WO2020173095A1 - 一种帕拉米韦溶液型吸入剂及其制备方法 - Google Patents

一种帕拉米韦溶液型吸入剂及其制备方法 Download PDF

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WO2020173095A1
WO2020173095A1 PCT/CN2019/110115 CN2019110115W WO2020173095A1 WO 2020173095 A1 WO2020173095 A1 WO 2020173095A1 CN 2019110115 W CN2019110115 W CN 2019110115W WO 2020173095 A1 WO2020173095 A1 WO 2020173095A1
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peramivir
solution
inhalant
concentration
osmotic pressure
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PCT/CN2019/110115
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English (en)
French (fr)
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张世喜
冯玉欢
缪栋
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广州南鑫药业有限公司
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Priority to JP2021572693A priority Critical patent/JP7241928B2/ja
Priority to EP19917241.2A priority patent/EP3932400A4/en
Publication of WO2020173095A1 publication Critical patent/WO2020173095A1/zh
Priority to US17/411,044 priority patent/US20210386697A1/en

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/08—Solutions
    • 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
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/02—Inorganic compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/26—Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
    • 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
    • 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 relates to the technical field of medicine, in particular to a peramivir solution type inhalant and a preparation method thereof.
  • Peramivir the chemical name is (-)-(1S, 2S, 3R, 4R)-2-hydroxy-3-[(1S)-1-acetamido-2-ethyl]butyl-4-guanidine
  • Cyclopenta-1-carboxylic acid is a cyclopentane derivative influenza virus neuraminidase (NA) inhibitor.
  • Peramivir is a cyclopentane derivative.
  • the groups connected to the ring include hydrophilic carboxyl and guanidino groups, as well as hydrophobic isopentyl and acetamido groups.
  • Four groups with different polarities act on influenza virus NA. Different active site regions in the structure.
  • the carboxyl part and the three arginine residues Arg118, Arg292 and Arg371 in the active site of NA form a strong intermolecular interaction.
  • the methyl part of the acetamido group interacts with Trp178 and Ile 222 in the NA hydrophobic pocket, while the carbonyl oxygen interacts with Arg152 action;
  • guanidine group and NA active site Asp 151, Glu 119, Glu 227 and Trp 227 have strong intermolecular interactions;
  • influenza B virus NA the isoamyl part is composed of Ala 246, Arg 224 and Ile222
  • the hydrophobic pocket has a strong effect, and for influenza A virus NA, the isopentyl part acts on the hydrophobic part of Glu 276.
  • Multiple groups on the peramivir molecule act on multiple active sites of the influenza virus NA molecule to strongly inhibit the activity of NA and prevent the replication and release of offspring virus particles in host cells.
  • CN101314579 A discloses anhydrous peramivir crystals and their pharmaceutical compositions, including injections containing 200mg peramivir crystals Liquid: 200mg of anhydrous peramivir crystals, mannitol, appropriate amount of hydrochloric acid and water for injection to 100mL. And freeze-dried powder injection: 200mg of anhydrous peramivir crystals, mannitol, appropriate amount of hydrochloric acid and water for injection to 20mL to freeze-dry.
  • CN102058522 A discloses a piperamivir injection and a preparation method thereof, which are composed of piperamivir, a non-aqueous solvent, a co-solvent and water for injection.
  • the weight-volume ratio (g/ml) of piperamavir and non-aqueous solvent is 1:10-100, the dosage ratio of non-aqueous solvent in the prescription is 20-60% (v/v), and the amount of co-solvent is 1 ⁇ 20% (w/v),
  • the non-aqueous solvent is one or a mixed solvent of ethanol, propylene glycol, glycerin, and polyethylene glycol, and the co-solvent is glucose, sorbitol, mannitol, cyclic One or more of hexanol.
  • a peramivir injection that can be diluted with water for injection, sodium chloride or glucose infusion in any proportion, while maintaining the clarity of the solution, and a preparation method thereof.
  • the injection can not only improve the solubility of peramivir, but also can meet the requirements of injection drugs with a reasonable formulation prescription and preparation method.
  • the solubility of peramivir and the maintenance of the solution can be increased. Stability, to avoid problems such as turbidity and inability to administer the solution during clinical dilution, reduce the amount of non-aqueous solvents as much as possible, and increase the concentration of the original drug.
  • CN102702033 A discloses amorphous peramivir and its preparation method and pharmaceutical composition, injection: amorphous peramivir 200mg, mannitol, appropriate amount of hydrochloric acid and water for injection are added to 100mL.
  • Peramivir can play an anti-influenza effect by staying in the respiratory organs of the patient. Therefore, peramivir is made into an inhalant to directly reach the respiratory organ tissue lesions through non-oral routes, reducing the potential for other tissues of the body. reaction. Since inhalers have a variety of dosage forms, including dry powder inhalants, sprays, solution inhalants, etc., for children, the elderly, patients with low respiratory function, and other people who have difficulty breathing on their own, it is difficult to inhale sufficient amounts of drugs with dry powder inhalants. However, solution inhalants are more convenient for such patients. Although peramivir is made into a solution inhalant, there are still many challenges.
  • Particle size and dosage form are the main factors that affect the effect of inhaled preparations. Particle size is one of the main factors. Drug delivery through inhalation can make the drug deposit in different parts of the respiratory tract, such as the throat, trachea, bronchi and alveoli. Generally, the smaller the particle size, the longer the particles stay suspended in the air, and the drug can be delivered to the deeper parts of the respiratory tract.
  • Both particle size and dosage form affect the effect of inhaled corticosteroids.
  • the dosage form of the drug has an important effect on the delivery of the drug to the lungs and therefore affects its efficacy.
  • the most important thing in the delivery of drugs to the lungs is the carrier of the aerosol and the particle size delivered.
  • a decrease in lung deposition indicates an increase in oropharyngeal deposition. Due to the specific dosage form used, some corticosteroids are more likely to deposit in the mouth and pharynx and may cause local side effects.
  • the droplets of the mucus blanket deposited on the airways and nasal passages of the lungs move to the pharynx under the action of cilia.
  • co-solvents and surfactants are usually added to the inhalation prescription.
  • the co-solvents such as ethanol, polyethylene glycol and propylene glycol are short-chain fatty alcohols during inhalation. It can only tolerate small amounts, especially not suitable for children. Most surfactants are toxic. Therefore, these conditions limit the development of inhalation preparations.
