WO2022226778A1 - 经直肠施用的奥司他韦或其药学上可接受的盐的药物组合物、及其制备方法和用途 - Google Patents

经直肠施用的奥司他韦或其药学上可接受的盐的药物组合物、及其制备方法和用途 Download PDF

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WO2022226778A1
WO2022226778A1 PCT/CN2021/090233 CN2021090233W WO2022226778A1 WO 2022226778 A1 WO2022226778 A1 WO 2022226778A1 CN 2021090233 W CN2021090233 W CN 2021090233W WO 2022226778 A1 WO2022226778 A1 WO 2022226778A1
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weight
pharmaceutically acceptable
pharmaceutical composition
oseltamivir
rectal administration
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PCT/CN2021/090233
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English (en)
French (fr)
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陈燕娜
杨伟
彭军波
曾铭健
梁茜茜
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广州共禾医药科技有限公司
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Priority to CN202180003795.XA priority Critical patent/CN115529815B/zh
Priority to PCT/CN2021/090233 priority patent/WO2022226778A1/zh
Publication of WO2022226778A1 publication Critical patent/WO2022226778A1/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
    • A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
    • A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
    • 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
    • A61K9/02—Suppositories; Bougies; Bases therefor; Ovules
    • 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

Definitions

  • the invention belongs to the field of pharmaceutical preparations, and in particular, relates to a pharmaceutical composition of oseltamivir or a pharmaceutically acceptable salt thereof for rectal administration, and a preparation method and use thereof.
  • Influenza is an acute respiratory infection caused by influenza virus. Influenza viruses are classified into four types A, B, C, and D according to their nucleoproteins and matrix proteins. Influenza A and B are seasonally prevalent every year. Influenza virus is mainly transmitted through droplets such as sneezing and coughing, and is infected by direct or indirect contact with mucous membranes such as the mouth, nose, and eyes. Contact with virus-contaminated items can also be infected through the above routes. In certain places, such as densely crowded and closed or poorly ventilated rooms, it may also be transmitted by aerosols. Compared with adults, children have immature development of various organs of the body, and have poor immunity and resistance. Therefore, children are a susceptible high-risk group for influenza.
  • NA Neuraminidase
  • neuraminidase inhibitors have been shown to be effective against influenza viruses, such as peramivir (trade name: ), zanamivir (trade name: ), lanimivir (trade name: ) and oseltamivir (trade name: ), etc., these marketed product dosage forms include injection preparations, oral/nasal dry powder inhalation preparations and oral solid preparations.
  • Oseltamivir phosphate chemical name is (-)-(3R,4R,5S)-4-acetamide-5-amino-3-(1-ethylpropoxy)cyclohexyl-1-carboxylic acid ethyl ester Phosphate, the CAS number is 204255-11-8, the chemical structure is as follows:
  • Oseltamivir phosphate is an ethyl ester prodrug of its active metabolite, Oseltamivir carboxylate (GS4071). After oral administration, oseltamivir is rapidly converted to oseltamivir carboxylic acid by liver and intestinal enzymes.
  • the configuration of oseltamivir carboxylic acid is similar to the transition state of neuraminic acid, and its lipophilic pentoxy side chain at C-3 has a strong affinity with the hydrophobic pocket of the active site of influenza virus neuraminidase.
  • influenza virus neuraminidase A highly potent influenza virus neuraminidase inhibitor.
  • the parent nucleus of oseltamivir is a cyclohexene structure, which has been reported a lot (Yan Li et al., Journal of Molecular Graphics and Modelling 28(2009) 203–219; Jian Zhang et al., J.Med.Chem.2018, 61, 9976-9999) by modifying the side chain of the nucleus of oseltamivir to obtain oseltamivir derivatives with similar physiological functions, which may have higher activity or selectivity.
  • the approved antiviral NAI dosage forms include injection preparations, oral/nasal dry powder inhalers and oral solid preparations.
  • injection preparations for children, especially infants and young children, invasive injections or oral administration formulations have the problem of poor administration compliance, and other problems are unavoidable.
  • the currently marketed dosage forms of oseltamivir phosphate include granules, capsules, and dry suspensions.
  • Granules or dry suspensions are suitable for preparing liquid preparations before use, which are convenient for the elderly, children and people who are not suitable for swallowing.
  • it needs to be stored in a specific condition, which is easily affected by storage humidity, temperature, light and other conditions.
  • the stability of the drug during use will affect the safety of the drug, so it is very necessary to ensure the stability of the drug during use.
  • oseltamivir is a very bitter drug, so its oral pharmaceutical composition is difficult to swallow, or in the prior art, it has to be masked by adding additional sweeteners to the composition. The bitter taste of seltamivir.
  • CN106361728A discloses a percutaneously absorbed oseltamivir preparation, but it is conceivable that infants and young children have thin stratum corneum and fragile skin, and skin irritation is inevitably caused by using the patch for a long time; CN102225058A discloses an oseltamivir phosphate Tasvir inhalation powder spray and preparation method thereof, but it is difficult for young children to actively inhale the drug.
  • the drug acts systemically through rectal absorption.
  • the rectal route of administration is considered an ideal alternative to oral administration in the pediatric population.
  • the rectal route of administration avoids the need for chewing, allowing easy administration even in children with vomiting, coma, and crying.
  • the preparation for rectal administration does not need to mask the taste of the drug, which can avoid the discomfort caused by the oral administration of some bitter-tasting drugs to patients.
  • the object of the present invention is to provide a pharmaceutical composition for rectal administration comprising oseltamivir or a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable semi-solid matrix suitable for rectal administration and optionally other additive.
  • the present invention relates to a pharmaceutical composition dosage form for rectal administration as a suppository consisting of oseltamivir or a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable semi-solid base suitable for rectal administration and optionally other additives.
  • the rectally administered pharmaceutical composition can be administered into the rectal cavity alone or in conjunction with an applicator.
  • oseltamivir or a pharmaceutically acceptable salt thereof is characterized in that the pharmaceutically acceptable salt is hydrochloride, hydrobromide, sulfate, phosphate, acetate, Citrate, lactate, ascorbate, maleate, tartrate, malate or succinate, preferably phosphate.
  • the oseltamivir or a pharmaceutically acceptable salt thereof constitutes 0.45-39.2% by weight, preferably 0.9-9.8% or 1.2-9.8% by weight of the total weight of the pharmaceutical composition.
  • the pharmaceutically acceptable semi-solid matrix suitable for rectal administration comprises 60.8-99.55% by weight, preferably 90.2-99.1% by weight or 87.2-98.0% by weight of the total weight of the pharmaceutical composition .
  • the pharmaceutically acceptable semisolid base suitable for rectal administration is one of polyethylene glycols, glycerin gelatin, cocoa butter or glyceryl stearate. It is critical to choose a semi-solid matrix that provides the best physicochemical stability, drug dispersion and release properties.
