WO2021047437A1 - 一种用于治疗病毒性感冒的药物组合物及其制剂 - Google Patents

一种用于治疗病毒性感冒的药物组合物及其制剂 Download PDF

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WO2021047437A1
WO2021047437A1 PCT/CN2020/113105 CN2020113105W WO2021047437A1 WO 2021047437 A1 WO2021047437 A1 WO 2021047437A1 CN 2020113105 W CN2020113105 W CN 2020113105W WO 2021047437 A1 WO2021047437 A1 WO 2021047437A1
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compound
salt
active ingredient
pharmaceutical composition
oseltamivir
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PCT/CN2020/113105
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English (en)
French (fr)
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陈小新
李海军
刘卓伟
刘志强
万春喜
龙超峰
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广东众生睿创生物科技有限公司
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Priority to CN202080062567.5A priority Critical patent/CN114502150B/zh
Publication of WO2021047437A1 publication Critical patent/WO2021047437A1/zh

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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
    • A61K31/13—Amines
    • 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
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/14—Antivirals for RNA viruses
    • A61P31/16—Antivirals for RNA viruses for influenza or rhinoviruses
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems

Definitions

  • the invention belongs to the field of pharmaceutical preparations, and particularly relates to a pharmaceutical composition for treating viral influenza and a preparation containing the pharmaceutical composition.
  • Influenza virus known as influenza virus (IFV)
  • IVF Influenza virus
  • WHO World Health Organization
  • influenza pandemic Every influenza pandemic has a huge impact on global public health and the economy. Devastation.
  • the current clinical plan for influenza includes vaccination and antiviral drugs for chemotherapy and chemoprevention.
  • One of the important antiviral drugs is neuraminidase inhibitors, such as Oseltamivir (OSE), Zana Zanamivir, Peramivir, etc., such antiviral drugs have obvious effects on influenza A virus, and are commonly used clinical drugs for the treatment of viral influenza.
  • Oseltamivir OSE
  • Zana Zanamivir Zana Zanamivir
  • Peramivir Peramivir
  • antiviral drugs have obvious effects on influenza A virus, and are commonly used clinical drugs for the treatment of viral influenza.
  • the resulting drug resistance has become increasingly serious.
  • the proportion of oseltamivir-resistant strains of the seasonal A H1N1 influenza virus in China from 2008 to 2009 has reached 28%, and the resistance of influenza viruses affects existing anti-influenza viruses. The therapeutic effect of the drug.
  • oseltamivir is metabolized into its active metabolite oseltamivir carboxylic acid to exert its drug effect.
  • By competitively binding with the active site of influenza virus neuraminidase it interferes with the virus from the infected host cell. During the release process, thereby reducing the spread of influenza A or B viruses.
  • Patent WO2018041263 discloses a series of pyrimidine derivatives. In vitro activity data showed that some compounds showed positive effects in the test of inhibiting influenza virus replication. In further animal experiments, some compounds also showed significant therapeutic effects on influenza A virus H1N1 mouse infection model. Among them, compound 1 The comprehensive performance of (Example 4, WX-216) is relatively outstanding, and it is considered to have a better prospect of preparing medicines.
  • influenza virus has the characteristics of high mutation rate and multiple inter-virus recombination phenomena. Although new structures and new mechanisms of active compounds are constantly being discovered, in the long run, the use of a single antiviral drug may not be effective in a short time. Inhibiting/reducing the concentration of the virus in the body and curing the defects of the viral cold, the corresponding increase in the dosage and the lengthening of the treatment time also bring a greater risk of medication to the patient. Finberg RW et al., J Infect Dis, 2019 Mar 15; 219(7): 1026-1034. A combination experiment of Pimodivir and oseltamivir was published, and the results showed that the combination of 600 mg Pimodivir and 75 mg oseltamivir Use can minimize the load of influenza A virus.
  • the first object of the present invention is to overcome at least one of the above-mentioned shortcomings of the prior art and provide a pharmaceutical composition for the treatment of viral influenza, which utilizes the synergistic effect between the active ingredients to solve the problem of influenza Technical problems such as the drug resistance of the virus can effectively reduce the risk of clinical medication. After comprehensive evaluation, it is believed that the pharmaceutical composition has a better prospect for preparing a medicine.
  • a pharmaceutical composition comprising a first active ingredient and a second active ingredient, wherein the first active ingredient is compound 1, its corresponding ester, its corresponding salt, its corresponding ester salt, or a combination thereof
  • the second effective ingredient is a neuraminidase inhibitor; the mass ratio of the first effective ingredient to the second effective ingredient is 1-8:1.
  • the first active ingredient refers to a mixture obtained by mixing one or more of the compound 1, the ester corresponding to the compound 1, the salt of the compound 1, and the salt of the ester corresponding to the compound 1, in any ratio.
  • the compound 1, the ester corresponding to the compound 1, the salt of the compound 1, and the salt of the ester corresponding to the compound 1 each include the subordinate anhydrate, ansolvate, hydrate, and solvate thereof.
  • the ester corresponding to compound 1 refers to the ester formed by compound 1 and organic acid, including but not limited to methyl, ethyl, propyl, isopropyl, n-butyl, tert-butyl and the like of compound 1.
  • the salt of compound 1 is the salt formed by compound 1 and organic acid and/or inorganic acid, or the salt formed by compound 1 and organic base and/or inorganic base, including but not limited to the hydrochloride and hydrobromic acid of compound 1.
  • the salt of the corresponding ester of compound 1 refers to the salt of the ester formed by the aforementioned compound 1 with an organic acid and an organic base and/or an inorganic base and/or an organic acid and/or an inorganic acid, including but not limited to the salt of the methyl ester of compound 1 Acid salt, compound 1 methyl ester sulfate, compound 1 ethyl ester hydrochloride, compound 1 ethyl ester sulfate, etc.
  • the neuraminidase inhibitor referred to by the second active ingredient is oseltamivir (Oseltamivir) or its derivatives, zanamivir (zanamivir) or its derivatives, peramivir (Peramivir) or its derivatives
  • Oseltamivir Oseltamivir
  • zanamivir zanamivir
  • Peramivir peramivir
  • Acids and/or bases can also be esters, amides, or other derivatives such as carboxylic acids and their salts obtained after hydrolysis, and each includes its subordinate anhydrates, ansolvates, hydrates and solvents
  • oseltamivir or its derivatives can be selected as oseltamivir free state, or oseltamivir phosphate, oseltamivir carboxylic acid, oseltamivir carboxylate, and the like.