  • the purpose of the present invention is to overcome the defects of the prior art and provide a peramivir solution inhaler with better stability, which can effectively reduce the production of irrelevant substances, and has a smaller and more uniform particle size. Conducive to the deposition of drugs in the lung tissue.
  • the peramivir solution inhalant of the present invention has better stability at pH 5.5.
  • the peramivir solution inhaler of the present invention can be targeted to be distributed in the lung tissue.
  • the lung tissue drug concentration of the peramivir solution inhaler of the present invention is intravenous administration ( 10mg/kg) 1.58-5.31 times.
  • the peramivir solution inhalant of the present invention can better reduce the degradation of the drug and the chemical reaction caused by the ultrasonic process.
  • the present invention provides a peramivir solution inhaler, which is made of peramivir, an osmotic pressure regulator, a pH regulator and water, wherein the concentration of peramivir is greater than 15 mg/ml , The concentration of the osmotic pressure regulator is less than 8mg/ml, the pH value of the solution type inhalant is 5.0-6.0, and does not use heat sterilization, the osmotic pressure regulator is selected from sodium chloride or glucose, the solution After atomization of the type inhalant, its mass medium aerodynamic diameter (MMAD) is between 3-4um, and the effective deposition rate of fine particles (FPF) is between 60% and 80%.
  • MMAD mass medium aerodynamic diameter
  • FPF effective deposition rate of fine particles
  • the concentration of peramivir is greater than 15mg/ml and less than 25mg/ml, preferably 20mg/ml
  • the concentration of the osmotic pressure regulator is less than 8mg/ml and greater than 6mg/ml, preferably 7mg/ml
  • the osmotic pressure regulator It is sodium chloride.
  • the present invention does not use a heating sterilization process, preferably an aseptic process.
  • the pH adjuster is dilute hydrochloric acid, more preferably 5% dilute hydrochloric acid.
  • the water is water for injection.
  • the pH value of peramivir solution inhalant is 5.5, which has excellent stability under this pH condition.
  • the solution-type inhalant has a drug concentration in the lung tissue greater than 7 ug/g after aerosol inhalation for 1 hour, or a drug concentration in the lung tissue greater than 5 ug/g after 3 hours.
  • the fine particle dose (FPD) of the solution inhalant is greater than 10 mg, and the geometric standard deviation of the particles is less than 3.0.
  • the present invention further provides a peramivir solution inhalant, which is made of peramivir, an osmotic pressure regulator, a pH regulator, sodium dihydrogen phosphate and water, wherein peramivir
  • a peramivir solution inhalant which is made of peramivir, an osmotic pressure regulator, a pH regulator, sodium dihydrogen phosphate and water, wherein peramivir
  • the concentration of osmotic pressure regulator is greater than 15mg/ml, the concentration of osmotic pressure regulator is less than 8mg/ml, the concentration of sodium dihydrogen phosphate is 0.05-0.2mg/ml, the pH value of the solution type inhalant is 5.5, and heating sterilization is not used
  • the osmotic pressure regulator is selected from sodium chloride or glucose. After the solution-type inhalant is atomized, its mass mid-mass aerodynamic diameter (MMAD) is between 3-4um, and the effective deposition rate of fine particles (FPF) ) Is between 60%
  • the solution inhalant of the present invention has good thermal stability, and the content of related substances is less than 0.3% after 30 days of high temperature.
  • the present invention further provides a preparation method of peramivir solution inhalant, the preparation method comprising the following steps:
  • the peramivir solution inhalant of the present invention solves the problem that peramivir injection is not stable enough under acidic conditions, can effectively reduce the production of irrelevant substances, has a smaller and more uniform particle size, and is beneficial The drug is deposited in the lung tissue.
  • the peramivir solution inhalant of the present invention has better stability at pH 5.5.
  • the peramivir solution inhaler of the present invention can be targeted to be distributed in the lung tissue.
  • the lung tissue drug concentration of the peramivir solution inhaler of the present invention is intravenously administered (10 mg/ kg) 1.58-5.31 times.
  • the peramivir solution inhalant of the present invention can better reduce the degradation of the drug and the chemical reaction caused by the ultrasonic process.
  • HPLC Agilent 1260 Infinity USA
  • Column Eclipse Plus C 18 (5 ⁇ m, 4.6 ⁇ 250mm, Agilent, USA)
  • Mobile phase gradient elution is as follows:
  • Prescription 1 Prescription 2
  • Prescription 3 Prescription 4
  • Prescription 5 Prescription 6
  • Prescription 8 Prescription 9 0 days 0.11% 0.42% 0.10% 0.12% 0.13% 0.10% 0.08% 0.11% 0.13% High temperature 5 days 0.12% 1.31% 0.12% 0.14% 0.11% 0.13% 0.14% 0.21% 0.13% High temperature 10 days 0.13% 1.28% 0.12% 0.15% 0.16% 0.12% 0.32% 0.47% 0.18% 30 days of high temperature 0.18% 1.41% 0.47% 0.77% 0.44% 0.20% 1.11% 1.21% 0.58% Light for 5 days 0.12% 0.25% 0.06% 0.17% 0.06% 0.10% 0.11% 0.12% 0.14% 10 days of light 0.13% 0.41% 0.25% 0.19% 0.13% 0.13% 0.13% 0.13% 0.16% Light for 30 days 0.10% 0.64% 0.32% 0.20% 0.16% 0.14% 0.16% 0.15% 0.15% 0.15% 0.15% 0.15%
  • the inhalation solution prepared by peramivir and vitamin C begins to turn into a light yellow clear solution after 5 days of light and high temperature, and when placed under high temperature and strong light for 30 days, the related substances are significantly increased.
  • the remaining prescriptions are colorless and clear solutions at all time points under high temperature and strong light conditions.
  • the inhalation solution prepared by peramivir, sodium chloride, sodium citrate, disodium hydrogen phosphate, citric acid, and propylene glycol was placed at high temperature for 30 days, the related substances also increased significantly, and the stability was poor.
  • the inhalation solutions prepared by peramivir and sodium chloride, peramivir and sodium chloride, and sodium dihydrogen phosphate have good stability under high temperature and light conditions.
