WO2021203914A1 - 一种帕拉米韦干粉吸入剂及其制备方法 - Google Patents

一种帕拉米韦干粉吸入剂及其制备方法 Download PDF

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Publication number
WO2021203914A1
WO2021203914A1 PCT/CN2021/080768 CN2021080768W WO2021203914A1 WO 2021203914 A1 WO2021203914 A1 WO 2021203914A1 CN 2021080768 W CN2021080768 W CN 2021080768W WO 2021203914 A1 WO2021203914 A1 WO 2021203914A1
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Prior art keywords
dry powder
peramivir
powder
inhalation
preparation
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PCT/CN2021/080768
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English (en)
French (fr)
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缪栋
胡双华
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广州南鑫药业有限公司
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Priority to JP2022561678A priority Critical patent/JP2023521396A/ja
Priority to EP21783838.2A priority patent/EP4134074A4/en
Publication of WO2021203914A1 publication Critical patent/WO2021203914A1/zh
Priority to US17/963,176 priority patent/US20230052424A1/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
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • 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
    • A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
    • A61M15/00—Inhalators
    • A61M15/0028—Inhalators using prepacked dosages, one for each application, e.g. capsules to be perforated or broken-up
    • A61M15/003—Inhalators using prepacked dosages, one for each application, e.g. capsules to be perforated or broken-up using capsules, e.g. to be perforated or broken-up
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
    • A61M2202/00—Special media to be introduced, removed or treated
    • A61M2202/06—Solids
    • A61M2202/064—Powder

Definitions

  • the invention relates to the technical field of medicine, in particular to a peramivir dry powder inhaler and a preparation method thereof.
  • Cyclopenta-1-carboxylic acid is a cyclopentane derivative influenza virus neuraminidase (NA) inhibitor.
  • peramivir Due to the low oral availability of peramivir, it is mainly made into parenteral preparations such as injections. Peramivir can play an anti-influenza effect by staying in the respiratory organs of patients. Therefore, peramivir is made into The inhalant directly reaches the respiratory organ tissue lesions through non-oral routes, reducing potential adverse reactions to other tissues throughout the body. Since inhalants have a variety of dosage forms, including dry powder inhalants, sprays, solution inhalants and so on. The applicant protects a peramivir solution type inhalant in CN109771398B. The patent points out that it is difficult to inhale a sufficient amount of medicine with dry powder inhalation preparations for children or elderly people, patients with low respiratory function and other people who have difficulty breathing.
  • solution inhalants are more convenient for such patients.
  • solution formulations need to solve more stability problems, and dry powder inhalants have better formulation stability, convenient carrying, and a wide range of dosages. Therefore, the present invention focuses on the development of solid inhalation formulations of peramivir .
  • Peramivir has a good effect in the prevention and treatment of avian influenza.
  • the pandemic of the new crown pneumonia virus (COVID-19) has presented unprecedented challenges to the public health system. There are not many direct, fast and efficient drugs to choose from. With the evolution of the virus, the blurring of the boundary between humans and animals, the high degree of urbanization, the more frequent interpersonal communication, the developed transportation network, and the intensification of agriculture, the occurrence of virus epidemics in the future will become more frequent and more challenging, and avian influenza is one of them. Therefore, in order to prevent bird flu from hitting the public health system, the inventor focused on developing solid inhalation preparations to provide more efficient and effective solutions.
  • Miao Xu reported that the forces affecting the atomization and dispersion performance of particles mainly include cohesion and adhesion. These forces depend on many factors, such as the inherent properties of the powder (surface energy, chemical groups), particle characteristics (particle size distribution, morphology, Roughness, porosity), and environmental conditions (mechanical process, temperature, relative humidity), etc.
  • the main problem is the loss of the drug before it enters the lungs.
  • the following aspects need to be considered: (1) Preparation of drug powder; (2) Whether to add a carrier; (3) Atomization of the powder and delivery to the lungs through an inhalation device Department. All these factors will affect the deposition of drug particles in the lungs and the therapeutic effect.
  • the good dispersibility of the powder is conducive to the "atomization" of the powder into inhalable drug particles, which improves the accuracy of the inhaled dose.
  • the reasons that affect powder fluidity and dispersion mainly include 1. Van der Waals force: particle size, surface roughness, geometric shape and particle deformation can all significantly affect van der Waals force. 2. Electrostatic force: The static electricity generated by the friction between particles in the production process of dry powder inhalants will affect its fluidity, dispersion and adhesion and other powder properties, thereby affecting its formulation, production and use. 3.
  • Capillary force Due to the moisture absorption of the particles, surface tension and capillary attraction will be generated after the surface of the particles absorb water, which affects the size and crystal form of the particles, causing the powder to aggregate and destroying its dispersibility. 4. Shear force between particles with irregular shapes. 5. The friction generated when the particles move relative to each other.
  • Adding a carrier has the following advantages: improving the fluidity of the powder and improving the lung deposition performance of the drug. Increase single dose
  • the volume of the medicine enables the accurate dispensing of small doses of medicine to be realized, thereby improving the reproducibility of the delivery dose of inhaled medicine.
  • the addition of the carrier has also caused some problems.
  • the surface adsorption of the drug-containing fine powder and the carrier is too strong, so that the drug cannot be separated from the carrier after inhalation, and deposited together in the oropharynx, resulting in a decrease in the effective amount of drug entering the respiratory tract and a decrease in lung deposition performance. .
  • excipient-finer powder can also be added to the drug powder, which can significantly improve the flow properties of dry powder inhalants, such as leucine and phospholipids. But sometimes the addition of finer powder can not significantly improve the fluidity of the powder.
  • the type, particle size, surface roughness, particle deformation, gas adsorption, etc. of drug powder and finer powder can all affect the interaction between particles.
  • Tian Pei reported that the atomization of dry drug powder is a process that is affected by multiple factors. It is not only affected by the type, particle size, morphology, and surface charge of the carrier, but also by the surface roughness and crystallinity of the carrier.
  • Li Zhiwan reported that frictional electrification between particles and between particles and walls is a common phenomenon in powder aerosols. Static electricity is complicated and difficult to study and control. This is because the charge carried by the inhaled dry powder is related to the physical and chemical properties of the powder, the design of the inhalation device, and environmental factors, and is the result of a combination of many factors. Therefore, small changes in the physical and chemical properties of the powder or changes in methodology will seriously affect the electrostatic behavior of inhaled dry powder.
  • dry powder inhalants of medicines usually add carriers and/or excipients to improve the performance of the particles.
  • the inhalation effect of dry powder inhalers is affected by a combination of many factors, and various factors influence each other, resulting in changing one of the factors, and the other Factors and variables affect the reversal of the results. Therefore, the development of a clinically usable dry powder inhalant for pharmacy still faces many technical challenges.
  • the purpose of the present invention is to overcome the shortcomings of the prior art and provide a new formulation form of peramivir inhalation, that is, a solid dry powder inhalation preparation.
  • the dry powder inhalation does not require carriers and auxiliary materials; Uniform distribution of particle size range, shape, powder fluidity, not easy to agglomerate, can effectively increase the dose of one-time administration, and has suitable pharmaceutical stability.
  • the present invention also provides a more effective dry powder preparation method, which uses airflow to pulverize peramivir trihydrate to obtain micropowders with specific particle diameters and shapes, which can achieve effective pulmonary delivery of drugs.