  • the mass ratio of the first effective ingredient to the second effective ingredient is 1 to 8:1, preferably, the mass ratio of the first effective ingredient to the second effective ingredient is 100 to 600:75; specifically, the The mass ratio of the first active ingredient to the second active ingredient is about 100:75, 200:75, 300:75, 400:75, 500:75, 600:75.
  • the quality of the salt in the present invention refers to the mass based on free base/acid equivalent, and the hydrate/solvate refers to the mass based on dry matter (on an equivalent basis).
  • Anhydrous basis the mass of metabolites (such as ester hydrolysis to obtain carboxylic acid) refers to the mass of the compound before metabolism.
  • the first active ingredient in the pharmaceutical composition is compound 1, and the second active ingredient is oseltamivir phosphate; the combination of compound 1 and oseltamivir phosphate in the pharmaceutical composition
  • the mass ratio is 100-600:75; specifically, the mass ratio of the compound 1 to oseltamivir phosphate is about 100:75, 200:75, 300:75, 400:75, 500:75, 600:75.
  • the first active ingredient in the pharmaceutical composition is the sodium salt of compound 1, and the second active ingredient is oseltamivir phosphate; the sodium salt of compound 1 in the pharmaceutical composition is combined with oseltamivir phosphate.
  • the mass ratio of setavir phosphate is 100-600:75; specifically, the mass ratio of the sodium salt of compound 1 to oseltamivir phosphate is about 100:75, 200:75, 300:75, 400:75, 500:75, 600:75 .
  • the first active ingredient in the pharmaceutical composition is compound 1 hydrochloride
  • the second active ingredient is oseltamivir phosphate
  • in the pharmaceutical composition compound 1 hydrochloride
  • the mass ratio with oseltamivir phosphate is 100-600:75; specifically, the mass ratio of the hydrochloride of compound 1 to oseltamivir phosphate is about 100:75, 200:75, 300:75, 400:75, 500: 75,600:75.
  • the first active ingredient in the pharmaceutical composition is the potassium salt of compound 1, and the second active ingredient is oseltamivir phosphate;
  • the mass ratio of setavir phosphate is 100-600:75; specifically, the mass ratio of the potassium salt of compound 1 to oseltamivir phosphate is about 100:75, 200:75, 300:75, 400:75, 500:75, 600:75 .
  • the first active ingredient in the pharmaceutical composition is the calcium salt of compound 1, and the second active ingredient is oseltamivir phosphate;
  • the mass ratio of setavir phosphate is 100-600:75; specifically, the mass ratio of the calcium salt of compound 1 to oseltamivir phosphate is about 100:75, 200:75, 300:75, 400:75, 500:75, 600:75 .
  • the first active ingredient in the pharmaceutical composition is p-toluenesulfonate of compound 1
  • the second active ingredient is oseltamivir phosphate
  • the mass ratio of tosylate to oseltamivir phosphate is 100-600:75; specifically, the mass ratio of p-toluenesulfonate to oseltamivir phosphate of the compound 1 is about 100:75,200: 75,300:75,400:75,500:75,600:75.
  • the drug composition of inhibitor has a better drug synergistic effect, showing a significantly better anti-influenza virus effect than a single component, and also showing a better anti-influenza virus effect than the aforementioned specific range.
  • the pharmaceutical composition with the external mass ratio has significantly better anti-influenza virus effect. It can be known that when the mass ratio of the first active ingredient and the second active ingredient in the unit preparation is within the specific range, it has better anti-influenza virus effect. Effect: After comprehensive evaluation of other pharmaceutical properties (such as mixture stability, fluidity, etc.), it is believed that the pharmaceutical composition has a better prospect for pharmaceutical preparation.
  • Another object of the present invention is to disclose a preparation method of the aforementioned pharmaceutical composition, which can ensure the stable preparation of the aforementioned pharmaceutical composition.
  • the preparation method adopts a conventional mixing method in the art; more specifically, the preparation method may be a direct mixing method, an equal incremental method, etc., and the mixing equipment used may be a common mixing method in the field, depending on the preparation scale.
  • Equipment, such as V-type mixer, double cone mixer, rotary mixer, etc., can also be prepared by manual mixing in small-scale preparation.
  • the third object of the present invention is to disclose a preparation containing the aforementioned pharmaceutical composition.
  • the preparation includes the aforementioned pharmaceutical composition and a pharmaceutically acceptable carrier.
  • the pharmaceutically acceptable carrier is selected from any one or two or more of fillers, binders, disintegrants, glidants, lubricants, and flavoring agents.
  • the filler is selected from calcium carbonate, magnesium carbonate, calcium phosphate, calcium sulfate, magnesium oxide, calcium carboxymethyl cellulose, sodium carboxymethyl cellulose, sucrose, lactose, fructose, xylitol, mannitol , Starch or its derivatives, dextrin, microcrystalline cellulose, etc., a mixture obtained by mixing any one or two or more of them in any ratio.
  • the binder is selected from gum arabic, gelatin, tragacanth, dextrin, polyvinylpyrrolidone, starch and its derivatives, sodium alginate, sorbitol, syrup, hydroxypropyl methylcellulose, methyl cellulose Any one or two of cellulose, hydroxypropyl cellulose, hydroxyethyl cellulose, ethyl cellulose, sodium carboxymethyl cellulose, calcium carboxymethyl cellulose, glucose and polymethacrylate, etc. The mixture obtained by mixing more than one species in any ratio.
  • the disintegrant is selected from starch, alginic acid, calcium carboxymethyl cellulose, sodium carboxymethyl cellulose, croscarmellose sodium, cross-linked polyvinylpyrrolidone, low-substituted hydroxypropyl methyl A mixture obtained by mixing any one or two or more of base cellulose, microcrystalline cellulose, and methyl cellulose in an arbitrary ratio.
  • the glidant is a mixture obtained by mixing any one or more of colloidal silicon dioxide, powdered cellulose, magnesium trisilicate, silicon dioxide, and talc in any ratio.