  • Example 3 Stability experiment of peramivir inhalation solution under different pH conditions
  • Preparation method mix the raw materials of peramivir with the auxiliary materials in a liquid mixing tank, add water for injection at 75°C to 1000ml, stir to dissolve and cool, then adjust the pH of the solution to 5.5 with dilute hydrochloric acid (5%v/v) , And then pass the peramivir solution through pre-filtration and then aseptically filter, and it is obtained after aseptic filling.
  • Preparation method mix the raw materials of peramivir with the auxiliary materials in a liquid mixing tank, add water for injection at 75°C to 1000ml, stir to dissolve and cool, then adjust the pH of the solution to 5.5 with dilute hydrochloric acid (5%v/v) , And then pass the peramivir solution through pre-filtration and then aseptically filter, and it is obtained after aseptic filling.
  • Preparation method mix the raw materials of peramivir and the auxiliary materials in a mixing tank, add 70°C water for injection to 1000ml, stir to dissolve and cool, and then use dilute hydrochloric acid (5%v/v) to adjust the pH of the solution to 5.7 , And then pass the peramivir solution through pre-filtration and then aseptically filter, and it is obtained after aseptic filling.
  • Preparation method Mix the raw materials of peramivir with the auxiliary materials in a mixing tank, add 70°C water for injection to 1000ml, stir to dissolve and cool, and then adjust the pH of the solution to 5.5 with dilute hydrochloric acid (5%v/v) , And then pass the peramivir solution through pre-filtration and then aseptically filter, and it is obtained after aseptic filling.
  • Preparation method mix the raw materials of peramivir with the auxiliary materials in a liquid mixing tank, add water for injection at 75°C to 1000ml, stir to dissolve and cool, then adjust the pH of the solution to 5.5 with dilute hydrochloric acid (5%v/v) , And then pass the peramivir solution through pre-filtration and then aseptically filter, and it is obtained after aseptic filling.
  • Preparation method mix the raw materials of peramivir with the auxiliary materials in a liquid mixing tank, add water for injection at 75°C to 1000ml, stir to dissolve and cool, then adjust the pH of the solution to 5.5 with dilute hydrochloric acid (5%v/v) , And then pass the peramivir solution through pre-filtration and then aseptically filter, and it is obtained after aseptic filling.
  • the delivery rate and total delivery amount of the inhalation solution of prescription 1 and prescription 6 and the dose of fine particles were measured respectively. Measurement of fine particle dose
  • the test solution of the MOC collection layer is filtered through a 0.45 ⁇ m filter membrane, and the subsequent filtrate is taken as the test solution of the MOC collection layer. Other test solution can be directly injected.
  • Peramivir compound sodium chloride solution (prescription 1) was administered by nebulization inhalation.
  • the dosages were: low dose: 2.5 mg/ kg; medium dose: 5mg/kg; high dose: 10mg/kg; the time of nebulized inhalation administration is 30min; after administration 5min, 1h, and 3h respectively, 0.20ml of blood from the orbital venous plexus is taken, and the animal is taken after anesthesia Lung tissue (including trachea). After anticoagulation with heparin sodium, the whole blood was centrifuged (10000rpm, 5min), and the plasma was taken; the lung tissue was washed and weighed, and the plasma and lung tissue were stored at -20°C for testing.
  • the rats were anesthetized and sacrificed at 5 min, 1 h, and 3 h after the administration, their weight was weighed and recorded, and then the lung tissue (including the trachea) was dissected; the lung tissue was cleaned with saline and the remaining liquid was absorbed with filter paper. Place it in a peeled EP tube, weigh and record, and finally store it in a refrigerator at -20°C.
  • the ratio of lung tissue/physiological saline 1g/4mL
  • add the corresponding physiological saline to the lung tissue prepare a homogenate with a homogenizer, centrifuge (10000rpm, 10min), take 100 ⁇ L of supernatant, and place it in a 1.5mL centrifuge tube , Precisely add 400 ⁇ L of 1 ⁇ g/mL internal standard oseltamivir methanol solution, vortex for 1min to mix, centrifuge at 12000rpm for 10min, take 100 ⁇ L of supernatant, then add 100 ⁇ L of water to mix well, wait for LC-MS/MS analysis.
  • peramivir standard solutions with concentrations of 0.5, 1, 5, 10, 50, 100, and 200 ⁇ g/mL with 1 mg/mL mother liquor according to the gradient dilution method.
  • take 90 ⁇ L of blank lung tissue homogenate and add 10 ⁇ L of the above-mentioned standard solutions of each concentration accurately to configure the lung tissue standards with concentrations of 0.05, 0.1, 0.5, 1, 5, 10, 20 ⁇ g/mL, each lung tissue standard
  • the daily drug concentration in lung tissue is calculated by accompanying standards.
  • Mass spectrometry conditions ion source is electrospray ionization source (ESI); detection method: positive ion detection; scanning method: multiple reaction monitoring (MRM); injection voltage: 5500V; ion source temperature: 550°C; curtain air flow rate: 25L/ min, GS1: 50L/min, GS2: 50L/min, collision gas flow rate: 6L/min, scan time 0.2s, ion conditions for quantitative and qualitative are shown in Table 8 and Figure 2.
  • EI electrospray ionization source
  • detection method positive ion detection
  • scanning method multiple reaction monitoring (MRM)
  • injection voltage 5500V
  • ion source temperature 550°C
  • curtain air flow rate 25L/ min
  • GS1 50L/min
  • GS2 50L/min
  • collision gas flow rate 6L/min
  • scan time 0.2s ion conditions for quantitative and qualitative are shown in Table 8 and Figure 2.
  • the difference in the drug concentration of peramivir in the lung tissue between the two methods of administration increases with time.
  • the lung tissue concentration of peramivir atomized administration at each time point is 2.02-11.58 times that of intravenous administration; low-dose atomized inhalation administration (2.5mg/kg) each
  • the lung tissue concentration at the time point was 1.07-4.58 times that of intravenous administration (10mg/kg); the middle-dose aerosol inhalation administration (5mg/kg) at each time point was intravenous administration (10mg/kg). 1.58-5.31 times.
  • Example 1 The inhalation solutions of prescriptions 1 and 6 in Example 1 were ultrasonically atomized in an ultrasonic atomizer (2500KHz), and the related substance content was measured after 0min, 20min, 40min, 60min, and 90min. The experimental results are shown in Table 10. .

