Antiviral pharmaceutical composition and preparation method thereof

Abstract

The invention belongs to the field of pharmaceutical preparations, and particularly relates to a zanamivir compound composition. The zanamivir composition contains zanamivir and a medicine auxiliary material. The zanamivir inhalation powder inhalation is simple in preparation process, stable in process, good in aerodynamic characteristic, stable in quality, suitable for industrial production, and more suitable for clinical application of the pharmaceutical composition in treatment and antivirus.

Description

Technical Field

[0001] The present invention belongs to the field of pharmaceutical preparations, and specifically relates to a composition of a zanamivir compound. The composition contains zanamivir and pharmaceutical excipients and a preparation method, and is particularly suitable for a pharmaceutical composition administered through a dry powder inhaler (DPI). The zanamivir inhalation powder spray of the present invention has a simple preparation process, a stable process, good aerodynamic properties, stable quality, and is suitable for industrial production, making it more suitable for clinical use of the pharmaceutical composition in antiviral treatment. Background Art

[0002] Influenza is an acute respiratory infectious disease caused by influenza viruses. Influenza viruses are divided into four types: A, B, C, and D based on the antigenicity of the nucleoprotein and matrix protein M1. There are many differences in genome structure, polypeptide composition, infectivity, and pathogenicity. Among them, only influenza A and B viruses can cause important clinical diseases and seasonal epidemics in humans. Influenza A viruses are further divided into different subtypes based on the antigenicity of hemagglutinin (HA) and neuraminidase (NA) proteins. So far, 18 HA subtypes and 11 NA subtypes have been identified. Seasonal influenza is mainly caused by infection with new influenza A (H1N1), H3N2, and B viruses.

[0003] Zanamivir, chemically named 5-acetylamino-4-[(aminoiminomethyl)-amino]-2-[(1R,2R)-2,6-anhydro-3,4,5-trideoxy-D-glycerol-D-galactosyl-2-enoic acid, is an analog of neuraminidase (NA) synthesized based on the X-ray detection results of the virus's lipid membrane hemagglutinin and the crystal structure of NA. It is a slow-binding, high-affinity competitive inhibitor of influenza virus NA.

[0004] Zanamivir is the active ingredient of the Zanamivir inhalation powder produced by GlaxoSmithKline (GSK). The drug was first developed by Australian biotechnology company Biota Holdings Limited (Biota), and then licensed to GSK for global development. It was launched in Australia, the United States and the United Kingdom in 1999 under the trade name Relenza. It is used for the prevention and treatment of influenza A and B, and is also one of the effective candidate drugs for the treatment of highly pathogenic avian influenza (such as avian influenza caused by H5N1 subtype virus). This product is a highly selective influenza virus neuraminidase inhibitor that affects the release and replication of virus particles. Zanamivir is the first influenza treatment drug approved since the launch of rimantadine in 1993, and it is also the first neuraminidase inhibitor influenza virus treatment drug.

[0005] Zanamivir inhalation powder often has the following problems: 1. The carrier is lactose, which has low porosity and poor binding force with drug particles. 2. The aerodynamic performance of drug particles is insufficient. 3. The mixing uniformity of excipients and drugs is poor, affecting the consistency of dosage. The present invention solves the above problems by improving excipients, prescription composition and preparation process. Summary of the invention

[0006] The purpose of the present invention is to uniformly mix the ultrafine powder of zanamivir with the micro powder of a pharmaceutically acceptable carrier in the form of a dry powder, preferably containing a pharmaceutically acceptable carrier, and the pharmaceutically acceptable carrier is selected from substances known to be used as carriers of dry powder inhalation compositions, such as lactose, mannitol, sorbitol, glucose, a complex of lactose and mannitol, and amino acids; the amino acids include glycine, aspartic acid, alanine, tryptophan, isoleucine, threonine, glutamic acid, phenylalanine, leucine, cystine, proline, tyrosine, valine, etc., and the carrier is particularly preferably glycine. Provided is a zanamivir capsule-type inhalation powder aerosol with a simple preparation process, wherein the dry powder can be placed in a gelatin or plant capsule or blister of a dry powder inhalation device in the form of a single dose.

[0007] In order to achieve the purpose of the present invention, the inventors have explored the raw materials, auxiliary materials, particle size, dosage and preparation process of zanamivir capsule inhalation powder through experiments to improve the process and product stability.

[0008] The technical solution adopted by the present invention is as follows:

[0009] The present invention provides a pharmaceutical composition, which comprises a preparation and a device. The preparation comprises an active pharmaceutical ingredient zanamivir and is characterized in that the particle size D90 is ≤10 μm.

[0010] The pharmaceutically acceptable carrier of the present invention is selected from lactose, mannitol, sorbitol, glucose, lactose and mannitol complex and amino acids; the amino acids include glycine, aspartic acid, alanine, tryptophan, isoleucine, threonine, glutamic acid, phenylalanine, leucine, cystine, proline, tyrosine, valine, etc., and the particularly preferred carrier is glycine. It is characterized in that the particle size of the ultrafine powder is controlled at D90≤20μm, and the particle size of the ground powder is controlled within 40-200μm.

[0011] The composition is mixed, and the weight ratio of zanamivir to pharmaceutically acceptable carrier is 1:2 to 1:7, preferably 1:4.

[0012] The method for preparing the pharmaceutical composition of the present invention comprises the following steps:

[0013] 1) Micronization of API: Control the humidity of the operating environment to 25-45%, preferably 30%, and micronize the API by airflow milling, high-speed grinding, and ball milling. The pressure required by the airflow mill is 0.5-0.9Mpa;

[0014] 2) Preparation of pharmaceutical carriers: Control the humidity of the operating environment to 25-45%, preferably 30%, pass ≥90% of the pharmaceutical carrier crystals that cannot pass through the 80-mesh sieve through a hammer mill, install a 0.2mm screen, and crush to obtain pharmaceutical carrier powder. Put the pharmaceutical carrier powder into an ultrasonic vibration screen installed with a 60-150μm screen, and ultrasonically screen to obtain pharmaceutical carrier grinding powder; put the pharmaceutical carrier grinding powder into a jet mill and crush to obtain pharmaceutical carrier ultrafine powder. Ultrasonic screening to obtain pharmaceutical carrier grinding powder with D90 (μm) 50-300 and D50 (μm) 20-80;

[0015] In step 2, commercially available inhaled lactose, inhaled glycine, inhaled mannitol, inhaled sorbitol, inhaled glucose, or inhaled lactose and mannitol complex that meet the particle size control requirements can be purchased instead.