  • the lubricant is selected from calcium stearate, glyceryl monostearate, glyceryl palmitostearate, magnesium stearate, microcrystalline cellulose, sodium benzoate, sodium chloride, and lauryl sulfate A mixture obtained by mixing any one or two or more of sodium, sodium stearyl fumarate, talc, zinc stearate, and polyethylene glycol in an arbitrary ratio.
  • the flavoring agent is selected from any one or a mixture of two or more of stevioside, aspartame, and other flavors and sweeteners commonly used in the art in any ratio.
  • the preparation containing the aforementioned pharmaceutical composition is an oral preparation, specifically a powder, granule, pellet, capsule, tablet, solution or lozenge.
  • the preparations containing the aforementioned pharmaceutical composition also exhibit significantly better anti-influenza virus effects than those containing single-component preparations, and also show greater anti-influenza virus effects than those containing the aforementioned specific range.
  • the pharmaceutical composition preparations with other mass ratios have significantly better anti-influenza virus effects, and have a better market prospect.
  • the present invention has the following outstanding advantages and beneficial effects:
  • a pharmaceutical composition which comprises a first active ingredient (compound 1, its corresponding ester, its corresponding salt, its corresponding ester salt or a combination thereof) with a mass ratio in a specific range, and
  • the second active ingredient (neuraminidase inhibitor), which has a better drug synergistic effect, in which the neuraminidase inhibitor is hydrolyzed with oseltamivir and/or oseltamivir salt and/or oseltamivir
  • the oseltamivir carboxylic acid or oseltamivir carboxylate obtained later has the best effect, and after comprehensive evaluation, it is believed that the pharmaceutical composition has a better prospect for preparing medicines.
  • a preparation method of the pharmaceutical composition is provided, which can ensure the stable preparation of the aforementioned pharmaceutical composition.
  • a preparation containing the aforementioned pharmaceutical composition is provided, which correspondingly shows a significantly better anti-influenza virus effect than a preparation containing a single component, and is also shown to be more effective than a pharmaceutical combination containing a mass ratio outside the aforementioned specific range
  • the drug preparation has significantly better anti-influenza virus effect and has a better market prospect.
  • the contribution of the present invention lies in the discovery that a combination of drugs within a specific range has a synergistic effect. Therefore, those skilled in the art can understand that when the combination of drugs in a unit dosing unit is within the scope of the present invention, it can be considered to be used.
  • the technical solution protected by the present invention specifically, the aforementioned unit administration unit refers to the smallest unit for clinical use, such as: unit tablet, unit capsule, unit bottle of oral liquid, unit package of granules, etc. .
  • the oseltamivir phosphate used in the examples is the bulk drug of the commercially available Tamiflu, CAS: 204255-11-8, with a purity of >99%; the oseltamivir used is the free substance of the commercially available Tamiflu bulk drug, CAS :196618-13-0, purity>99%; the oseltamivir carboxylic acid used is a commercially available intermediate, CAS: 187227-45-8, purity>99%.
  • zanamivir CAS: 139110-80-8
  • peramivir CAS: 229614-55-5
  • the compound 1 was prepared by the method disclosed in Example 4 of WO2018041263, and the structure characterization proved that the obtained product was compound 1.
  • the mass ratios of the salt of compound 1 prepared in Examples 2-6 and oseltamivir or oseltamivir phosphate were 50:75 and 100:75, respectively. , 200:75, 300:75, 400:75, 500:75, 600:75, 700:75 pharmaceutical composition, the mass of the salt refers to the mass of the free substance (free base/acid equivalent) .
  • compound 1 and oseltamivir carboxylic acid active metabolite
  • H3N2 A/Aichi/2/1968 (H3N2), purchased from ATCC.
  • Dog kidney epithelial cell line (Madin-Darby Canine Kidney Cells, MDCK).
  • Drug dissolution method Compound 1 and the active metabolite of oseltamivir (oseltamivir carboxylic acid, calculated as oseltamivir) were dissolved in dimethyl sulfoxide (DMSO), prepared as a 100mM/L mother liquor, and stored for later use; Dilute with Medium Essential Medium (MEM) as a working solution (Note: the final concentration of DMSO is 1%).
  • DMSO dimethyl sulfoxide
  • MEM Medium Essential Medium
  • nM 0.25 ⁇ M (1:62.5 ⁇ 16000)
  • the specific manifestation is that the virus inhibition rate after the combination is higher than the single-agent virus inhibition rate; in view of compound 1 After entering the human body, the plasma protein binding rate can reach 99.9%. It can be seen that the compound 1 in the free state in the body accounts for about 0.1%, and the binding rate of oseltamivir carboxylic acid in the human plasma protein is 0.3%, which shows that the body is in a free state.
  • Oseltamivir carboxylic acid accounts for about 99.7%; after conversion, that is, in the body, the molar ratio of compound 1 to oseltamivir carboxylic acid should be about 1:16 to 16:1 when there is a good synergistic effect. That is, when the mass ratio of compound 1 to oseltamivir is approximately in the range of 1:11.3 to 22.5:1 (440:4992 to 7040:312), there is a good synergistic effect.
  • compound 1 has a synergistic effect with oseltamivir, zanamivir and peramivir, but compared with other groups, the oseltamivir group has a synergistic performance significantly better than other groups.
  • Mortality rate (%) number of dead mice in each group (only)/total number before infection (only) ⁇ 100%
  • mice developed symptoms such as shortness of breath, curled up and trembling, weight loss, and died; after 14 days of continuous observation, the mice in the blank group were in good condition and no death was observed, while the mortality of the mice in the virus group reached 100%; compound 1:30mg/kg group has a complete protective effect on infected mice, and its mortality rate is 0%; compound 1:20mg/kg group has obvious protective effect on infected mice, and its mortality rate is 20%; compound The mortality of mice in the 1:5 mg/kg administration group was 80%; the mortality of mice in the oseltamivir phosphate: 10 mg/kg administration group and the compound 1:1.5 mg/kg administration group was 100%. After compound 1 was used in combination with oseltamivir phosphate at the doses of 5 mg/kg and 20 mg/kg, the mortality rate was significantly reduced, and the synergistic effect was obvious.
  • Table 2 The results are shown in Table 2:
  • the synergistic effect of the composition of the present invention is inconsistent in vivo and in vitro; specifically, the composition exhibits inconsistent in vivo and in vitro regardless of the range of drug synergistic effects and the more effective range.