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Abstract

一种帕拉米韦溶液型吸入剂及其制备方法，所述溶液型吸入剂由帕拉米韦、渗透压调节剂、pH调节剂以及水或磷酸二氢钠和水制成，其中帕拉米韦的浓度大于15mg/ml，渗透压调节剂的浓度小于8mg/ml，所述溶液型吸入剂的pH值为5.0-6.0或5.5，且不采用加热灭菌，所述渗透压调节剂选自氯化钠或者葡萄糖。该溶液型吸入剂具有更好的稳定性，且具有优异的肺靶向作用，显著提高了药物的有效性和安全性。

Description

一种帕拉米韦溶液型吸入剂及其制备方法 技术领域
本发明涉及医药技术领域，具体涉及一种帕拉米韦溶液型吸入剂及其制备方法。
背景技术
帕拉米韦，化学名为(-)-(1S，2S，3R，4R)-2-羟基-3-[(1S)-1-乙酰胺基-2-乙基]丁基-4-胍基环戊-1-羧酸，是一种环戊烷衍生物类流感病毒神经氨酸酶(NA)抑制剂。帕拉米韦是环戊烷衍生物，与环连接的基团有亲水的羧基和胍基,以及疏水的异戊基和乙酰氨基，4个极性不同的基团分别作用于流感病毒NA结构中不同的活性位点区域。羧基部分与NA活性位点的3个精氨酸残基Arg118，Arg292，Arg371形成强烈的分子间作用，乙酰氨基的甲基部分与NA疏水口袋中的Trp 178和Ile 222作用，羰基氧则与Arg152作用；胍基与NA活性位点的Asp 151、Glu 119、Glu 227及Trp 227产生强烈的分子间作用；对于B型流感病毒NA，异戊基部分与Ala 246、Arg 224和Ile222构成的疏水性口袋强烈作用，而对于A型流感病毒NA，异戊基部分作用于Glu 276疏水部分。帕拉米韦分子上多个基团分别作用于流感病毒NA分子的多个活性位点，强烈抑制NA的活性，阻止子代的病毒颗粒在宿主细胞的复制和释放。
由于帕拉米韦口服利用度较低，主要制成注射液等胃肠外制剂，如CN101314579 A公开了无水帕拉米韦晶体及其药物组合物，包括含有200mg帕拉米韦晶体的注射液：无水帕拉米韦晶体200mg，甘露醇、盐酸适量以及注射用水加至100mL。以及冻干粉针：无水帕拉米韦晶体200mg，甘露醇、盐酸适量以及注射用水加至20mL冻干。
CN102058522 A公开了一种哌拉米韦注射液及其制备方法，由哌拉米韦、非水溶剂、助溶剂和注射用水组成。其中哌拉米韦与非水溶剂的重量体积比(g/ml)为1∶10-100，非水溶剂在处方中的用量比为20～60％(v/v)，助溶剂用量为1～20％(w/v)，所述非水溶剂为乙醇、丙二醇、甘油、聚乙二醇中的一种或几种的混合溶剂，所述助溶剂为葡萄糖、山梨醇、甘露醇、环己六醇中的一种或几种。提供一种可以用任意比例的注射用水、氯化钠或葡萄糖输液稀释，而保持溶液澄 明度的哌拉米韦注射液及其制备方法。该注射液既可提高帕拉米韦溶解性，又可以满足注射用药要求的合理的制剂处方和制备方法，通过使用适量的非水溶剂和助溶剂，增加帕拉米韦的溶解度和保持溶液的稳定性，避免在临床稀释使用时出现溶液浑浊、无法给药等问题的发生，尽可能降低非水溶剂的用量，提高了原药浓度。CN102702033 A公开无定型帕拉米韦及其制备方法与药物组合物，注射液：无定型帕拉米韦200mg，甘露醇、盐酸适量以及注射用水加至100mL。
帕拉米韦能通过滞留于患者的呼吸器官组织而发挥抗流感作用，因此，将帕拉米韦制成吸入剂通过非经口途径直接到达呼吸器官组织病灶，减少对全身其它组织的潜在不良反应。由于吸入剂存在多种剂型，包括干粉吸入剂、喷雾剂、溶液型吸入剂等，对于儿童或高龄者、呼吸功能低下患者等自主呼吸困难者，采用干粉末吸入制剂存在难以吸入充分量的药物的情形，而溶液型吸入剂则更便于这类患者的应用。虽然将帕拉米韦做成溶液型吸入剂，但仍存在诸多挑战。
对于适宜雾化的溶液型吸入剂，通常需要满足一些基本性质，包括：1)无菌介质；2)低粘稠液体、低表面张力；3)适度的pH；4)能够形成平均直径小于5μm或者小于3μm的液滴；5)处方对喷雾器相对稳定；6)不含刺激性的防腐剂和稳定剂。粒度和剂型是影响被吸入制剂效果的主要因素，其中粒度是主要因素之一，药物通过吸入传递药物可以使药物沉积于呼吸道的不同部位，如喉咙、气管、支气管以及肺泡。通常，粒度越小，颗粒保持悬浮在空气中的时间就越长，药物就能够传递到呼吸道的更深部位。
粒度和剂型两者都会影响被吸入的皮质甾类的效果。药物的剂型对该药物传递至肺部具有重要的影响，并因此影响其功效。在药物到肺的传递中最重要的是气雾剂的载体和所传递的粒度。此外，肺部的沉积程度降低表明口咽沉积程度增大。由于所应用的特定剂型，一些皮质甾类更有可能沉积在口腔和咽部并可能引起局部副作用。其中沉积在覆盖肺部气道和鼻道的粘液毯液滴在纤毛的作用下向咽部移动，这种颗粒通常是沉积在上呼吸道的较大药物颗粒，而来自鼻腔和肺的粘液、细胞和碎片在咽部汇集，与唾液一起混合，并经吞咽进入胃肠道。因此，制备较小粒径并且具有较窄粒度分布的雾化液滴是所期望，然而制备这种颗粒却又是困难的。
为实现更好的雾化，在吸入剂处方中通常加入助溶剂、表面活性剂来制备， 但是由于对呼吸道的刺激，吸入给药时助溶剂如乙醇、聚乙二醇和丙二醇这些短链脂肪醇只能耐受较小的量，尤其对于儿童群体不适宜。而大部分的表面活性剂均具有一定毒性。因此，这些情况限制了吸入制剂的研发。
有研究(“超声雾化时药物分解的研究”)报道，林肯霉素溶液在雾化成气溶胶后可产生硫化物，从而导致头痛、眩晕、恶心临床症状。进一步研究发现林超声雾化后发生腐败臭的林肯霉素气溶胶中含有二硫甲基和硫化氢，还混有一种不明的硫化物，林肯霉素含SCH3的侧链结合部容易被超声波的能量分解变为其它硫化物，因而认为其它药物在超声雾化时也可能产生潜在的裂解变化。因此，在帕拉米韦溶液型吸入剂研发中，同样面临帕拉米韦被超声裂解的潜在问题。
