WO2015027848A1 - Method of administering formulation comprising peramivir and/or derivative thereof - Google Patents

Method of administering formulation comprising peramivir and/or derivative thereof Download PDF

Info

Publication number
WO2015027848A1
WO2015027848A1 PCT/CN2014/084836 CN2014084836W WO2015027848A1 WO 2015027848 A1 WO2015027848 A1 WO 2015027848A1 CN 2014084836 W CN2014084836 W CN 2014084836W WO 2015027848 A1 WO2015027848 A1 WO 2015027848A1
Authority
WO
WIPO (PCT)
Prior art keywords
administration
peramivir
derivatives
administration method
inhalation
Prior art date
Application number
PCT/CN2014/084836
Other languages
French (fr)
Chinese (zh)
Inventor
陈永奇
白仲虎
丁玉龙
Original Assignee
Chen Yongqi
Bai Zhonghu
Ding Yulong
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Chen Yongqi, Bai Zhonghu, Ding Yulong filed Critical Chen Yongqi
Publication of WO2015027848A1 publication Critical patent/WO2015027848A1/en

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
    • A61K31/196—Carboxylic acids, e.g. valproic acid having an amino group the amino group being directly attached to a ring, e.g. anthranilic acid, mefenamic acid, diclofenac, chlorambucil
    • 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
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/007—Pulmonary tract; Aromatherapy
    • A61K9/0073—Sprays or powders for inhalation; Aerolised or nebulised preparations generated by other means than thermal energy
    • A61K9/0075—Sprays or powders for inhalation; Aerolised or nebulised preparations generated by other means than thermal energy for inhalation via a dry powder inhaler [DPI], e.g. comprising micronized drug mixed with lactose carrier particles
    • 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
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/007—Pulmonary tract; Aromatherapy
    • A61K9/0073—Sprays or powders for inhalation; Aerolised or nebulised preparations generated by other means than thermal energy
    • A61K9/0078—Sprays or powders for inhalation; Aerolised or nebulised preparations generated by other means than thermal energy for inhalation via a nebulizer such as a jet nebulizer, ultrasonic nebulizer, e.g. in the form of aqueous drug solutions or dispersions
    • 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
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/007—Pulmonary tract; Aromatherapy
    • A61K9/0073—Sprays or powders for inhalation; Aerolised or nebulised preparations generated by other means than thermal energy
    • A61K9/008—Sprays or powders for inhalation; Aerolised or nebulised preparations generated by other means than thermal energy comprising drug dissolved or suspended in liquid propellant for inhalation via a pressurized metered dose inhaler [MDI]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • 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, in particular to (1S, 2S, 3S, 4R)-3-[(lS)-l-acetylamino-2-ethyl-butyl]-4-mercapto-2-hydroxy-cyclo Amyl-1-carboxylic acid (C 15 H 28 N 4 0 4 : peramivir) and derivatives thereof such as pharmaceutically acceptable salts, esters, hydrates or amorphous compounds as neuraminidase inhibitors, A method for treating influenza by direct respiratory administration through a lung target.
  • Influenza is an acute respiratory infection caused by influenza virus. It is highly contagious, has a high incidence, and is prone to outbreaks or pandemics.
  • Hemagglutinin and neuraminidase are two large glycoproteins outside the viral particle. Hemagglutinin is a lectin-mediated viral binding to a target cell and allows the viral genome to enter the target cell, while neuraminidase It involves the release of progeny virus from infected cells by cleavage of mature viral particles bound to sugars. Therefore, these proteins are the targets of antiviral drugs, and they are also antigens that cause antibodies. For example, influenza A virus can be divided into different serotypes according to the response of antibodies to HA and NA, such as H1N1, H2N2, H3N2, etc. The popular one is H7N9.
  • RNA polymerase Since RNA polymerase does not have a proofreading function, an RNA polymerase that relies on the RNA replication viral genome causes an error of approximately every 10,000 bases, which is approximately the length of the influenza virus RNA. Therefore, most newly generated influenza viruses are mutants that cause antigenic drift, and the antigen slowly changes over the surface of the virus over time. If more than one virus simultaneously infects one cell, the genomic separation of the eight isolated fragments on the viral RNA allows for the mixing or recombination of multiple viral RNAs. This produces rapid antigenic changes in the genetic changes caused by the virus, forming a sudden shift from one antigen to another. This sudden and large change causes the virus to infect new host species and quickly overcome protective immunity, becoming a highly pathogenic virus.
  • Neuraminidase is a glycoside hydrolase that cleaves the glycosidic bond of neuraminidase, catalyzes the hydrolysis of sialic acid, assists in the mobility of mucus virus particles through the respiratory tract and the release of host cells from influenza virus. Dye new cells. Because of the relatively deep activation sites, low molecular weight inhibitors can have a number of favorable interactions and accessible methods to competitively occupy the site of neuraminidase, thereby inhibiting viral flow and progeny virus detachment. If the activity of neuraminidase is blocked, the newly produced virus
  • Peramivir C 15 H 28 N 4 0 4 (IS , 2S, 3S, 4R)-3-[(lS)-l-acetylamino-2-ethyl-indenyl]-4-indolyl-2 -Hydroxy-cyclopentyl-1-carboxylic acid is a compound with some sort of oseltamivir, zanamivir structure, Johnson and Johnson have been developed as oral drugs, but due to poor bioavailability BioCryst is now being developed as an intravenous dosage form with an intravenous infusion of 300 or 600 mg ⁇ 30 minutes. The US FDA in 2009 authorized the emergency use of patients with suspected H1N1 infections in hospitals.
  • the peramivir and/or its derivative according to the present invention means a compound such as peramivir and/or a physiologically acceptable pharmaceutically acceptable salt, or ester, hydrate or amorphous substance thereof.
  • a method of administration comprising a formulation of peramivir and/or a derivative thereof, said administration being carried out by inhalation.
  • the present invention proposes that the treatment of respiratory diseases should be carried out by inhalation administration, so that the target can be directly administered to the lungs directly.
  • the target here refers to a partially infected cell in the lung where the influenza virus is located or the virus itself in the lungs.
  • the flu virus is characterized by the passage of the respiratory tract into the lungs of the human body, with the help of hemagglutinin on the surface of the virus.
  • HA hemagglutinin
  • the neuraminidase (NA) on the surface of the virus acts on the receptor of the nuclear protein, binds the nucleoprotein of the virus and the epithelial cells, forms an RNA-type soluble antigen in the nucleus, and exudes to the periphery of the cytoplasm, and copies the progeny.
  • the virus through the action of neuraminidase, excretes epithelial cells in a budding manner.
  • the period of a replication process is 4 to 6 hours, and the discharged virus spreads to nearby cells, which are exhaled by the respiratory tract and spread the virus particles through the air. Therefore, the virus is mainly confined to the respiratory tract, and there is little evidence that the highly pathogenic virus replicates in other organs.
  • the traditional mode of administration such as oral administration, must be absorbed into the bloodstream, enter the blood circulation, and then metabolized by the enzymes in the liver to become active substances, and then reach the lungs of the virus where it is located through the systemic blood circulation.
  • the intravenous injection method has less steps of intestinal absorption, the other steps and oral administration require enzymatic hydrolysis and then blood circulation to the lungs.
  • the present invention selects the direct pulmonary administration of peramivir and/or its derivative by respiratory inhalation, and delivers the active antiviral drug directly to the place where the respiratory target virus gathers, and the drug quickly reaches the infected area to be localized.
  • High concentrations occupy the site of viral neuraminidase, making it impossible for the virus to move and progeny to regenerate and spread, so as to improve the efficiency of treatment and reduce side effects should be the ideal choice.
  • each compound is administered as a pharmaceutical preparation component by inhalation.
  • Micronization can be prepared by any of the techniques well known in the art of pharmacy, such as jet milling, spray drying, spray freeze drying, supercritical fluids.
  • the present invention further provides a pharmaceutical preparation for treating a cold caused by influenza virus on the basis of 2-6 times, preferably 3 times to 4 times per day, the pharmaceutical preparation comprising peramivir or its physiologically acceptable a salt, an ester, a hydrate, or an amorphous substance, and a pharmaceutically acceptable carrier or excipient or adjuvant.
  • the pharmaceutical preparation herein means a form suitable for administration by inhalation.
  • the permeation method of the peramivir and/or its derivative has a maximum particle diameter of not more than 50 ⁇ m, for example, 2 ⁇ m, 4 ⁇ m, 7 ⁇ m, 11 ⁇ m, 15 ⁇ m, 19 ⁇ m, 22 ⁇ m, and 26 ⁇ , 29 ⁇ , 33 ⁇ , 38 ⁇ , 42 ⁇ , 46 ⁇ , 49 ⁇ , etc., preferably not more than 20 ⁇ , further preferably 1-10 ⁇ , particularly preferably 1-5 ⁇ .
  • the active ingredient has a maximum particle size of less than 50 ⁇ , preferably less than 20 ⁇ , preferably in the range of 1-10 ⁇ , more preferably 1-5 ⁇ .
  • Example 3 Inhalation of a 5 mg peramivir metered dose inhaler

Abstract

A method of administering a formulation comprising peramivir and/or derivative thereof; the method can treat colds caused by an influenza virus; and the administration is performed via more than one or two of dry powder, a powder blower, a quantified dosage inhaler or atomizer.