  • the specific performance is that the mass ratio of oseltamivir and compound 1 is about 1:22.5 to 11.3:1 according to the range of drug synergy in vitro, and the range of drug synergy is surprisingly large in in vivo experiments.
  • the mass ratio of compound 1 and oseltamivir phosphate is 75 ⁇ 600:75 (1 ⁇ 8:1), which is synergistic; further, the mass ratio of compound 1 and oseltamivir phosphate is 75: 75,100:75,200:75,300:75,400:75,500:75,600:75, it shows a good synergy of drugs in the body;
  • Example 7 The pharmaceutical composition obtained in Example 7 was mixed with an appropriate amount of filler, binder, and disintegrant, and then directly compressed to prepare a tablet (200mg+75mg).

Abstract

一种药物组合物及其制剂，该药物组合物包含质量比在特定范围两种有效成分，该药物组合物具有明显更优的抗流感病毒的效果，综合评价后认为所述药物组合物具有较好的成药前景。

Description

一种用于治疗病毒性感冒的药物组合物及其制剂 技术领域
本发明属于药物制剂领域，特别涉及一种用于治疗病毒性感冒的药物组合物及含有该药物组合物的制剂。
背景技术
流行性感冒病毒，即流感病毒(influenza virus,IFV)，是一种能够导致人和动物患流行感冒的分节状单链反义RNA病毒。根据世界卫生组织(WHO)统计，每年流感的季节性流行可导致全球300万至500万例的重症病例，29万至65万病例死亡，每一次流感大流行都给全球公共卫生、经济造成极大破坏。
目前的流感的临床方案包括接种疫苗和用抗病毒药物进行化疗和化学预防，其中重要的抗病毒药物之一即为神经氨酸酶抑制剂，如奥司他韦(Oseltamivir，OSE)、扎那米韦(zanamivir)、帕拉米韦(Peramivir)等，该类抗病毒药物对于甲型流感病毒效果明显，是临床用于治疗病毒性流感的常用药品。但是，与抗生素产品类似，随着抗病毒类产品的长期使用，随之产生的耐药作用也日益严重。据WHO西太平洋地区的监测数据显示：中国2008-2009年度的季节性甲型H1N1流感病毒的奥司他韦耐药株的比例已达28％，流感病毒的耐药性影响现有抗流感病毒药物的治疗效果。
Figure PCTCN2020113105-appb-000001
其中，奥司他韦口服后代谢转化为其活性代谢物奥司他韦羧酸发挥药效，通过竞争性地与流感病毒神经氨酸酶的活动位点结合，干扰病毒从被感染的宿主细胞中释放的过程，从而减少甲型或乙型流感病毒的传播。
Figure PCTCN2020113105-appb-000002
专利WO2018041263公开了一系列嘧啶衍生物。体外活性数据表明，部分化合物在抑制流感病毒复制试验中表现出积极效应，在进一步的动物试验中，部分化合物亦表现出对甲型流感病毒H1N1小鼠感染模型有显著的治疗效果，其中化合物1(实施例4，WX-216)的综合表现相对突出，被认为具有较好的成药前景。
Figure PCTCN2020113105-appb-000003
另一方面，流感病毒具有突变率高、病毒间重组现象多等特点，尽管新结构、新机制活性化合物不断被发现，但在长远看来，使用单一抗病毒药物可能存在无法在短时间内有效抑制/降低体内病毒浓度，治愈病毒性感冒的缺陷，其对应的使用剂量增大及治疗时间拉长也给患者带来了较大的用药风险。Finberg RW et al.,J Infect Dis,2019 Mar 15；219(7):1026-1034.公开了一种Pimodivir与奥司他韦的联合用药实验，结果表明600mg Pimodivir与75mg奥司他韦的联合使用可以最大程度降低甲型流感病毒负载。
因此，寻找新的解决方案，解决有临床前景新产品的耐药性问题，降低药物不良反应发生概率，以应对目前临床上未被满足的抗流感病毒药物的巨大需求是现有技术亟待解决的技术问题。
发明内容
本发明的第一个目的在于至少克服上述现有技术的不足之一，提供一种用于治疗病毒性感冒的药物组合物，该药物组合物利用有效成分之间的协同作用，解决了的流感病毒的耐药性等技术问题，并可以有效降低临床用药风险，综合评价后认为，该药物组合物具有较好的成药前景。
本发明的目的通过下述技术方案实现：
一种药物组合物，所述药物组合物包含第一有效成分和第二有效成分，其中第一有效成分为化合物1、其对应的酯、其对应的盐、其对应的酯的盐或其组合；第二有效成分为神经氨酸酶抑制剂；所述第一有效成分与第二有效成分的质量比为1～8:1。
Figure PCTCN2020113105-appb-000004
所述第一有效成分指代的为化合物1、化合物1对应的酯、化合物1的盐、化合物1对应的酯的盐中一种或两种以上以任意比例混合所得的混合物。
所述化合物1、化合物1对应的酯、化合物1的盐、化合物1对应的酯的盐各自包含其下位的无水合物、无溶剂合物、水合物及溶剂合物。