[0016] 3) Controlling the humidity of the operating environment to 25-45%, preferably 30%, mixing the zanamivir and the pharmaceutically acceptable carrier by one or more of the following methods: sieving mixing, V-shaped mixing, three-dimensional mixing, shear mixing, etc., preferably shear mixing.

[0017] The composition is mixed, and the weight ratio of zanamivir to pharmaceutically acceptable carrier is 1:2 to 1:7, preferably 1:4.

[0018] 4) The mixed composition is loaded into a gelatin hollow capsule or a hypromellose capsule by quantitative cannula filling or vacuum drum filling, preferably a hypromellose capsule, with a filling amount of 15 to 35 mg.

[0019] 5) The filled capsules are packaged in aluminum-plastic (aluminum) packaging to prepare commercially available packaging products.

[0020] The capsule content composition is administered by oral inhalation using an inhalation device and delivered to the lungs. Preferably, a powder mist inhalation device CN219423486U disclosed by Nanchang Hongyi Pharmaceutical Co., Ltd. is used.

[0021] The detection index and method of the present invention are:

[0022] (1) Particle size detection of zanamivir ultrafine powder and carrier: Take the ultrafine powder of the present invention, add a small amount of acetone, and place it on a laser particle size analyzer for detection.

[0023] (2) Uniformity of delivered dose: Take 1 capsule of this product and operate according to the law (Chinese Pharmacopoeia 2020 Edition Part IV General Rules 0111), using acetonitrile-water (50:50) solution as the eluent. Combine the washing solution and place it in a 50ml volumetric flask, dilute it to the mark with acetonitrile-water (50:50) solution, shake well, filter, and take the filtrate. Prepare 10 portions in the same way. Take an appropriate amount of zanamivir reference substance, weigh it accurately, dissolve it in acetonitrile-water (50:50) solution, and quantitatively dilute it to make a solution containing about 100μg per 1ml. According to the method under the content determination item, the average delivered dose of 10 capsules should be 80% to 120% of the labeled delivered dose.

[0024] (3) Fine particle dosage: Take 10 particles of this product and operate according to the method. The eluent is acetonitrile-water (50:50) solution. Add 15ml of eluent to the pre-separator and operate according to the method. Use the eluent to clean the adapter, airway, pre-separator, 1-7 level collection cups and MOC respectively. The washing solution is placed in a 100ml volumetric flask, diluted to the scale with the eluent, and shake well. Take an appropriate amount of tiotropium bromide reference substance, accurately weigh it, add acetonitrile-water (50:50) solution to dissolve it and quantitatively dilute it to make a solution containing about 100μg per 1ml. The determination method is shown under the content determination item. Divide the result by 10 and calculate the content of each drug collected at the adapter, airway, pre-separator, 1-7 level collection cups and MOC level.

[0025] (4) Content determination: Determined by high performance liquid chromatography (Appendix VD, Part II of the Chinese Pharmacopoeia 2010 edition).

[0026] The chromatographic conditions and system suitability test used benzenesulfonic acid-based cation exchange bonded silica gel as the filler; acetonitrile-0.02 mol / L phosphate buffer (pH 3.5) (60:40) as the mobile phase, the detection wavelength was 233 nm, and the column temperature was 30°C; the theoretical plate number should be no less than 2000 based on the zanamivir peak.

[0027] Determination method: Take 10 capsules of this product, pour out the contents and place them in a 500ml volumetric flask, add an appropriate amount of acetonitrile-water (50:50), dissolve by ultrasonication, cool, add acetonitrile-water (50:50) to dilute to the scale, shake well, filter, and take the filtrate as the test solution; accurately weigh an appropriate amount of zanamivir reference substance that has been dried to constant weight at 105°C, add acetonitrile-water (50:50) to dissolve and dilute to make a solution containing about 100μg of zanamivir per 1ml, as the reference substance solution; accurately measure 20ul of the reference substance solution and the test substance solution respectively, inject them into the liquid chromatograph, record the chromatogram, and calculate the peak area according to the external standard method. DETAILED DESCRIPTION

[0028] The beneficial effects of the present invention are further described by the following examples. The examples are only for illustrative purposes and do not limit the scope of the present invention. At the same time, obvious changes and modifications made by ordinary technicians in the field according to the present invention are also included in the scope of the present invention.

[0029] All fine particle quantity and delivery uniformity tests were conducted using a powder mist inhalation device CN219423486U disclosed by Nanchang Hongyi Pharmaceutical Co., Ltd. unless otherwise specified.

[0030] Example 1: Zanamivir superfine powder

[0031] Take zanamivir API, use DecJet 30 air flow mill, connect to compressed air with a dew point temperature below -40°C (-41.3°C on the meter), the air source pressure is greater than 12 bar, adjust the Venturi pressure to 11 bar, the rotary pressure to 10 bar, control the feed rate to 0.5 g per minute for pulverization, and collect the pulverized material for later use.

[0032] Example 2: Preparation of glycine carrier: Control the operating environment humidity to 35±5%;

[0033] A Quadro U5c hammer mill was used, with the main cutter head crushing speed set to 8000 rpm, the feeding speed set to 25 rpm, and a 0.2 mm sieve installed. ≥90% of glycine (for injection) that could not pass through an 80-mesh sieve was put into the hammer mill to collect the glycine powder. A RUSSELL Finex Separator grading screen was installed with a 90 μm sieve, and the glycine powder was put in for sieving, and the material under the sieve was collected to obtain ground glycine.

[0034] Take part of the ground glycine and use a DecJet 30 air flow mill with an air source pressure greater than 12 bar, adjust the Venturi pressure to 10 bar, and the rotation pressure to 5 bar. Control the feed rate to 0.5 g per minute for pulverization. After pulverization, collect and set aside as glycine ultrafine powder.