Description

说 明 书 含有帕拉米韦和 /或其衍生物制剂的给药方法 技术领域  Description of the invention for the administration of formulations containing peramivir and/or derivatives thereof
本发明属于药物制剂领域， 尤其涉及 (1S， 2S， 3S， 4R)-3-[(lS)-l-乙酰氨 -2-乙基-丁 基] -4-胍基 -2-羟基-环戊基 -1-羧酸 (C15H28N404： 帕拉米韦） 及其衍生 物如可药用盐， 酯， 水合物或无定形物等化合物作为神经氨酸酶抑制剂， 通过 肺部靶点直接呼吸给药用于治疗流感的方法。 The invention belongs to the field of pharmaceutical preparations, in particular to (1S, 2S, 3S, 4R)-3-[(lS)-l-acetylamino-2-ethyl-butyl]-4-mercapto-2-hydroxy-cyclo Amyl-1-carboxylic acid (C 15 H 28 N 4 0 4 : peramivir) and derivatives thereof such as pharmaceutically acceptable salts, esters, hydrates or amorphous compounds as neuraminidase inhibitors, A method for treating influenza by direct respiratory administration through a lung target.
背景技术 Background technique
众所周知， 流行性感冒 （Influenza) 是由流感病毒引起的一种急性呼吸道 传染病， 传染性强， 发病率高， 容易引起暴发流行或大流行。  It is well known that Influenza is an acute respiratory infection caused by influenza virus. It is highly contagious, has a high incidence, and is prone to outbreaks or pandemics.
据世界卫生组织 WHO的数据 2013年爆发的 H7N9禽流感截止到 5月 30 日已造成 132人感染， 其中 37人死亡， 死亡率高达 28%。 2009年到 2010年流 行的 H1N1猪流感 （Swine Flu) 得到实验室证实的案例超过 214个国家和地区 遭到感染， 导致超过 18， 138 人死亡。 1957 年爆发的亚洲流感甲型 H2N2 (Asian Flu) 和 1967年爆发的香港流感甲型 H3N2 (Hong Kong Flu) 造成约 4 百万人死亡。 1918年到 1919年流行的西班牙流感 H1N1亚型（Spanish Flu)造 成约 5千万到 1亿人死亡。 WHO估计全世界每年的季节性流行流感造成约 3 百万到 5百万严重病例， 约 25万到 50万死亡。 除此之外， 造成的经济损失也 相当严重， 如仅在美国每年的流感造成的费用超过 100亿美元， 并估计未来如 有大流行可能会导致直接或间接超过几千亿美元的费用。 一项研究估计， 如果 今天出现了类似 1918年毒力菌株的流感， 可以造成死亡人数在 5千万到 8千万 之间。  According to the World Health Organization's WHO data, the outbreak of H7N9 avian influenza in 2013 has caused 132 infections as of May 30, of which 37 were fatal and the mortality rate was as high as 28%. The H1N1 swine flu (Swine Flu), which was published between 2009 and 2010, was confirmed by laboratories in more than 214 countries and regions, resulting in more than 18,138 deaths. The Asian flu type H2N2 (Asian Flu) that broke out in 1957 and the Hong Kong flu type H3N2 (Hong Kong Flu) that broke out in 1967 caused about 4 million deaths. The Spanish flu H1N1 subtype (Spanish Flu), which was popular between 1918 and 1919, caused about 50 to 100 million deaths. The WHO estimates that the annual seasonal pandemic worldwide causes approximately 3 to 5 million serious cases, with approximately 250,000 to 500,000 deaths. In addition, the economic losses are also quite serious. For example, the annual flu caused by the US alone exceeds $10 billion, and it is estimated that a pandemic in the future may result in direct or indirect costs of several hundred billion dollars. A study estimates that if there is a flu similar to the 1918 virulence strain today, the number of deaths can range from 50 to 80 million.
突发性流感之所以造成很大危害， 在于流感病毒易于变异。 流感病毒系正 粘病毒科的 RNA病毒， 感染鸟类和哺乳类动物。 流感病毒有甲， 乙， 丙三 种， 其组成基本类似， 由两种糖蛋白组成病毒包膜包裹核心芯， 核心芯含有 RNA基因组和其它病毒蛋白保护 RNA。 通常基因组含有 7到 8个负链 RNA片 断， 每一个含有一到 2个基因， 用于为基因产品 （蛋白） 编码， 例如甲型流感 病毒在 8 个 RNA 片断上含有 11 个基因， 编码 11 种蛋白， 如血凝素 hemagglutinin ( HA )， 神经氨酸酉每 neuraminidase ( NA )， 基质蛋白 matrix protein (M)和离子通道蛋白 Ion Channel (M2)等。 血凝素和神经氨酸酶是病毒颗粒外 部的两个大的糖蛋白， 血凝素是凝集素介导病毒结合到靶点细胞并使病毒基因 组进入到靶点细胞内， 而神经氨酸酶涉及到通过裂解与糖结合的成熟病毒颗 粒， 从感染细胞释放子代病毒。 因而这些蛋白是抗病毒药物的目标， 它们也是 引起抗体的抗原， 如甲型流感病毒根据抗体对 HA和 NA的应答响应又可分为 不同的血清型， 如 H1N1， H2N2, H3N2等等， 最新流行的是 H7N9。 The serious harm caused by sudden influenza is that the influenza virus is prone to mutation. Influenza virus RNA virus of the genus Visavirus, infecting birds and mammals. There are three kinds of influenza viruses: A, B, and C. The composition is basically similar. The core envelope is composed of two glycoproteins, and the core core contains RNA genome and other viral proteins to protect RNA. Usually the genome contains 7 to 8 negative-strand RNA fragments, each containing one or two genes, which are used to encode gene products (proteins). For example, influenza A virus contains 11 genes on 8 RNA fragments, encoding 11 species. Proteins such as hemagglutinin (HA), neuraminidase per neuraminidase (NA), matrix protein matrix protein (M) and ion channel protein Ion Channel (M2). Hemagglutinin and neuraminidase are two large glycoproteins outside the viral particle. Hemagglutinin is a lectin-mediated viral binding to a target cell and allows the viral genome to enter the target cell, while neuraminidase It involves the release of progeny virus from infected cells by cleavage of mature viral particles bound to sugars. Therefore, these proteins are the targets of antiviral drugs, and they are also antigens that cause antibodies. For example, influenza A virus can be divided into different serotypes according to the response of antibodies to HA and NA, such as H1N1, H2N2, H3N2, etc. The popular one is H7N9.
由于 RNA聚合酶不存在校对功能， 依赖 RNA复制病毒基因组的 RNA聚 合酶大约每 1万个碱基造成一个错误， 这大约是流感病毒 RNA的长度。 因此， 多数新产生的流感病毒是突变体， 造成抗原飘移， 随着时间推移抗原在病毒表 面缓慢变化。 如果超过一种以上的病毒同时感染了一个细胞， 病毒 RNA上的 8 个分离片段的基因组分离容许混合或重组多个病毒 RNA。 这样在病毒遗传导 致的快速变化产生抗原漂移， 形成从一个抗原到另一个抗原的突然转变。 这种 突然大的改变使得病毒感染新的宿主种类并且迅速克服保护性免疫， 成为高致 病性病毒。 这是突发性致命流感出现的重要原因。 流感基因易于在不同品种之 间交叉重组， 因而形成新的致命病毒， 如 2009 年的大流行， 从来自美国病人 分离出的病毒含有四种不同流感病毒， 北美猪流感， 北美禽流感， 人流感以及 典型的在亚洲和欧洲猪流感病毒。 这一新毒株的出现是由于在所有四个不同Since RNA polymerase does not have a proofreading function, an RNA polymerase that relies on the RNA replication viral genome causes an error of approximately every 10,000 bases, which is approximately the length of the influenza virus RNA. Therefore, most newly generated influenza viruses are mutants that cause antigenic drift, and the antigen slowly changes over the surface of the virus over time. If more than one virus simultaneously infects one cell, the genomic separation of the eight isolated fragments on the viral RNA allows for the mixing or recombination of multiple viral RNAs. This produces rapid antigenic changes in the genetic changes caused by the virus, forming a sudden shift from one antigen to another. This sudden and large change causes the virus to infect new host species and quickly overcome protective immunity, becoming a highly pathogenic virus. This is an important cause of the sudden onset of deadly flu. Influenza genes are easily cross-recombined between different breeds, resulting in new deadly viruses, such as the 2009 pandemic. Viruses isolated from American patients contain four different influenza viruses, North American swine flu, North American avian flu, human flu as well as Typical swine flu viruses in Asia and Europe. The emergence of this new strain is due to all four different
H1N1亚型菌株的人流感和猪流感基因重组的结果。 Results of human influenza and swine influenza gene recombination of the H1N1 subtype strain.
疫苗防治由 WHO推荐作为高危群体， 如儿童， 老年人， 健康护理工作人 员， 以及由慢性疾病诸如哮喘， 糖尿病， 心脏疾病或者免疫损害的病人的首选 防治手段。 疫苗生产通常需要根据预期的菌株来生产。 疫苗只能选择有限几 种， 不可能包括所有的菌株。 然而如上所述由于流感病毒血清型众多， 一旦流 感病毒疫苗株和流行株的抗原性不匹配， 就会导致疫苗对新的病毒失效， 无法 提供相应的保护。 一般疫苗保护不超过一年。 更为严重的是由于病毒的高变异 性， 流感病毒变异的速度很快， 疫苗研发的速度落后于病毒变异的速度， 新的 流行株出现后， 发生新的突发流感或者未预测到的流感病毒菌株爆发时， 其对 应疫苗的制备及生产至少需要 6个月的时间来满足要求， 造成疫苗制备一直处 于被动状态， 故无论传统灭活疫苗， 还是基因工程疫苗、 核酸疫苗等新型疫苗 都无法对所有类型的流感病毒提供交叉保护。 何况疫苗从注射到起作用需要两 周的时间， 期间可能已经遭到感染。 因此化学药物治疗仍是必不可缺的防线。  Vaccine control is recommended by WHO as a high-risk group, such as children, the elderly, health care workers, and the preferred means of prevention for patients with chronic diseases such as asthma, diabetes, heart disease or immune damage. Vaccine production usually requires production according to the intended strain. There are only a limited number of vaccines to choose from, and it is not possible to include all strains. However, as described above, due to the large number of influenza virus serotypes, once the antigenicity of the influenza virus vaccine strain and the epidemic strain does not match, the vaccine will fail the new virus and will not provide corresponding protection. General vaccine protection does not exceed one year. More serious is the high variability of the virus, the speed of influenza virus mutation is very fast, the speed of vaccine development lags behind the speed of virus mutation. After the emergence of new epidemic strains, new flu or unpredicted flu occurs. When a virus strain breaks out, it takes at least 6 months for the preparation and production of the corresponding vaccine to meet the requirements, resulting in the vaccine preparation being passive. Therefore, no matter whether the traditional inactivated vaccine or the new vaccine such as genetic engineering vaccine or nucleic acid vaccine can be used, Cross protection is provided for all types of influenza viruses. It takes two weeks for the vaccine to go from injection to function, and it may have been infected during the period. Therefore, chemical drug treatment is still an indispensable line of defense.