另有文献(“帕拉米韦原料药的稳定性研究”，甘薇等，现代药物与临床，2018年)报道帕拉米韦原料药在100℃条件下48h内是稳定的；在光照10d的情况下，帕拉米韦的稳定性良好；帕拉米韦在碱性和中性环境下稳定性良好，在酸性条件下不稳定，随着pH值的降低，稳定性越差。帕拉米韦在酸性环境中极不稳定，在碱性和中性条件下稳定性良好。因而，如何改进帕拉米韦溶液型吸入剂的稳定性也同样是亟待解决的问题。
发明内容
本发明的目的是克服现有技术的缺陷，提供了一种稳定性更好的帕拉米韦溶液型吸入剂，能有效减少不有关物质的产生，具有更小、分布更均匀的粒径，有利于药物沉积在肺组织。另一方面，本发明帕拉米韦溶液型吸入剂在pH5.5下具有更好的稳定性。另一方面，本发明帕拉米韦溶液型吸入剂能靶向分布在肺组织，相对帕拉米韦注射液，本发明帕拉米韦溶液型吸入剂的肺组织药物浓度是静脉给药(10mg/kg)的1.58-5.31倍。另一方面，本发明帕拉米韦溶液型吸入剂能更好的减少超声过程带来的药物降解以及化学反应。
本发明解决该技术问题的技术方案是：
本发明提供一种帕拉米韦溶液型吸入剂，所述溶液型吸入剂由帕拉米韦、渗透压调节剂、pH调节剂和水制成，其中帕拉米韦的浓度大于15mg/ml，渗透压调节剂的浓度小于8mg/ml,所述溶液型吸入剂的pH值为5.0-6.0,且不采用加热灭菌，所述渗透压调节剂选自氯化钠或者葡萄糖，所述溶液型吸入剂雾化后，其质 量中质空气流动力学直径(MMAD)在3-4um之间，细微粒子有效沉积率(FPF)在60％-80％之间。
其中，帕拉米韦的浓度大于15mg/ml且小于25mg/ml，优选20mg/ml，渗透压调节剂的浓度小于8mg/ml且大于6mg/ml，优选7mg/ml，所述渗透压调节剂为氯化钠。
本发明不采用加热灭菌工艺，优选无菌工艺。
所述pH调节剂为稀盐酸，更优选5％的稀盐酸。
所述水为注射用水。
其中帕拉米韦溶液型吸入剂的pH值为5.5，在该pH条件具有优异的稳定性。
所述溶液型吸入剂雾化吸入1h后在肺组织药物浓度大于7ug/g,或者3h后在肺组织药物浓度大于5ug/g。
所述溶液型吸入剂的微细粒子剂量(FPD)大于10mg，粒子几何标准偏差小于3.0。
本发明进一步提供一种帕拉米韦溶液型吸入剂，所述溶液型吸入剂由帕拉米韦、渗透压调节剂、pH调节剂、磷酸二氢钠和水制成，其中帕拉米韦的浓度大于15mg/ml，渗透压调节剂的浓度小于8mg/ml,磷酸二氢钠的浓度为0.05-0.2mg/ml，所述溶液型吸入剂的pH值为5.5,且不采用加热灭菌，所述渗透压调节剂选自氯化钠或者葡萄糖，所述溶液型吸入剂雾化后，其质量中质空气流动力学直径(MMAD)在3-4um之间，细微粒子有效沉积率(FPF)在60％-80％之间。
本发明的溶液型吸入剂具有较好的热稳定性，在高温30天后，有关物质含量小于0.3％。
本发明进一步提供帕拉米韦溶液型吸入剂的制备方法，所述制备方法包括如下步骤：
将帕拉米韦原料与辅料混合，加70-80℃的水至1000ml，搅拌溶解后冷却，再用稀盐酸将溶液pH值调节在5.0-6.0之间，然后将帕拉米韦溶液通过预过滤后，再无菌过滤，无菌灌装后即得。
本发明的有益效果：
1、本发明的帕拉米韦溶液型吸入剂解决了帕拉米韦注射液在酸性条件下不够稳定，能有效减少不有关物质的产生，具有更小、分布更均匀的粒径，有利于药物沉积在肺组织。另一方面，本发明帕拉米韦溶液型吸入剂在pH5.5下具有更好的稳定性。
2、本发明帕拉米韦溶液型吸入剂能靶向分布在肺组织，相对帕拉米韦注射液，本发明帕拉米韦溶液型吸入剂的肺组织药物浓度是静脉给药(10mg/kg)的1.58-5.31倍。
3、本发明帕拉米韦溶液型吸入剂能更好的减少超声过程带来的药物降解以及化学反应。
具体实施方式
下面结合具体实施例，进一步阐述本发明。应理解，这些实施例仅用于说明本发明而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，通常按照常规条件或按照制造厂商所建议的条件。
除非另行定义，文中所使用的所有专业与科学用语与本领域熟练人员所熟悉的意义相同。此外，任何与所记载内容相似或均等的方法及材料皆可应用于本发明方法中。文中所述的较佳实施方法与材料仅作示范之用。
实施例1：吸入剂处方
按表1的处方，将帕拉米韦原料与辅料在配液罐中混合，加70-80℃的注射用水至1000ml，搅拌溶解后冷却，再用稀盐酸(5％v/v)将溶液pH值调节在5.0～6.0之间，然后将帕拉米韦溶液通过预过滤后再无菌过滤，无菌灌装后即得。
将表1中的处方1-9分别放置在密闭高温(60℃)、光照(4500lx±500lx)条件下放置0天、5天、10天、30天，考察有关物质情况。
有关物质含量测定方法：HPLC：Agilent 1260 Infinity USA；色谱柱：Eclipse Plus C 18(5μm，4.6×250mm，Agilent，USA)；流动相：梯度洗脱如下：
表1 流动相梯度洗脱
时间(min) 0.01M磷酸二氢钾溶液 甲醇
0 95 5
30 80 20
45 50 50
65 50 50
流速1mL/min；进样量20μL；检测波长210nm；柱温：室温。
表2 不同吸入剂处方配伍
Figure PCTCN2019110115-appb-000001
表3 不同条件下有关物质含量(％)
组别 处方1 处方2 处方3 处方4 处方5 处方6 处方7 处方8 处方9
0天 0.11％ 0.42％ 0.10％ 0.12％ 0.13％ 0.10％ 0.08％ 0.11％ 0.13％