所述化合物1对应的酯指代化合物1与有机酸形成的酯，包括但不限于化合物1的甲酯、乙酯、丙酯、异丙酯、正丁酯、叔丁酯等。
所述化合物1的盐为化合物1与有机酸和/或无机酸形成的盐、或化合物1与有机碱和/或无机碱形成的盐，包括但不限于化合物1的盐酸盐、氢溴酸盐、硫酸盐、磷酸盐、苯磺酸盐、对甲苯磺酸盐、甲磺酸盐、酒石酸盐、樟脑磺酸盐、锂盐、钠盐、钾盐、钙盐、镁盐、铝盐、铵盐、乙二胺盐、三乙胺盐等。
化合物1对应的酯的盐指代前述化合物1与有机酸形成的酯与有机碱和/或无机碱和/或有机酸和/或无机酸形成的盐，包括但不限于化合物1甲酯的盐酸盐、化合物1甲酯的硫酸 盐、化合物1乙酯的盐酸盐、化合物1乙酯的硫酸盐等。
所述第二有效成分指代的神经氨酸酶抑制剂为奥司他韦(Oseltamivir)或其衍生物、扎那米韦(zanamivir)或其衍生物、帕拉米韦(Peramivir)或其衍生物等中的一种或两种以上以任意比例混合所得的混合物；所述奥司他韦(Oseltamivir)、扎那米韦(zanamivir)、帕拉米韦(Peramivir)的衍生物独立选自其酸和/或碱，也可以是化合物进一步形成的酯、酰胺，或水解后所得羧酸及其盐等其它衍生物，并且各自包含其下位的无水合物、无溶剂合物、水合物及溶剂合物，比如奥司他韦或其衍生物可以选择是奥司他韦游离态，也可以选择是奥司他韦磷酸盐、奥司他韦羧酸、奥司他韦羧酸盐等。
所述第一有效成分与第二有效成分的质量比为1～8:1，优选地，所述第一有效成分与第二有效成分的质量比为100～600:75；具体地，所述第一有效成分与第二有效成分的质量比约为100:75,200:75,300:75,400:75,500:75,600:75。
如无特别说明，本发明中所述盐的质量均指代以游离物计的质量(free base/acid equivalent)，水合物/溶剂合物均指代以折干折纯计的质量(on an anhydrous basis)，代谢产物(如酯水解得到羧酸)的质量均指代以代谢前化合物的质量计。
本发明的一个优选的技术方案，所述药物组合物中第一有效成分为化合物1，第二有效成分为奥司他韦磷酸盐；该药物组合物中化合物1与奥司他韦磷酸盐的质量比为100～600:75；具体地，所述化合物1与奥司他韦磷酸盐的质量比约为100:75,200:75,300:75,400:75,500:75,600:75。
本发明的一个优选的技术方案，所述药物组合物中第一有效成分为化合物1的钠盐，第二有效成分为奥司他韦磷酸盐；该药物组合物中化合物1的钠盐与奥司他韦磷酸盐的质量比为100～600:75；具体地，所述化合物1的钠盐与奥司他韦磷酸盐的质量比约为100:75,200:75,300:75,400:75,500:75,600:75。
本发明的一个优选的技术方案，所述药物组合物中第一有效成分为化合物1的盐酸盐，第二有效成分为奥司他韦磷酸盐；该药物组合物中化合物1的盐酸盐与奥司他韦磷酸盐的质量比为100～600:75；具体地，所述化合物1的盐酸盐与奥司他韦磷酸盐的质量比约为100:75,200:75,300:75,400:75,500:75,600:75。
本发明的一个优选的技术方案，所述药物组合物中第一有效成分为化合物1的钾盐，第二有效成分为奥司他韦磷酸盐；该药物组合物中化合物1的钾盐与奥司他韦磷酸盐的质量比为100～600:75；具体地，所述化合物1的钾盐与奥司他韦磷酸盐的质量比约为100:75,200: 75,300:75,400:75,500:75,600:75。
本发明的一个优选的技术方案，所述药物组合物中第一有效成分为化合物1的钙盐，第二有效成分为奥司他韦磷酸盐；该药物组合物中化合物1的钙盐与奥司他韦磷酸盐的质量比为100～600:75；具体地，所述化合物1的钙盐与奥司他韦磷酸盐的质量比约为100:75,200:75,300:75,400:75,500:75,600:75。
本发明的一个优选的技术方案，所述药物组合物中第一有效成分为化合物1的对甲苯磺酸盐，第二有效成分为奥司他韦磷酸盐；该药物组合物中化合物1的对甲苯磺酸盐与奥司他韦磷酸盐的质量比为100～600:75；具体地，所述化合物1的对甲苯磺酸盐与奥司他韦磷酸盐的质量比约为100:75,200:75,300:75,400:75,500:75,600:75。
发明人在实验中令人吃惊地发现：前述包含第一有效成分(化合物1、其对应的酯、其对应的盐其对应的酯的盐或其组合)和第二有效成分(神经氨酸酶抑制剂)的药物组合物，当二者质量比在特定范围时，其具有较好的药物协同作用，表现为较单一成分明显更好的抗流感病毒的效果，也表现为较前述特定范围之外质量比的药物组合物明显更优的抗流感病毒的效果，可知当单位制剂中第一有效成分和第二有效成分的质量比在该特定范围内时，其具有更优的抗流感病毒的效果；综合其余成药性能(如：混合物稳定性、流动性等)评价后认为该药物组合物具有更好的成药前景。
本发明的另一目的在于公开一种前述药物组合物的制备方法，该制备方法可以保证稳定制备前述药物组合物。具体地，所述制备方法采用本领域常规的混合方法；更具体地，所述制备方法可以为直接混合法、等量递增法等方法，所用混合设备视其制备规模可以是本领域常见的混合设备，如V型混合机、双锥混合机、旋转混合机等，小规模制备时亦可采用手动混合方式制备。
本发明的第三个目的在于公开一种含有前述药物组合物的制剂。具体地，该制剂包含前述药物组合物及药学上可接受的载体。所述药学上可接受的载体选自填充剂、粘合剂、崩解剂、助流剂、润滑剂、矫味剂等中的任意一种或两种以上。
具体地，所述填充剂选自碳酸钙、碳酸镁、磷酸钙、硫酸钙、氧化镁、羧甲基纤维素钙、羧甲基纤维素钠、蔗糖、乳糖、果糖、木糖醇、甘露醇、淀粉或其衍生物、糊精、微晶纤维素等中的任意一种或两种以上以任意比例混合所得的混合物。