  • the semi-solid matrix should have appropriate hardness (mechanical assistance) at room temperature, not deformed or broken when inserted into the cavity; easily softened, melted or dissolved at body temperature; does not react with the main drug; has no effect on mucous membranes. Irritant, non-toxic, non-allergic; stable in physical and chemical properties, not easy to mildew during storage.
  • Stearin also known as mixed fatty acid glycerides, is composed of triglycerides of supersaturated fatty acids with long carbon chains (C 8 H 17 COOH ⁇ C 18 H 37 COOH) and different proportions of monoglycerides and diglycerides Glycerides of fatty acids are commonly used oil-soluble bases for suppositories. According to different preparation methods and components, different types of stearin can be obtained, which determine the main physical and chemical properties of the matrix, such as melting point range and hydroxyl value. In addition, emulsifiers, phospholipid additives, etc. can also be added during the synthesis of stearin. , to further improve the matrix adaptation performance.
  • the main stearin products currently on the market include: and These well-established stearin products contain dozens of stearin types with performance options.
  • the inventors have surprisingly found that by using stearin with a specific hydroxyl value and melting point range as a semi-solid matrix, suppositories of oseltamivir or its pharmaceutically acceptable salts with moderate hardness, stable physicochemical properties and simple prescription can be prepared .
  • the stearin of the present invention has a hydroxyl value of less than 30, preferably less than 15.
  • the stearin of the present invention has a melting point in the range of 34.0-41.0°C, preferably 36.0-38.5°C.
  • the pharmaceutical composition of the present invention is made into a unit weight of about 0.25-2 g.
  • the pharmaceutical composition of the present invention is preferably made. into a unit weight of about 0.5-1.5g.
  • oseltamivir or a pharmaceutically acceptable salt thereof is 9-98 mg.
  • the pharmaceutical compositions of the present invention optionally comprise one or more additives such as surfactants, lubricants or wetting agents, pH adjusters, preservatives, antioxidants, thickeners or its combination.
  • additives such as surfactants, lubricants or wetting agents, pH adjusters, preservatives, antioxidants, thickeners or its combination.
  • These pharmaceutical excipients may further improve the properties of the pharmaceutical compositions of the present invention, especially suppositories, and the above-mentioned combinations may be incorporated into the pharmaceutical compositions if desired, as long as they do not interfere with the safety or efficacy of the compositions of the present invention.
  • the surfactant may be selected from, but not limited to, soy lecithin, (3-sn-phosphatidyl) choline (soy), polyethylene glycol stearate, polyoxyethylene stearate, polyoxyethylene 40 Stearates, Polyethylene Glycol Cetadecyl Ether, Polyethylene Glycol Esters, Polysorbate 80, Polysorbate 60, Polyoxyethylene Alcohol, Alkyl Phenol Ethoxylates, Polymethyl Silicon Oxane, Alkylphenol Ethoxylate, Poloxamer 407, Sorbitan Monostearate, Sorbitan Monolaurate, Sorbitan Monopalmitate, Sorbitan Monostearate Oleate, polyethylene glycol stearate;
  • Suitable wetting agents or lubricants provide lubricity and lubricity to facilitate loading and dispersion of the formulation.
  • Wetting agents or lubricants are selected from polyols such as glycols and polysaccharides, such as ethylene glycol, propylene glycol, butylene glycol, diethylene glycol, dipropylene glycol, glycerol, diglycerol, sorbitol, maltitol, Trehalose, Raffinose, Xylitol, Mannitol, Polyethylene Glycol, Polyglycerol, Cholesterol, Squalene, Fatty Acids, Octyl Lauryl Alcohol, Myristyl Alcohol, Urea, Lanolin, Lactic Acid, Esters such as Hard Isopropyl fatty acid, isopropyl myristate, isopropyl palmitate and isopropyl laurate, vegetable oils, hydrogenated vegetable oils, hydrogenated fats;
  • the pH adjusting agent can be selected from but not limited to lactic acid, malic acid, acetic acid, citric acid, tartaric acid, phosphoric acid, fumaric acid, ascorbic acid, succinic acid;
  • the preservative can be selected from, but not limited to, butylated hydroxytoluene, benzyl alcohol, hydroxyphenyl esters, sodium benzoate, chlorphenesin, sorbic acid, phenoxyethanol, etc.;
  • the antioxidant may be selected from, but is not limited to, the antioxidant is selected from ascorbate, dibutylhydroxytoluene (BHT), butylated hydroxyanisole (BHA), sodium metabisulfite, alpha-tocopherol or its synthetic derivatives and Ethylenediaminetetraacetic acid (EDTA), etc.;
  • BHT dibutylhydroxytoluene
  • BHA butylated hydroxyanisole
  • EDTA Ethylenediaminetetraacetic acid
  • the thickener can be selected from, but not limited to, silica, anhydrous silicic acid.
  • the other additives comprise 0-3.0 wt%, preferably 0 wt% or 0.8-3.0 wt%, based on the total weight of the pharmaceutical composition.
  • compositions for rectal administration of the present invention comprise or consist of the following components:
  • the pharmaceutically acceptable salt is phosphate
  • the pharmaceutically acceptable semi-solid base suitable for rectal administration is selected from the group consisting of hard fat, cocoa butter, glycerin gelatin and polyethylene glycol 4000, wherein the hard fat is preferably or
  • the hydroxyl value of the stearin is less than 30, preferably the hydroxyl value is less than 15, and the melting point of the stearin is in the range of 34.0-41.0°C, preferably 36.0-38.5°C;
  • the other additives are selected from the group consisting of soy lecithin, citric acid, propylene glycol, sodium benzoate, glycerol and butylated hydroxyanisole.
  • composition for rectal administration of the present invention consists of the following components:
  • 0.45-39.2 wt% (eg 0.45 wt%, 2.0 wt%, 9.0 wt%, 30.0 wt%, 0.6 wt%, 2.6 wt%, 11.8 wt% or 39.2 wt%), preferably 0.9-9.8 wt% (eg 0.9 wt% %, 3.0 wt %, 7.5 wt %, 1.2 wt %, 3.9 wt % or 9.8 wt %) of oseltamivir or a pharmaceutically acceptable salt thereof and 60.8-99.55 wt % (eg 99.55 wt %, 98.0 wt %) , 91.0 wt%, 70.0 wt%, 99.4 wt%, 97.4 wt%, 88.2 wt% or 60.8 wt%), preferably 90.2-99.1 wt% (eg 99.1 wt%, 97.0
  • oseltamivir or a pharmaceutically acceptable salt thereof, 98.0% by weight of stearin H37 and 0.8% by weight of soybean lecithin;
  • oseltamivir or a pharmaceutically acceptable salt thereof, 89.2% by weight of cocoa butter, 0.5% by weight of soy lecithin and 0.5% by weight of citric acid;
  • oseltamivir or a pharmaceutically acceptable salt thereof, 89.0% by weight of glycerin gelatin, 1.175% by weight of citric acid, 0.024% by weight of sodium benzoate, and 0.001% by weight of butylated hydroxyanisole;
  • oseltamivir or a pharmaceutically acceptable salt thereof, 96.8 wt% polyethylene glycol 4000, 0.8 wt% glycerol, 1.19 wt% propylene glycol, and 0.01 wt% butylated hydroxyanisole; or
  • oseltamivir or a pharmaceutically acceptable salt thereof, 87.2 wt% polyethylene glycol 4000, 2.24 wt% glycerol, 0.7 wt% citric acid, and 0.06 wt% sodium benzoate.