因为流感是由病毒造成的， 因此抗生素对感染没有效， 除非是继发性感染 如细菌性肺炎。 主要的治疗应是抗病毒治疗。 目前主要有两类抗病毒药， M2 蛋白抑制剂 （金刚烷衍生物） 和神经氨酸酶抑制剂 （奥司他韦， 扎那米韦和帕 拉米韦） 。 M2蛋白抑制剂（金刚烷和金刚乙烷）通过阻断病毒的离子通道来防 止病毒感染细胞， 这对甲型流感有效， 但对乙型病毒无效因为缺乏 M2药物的 靶标。  Because the flu is caused by a virus, antibiotics are not effective for infection unless it is a secondary infection such as bacterial pneumonia. The main treatment should be antiviral therapy. There are currently two main classes of antiviral drugs, M2 protein inhibitors (adamantan derivatives) and neuraminidase inhibitors (oseltamivir, zanamivir and peramivir). M2 protein inhibitors (adamantane and adamantane) prevent viral infection of cells by blocking the ion channel of the virus, which is effective against influenza A, but is ineffective against type B because of the lack of targets for M2 drugs.
神经氨酸酶是糖苷水解酶， 切割神经氨糖酸的糖苷键， 催化唾液酸水解， 协助在通过呼吸道粘液病毒颗粒的流动性和流感病毒的子代脱离宿主细胞去感 染新的细胞。 因为相对较深的活化位点， 低分子量的抑制剂可以有多种有利的 相互作用和易接近的方法竞争性的占据神经氨酸酶的位点， 从而达到抑制病毒 流动和子代病毒脱离的作用， 如果神经氨酸酶的活性被阻断， 新产生的病毒 |( 会仍然绑定在原来的宿主细胞上， 从而防止病毒的复制。 所以神经氨酸酶抑帝 剂成为目前抗病毒首选。 Neuraminidase is a glycoside hydrolase that cleaves the glycosidic bond of neuraminidase, catalyzes the hydrolysis of sialic acid, assists in the mobility of mucus virus particles through the respiratory tract and the release of host cells from influenza virus. Dye new cells. Because of the relatively deep activation sites, low molecular weight inhibitors can have a number of favorable interactions and accessible methods to competitively occupy the site of neuraminidase, thereby inhibiting viral flow and progeny virus detachment. If the activity of neuraminidase is blocked, the newly produced virus | will still bind to the original host cell, thus preventing the virus from replicating. Therefore, the neuraminidase inhibitor is the current antiviral first choice.
目前常用的神经氨酸酶抑制剂有奥司他韦和扎那米韦， 均已经上市即罗 的 Tamiflu (达菲） 和 GSK的 Relenza (乐感清） 。 然而二者也有一定局限性。 如奥司他韦是前体药， 本身没有效果， 需要经肝脏代谢水解成其活性代谢产^ -奥司他韦的自由羧酸盐才起作用。 常有严重副作用报道， 如中毒性表皮坏^ 松解症， 心律失常， 癫痫， 神志不清， 加重糖尿病， 出血性结肠炎。 扎那米 也存在问题， 其生物利用度低， 为 2%， 其中最多 15%的剂量被吸收并从尿^ ***。 更为重要的是由于流感病毒基因易变， 单一品种大量使用会造成新的而 药病毒菌株。  The currently used neuraminidase inhibitors are oseltamivir and zanamivir, both of which have been marketed as Tamiflu (Duffy) and GSK's Relenza (Leganqing). However, the two also have certain limitations. For example, oseltamivir is a prodrug that has no effect in itself and requires a free carboxylate that is metabolized by the liver to its active metabolic product, oseltamivir. There are often reports of serious side effects, such as toxic epidermal dysfunction, arrhythmia, epilepsy, unconsciousness, aggravation of diabetes, and hemorrhagic colitis. Zanami is also problematic, with a low bioavailability of 2%, with up to 15% of the dose being absorbed and excreted from the urine. More importantly, due to the variability of influenza virus genes, the large-scale use of a single variety will result in new strains of drug viruses.
帕拉米韦 C15H28N404 : (IS , 2S， 3S， 4R)-3-[(lS)-l-乙酰氨 -2-乙基 -Ί 基] -4-胍基 -2-羟基-环戊基 -1-羧酸是一种与奥司他韦， 扎那米韦结构有某种类化 的化合物， Johnson and Johnson 曾作为口服药研发， 但因生物利用度差而 ¾ 弃 ， BioCryst现在作为静脉注射剂型在开发 ， 其用药量为 300或 600毫克^ 30分钟静脉滴注。 美国 FDA 2009年曾授权作为在医院治疗疑似 H1N1感染 病人紧急使用。 已有报道帕拉米韦比奥司他韦， 扎那米韦结构在体外试验更 效。 即便低剂量时也有效。 2011年的一项研究报道亚洲出现的猪流感的新变 已对罗氏的达菲和 GSK 的乐感清产生某些耐药性， 而对帕拉米韦的敏感度 2 有显著减少。 关于帕拉米韦已有专利报道， 主要是帕拉米韦的合成方法， 以及静脉给药 的配方。 如 WO 1999033781A1， WO 2009021404A1， CN 1986521A , CN 101538228A, CN 102372657 A, WO 2012145932 Al , CN 102633686 A, CN 102584637A, WO 2009129305 A2, WO 2012145932 Al , CN 101314579A, US 2004062801 Al , CN 102058522A。 然而静脉滴注存在很大问题， 即只能在医院 进行， 病人无法自行服药， 且经济费用高， 更为重要的是用药剂量大， 一次滴 注要 600mg， 用时 30分钟。 而达菲的剂量是口服 75mg， 乐感清的剂量更小为 5mg。 帕拉米韦用药已有副作用报道， 腹泻， 恶心， 呕吐， 白细胞减少。 尤其 对孕妇大剂量使用是否有害是未知数。 Peramivir C 15 H 28 N 4 0 4 : (IS , 2S, 3S, 4R)-3-[(lS)-l-acetylamino-2-ethyl-indenyl]-4-indolyl-2 -Hydroxy-cyclopentyl-1-carboxylic acid is a compound with some sort of oseltamivir, zanamivir structure, Johnson and Johnson have been developed as oral drugs, but due to poor bioavailability BioCryst is now being developed as an intravenous dosage form with an intravenous infusion of 300 or 600 mg^30 minutes. The US FDA in 2009 authorized the emergency use of patients with suspected H1N1 infections in hospitals. It has been reported that peramivir, zanamivir, is more effective in vitro. It is effective even at low doses. A 2011 study reported that new changes in swine flu in Asia have produced some resistance to Roche's Tamiflu and GSK's sensitization, while there is a significant reduction in sensitivity to peramivir. There are patent reports on peramivir, mainly synthetic methods of peramivir, and formulations for intravenous administration. For example, WO 1999033781 A1, WO 2009021404A1, CN 1986521A, CN 101538228A, CN 102372657 A, WO 2012145932 Al, CN 102633686 A, CN 102584637A, WO 2009129305 A2, WO 2012145932 Al, CN 101314579A, US 2004062801 Al, CN 102058522A. However, there is a big problem with intravenous drip, that is, it can only be carried out in a hospital. The patient cannot take the medicine by himself, and the economic cost is high. More importantly, the dosage is large, and the infusion is 600 mg for 30 minutes. The dose of Tamiflu is 75 mg orally, and the dose of Leganqing is 5 mg. There are side effects reported in the use of peramivir, diarrhea, nausea, vomiting, and leukopenia. It is unclear whether it is harmful to the use of large doses in pregnant women.
因此需要研发新的更为经济有效方便， 无须到医院， 受感染病人自己可以 服用， 且低毒的给药途径。 然而因为遇到极大困难帕拉米韦的口服剂型已经停 研， 连较为方便的肌肉注射剂型都作不到， 目前只有静脉滴注在做临床研究。 发明内容  Therefore, it is necessary to develop new and more economical and convenient, without having to go to the hospital, the infected patient can take it himself, and the drug delivery route is low. However, because of the great difficulty encountered, the oral dosage form of peramivir has been discontinued, and even more convenient intramuscular injections are not available. Currently, only intravenous drip is used for clinical research. Summary of the invention
针对服用帕拉米韦遇到的问题， 本发明提供了一种含帕拉米韦和 /或其衍 生物 （既可以是帕拉米韦或其衍生物单独使用， 也可以帕拉米韦与其衍生物混 合使用） 制剂的吸入给药方法， 用于治疗流行性感冒病毒引起的感冒。 本发明 还提供了利用帕拉米韦和 /或其衍生物制备可吸入药物的配方， 从而给出了一 种用于治疗由流行性感冒病毒引起的危重病人对其他药物如奥司他韦， 扎那米 韦产生耐药性的情况下的一种替代方案。  In view of the problems encountered with the administration of peramivir, the present invention provides a peramivir-containing and/or derivative thereof (either parimite or a derivative thereof alone or in combination with peramivir A mixture of derivatives is used for inhalation administration of a preparation for treating a cold caused by an influenza virus. The present invention also provides a formulation for the preparation of an inhalable drug using peramivir and/or a derivative thereof, thereby providing a method for treating a critically ill patient caused by an influenza virus to other drugs such as oseltamivir. An alternative to the case where zanamivir produces resistance.
本发明提供的帕拉米韦和 /或其衍生物给药方法可减少对单一品种药物如 奥司他韦， 扎那米韦的依赖， 避免单一品种大量使用产生新的耐药病毒菌株； 其次为帕拉米韦和 /或其衍生物提供一种比静脉滴注射更为简单方便经济的给 药方法； 更为重要的是提供一种药物剂量小， 副作用少， 起效快的方法。 The method for administering paramivir and/or its derivative provided by the invention can reduce the dependence on a single variety of drugs such as oseltamivir and zanamivir, and avoid the use of a single variety to produce a new strain of resistant virus; Providing a combination of peramivir and/or its derivatives is simpler, more convenient and more economical than intravenous drip injection The method of medicine; more importantly, it provides a method of small dose, less side effects and quick onset.
本发明所述的帕拉米韦和 /或其衍生物是指帕拉米韦和 /或其生理上可接受 的药用盐， 或酯， 水合物或无定形物等化合物。  The peramivir and/or its derivative according to the present invention means a compound such as peramivir and/or a physiologically acceptable pharmaceutically acceptable salt, or ester, hydrate or amorphous substance thereof.
为达此目的， 本发明采用如下技术方案：  To achieve this, the present invention adopts the following technical solutions:
含帕拉米韦和 /或其衍生物制剂的给药方法， 所述的给药通过吸入进行。 本发明提出治疗呼吸***疾病要利用吸入给药方式进行， 做到靶点直接给 药， 直接作用于肺部。 这里靶点指的是流感病毒所在的肺部局部被感染的细胞 或在肺部的病毒本身。  A method of administration comprising a formulation of peramivir and/or a derivative thereof, said administration being carried out by inhalation. The present invention proposes that the treatment of respiratory diseases should be carried out by inhalation administration, so that the target can be directly administered to the lungs directly. The target here refers to a partially infected cell in the lung where the influenza virus is located or the virus itself in the lungs.