具体地，所述粘合剂选自***胶、明胶、黄蓍胶、糊精、聚乙烯吡咯烷酮、淀粉及其衍生物、藻酸钠、山梨醇、糖浆、羟丙基甲基纤维素、甲基纤维素、羟丙基纤维素、羟乙基 纤维素、乙基纤维素、羧甲基纤维素钠、羧甲基纤维素钙、葡萄糖和聚甲基丙烯酸酯等中的任意一种或两种以上以任意比例混合所得的混合物。
具体的，所述崩解剂选自淀粉、藻酸、羧甲基纤维素钙、羧甲基纤维素钠、交联羧甲基纤维素钠、交联聚乙烯吡咯烷酮、低取代羟丙基甲基纤维素、微晶纤维素和甲基纤维素等中的任意一种或两种以上以任意比例混合所得的混合物。
具体的，所述助流剂选自胶体二氧化硅、粉状纤维素、三硅酸镁、二氧化硅和滑石粉等中的任意一种或两种以上以任意比例混合所得的混合物。
具体的，所述润滑剂选自硬脂酸钙、单硬脂酸甘油酯、棕榈硬脂酸甘油酯、硬脂酸镁、微晶纤维素、苯甲酸钠、氯化钠、十二烷基硫酸钠、硬脂基富马酸钠、滑石粉、硬脂酸锌和聚乙二醇等中的任意一种或两种以上以任意比例混合所得的混合物。
具体地，所述矫味剂选自甜叶菊甙、阿司巴甜和本领域常用的其它香精及甜味剂等中的任意一种或两种以上以任意比例混合所得的混合物。
所述含有前述药物组合物的制剂为口服制剂，具体可为散剂、颗粒剂、微丸、胶囊、片剂、溶液剂或锭剂。
基于前述药物组合物的有益效果，如：药物协同作用等，含有前述药物组合物的制剂也对应表现为较含有单一成分制剂明显更好的抗流感病毒的效果，也表现为较含有前述特定范围之外质量比的药物组合物制剂明显更优的抗流感病毒的效果，具有较好的市场前景。
本发明与现有技术相比具有如下突出的优点及有益效果：
1、提供了一种药物组合物，该药物组合物包含质量比在特定范围的第一有效成分(化合物1、其对应的酯、其对应的盐、其对应的酯的盐或其组合)和第二有效成分(神经氨酸酶抑制剂)，其具有较好的药物协同作用，其中神经氨酸酶抑制剂以奥司他韦和/或奥司他韦盐和/或奥司他韦水解后所得奥司他韦羧酸或奥司他韦羧酸盐的效果最好，综合评价后认为所述药物组合物具有较好的成药前景。
2、提供了一种药物组合物的制备方法，该制备方法可以保证稳定制备前述药物组合物。
3、提供了一种含有前述药物组合物的制剂，该制剂也对应表现为较含有单一成分制剂明显更好的抗流感病毒的效果，也表现为较含有前述特定范围之外质量比的药物组合物制剂明显更优的抗流感病毒的效果，具有较好的市场前景。
本发明的贡献在于发现了特定范围内的药物组合具有协同作用，因此本领域的技术人员可以理解，当单位给药单元中的药物组合在本发明所述的范围内，均可认为是使用了本发明 所保护的技术方案；具体的，前述单位给药单元指代用于临床使用的最小单元，如：单位片的片剂、单位粒的胶囊、单位瓶的口服液、单位包的颗粒剂等。
具体实施方式
下面结合实施例对本发明作进一步详细的描述，但发明的实施方式不限于此。
实施例所用奥司他韦磷酸盐为市售制剂达菲的原料药，CAS：204255-11-8，纯度>99％；所用奥司他韦为市售制剂达菲原料药的游离物，CAS：196618-13-0，纯度>99％；所用奥司他韦羧酸为市售中间体，CAS：187227-45-8，纯度>99％。
实施例所用扎那米韦(CAS：139110-80-8)和帕拉米韦(CAS：229614-55-5)均为市售制剂的原料药，纯度＞99％。
实施例1 制备化合物1
采用WO2018041263实施例4公开的方法制备得到化合物1，结构表征证明所得产物为化合物1。
实施例2 制备化合物1的盐酸盐
取5g化合物1加入250mL茄形瓶中，加入THF(100mL)，加入盐酸0.98mL(浓盐酸溶于9mL THF)，30℃搅拌12小时，固体过滤，滤饼在40℃真空干燥，得到化合物1的盐酸盐。
实施例3 制备化合物1的对甲苯磺酸盐
取5g化合物1加入250mL茄形瓶中，加入THF(100mL)，加入对甲苯磺酸一水合物(2.26g，溶于10mL THF)，30℃搅拌12小时，固体过滤，滤饼在40℃真空干燥，得固体(0.425g)。将此固体(0.101g)加入到丙酮(2mL)中打浆12h，得到化合物1的对甲苯磺酸盐。
实施例4 制备化合物1的钠盐
取5g化合物1加入250mL茄形瓶中，加入THF(100mL)，加入NaOH水溶液(0.477g，溶于1mL水)，30℃搅拌12小时，固体过滤，滤饼在40℃真空干燥，得到化合物1的 钠盐。
实施例5 制备化合物1的钾盐
称取2g化合物1加入100mL茄形瓶中，加入THF(35mL)，加入KOH水溶液(0.255g，溶于0.5mL水和5mL THF)，30℃搅拌12小时，固体过滤，滤饼在40℃真空干燥，得到化合物1的钾盐。
实施例6 制备化合物1的钙盐
取2g化合物1加入100mL茄形瓶中，加入THF(35mL)，加入氢氧化钙水溶液(0.168g，溶于0.5mL水和5mL THF)，25℃搅拌12小时，固体过滤，滤饼在40℃真空干燥，得固体(1.440g)，将此固体(0.204g)溶于乙醇和水的混合溶剂(乙醇:水＝3:1)(4mL)中打浆，在25℃下搅拌12小时，固体过滤，滤饼在40℃真空干燥，得到化合物1的钙盐。
实施例7
取200g实施例1制备所得化合物1，将其与75g奥司他韦磷酸盐(以奥司他韦计)混合均匀，得到质量比为200:75的药物组合物。
实施例8
采用与实施例7相同的方法，分别制备得到化合物1与奥司他韦磷酸盐质量比为50:75，100:75，300:75，400:75，500:75，600:75，700:75的药物组合物。
采用与实施例7相同的方法，分别采用实施例2-6制备得到的化合物1的盐，和奥司他韦或奥司他韦磷酸盐制备二者质量比分别为50:75，100:75，200:75，300:75，400:75，500:75，600:75，700:75的药物组合物，所述盐的质量均指代以游离物计的质量(free base/acid equivalent)。
实施例9 体外活性比较实验
1、实验目的