  • the present invention also provides a method of preparing a pharmaceutical composition for rectal administration, the pharmaceutical composition being a suppository, wherein the method comprises the steps of:
  • step 2) take oseltamivir or its pharmaceutically acceptable salt and optional other additives, add it in step 1), fully stir and disperse it uniformly;
  • step 2) The product of step 2) is cooled and formed in a mold.
  • the present invention also relates to the use of the pharmaceutical composition for rectal administration in the manufacture of a medicament for the prevention and treatment of influenza.
  • the present invention also relates to the pharmaceutical composition for rectal administration for its use in the prevention and treatment of influenza.
  • the present invention also relates to a method of preventing and treating influenza comprising administering to a subject in need thereof a rectally administered pharmaceutical composition of the underlying invention.
  • influenza is influenza A, B, C or D, preferably influenza A and B.
  • the pharmaceutical composition of the present invention has high compliance, and is especially suitable for subjects such as children who have difficulty in taking oral medicines.
  • the rectal route of administration avoids the need for chewing and allows for easy administration even in children with vomiting, coma, and crying.
  • the rectal administration formulation does not need to taste masking the drug, which can avoid the discomfort caused by the bitter taste to the patient during oral administration.
  • any numerical value (such as a concentration or concentration range described herein) should be understood to be modified by the term "about" in all instances. Therefore, numerical values generally include ⁇ 10% of the stated value. For example, a concentration of 1 mg/mL includes 0.9 mg/mL to 1.1 mg/mL. Likewise, the range of 1 to 10 wt % includes 0.9 to 11 wt %. As used herein, the use of numerical ranges expressly includes all possible subranges, all individual numerical values within that range, including integers and fractions of values within those ranges, unless the context clearly dictates otherwise.
  • pharmaceutically acceptable is understood to mean its use in the preparation of pharmaceutical compositions that are generally safe, non-toxic, biologically or otherwise desirable and that the combination The substance is acceptable for veterinary and human pharmaceutical use.
  • an "effective amount” as used herein includes an amount sufficient to ameliorate or prevent a symptom or condition of a medical condition.
  • An effective amount also means an amount sufficient to allow or facilitate diagnosis.
  • the effective amount for a particular patient or veterinary subject may vary depending on factors such as the condition being treated, the general health of the patient, the method, route and dosage of administration, and the severity of side effects.
  • An effective amount can be the maximum dose or dosing regimen that avoids significant side effects or toxic effects.
  • the subject is preferably a mammal, especially a human, pet or commercial animal.
  • Embodiment 3 prescription and preparation of different types of oseltamivir stearyl phosphate suppository
  • the suppositories prepared by taking the prescriptions 1-14 of Example 1, the prescriptions 15-22 of Example 2 and the prescriptions 23-27 of Example 3 were stored under high temperature and high humidity (60° C., 75% RH) for 10 days, and the appearances were compared and adopted.
  • the change of oseltamivir impurity was detected by high performance liquid chromatography, and the stability was as follows:
  • cocoa butter When cocoa butter is used as a semi-solid matrix, a suppository with qualified properties can be obtained by using cocoa butter alone, but the stability of oseltamivir phosphate suppository can be further improved by adding other additives; compare prescription 18-22 and prescription 23 -27, the use of cocoa butter, glycerin gelatin and polyethylene glycol 4000 as the semi-solid base can prepare stable oseltamivir phosphate suppository, but compared with the use of a specific type of stearin as the semi-solid base, the formulation components More complex, and stability does not appear to be optimal.
  • Healthy rabbits purchased from Southern Medical University, SCXK (Guangdong) 2016-0041
  • 6 per group were fasted for 12 hours, embedded and fixed indwelling needles in the ear artery, and given commercially available osphate phosphate by oral gavage Tasvir dry suspension (Certificate holder: Roche, Germany, specification: 6 mg/ml, calculated as free base) and rectal administration of 1 tablet of the present invention
  • blood was drawn from the indwelling needle at different time points before and after administration, and the samples were processed using high-performance liquid chromatography. Chromatography was used to determine the concentration of oseltamivir, and the relative bioavailability of oseltamivir was compared between the two routes of administration at equal doses.
  • the high-dose (75mg/capsule, calculated as free base) oseltamivir suppository or oseltamivir phosphate suppository of prescription 18 and prescription 23 can obtain similar bioavailability to the commercially available oral oseltamivir phosphate formulation.
  • Test animals adult New Zealand rabbits (purchased from Southern Medical University, SCXK (Guangdong) 2016-0041), body weight (2.5 ⁇ 0.5) kg.
  • Dosing frequency 1 capsule/time, 2 times a day, for 7 consecutive days.
  • Test method The rabbits were divided into 7 groups, 8 in each group, the suppositories (prescriptions 12, 14, 17, 18, 23) prepared by the present invention and the blank control suppository of stearin excipients were placed in the rectum of the rabbits, Another blank control group was not given any treatment.
  • the clinical manifestations (such as pain symptoms) and feces (such as blood, mucus) of animals in each group were observed once 2-3 hours after the administration, and the animals were dissected 24 hours after the last administration for histopathological examination.