  • a peramivir dry powder inhalation is made of peramivir or an acceptable salt or hydrate thereof, wherein the single-dose preparation is 5-30 mg, and the dry powder particle size distribution D10 is 1.3-3um; D50 is 3-6um; D90 is 6-13um.
  • the dry powder has an angle of repose of 33-37 degrees, preferably 34, 35, 36 degrees, a bulk density of 0.23-0.28g/cm 3 , preferably 0.24, 0.25, 0.26, 0.27g/cm 3 , and a tap density of 0.39-0.44g/cm 3 , preferably 0.40, 0.41, 0.42, 0.43 g/cm 3 .
  • the Carr flow index of the above dry powder is 58-65, preferably 59, 60, 61, 62.
  • the percentage of fine drug particles (FPF) of the dry powder smaller than 4.46 ⁇ m is greater than 30% and less than 45%, preferably 32%, 33%, 34%, 35%, 36%, 37%, 38%, 40%, 41%, more preferably 34-38%.
  • the aerodynamic particle size of the above dry powder is greater than 2.5um and less than 3.6um, preferably 2.8-3.5um or 2.6-3.1um or 2.9-3.4um, more preferably 3.0-3.2um or 3.1-3.3um.
  • the dry powder particle size distribution D10 is 1.3-2.5um, D10 is preferably 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2.1, 2.2, 2.3, 2.4um; D50 is preferably 3.5, 4.5, 5, 5.5um; D90 is preferably 6.2, 6.5, 7, 7.5, 7.8, 8.0, 8.4, 9.0, 10, 11, 12um.
  • the above dry powder inhalant is made of peramivir trihydrate.
  • the present invention also provides a single-dose peramivir dry powder inhalation preparation, which is prepared from the above dry powder into a capsule dosage form, a vesicle dosage form, and a storage dosage form, and the dry powder loading amount per unit preparation dosage form is 5-30 mg, preferably 20 mg.
  • the capsule is prepared by adding the above-mentioned dry powder to the hypromellose capsule shell, and the dry powder in each capsule is 10-30 mg, preferably 20 mg.
  • the peramivir dry powder inhalation preparation of the present invention further contains a carrier and/or auxiliary material, or does not contain a carrier and/or auxiliary material. More preferably, it does not contain carriers and/or auxiliary materials.
  • the aforementioned carrier and/or auxiliary material is selected from one or more of lactose, mannitol, leucine, and phospholipids.
  • the present invention also provides a preparation method of peramivir dry powder inhalant, which pulverizes the peramivir trihydrate compound by airflow at a feed rate of 120-140V and a feed pressure of 0.4-0.55 MPa, preferably 0.42, 0.45, 0.48 , 0.5, 0.52, 0.55 MPa; pulverized to obtain a dry powder under the conditions of a pulverizing pressure of 0.4-0.6 MPa, preferably 0.42, 0.45, 0.5, 0.52, 0.55, 0.58 MPa.
  • the present invention also provides another preparation method of peramivir dry powder inhalation medicine, which is prepared by filling the dry powder prepared above and adding suitable auxiliary materials into hypromellose capsules, and mixing the above dry powder with suitable auxiliary materials
  • the mixed micropowder is obtained uniformly or processed by a suitable method, and each capsule is made by adding the mixed micropowder, and each capsule contains 10-30mg of the micropowder, preferably 20mg.
  • the present invention also provides a peramivir dry powder inhalant, which is prepared from peramivir or an acceptable salt or hydrate thereof, and mannitol, wherein the mass ratio of the active ingredient of the drug to the mannitol is 1: (1-5), preferably 1:1, 1:2.
  • a peramivir dry powder inhalant which is prepared from peramivir or an acceptable salt or hydrate thereof, and mannitol, wherein the mass ratio of the active ingredient of the drug to the mannitol is 1: (1-5), preferably 1:1, 1:2.
  • it is prepared by mixing peramivir or its acceptable salt or its hydrate spray-dried powder and mannitol.
  • the dry powder ⁇ bulk density (g/cm 3 ) is 0.13-0.35, preferably 0.14, 0.18, 0.20, 0.23, 0.25, 0.28, 0.3.
  • the ⁇ tap density (g/cm 3 ) is 0.13-0.36, preferably 0.14, 0.18, 0.20, 0.23, 0.25, 0.28, 0.3, 0.33.
  • Median particle diameter D g ( ⁇ m) 3.4-9um, preferably 3.5, 3.6, 3.8, 4.0, 4.4, 4.6, 4.8, 5.0, 5.2, 5.5, 6.0, 6.5, 7.0, 7.4, 7.8, 8.0, 8.5, 9.0um .
  • the angle of repose is 29-35 degrees, preferably 30, 31, 32, 33, 34 degrees.
  • the present invention also provides a peramivir dry powder inhalant, which is prepared from peramivir or its acceptable salt or hydrate thereof, and mannitol, wherein the mass ratio of the active ingredient of the drug to lactose is 1:( 1-4), preferably 1:1, 1:2.
  • a peramivir dry powder inhalant which is prepared from peramivir or its acceptable salt or hydrate thereof, and mannitol, wherein the mass ratio of the active ingredient of the drug to lactose is 1:( 1-4), preferably 1:1, 1:2.
  • it is prepared by mixing peramivir or its acceptable salt or its hydrate with jet pulverized powder and lactose.
  • the lactose is selected from Inhalac 120 or Inhalac 400, more preferably Inhalac 120.
  • the dry powder ⁇ bulk density (g/cm 3 ) is 0.3-0.5, preferably 0.32, 0.36, 0.4, 0.45, 0.5.
  • the ⁇ tap density (g/cm 3 ) is 0.5-0.7, preferably 0.55, 0.56, 0.58, 0.6, 0.62, 0.64, 0.66, 0.68.
  • Aerodynamic particle diameter D a ( ⁇ m) of 5.5-6.5um, preferably 5.2,5.4,5.6,5.8,6.0,6.2um.
  • the angle of repose is 34-40 degrees, preferably 34.5, 35, 35.5, 36, 37, 38 degrees.
  • the preparation method of the peramivir dry powder inhalant of the present invention is simple and convenient, which ensures the safety of the medicine while ensuring the effectiveness of the medicine.
  • the peramivir dry powder inhalant of the present invention has a suitable particle size range, shape, powder fluidity, is not easy to agglomerate, can effectively reduce a single dose, and has suitable pharmaceutical stability.
  • the peramivir dry powder inhalant of the present invention uses airflow to pulverize peramivir trihydrate, which can obtain micropowders with specific particle diameters, shapes, etc., and achieve effective pulmonary delivery of the drug.
  • the peramivir dry powder inhalant of the present invention can effectively reduce the titer of influenza A virus in the lungs of mice, has a significant antiviral effect, can significantly prolong survival time, reduce mortality, and has better efficacy than Peramivir sodium chloride injection and oseltamivir phosphate.
  • the method of the present invention is as follows:
  • Measurement of bulk density and tapped density transfer the drug powder evenly to a graduated cylinder, tap the drug powder in the graduated cylinder 100 times, and record the weight and volume of the drug before and after tapping.
  • Measurement of powder particle size Take the drug powder and measure its powder particle size on a laser particle size analyzer.