以化合物1与奥司他韦羧酸(活性代谢产物)为研究对象，分析在一定比例下化合物1和奥司他韦(或奥司他韦羧酸)联合用药，对甲型流感病毒的协同抑制作用，并结合二者血 浆蛋白结合率情况，换算并预测其体内联用效果。
2、实验材料
病毒：A/Aichi/2/1968(H3N2)，购于ATCC。
细胞：狗肾上皮细胞系(Madin-Darby Canine Kidney Cells，MDCK)。
药物溶解方法：化合物1和奥司他韦活性代谢产物(奥司他韦羧酸，以奥司他韦计)用二甲基亚砜(DMSO)溶解，配成100mM/L母液存储备用；再用培养基Minimum Essential Medium(MEM)稀释作为工作液(注：DMSO终浓度为1％)。
3、实验方法
MDCK细胞按每孔约2.5×10 4的浓度，将接种到96孔板，待细胞长成单层后(约24h)，弃去培养液，以PBS洗涤细胞表面2次。加入含MOI＝0.01的病毒稀释液100μL/孔，37℃、5％CO 2培养箱中孵育2h后弃去病毒液，加入含化合物1和奥司他韦羧酸2倍稀释成不同浓度及0nM联合用药(即化合物1分别为：1、0.5、0.25、0.125、0.0625、0.03125、0.015625、0nM；奥司他韦羧酸分别为：0.25、0.125、0.0625、0.03125、0μM)。将联合药物100μL/孔加入96孔细胞上，每个浓度设立3个复孔，同时设置正常细胞组、病毒对照、药物对照组；置37℃、5％CO 2培养箱中孵育，每天观察细胞病变情况，然后用MTT检测每个孔细胞活力，观察72小时后病毒抑制结果如下表1所示。
表1 化合物1与奥司他韦羧酸抗A/Aichi/2/1968(H3N2)联合用药(抑制率％)
由以上数据可知，当化合物1：奥司他韦羧酸的摩尔比在0.5nM:0.03125μM至0.015625
Figure PCTCN2020113105-appb-000005
nM:0.25μM(1：62.5～16000)之间时，表现为对供试流感病毒有明显的协同抑制作用，具 体表现为联用后的病毒抑制率高于单药病毒抑制率；鉴于化合物1进入人体后，血浆蛋白结合率可达99.9％，可知体内处于游离状态下的化合物1约占0.1％，而奥司他韦羧酸在人体血浆蛋白结合率为0.3％，可知体内处于游离状态下的奥司他韦羧酸约占99.7％；经由转换，即在体内，化合物1与奥司他韦羧酸摩尔比应该约在1：16至16：1范围内时均有较好的协同作用，即化合物1与奥司他韦的质量比约在1：11.3至22.5：1(440：4992至7040：312)的范围内时均有较好的协同作用。
后续实验中发现，化合物1与奥司他韦、扎那米韦和帕拉米韦均有协同作用，但相较于其他组，奥司他韦组协同表现明显优于其他组。
实施例10 体内活性实验
药物对PR8流感病毒药效研究
1、药物对PR8流感病毒死亡保护作用研究(提前给PR8病毒2h)
培养滴度较高的流感病毒，2LD50(致死剂量)滴鼻感染BALB/C小鼠。
连续5天给药组：感染后2h，灌胃给药，每天2次，连续灌胃5天，设置药物组化合物1：30mg/kg，化合物1：20mg/kg，化合物1：5mg/kg，化合物1：1.5mg/kg，奥司他韦磷酸盐：10mg/kg，奥司他韦磷酸盐+化合物1＝10mg/kg+30mg/kg，奥司他韦磷酸盐+化合物1＝10mg/kg+20mg/kg，奥司他韦磷酸盐+化合物1＝10mg/kg+5mg/kg，奥司他韦磷酸盐+化合物1＝10mg/kg+1.5mg/kg；并设置空白对照组和病毒对照组，每组10只；从病毒感染第一天开始观察，连续观察14d，每天观察并记录感染小鼠的体重变化及死亡情况等，并按以下公式计算：
死亡率(％)＝各组死亡小鼠的数量(只)/感染前总数量(只)×100％
结果表明，病毒感染后，小鼠出现呼吸短促，蜷缩颤抖，体重减轻等症状，并出现死亡情况；连续观察14d后，空白组小鼠状态良好，未见死亡，而病毒组小鼠死亡率达到100％；化合物1：30mg/kg组对感染小鼠具有完全的保护作用，其死亡率0％；化合物1：20mg/kg组对感染小鼠具有明显的保护作用，其死亡率20％；化合物1：5mg/kg给药组的小鼠死亡率为80％；奥司他韦磷酸盐：10mg/kg给药组以及化合物1：1.5mg/kg给药组的小鼠死亡率为100％。化合物1在5mg/kg和20mg/kg剂量下与奥司他韦磷酸盐联合用药后，死亡率均显著下调，协同效果明显，结果如表2所示：
表2 各组小鼠死亡率与生存率
Figure PCTCN2020113105-appb-000006
可以看出，5mg/kg、20mg/kg化合物1和10mg/kg奥司他韦磷酸盐联用后，在小鼠药效模型上展现了良好的协同抗病毒作用。基于化合物1及奥司他韦磷酸盐在不同种属(小鼠与健康人)药代动力学试验结果换算，给予小鼠5mg/kg、20mg/kg化合物1与给予人体75mg、600mg体内暴露量类似，以及给予小鼠10mg/kg奥司他韦磷酸盐与给予人体75mg体内活性代谢物暴露量类似，可知600、75mg化合物1与奥司他韦磷酸盐75mg联用药效明显，提示当化合物1与奥司他韦磷酸盐质量比在75～600:75(1～8:1)时，组合物具有较好的体内协同作用。
综合以上可知，本发明所述组合物的协同作用存在体内外表现不一致的情形；具体地，所述组合物无论在体现出药物协同作用的范围以及更优效的范围均表现出体内外不一致，具体表现为根据体外体现出药物协同的范围换算至体内为奥司他韦与化合物1的质量比约在1:22.5至11.3:1，而体内实验则令人吃惊的表现为药物协同的范围大大缩小，为化合物1与奥司他韦磷酸盐质量比在75～600:75(1～8:1)时体现为协同作用；进一步地，化合物1与奥司他韦磷酸盐质量比为75:75，100:75，200:75，300:75，400:75，500:75，600:75时体现出具有较好的体内药物协同作用；