高温5天 0.12％ 1.31％ 0.12％ 0.14％ 0.11％ 0.13％ 0.14％ 0.21％ 0.13％
高温10天 0.13％ 1.28％ 0.12％ 0.15％ 0.16％ 0.12％ 0.32％ 0.47％ 0.18％
高温30天 0.18％ 1.41％ 0.47％ 0.77％ 0.44％ 0.20％ 1.11％ 1.21％ 0.58％
光照5天 0.12％ 0.25％ 0.06％ 0.17％ 0.06％ 0.10％ 0.11％ 0.12％ 0.14％
光照10天 0.13％ 0.41％ 0.25％ 0.19％ 0.13％ 0.13％ 0.13％ 0.13％ 0.16％
光照30天 0.10％ 0.64％ 0.32％ 0.20％ 0.16％ 0.14％ 0.16％ 0.15％ 0.15％
以上实验结果表明，其中帕拉米韦与维生素C配制的吸入液，在光照和高温5天时开始变为淡黄色澄清溶液，而且在高温和强光条件放置30天时，有关物质均显著大幅增加，其余处方在高温和强光条件下各时间点均为无色澄清溶 液。另外，帕拉米韦、氯化钠与枸橼酸钠、磷酸氢二钠、柠檬酸、丙二醇配制的吸入溶液在高温放置30天后，有关物质也明显增加，稳定较差。而帕拉米韦与氯化钠、帕拉米韦与氯化钠、磷酸二氢钠配制的吸入溶液在高温、光照条件下均具有良好的稳定性。
实施例2：不同pH对帕拉米韦溶解度影响实验
称取过量的帕拉米韦原料药加入25ml容量瓶中，用0.7％的盐水定容至刻度，置于摇床震摇(25℃，75rpm)24h后，用稀盐酸(5％，V/V)分别调节pH至4、4.5、5.0、5.5，继续放置48h，用0.45μm滤膜过滤，滤液用去离子水稀释250倍，样品采用帕拉米韦标准中HPLC法测定帕拉米韦含量。
表4 帕拉米韦在不同pH生理盐水溶液的平衡溶解度
Figure PCTCN2019110115-appb-000002
实验结果表明，帕拉米韦平衡溶解度具有pH依赖性，随pH降低其平衡溶解度随之增加。结合制剂pH的要求(3-8)和生理刺激性等因素，帕拉米韦吸入溶液的pH在4.5-6.0之间更适合。
实施例3：不同pH条件下帕拉米韦吸入溶液的稳定性实验
将处方1、6分别用稀盐酸(5％v/v)将溶液pH值调节在4.5、4.5、5.0、5.5，以及未用稀盐酸调节的溶液，然后将帕拉米韦溶液分别放置在密闭高温(60℃)、光照(4500lx±500lx)条件下放置0天、30天，考察有关物质情况。
表5 不同pH条件下有关物质含量(％)
Figure PCTCN2019110115-appb-000003
Figure PCTCN2019110115-appb-000004
实验结果表明，帕拉米韦吸入溶液在pH值5.5条件下最稳定，在高温条件下仍能保持较好的稳定性。
实施例4
处方：
Figure PCTCN2019110115-appb-000005
制备方法：将帕拉米韦原料与辅料在配液罐中混合，加75℃的注射用水至1000ml，搅拌溶解后冷却，再用稀盐酸(5％v/v)将溶液pH值调节在5.5，然后将帕拉米韦溶液通过预过滤后再无菌过滤，无菌灌装后即得。
实施例5
处方：
Figure PCTCN2019110115-appb-000006
制备方法：将帕拉米韦原料与辅料在配液罐中混合，加75℃的注射用水至1000ml，搅拌溶解后冷却，再用稀盐酸(5％v/v)将溶液pH值调节在5.5，然后将帕拉米韦溶液通过预过滤后再无菌过滤，无菌灌装后即得。
实施例6
处方：
Figure PCTCN2019110115-appb-000007
Figure PCTCN2019110115-appb-000008
制备方法：将帕拉米韦原料与辅料在配液罐中混合，加70℃的注射用水至1000ml，搅拌溶解后冷却，再用稀盐酸(5％v/v)将溶液pH值调节在5.7，然后将帕拉米韦溶液通过预过滤后再无菌过滤，无菌灌装后即得。
实施例7
处方：
Figure PCTCN2019110115-appb-000009
制备方法：将帕拉米韦原料与辅料在配液罐中混合，加70℃的注射用水至1000ml，搅拌溶解后冷却，再用稀盐酸(5％v/v)将溶液pH值调节在5.5，然后将帕拉米韦溶液通过预过滤后再无菌过滤，无菌灌装后即得。
实施例8
处方：
Figure PCTCN2019110115-appb-000010
制备方法：将帕拉米韦原料与辅料在配液罐中混合，加75℃的注射用水至1000ml，搅拌溶解后冷却，再用稀盐酸(5％v/v)将溶液pH值调节在5.5，然后将帕拉米韦溶液通过预过滤后再无菌过滤，无菌灌装后即得。
实施例9
处方：
Figure PCTCN2019110115-appb-000011
Figure PCTCN2019110115-appb-000012
制备方法：将帕拉米韦原料与辅料在配液罐中混合，加75℃的注射用水至1000ml，搅拌溶解后冷却，再用稀盐酸(5％v/v)将溶液pH值调节在5.5，然后将帕拉米韦溶液通过预过滤后再无菌过滤，无菌灌装后即得。
实验例1：帕拉米韦雾化吸入溶液质量评价实验
分别测定处方1、处方6的吸入溶液的递送速率与递送总量、微细粒子剂量。微细粒子剂量的测定
将NGI置于降温柜中，待降温柜温度降至4℃后，开始进行试验，将NGI与低流速真空泵及流速计连接，调节流速为15L/min(±5％)。取装有2ml帕拉米韦雾化吸入溶液(20mg/ml)的塑料安瓿，充分摇匀后，挤压安瓿瓶，将帕拉米韦雾化吸入溶液加入雾化杯中，将雾化杯与压缩机连接，先开启低流速真空泵再开启压缩机，利用压缩机产生的压缩空气进行雾化，16min(雾化完全)后关闭压缩机，移出雾化杯，再关闭低流速真空泵。取下并分解添加样品的NGI和雾化杯，用去离子水/甲醇(60:40)的混合溶剂清洗安瓿瓶回收药液至5ml容量瓶，清洗雾化杯回收残留药液至100ml容量瓶，用稀释液清洗喉管至50ml容量瓶中；分别用稀释液清洗回收第1收集层，第2收集层、第3收集层、第4收集层、第5收集层、第6收集层、第7收集层及带滤纸的MOC收集层至相应的50ml容量瓶中，平行测定3次。MOC收集层的供试品溶液经0.45μm滤膜过滤，取续滤液作为MOC收集层供试品溶液，其他供试品溶液可直接进样。