  • D g and aerodynamic diameter D a determine the median diameter (D g ); the calculation formula of aerodynamic diameter (D a , MMAD) is:
  • the spray drying process parameters are the inlet air temperature of 200°C, the outlet air temperature of 100°C, and the speed: 400ml/h.
  • the powder obtained was passed through a 180-mesh sieve.
  • the experimental results are as follows:
  • the spray-dried powder is mixed with mannitol as a dry powder, and the ratio (w/w) of the spray-dried powder of peramivir and mannitol of the composition 1 above (w/w): 1:1; 1:2; 1:5 is thoroughly mixed.
  • the experimental results are as follows:
  • Prescription 1 Peramivir micronized dry powder, the raw material of Peramivir is pulverized by airflow, and the dry powder is prepared under the conditions of a feed rate of 130V, a feed pressure of 0.45MPa, and a crushing pressure of 0.45MPa.
  • Recipe 2 Mix the dry powder prepared above and Inhalac 120 lactose to make a mixed powder, and mix it according to a mass ratio of 1:1.
  • Recipe 3 Mix the above-prepared dry powder and lactose Inhalac 400 to make a mixed powder, which is mixed according to a mass ratio of 1:1.
  • prescription one is close to prescription two, while prescription three is much smaller, and prescription three is similar to the 10% stipulated in the pharmacopoeia.
  • the three particles of Pain Prescription are mainly blocked in the throat, which may be blocked due to the fact that too fine lactose particles are prone to generate static electricity. It can be seen that prescription 3 is not suitable as a prescription for peramivir dry powder.
  • the capsules of the above prescription 1-2 were placed at 60°C for 0 days, 5 days and 10 days respectively, the appearance changes of the mixture were observed, and the following indexes were tested.
  • each capsule has a sample volume of 20mg, connect the delivery volume equalization device, turn on the pump, connect the flow meter to the collection tube, place filter paper on one end of the collection tube, connect the flow meter to the other end, and connect the DUSA tube to Flow meter, install the empty capsule with a written test device and make a hole to measure the flow rate.
  • Turn on the TPK instrument press the set up button on the TPK instrument to set, then press “OK”, then press “set P1, adjust the flow rate to 60L/min. Press “set flow”, and press “Yes” when flow (Q) appears , And then press “Yes” to record the value on the screen and remove the flow meter.
  • the sample (20mg/capsule) is accurately quantified by manual capsule filling, so the delivered dose meets the pharmacopoeial standard (the average value is between 75% and 125%), and High temperature has little effect on the uniformity of delivered dose.
  • Crush 1.3 kg of peramivir trihydrate raw material with a jet mill, pulverize at a feed rate of 130V, feed pressure of 0.45MPa, and crushing pressure of 0.40MPa to obtain a dry powder, and then fill the dry powder into hypromellose fiber Vegetarian capsules, each capsule is filled with 20mg dry powder.
  • the dry powder particle size D10 is 1.934um; D50 is 4.415um; D90 is 8.858um.
  • the angle of repose is 34.8 degrees, the bulk density is 0.25g/cm 3 , the tap density is 0.41g/cm 3 , and the Carr flow index is 59.0.
  • Crush 1.3 kg of peramivir trihydrate raw material with a jet mill, pulverize at a feeding speed of 125V, a feed pressure of 0.50MPa, and a crushing pressure of 0.45MPa to obtain a dry powder, and then fill the dry powder into hypromellose fiber Vegetarian capsules, each capsule is filled with 20mg dry powder.
  • the dry powder particle size D10 is 1.447um; D50 is 3.269um; D90 is 6.988um.
  • the angle of repose is 35.3 degrees, the bulk density is 0.26g/cm 3 , the tap density is 0.43g/cm 3 , and the Carr flow index is 60.0.
  • Crush 1.3 kg of peramivir trihydrate raw material with a jet mill, pulverize at a feed speed of 135V, feed pressure 0.42MPa, and crush pressure 0.40MPa to obtain a dry powder, and then fill the dry powder into hypromellose fiber Vegetarian capsules, each capsule is filled with 20mg dry powder.
  • the dry powder particle size D10 is 2.034um; D50 is 5.716um; D90 is 12.67um.
  • the angle of repose is 34.1 degrees, the bulk density is 0.23 g/cm 3 , the tap density is 0.39 g/cm 3 , and the Carr flow index is 61.0.
  • Crush 1.3 kg of peramivir trihydrate raw materials with a jet mill, pulverize at a feed rate of 140V, feed pressure of 0.40 MPa, and crush pressure of 0.35 MPa to obtain a dry powder, and then fill the dry powder into hypromellose fiber Vegetarian capsules, each capsule is filled with 15mg dry powder.
  • the dry powder particle size D10 is 2.89um; D50 is 7.78um; D90 is 16.39um.
  • the angle of repose is 33.7 degrees, the bulk density is 0.24 g/cm 3 , the tap density is 0.41 g/cm 3 , and the Carr flow index is 65.0.
  • Crush 1.3 kg of peramivir trihydrate raw material with a jet mill, pulverize at a feed rate of 120V, feed pressure of 0.60 MPa, and crush pressure of 0.40 MPa to obtain a dry powder, and then fill the dry powder into hypromellose fiber Vegetarian capsules, each capsule is filled with 15mg dry powder.
  • the dry powder particle size D10 is 1.332um; D50 is 3.015um; D90 is 5.658um. 38.4 degree angle of repose, bulk density 0.28g / cm3, a tap density of 0.47g / cm 3, Carr flow index 66.0.
  • Example 1 The dry powder of Example 1 was subjected to NGI delivery to test the in vitro deposition rate of the sample.
  • the samples were filled with single-dose capsules, tested three times, and delivered 10 capsules each time.
  • the sample passes the NGI delivery test.
  • Each NGI receiving cup/pan sample tray is cleaned separately and the volume is fixed with a volumetric flask, and the HPLC content detection method is used for content detection.
  • Example 4 has an excellent in vitro deposition rate.
  • Example 3 The samples of Example 3 were taken at high temperature (60° C.) on the 0th day, the 5th day, the 10th day, and the 30th day respectively, and the NGI deposition rate in vitro was investigated.
  • the dry powder inhalant of the present invention has excellent stability at high temperature.
  • mice half male and half male, weighing 16.9-22.6g, were randomly divided into 8 groups according to gender and body weight, namely the normal control group, the virus model group, and the oseltamivir phosphate capsule group (Tamiflu ) (10mg/kg), Peramivir intravenous injection group (10mg/kg), Peramivir powder aerosol (Example 3) Group I to IV (0.1, 0.3, 0.9, 2.7 mg/kg), each Group of 10 animals.
  • Tamiflu oseltamivir phosphate capsule group
  • Tamiflu Peramivir intravenous injection group
  • Peramivir powder aerosol Example 3
  • Group I to IV 0.1, 0.3, 0.9, 2.7 mg/kg
  • mice in each group were lightly anesthetized with ether and instilled into the A/PR/8/34 influenza virus liquid (diluted influenza virus stock solution with 4°C pre-cooled blank medium to 5LD 50 concentration dilution liquid) 60 ⁇ L/mouse, normal In the control group, an equal volume of blank medium was dripped through the nose.