本发明提供的吸入给药方式相较传统途径给药方式， 可以较高浓度迅速到 达病变部位， 因此起效迅速， 具有直接作用于局部， 所需药物剂量小， 全身吸 收少， 全身不良反应轻的优点。 避免了肝脏的首过效应， 提高药物的生物利用 度， 具有副作用轻微， 方便快捷、 安全可靠的优点。 本发明药物以固体颗粒、 雾滴或溶胶微粒的方式送达肺部病变部位， 因此药物在肺内滞留时间长， 延长 药物作用时间。  The inhaled administration mode provided by the invention can reach the lesion site quickly at a higher concentration than the conventional route of administration, so that the onset effect is rapid, has a direct action on the local part, requires a small dose of the drug, has less systemic absorption, and has less systemic adverse reactions. The advantages. It avoids the first-pass effect of the liver, improves the bioavailability of the drug, and has the advantages of mild side effects, convenience, safety, and reliability. The drug of the present invention is delivered to the lung lesion by solid particles, droplets or sol particles, so that the drug stays in the lung for a long time and prolongs the action time of the drug.
传统给药途径如静脉滴注方法或口服方法， 药物首先要被吸收经过溶解进 入血液， 再经肝脏代谢和血液全身***循环到达肺部， 因此所用剂量要求大。 达菲被报道的副作用很多， 原因就在于活性组分口服后部分经肾脏或肝脏， 有 些被消化 （清除） 如通过尿液排放， 有些通过肝脏肾脏被代谢灭活， 大多数活 性剂量并未到达病毒所在的靶点； 其次药物在肺部靶点的累积是特例而并非规 律， 大部分的药物在全身循环并分布在其它器官释放出毒性例如胃肠道副作 用。  Conventional routes of administration, such as intravenous drip or oral methods, are first absorbed and dissolved into the bloodstream, and then metabolized by the liver and the systemic circulation of the blood to the lungs, so the dosage requirements are large. Tamiflu has been reported to have many side effects, because the active ingredient is partially passed through the kidney or liver after oral administration, some are digested (cleared), such as through the urine, some are metabolized by the liver and kidney, and most active doses are not reached. The target of the virus; Secondly, the accumulation of drugs in the lung target is a special case and not regular. Most drugs are circulating throughout the body and distributed in other organs to release toxicity such as gastrointestinal side effects.
流感病毒的特点是由呼吸道进入人体肺部， 借助病毒表面的血凝素 (HA)， 与呼吸道黏膜上皮细胞表面的相应受体结合， 吸附可宿主的呼吸道上 皮细胞上。 又借助病毒表面的神经氨酸酶（NA)作用于核蛋白的受体， 使病毒 和上皮细胞的核蛋白结合， 在核内组成 RNA型可溶性抗原， 并渗出至胞质周 围， 复制子代病毒， 通过神经氨酸酶作用， 以出芽方式排出上皮细胞。 一个复 制过程的周期为 4〜6h， 排出的病毒扩散至附近细胞， 再由呼吸道呼出， 通过 空气传播病毒微粒。 因此病毒主要局限在呼吸道， 高致病病毒在其它器官复制 的证据很少。 The flu virus is characterized by the passage of the respiratory tract into the lungs of the human body, with the help of hemagglutinin on the surface of the virus. (HA), which binds to the corresponding receptor on the surface of the airway mucosal epithelial cells and adsorbs on the host's respiratory epithelial cells. The neuraminidase (NA) on the surface of the virus acts on the receptor of the nuclear protein, binds the nucleoprotein of the virus and the epithelial cells, forms an RNA-type soluble antigen in the nucleus, and exudes to the periphery of the cytoplasm, and copies the progeny. The virus, through the action of neuraminidase, excretes epithelial cells in a budding manner. The period of a replication process is 4 to 6 hours, and the discharged virus spreads to nearby cells, which are exhaled by the respiratory tract and spread the virus particles through the air. Therefore, the virus is mainly confined to the respiratory tract, and there is little evidence that the highly pathogenic virus replicates in other organs.
而传统给药方式如口服必须经过肠道吸收后， 进入血液循环， 然后再经肝 脏内的酶水解代谢， 成为活性物， 再经全身血液循环到达病毒所在部位肺部， 才能起到作用。 静脉注射方式虽少了肠道吸收这一步骤， 但其余步骤和口服同 样需要经过酶解再经血液循环到达肺部。 根据这一特点， 本发明选用呼吸吸入 途经直接肺部给药帕拉米韦和 /或其衍生物， 输送活性抗病毒药物直接到呼吸 道靶点病毒聚集的地方， 药物快速到达感染区域， 以局部高浓度占据病毒神经 氨酸酶的位点， 使得病毒无法移动和子代再生并传播， 以提高治疗的效率并减 少副作用应该是理想的选择。  The traditional mode of administration, such as oral administration, must be absorbed into the bloodstream, enter the blood circulation, and then metabolized by the enzymes in the liver to become active substances, and then reach the lungs of the virus where it is located through the systemic blood circulation. Although the intravenous injection method has less steps of intestinal absorption, the other steps and oral administration require enzymatic hydrolysis and then blood circulation to the lungs. According to this feature, the present invention selects the direct pulmonary administration of peramivir and/or its derivative by respiratory inhalation, and delivers the active antiviral drug directly to the place where the respiratory target virus gathers, and the drug quickly reaches the infected area to be localized. High concentrations occupy the site of viral neuraminidase, making it impossible for the virus to move and progeny to regenerate and spread, so as to improve the efficiency of treatment and reduce side effects should be the ideal choice.
作为优选技术方案， 所述的给药方法为每天 2-6次服用含有效量的帕拉米 韦和 /或其衍生物的制剂， 优选每天 3-4次。  As a preferred embodiment, the administration method is a preparation containing an effective amount of peramivir and/or a derivative thereof 2 to 6 times a day, preferably 3-4 times a day.
作为优选技术方案， 所述的给药方法， 所述有效量为每天 5-300mg， 例如 为 6mg、 9mg、 12mg、 16mg、 19mg、 24mg、 28mg、 33mg、 37mg、 40mg、 44mg、 49mg、 60mg、 80mg、 100mg、 130mg、 160mg、 190mg、 240mg、 270mg、 295mg等。  According to a preferred embodiment, the effective amount is 5 to 300 mg per day, for example, 6 mg, 9 mg, 12 mg, 16 mg, 19 mg, 24 mg, 28 mg, 33 mg, 37 mg, 40 mg, 44 mg, 49 mg, 60 mg, 80 mg, 100 mg, 130 mg, 160 mg, 190 mg, 240 mg, 270 mg, 295 mg, and the like.
作为优选技术方案， 所述的给药方法， 每次剂量吸入由 1-4次吸入完成。 作为优选技术方案， 本发明所述的给药方法， 所述给药是通过干粉吸入器As a preferred technical solution, the administration method is completed by one to four inhalations per dose inhalation. As a preferred technical solution, the administration method according to the present invention, the administration is by a dry powder inhaler
(Dry Powder Inhaler)或喷粉器（Insufflator)、 定量剂量吸入器 (Metered Dose Inhaler) 或雾化器 (Nebulizer)中的 1种或两种以上的方式完成。 (Dry Powder Inhaler) or one or more of the Insufflator, Metered Dose Inhaler, or Nebulizer.
本发明所需要的帕拉米韦或其生理上可接受的盐， 酯， 水合物或无定形物 的量， 当然需要随其形式， 所治疗的主体， 疾病严重的程度， 所需要达到的治 疗效果， 所用呼吸给药具体途径 （如干粉吸入器， 喷粉器、 定量剂量吸入器， 或雾化器） 来决定。 本发明对一个成年人的剂量可通过吸入给药为每天从 5mg-300mg, 适宜每天 10mg-150mg， 更合适的 15mg-60mg。 本发明， 优选一 个成年人给药吸入帕拉米韦和 /或其衍生物 30mg的剂量， 可任选帕拉米韦或其 可药用盐， 酯， 水合物或无定形物的形式， 优选帕拉米韦。 本发明的每日总剂 量可以分 2-6次， 优选 3次到 4次吸入， 每次用吸入器吸入 1吸， 例如干粉吸 入器或计量吸入器或雾化器， 或者多于 1吸， 如 2， 3， 4吸或 "抽吸" 。  The amount of peramivir or a physiologically acceptable salt, ester, hydrate or amorphous substance required by the present invention, of course, depends on the form, the subject being treated, the severity of the disease, and the desired treatment. The effect is determined by the specific route of administration of the breath (eg dry powder inhaler, duster, metered dose inhaler, or nebulizer). The dose to an adult of the present invention can be administered by inhalation from 5 mg to 300 mg per day, suitably from 10 mg to 150 mg per day, more suitably from 15 mg to 60 mg. In the present invention, it is preferred that an adult administered a dose of 30 mg of inhaled peramivir and/or a derivative thereof, optionally in the form of peramivir or a pharmaceutically acceptable salt, ester, hydrate or amorphous form thereof, preferably Paramivir. The total daily dose of the present invention may be divided into 2-6 times, preferably 3 to 4 inhalations, each time inhaling 1 inhalation with an inhaler, such as a dry powder inhaler or metered dose inhaler or nebulizer, or more than 1 inhalation, Such as 2, 3, 4 suction or "pumping".
本发明利用呼吸给药方式通过吸入器将含帕拉米韦和 /或其衍生物的药物 和溶剂散成雾粒或微粒借助于吸气动作吸入药物， 沉降在各级支气管及肺泡 内， 而达到抑制并杀死流感病毒的一种方法。 肺部的吸收表面积大， 成人约有 3、 4亿个肺泡， 总面积可达 70-100 m2。 肺部毛细血管网丰富， 肺部的血流量 大， 高达 5000ml/min， 便于吸入药物的吸收。 药物从肺泡进入血液方便， 肺泡 与其周围的毛细血管上皮之间的间隔仅为 0.5μηι， 而小肠黏膜微绒毛入血的距 离约为 40μηι， 皮肤表面到达皮下毛细血管的距离为 100μηι。 肺部上皮细胞层 薄， 所有这些利于药物被快速吸收， 同时肺部化学降解和酶活性较低， 因而药 物被破坏的程度小。 The present invention utilizes a respiratory administration method to disperse a drug and a solvent containing peramivir and/or a derivative thereof into a mist or a microparticle by inhalation, and inhale the drug by an inhalation action, and settle in each of the bronchus and the alveoli. A way to suppress and kill the flu virus. The absorption surface area of the lungs is large, and there are about 300 to 400 million alveoli in adults, with a total area of 70-100 m 2 . The pulmonary capillary network is abundant, and the blood flow in the lungs is large, up to 5000 ml/min, which is convenient for absorption of inhaled drugs. The drug is convenient to enter the blood from the alveoli, and the interval between the alveoli and the surrounding capillary epithelium is only 0.5 μηι, while the small intestine mucosal microvilli is about 40 μηι, and the skin surface reaches the subcutaneous capillaries at a distance of 100 μm. The epithelial cell layer of the lungs is thin, all of which facilitate the rapid absorption of the drug, while the chemical degradation of the lungs and the enzymatic activity are low, so that the degree of drug destruction is small.