[0035] Example 3: Preparation of lactose carrier: Control the operating environment humidity to 35±5%

[0036] The D10 of lactose SV001 is 139; D50 is 226; D90 is 312.

[0037] A Quadro U5c hammer mill was used, with the main cutter head crushing speed set to 8000 rpm, the feeding speed set to 25 rpm, and a 0.2 mm sieve installed. Lactose SV001 was put into the hammer mill, and the lactose SV001 powder (to be screened) was obtained.

[0038] Use RUSSELL's Finex Separator grading sieve to install a 90μm sieve, put in lactose SV001 powder (to be sieved), sieve and collect the sieve under to obtain ground lactose SV001.

[0039] Lactose L100 is commercially available inhaled lactose, with D10 of 58, D50 of 132, and D90 of 214, vacuum packed.

[0040] Lactose L200 is commercially available inhaled lactose, with D10 of 9, D50 of 72, D90 of 149, and vacuum packaging.

[0041] Lactose L201 is commercially available inhaled lactose, with D10 of 3, D50 of 22, and D90 of 59, and is vacuum packed.

[0042] Take part of the ground lactose and use a DecJet 30 air flow mill with an air source pressure greater than 12 bar, adjust the Venturi pressure to 10 bar, and the rotation pressure to 5 bar. Control the feed rate to 0.5 g per minute for pulverization. After pulverization, collect and set aside as lactose ultrafine powder.

[0043] Example 4: Preparation of mannitol carrier: Control the operating environment humidity to 35±5%;

[0044] A Quadro U5c hammer mill was used, with the main cutter head crushing speed set to 8000 rpm and the feeding speed set to 25 rpm. A 0.2 mm sieve was installed, and ≥ 90% of the mannitol (for injection) that could not pass through the 80-mesh sieve was put into the hammer mill to obtain mannitol powder. A RUSSELL Finex Separator grading screen was installed with a 90 μm sieve, and the mannitol powder was put in for sieving and the material under the sieve was collected to obtain ground mannitol.

[0045] Take part of the ground mannitol and use a DecJet 30 air flow mill with an air source pressure greater than 12 bar, adjust the Venturi pressure to 10 bar, and the rotation pressure to 5 bar. Control the feed rate to 0.5 g per minute for pulverization. After pulverization, collect and set aside as mannitol ultrafine powder.

[0046] Example 5: Preparation of sorbitol carrier: Control the operating environment humidity to 35±5%;

[0047] A Quadro U5c hammer mill was used, the main cutter head crushing speed was set to 8000 rpm, the feeding speed was set to 25 rpm, a 0.2 mm sieve was installed, and ≥90% of the sorbitol that could not pass through the 80-mesh sieve was put into the hammer mill to collect the sorbitol powder; a RUSSELL Finex Separator grading screen was installed with a 90 μm sieve, and the sorbitol powder was put in for sieving and the sieve-under was collected to obtain ground sorbitol.

[0048] Take part of the ground sorbitol and use a DecJet 30 air flow mill with an air source pressure greater than 12 bar, adjust the Venturi pressure to 10 bar, and the rotation pressure to 5 bar. Control the feed rate to 0.5 g per minute for pulverization. After pulverization, collect and set aside as sorbitol ultrafine powder.

[0049] Example 6: Preparation of glucose carrier: Control the operating environment humidity to 35±5%;

[0050] A Quadro U5c hammer mill was used, with the main cutter head crushing speed set to 8000 rpm and the feeding speed set to 25 rpm. A 0.2 mm sieve was installed, and ≥ 90% of the glucose (for injection) that could not pass through the 80-mesh sieve was put into the hammer mill to collect the glucose powder. A RUSSELL Finex Separator grading screen was installed with a 90 μm sieve, and the glucose powder was put in for sieving and the material under the sieve was collected to obtain ground glucose.

[0051] Take part of the ground glucose and use a DecJet 30 air flow mill with an air source pressure greater than 12 bar, adjust the Venturi pressure to 10 bar, and the rotation pressure to 5 bar. Control the feed rate to 0.5 g per minute for pulverization. After pulverization, collect and set aside as ultrafine glucose powder.

[0052] Example 7: Preparation of lactose and mannitol complex (1:1) carrier: Control the operating environment humidity to 35±5%;

[0053] A Quadro U5c hammer mill was used, with the main cutter head crushing speed set at 8000 rpm, the feeding speed set at 25 rpm, and a 0.2 mm sieve installed. Lactose and mannitol that were ≥90% unable to pass through an 80-mesh sieve were put into the hammer mill, respectively, and the materials were collected to obtain lactose and mannitol micropowders, respectively. A RUSSELL Finex Separator grading sieve was installed with a 90 μm sieve, and lactose and mannitol micropowders were put in for sieving, and the sieved materials were collected to obtain lactose and mannitol micropowders; and then the mixture was evenly mixed in a ratio of 1:1 to obtain a ground lactose and mannitol complex (1:1).

[0054] Take part of the ground lactose and mannitol complex (1:1) and use a DecJet 30 air flow mill with an air source pressure greater than 12 bar, adjust the Venturi pressure to 10 bar, and the rotation pressure to 5 bar. Control the feed rate to 0.5 g per minute for pulverization. After pulverization, collect and set aside as ultrafine powder of lactose and mannitol complex (1:1).

[0055] The preparation methods of other ratios of lactose and mannitol complexes: 1:2, 2:1, 1:3, 3:1 are the same.

[0056] The particle sizes are shown in Table 1.