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Abstract

一种经直肠施用的奥司他韦或其药学上可接受的盐的药物组合物、及其制备方法和用途。该药物组合物包含奥司他韦或其药学上可接受的盐、适用于直肠施用的药学上可接受的半固体基质和任选的其他添加剂。该直肠施用的药物组合物用于预防和治疗流行性感冒。

Description

经直肠施用的奥司他韦或其药学上可接受的盐的药物组合物、及其制备方法和用途 技术领域
本发明属于药物制剂领域，特别是，涉及经直肠施用的奥司他韦或其药学上可接受的盐的药物组合物、及其制备方法和用途。
背景技术
流行性感冒是流感病毒引起的一种急性呼吸道传染病。流感病毒根据核蛋白和基质蛋白不同，分为甲、乙、丙、丁四型，甲型和乙型流感病毒每年呈季节性流行。流感病毒主要通过打喷嚏和咳嗽等飞沫传播，经口腔、鼻腔、眼睛等粘膜直接或间接接触感染。接触被病毒污染的物品也可通过上述途径感染。在特定场所，如人群密集且密闭或通风不良的房间内，也可能通过气溶胶的形式传播。儿童相对于成年人，机体各个器官发育不成熟，免疫力以及抵抗力不佳，因此儿童是流行性感冒的易感高危人群。
神经氨酸酶(Neuraminidase，NA)在流感病毒的复制和扩散中具有重要作用，通过抑制神经氨酸酶活性能够导致子代病毒颗粒聚集在细胞表面不能释放，从而限制了病毒在机体的扩散。一些神经氨酸酶抑制剂(Neuraminidase inhibitor，NAI)已被证实能有效防治流感病毒，如帕拉米韦(商品名：
Figure PCTCN2021090233-appb-000001
)、扎那米韦(商品名：
Figure PCTCN2021090233-appb-000002
)、拉尼米韦(商品名：
Figure PCTCN2021090233-appb-000003
)和奥司他韦(商品名：
Figure PCTCN2021090233-appb-000004
)等，这些已上市的产品剂型包括注射给药制剂、经口/鼻给药的干粉吸入剂和经口服用的固体制剂。
磷酸奥司他韦，化学名为(-)-(3R,4R,5S)-4-乙酰胺-5-氨基-3-(1-乙基丙氧基)环己-1-羧酸乙酯磷酸盐，CAS号为204255-11-8，化学结构式如下：
Figure PCTCN2021090233-appb-000005
其由瑞士罗氏公司研发推出，已在全球多个地区被批准用于婴幼儿、儿童和成人甲型、乙型流感病毒的预防和治疗。
磷酸奥司他韦是其活性代谢物奥司他韦羧酸(Oseltamivir carboxylate，GS4071)的乙酯型前药。口服后，奥司他韦经肝脏和肠道酶催化迅速转化为奥司 他韦羧酸。奥司他韦羧酸的构型与神经氨酸的过渡态相似，其C-3位亲脂性的戊氧基侧链与流感病毒神经氨酸酶活性部位的疏水性口袋有较强的亲和力，能竞争性地与流感病毒神经氨酸酶的活性位点结合，阻断流感病毒神经氨酸酶对病毒感染细胞表面的唾液酸残基的裂解，抑制病毒颗粒从感染细胞释放，是一种选择性很高的流感病毒神经氨酸酶抑制剂。
奥司他韦的母核为环己烯类结构，已有不少报道(Yan Li等，Journal of Molecular Graphics and Modelling 28(2009)203–219；Jian Zhang等，J.Med.Chem.2018,61,9976-9999)对奥司他韦母核侧链进行修饰改造，可获得具有相似生理学功能的奥司他韦衍生物，并可能具有更高的活性或选择性。
目前，已获批上市的抗病毒NAI剂型包括注射给药制剂、经口/鼻给药的干粉吸入剂和经口服用的固体制剂。对于儿童人群而言，尤其是婴幼儿，侵入型的注射剂或口服给药制剂存在给药依从性差的问题，且仍不可避免的存在其他问题。
以磷酸奥司他韦为例，磷酸奥司他韦目前上市的剂型有颗粒剂、胶囊剂、和干混悬剂等。颗粒剂或干混悬剂适合于临用前配制成液体制剂，便于老人、小孩以及不适合吞咽人群服用。通常在打开颗粒剂或干混悬剂包装至使用完成期间，需要保存在特定的条件，容易受到保存湿度、温度、光照等条件的影响。在使用期间药物稳定性将影响药物的安全性，因此保证药物在使用期间的稳定性是非常必要的。此外，奥司他韦是一种苦味特别大的药物，因此其经口服的药物组合物难以下咽，或者在现有技术中，不得不通过在组合物中加入额外的甜味剂来掩盖奥司他韦的苦味。
CN106361728A公开了一种经皮吸收的奥司他韦制剂，但可以想象的是，婴幼儿角质层薄，皮肤脆弱，长时间使用贴剂仍不可避免产生皮肤刺激；CN102225058A公开了一种磷酸奥司他韦吸入粉雾剂及其制备方法，但对于低龄儿童而言，主动吸入药物是困难的。
药物可通过直肠吸收发挥全身作用。直肠给药途径是一种被认为在儿童人群中可替代经口途径给药的理想剂型。直肠给药途径避免了咀嚼的过程，即使在儿童出现呕吐、昏迷和哭闹等情况下，也可实现轻松给药。此外，直肠给药制剂无需对药物进行掩味，可避免一些带苦味药物给患者口服给药过程中造成的不适感。
发明内容
因此，本发明的目的在于提供一种直肠施用的药物组合物，其包含奥司他韦或其药学上可接受的盐、适用于直肠施用的药学上可接受的半固体基质和任选的其他添加剂。特别地，本发明涉及一种直肠施用的药物组合物剂型为栓剂，其由奥司他韦或其药学上可接受的盐、适用于直肠施用的药学上可接受的半固体基质和任选的其他添加剂组成。
在一些优选的实施方案中，所述直肠施用的药物组合物可以单独或配合给药器施用至直肠腔体中。
在一些优选的实施方案中，奥司他韦或其药学上可接受的盐，其特征在于药学上可接受的盐为盐酸盐、氢溴酸盐、硫酸盐、磷酸盐、醋酸盐、柠檬酸盐、乳酸盐、抗坏血酸盐、马来酸盐、酒石酸盐、苹果酸盐或琥珀酸盐，优选为磷酸盐。
在一些优选的实施方案中，所述奥司他韦或其药学上可接受的盐占所述药物组合物总重量的0.45-39.2重量％，优选0.9-9.8重量％或1.2-9.8重量％。
在一些优选的实施方案中，所述适用于直肠施用的药学上可接受的半固体基质占所述药物组合物总重量的60.8-99.55重量％，优选90.2-99.1重量％或87.2-98.0重量％。
在一些优选的实施方案中，所述的适用于直肠施用的药学上可接受的半固体基质为聚乙二醇类、甘油明胶、可可豆脂或硬脂酸甘油脂中的一种。选择提供最佳的物理化学稳定性、药物分散和释放性能的半固体基质是至关重要的。半固体基质应在室温时应有适当的硬度(机械助力)，当塞入腔道时不变形，不碎裂；在体温下易软化、熔化或溶解；不与主药起反应；对黏膜无刺激性，无毒性，无过敏性；理化性质稳定，在贮藏过程中不易霉变等。