  • peramivir intravenous injection was prepared with 0.9% sodium chloride injection to prepare 1.0 mg/mL liquid, and oseltamivir phosphate capsules were prepared with pure water to prepare 0.5 mg/mL liquid.
  • Mice in each group were administered 2 hours after nasal infusion and modeling, among which peramivir powder mist was given to each group of animals with the corresponding dose of peramivir powder mist.
  • Peramivir intravenous injection group was given 10 mL Peramivir solution was given by intravenous injection per kg, the oseltamivir phosphate capsule group was given 20mL/kg intragastrically with oseltamivir phosphate solution, the normal control group and the model control group were sprayed with equal volume of air through the trachea.
  • the drug was administered once a day for 5 consecutive days, and the day after the nasal drip was used as the first day after virus infection (D1).
  • the average survival time of mice in the virus control group was 6.2 days, and the average survival time was significantly shortened (P ⁇ 0.01).
  • the average survival time of peramivir powder in the I and II groups was prolonged to a certain extent, there was no statistical difference (P>0.05).
  • Oseltamivir phosphate group and peramivir intravenous injection Compared with the virus control group, the average survival time of the peramivir powder spray group III-IV group was significantly prolonged (P ⁇ 0.05 or P ⁇ 0.01).
  • peramivir inhalation powder administered 2 hours after exposure can significantly prolong survival time, reduce mortality, have obvious protective effects in vivo, and have a significant dose-effect relationship.
  • 0.9mg/kg paramivir The medicinal effect of mivir inhalation powder mist is better than peramivir sodium chloride injection (10mg/kg) and oseltamivir phosphate capsules (10mg/kg).
  • mice half male and half male, weighing 21.2-26.6g, were randomly divided into 7 groups according to gender and body weight, namely the normal control group, the virus model group, and the oseltamivir phosphate capsule group (Tamiflu ) (10mg/kg), Peramivir intravenous injection group (10mg/kg), Peramivir powder aerosol (Example 3) Groups I to III (0.1, 0.3, 0.9 mg/kg), 12 per group Animals (F04 ⁇ F06, M04 ⁇ M06 in the group are used for 24h blood coagulation titer measurement, F01 ⁇ F03, M01 ⁇ M03 are used for 48h blood clot titer measurement).
  • Tamiflu oseltamivir phosphate capsule group
  • Tamiflu oseltamivir phosphate capsule group
  • Peramivir intravenous injection group 10mg/kg
  • Peramivir powder aerosol Example 3
  • Groups I to III 0.1, 0.3, 0.9 mg/kg
  • mice in each group were lightly anesthetized with ether and instilled into the A/PR/8/34 influenza virus liquid (diluted influenza virus stock solution with 4°C pre-cooled blank medium to 5LD 50 concentration dilution liquid) 60 ⁇ L/mouse, normal In the control group, an equal volume of blank medium was dripped through the nose.
  • peramivir intravenous injection was prepared with 0.9% sodium chloride injection to prepare 1.0 mg/mL liquid, and oseltamivir phosphate capsules were prepared with pure water to prepare 0.5 mg/mL liquid.
  • Mice in each group were given administration 2 hours after nasal infusion, and peramivir powder aerosol. Each group of animals was given peramivir powder aerosol of corresponding quality.