表6 微细粒子剂量实验结果
  处方1 处方6
Ampoule[mg] 0.257 0.272
Device[mg] 27.793 20.931
Throat[mg] 0.389 0.588
Stage1[mg] 1.123 1.353
Stage2[mg] 1.496 2.000
Stage3[mg] 2.531 3.044
Stage4[mg] 3.308 3.735
Stage5[mg] 3.419 3.802
Stage6[mg] 2.355 2.506
Stage7[mg] 0.919 1.001
MOC[mg] 0.593 1.024
Flow Rate[L/min] 15 15
Doses to NGI 1 1
Delivery Dose[mg] 40 40
Total Dose Per Shot[mg] 43.926 39.984
Calc.Delivered Dose[mg] 16.133 19.053
Fine Particle Dose[mg] 10.115 11.520
Fine Particle Fraction[％] 62.696 60.464
MMAD[um] 3.592 3.706
GSD 2.473 2.523
R 2 0.999 0.999
递送速率与递送总量的测定
依法安装呼吸模拟器和装有滤纸的滤纸装置。取装有2ml帕拉米韦雾化吸入溶液(20mg/ml)的塑料安瓿，充分摇匀后，挤压安瓿瓶，将帕拉米韦雾化吸入溶液加入雾化杯中，将雾化杯与压缩机连接，将呼吸模拟器设定为成人模式(15循环/分钟的呼吸频率，潮汐量500ml，吸入与呼出时间之比1：1)。开启呼吸模拟器，将第一阶段的时间设置为1分钟，在呼吸循环的起始时启动压缩机，呼吸循环结束时同时关闭压缩机。用稀释液清洗回收滤纸、滤纸装置至同一100ml量瓶中，作为第一阶段供试品溶液。再依法安装呼吸模拟器、装有滤纸的滤纸装置、雾化杯、及配套的压缩机，开启呼吸模拟器，将第二阶段的时间设置为15分钟，在呼吸循环的起始时启动压缩机，呼吸循环结束时同时关闭压缩机。用稀释液清洗回收滤纸、滤纸装置至同一100ml量瓶中，作为第二阶段供试品溶液。
表7 递送速率与递送总量实验结果
  处方1 处方6
递送速率(mg/min) 2.23 2.27
递送总量(mg) 8.95 9.64
实验结果表明，高浓度的帕拉米韦雾化吸入溶液(20mg/ml)，递送总量大于8mg；FPD(微细粒子剂量)大于10mg，FPF(细微粒子有效沉积率)大于61％；MMAD(质量中质空气流动力学直径)为小于4μm，GSD(几何标准偏差)小于3.0，符合雾化吸入溶液制剂的质量要求
实验例2组织分布试验
实验方法：取SD雄性大鼠15只，随机分为3组，每组5只，通过静脉注射给予帕拉米韦 氯化钠注射液(批号：3139262，广州南新制药有限公司)，剂量为10mg/kg；分别于给药后5min,1h,3h眼眶静脉丛取血0.20ml后，动物麻醉处死后取肺组织(含气管)。全血经肝素钠抗凝后，离心(10000rpm,5min),取血浆部分；肺组织洗干净并称重，血浆与肺组织置于-20℃保存待测。
取SD雄性大鼠54只，随机分为9组，每组6只，通过雾化吸入给予帕拉米韦复方氯化钠溶液(处方1)，给药剂量分别为：低剂量：2.5mg/kg；中剂量：5mg/kg；高剂量：10mg/kg；，雾化吸入给药时间为30min；分别于给药后5min,1h,3h眼眶静脉丛取血0.20ml后，动物麻醉处死后取肺组织(含气管)。全血经肝素钠抗凝后，离心(10000rpm,5min),取血浆部分；肺组织洗干净并称重，血浆与肺组织置于-20℃保存待测。
收集处理分析：
肺组织收集
分别于给药后5min,1h,3h麻醉处死大鼠，称其体重并记录，随后解剖，取其肺组织(含气管)；用生理盐水将肺组织洗剂干净，用滤纸吸干残留液体，置于去皮的EP管中，称重并记录，最后置于-20℃冰箱中保存。
肺组织预处理
按照肺组织/生理盐水＝1g/4mL的比例，在肺组织中加入相应的生理盐水，用匀浆机制成匀浆液，离心(10000rpm,10min)，取上清液100μL，置于1.5mL离心管内，精密加入400μL 1μg/mL内标奥司他韦甲醇溶液，旋涡振荡1min混匀，12000rpm离心10min，取上清液100μL，然后加入100μL的水充分混匀后，待LC-MS/MS分析。
随行标准的肺组织预处理
用1mg/mL母液按照梯度稀释法配制浓度为0.5，1，5，10，50，100，200μg/mL的帕拉米韦标准液。取空白肺组织匀浆液90μL，分别精密加入上述各浓度标准液10μL，配置成浓度分别为0.05，0.1，0.5，1，5，10，20μg/mL的肺组织标准品，每种肺组织标准品加入400μL 1μg/mL内标奥司他韦甲醇溶液，旋涡振荡1min混匀，12000rpm离心10min，取上清液100μL，然后加入100μL的水充分混匀后，待做LC-MS-MS分析。每天肺组织的药物浓度均通过随行标准进行计算。
测定条件：
色谱条件：Agela公司Venusil XBP Phenyl column(100mm×2.1mm,5μm)；流动相A(0.1％甲酸水溶液，含2mM醋酸铵)：B(0.1％甲酸的甲醇)＝60：40；流速0.40mL/min；柱温40℃；进样量5μL。