硬脂，又称混合脂肪酸甘油酯，是由碳链较长的过饱和脂肪酸(C 8H 17COOH～C 18H 37COOH)的甘油三酯及不同比例的甘油单酯和甘油二酯组成的脂肪酸甘油酯，是栓剂常用的油溶性基质。根据制备方法和组分不同，可以获得不同类型的硬脂，它决定了基质的主要理化性质，如熔点范围和羟值，此外，还可以通过在硬脂合成过程中加入乳化剂、磷脂添加剂等，进一步改善基质适配性能。目前市售产品中主要的硬脂商品包括
Figure PCTCN2021090233-appb-000006
和
Figure PCTCN2021090233-appb-000007
这些成熟的硬脂商品中包含了数十种性能可选的硬脂类型。
本发明人令人惊奇地发现，采用特定羟值和熔点范围的硬脂作为半固体基质，可制备硬度适中、理化性质稳定和处方简单的奥司他韦或其药学上可接受的盐的栓剂。
在一些优选的实施方案中，本发明的硬脂的羟值小于30，优选地为小于15。
在一些优选的实施方案中，本发明的硬脂的熔点范围为34.0-41.0℃，优选地为36.0-38.5℃。
在一些优选的实施方案中，本发明的药物组合物被制作成约0.25-2g的单位重量，在婴幼儿及儿童人群中，由于直肠腔体较成人小，本发明的药物组合物优选被制作成约0.5-1.5g的单位重量。特别地，在药物组合物的单位重量中，奥司他韦或其药学上可接受的盐为9-98mg。
在一些优选的实施方案中，本发明的药物组合物任选包含一种或多种添加剂，如表面活性剂、润滑剂或润湿剂、pH调节剂、防腐剂、抗氧化剂、增稠剂或其组合。这些药物辅料可能进一步改善本发明的药物组合物，特别是栓剂的特性，如 果需要，上述组合可以掺入药物组合物中，只要它们不干扰本发明的组合物的安全性或有效性。
所述表面活性剂可以选自但不限于大豆卵磷脂、(3-sn-磷脂酰)胆碱(大豆)、聚乙二醇硬脂酸酯、聚氧乙烯硬脂酸酯、聚氧乙烯40硬脂酸酯、聚乙二醇十六十八烷基醚、聚乙二醇酯、聚山梨酯80、聚山梨酯60、聚氧乙烯醇、烷基酚乙氧基化物、聚甲基硅氧烷、烷基酚乙氧基化物、泊洛沙姆407、脱水山梨糖醇单硬脂酸酯、脱水山梨糖醇单月桂酸酯、脱水山梨糖醇单棕榈酸酯、脱水山梨糖醇单油酸酯、聚乙二醇硬脂酸酯；
适合的润湿剂或润滑剂提供光滑性和润滑性，从而有利于所述制剂的装载和分散。润湿剂或润滑剂选自多元醇如二醇类和多糖类，如乙二醇、丙二醇、丁二醇、二乙二醇、双丙二醇、甘油、双甘油、山梨糖醇、麦芽糖醇、海藻糖、棉子糖、木糖醇、甘露醇、聚乙二醇、聚甘油、胆固醇、角鲨烯、脂肪酸、辛基月桂醇、肉豆蔻醇、尿素、羊毛脂、乳酸、酯类如硬脂酸异丙酯、肉豆蔻酸异丙酯、棕榈酸异丙酯和月桂酸异丙酯、植物油、氢化植物油、氢化脂肪；
所述pH调节剂可以选自但不限于乳酸、苹果酸、醋酸、柠檬酸、酒石酸、磷酸、富马酸、抗坏血酸、琥珀酸；
所述防腐剂可以选自但不限于丁羟甲苯、苯甲醇、羟苯酯类、苯甲酸钠、氯苯甘醚、山梨酸、苯氧乙醇等；
所述抗氧化剂可以选自但不限于所述抗氧化剂选自抗坏血酸盐、二丁基羟基甲苯(BHT)、丁基羟基茴香醚(BHA)、焦亚硫酸钠、α-生育酚或其合成衍生物和乙二胺四乙酸(EDTA)等；
所述增稠剂可以选自但不限于二氧化硅、无水硅酸。
在一些优选的实施方案中，所述其他添加剂占所述药物组合物总重量的0-3.0重量％，优选0重量％或0.8-3.0重量％。
在一些优选的实施方案中，本发明的直肠施用的药物组合物其包括或由以下组分组成：
占所述药物组合物总重量的0.45-39.2重量％的奥司他韦或其药学上可接受的盐，和
占所述药物组合物总重量的60.8-99.55重量％的适用于直肠施用的药学上可接受的半固体基质；
或者
占所述药物组合物总重量的1.2-9.8重量％的奥司他韦或其药学上可接受的盐，
占所述药物组合物总重量的87.2-98.0重量％的适用于直肠施用的药学上可接受的半固体基质；和
占所述药物组合物总重量的0.8-3.0重量％的其他添加剂；
其中，所述药学上可接受的盐为磷酸盐；
所述适用于直肠施用的药学上可接受的半固体基质选自硬脂、可可豆脂、甘油明胶和聚乙二醇4000，其中所述硬脂优选为
Figure PCTCN2021090233-appb-000008
或
Figure PCTCN2021090233-appb-000009
特别地，所述硬脂的羟值小于30，优选地羟值小于15，和所述硬脂的熔点范围为34.0-41.0℃，优选地为36.0-38.5℃；
所述其他添加剂选自大豆卵磷脂、柠檬酸、丙二醇、苯甲酸钠、甘油和丁基羟基茴香醚。
特别地，本发明的直肠施用的药物组合物由以下组分组成：
0.45-39.2重量％(例如0.45重量％、2.0重量％、9.0重量％、30.0重量％、0.6重量％、2.6重量％、11.8重量％或39.2重量％)，优选0.9-9.8重量％(例如0.9重量％、3.0重量％、7.5重量％、1.2重量％、3.9重量％或9.8重量％)的奥司他韦或其药学上可接受的盐和60.8-99.55重量％(例如99.55重量％、98.0重量％、91.0重量％、70.0重量％、99.4重量％、97.4重量％、88.2重量％或60.8重量％)，优选90.2-99.1重量％(例如99.1重量％、97.0重量％、92.5重量％、98.8重量％、96.1重量％或90.2重量％)的硬脂
Figure PCTCN2021090233-appb-000010
H37、硬脂
Figure PCTCN2021090233-appb-000011
BM、硬脂
Figure PCTCN2021090233-appb-000012
B、硬脂
Figure PCTCN2021090233-appb-000013
BP、硬脂
Figure PCTCN2021090233-appb-000014
AM或硬脂
Figure PCTCN2021090233-appb-000015
CM；
1.2重量％的奥司他韦或其药学上可接受的盐、98.0重量％的硬脂
Figure PCTCN2021090233-appb-000016
H37和0.8重量％的大豆卵磷脂；
1.2重量％的奥司他韦或其药学上可接受的盐和98.8重量％的可可豆脂；
1.2重量％的奥司他韦或其药学上可接受的盐、98.0重量％的可可豆脂和0.8重量％的柠檬酸；
9.8重量％的奥司他韦或其药学上可接受的盐、89.2重量％可可豆脂、0.5重量％的大豆卵磷脂和0.5重量％的柠檬酸；