本发明虽然可以用帕拉米韦或其生理上可接受的盐， 酯， 水合物， 或无定 形物作为原药， 经加工成微粉后直接吸入给药， 优选的是以每一种化合物作为 一种药物制剂组分吸入给药。 微粉化可以用药学领域中公知的任何一种技术方 法制备， 例如气流粉碎， 喷雾干燥， 喷雾冷冻干燥， 超临界流体。 Although the present invention may be used with peramivir or a physiologically acceptable salt, ester, hydrate thereof, or amorphous The form is used as a crude drug, and is directly inhaled after being processed into a fine powder. Preferably, each compound is administered as a pharmaceutical preparation component by inhalation. Micronization can be prepared by any of the techniques well known in the art of pharmacy, such as jet milling, spray drying, spray freeze drying, supercritical fluids.
因此， 本发明进一步提供一种药物制剂， 用于以每日 2-6次， 优选 3次到 4 次的基础上治疗流感病毒引起的感冒， 药物制剂包括帕拉米韦或其生理上可接 受的盐， 酯， 水合物， 或无定形物， 和一种药学上可接受的载体或赋形剂或辅 药。 这里药物制剂是指以一种适合用吸入法给药的形式。  Accordingly, the present invention further provides a pharmaceutical preparation for treating a cold caused by influenza virus on the basis of 2-6 times, preferably 3 times to 4 times per day, the pharmaceutical preparation comprising peramivir or its physiologically acceptable a salt, an ester, a hydrate, or an amorphous substance, and a pharmaceutically acceptable carrier or excipient or adjuvant. The pharmaceutical preparation herein means a form suitable for administration by inhalation.
本发明的吸入制剂包括由各种类型的定量剂量吸入器的加压气溶胶， 雾化 器或充气装置或干粉吸入器产生的微粒粉尘或烟雾。 该制剂可方便地以单位剂 量形式， 利用任何药学领域中公知的一种技术方法制备。 所有的方法都包括将 活性成分与构成一种或多种辅助成分的载体关联成一体的步骤。 一般来说， 制 剂的制备通过把活性成分与液体载体或粉末的固体载体或两者均匀且紧密关联 合成为一体。  Inhalation formulations of the present invention include particulate aerosols or fumes produced by pressurized aerosols, nebulizers or inflators or dry powder inhalers of various types of metered dose inhalers. The formulations are conveniently prepared in unit dosage form using any of the techniques known in the art. All methods include the step of associating the active ingredient with a carrier which constitutes one or more accessory ingredients. In general, the preparation of the preparation is carried out by integrating the active ingredient with a liquid carrier or a solid carrier of the powder or both.
作为优选技术方案， 所述的给药方法， 所述干粉吸入器的吸入剂或喷粉器 的喷出剂含有有效量的帕拉米韦和 /或其衍生物和稀释剂； 该吸入剂可为粉末 状的。  According to a preferred embodiment, the inhalation agent of the dry powder inhaler or the sprayer of the duster contains an effective amount of peramivir and/or a derivative thereof and a diluent; It is in powder form.
干粉吸入剂的成分用于干粉吸入器 （Dry Powder Inhaler ) 或喷粉器 (Insufflator) 给药， 干粉可以载入胶囊和药舱内， 例如明胶胶囊， 或层叠的铝 箔泡罩， 也可用于储库性干粉吸入器。 用于以上吸入器械的配方可以是由帕拉 米韦或其生理上可接受的盐， 酯， 水合物， 或无定形物， 作为原药经加工成微 粉后直接吸入给药， 优选的是， 以每一种帕拉米韦或其生理上可接受的盐， 酯， 水合物， 或无定形物作为一种药物制剂活性成分组分吸入给药。 制剂制备是首先将活性成分微粉化， 从而使得吸入给药后粉末制剂中活性 成分基本上进入肺部， 活性成分的微粉化可以用药学领域中公知的任何一种技 术方法制备， 例如气流粉碎， 喷雾干燥， 喷雾冷冻干燥， 超临界流体。 制备好 的活性组分微粉再与合适的辅料粉末混合成含有适合吸入给药的有一定微结构 的配方， 微结构指的是活性组分颗粒在辅料组分颗粒的恰当附着， 使得在配方 添加入给药载体如胶囊， 泡罩或储库时有很好的流动性， 且活性组分颗粒与辅 料组分颗粒不分离， 而当吸入动作产生后， 活性组分颗粒与辅料易于分离， 这 样活性组分随吸气气流进入并沉降在肺部， 而大的辅料颗粒留在咽喉部。 The ingredients of the dry powder inhaler are used in Dry Powder Inhaler or Insufflator, and the dry powder can be loaded into capsules and capsules, such as gelatin capsules, or laminated aluminum foil blister, or used for storage. Library dry powder inhaler. The formulation for the above inhalation device may be administered directly by inhalation of peramivir or a physiologically acceptable salt, ester, hydrate, or amorphous substance thereof as a crude drug, preferably after inhalation. Each of palamivir or a physiologically acceptable salt, ester, hydrate, or amorphous substance thereof is administered as an active ingredient component of a pharmaceutical preparation. The preparation is prepared by first micronizing the active ingredient so that the active ingredient in the powder preparation substantially enters the lungs after inhalation administration, and the micronization of the active ingredient can be prepared by any technical method known in the pharmaceutical art, such as jet milling. Spray drying, spray freeze drying, supercritical fluid. The prepared active component micropowder is then mixed with a suitable excipient powder to form a formulation having a certain microstructure suitable for inhalation administration. The microstructure refers to the proper attachment of the active component particles to the excipient component particles, so that the formulation is added. It has good fluidity when administered into a carrier such as a capsule, a blister or a reservoir, and the active ingredient particles are not separated from the auxiliary component particles, and when the inhalation action is generated, the active ingredient particles and the auxiliary material are easily separated, so that The active component enters and settles in the lungs with the inspiratory flow, while the large excipient particles remain in the throat.
本发明的干粉吸入剂制备还可以通过将帕拉米韦或其生理上可接受的盐， 酯， 水合物， 或无定形物与辅药赋形剂用药学领域中公知的一种技术方法同时 加工， 例如气流粉碎， 喷雾干燥， 喷雾冷冻干燥， 这样制备的制剂不再需要进 行第二步和辅料的混合， 可直接用于载入胶囊和药舱内， 例如明胶胶囊， 或层 叠的铝箔泡罩， 或直接装入储库性干粉吸入器。 采用这种方法的制备的制剂活 性组分与辅料有机的结合在一起， 吸入给药后， 活性组分与辅料一起进入肺 部， 在肺部沉积。 这种方法制备的干粉药剂颗粒尺寸小于 20μηι， 最好小于 ΙΟμηι, 优选的范围为 1-10μηι， 例如， 大部分在 2-3μηι。  The dry powder inhaler of the present invention can also be prepared by simultaneously administering a peramivir or a physiologically acceptable salt, ester, hydrate, or amorphous substance thereof to adjunctive excipients by a technical method well known in the art of pharmacy. Processing, such as jet milling, spray drying, spray freeze drying, the preparation thus prepared no longer needs to be mixed with the second step and the auxiliary materials, and can be directly used for loading capsules and medicine chambers, such as gelatin capsules, or laminated aluminum foil bubbles. Cover, or directly into a depot dry powder inhaler. The active ingredient of the preparation prepared by this method is organically combined with the excipient, and after inhalation administration, the active ingredient enters the lung together with the excipient and deposits in the lung. The dry powder medicament prepared by this method has a particle size of less than 20 μm, preferably less than ΙΟμηι, preferably in the range of 1-10 μm, for example, mostly at 2-3 μm.
优选地， 所述稀释剂为乳糖、 海藻糖、 淀粉、 木醇糖、 甘露醇、 憎水性氨 基酸如缬氨酸， 亮氨酸， 异亮氨酸， 脯氨酸， 苯丙氨酸， 色氨酸， 蛋氨酸等或 药用润滑剂如硬脂酸镁， 硬脂富马酸钠等中的 1种或 2种以上的混合物。 如为 乳糖或木醇糖或医用润滑剂， 或乳糖和淀粉的粉末混合物， 海藻糖的淀粉混合 物， 或为其中 3、 4、 5或更多种物质的混合。 Preferably, the diluent is lactose, trehalose, starch, xylitol, mannitol, hydrophobic amino acids such as valine, leucine, isoleucine, valine, phenylalanine, color ammonia One or a mixture of two or more of acid, methionine or the like or a pharmaceutically acceptable lubricant such as magnesium stearate, sodium stearyl fumarate or the like. Such as lactose or xylitol sugar or medical lubricant, or a powder mixture of lactose and starch, a starch mixture of trehalose, or a mixture of 3 , 4 , 5 or more thereof.
作为优选技术方案， 所述的给药方法， 所述定量剂量吸入器的吸入剂或所 述雾化器的雾化剂含有效量的帕拉米韦和 /或其衍生物和抛射剂。 其中定量剂 量吸入器的吸入剂或雾化器的雾化剂可为喷雾状的， 水溶液或悬浮液， 或作为 从加压容器中提供的气溶胶。 对于悬浮液气雾剂， 活性成分应被微粉化， 活性 成分的微粉化可以任何药学领域中公知的一种技术方法制备， 例如气流粉碎， 喷雾干燥， 喷雾冷冻干燥， 超临界流体。 As a preferred technical solution, the administration method, the inhalant or the solution of the metered dose inhaler The nebulizer of the nebulizer contains an effective amount of peramivir and/or its derivatives and propellants. The aerosol of the inhalant or nebulizer of the metered dose inhaler may be in the form of a spray, an aqueous solution or suspension, or as an aerosol provided from a pressurized container. For suspension aerosols, the active ingredient should be micronized, and micronization of the active ingredient can be prepared by any of the techniques well known in the art of pharmacy, such as jet milling, spray drying, spray freeze drying, supercritical fluids.
而且雾化剂的非活性组分可以配制含水载剂， 例如酸或碱， 缓冲盐等渗调 节剂或抗微生物剂的加入， 例如乙二胺四乙酸二钠， 氯化钠， 柠檬酸钠， 柠檬 酸， 聚山梨酯 80; 可以在高压釜中， 通过过滤或加热消毒， 或者作为一个非无 菌的产品。 活性成分的微粉化可以任何药学领域中公知的一种技术方法制备， 例如气流粉碎， 喷雾干燥， 喷雾冷冻干燥， 超临界流体。  Furthermore, the inactive component of the atomizing agent may be formulated with an aqueous carrier such as an acid or a base, a buffer salt isotonicity adjusting agent or an antimicrobial agent such as disodium edetate, sodium chloride, sodium citrate, Citric acid, polysorbate 80; can be sterilized by filtration or heat in an autoclave, or as a non-sterile product. Micronization of the active ingredient can be prepared by any of the techniques well known in the art of pharmacy, such as jet milling, spray drying, spray freeze drying, supercritical fluids.