[0057] Table 1: Particle size table of Examples 1-7

[0058] Material Name <![CDATA[D 10 (μm)]]> <![CDATA[D 50 (μm)]]> <![CDATA[D 90 (μm)]]> Zanamivir 3 6 9 Glycine Ultrafine Powder 10 17 25 Grinding Glycine 5～20 26～80 76～300 Lactose Ultrafine Powder 10 15 21 Grind lactose 6～20 45～80 95～300 Mannitol Ultrafine Powder 12 22 31 Grinding Mannitol 5～20 35～80 88～280 Sorbitol superfine powder 10 18 26 Grinding Sorbitol 10～20 55～80 101～300 Glucose superfine powder 14 29 37 Grinding glucose 26～20 77～80 150～300 Lactose and mannitol complex (1:1) ultrafine powder 10 18 29 Ground lactose and mannitol complex (1:1) 11 52 99 Lactose and mannitol complex (1:2) ultrafine powder 10 17 25 Ground lactose and mannitol complex (1:2) 12 67 89 Lactose and mannitol complex (2:1) ultrafine powder 10 17 25 Milled lactose and mannitol complex (2:1) 15 58 96 Lactose and mannitol complex (1:3) ultrafine powder 10 17 25 Ground lactose and mannitol complex (1:3) 13 55 110 Lactose and mannitol complex (3:1) ultrafine powder 10 17 25 Milled lactose and mannitol complex (3:1) 12 35 85

[0059] Example 8

[0060] Zanamivir superfine powder 250g

[0061] Lactose superfine powder 250g

[0062] 750g ground lactose

[0063] A total of 50,000 tablets

[0064] 1 / 3 of the prescribed amount of ultrafine lactose powder was placed in a high shear mixer and mixed at a low speed of 500 rpm for 30 seconds. Zanamivir ultrafine powder and 2 / 3 of the prescribed amount of ultrafine lactose powder were placed in the high shear mixer together, and the mixture was mixed at a high speed of 1500 rpm for 3 minutes (the operating environment humidity was 30±5%). Then, the prescribed amount of ground lactose (D90μm 50-200) was added and mixed at a high speed of 1500 rpm for 15 minutes. After mixing at a low speed for 60 seconds, the zanamivir mixed powder was obtained, and the content was determined and the loading amount was calculated.

[0065] The mixed powder (operating environment humidity 35±5%) is loaded into gelatin hollow capsules (manufacturer: Suzhou Capsule Co., Ltd.; specification: 3#; batch number: 12888616) by Hanhui vacuum drum filling. The filled composition is aluminum-plastic packaged by an aluminum-plastic blister packaging machine within 6 hours, and the heat sealing temperature is 130°C. The aluminum-plastic composition is manually simulated and packaged into the finished product, and the packaging environment temperature is ≤30°C. The finished product is tested for delivery dose uniformity, fine particle dose, and content determination. Flowability of dry powder: angle of repose is 52°. Hygroscopicity of dry powder: relative weight gain is 2.7%.

[0066] Example 9

[0067] Zanamivir superfine powder 250g

[0068] Glycine superfine powder 250g

[0069] Glycine 750g

[0070] A total of 50,000 tablets

[0071] 1 / 3 of the prescribed amount of glycine ultrafine powder was placed in a high shear mixer and mixed at a low speed of 500 rpm for 30 seconds. Zanamivir ultrafine powder and 2 / 3 of the prescribed amount of glycine ultrafine powder were placed in the high shear mixer together, and the mixture was mixed at a high speed of 1500 rpm for 3 minutes (the operating environment humidity was 30±5%). Then, the prescribed amount of ground glycine (D90μm 50-200) was added and mixed at a high speed of 1500 rpm for 15 minutes. After mixing at a low speed for 60 seconds, the zanamivir mixed powder was obtained, and the content was determined and the loading amount was calculated.

[0072] The mixed powder (operating environment humidity 35±5%) is loaded into gelatin hollow capsules (manufacturer: Suzhou Capsule Co., Ltd.; specification: 3#; batch number: 12888616) by Hanhui vacuum drum filling. The filled composition is aluminum-plastic packaged by an aluminum-plastic blister packaging machine within 6 hours, and the heat sealing temperature is 130°C. The aluminum-plastic composition is manually simulated and packaged into the finished product, and the packaging environment temperature is ≤30°C. The finished product is tested for delivery dose uniformity, fine particle dose, and content determination. Flowability of dry powder: angle of repose is 66°. Hygroscopicity of dry powder: relative weight gain is 4.8%.

[0073] Example 10

[0074] Zanamivir superfine powder 250g

[0075] Lactose superfine powder 250g

[0076] 250g ground lactose

[0077] A total of 50,000 tablets

[0078] 1 / 3 of the prescribed amount of ultrafine lactose powder was placed in a high shear mixer and mixed at a low speed of 500 rpm for 30 seconds. Zanamivir ultrafine powder and 2 / 3 of the prescribed amount of ultrafine lactose powder were placed in the high shear mixer together, and the mixture was mixed at a high speed of 1500 rpm for 3 minutes (the operating environment humidity was 30±5%). Then, the prescribed amount of ground lactose (D90μm 200-300) was added and mixed at a high speed of 1500 rpm for 15 minutes. After mixing at a low speed for 60 seconds, the zanamivir mixed powder was obtained, and the content was determined and the loading amount was calculated.

[0079] The mixed powder (operating environment humidity 35±5%) is loaded into gelatin hollow capsules (manufacturer: Suzhou Capsule Co., Ltd.; specification: 3#; batch number: 12888616) by Hanhui vacuum drum filling. The filled composition is aluminum-plastic packaged by an aluminum-plastic blister packaging machine within 6 hours, and the heat sealing temperature is 130°C. The aluminum-plastic composition is packaged into finished products by manual simulation, and the packaging environment temperature is ≤30°C. The finished product is tested for delivery dose uniformity, fine particle dose, and content determination. Flowability of dry powder: angle of repose is 61°. Hygroscopicity of dry powder: relative weight gain is 2.5%.

[0080] Embodiment 11

[0081] Zanamivir superfine powder 250g

[0082] Glycine superfine powder 250g

[0083] Glycine 250g

[0084] A total of 50,000 tablets

[0085] 1 / 3 of the prescribed amount of glycine ultrafine powder was placed in a high shear mixer and mixed at a low speed of 500 rpm for 30 seconds. Zanamivir ultrafine powder and 2 / 3 of the prescribed amount of glycine ultrafine powder were placed in the high shear mixer together, and the mixture was mixed at a high speed of 1500 rpm for 3 minutes (the operating environment humidity was 30±5%). Then, the prescribed amount of ground glycine (D90μm 200-300) was added and mixed at a high speed of 1500 rpm for 15 minutes. After mixing at a low speed for 60 seconds, the zanamivir mixed powder was obtained, and the content was determined and the loading amount was calculated.