1.2重量％的奥司他韦或其药学上可接受的盐、97.95重量％的甘油明胶、0.8重量％的丙二醇和0.05重量％的苯甲酸钠；
9.8重量％的奥司他韦或其药学上可接受的盐、89.0重量％的甘油明胶、1.175重量％的柠檬酸、0.024重量％的苯甲酸钠和0.001重量％的丁基羟基茴香醚；
1.2重量％的奥司他韦或其药学上可接受的盐、96.8重量％的聚乙二醇4000、0.8重量％的甘油、1.19重量％的丙二醇和0.01重量％的丁基羟基茴香醚；或
9.8重量％的奥司他韦或其药学上可接受的盐、87.2重量％的聚乙二醇4000、2.24重量％的甘油、0.7重量％的柠檬酸和0.06重量％的苯甲酸钠。
本发明还提供一种制备直肠施用的药物组合物的方法，所述药物组合物为栓剂，其中所述方法包括以下步骤：
1)将适用于直肠施用的药学上可接受的半固体基质溶解或熔融；
2)称取奥司他韦或其药学上可接受的盐和任选的其他添加剂，加入步骤1)中，充分搅拌分散均匀；和
3)将步骤2)的产物在模具中冷却成型。
本发明还涉及所述直肠施用的药物组合物在制备用于预防和治疗流行性感冒的药物中的用途。
本发明还涉及所述直肠施用的药物组合物，其用于预防和治疗流行性感冒的用途。
本发明还涉及一种预防和治疗流行性感冒的方法，其包括向需要其的受试者施用根本发明的直肠施用的药物组合物。
在一些优选的实施方案中，流行性感冒为甲、乙、丙或丁型流行性感冒，优选甲型和乙型流行性感冒。
本发明的有益效果
与现有技术相比，本发明的技术方案具有以下优点：
本发明的药物组合物依从性高，特别适合口服药物困难的受试者如儿童。直肠施用途径避免了咀嚼的过程，即使在儿童出现呕吐、昏迷和哭闹等情况下，也可实现轻松施用。此外，直肠施用制剂无需对药物进行掩味，可避免苦味给患者口服给药过程中造成的不适感。
定义
除非另外定义，本文所使用的所有技术和科学术语具有与本发明所属领域的普通技术人员通常所理解的相同含义。否则，本文使用的某些术语具有说明书中设定的含义。
除非另有说明，任何数值(如本文所描述的浓度或浓度范围)应被理解为在所有情况下均由术语“约”修饰。因此，数值通常包括所述值的±10％。例如，1mg/mL的浓度包括0.9mg/mL至1.1mg/mL。同样，1至10重量％范围包括0.9至11重量％。如本文所使用，数值范围的使用明确地包括所有可能的子范围，该范围内的所有单独数值，包括在这些范围内的整数和值的分数，除非上下文另有明确说明。
在本发明中，“药学上可接受的”被理解为是指其用于制备药物组合物，所述组合物一般是安全的，无毒的，在生物学或其他方面满足需要并且所述组合物可以被接受用于兽类和人类药物用途。
本发明所述的“有效量”包含足以改善或预防医学病症的症状或病症的量。有效量还意指足以允许或促进诊断的量。用于特定患者或兽医学受试者的有效量可依据以下因素而变化：如待治疗的病症、患者的总体健康情况、给药的方法途径和剂量以及副作用严重性。有效量可以是避免显著副作用或毒性作用的最大剂量或给药方案。
需要说明的是，本领域技术人员可以根据实际需要选定混合方式，既可以将所有药物制剂同时进行混合，也可以按照各组分的物化性质分类混合，再将各类的混合物全部混合在一起。
受试者优选为哺乳动物，特别是人、宠物或商业动物。
“任选”或“任选地”意味着随后所描述地事件或环境可以但不必发生，该说明包括该事件或环境发生或不发生地场合。例如，“任选包含一种或多种药物辅料”意味着药物辅料可以但不必须存在，该说明包括包含药物辅料的情形和不包含沉降抑制剂的情形。
具体实施方式
通过以下实施例进一步详细说明本发明。这些实施例和实验例仅用于说明性目的，而并不用于限制本发明的范围。
下列实施例中未注明具体条件的实验方法，按照常规方法和条件，或按照商品说明书选择。实施例中的已知的试剂、溶剂、材料可以采用或按照本领域已知的方法来合成，或商业上可购买。
实施例1：不同比例组分的奥司他韦栓/磷酸奥司他韦栓处方及制备
处方：
Figure PCTCN2021090233-appb-000017
处方：
Figure PCTCN2021090233-appb-000018
处方：
Figure PCTCN2021090233-appb-000019
制备方法：
称取处方量市售半固体基质硬脂(型号：
Figure PCTCN2021090233-appb-000020
H37，生产商：IOI Oleo GmbH PHARMA，羟值＜15；熔点范围：36.0-38.0℃)，加热熔融；称取处方量奥司他韦游离碱或磷酸奥司他韦(依据专利申请WO9807685A1合成)，加入熔融的硬脂中，充分搅拌分散均匀，分装冷却成型，得到奥司他韦栓或磷酸奥司他韦栓。
实施例2：不同基质的磷酸奥司他韦栓处方及制备
处方：
Figure PCTCN2021090233-appb-000021
处方：
物料 处方19 处方20 处方21 处方22
磷酸奥司他韦 12mg 98mg 12mg 98mg
甘油明胶 979.5mg 890mg - -
聚乙二醇4000 - - 968mg 872mg
甘油 - - 8mg 22.4mg
丙二醇 8mg - 11.9mg -
柠檬酸 - 11.75mg - 7mg
苯甲酸钠 0.5mg 0.24mg - 0.6mg
丁基羟基茴香醚(BHA) - 0.01mg 0.1mg -
总重 1000mg 1000mg 1000mg 1000mg
制备方法：
称取处方量半固体基质，加热熔融；称取处方量磷酸奥司他韦和其他添加剂(处方16不含添加剂)，加入熔融的半固体基质中，充分搅拌分散均匀，分装冷却成型，得到磷酸奥司他韦栓。
实施例3：不同型号硬脂磷酸奥司他韦栓处方及制备
处方：
Figure PCTCN2021090233-appb-000022
处方：
Figure PCTCN2021090233-appb-000023
制备方法：
称取购自嘉法狮公司特定对应型号的处方量半固体基质硬脂，加热熔融；称取处方量磷酸奥司他韦，加入熔融的硬脂中，充分搅拌分散均匀，分装冷却成型，得到磷酸奥司他韦栓。
实施例4：稳定性对比结果
取实施例1处方1-14、实施例2处方15-22及实施例3处方23-27制备的栓剂在高温高湿(60℃，75％RH)条件下保存10天，进行外观比较和采用高效液相色谱法检测奥司他韦杂质变化，稳定性情况如下：
Figure PCTCN2021090233-appb-000024