进一步扩大的实验表明，当化合物1、其对应的酯、其对应的盐、其对应的酯的盐或其组合，和奥司他韦或奥司他韦磷酸盐亦表现为基本一致的表现，其中以化合物1与奥司他韦磷酸盐的药物组合物、化合物1的钠盐与奥司他韦磷酸盐的药物组合物的效果最好，且在本专利要求保护的范围内体现对更广范围病毒均具有较好的体内药物协同作用，因此认为具有 更好的临床前景。
实施例11
将实施例7所得药物组合物与适量填充剂、粘合剂、崩解剂混合后直压制备成片剂(200mg+75mg)。
上述实施例为本发明较佳的实施方式，但本发明的实施方式并不受上述实施例的限制，其他的任何未背离本发明的精神实质与原理下所作的改变、修饰、替代、组合、简化，均应为等效的置换方式，都包含在本发明的保护范围之内。

Claims (13)

  1. 一种药物组合物，其特征在于所述药物组合物包含第一有效成分和第二有效成分，其中第一有效成分为化合物1、其对应的酯、其对应的盐、其对应的酯的盐或其组合；第二有效成分为神经氨酸酶抑制剂；所述第一有效成分与第二有效成分的质量比为1～8:1
    Figure PCTCN2020113105-appb-100001
  2. 根据权利要求1所述的药物组合物，其中，所述第一有效成分为化合物1、化合物1对应的酯、化合物1的盐、化合物1对应的酯的盐中一种或两种以上以任意比例混合所得的混合物。
  3. 根据权利要求2所述的药物组合物，其中，所述化合物1对应的酯指代化合物1与有机酸形成的酯，优选化合物1的甲酯、乙酯、正丙酯、异丙酯、正丁酯、叔丁酯；所述化合物1的盐为化合物1与有机酸和/或无机酸形成的盐、或化合物1与有机碱和/或无机碱形成的盐，优选盐酸盐、氢溴酸盐、硫酸盐、磷酸盐、苯磺酸盐、对甲苯磺酸盐、甲磺酸盐、酒石酸盐、樟脑磺酸盐、锂盐、钠盐、钾盐、钙盐、镁盐、铝盐、铵盐、乙二胺盐、三乙胺盐；化合物1对应的酯的盐指代前述化合物1与有机酸形成的酯与有机碱和/或无机碱和/或有机酸和/或无机酸形成的盐，优选盐酸盐、化合物1甲酯的硫酸盐、化合物1乙酯的盐酸盐、化合物1乙酯的硫酸盐。
  4. 根据权利要求1-3任意一项所述的药物组合物，其中，所述神经氨酸酶抑制剂为奥司他韦(Oseltamivir)或其衍生物、扎那米韦(zanamivir)或其衍生物、帕拉米韦(Peramivir)或其衍生物中的一种或两种以上以任意比例混合所得的混 合物；所述奥司他韦、扎那米韦、帕拉米韦的衍生物独立选自其酸和/或碱，或化合物的酯、酰胺，或水解后所得羧酸及其盐。
  5. 根据权利要求1-4任意一项所述的药物组合物，其中，所述第二有效成分为奥司他韦游离态和/或奥司他韦磷酸盐和/或奥司他韦羧酸和/或奥司他韦羧酸盐。
  6. 根据权利要求1-5任意一项所述的药物组合物，其中，所述第一有效成分与第二有效成分的质量比为100～600:75。
  7. 根据权利要求1-6任意一项所述的药物组合物，其中，所述第一有效成分与第二有效成分的质量比约为100:75,200:75,300:75,400:75,500:75,600:75。
  8. 根据权利要求1所述的药物组合物，其中，所述第一有效成分为化合物1和/或化合物1的钠盐和/或化合物1的钾盐和/或化合物1的盐酸盐和/或化合物1的钙盐和/或化合物1的对甲苯磺酸盐；第二有效成分为奥司他韦磷酸盐；化合物1与奥司他韦磷酸盐的质量比为100～600:75。
  9. 根据权利要求1所述的药物组合物，其中，所述第一有效成分为化合物1和/或化合物1的钠盐和/或化合物1的钾盐和/或化合物1的盐酸盐和/或化合物1的钙盐和/或化合物1的对甲苯磺酸盐，第二有效成分为奥司他韦磷酸盐，化合物1与奥司他韦磷酸盐的质量比为100:75,200:75,300:75,400:75,500:75,600:75。
  10. 一种制剂，其特征在于，所述制剂包含如权利要求1-9任意一项所述药物组合物及药学上可接受的载体。
  11. 根据权利要求10所述的制剂，其特征在于，所述药学上可接受的载体选自填充剂、粘合剂、崩解剂、助流剂、润滑剂、矫味剂中的任意一种或两种以上。
  12. 根据权利要求11所述的制剂，其特征在于，所述填充剂选自碳酸钙、碳酸镁、磷酸钙、硫酸钙、氧化镁、羧甲基纤维素钙、羧甲基纤维素钠、蔗糖、乳糖、果糖、木糖醇、甘露醇、淀粉或其衍生物、糊精、微晶纤维素等中的任意一种或两种以上以任意比例混合所得混合物；
    所述粘合剂选自***胶、明胶、黄蓍胶、糊精、聚乙烯吡咯烷酮、淀粉及其衍 生物、藻酸钠、山梨醇、糖浆、羟丙基甲基纤维素、甲基纤维素、羟丙基纤维素、羟乙基纤维素、乙基纤维素、羧甲基纤维素钠、羧甲基纤维素钙、葡萄糖和聚甲基丙烯酸酯中的任意一种或两种以上以任意比例混合所得的混合物；
    所述崩解剂选自淀粉、藻酸、羧甲基纤维素钙、羧甲基纤维素钠、交联羧甲基纤维素钠、交联聚乙烯吡咯烷酮、低取代羟丙基甲基纤维素、微晶纤维素和甲基纤维素中的任意一种或两种以上以任意比例混合所得的混合物；
    所述助流剂选自胶体二氧化硅、粉状纤维素、三硅酸镁、二氧化硅和滑石粉中的任意一种或两种以上以任意比例混合所得的混合物；
    所述润滑剂选自硬脂酸钙、单硬脂酸甘油酯、棕榈硬脂酸甘油酯、硬脂酸镁、微晶纤维素、苯甲酸钠、氯化钠、十二烷基硫酸钠、硬脂基富马酸钠、滑石粉、硬脂酸锌和聚乙二醇中的任意一种或两种以上以任意比例混合所得的混合物；
    所述矫味剂选自甜叶菊甙、阿司巴甜和本领域常用的其它香精及甜味剂中的任意一种或两种以上以任意比例混合所得的混合物。
  13. 根据权利要求10-12任意一项所述的制剂，其特征在于，所述制剂为口服制剂；优选散剂、颗粒剂、微丸、胶囊、片剂、溶液剂或锭剂。
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