.5-5%;
    d.填充剂≤15％，优选≤12％；d. Filler≤15%, preferably≤12%;
    e.抗粘剂0.5-5％，优选2-5％；e. Anti-sticking agent 0.5-5%, preferably 2-5%;
    所述组合物为粉末状颗粒。The composition is powdered granules.
  11. 根据权利要求10所述的组合物，按照组合物重量百分比计，其还包含The composition according to claim 10, based on the weight percentage of the composition, further comprising
    f.0.1-5％、优选0.5％-2％的润滑剂和任选的其它添加剂，所述润滑剂选自硬脂酸、硬脂酸镁、硬脂富马酸钠、滑石粉中的一种或其任意组合，优选硬脂富马酸钠；所述其他添加剂选自着色剂、包衣剂、矫味剂、表面活性剂、增塑剂或芳香剂；和f. 0.1-5%, preferably 0.5%-2% lubricant and optional other additives, the lubricant is selected from one of stearic acid, magnesium stearate, sodium stearyl fumarate, talc Species or any combination thereof, preferably sodium stearyl fumarate; the other additives are selected from colorants, coating agents, flavoring agents, surfactants, plasticizers or fragrances; and
    g.任选地1-4％、优选1.5-3％的外加崩解剂，所述外加崩解剂选自交联聚维酮、羧甲基淀粉钠、羧甲基纤维素钙，优选交联聚维酮；g. Optionally 1-4%, preferably 1.5-3% of an external disintegrant selected from the group consisting of crospovidone, sodium carboxymethyl starch, calcium carboxymethyl cellulose, preferably cross-linked Dipovidone;
    所述组合物为片剂。The composition is a tablet.
  12. 一种用于制备根据权利要求10所述的法匹拉韦组合物的方法，所述 方法包括：A method for preparing the favipiravir composition according to claim 10, the method comprising:
    (1)将粘合剂溶于水中，加入抗粘剂得到粘合剂溶液；(1) Dissolve the adhesive in water, add an anti-sticking agent to obtain an adhesive solution;
    (2)将法匹拉韦或其盐、填充剂和选自羧甲基淀粉钠或羧甲基纤维素钙中的一种或其组合的崩解剂混合；和(2) Mixing favipiravir or its salt, a filler, and a disintegrant selected from one or a combination of sodium carboxymethyl starch or calcium carboxymethyl cellulose; and
    (3)将步骤(1)中得到的粘合剂溶液加入步骤(2)中得到的混合物中，进行湿法制粒，任选地干燥，过筛整粒，得到粉末状颗粒。(3) Add the binder solution obtained in step (1) to the mixture obtained in step (2), and perform wet granulation, optionally drying, and sieving to obtain powdery granules.
  13. 一种用于制备根据权利要求11所述的法匹拉韦组合物的方法，包括：A method for preparing the favipiravir composition according to claim 11, comprising:
    (1)通过使用根据权利要求12所述的方法得到粉末状颗粒；和(1) Obtain powdery particles by using the method according to claim 12; and
    (2)向所得到的粉末状颗粒中加入润滑剂和任选的其它添加剂、任选地外加崩解剂，混合，进行压片。(2) Add lubricant and optional other additives, optionally external disintegrating agent, to the obtained powdery granules, mix, and perform tableting.
PCT/CN2020/118723 2020-06-19 2020-09-29 Favipiravir composition and preparation method thereof WO2021253681A1 (en)

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