已知的磷酸奥司他韦胶囊美国药典标准(USP40)要求总杂质不高于3.0％。由上述稳定性对比研究结果看出：
1) 硬脂羟值影响：对比处方23-25：当选择硬脂羟值小于30时，所制备的磷酸奥司他韦栓经过10天加速试验后，外观无变化，总杂质低于药典标准要求，且羟值＜15时，杂质变化更小。当选择硬脂羟值大于30时，所制备的栓剂经过10 天加速试验后，外观变黄棕色，且总杂质高于药典标准要求。
2) 硬脂熔点范围影响：对比处方23和处方26-27：当选择硬脂熔点范围为34.0-41.0℃时，所制备的磷酸奥司他韦栓经过10天加速试验后，外观无变化，总杂质低于药典标准要求，且硬脂熔点范围为36.0-38.5℃时，杂质变化最小。
3) 不同品牌硬脂影响：对比处方1-14和处方23，采用不同品牌的硬脂，适宜的羟值和熔点范围，可制备性质稳定的奥司他韦栓和磷酸奥司他韦栓。
4) 不同基质和添加剂影响：对比处方12和处方15，采用特定型号的硬脂即可制备处方简单，性质稳定的磷酸奥司他韦栓，且其他添加剂并未进一步提高稳定性；对比处方16-18，采用可可豆脂作为半固体基质时，单独使用可可豆脂可获得性质合格的栓剂，但通过加入其他添加剂可进一步提高磷酸奥司他韦栓稳定性；对比处方18-22及处方23-27，采用可可豆脂、甘油明胶和聚乙二醇4000作为半固体基质可制备性质稳定的磷酸奥司他韦栓，但与采用特定型号的硬脂作为半固体基质相比，处方组分更复杂，且稳定性未显示最优。
实施例5：药效学试验
取健康家兔(购自南方医科大学，SCXK(粤)2016-0041)，6只/组，禁食12小时后，在耳动脉埋入并固定留置针，口服灌胃给予市售磷酸奥司他韦干混悬剂
Figure PCTCN2021090233-appb-000025
(持证商：Roche，德国，规格：6mg/ml，按游离碱计)和直肠给予本发明处方1粒，于给药前后不同时间点从留置针取血，经样品处理后采用高效液相色谱仪进行奥司他韦的浓度测定，比较等剂量下两种给药途径的奥司他韦相对生物利用度。
表1家兔口服及直肠等剂量(9mg，按游离碱计)奥司他韦生物利用度对比
Figure PCTCN2021090233-appb-000026
*直肠途径/口服途径
表2家兔口服及直肠等剂量(75mg，按游离碱计)奥司他韦生物利用度对比
Figure PCTCN2021090233-appb-000027
*直肠途径/口服途径
由表1和表2可见，本发明处方9、处方12和处方17的低剂量(9mg/粒，按游离碱计)奥司他韦或磷酸奥司他韦栓，本发明处方11、处方14、处方18和处方23的高剂量(75mg/粒，按游离碱计)奥司他韦栓或磷酸奥司他韦栓均可获 得与市售口服磷酸奥司他韦制剂相似的生物利用度。
实施例6：直肠刺激性试验
考察高、低剂量的磷酸奥司他韦栓直肠给药后的刺激性，为临床应用安全性提供参考。
试验动物：成年新西兰家兔(购自南方医科大学，SCXK(粤)2016-0041)，体重(2.5±0.5)kg。
给药频次：1粒/次，每日2次，连续给药7日。
试验方法：将家兔分为7组，每组8只，将本发明制备的栓剂(处方12、14、17、18、23)和硬脂赋形剂空白对照栓置入家兔直肠内，另一空白对照组不设任何处理。各组于给药后2-3小时各观察1次动物临床表现(如疼痛症状)和粪便(如血、粘液)，末次给药后24小时解剖，进行组织病理学检查。
试验结果：
Figure PCTCN2021090233-appb-000028
Figure PCTCN2021090233-appb-000029
文献报道正常动物镜检可见直肠黏膜炎细胞浸润改变和肛门炎细胞浸润改变，本试验中各组镜检均可见部分或个别动物直肠黏膜出现炎细胞浸润或偶见肛门组织炎症反应，与文献报道基本一致且空白对照组也有相同病理改变发生，考虑上述病理改变为动物自身原因，与受试物无相关性。在本试验条件下，多次直肠给予高、低剂量的磷酸奥司他韦栓对兔直肠均无刺激性。

Claims (15)

  1. 一种直肠施用的药物组合物，其包含奥司他韦或其药学上可接受的盐、适用于直肠施用的药学上可接受的半固体基质和任选的其他添加剂，其中，所述奥司他韦或其药学上可接受的盐占所述药物组合物总重量的0.45-39.2重量％，优选0.9-9.8重量％或1.2-9.8重量％。
  2. 根据权利要求1所述的直肠施用的药物组合物，其为栓剂形式。
  3. 根据权利要求1或2所述的直肠施用的药物组合物，其中所述药学上可接受的盐为盐酸盐、氢溴酸盐、硫酸盐、磷酸盐、醋酸盐、柠檬酸盐、乳酸盐、抗坏血酸盐、马来酸盐、酒石酸盐、苹果酸盐或琥珀酸盐，优选为磷酸盐。
  4. 根据权利要求1-3中任一项所述的直肠施用的药物组合物，其中所述的适用于直肠施用的药学上可接受的半固体基质为聚乙二醇类、甘油明胶、可可豆脂或硬脂酸甘油脂中的一种或两种及以上组合，优选为硬脂酸甘油脂，更优选为硬脂，甚至更优选为
    Figure PCTCN2021090233-appb-100001
    或
    Figure PCTCN2021090233-appb-100002
  5. 根据权利要求1-4中任一项所述的直肠施用的药物组合物，其中所述适用于直肠施用的药学上可接受的半固体基质为硬脂，优选为
    Figure PCTCN2021090233-appb-100003
    或
    Figure PCTCN2021090233-appb-100004
    特别地，
    所述硬脂的羟值小于30，优选地羟值小于15，和
    所述硬脂的熔点范围为34.0-41.0℃，优选地为36.0-38.5℃。
  6. 根据权利要求1-5中任一项所述的直肠施用的药物组合物，其中所述适用于直肠施用的药学上可接受的半固体基质占所述药物组合物总重量的60.8-99.55重量％，优选90.2-99.1重量％或87.2-98.0重量％。
  7. 根据权利要求1-6中任一项所述的直肠施用的药物组合物，其中所述其他添加剂选自表面活性剂、润滑剂或润湿剂、pH调节剂、防腐剂、抗氧化剂、增稠剂中的一种或多种；特别地，
    所述表面活性剂选自大豆卵磷脂、(3-sn-磷脂酰)胆碱(大豆)、聚乙二醇硬脂酸酯、聚氧乙烯硬脂酸酯、聚氧乙烯40硬脂酸酯、聚乙二醇十六十八烷基醚、聚乙二醇酯、聚山梨酯80、聚山梨酯60、聚氧乙烯醇、烷基酚乙氧基化物、聚甲基硅氧烷、烷基酚乙氧基化物、泊洛沙姆407、脱水山梨糖醇单硬脂酸酯、脱水山梨糖醇单月桂酸酯、脱水山梨糖醇单棕榈酸酯、脱水山梨糖醇单油酸酯和聚乙二醇硬脂酸酯；