[0086] The mixed powder (operating environment humidity 35±5%) is loaded into gelatin hollow capsules (manufacturer: Suzhou Capsule Co., Ltd.; specification: 3#; batch number: 12888616) by Hanhui vacuum drum filling. The filled composition is aluminum-plastic packaged by an aluminum-plastic blister packaging machine within 6 hours, and the heat sealing temperature is 130°C. The aluminum-plastic composition is packaged into finished products by manual simulation, and the packaging environment temperature is ≤30°C. The finished product is tested for delivery dose uniformity, fine particle dose, and content determination. Flowability of dry powder: angle of repose is 69°. Hygroscopicity of dry powder: relative weight gain 5.0%.

[0087] Example 12

[0088] Zanamivir superfine powder 250g

[0089] Mannitol superfine powder 250g

[0090] Grinded mannitol 750g

[0091] A total of 50,000 tablets

[0092] 1 / 3 of the prescribed amount of mannitol ultrafine powder was placed in a high shear mixer and mixed at a low speed of 500 rpm for 30 seconds. Zanamivir ultrafine powder and 2 / 3 of the prescribed amount of mannitol ultrafine powder were placed in the high shear mixer together, and the mixture was mixed at a high speed of 1500 rpm for 3 minutes (operating environment humidity 30±5%). Then, the prescribed amount of ground mannitol (D90μm 50-200) was added and mixed at a high speed of 1500 rpm for 15 minutes, and then mixed at a low speed for 60 seconds, and then the zanamivir mixed powder was obtained, and the content was determined and the loading amount was calculated.

[0093] The mixed powder (operating environment humidity 35±5%) is loaded into gelatin hollow capsules (manufacturer: Suzhou Capsule Co., Ltd.; specification: 3#; batch number: 12888616) by Hanhui vacuum drum filling. The filled composition is aluminum-plastic packaged by an aluminum-plastic blister packaging machine within 6 hours, and the heat sealing temperature is 130°C. The aluminum-plastic composition is packaged into finished products by manual simulation, and the packaging environment temperature is ≤30°C. The finished product is tested for delivery dose uniformity, fine particle dose, and content determination. Flowability of dry powder: angle of repose is 58°. Hygroscopicity of dry powder: relative weight gain is 3.3%.

[0094] Embodiment 13

[0095] Zanamivir superfine powder 250g

[0096] Sorbitol superfine powder 250g

[0097] 750g ground sorbitol

[0098] A total of 50,000 tablets

[0099] 1 / 3 of the prescribed amount of sorbitol ultrafine powder was placed in a high shear mixer and mixed at a low speed of 500 rpm for 30 seconds. Zanamivir ultrafine powder and 2 / 3 of the prescribed amount of sorbitol ultrafine powder were placed in the high shear mixer together, and the mixture was mixed at a high speed of 1500 rpm for 3 minutes (operating environment humidity 30±5%). Then, the prescribed amount of ground sorbitol (D90μm50-200) was added and mixed at a high speed of 1500 rpm for 15 minutes. After mixing at a low speed for 60 seconds, the zanamivir mixed powder was obtained, and the content was determined and the loading amount was calculated.

[0100] The mixed powder (operating environment humidity 35±5%) is loaded into gelatin hollow capsules (manufacturer: Suzhou Capsule Co., Ltd.; specification: 3#; batch number: 12888616) by Hanhui vacuum drum filling. The filled composition is aluminum-plastic packaged by an aluminum-plastic blister packaging machine within 6 hours, and the heat sealing temperature is 130°C. The aluminum-plastic composition is packaged into finished products by manual simulation, and the packaging environment temperature is ≤30°C. The finished product is tested for delivery dose uniformity, fine particle dose, and content determination. Flowability of dry powder: angle of repose is 61°. Hygroscopicity of dry powder: relative weight gain 4.5%.

[0101] Embodiment 14

[0102] Zanamivir superfine powder 250g

[0103] Glucose superfine powder 250g

[0104] Grinded glucose 750g

[0105] A total of 50,000 tablets

[0106] 1 / 3 of the prescribed amount of glucose ultrafine powder was placed in a high shear mixer and mixed at a low speed of 500 rpm for 30 seconds. Zanamivir ultrafine powder and 2 / 3 of the prescribed amount of glucose ultrafine powder were placed in the high shear mixer together, and the mixture was mixed at a high speed of 1500 rpm for 3 minutes (the operating environment humidity was 30±5%). Then, the prescribed amount of ground glucose (D90μm 50-200) was added and mixed at a high speed of 1500 rpm for 15 minutes. After mixing at a low speed for 60 seconds, the zanamivir mixed powder was obtained, and the content was determined and the loading amount was calculated.

[0107] The mixed powder (operating environment humidity 35±5%) is loaded into gelatin hollow capsules (manufacturer: Suzhou Capsule Co., Ltd.; specification: 3#; batch number: 12888616) by Hanhui vacuum drum filling. The filled composition is aluminum-plastic packaged by an aluminum-plastic blister packaging machine within 6 hours, and the heat sealing temperature is 130°C. The aluminum-plastic composition is packaged into finished products by manual simulation, and the packaging environment temperature is ≤30°C. The finished product is tested for delivery dose uniformity, fine particle dose, and content determination. Flowability of dry powder: angle of repose is 62°. Hygroscopicity of dry powder: relative weight gain is 5.8%.

[0108] Embodiment 15

[0109] Zanamivir superfine powder 250g

[0110] Lactose and mannitol complex (1:1) ultrafine powder 250g

[0111] Ground lactose and mannitol complex (1:1) 750g

[0112] A total of 50,000 tablets

[0113] 1 / 3 of the prescribed amount of lactose and mannitol complex (1:1) ultrafine powder was placed in a high shear mixer and mixed at a low speed of 500 rpm for 30 seconds. Zanamivir ultrafine powder and 2 / 3 of the prescribed amount of lactose and mannitol complex (1:1) ultrafine powder were placed in the high shear mixer together, and the mixture was mixed at a high speed of 1500 rpm for 3 minutes (operating environment humidity 30±5%). Then, the prescribed amount of ground lactose and mannitol complex (1:1) (D90μm 50-200) was added and mixed at a high speed of 1500 rpm for 15 minutes, and then mixed at a low speed for 60 seconds, and then the zanamivir mixed powder was obtained, and the content was determined and the filling amount was calculated.