  • Peramivir intravenous injection group was given 10 mL Peramivir solution was given by intravenous injection per kg, the oseltamivir phosphate capsule group was given 20mL/kg intragastrically with oseltamivir phosphate solution, the normal control group and the model control group were sprayed with equal volume of air through the trachea. It is administered once a day for 2 consecutive days.
  • mice in the normal control group were not infected with the virus, and the hemagglutination titer was zero.
  • the pulmonary blood coagulation titer of the virus control group increased significantly at 24h and 48h after infection (P ⁇ 0.01).
  • the pulmonary blood coagulation titers of the oseltamivir phosphate capsule group, the peramivir intravenous injection group, and the peramivir inhalation group I ⁇ III were significantly reduced at 24h and 48h after infection (P ⁇ 0.01 ).
  • peramivir inhalation powder can effectively reduce the titer of influenza A virus in the lungs of mice after 2 hours of exposure, indicating that it has a significant antiviral effect and a significant dose-effect relationship.
  • peramivir inhalation powder mist per kg is better than peramivir sodium chloride injection (10mg/kg) and oseltamivir phosphate capsules (10mg/kg).

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Abstract

本发明涉及一种帕拉米韦干粉吸入剂，由帕拉米韦或其可接受的盐或其水合物制成，其中单剂量制剂为5-30mg，所述干粉粒径D10为1.3-2.2um；D50为3-6um；D90为6-13um。能有效的降低小鼠肺脏内甲型流感病毒的效价，具有显著的抗病毒作用，能显著延长生存时间，降低死亡率，药效作用优于帕拉米韦氯化钠注射液以及磷酸奥司他韦。具由明确的肺靶向作用，显著提高了药物的有效性和安全性。

Description

一种帕拉米韦干粉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干粉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。
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，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。申请人在CN109771398B中保护一种帕拉米韦溶液型吸入剂，该专利指出对于儿童或高龄者、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。但是在研究过程中也发现溶液型制剂，需要解决更多稳定性问题，而干粉吸入剂药物处方稳定性更好、携带方便、剂量范围广，因而本发明着重开发帕拉米韦的固体吸入制剂。
帕拉米韦在防治禽流感具有较好的作用，新冠肺炎病毒(COVID-19)疫情的大流行，对公共卫生系统提出了前所未有的挑战，可直接、快速高效的药物选择不多，而随着病毒的进化、人类与动物边界模糊、高度城市化、人际交往越频繁、发达的交通网络以及农业的集约化，未来病毒流行病发生更加频繁、更具挑战，而禽流感即是其中一种，因此，为预防禽流感冲击公共卫生系统，发明人着眼开发固体吸入制剂，以提供更高效、有效的解决方案。
缪旭报道影响粒子雾化分散性能的作用力主要包括内聚力和黏附力，这些作用力取决于诸多因素，如粉末的固有性质(表面能、化学基团)，粒子特征(粒径分布、形态、粗糙度、孔隙率)，以及环境条件(机械过程、温度、相对湿度)等。一直制约肺部给药制剂发展的一
个主要问题是药物进入肺部前的损失。肺部给药要达到很好的临床治疗效果，需要着重考虑以下几个方面：(1)药物粉末的制备；(2)是否加入载体；(3)粉末的雾化及通过吸入装置传递到肺部。所有这些因素都会影响药物颗粒在肺部的沉积及治疗效果。
王晓波报道干粉吸入剂通常可分成无载体、药物-载体、药物-辅料、药物-载体-辅料4种类型,而粒子粒径、形态、密度都是重要影响因素，粒子的形态千变万化,有球形、针形、多角形、枝状、纤维状和片状等。如果粒子形态不规则或偏离球体较远,会显著影响空气动力学行为,一般认为,球形的气雾粒子较好。颗粒密度也是影响干粉吸入剂肺部沉积性能的重要因素。另外，粉末的分散性好,则有利于粉末“雾化”成可吸入的药物粒子,提高吸入剂量的准确性。影响粉末流动性及分散性的原因,主要包括1、范德华力:粒子粒径大小、表面粗糙度、几何形态及粒子的形变等均能显著影响范德华力。2、静电力:干粉吸入剂在生产过程中由于颗粒间的摩擦产生的静电会影响其流动性、分散性和粘附性等粉体学性质,从而影响其组方、生产和使用。3、毛细管力:由于粒子的引湿性,其表面吸附水分后会产生表面张力及毛细管引力,影响粒子的大小、结晶形态,使粉末聚集,破坏其分散性。4、形态不规则粒子间的剪切力。5、粒子间作相对运动时产生的摩擦力。
加入载体具有以下优点:改善粉末流动性,提高药物的肺沉积性能。增加单剂量的给
药体积,使小剂量药物的准确分装得以实现,从而提高吸入药物转运剂量的重现性。但载体的加入也引发了一些问题,含药细粉与载体的表面吸附太强,以致药物吸入后不能脱离载体,一起沉积于口咽部,导致进入呼吸道的有效药量降低、肺沉积性能下降。
还可以在药物粉末中加入另一种辅料-更细粉,能够显著提高干粉吸入剂的流动性能，如亮氨酸、磷脂等。但是有时更细粉的加入并不能明显改善粉末的流动性,药物粉末和更细粉的类型、粒径大小、表面粗糙度、粒子的形变、气体吸附等均能影响颗粒间的相互作用。
田沛报道药物干粉的雾化是一个多因素共同影响的过程，不仅受载体种类、粒径、形态和表面电荷影响，还受载体表面粗糙度和结晶度影响。
李志万报道颗粒之间与颗粒-器壁间的摩擦起电是粉雾剂较为常见的现象。静电现象是复 杂的并且较难研究与把控。这是因为吸入干粉携带的电荷与粉末的理化性质、吸入装置的设计以及环境因素相关，并且是许多因素综合作用的结果。因此粉末理化性质的微小变化或方法学的改变都将严重影响吸入干粉的静电行为。
朱万辉报道流动性、分散性等宏观特性取决于粒子间内聚力(药物/药物)和黏附力(药物/载体)的相对强度。粒子间作用力必须足够大以保持贮存和使用中制剂稳定性，又能在吸入前或吸入中允许药物解聚。药物、载体及辅料的物料性质、环境以及处理条件则决定了各种粒子间作用力(主要是范德华力、毛细管力、静电作用力以及表面粗糙引起的机械交联等)的相对大小。在制备过程中，必须在贮存和处理过程中的混合稳定性与吸入分散过程中取得平衡，这就要求控制粒子间作用力。与这些过程相关的变量会以不同的方式影响彼此，通过改变其中一个变量，其他变量影响的结果就可能逆转，这就发生一些关于单个变量影响的文献得出相反结论的现象。
