CN111202722A - Lopinavir inhalation dry powder pharmaceutical composition and preparation method thereof - Google Patents
Lopinavir inhalation dry powder pharmaceutical composition and preparation method thereof Download PDFInfo
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- CN111202722A CN111202722A CN202010090402.0A CN202010090402A CN111202722A CN 111202722 A CN111202722 A CN 111202722A CN 202010090402 A CN202010090402 A CN 202010090402A CN 111202722 A CN111202722 A CN 111202722A
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- lopinavir
- dry powder
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- inhalation
- pharmaceutical composition
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Abstract
The invention belongs to the technical field of medicines, and discloses a lopinavir inhalation dry powder pharmaceutical composition, a preparation method and a medical application thereof. The dry powder medicine composition contains lopinavir as an active ingredient and pharmaceutically acceptable auxiliary materials, and is formed by shearing and mixing, and targeted lung administration can be realized through a dry powder inhalation device.
Description
Technical Field
The invention belongs to the technical field of medicinal preparations, and particularly relates to a preparation method of an inhalation dry powder medicinal composition.
Background
Aiming at 2019-nCoV, no specific antiviral drug exists at present all over the world, the specific antiviral drug is mainly used for symptomatic treatment of symptoms of patients, no effective antiviral drug exists, and a proper antiviral drug needs to be quickly found according to the current epidemic situation, so that the medicine has important significance for treating infectors, controlling epidemic spread and reducing fatality rate at a reasonable medicine application time.
2019-nCoV virus and SARS coronavirus have similar receptor binding path, and through the molecular mechanism of the binding interaction of S-protein and human ACE2 receptor, ACE2 exists in pulmonary alveoli and small intestine epithelial cells, and is expressed on the surfaces of arteriovenous epithelial cells and arterial smooth muscle cells of all organs, wherein the respiratory tract epithelial cells are distributed most, so that the respiratory tract and the lung are most susceptible to infection.
2019-nCoV virus can be detected in the excrement of severe patients, and no virus is detected in the urine, which indicates that the virus is gathered in alveoli after invading from respiratory tract and exists in large amount in digestive tract at later stage. However, the literature reports that the serum detection of 2019-nCoV of the American patient is negative, the detection result of the plasma of the 2019-nCoV of the Wuhan patient in China is corresponding to the detection result, the positive rate is only (6/41) 15%, and compared with the detection rate of SARS-CoV plasma virus being 79%, the detection rate of the SARS-CoV plasma virus is 79%, so that the antiviral drug for treating SARS-CoV can be absorbed into the blood from the gastrointestinal tract after oral administration, and the 2019-nCoV virus with very low concentration in the blood can not be killed.
By analyzing the symptoms of patients, the symptoms of upper respiratory tract such as nasal obstruction, nasal discharge, sore throat and the like are not obvious, and the 2019-nCoV virus of the upper respiratory tract (including nasopharynx part and oropharynx part) of most patients is negative in detection, and the 2019-nCoV virus can be detected only by collecting alveolar lavage fluid, which shows that the virus has extremely high affinity to lung, so that the medicine needs to directly reach a target point, namely alveolus.
Oral absorption of Ritonavir (Ritonavir) is effective in inhibiting aspartic protease, blocking the enzymatic activity of the polypeptide required to produce morphologically mature HIV granules, thereby maintaining the HIV granules in an immature state and inhibiting cytochrome P450 enzymes CYP3A and CYP2D 6. The common adverse reactions include fatigue, gastrointestinal symptoms, nerve dysfunction and the like. Lopinavir is SARS-CoV main protease activity MproAlso in the low micromolar range, MERS-CoV activity. And clinical studies show thatLopinavir-ritonavir treatment reduced mortality from MERS-CoV marmosets. In the ' diagnosis and treatment of SARS ' infection ' it is explicitly mentioned that in the course of antiviral therapy the protease inhibitor-type medicaments such as lopinavir/ritonavir can be used.
A lopinavir/ritonavir combination formulation approved for sale, developed by AbbVie (AbbVie), under the trade name: the gram-force ganoderma lucidum has two dosage forms of tablets and oral liquid, is administrated by an oral route, is less distributed at key focus positions such as respiratory tract, lung and the like, and causes the slow effect of the medicine. Lopinavir inhalant has the possibility of being the first small-molecule compound inhalant for treating coronavirus, and the inhalant has the following advantages: the ritonavir is clinically effective, in an oral compound preparation, the ritonavir is used as a reinforcing agent of the lopinavir, so that the condition that the blood concentration is too low and the treatment effect is lost due to too fast metabolism of the lopinavir is avoided; the lopinavir inhalant directly acts on the lung, targeted administration is carried out on the lung, the lopinavir inhalant directly reaches the focus, and the lung has large absorption surface area, rich capillary vascular network and thin alveolar epithelial cell layer, so that the substance exchange distance is short, the speed is high, and the effect of quick response is achieved; the preparation targets the focus, has accurate dosage and quick response, can quickly improve the pulmonary infection condition, and is beneficial to improving the adaptability of infected people; the targeted drug delivery avoids the absorption through the gastrointestinal tract and reduces the side effect of the gastrointestinal tract.