[0114] The mixed powder (operating environment humidity 35±5%) was loaded into gelatin hollow capsules (manufacturer: Suzhou Capsule Co., Ltd.; specification: 3#; batch number: 12888616) by Hanhui vacuum drum filling. The filled composition was aluminum-plastic packaged by an aluminum-plastic blister packaging machine within 6 hours, and the heat sealing temperature was 130°C. The aluminum-plastic composition was manually simulated and packaged into the finished product, and the packaging environment temperature was ≤30°C. The finished product was tested for delivery dose uniformity, fine particle dose, and content determination. Flowability of dry powder: angle of repose was 57°. Hygroscopicity of dry powder: relative weight gain was 3.8%.

[0115] Example 16

[0116] Zanamivir superfine powder 250g

[0117] Lactose and mannitol complex (1:2) ultrafine powder 250g

[0118] Ground lactose and mannitol complex (1:2) 750g

[0119] A total of 50,000 tablets

[0120] 1 / 3 of the prescribed amount of ultrafine powder of lactose and mannitol complex (1:2) was placed in a high shear mixer and mixed at a low speed of 500 rpm for 30 seconds. Zanamivir ultrafine powder and 2 / 3 of the prescribed amount of ultrafine powder of lactose and mannitol complex (1:2) were placed in the high shear mixer together, and the mixture was mixed at a high speed of 1500 rpm for 3 minutes (operating environment humidity 30±5%). Then, the prescribed amount of ground lactose and mannitol complex (1:2) (D90μm 50-200) was added and mixed at a high speed of 1500 rpm for 15 minutes, and then mixed at a low speed for 60 seconds, and then the zanamivir mixed powder was obtained, and the content was determined and the filling amount was calculated.

[0121] The mixed powder (operating environment humidity 35±5%) is loaded into gelatin hollow capsules (manufacturer: Suzhou Capsule Co., Ltd.; specification: 3#; batch number: 12888616) by Hanhui vacuum drum filling. The filled composition is aluminum-plastic packaged by an aluminum-plastic blister packaging machine within 6 hours, and the heat sealing temperature is 130°C. The aluminum-plastic composition is manually simulated and packaged into the finished product, and the packaging environment temperature is ≤30°C. The finished product is tested for delivery dose uniformity, fine particle dose, and content determination. Flowability of dry powder: angle of repose is 62°. Hygroscopicity of dry powder: relative weight gain 4.1%.

[0122] Embodiment 17

[0123] Zanamivir superfine powder 250g

[0124] Lactose and mannitol complex (1:3) ultrafine powder 250g

[0125] Ground lactose and mannitol complex (1:3) 750g

[0126] A total of 50,000 tablets

[0127] 1 / 3 of the prescribed amount of ultrafine powder of lactose and mannitol complex (1:3) was placed in a high shear mixer and mixed at a low speed of 500 rpm for 30 seconds. Zanamivir ultrafine powder and 2 / 3 of the prescribed amount of ultrafine powder of lactose and mannitol complex (1:3) were placed in the high shear mixer together, and the mixture was mixed at a high speed of 1500 rpm for 3 minutes (operating environment humidity 30±5%). Then, the prescribed amount of ground lactose and mannitol complex (1:3) (D90μm 50-200) was added and mixed at a high speed of 1500 rpm for 15 minutes, and then mixed at a low speed for 60 seconds, and then the zanamivir mixed powder was obtained, and the content was determined and the filling amount was calculated.

[0128] The mixed powder (operating environment humidity 35±5%) is loaded into gelatin hollow capsules (manufacturer: Suzhou Capsule Co., Ltd.; specification: 3#; batch number: 12888616) by Hanhui vacuum drum filling. The filled composition is aluminum-plastic packaged by an aluminum-plastic blister packaging machine within 6 hours, and the heat sealing temperature is 130°C. The aluminum-plastic composition is manually simulated and packaged into the finished product, and the packaging environment temperature is ≤30°C. The finished product is tested for delivery dose uniformity, fine particle dose, and content determination. Flowability of dry powder: angle of repose is 63°. Hygroscopicity of dry powder: relative weight gain is 3.8%.

[0129] Embodiment 18

[0130] Zanamivir superfine powder 250g

[0131] Lactose and mannitol complex (2:1) ultrafine powder 250g

[0132] Ground lactose and mannitol complex (2:1) 750g

[0133] A total of 50,000 tablets

[0134] 1 / 3 of the prescribed amount of ultrafine powder of lactose and mannitol complex (2:1) was placed in a high shear mixer and mixed at a low speed of 500 rpm for 30 seconds. Zanamivir ultrafine powder and 2 / 3 of the prescribed amount of ultrafine powder of lactose and mannitol complex (2:1) were placed in the high shear mixer together, and the mixture was mixed at a high speed of 1500 rpm for 3 minutes (operating environment humidity 30±5%). Then, the prescribed amount of ground lactose and mannitol complex (2:1) (D90μm 50-200) was added and mixed at a high speed of 1500 rpm for 15 minutes, and then mixed at a low speed for 60 seconds, and then the zanamivir mixed powder was obtained, and the content was determined and the filling amount was calculated.

[0135] The mixed powder (operating environment humidity 35±5%) is loaded into gelatin hollow capsules (manufacturer: Suzhou Capsule Co., Ltd.; specification: 3#; batch number: 12888616) by Hanhui vacuum drum filling. The filled composition is aluminum-plastic packaged by an aluminum-plastic blister packaging machine within 6 hours, and the heat sealing temperature is 130°C. The aluminum-plastic composition is manually simulated and packaged into the finished product, and the packaging environment temperature is ≤30°C. The finished product is tested for delivery dose uniformity, fine particle dose, and content determination. Flowability of dry powder: angle of repose is 55°. Hygroscopicity of dry powder: relative weight gain is 3.9%.