目前药物干粉吸入剂通常会加入载体和/或辅料，以改善粒子性能，但干粉吸入剂的吸入效果受多种因素综合影响，而各种因素之间又相互影响，导致改变其中一个因素，其它因素变量影响结果发生逆转的情况，因此，开发一个药学临床可用的干粉吸入剂仍面临多种技术挑战。
发明内容
本发明的目的是克服现有技术的缺陷，提供了一种帕拉米韦吸入剂新的制剂形式，即固体干粉吸入制剂，该干粉吸入剂无需载体、辅料；具有适宜的肺部可吸收的分布均匀粒径范围、形态、粉体流动性，不易聚集成团，能有效提高一次给药剂量，具有适宜的药学稳定性。另一方面本发明还提供了一种更有效的干粉制备方法，采用气流粉碎帕拉米韦三水合物，获得特定粒径、形态等的微粉，能实现药物的有效肺部递送。
本发明解决该技术问题的技术方案是：
一种帕拉米韦干粉吸入剂，所述干粉吸入剂由帕拉米韦或其可接受的盐或其水合物制成，其中单剂量制剂为5-30mg，所述干粉粒径分布D10为1.3-3um；D50为3-6um；D90为6-13um。
所述干粉休止角33-37度，优选34、35、36度，松密度0.23-0.28g/cm 3，优选0.24、0.25、0.26、0.27g/cm 3，振实密度0.39-0.44g/cm 3，优选0.40、0.41、0.42、0.43g/cm 3。
上述干粉Carr流动指数58-65，优选59、60、61、62。
上述干粉小于4.46μm微细药物粒子百分比(FPF)大于30％且小于45％，优选32％、33％、34％、35％、36％、37％、38％、40％、41％，更优选34-38％。
上述干粉的空气动力学粒径大于2.5um且小于3.6um，优选2.8-3.5um或2.6-3.1um或2.9-3.4um，更优选3.0-3.2um或3.1-3.3um。
上述干粉粒径分布D10为1.3-2.5um，D10优选1.4、1.5、1.6、1.7、1.8、1.9、2.1、2.2、2.3、2.4um；D50优选3.5、4.5、5、5.5um；D90优选6.2、6.5、7、7.5、7.8、8.0、8.4、9.0、10、11、12um。
上述干粉吸入剂由帕拉米韦三水化合物制成。
本发明还提供一种单剂量帕拉米韦干粉吸入制剂，其由上述干粉制成胶囊剂型、囊泡剂型、储库剂型，每单位制剂剂型干粉载药量为5-30mg，优选20mg。
优选胶囊剂，其由上述干粉加入羟丙甲纤维素胶囊壳制成，每粒胶囊中干粉10-30mg，优选20mg。
本发明的帕拉米韦干粉吸入制剂进一步含有载体和/或辅料，或者不含有载体和/或辅料。更优选不含有载体和/或辅料。
上述载体和/或辅料选自乳糖、甘露醇、亮氨酸、磷脂中的一种或多种。本发明还提供一种帕拉米韦干粉吸入剂的制备方法，将帕拉米韦三水化合物用气流粉碎，在进料速度120-140V进料压力0.4-0.55MPa，优选0.42、0.45、0.48、0.5、0.52、0.55MPa；粉碎压力0.4-0.6MPa条件下粉碎制得干粉，优选0.42、0.45、0.5、0.52、0.55、0.58MPa。
本发明还提供另一种帕拉米韦干粉吸入药物的制备方法，将上述制备得到的干粉，以及添加合适的辅料装入到羟丙甲纤维素胶囊中制得，将上述干粉与合适辅料混合均匀或经过合适的方法处理得到混合微粉，每粒胶囊中加入混合后的微粉制成，每粒胶囊含有微粉10-30mg，优 选20mg。
本发明还提供一种帕拉米韦干粉吸入剂，其由帕拉米韦或其可接受的盐或其水合物，和甘露醇制成，其中药物活性成分和甘露醇的质量比为1：(1-5)，优选1：1，1：2。优选由帕拉米韦或其可接受的盐或其水合物的喷雾干燥粉末，和甘露醇混合制成。其干粉剂ρ松密度(g/cm 3)为0.13-0.35，优选0.14，0.18，0.20，0.23，0.25，0.28，0.3。ρ振实密度(g/cm 3)为0.13-0.36，优选0.14，0.18，0.20，0.23，0.25，0.28，0.3，0.33。中位粒径D g(μm)3.4-9um，优选3.5，3.6，3.8，4.0，4.4，4.6，4.8，5.0，5.2，5.5，6.0，6.5，7.0，7.4，7.8，8.0，8.5，9.0um。空气动力学粒径D a(μm)为1.8-6um，优选2.0，2.2，2.4，2.6，2.8，3.0，3.2，3.4，3.6，3.8，4.0，4.4，4.8，5.2，5.4，5.6，5.8um。休止角为29-35度，优选30，31，32，33，34度。
本发明还提供一种帕拉米韦干粉吸入剂，其由帕拉米韦或其可接受的盐或其水合物，和甘露醇制成，其中药物活性成分和乳糖的质量比为1：(1-4)，优选1：1，1：2。优选由帕拉米韦或其可接受的盐或其水合物的气流粉碎粉末，和乳糖混合制成。所述乳糖选自Inhalac 120或Inhalac 400，更优选Inhalac 120。其干粉剂ρ松密度(g/cm 3)为0.3-0.5，优选0.32，0.36，0.4，0.45，0.5。ρ振实密度(g/cm 3)为0.5-0.7，优选0.55，0.56，0.58，0.6，0.62，0.64，0.66，0.68。空气动力学粒径D a(μm)为5.5-6.5um，优选5.2，5.4，5.6，5.8，6.0，6.2um。休止角为34-40度，优选34.5，35，35.5，36，37，38度。
本发明的有益效果：
1、本发明的帕拉米韦干粉吸入剂制备方法简便，在保证药物有效性的同时，确保了药物的安全性。
2、本发明的帕拉米韦干粉吸入剂具有适宜的粒径范围、形态、粉体流动性，不易聚集成团，能有效降低单次给药剂量，具有适宜的药学稳定性。
3、本发明的帕拉米韦干粉吸入剂采用气流粉碎帕拉米韦三水合物，能够获得特定粒径、形态等的微粉，并实现药物的有效肺部递送。
4、本发明的帕拉米韦干粉吸入剂能有效的降低小鼠肺脏内甲型流感病毒的效价，具有显著的抗病毒作用，能显著延长生存时间，降低死亡率，药效作用优于帕拉米韦氯化钠注射液以及磷酸奥司他韦。
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。
本发明涉及测定的方法如下：
1.休止角测定：采用固定漏斗法，将药物粉末从漏斗中以一定速度流出，测量粉体堆积的直径(D)及高度(h)，r＝D/2，计算公式tanα＝h/r。
2.松密度与振实密度测定：将药物粉末均匀转移至量筒，将量筒中药物粉末振实100次，记录振实前后药物重量与体积。
3.粉体粒径测定：取药物粉末于激光粒度仪上测定其粉体粒径。
D g与空气动力学粒径D a：测定中位粒径(D g)；空气动力学直径(D a，MMAD)计算公式为：
Figure PCTCN2021080768-appb-000001
实施例1
1、帕拉米韦喷雾干燥粉末处方如下
表1.帕拉米韦喷雾干燥处方
Figure PCTCN2021080768-appb-000002
工艺条件：喷雾干燥工艺参数为进风温度200℃，出风温度100℃，速度：400ml/h。得到的粉末过180目筛。实验结果如下：
表2帕拉米韦喷雾干燥粉末实验结果(n＝3)
Figure PCTCN2021080768-appb-000003
实验结果表明，加磷脂和氨基酸优化后处方喷雾干燥粉末的密度和粒径都有所减小，但流动性变差。
2、喷雾干燥粉末与甘露醇混合干粉，将上述组成1的帕拉米韦喷雾干燥粉末与甘露醇比例(w/w)：1:1；1:2；1:5进行充分混合。实验结果如下：
表3帕拉米韦喷雾粉末与甘露醇混合实验结果(n＝3)
Figure PCTCN2021080768-appb-000004
实验结果表明，与甘露醇混合后粒径、密度明显增加，但流行性有所改善。
3、喷雾干燥粉末与乳糖混合干粉，将上述组成1的帕拉米韦喷雾干燥粉末与乳糖(1:1，w/w)混合。
表4帕拉米韦喷雾粉末与乳糖实验结果(n＝3)
Figure PCTCN2021080768-appb-000005