    所述润湿剂或润滑剂选自多元醇如二醇类和多糖类，如乙二醇、丙二醇、丁二醇、二乙二醇、双丙二醇、甘油、双甘油、山梨糖醇、麦芽糖醇、海藻糖、棉子糖、木糖醇、甘露醇、聚乙二醇、聚甘油、胆固醇、角鲨烯、脂肪酸、辛基月桂醇、肉豆蔻醇、尿素、羊毛脂、乳酸、酯类如硬脂酸异丙酯、肉豆蔻酸异丙酯、棕榈酸异丙酯和月桂酸异丙酯、植物油、氢化植物油和化脂肪；
    所述pH调节剂选自乳酸、苹果酸、醋酸、柠檬酸、酒石酸、磷酸、富马酸、抗坏血酸和琥珀酸；
    所述防腐剂选自丁羟甲苯、苯甲醇、羟苯酯类、苯甲酸钠、氯苯甘醚、山梨酸和苯氧乙醇；
    所述抗氧化剂选自抗坏血酸盐、二丁基羟基甲苯(BHT)、丁基羟基茴香醚(BHA)、焦亚硫酸钠、α-生育酚或其合成衍生物和乙二胺四乙酸(EDTA)；
    所述增稠剂选自二氧化硅和无水硅酸。
  8. 根据权利要求1-7中任一项所述的直肠施用的药物组合物，其中所述其他添加剂占所述药物组合物总重量的0-3.0重量％，优选0重量％或0.8-3.0重量％。
  9. 根据权利要求1-8中任一项所述的直肠施用的药物组合物，其中药物组合物的单位重量为0.25-2g，优选为0.5-1.5g；
    特别地，在药物组合物的单位重量中，奥司他韦或其药学上可接受的盐为9-98mg。
  10. 根据权利要求1-9中任一项所述的直肠施用的药物组合物，其包括或由以下组分组成：
    占所述药物组合物总重量的0.45-39.2重量％的奥司他韦或其药学上可接受的盐，和
    占所述药物组合物总重量的60.8-99.55重量％的适用于直肠施用的药学上可接受的半固体基质；
    或者
    占所述药物组合物总重量的1.2-9.8重量％的奥司他韦或其药学上可接受的盐，
    占所述药物组合物总重量的87.2-98.0重量％的适用于直肠施用的药学上可接受的半固体基质；和
    占所述药物组合物总重量的0.8-3.0重量％的其他添加剂；
    其中，所述药学上可接受的盐为磷酸盐；
    所述适用于直肠施用的药学上可接受的半固体基质选自硬脂、可可豆脂、甘油明胶和聚乙二醇4000，其中所述硬脂优选为
    Figure PCTCN2021090233-appb-100005
    或
    Figure PCTCN2021090233-appb-100006
    特别地，所述硬脂的羟值小于30，优选地羟值小于15，和所述硬脂的熔点范围为 34.0-41.0℃，优选地为36.0-38.5℃；
    所述其他添加剂选自大豆卵磷脂、柠檬酸、丙二醇、苯甲酸钠、甘油和丁基羟基茴香醚。
  11. 根据权利要求1-10中任一项所述的直肠施用的药物组合物，其由以下组分组成：
    0.45-39.2重量％，优选0.9-9.8重量％的奥司他韦或其药学上可接受的盐和60.8-99.55重量％，优选90.2-99.1重量％的硬脂
    Figure PCTCN2021090233-appb-100007
    H37、硬脂
    Figure PCTCN2021090233-appb-100008
    BM、硬脂
    Figure PCTCN2021090233-appb-100009
    B、硬脂
    Figure PCTCN2021090233-appb-100010
    BP、硬脂
    Figure PCTCN2021090233-appb-100011
    AM或硬脂
    Figure PCTCN2021090233-appb-100012
    CM；
    1.2重量％的奥司他韦或其药学上可接受的盐、98.0重量％的硬脂
    Figure PCTCN2021090233-appb-100013
    H37和0.8重量％的大豆卵磷脂；
    1.2重量％的奥司他韦或其药学上可接受的盐和98.8重量％的可可豆脂；
    1.2重量％的奥司他韦或其药学上可接受的盐、98.0重量％的可可豆脂和0.8重量％的柠檬酸；
    9.8重量％的奥司他韦或其药学上可接受的盐、89.2重量％可可豆脂、0.5重量％的大豆卵磷脂和0.5重量％的柠檬酸；
    1.2重量％的奥司他韦或其药学上可接受的盐、97.95重量％的甘油明胶、0.8重量％的丙二醇和0.05重量％的苯甲酸钠；
    9.8重量％的奥司他韦或其药学上可接受的盐、89.0重量％的甘油明胶、1.175重量％的柠檬酸、0.024重量％的苯甲酸钠和0.001重量％的丁基羟基茴香醚；
    1.2重量％的奥司他韦或其药学上可接受的盐、96.8重量％的聚乙二醇4000、0.8重量％的甘油、1.19重量％的丙二醇和0.01重量％的丁基羟基茴香醚；或
    9.8重量％的奥司他韦或其药学上可接受的盐、87.2重量％的聚乙二醇4000、2.24重量％的甘油、0.7重量％的柠檬酸和0.06重量％的苯甲酸钠。
  12. 一种制备根据权利要求1-11中任一项所述的直肠施用的药物组合物的方法，其中所述方法包括以下步骤：
    1)将适用于直肠施用的药学上可接受的半固体基质溶解或熔融；
    2)称取奥司他韦或其药学上可接受的盐和任选的其他添加剂，加入步骤1)中，充分搅拌分散均匀；和
    3)将步骤2)的产物在模具中冷却成型。
  13. 根据权利要求1-11中任一项所述的直肠施用的药物组合物在制备用于预防和治疗流行性感冒的药物中的用途。
  14. 根据权利要求1-11中任一项所述的直肠施用的药物组合物，其用于预防 和治疗流行性感冒的用途。
  15. 一种治疗流行性感冒的方法，其包括向需要其的受试者施用根据权利要求1-11中任一项所述的直肠施用的药物组合物。
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CN102000341A (zh) * 2010-07-16 2011-04-06 钟术光 在栓剂组合物中的聚氧化乙烯及基质型表面活性剂
CN104173338A (zh) * 2013-05-23 2014-12-03 天士力控股集团有限公司 一种治疗癌症用栓剂
CN105687205A (zh) * 2016-03-08 2016-06-22 中国医学科学院药用植物研究所 一种三萜类化合物的医药用途

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