[0136] Embodiment 19

[0137] Zanamivir superfine powder 250g

[0138] Lactose and mannitol complex (3:1) ultrafine powder 250g

[0139] Ground lactose and mannitol complex (3:1) 750g

[0140] A total of 50,000 tablets

[0141] 1 / 3 of the prescribed amount of ultrafine powder of lactose and mannitol complex (3:1) was placed in a high shear mixer and mixed at a low speed of 500 rpm for 30 seconds. Zanamivir ultrafine powder and 2 / 3 of the prescribed amount of ultrafine powder of lactose and mannitol complex (3:1) were placed in the high shear mixer together, and the mixture was mixed at a high speed of 1500 rpm for 3 minutes (operating environment humidity 30±5%). Then, the prescribed amount of ground lactose and mannitol complex (3:1) (D90μm 50-200) was added and mixed at a high speed of 1500 rpm for 15 minutes, and then mixed at a low speed for 60 seconds, and then the zanamivir mixed powder was obtained, and the content was determined and the filling amount was calculated.

[0142] The mixed powder (operating environment humidity 35±5%) is loaded into gelatin hollow capsules (manufacturer: Suzhou Capsule Co., Ltd.; specification: 3#; batch number: 12888616) by Hanhui vacuum drum filling. The filled composition is aluminum-plastic packaged by an aluminum-plastic blister packaging machine within 6 hours, and the heat sealing temperature is 130°C. The aluminum-plastic composition is manually simulated and packaged into the finished product, and the packaging environment temperature is ≤30°C. The finished product is tested for delivery dose uniformity, fine particle dose, and content determination. Flowability of dry powder: angle of repose is 60°. Hygroscopicity of dry powder: relative weight gain is 3.7%.

[0143] Embodiment 20

[0144] Zanamivir superfine powder 250g

[0145] Mannitol superfine powder 250g

[0146] Grind mannitol 250g

[0147] A total of 50,000 tablets

[0148] 1 / 3 of the prescribed amount of mannitol ultrafine powder was placed in a high shear mixer and mixed at a low speed of 500 rpm for 30 seconds. Zanamivir ultrafine powder and 2 / 3 of the prescribed amount of mannitol ultrafine powder were placed in the high shear mixer together, and the mixture was mixed at a high speed of 1500 rpm for 3 minutes (operating environment humidity 30±5%). Then, the prescribed amount of ground mannitol (D90μm 50-200) was added and mixed at a high speed of 1500 rpm for 15 minutes, and then mixed at a low speed for 60 seconds, and then the zanamivir mixed powder was obtained, and the content was determined and the loading amount was calculated.

[0149] The mixed powder (operating environment humidity 35±5%) is loaded into gelatin hollow capsules (manufacturer: Suzhou Capsule Co., Ltd.; specification: 3#; batch number: 12888616) by Hanhui vacuum drum filling. The filled composition is aluminum-plastic packaged by an aluminum-plastic blister packaging machine within 6 hours, and the heat sealing temperature is 130°C. The aluminum-plastic composition is manually simulated and packaged into the finished product, and the packaging environment temperature is ≤30°C. The finished product is tested for delivery dose uniformity, fine particle dose, and content determination. Flowability of dry powder: angle of repose is 63°. Hygroscopicity of dry powder: relative weight gain is 3.4%.

[0150] Embodiment 21

[0151] Zanamivir superfine powder 250g

[0152] Sorbitol superfine powder 250g

[0153] 250g ground sorbitol

[0154] A total of 50,000 tablets

[0155] 1 / 3 of the prescribed amount of sorbitol ultrafine powder was placed in a high shear mixer and mixed at a low speed of 500 rpm for 30 seconds. Zanamivir ultrafine powder and 2 / 3 of the prescribed amount of sorbitol ultrafine powder were placed in the high shear mixer together, and the mixture was mixed at a high speed of 1500 rpm for 3 minutes (operating environment humidity 30±5%). Then, the prescribed amount of ground sorbitol (D90μm50-200) was added and mixed at a high speed of 1500 rpm for 15 minutes. After mixing at a low speed for 60 seconds, the zanamivir mixed powder was obtained, and the content was determined and the loading amount was calculated.

[0156] The mixed powder (operating environment humidity 35±5%) is loaded into gelatin hollow capsules (manufacturer: Suzhou Capsule Co., Ltd.; specification: 3#; batch number: 12888616) by Hanhui vacuum drum filling. The filled composition is aluminum-plastic packaged by an aluminum-plastic blister packaging machine within 6 hours, and the heat sealing temperature is 130°C. The aluminum-plastic composition is manually simulated and packaged into the finished product, and the packaging environment temperature is ≤30°C. The finished product is tested for delivery dose uniformity, fine particle dose, and content determination. Flowability of dry powder: angle of repose is 65°. Hygroscopicity of dry powder: relative weight gain is 5.7%.

[0157] Embodiment 22

[0158] Zanamivir superfine powder 250g

[0159] Lactose superfine powder 250g

[0160] 1250g ground lactose

[0161] A total of 50,000 tablets

[0162] 1 / 3 of the prescribed amount of ultrafine lactose powder was placed in a high shear mixer and mixed at a low speed of 500 rpm for 30 seconds. Zanamivir ultrafine powder and 2 / 3 of the prescribed amount of ultrafine lactose powder were placed in the high shear mixer together, and the mixture was mixed at a high speed of 1500 rpm for 3 minutes (the operating environment humidity was 30±5%). Then, the prescribed amount of ground lactose (D90μm 50-200) was added and mixed at a high speed of 1500 rpm for 15 minutes. After mixing at a low speed for 60 seconds, the zanamivir mixed powder was obtained, and the content was determined and the loading amount was calculated.

[0163] The mixed powder (operating environment humidity 35±5%) was loaded into gelatin hollow capsules (manufacturer: Suzhou Capsule Co., Ltd.; specification: 3#; batch number: 12888616) by Hanhui vacuum drum filling. The filled composition was aluminum-plastic packaged by an aluminum-plastic blister packaging machine within 6 hours, and the heat sealing temperature was 130°C. The aluminum-plastic composition was manually simulated and packaged into the finished product, and the packaging environment temperature was ≤30°C. The finished product was tested for delivery dose uniformity, fine particle dose, and content determination. Flowability of dry powder: angle of repose was 53°. Hygroscopicity of dry powder: relative weight gain was 3.3%.