质谱条件：离子源为电喷雾电离源(ESI)；检测方式：正离子检测；扫描方式：多反应监测(MRM)；喷射电压：5500V；离子源温度：550℃；气帘气流速为:25L/min，GS1:50L/min，GS2:50L/min，碰撞气流速为:6L/min，扫描时间0.2s，用于定量和定性的离子条件见表8与图2。
表8 帕拉米韦质谱分析参数表
  Q1(m/z) Q3(m/z) CE(V) DP(V) EP(V) CXP(V)
帕拉米韦 329.3 270.3 27 108 10.0 12.0
内标(磷酸奥司他韦) 313.3 225.2 14 67 10.0 12.0
肺组织药物浓度
经不同的给药方式、给药剂量，在5min，1h，3h时，研究结果(表9)表明，帕拉米韦静脉注射给药(10mg/kg)后在1h与3h时，肺组织中药物浓度均显著性低于雾化吸入给药各剂量组(P<0.001)；在5min时，静脉给药的肺组织药物浓度显著低于雾化吸入给药的中、高剂量组，但与低剂量雾化给药未有统计学意义的差异(P>0.05)。帕拉米韦肺组织的药物浓度与雾化吸入给药呈现剂量依赖性的特征，随剂量增加而增加。帕拉米韦两种给药方式在肺组织药物浓度的差异随时间延长差异愈大。同等剂量条件下(10mg/kg)，帕拉米韦雾化给药在各时间点的肺组织浓度是静脉给药的2.02-11.58倍；低剂量雾化吸入给药(2.5mg/kg)各时间点的肺组织浓度是静脉给药(10mg/kg)的1.07-4.58倍；中剂量雾化吸入给药(5mg/kg)各时间点的肺组织浓度是静脉给药(10mg/kg)的1.58-5.31倍。
Figure PCTCN2019110115-appb-000013
Figure PCTCN2019110115-appb-000014
表9 肺组织药物浓度实验结果
实验例3
超声雾化稳定性实验
将实施例1中的处方1、6的吸入溶液置于超声雾化器(2500KHz)中超声雾化，分别在0min、20min、40min、60min、90min后测定其有关物质含量，实验结果如表10。
表10 超声雾化稳定性结果
组别 0min 20min 40min 60min 90min
处方1 0.11％ 0.14％ 0.17％ 0.52％ 1.01％
处方6 0.10％ 0.16％ 0.19％ 0.23％ 0.39％
实验结果表明，处方1的帕拉米韦氯化钠溶液型吸入剂在2500KHz功率超声雾化40min以内，能保持较好的稳定性，但在1小时后，有关物质含量开始显著增加，可能超声对药物成分发生了降解以及进一步化学反应；而在处方中进一步加入磷酸二氢钠后，在超声雾化90min内有关物质相对增加不显著，显著提高了药物的超声稳定性。
以上所述仅为本发明的较佳实施例而已，并非用以限定本发明的实质技术内容范围，本发明的实质技术内容是广义地定义于申请的权利要求范围中，任何他人完成的技术实体或方法，若是与申请的权利要求范围所定义的完全相同，也或是一种等效的变更，均将被视为涵盖于该权利要求范围之中。

Claims (9)

  1. 一种帕拉米韦溶液型吸入剂，其特征在于，所述溶液型吸入剂由帕拉米韦、渗透压调节剂、pH调节剂和水制成，其中帕拉米韦的浓度大于15mg/ml，渗透压调节剂的浓度小于8mg/ml,所述溶液型吸入剂的pH值为5.0-6.0,且不采用加热灭菌，所述渗透压调节剂选自氯化钠或者葡萄糖，所述溶液型吸入剂雾化后，其质量中质空气流动力学直径(MMAD)在3-4um之间，细微粒子有效沉积率(FPF)在60％-80％之间。
  2. 如权利要求1所述的帕拉米韦溶液型吸入剂，其特征在于，帕拉米韦的浓度大于15mg/ml且小于25mg/ml，优选20mg/ml，渗透压调节剂的浓度小于8mg/ml且大于6mg/ml，优选7mg/ml，所述渗透压调节剂为氯化钠。
  3. 如权利要求1所述的帕拉米韦溶液型吸入剂，其特征在于，所述pH调节剂为稀盐酸。
  4. 如权利要求1所述的帕拉米韦溶液型吸入剂，其特征在于，所述pH值为5.5。
  5. 如权利要求1-4任意一项所述的帕拉米韦溶液型吸入剂，其特征在于，所述溶液型吸入剂雾化吸入1h后在肺组织药物浓度大于7ug/g,或者3h后在肺组织药物浓度大于5ug/g。
  6. 如权利要求1-4任意一项所述的帕拉米韦溶液型吸入剂，其特征在于，所述溶液型吸入剂的微细粒子剂量(FPD)大于10mg，粒子几何标准偏差小于3.0。
  7. 一种帕拉米韦溶液型吸入剂，其特征在于，所述溶液型吸入剂由帕拉米韦、渗透压调节剂、pH调节剂、磷酸二氢钠和水制成，其中帕拉米韦的浓度大于15mg/ml，渗透压调节剂的浓度小于8mg/ml,磷酸二氢钠的浓度为0.05-0.2mg/ml，所述溶液型吸入剂的pH值为5.5,且不采用加热灭菌，所述渗透压调节剂选自氯化钠或者葡萄糖，所述溶液型吸入剂雾化后，其质量中质空气流动力学直径(MMAD)在3-4um之间，细微粒子有效沉积率(FPF)在60％-80％之间。
  8. 权利要求1-7任意一项所述的帕拉米韦溶液型吸入剂，其特征在于，所述溶液型吸入剂在高温30天后，有关物质含量小于0.3％。
  9. 根据权利要求1-8任意一项所述的帕拉米韦溶液型吸入剂的制备方法， 其特征在于，所述制备方法包括如下步骤：
    将帕拉米韦原料与辅料混合，加70-80℃的水至1000ml，搅拌溶解后冷却，再用稀盐酸将溶液pH值调节在5.0-6.0之间，然后将帕拉米韦溶液通过预过滤后，再无菌过滤，无菌灌装后即得。
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