优选地， 所述抛射剂为二氧化碳、 1,1,1,2-四氟乙烷、 1,1,1,2,3,3,3-七氟丙 烷、 单氟三氯甲烷、 二氯二氟甲烷、 氯氟化碳或其衍生物中的 1种或至少 2种 以上的混合物， 或其他任何合适的气体， 优选为氢氟烷烃， 进一步优选为 1,1, 1,2-四氟乙烷。  Preferably, the propellant is carbon dioxide, 1,1,1,2-tetrafluoroethane, 1,1,1,2,3,3,3-heptafluoropropane, monofluorotrichloromethane, dichlorodifluoromethane One or a mixture of at least two or more of chlorofluorocarbons or derivatives thereof, or any other suitable gas, is preferably a hydrofluoroalkane, and more preferably 1,1,1,2-tetrafluoroethane.
作为优选技术方案， 所述的给药方法， 所述定量剂量吸入器的吸入剂还含 有助溶剂和表面活性剂；  In a preferred embodiment, the inhalation agent of the metered dose inhaler further comprises a co-solvent and a surfactant;
优选地， 所述助溶剂为乙醇、 异丙醇或丙二醇中的 1种或 2种以上的混合 物； 优选助溶剂占总剂量的 0.1-15wt%， 例如为 0.5 wt%、 l. l wt%、 1.8 wt%、 3 wt%、 6 wt%、 8 wt%、 10 wt%、 12 wt%、 14 wt%等。  重量百分比,优选为优选为优选为为为为为为为为为为为为为为为为为为为为为为为为为为为为为为为为为为为为为为为为为为为为为为为为为为为为为为为为为为为为为为为为为为为为为为为为为为为为为为为为为为为为为为为为为为1.8 wt%, 3 wt%, 6 wt%, 8 wt%, 10 wt%, 12 wt%, 14 wt%, and the like.
作为优选技术方案， 所述的给药方法， 所述表面活性剂为油酸、 卵磷脂或 司盘 85中的 1种或 2种以上的混合物； 优选基于帕拉米韦和 /或其衍生物的量 表面活性剂的含量为 0.001-0.5wt %， 例如为 0.004 wt %、 0.008 wt %、 0.01 wt %, 0.06 wt %, 0.09 wt %, 0.14 wt %, 0.18 wt %, 0.26 wt %, 0.31 wt %, 0.37 wt %、 0.41 wt %, 0.46 wt %, 0.48 wt %等， 进一步优选 0.01-0. lwt%。 In a preferred embodiment, the surfactant is one or a mixture of two or more of oleic acid, lecithin or Span 85; preferably based on peramivir and/or a derivative thereof The amount of surfactant is 0.001-0.5 wt%, for example 0.004 wt%, 0.008 wt%, 0.01 Wt %, 0.06 wt %, 0.09 wt %, 0.14 wt %, 0.18 wt %, 0.26 wt %, 0.31 wt %, 0.37 wt %, 0.41 wt %, 0.46 wt %, 0.48 wt %, etc., further preferably 0.01-0. Lwt%.
作为优选技术方案， 所述的给药方法， 所述帕拉米韦和 /或其衍生物的最 大颗粒粒径为不大于 50μηι， 例如为 2μηι、 4μηι、 7μηι、 11μηι、 15μηι、 19μηι、 22μιτι、 26μιτι、 29μιτι、 33μιτι、 38μιτι、 42μιτι、 46μιτι、 49μιτι等， 优选为不大于 20μηι， 进一步优选为 1-10μηι， 特别优选为 1-5μηι。 为使得吸入给药后气溶胶 组分中活性成分基本上进入肺部， 活性成分的最大颗粒尺寸小于 50μη， 最好 小于 20μηι， 优选的范围为 1-10μηι， 更优选 1-5μηι。  As a preferred technical solution, the permeation method of the peramivir and/or its derivative has a maximum particle diameter of not more than 50 μm, for example, 2 μm, 4 μm, 7 μm, 11 μm, 15 μm, 19 μm, 22 μm, and 26μιτι, 29μιτι, 33μιτι, 38μιτι, 42μιτι, 46μιτι, 49μιτι, etc., preferably not more than 20μηι, further preferably 1-10μηι, particularly preferably 1-5μηι. In order to allow the active ingredient in the aerosol component to substantially enter the lungs after administration by inhalation, the active ingredient has a maximum particle size of less than 50 μη, preferably less than 20 μη, preferably in the range of 1-10 μηι, more preferably 1-5 μηι.
本文中语 "活性成分" 是指帕拉米韦和 /或其衍生物。 优选的单位剂量制 剂是含有药学上有效剂量的， 如上文所记载的， 或其活性成分的适当的分数。 如在呼吸给药时， 一吸的剂量是有效疗效的一半， 那么每次吸入两吸是必要 本发明的有益效果在于容许剂: 71、. 物直达肺部靶点， 起效快， 肺部药 物局部浓度高， 全身吸收少， 减少了经肝脏首过代谢问题， 副作用轻微， 提高 了药物的生物利用 物以固体微粒、 雾滴或溶胶微粒的形式到达肺部， 在 肺部病毒积聚区域停留时间长， 延长药物作用时间。 危重病人可通过雾化器吸 入， 方便快捷、 安全可靠的优点。  The term "active ingredient" as used herein refers to peramivir and/or its derivatives. Preferred unit dosage formulations are those containing a pharmaceutically effective amount, as described above, or an appropriate fraction of the active ingredient thereof. For example, when breathing is administered, the dose of one suck is half of the effective curative effect, then the inhalation of two breaths is necessary. The beneficial effect of the present invention is that the adjunct: 71, the substance reaches the lung target, the onset is fast, the lungs The local concentration of the drug is high, the systemic absorption is small, the first-pass metabolism problem of the liver is reduced, the side effects are slight, and the bio-utilization of the drug is increased to the lungs in the form of solid particles, droplets or sol particles, and stays in the pulmonary virus accumulation area. Long time, prolong the duration of drug action. Critical patients can be inhaled through the nebulizer, which is convenient, safe and reliable.
具体实 H ^式 Concrete H ^
为便于理解本发明， 本发明列举实施例如下。 本领域技术人员应该明了， 所述实施例仅仅是帮助理解本发明， 不应视为对本发明的具体限制。  In order to facilitate the understanding of the present invention, the present invention is exemplified by the following. It should be understood by those skilled in the art that the present invention is not to be construed as limited.
；施例 1 : 1毫克帕拉米韦定量剂量吸入器的吸入剂  Example 1 : Inhalation of 1 mg of peramivir metered dose inhaler
组分 帕拉米韦 1毫克 Component Peramivir 1 mg
HFA134a 加到 75.0 毫克  HFA134a is added to 75.0 mg
称取微粉化的活性成分加入到铝罐内， 然后从真空容量瓶中加入氢氟烷烃 Weigh the micronized active ingredient into an aluminum can, and then add the hydrofluoroalkane from the vacuum volumetric flask.
(HFA) 134a, 再将计量阀按压就位。 类似的方法可用于实施例 2到 4的配方 中。 (HFA) 134a, then press the metering valve in place. A similar method can be used in the formulations of Examples 2 to 4.
上述的加到 75.0毫克是指加 HFA134a至帕拉米韦和 HFA134a的总重为 75.0 毫克。 下述 "加到" 的意思同此。  The above addition of 75.0 mg means that the total weight of HFA 134a to peramivir and HFA 134a is 75.0 mg. The meaning of "adding" below is the same.
实施例 2: 2毫克帕拉米韦定量剂量吸入器的吸入剂 Example 2: Inhalation of a 2 mg peramivir metered dose inhaler
Figure imgf000014_0001
Figure imgf000014_0001
实施例 3: 5毫克帕拉米韦定量剂量吸入器的吸入剂 Example 3: Inhalation of a 5 mg peramivir metered dose inhaler
Figure imgf000014_0002
Figure imgf000014_0002
实施例 5， 6， 7， 8 的定量剂量吸入器的吸入剂中抛射剂基的总量是 9.6 克， 其中抛射剂基总量是指抛射剂、 活性成分和表面活性剂后的总量。 组分 量 /罐 The total amount of propellant base in the inhaler of the metered dose inhalers of Examples 5, 6, 7, 8 is 9.6 grams, wherein the total amount of propellant base refers to the total amount of the propellant, active ingredient and surfactant. Group weight / can
帕拉米韦 600毫克  Peramivir 600 mg
HFA134a  HFA134a
实施例 6 Example 6
Figure imgf000015_0001
Figure imgf000015_0001
实施例 7 Example 7
面  Face
网  network
Figure imgf000015_0002
Figure imgf000015_0002
实施例 8 Example 8
Figure imgf000015_0003
Figure imgf000015_0003
对于上述实施例 5-8， 活性成分首先被称量在一个普通的铝罐（可容纳 120 剂量以 5毫克计） 。 然后加入乙醇 （和表面活性剂， 如果需要的话） ， 并将该 溶液超声处理 5分钟。 然后安装计量阀轧盖。 然后通过计量阀注入 HFA227或 HFA134a抛射剂。 For the above Examples 5-8, the active ingredient was first weighed in a conventional aluminum can (accommodating 120 doses in 5 mg). Then add ethanol (and surfactant, if needed) and The solution was sonicated for 5 minutes. Then install the metering valve cap. The HFA 227 or HFA 134a propellant is then injected through a metering valve.
实施例 9， 10， 11， 12的干粉吸入器吸入剂的剂量总重是 12 毫克或 25毫 克每胶囊或每仓泡罩。  The total dose of dry powder inhaler inhalers of Examples 9, 10, 11, 12 is 12 mg or 25 mg per capsule or per blister.
实施例 9: 1毫克帕拉米韦干粉吸入器的吸入剂 Example 9: Inhalation of 1 mg of paramivir dry powder inhaler
Figure imgf000016_0001
Figure imgf000016_0001
过程： 活性成分微粉化， 并与稀释剂 （乳糖） 以上面给定的比例混合。 混 合物装入硬胶囊或药舱或铝箔泡罩包装， 然后用相应适合的干粉吸入器服用。 类似的方法可用于实施例 10到 15的配方中。  Procedure: The active ingredient is micronized and mixed with a diluent (lactose) in the ratio given above. The mixture is packed in hard capsules or in a pharmacy or foil blister pack and then taken with a suitable dry powder inhaler. A similar method can be used in the formulations of Examples 10 to 15.
实施例 10: 2毫克帕拉米韦干粉吸入器的吸入剂 Example 10: Inhalation of 2 mg of paramivir dry powder inhaler
Figure imgf000016_0002
Figure imgf000016_0002
实施例 11 : 5毫克帕拉米韦干粉吸入器的吸入剂 Example 11: Inhalation of a 5 mg paramivir dry powder inhaler
Figure imgf000016_0003
Figure imgf000016_0003
实施例 12: 10毫克帕拉米韦干粉吸入器的吸入剂 Example 12: Inhalation of 10 mg of paramivir dry powder inhaler
组分 每舱或每泡罩  Component per compartment or per blister
帕拉米韦 10毫克 1到 12 ：或加到 25 Peramivir 10 mg 1 to 12: or added to 25
实施例 13， 14， 15的干粉吸入器吸入剂的剂量活性成分剂量是 20-30 Example 13, 14, 15 dry powder inhaler inhalation dose of active ingredient dose is 20-30
；胶囊或每仓泡罩， 稀释剂的量以占活性成分计算。 Capsule or per blister, the amount of diluent is calculated as the active ingredient.
；施例 13 : 25毫克帕拉米韦干粉吸入器的吸入剂  Example 13 : 25 mg of peramivir dry powder inhaler for inhalation
Figure imgf000017_0001
Figure imgf000017_0001
过程： 1 : 活性成分微粉化。 2: 活性组分和稀释剂（硬脂酸镁）先混合（可 通过气流粉碎或通过喷雾干燥同时混合） 。 3 : 混合物灌入泡罩。 4: 泡罩放入 干粉吸入器应用。  Process: 1 : Micronization of the active ingredient. 2: The active ingredient and the diluent (magnesium stearate) are mixed first (either by air jet pulverization or by spray drying while mixing). 3 : The mixture is poured into the blister. 4: The blister is placed in a dry powder inhaler application.
实施例 14: 25毫克帕拉米韦干粉吸入器的吸入剂 Example 14: Inhalation of 25 mg of paramivir dry powder inhaler
Figure imgf000017_0002
Figure imgf000017_0002
过程： 1 : 活性成分微粉化。 2: 活性组分和稀释剂 （亮氨酸） 先混合 （可 通过气流粉碎或通过喷雾干燥同时混合） 。 3 : 混合物灌入泡罩。 4: 泡罩放入 干粉吸入器应用。  Process: 1 : Micronization of the active ingredient. 2: The active ingredient and diluent (leucine) are mixed first (either by air jet pulverization or by spray drying while mixing). 3 : The mixture is poured into the blister. 4: The blister is placed in a dry powder inhaler application.
实施例 15 : 20毫克帕拉米韦无定形物干粉吸入器的吸入剂 Example 15: Inhalation of 20 mg of paramivir amorphous dry powder inhaler