实验结果表明，干燥后所得粉末与乳糖(1:1，w/w)混合后，密度和粒径有所增加，流动性变得较差。
同时实验中发现喷雾干燥后粉末之间静电吸附力增大易结块，喷雾干燥制得的帕拉米韦干粉不适宜干粉吸入制药，加入乳糖混合后该现象仍存在，并未获得改善。
实施例2
1、处方1：帕拉米韦微粉干粉，将帕拉米韦原料药采用气流粉碎，在进料速度130V，进料压力0.45MPa，粉碎压力0.45MPa条件下制备干粉。
2、处方2：将上述制得干粉和乳糖Inhalac 120混合制成混合粉末，按质量比1：1进行混合。
3、处方3：将上述制得干粉和乳糖Inhalac 400混合制成混合粉末，按质量比1：1进行混合。
肺部沉积率实验
将上述处方1-3的粉末分别装入胶囊，每粒20mg。将NGI仪器盖好，装上喉部，用封口膜封紧，先开泵，再开流量计，开TPK仪器，之后将流量计连接到喉部，用笔试装置装好空胶囊扎个孔，连接到流量计上测流速。设置DPI吸入药物粒度分布仪设置条件：Flow(流速)＝60； P3＝14.4；P2＝66.8；设置进样胶囊数为20粒，进样时间为7秒。然后把适配器装到喉部口处。然后将上述含药胶囊连接到药物粒度分布仪吸入装置上，点击吸入按钮，重复操作20次。待20粒胶囊完成吸入操作后，喉部、1级，2级、3级、4级，分别用10ml去离子水洗涤收集盘中吸入的药粉，重复2次，将洗涤后的超纯水转移至50ml容量瓶中，同时用超纯水洗涤吸入装置及喉部装置，分别收集于容量瓶中；装置、6级、7级及8级使用25ml容量瓶，分别用10ml去离子水洗涤收集盘中吸入的药粉，重复2次，将洗涤后的超纯水转移至容量瓶中。测定每种处方的微细药物粒子百分比FPF(Fine Particle Fraction,FPF，<4.46μm),结果如下：
表5微细药物粒子百分比(n＝3)
Figure PCTCN2021080768-appb-000006
表6粉雾剂在NGI各级中的分布(n＝3)
Figure PCTCN2021080768-appb-000007
从FPF值看，处方一和处方二接近，而处方三减小较多，处方三与药典规定的10％相近。痛处方三粒子主要阻滞在喉部，可能是因为过细的乳糖颗粒易产生静电而被阻滞。可见处方3 不适宜作为帕拉米韦干粉处方。
稳定性实验
分别将上述处方1-2的胶囊在60℃条件下放置0天，5天和10天，观察混合物外观变化，并检测以下指标。
(1)递送剂量均一性
取处方1-2的胶囊，每个胶囊装样量为20mg，连接好递送量均一装置，打开泵，流量计连接至收集管，收集管一端放置滤纸，另一端连接流量计，DUSA管连接至流量计，用笔试装置装好空胶囊扎个孔，测流速。打开TPK仪器，按TPK仪器上的set up按钮设定，之后按“OK”，再按“set P1，调流速为60L/min。按“set flow”,待出现flow(Q)按“Yes”,再按“Yes”，将屏幕上的数值记录，卸下流量计。递送量均一性参数条件：Flow(流速)＝60；P3＝14.4；P2＝66.8。将含药胶囊放置苏州万通的吸入装置中，点击吸入按钮，每次1粒。用超纯水冲洗滤纸和收集管中的药物于50ml烧杯中，烧杯涮洗3次，将收集液转移至50ml容量瓶，超纯水定容。收集10份收集液，进高效液相检测。测定每份收集液中药物的含量。
(2)微细药物粒子百分比(FPF<4.46μm)，利用NGI检测微细药物粒子百分比。
表7.高温(60℃)下干粉吸入剂的稳定性实验结果
Figure PCTCN2021080768-appb-000008
各处方及在不同影响因素条件下的递送剂量，样品(20mg/胶囊)由于经过手工装胶囊精确定量，故递送剂量均符合药典规定标准(平均值均在75％～125％之间)，且高温对递送剂量均一性影响不大。
微细药物粒子百分比(FPF<4.46μm)的结果显示：高温对处方1的FPF影响不大，对处方2的FPF有较大影响。因此不加辅料、载体的帕拉米韦干粉相对于加入辅料、载体具有更好的粉体性能。
实施例3
将1.3kg的帕拉米韦三水合物原料用气流粉碎机粉碎，在进料速度130V，进料压力0.45MPa，粉碎压力0.40MPa条件下粉碎制得干粉，再将干粉装入羟丙甲纤维素胶囊，每粒胶囊装入20mg干粉。其中干粉粒径D10为1.934um；D50为4.415um；D90为8.858um。休止角34.8度，松密度0.25g/cm 3，振实密度0.41g/cm 3，Carr流动指数59.0。
实施例4
将1.3kg的帕拉米韦三水合物原料用气流粉碎机粉碎，在进料速度125V，进料压力0.50MPa，粉碎压力0.45MPa条件下粉碎制得干粉，再将干粉装入羟丙甲纤维素胶囊，每粒胶囊装入20mg干粉。其中干粉粒径D10为1.447um；D50为3.269um；D90为6.988um。休止角35.3度，松密度0.26g/cm 3，振实密度0.43g/cm 3，Carr流动指数60.0。
实施例5
将1.3kg的帕拉米韦三水合物原料用气流粉碎机粉碎，在进料速度135V，进料压力0.42MPa，粉碎压力0.40MPa条件下粉碎制得干粉，再将干粉装入羟丙甲纤维素胶囊，每粒胶囊装入20mg干粉。其中干粉粒径D10为2.034um；D50为5.716um；D90为12.67um。休止角34.1度，松密度0.23g/cm 3，振实密度0.39g/cm 3，Carr流动指数61.0。
实施例6
将1.3kg的帕拉米韦三水合物原料用气流粉碎机粉碎，在进料速度140V，进料压力0.40MPa，粉碎压力0.35MPa条件下粉碎制得干粉，再将干粉装入羟丙甲纤维素胶囊，每粒胶囊装入15mg干粉。其中干粉粒径D10为2.89um；D50为7.78um；D90为16.39um。休止角33.7度，松密度0.24g/cm 3，振实密度0.41g/cm 3，Carr流动指数65.0。
实施例7
将1.3kg的帕拉米韦三水合物原料用气流粉碎机粉碎，在进料速度120V，进料压力0.60MPa，粉碎压力0.40MPa条件下粉碎制得干粉，再将干粉装入羟丙甲纤维素胶囊，每粒胶囊装入15mg干粉。其中干粉粒径D10为1.332um；D50为3.015um；D90为5.658um。休止角38.4度，松密度0.28g/cm3，振实密度0.47g/cm 3，Carr流动指数66.0。
实验例1
吸入粉雾剂NGI递送实验
1.样品准备
将实施例1的干粉进行NGI递送测试样品的体外沉积率。样品采用单剂量胶囊灌装，测试三次，每次递送10粒胶囊。
2.样品NGI检测结果
样品通过NGI递送测试，NGI每个接收杯/盘内样盘分别清洗并用容量瓶定容，使用HPLC含量检测方法进行含量检测。
表8实施例3体外沉积率测试结果
Figure PCTCN2021080768-appb-000009
Figure PCTCN2021080768-appb-000010
实验例2
不同粒径体外沉积率对比实验
将实施例3-6样品进行NGI体外沉积率测试，实验结果如下：
表9不同粒径进行NGI测试体外沉积率测试结果
Figure PCTCN2021080768-appb-000011
样品粒径D90大于12.67um的样品，其体外沉积率难以能到达药典的要求(药典要求微细粒级剂量不小于10％)。而实施例4具有优异的体外沉积率。
实验例3
稳定性实验
将实施例3的样品在高温(60℃)条件，分别于第0天，第5天，第10天，30天取样，并考察其NGI体外沉积率。
表10高温(60℃)下实施例3干粉稳定性实验
Figure PCTCN2021080768-appb-000012
实验结果，本发明的干粉吸入剂在高温下具有优异的稳定性。
实验例4
帕拉米韦粉雾剂雾化给药对小鼠感染甲型A/PR/8/34流感病毒后的体内保护作用