[0164] Embodiment 23

[0165] Zanamivir superfine powder 250g

[0166] Glycine superfine powder 250g

[0167] Glycine 1250g

[0168] A total of 50,000 tablets

[0169] 1 / 3 of the prescribed amount of glycine ultrafine powder was placed in a high shear mixer and mixed at a low speed of 500 rpm for 30 seconds. Zanamivir ultrafine powder and 2 / 3 of the prescribed amount of glycine ultrafine powder were placed in the high shear mixer together, and the mixture was mixed at a high speed of 1500 rpm for 3 minutes (the operating environment humidity was 30±5%). Then, the prescribed amount of ground glycine (D90μm 50-200) was added and mixed at a high speed of 1500 rpm for 15 minutes. After mixing at a low speed for 60 seconds, the zanamivir mixed powder was obtained, and the content was determined and the loading amount was calculated.

[0170] The mixed powder (operating environment humidity 35±5%) was loaded into gelatin hollow capsules (manufacturer: Suzhou Capsule Co., Ltd.; specification: 3#; batch number: 12888616) by Hanhui vacuum drum filling. The filled composition was aluminum-plastic packaged by an aluminum-plastic blister packaging machine within 6 hours, and the heat sealing temperature was 130°C. The aluminum-plastic composition was manually simulated and packaged into the finished product, and the packaging environment temperature was ≤30°C. The finished product was tested for delivery dose uniformity, fine particle dose, and content determination. Flowability of dry powder: angle of repose was 59°. Hygroscopicity of dry powder: relative weight gain was 3.7%.

[0171] Example 24: Delivered Dose Uniformity

[0172] The samples under Examples 8 to 23 were tested according to the dosage uniformity method of this product. The results are shown in Table 2.

[0173] Table 2: Zanamivir delivery uniformity

[0174] prescription Zanamivir (%) Example 8 98.5 Example 9 101.5 Example 10 99.5 Embodiment 11 97.5 Example 12 100.5 Embodiment 13 95.5 Embodiment 14 92.5 Embodiment 15 98.1 Example 16 99.3 Embodiment 17 100.2 Embodiment 18 98.9 Embodiment 19 99.0 Embodiment 20 96.6 Embodiment 21 98.5 Embodiment 22 97.4 Embodiment 23 97.0

[0175] Example 25: Fine Particle Dosage

[0176] The samples under Examples 8 to 23 were tested according to the dosage uniformity method of this product. The results are shown in Table 3.

[0177] Table 3: Zanamivir fine particle dosage

[0178] prescription MMAD (μm) Example 8 5.03 Example 9 4.88 Example 10 4.04 Embodiment 11 4.12 Example 12 5.56 Embodiment 13 5.77 Embodiment 14 6.93 Embodiment 15 5.23 Example 16 5.19 Embodiment 17 5.23 Embodiment 18 5.67 Embodiment 19 4.99 Embodiment 20 4.54 Embodiment 21 4.32 Embodiment 22 6.12 Embodiment 23 6.23

[0179] Example 26: Take the samples under Example 8 to Example 23 and test them according to the content determination method of this product. The results are shown in Table 4.

[0180] Table 4: Zanamivir content determination results

[0181] prescription Zanamivir (%) Example 8 99.9 Example 9 99.7 Example 10 100.9 Embodiment 11 101.2 Example 12 99.1 Embodiment 13 100.3 Embodiment 14 100.5 Embodiment 15 99.2 Example 16 99.3 Embodiment 17 100.5 Embodiment 18 101.0 Embodiment 19 99.7 Embodiment 20 99.6 Embodiment 21 100.9 Embodiment 22 99.9 Embodiment 23 100.8

[0182] Effect evaluation:

[0183] The above examples 8-23 illustrate that the dry powder composition of the present invention, the zanamivir inhalation powder prepared by using different carriers and different processes, has good test results, better particle flowability, less hygroscopicity, better delivery dose uniformity, and fine particle dose. The preparation process of the present invention is simple and suitable for industrial production and clinical application.

Claims

1. A pharmaceutical composition, comprising a preparation and a device, wherein the preparation comprises an active pharmaceutical ingredient, wherein the active pharmaceutical ingredient is zanamivir; the preparation further comprises a pharmaceutically acceptable carrier; and the device is a powder mist inhalation device disclosed in CN219423486U.

2. The pharmaceutically acceptable carrier according to claim 1 is selected from lactose, mannitol, sorbitol, glucose, a complex of lactose and mannitol, and amino acids; the amino acids include glycine, aspartic acid, alanine, tryptophan, isoleucine, threonine, glutamic acid, phenylalanine, leucine, cystine, proline, tyrosine, valine, etc., and a particularly preferred carrier is glycine.

3. The pharmaceutical composition according to claim 1, wherein the weight ratio of zanamivir to pharmaceutically acceptable carrier is 1:2 to 1:7, preferably 1:

4.

4. The pharmaceutical composition according to claim 1, characterized in that The particle size D90 of the active ingredient is ≤10 μm.

5. The pharmaceutical composition according to claim 1, wherein the pharmaceutically acceptable carrier is preferably glycine or lactose monohydrate, characterized in that The particle size of fine powder is controlled within D90≤20μm, and the particle size of coarse powder is controlled within 40~200μm.

6. A method for preparing a pharmaceutical composition according to any one of claims 1 to 5, comprising the steps of: Step 1) micronizing zanamivir for later use, the air flow mill requires a pressure of 0.5-0.9 MPa; Step 2) crushing the carriers of claim 2 for later use, including ultrafine crushing and hammer crushing; Step 3) weighing the micronized zanamivir and the carrier according to a predetermined ratio and mixing them uniformly by high shearing method; Step 4) The mixed composition is loaded into empty gelatin capsules or hypromellose capsules by quantitative cannula filling or vacuum drum filling, preferably hypromellose capsules, with a filling amount of 15 to 35 mg, and packaged into a commercial product.

7. The method according to claim 4, characterized in that The linear speed of the cutter or stirring paddle of the equipment is 5-8 m / s; the gap between the blade of the stirring paddle and the wall of the equipment container is 0.5-1.0 mm.

8. The method according to claim 4, characterized in that During the micronization process, the humidity of the operating environment is controlled at 25% to 45%, preferably 30%.

9. The method according to any one of claims 4, characterized in that: The capsule content composition is administered by oral inhalation using a dry powder inhalation device and delivered to the lungs.