组分 量 /泡罩  Component amount / blister
帕拉米韦无定形物 20毫克  Peramivir amorphous 20 mg
海藻糖 5wt%~20wt% (占活性成分的） 通过气流粉碎或通过喷雾干燥同时混合） 。 3 : 混合物灌入泡罩。 4: 泡罩放入 干粉吸入器应用。 Trehalose 5wt%~20wt% (accounting for active ingredients) Mix by air jet or by spray drying). 3 : The mixture is poured into the blister. 4: The blister is placed in a dry powder inhaler application.
实施例 16: 20毫克帕拉米韦无定形物干粉吸入器的吸入剂 Example 16: Inhalation of 20 mg of paramivir amorphous dry powder inhaler
Figure imgf000018_0001
Figure imgf000018_0001
过程： 1 : 活性成分微粉化。 2: 活性组分和稀释剂 （海藻糖、 亮氨酸） 先 混合 （可通过气流粉碎或通过喷雾干燥同时混合） 。 3 : 混合物灌入泡罩。 4: 泡罩放入干粉吸入器应用。  Process: 1 : Micronization of the active ingredient. 2: The active ingredient and diluent (trehalose, leucine) are mixed first (either by air jet pulverization or by spray drying while mixing). 3 : The mixture is poured into the blister. 4: The blister is placed in a dry powder inhaler application.
以上稀释剂也可以是几种成分的相互组合。 稀释剂还包括发明书文中提到 的其他成分。 稀释剂的含量也可相应调整。 本发明选用呼吸吸入途经直接肺部给药帕拉米韦。 FDA授权发布了在成人 一期临床测试的帕拉米韦的药代动力学参数， 给药剂量为 0.5毫克 /公斤到 8毫 克 /公斤数据显示了剂量和暴露参数血浆药物浓度-时间曲线下面积 （AUC ) 和 最大血药浓度 Λ)成线形关系。 对肾功能正常的患者， 以 0.5毫克 /公斤到 8 毫克 /公斤单次剂量或每天两次 4 毫克 /公斤给药半衰期范围为从 7.7 小时至 20.8小时。 消除帕拉米韦的主要途径是通过肾脏。 占总量 90%的帕拉米韦以不 变的形式从肾脏清除。 从 FDA 公开确认的药代动力学数据可以看出该药可以 用于临床治疗， 具有实用性。 The above diluent may also be a combination of several components. The diluent also includes other ingredients mentioned in the invented text. The amount of diluent can also be adjusted accordingly. The invention selects paramivir for direct pulmonary administration through respiratory inhalation. The FDA authorizes the release of the pharmacokinetic parameters of peramivir in the adult phase I clinical trial, with doses ranging from 0.5 mg/kg to 8 mg/kg. Data showing dose and exposure parameters. Plasma drug concentration-time curve area. (AUC) and maximum blood concentration Λ ) in a linear relationship. For patients with normal renal function, the half-life of a single dose of 0.5 mg/kg to 8 mg/kg or twice a day for 4 mg/kg ranges from 7.7 hours to 20.8 hours. The main way to eliminate peramivir is through the kidneys. Peramivir, which accounts for 90% of the total, is cleared from the kidneys in a constant form. It can be seen from the FDA's publicly confirmed pharmacokinetic data that the drug can be used for clinical treatment and has practicality.
体外活性试验验证了帕拉米韦能有效地抑制所有被测试的甲型和乙型流感 病毒的神经氨酸酶， 其半数 （50%) 抑制浓度 （IC50) 对 7株甲型流感神经氨 酸酶为 0.09-1.4 nM对 4株乙型流感神经氨酸酶为 0.09-11 nM，该值相当于或不 低于奥司他韦， 扎那米韦。 体内活性显示即使 0.01mg/kg/天的量也可完全保护 小鼠不至死亡， 而奥司他韦和扎那米韦只能做到部分保护。 体内活性试验证实 了帕拉米韦可有效保护小鼠对香港 H5N1和香港 H9N2致命禽流感的感染， 所 有对照控制组小鼠在感染 H5N1后 4到 9天后死亡， 感染 H9N2流感病毒后 7 到 10天死亡， 而用 0.1mg/kg/天剂量治疗组死亡小鼠的生存天数加倍， 并且存 活率达 70% ( P=0.0002) o 而用 10mg/kg/天的剂量组的小鼠存活率达 100%。 帕 拉米韦在第 6天还可降低肺组织病毒滴度并抑制肺病变， 比奥司他韦作用时间 长。其原因可能在于现场解离研究表明， 在（t1/2>24h)时， 帕拉米韦仍与 N9NA 紧密结合， 而奥司他韦， 扎那米韦在 （t1/2=1.25h) 时已离开该酶。 药效学研究 表明， 单一的帕拉米韦注射在防止致命性 H3N2和 H1N1流感方面相当于口服 奥司他韦 （2-20mg/kg/day) 每天一次 5天 （Q.dx5天） 疗程的疗效。 In vitro activity assays demonstrate that peramivir is effective in inhibiting all tested influenza A and B The viral neuraminidase, half (50%) of its inhibitory concentration (IC50) is 0.09-1.4 nM for 7 strains of influenza A neuraminidase and 0.09-11 nM for 4 strains of influenza B neuraminidase. The value is equivalent to or not lower than oseltamivir, zanamivir. In vivo activity showed that even in the amount of 0.01 mg/kg/day, the mice were completely protected from death, while oseltamivir and zanamivir were only partially protected. In vivo activity assay confirmed that peramivir can effectively protect mice from Hong Kong H5N1 and Hong Kong H9N2 deadly avian influenza infection. All control control mice died 4 to 9 days after infection with H5N1, 7 to 10 after infection with H9N2 influenza virus. Days of death, and the number of days of survival in the dead group treated with 0.1 mg/kg/day was doubled, and the survival rate was 70% (P=0.0002). However, the survival rate of the mice in the dose group of 10 mg/kg/day was up to 100%. On the 6th day, peramivir also reduced lung tissue virus titer and inhibited lung lesions, and it took longer than oseltamivir. The reason may be that on-site dissociation studies show that at (t 1/2 >24h), peramivir is still tightly bound to N9NA, while oseltamivir and zanamivir are at (t 1/2 =1.25h) ) The enzyme has been left. Pharmacodynamic studies have shown that a single peramivir injection is equivalent to oral oseltamivir (2-20 mg/kg/day) in the prevention of lethal H3N2 and H1N1 flu, once daily for 5 days (Q.dx 5 days). Efficacy.
为建立呼吸给药药代动力学药效学和静脉注射给药关系， 以实施例 1 和 9 为例， 本发明参考了 Cooper等通过大鼠试验建立的基于 23种化合物 （代表一 系列各种官能基团和结构） 静脉注射给药和吸入给药定量结构-活性关联模型 quantitative structure-activity relationship (QSAR) model , 石 if究表明口乎吸给药 6微 克 /公斤在肺部的浓度与静脉注射 1毫克 /公斤的初始浓度相当，在 1000〜5000 nM 之间， 而在给药 5和 8小时取样， 呼吸给药肺部药物浓度在 30 nM左右， 高于 静脉注射给药的 10nM的水平。 而呼吸给药 6微克 /公斤在体循环血浆中的浓度 却很低， 初始浓度不到 2nM， 而 5到 6小时后低到小于 0.1 nM。 对于治疗肺部 疾病而言，呼吸给药以 6微克 /公斤的药量取得超过静脉注射 1毫克 /公斤给药量 的效果。 这说明肺部靶点直接呼吸给药帕拉米韦可以达到肺部局部浓度远高于To establish the pharmacokinetic pharmacodynamics and intravenous administration relationship of respiratory administration, taking Examples 1 and 9 as examples, the present invention refers to a compound based on 23 compounds established by Cooper et al. in a rat test (representing a series of various Functional group and structure) Quantitative structure-activity relationship (QSAR) model for intravenous administration and inhalation administration, and the concentration of 6 μg/kg in the lungs and veins The initial concentration of 1 mg/kg was equivalent, between 1000 and 5000 nM, and at 5 and 8 hours of administration, the concentration of pulmonary drug in respiratory administration was around 30 nM, which was higher than the level of 10 nM administered intravenously. . The concentration of 6 μg/kg of respiratory administration in systemic plasma was very low, with an initial concentration of less than 2 nM and a low to less than 0.1 nM after 5 to 6 hours. For the treatment of lung diseases, respiratory administration takes more than 1 mg/kg of intravenous injection at a dose of 6 μg/kg. Effect. This indicates that the direct target administration of peramivir to the lung target can reach a local concentration in the lungs that is much higher than
IC90而体循环浓度可以很低。因此根据帕拉米韦药代动力学和药效学研究结果， 呼吸吸入帕拉米韦会更有效的防治流感病毒同时极大降低肝脏血液中经酶代谢 产生的毒副作用。 IC90 and systemic circulation concentrations can be very low. Therefore, according to the results of the pharmacokinetics and pharmacodynamics of peramivir, respiratory inhalation of peramivir is more effective in preventing and treating influenza virus while greatly reducing the side effects of enzyme metabolism in the liver.
本发明创造性的提出生物利用度应该根据靶点器官需药局部浓度来计算。 因为固体口服药物占到总药物品种的 70%以上， 因此主流的观点计算生物利用 度主要是计算口服相同药物剂量后体循环所能达到浓度， 药代动力学虽对建立 体循环吸收有用， 但不能代替局部有效浓度， 即靶点药物浓度对疗效更为重 要。 增加靶点给药浓度， 减少体循环浓度应该成为有效提高疗效而减少严重副 作用的未来药物发展方向。 药效学显示， 治疗效果与局部浓度关系直接相关而 与体循环浓度没有必然联系。  The inventiveness of the present invention suggests that the bioavailability should be calculated based on the local concentration of the target organ. Because solid oral drugs account for more than 70% of the total drug varieties, the mainstream view of calculating bioavailability is mainly to calculate the concentration of systemic circulation after oral administration of the same drug dose. Pharmacokinetics is useful for establishing systemic absorption, but it cannot replace The local effective concentration, ie the target drug concentration, is more important for efficacy. Increasing the concentration of target administration and reducing the circulating concentration should be the future direction of drug development to effectively improve the efficacy and reduce serious side effects. Pharmacodynamics showed that the therapeutic effect was directly related to the local concentration and was not necessarily related to the systemic circulation concentration.
申请人声明， 本发明通过上述实施例来说明本发明的详细工艺流程， 但本 发明并不局限于上述详细工艺流程， 即不意味着本发明必须依赖上述详细工艺 流程才能实施。 所属技术领域的技术人员应该明了， 对本发明的任何改进， 对 本发明产品各原料的等效替换及辅助成分的添加、 具体方式的选择等， 均落在 本发明的保护范围和公开范围之内。  The Applicant claims that the detailed process flow of the present invention is illustrated by the above embodiments, but the present invention is not limited to the above detailed process flow, that is, it does not mean that the present invention must be implemented by the above detailed process flow. It will be apparent to those skilled in the art that any modifications of the present invention, equivalent substitution of the various materials of the products of the present invention, addition of auxiliary components, selection of specific means, etc., are all within the scope of the present invention.