SPF级Balb/c小鼠80只，雌雄各半，体重16.9～22.6g，按性别和体重随机分为8组，分别为正常对照组、病毒模型组、磷酸奥司他韦胶囊组(达菲)(10mg/kg)，帕拉米韦静脉注射组(10mg/kg)，帕拉米韦粉雾剂(实施例3)Ⅰ～Ⅳ组(0.1、0.3、0.9、2.7mg/kg)，每组10只动物。乙醚轻微麻醉各组小鼠并经鼻滴入甲型A/PR/8/34流感病毒液(用4℃预冷空白培养基将流感病毒原液稀释为5LD 50浓度稀释液)60μL/只，正常对照组经鼻滴入等体积的空白培养基。每日给药前将帕拉米韦静脉注射剂用0.9％氯化钠注射液配制成1.0mg/mL药液，磷酸奥司他韦胶囊用纯水配制成0.5mg/mL药液。各组小鼠均于滴鼻染毒造模后2h进行给药，其中帕拉米韦粉雾剂各组动物给予相应剂量的帕拉米韦粉雾剂，帕拉米韦静脉注射组按10mL/kg经静脉注射给予帕拉米韦药液，磷酸奥司他韦胶囊组按20mL/kg灌胃给予磷酸奥司他韦药液，正常对照组和模型对照组经气管喷入等体积空气，每日给药1次，连续给药5天，以滴鼻造模的次日为病毒染毒后第1天(D1)。
自感染造模当日开始，连续观察15天，记录各组动物体重、死亡时间和死亡数，比较给药期间体重变化，并计算死亡率＝死亡动物数/总动物数*100％、平均存活时间＝动物总存活天数/动物数。
表11帕拉米韦对甲型A/PR/8/34流感病毒感染小鼠死亡保护作用
Figure PCTCN2021080768-appb-000013
Figure PCTCN2021080768-appb-000014
与正常对照组比较， ++P≤0.01；与病毒对照组比较， *P≤0.05， **P≤0.01
如表11所示，实验期间内，正常对照组未用病毒侵染，动物未出现死亡；病毒对照组共计死亡10/10只小鼠，死亡率达到100％，较正常对照组具有显著统计学差异(P≤0.01)。与病毒对照组比较，磷酸奥司他韦组、帕拉米韦静脉注射组、帕拉米韦粉雾剂Ⅱ-Ⅳ组动物的死亡率均显著下降(P≤0.05或P≤0.01)；而帕拉米韦粉雾剂Ⅰ组与病毒对照组比较，无统计学意义(P>0.05)。与正常对照组比较，病毒对照组小鼠的平均存活天数为6.2天，平均生存时间显著缩短(P≤0.01)。与病毒对照组比较，帕拉米韦粉雾剂Ⅰ、Ⅱ组平均生存时间虽有一定程度延长，但无统计学差异(P>0.05)，磷酸奥司他韦组、帕拉米韦静脉注射组、帕拉米韦粉雾剂Ⅲ-Ⅳ组平均生存时间较病毒对照组均明显延长(P≤0.05或P≤0.01)。
由上述结果分析，染毒后2h给予帕拉米韦吸入粉雾剂能显著延长生存时间，降低死亡率，具有明显的体内保护作用，并具有明显的量效关系，同时0.9mg/kg帕拉米韦吸入粉雾剂的药效作用优于帕拉米韦氯化钠注射液(10mg/kg)以及磷酸奥司他韦胶囊(10mg/kg)。
实验例5
帕拉米韦吸入粉雾剂雾化给药对小鼠感染甲型A/PR/8/34流感病毒后的肺组织病毒滴度的影响
SPF级Balb/c小鼠84只，雌雄各半，体重21.2～26.6g，按性别和体重随机分为7组，分别为正常对照组、病毒模型组、磷酸奥司他韦胶囊组(达菲)(10mg/kg)，帕拉米韦静脉注射组(10mg/kg)，帕拉米韦粉雾剂(实施例3)Ⅰ～Ⅲ组(0.1、0.3、0.9mg/kg)，每组12只动物(其中组内F04～F06、M04～M06用于24h血凝滴度测定、F01～F03、M01～M03用于48h血凝滴度测定)。乙醚轻微麻醉各组小鼠并经鼻滴入甲型A/PR/8/34流感病毒液(用4℃预冷空白培养基将流感病毒原液稀释为5LD 50浓度稀释液)60μL/只，正常对照组经鼻滴入等体积的空白培养基。每日给药前将帕拉米韦静脉注射剂用0.9％氯化钠注射液配制成1.0mg/mL药液，磷酸奥司他韦胶囊用纯水配制成0.5mg/mL药液。各组小鼠均于滴鼻染毒造模后2h进行给药，其中帕拉米韦粉雾剂各组动物给予相应质量的帕拉米韦粉雾剂，帕拉米韦静脉注射组 按10mL/kg经静脉注射给予帕拉米韦药液，磷酸奥司他韦胶囊组按20mL/kg灌胃给予磷酸奥司他韦药液，正常对照组和模型对照组经气管喷入等体积空气，每日1次，连续给药2天。
于给药24h和48h后分别从各组中随机选取6只动物，雌雄各半，颈椎脱臼安乐死，解剖取肺脏，然后置匀浆器中，按肺质量(g)：0.9％氯化钠注射液(mL)＝1：9加入0.9％氯化钠注射液，研磨匀浆，制成鼠肺悬液，4℃环境中2500rpm离心20min，取上清待用。除第1列外，在血凝板孔中均加入50μL PBS，在第1列的每孔中分别加入100μL待测上清液，依次作倍比稀释至第11列，再分别加入0.5％的鸡红细胞50μL，静置40min，将血凝板倾斜，观察红细胞有无呈泪滴状流淌，以完全引起鸡红细胞凝集最大稀释倍数的对数值来表示血凝滴度，其中血凝滴度越大，代表鼠肺悬液中的病毒效价越高。
表12帕拉米韦吸入粉雾剂对甲型A/PR/8/34流感病毒感染小鼠肺组织病毒滴度的影响(
Figure PCTCN2021080768-appb-000015
n＝6)
Figure PCTCN2021080768-appb-000016
注：与正常对照组比较 ++P≤0.01；与病毒对照组比较 **P≤0.01
如表12所示，正常对照组小鼠未进行病毒感染，血凝滴度为0。与正常对照组比较，感染后24h、48h，病毒对照组肺脏血凝滴度均显著增大(P≤0.01)。与病毒对照组比较，感染后24h、48h，磷酸奥司他韦胶囊组、帕拉米韦静脉注射组、帕拉米韦吸入Ⅰ～Ⅲ组肺脏血凝滴度均显著减小(P≤0.01)。提示染毒2h后经给予帕拉米韦吸入粉雾剂能有效的降低小鼠肺脏内甲型流感病毒的效价，表明其具有显著的抗病毒作用，并具有明显量效关系，同时0.9mg/kg的帕拉米韦吸入粉雾剂药效作用优于帕拉米韦氯化钠注射液(10mg/kg)以及磷酸奥司他韦胶 囊(10mg/kg)。
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. 一种帕拉米韦干粉吸入剂，其特征在于，所述干粉吸入剂由帕拉米韦或其可接受的盐或其水合物制成，其中单剂量制剂的干粉载药量为5-30mg，所述干粉粒径分布为D10:1.3-3um；D50:3-6um；D90:6-13um。
  2. 根据权利要求1所述的帕拉米韦干粉吸入剂，其特征在于，所述干粉休止角33-37度，优选34、35、36度，松密度0.23-0.28g/cm 3，优选0.24、0.25、0.26、0.27g/cm 3，振实密度0.39-0.44g/cm 3，优选0.40、0.41、0.42、0.43g/cm 3。
  3. 根据上述任一项所述的帕拉米韦干粉吸入剂，其特征在于，所述干粉Carr流动指数58-65，优选59、60、61、62。
  4. 根据上述任一项所述的帕拉米韦干粉吸入剂，其特征在于，所述干粉小于4.46μm微细药物粒子百分比(FPF)大于30％且小于45％，优选32％、33％、34％、35％、36％、37％、38％、40％、41％，更优选34-38％。
  5. 根据上述任一项所述的帕拉米韦干粉吸入剂，其特征在于，所述干粉的空气动力学粒径大于2.5um且小于3.6um，优选2.8-3.5um或2.6-3.1um或2.9-3.4um，更优选3.0-3.2um或3.1-3.3um。
  6. 根据上述任一项所述的帕拉米韦干粉吸入剂，其特征在于，所述干粉粒径D10为1.3-2.0um，D10优选1.4、1.5、1.6、1.7、1.8、1.9、2.1um；D50优选3.5、4.5、5、5.5um；D90优选6.2、6.5、7、7.5、7.8、8.0、8.4、9.0、10、11、12um。
  7. 根据上述任一项所述的帕拉米韦干粉吸入剂，其特征在于，干粉吸入剂由帕拉米韦三水化合物制成。
  8. 一种帕拉米韦干粉吸入制剂，其特征在于，将权利要求1-6任意一项所述的干粉制成胶囊剂型、囊泡剂型、储库剂型，每单位制剂剂型干粉载药量为5-30mg，优选20mg。
  9. 根据权利要求1-6任意一项所述的一种帕拉米韦干粉吸入剂的制备方法，其特征在于，将帕拉米韦三水化合物用气流粉碎，在进料压力0.4-0.5MPa，粉碎压力0.4-0.6MPa条件下粉碎制得干粉。
PCT/CN2021/080768 2020-04-10 2021-03-15 一种帕拉米韦干粉吸入剂及其制备方法 WO2021203914A1 (zh)

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