Claims

权 利 要 求 书 claims
1、 含帕拉米韦和 /或其衍生物制剂的给药方法， 其特征在于， 所述的给药 通过吸入进行。 1. The method of administration of preparations containing peramivir and/or its derivatives, characterized in that the administration is carried out by inhalation.
2、 根据权利要求 1所述的给药方法， 其特征在于， 所述方法为每天 2-6次 服用含有效量的帕拉米韦和 /或其衍生物的制剂。 2. The administration method according to claim 1, characterized in that the method is to take a preparation containing an effective amount of peramivir and/or its derivatives 2-6 times a day.
3、 根据权利要求 2所述的给药方法， 其特征在于， 所述方法为每天 3-4次 服用含有效量的帕拉米韦和 /或其衍生物的制剂。 3. The administration method according to claim 2, characterized in that the method is to take a preparation containing an effective amount of peramivir and/or its derivatives 3-4 times a day.
4、 根据权利要求 2或 3所述的给药方法， 其特征在于， 所述有效量为每天 5-300mg。 4. The administration method according to claim 2 or 3, characterized in that the effective dose is 5-300 mg per day.
5、 根据权利要求 2或 3所述的给药方法， 其特征在于， 每次剂量吸入由 1-4次吸入完成。 5. The administration method according to claim 2 or 3, characterized in that each dose of inhalation is completed by 1-4 inhalations.
6、 根据权利要求 1-3任一项所述的给药方法， 其特征在于， 所述给药是通 过干粉、 喷粉器、 定量剂量吸入器或雾化器中的 1种或两种以上的方式完成。 6. The method of administration according to any one of claims 1 to 3, characterized in that the administration is through one or more of dry powder, duster, metered dose inhaler or atomizer. way to complete.
7、 根据权利要求 6所述的给药方法， 其特征在于， 所述干粉吸入器的吸 入剂或喷粉器的喷出剂含有有效量的帕拉米韦和 /或其衍生物和稀释剂。 7. The method of administration according to claim 6, wherein the inhalant of the dry powder inhaler or the spray agent of the duster contains an effective amount of peramivir and/or its derivatives and diluent. .
8、根据权利要求 7所述的给药方法， 其特征在于， 所述稀释剂为乳糖、 海 藻糖、 淀粉、 木醇糖、 甘露醇、 憎水性氨基酸或药用润滑剂中的 1种或 2种以 上的混合物。 8. The method of administration according to claim 7, wherein the diluent is one or two of lactose, trehalose, starch, xyloose, mannitol, hydrophobic amino acids or pharmaceutical lubricants. A mixture of more than one species.
9、 根据权利要求 6所述的给药方法， 其特征在于， 所述定量剂量吸入器 的吸入剂或所述雾化器的雾化剂含有效量的帕拉米韦和 /或其衍生物和抛射剂。 9. The method of administration according to claim 6, wherein the inhalant of the metered-dose inhaler or the atomizer of the atomizer contains an effective amount of peramivir and/or its derivatives. and propellants.
10、 根据权利要求 9所述的给药方法， 其特征在于， 所述抛射剂为二氧化 碳、 1 ,1 , 1,2-四氟乙垸、 1,1, 1,2,3,3,3-七氟丙烷、 单氟三氯甲烷、 二氯二氟甲 垸、 氯氟化碳或其衍生物中的 1种或至少 2种以上的混合物。 。 10. The drug administration method according to claim 9, characterized in that the propellant is carbon dioxide, 1,1,1,2-tetrafluoroethane, 1,1, 1,2,3,3,3 - One or a mixture of at least two of heptafluoropropane, monofluorotrichloromethane, dichlorodifluoromethane, chlorofluorocarbons or their derivatives. .
11、根据权利要求 10所述的给药方法， 其特征在于， 所述抛射剂为氢氟烷 烃。 11. The drug administration method according to claim 10, characterized in that the propellant is hydrofluoroalkane Hydrocarbons.
12、根据权利要求 11任一项所述的给药方法， 其特征在于， 所述抛射剂为 1，1，1，2-四氟乙垸。 12. The drug administration method according to any one of claims 11, characterized in that the propellant is 1,1,1,2-tetrafluoroethane.
13、 根据权利要求 9所述的给药方法， 其特征在于， 所述定量剂量吸入器 的吸入剂还含有助溶剂和表面活性剂。 13. The drug administration method according to claim 9, characterized in that the inhalant of the metered dose inhaler also contains a co-solvent and a surfactant.
14、根据权利要求 13所述的给药方法， 其特征在于， 所述助溶剂为乙醇、 异丙醇或丙二醇中的 1种或 2种以上的混合物。 14. The administration method according to claim 13, characterized in that the co-solvent is one or a mixture of two or more of ethanol, isopropyl alcohol or propylene glycol.
15、 根据权利要求 13或 14所述的给药方法， 其特征在于， 所述助溶剂占 总剂量的 0.1-15wt%。 15. The administration method according to claim 13 or 14, characterized in that the co-solvent accounts for 0.1-15wt% of the total dose.
16、 根据权利要求 13 所述的给药方法， 其特征在于， 所述表面活性剂为 油酸、 卵磷脂或司盘 85中的 1种或 2种以上的混合物。 16. The method of administration according to claim 13, wherein the surfactant is one or a mixture of two or more of oleic acid, lecithin or Span 85.
17、 根据权利要求 13或 16所述的给药方法， 其特征在于， 基于帕拉米韦 和 /或其衍生物的量表面活性剂的含量为 0.001-0.5wt %。 17. The administration method according to claim 13 or 16, characterized in that the content of the surfactant based on the amount of peramivir and/or its derivatives is 0.001-0.5wt%.
18、 根据权利要求 17所述的给药方法， 其特征在于， 基于帕拉米为和 /或 其衍生物的量表面活性剂的含量为 0.01-0.1wt%。 18. The administration method according to claim 17, wherein the content of the surfactant is 0.01-0.1wt% based on the amount of paramid and/or its derivatives.
19、 根据权利要求 1-3、 7或 9所述的给药方法， 其特征在于， 所述帕拉米 韦和 /或其衍生物的最大颗粒粒径为不大于 50μηι。 19. The administration method according to claims 1-3, 7 or 9, characterized in that the maximum particle size of the peramivir and/or its derivatives is no more than 50 μm.
20、 根据权利要求 19所述的给药方法， 其特征在于， 所述帕拉米韦和 /或 其衍生物的最大颗粒粒径为不大于 20μιη。 20. The drug administration method according to claim 19, wherein the maximum particle size of peramivir and/or its derivatives is no more than 20 μm.
21、 根据权利要求 20所述的给药方法， 其特征在于， 所述帕拉米韦和 /或 其衍生物的颗粒粒径为 1-10μη。 21. The drug administration method according to claim 20, characterized in that the particle size of the peramivir and/or its derivatives is 1-10 μn.
22、 根据权利要求 21 所述的给药方法， 其特征在于， 所述帕拉米韦和 /或 其衍生物的颗粒粒径为 1-5μπι。 22. The administration method according to claim 21, characterized in that, the peramivir and/or The particle size of its derivatives is 1-5 μm.
PCT/CN2014/084836 2013-08-26 2014-08-20 Method of administering formulation comprising peramivir and/or derivative thereof WO2015027848A1 (en)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
CN201310376626.8 2013-08-26
CN2013103766268A CN103446051A (en) 2013-08-26 2013-08-26 Method for administrating preparations containing peramivir and/or derivatives thereof

Publications (1)

Publication Number Publication Date
WO2015027848A1 true WO2015027848A1 (en) 2015-03-05

Family

ID=49729173

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/CN2014/084836 WO2015027848A1 (en) 2013-08-26 2014-08-20 Method of administering formulation comprising peramivir and/or derivative thereof

Country Status (2)

Country Link
CN (1) CN103446051A (en)
WO (1) WO2015027848A1 (en)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP3932400A4 (en) * 2019-02-25 2022-09-21 Guangzhou Nanxin Pharmaceutical Co., Ltd. Peramivir solution type inhalant and preparation method therefor

Families Citing this family (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN106420621A (en) * 2016-10-09 2017-02-22 默栢瑞成都生物技术有限公司 Preparation method of peramivir powder
CN111067879B (en) * 2020-01-20 2022-08-09 珠海瑞思普利医药科技有限公司 Anti-tumor composition powder inhalation and preparation method thereof
CN111265499B (en) * 2020-02-17 2022-11-15 江苏艾立康医药科技有限公司 Lopinavir inhalation aerosol and preparation method thereof
CN113491678B (en) * 2020-04-07 2023-01-20 知和(山东)大药厂有限公司 Arbidol hydrochloride inhalant and preparation method thereof
CN111358773B (en) * 2020-04-10 2021-03-30 广州南鑫药业有限公司 Peramivir dry powder inhalant and preparation method thereof

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2009143011A1 (en) * 2008-05-20 2009-11-26 Novartis Ag Antiviral compositions, methods of making and using such compositions, and systems for pulmonary delivery of such compositions
WO2011035128A1 (en) * 2009-09-17 2011-03-24 Mutual Pharmaceutical Company, Inc. Method of treating asthma with antiviral agents

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2009143011A1 (en) * 2008-05-20 2009-11-26 Novartis Ag Antiviral compositions, methods of making and using such compositions, and systems for pulmonary delivery of such compositions
WO2011035128A1 (en) * 2009-09-17 2011-03-24 Mutual Pharmaceutical Company, Inc. Method of treating asthma with antiviral agents

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP3932400A4 (en) * 2019-02-25 2022-09-21 Guangzhou Nanxin Pharmaceutical Co., Ltd. Peramivir solution type inhalant and preparation method therefor

Also Published As

Publication number Publication date
CN103446051A (en) 2013-12-18

Similar Documents

Publication Publication Date Title
WO2015027848A1 (en) Method of administering formulation comprising peramivir and/or derivative thereof
US20230218614A1 (en) Compound for the treatment of coronaviral infections
US20230113516A1 (en) 5-amino-2,3-dihydro-1,4-phthalazinedione for treatment of acute lung injury
Saha et al. Inhaled therapy for COVID-19: Considerations of drugs, formulations and devices
AU2021261049A1 (en) Products of manufacture and methods for treating, ameliorating or preventing microbial infections
TW200815003A (en) Treating cystic fibrosis with antibiotics via a swirler delivery
Nainwal Treatment of respiratory viral infections through inhalation therapeutics: Challenges and opportunities
WO2015027847A2 (en) Administration method for preparation containing oseltamivir carboxylate guanidino analogues and/or ethyl esters thereof
CN113350323A (en) Inhalant for inhibiting coronavirus, and preparation method and application thereof
JP2023520929A (en) Methods for treatment of coronavirus infection
TW201016215A (en) Compositions and uses of antiviral active pharmaceutical agents
US20210353650A1 (en) Pharmaceutical formulation containing remdesivir and its active metabolites for dry powder inhalation
CN115666510A (en) Clofazimine compositions and methods for treating or preventing viral infections
EP3981405A1 (en) Compound for the treatment of coronaviral infections
KR20180030399A (en) Composition for nebulizers
EP4143150A2 (en) Virus treatment methods, and related pharmaceutical compositions, vaccine compositions, sanitizing compositions, and drug discovery methods
Abdalaziz et al. Formulation strategy for hydroxychloroquine as inhaler dosage from as a potential for COVID-19 treatment
AU2022209720A1 (en) Methods and compositions for treating infections
WO2023104327A1 (en) Combination of 5-amino-2,3-dihydro-1,4-phtalazinedione and a 6'-methoxycinchonan-9-ol for use in the treatment of coronaviral infections
WO2023177366A1 (en) Use of active ingredient used against viral diseases with pressurized metered dose inhaler in the treatment of covid-19 and other viral lung diseases
CA3179187A1 (en) Compositions and methods for treating lung injuries associated with viral infections
CN113456619A (en) Dipyridamole inhalant and preparation method thereof
JP2004352712A (en) Agent for preventing or treating influenza

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 14839336

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 14839336

Country of ref document: EP

Kind code of ref document: A1