The Pulmonary Drug Delivery System (PDDS) refers to a drug delivery system in which a drug is delivered directly into the respiratory tract via a special drug delivery device to perform local or systemic therapeutic action. Current pulmonary delivery systems include Metered Dose Inhalation (MDI), inhalation spray (inhalation), Dry Powder Inhalation (DPI), and Dry Powder Inhaler (DPI). Wherein, the aerosol needs a propellant, can destroy the atmospheric ozone layer, and requires the synergistic action of patients when in use. The spraying device of the spraying agent is too large, inconvenient to carry, low in efficiency, poor in repeatability, large in individual difference and long in inhalation process. Compared with aerosol and spray, the dry powder inhalation has no requirement of synergistic effect, does not need a propellant, has larger delivery dose and is more suitable for macromolecular drugs.
The dry powder inhalant is a new dosage form developed on the basis of quantitative inhalation aerosol and by integrating the knowledge of powder engineering, and is a drug delivery system which disperses micronized drugs alone or after being sheared and mixed with a carrier into mist to enter respiratory tracts through the active inhalation of patients by a special drug delivery device and plays a local or systemic role.
The physiological structure of the lung requires that the drug particles of the dry powder inhalant are very fine, generally, the ideal drug particle size is 1-5 μm, particles larger than the range can not enter the bronchioles, and smaller particles are easy to breathe and exhale. The drug carrier is mainly used for adsorbing drug particles, enhancing the stability of the drug during storage and keeping the drug in an amorphous glass state. When the patient inhales, the shear forces created by the turbulent air flow separate the drug from the carrier, with particles smaller than 5 μm entering the lower respiratory tract, and large particles of carrier or drug falling into the mouth and throat. The greater the shear force generated by the air turbulence, the higher the proportion of particulate drug successfully separated from the carrier, and the higher the lung deposition rate.
Lopinavir (Lopinavir) is easily soluble in methanol and ethanol, soluble in isopropanol, hardly soluble in water, poor in water solubility, better in lipid solubility, high in first pass effect and extremely poor in systemic bioavailability, but the Lopinavir is high in lung affinity and quick in inactivation effect, and is clinically suitable for being developed into a pulmonary inhalation preparation for treating pulmonary virus infection, wherein the Lopinavir is mentioned in the Rapid suggestion (standard version) for diagnosis and treatment of pneumonia infected by novel coronavirus (2019-nCoV), (1) a medicament for treating suspected or confirmed cases of specific anti-novel coronavirus in which no evidence from RCT exists at present, (2) the Lopinavir/ritonavir is taken as an oral administration dosage, 2 tablets/time and 2 times/day, the daily administration dosage recommended by the Lopinavir is 800mg according to the suggestion, the dosage conditions are particularly low in self-solubility and large in side effect, become a bottleneck of other administration technologies, particularly colloidal state of Lopinavir is developed, the Lopinavir is a dry injection preparation containing no povidone-inhalation active ingredient, particularly no povidone-vitamin A vitamin E is mentioned in a hot-melt inhalation test method, and a dry inhalation test method is adopted, wherein no povidone-vitamin A is mentioned in the dry injection test, no more suitable for improving bioavailability experiment, no toxic and no toxicity test is mentioned in the dry injection by the dry injection method of Lopinavir, no toxicity test of Lopinavir, No. 1000.
The invention adopts the spray drying method to prepare the amorphous lopinavir, greatly increases the solubility and the bioavailability, reduces the administration dosage, simultaneously considers adding the dispersing auxiliary agent into the spray drying solution, improves the physicochemical property and the inhalation performance of the medicine particles, and is convenient to be uniformly mixed with an external carrier.
Disclosure of Invention
In order to overcome the disadvantages of the prior art, the present invention provides a novel dry powder pharmaceutical composition for inhalation comprising lopinavir, a dispersion aid and a pharmaceutically acceptable carrier, which can be administered to the lung via a dry powder inhalation device, and a method for preparing the same.
The active ingredient is lopinavir, is used for treating viral diseases, is amorphous, and accounts for 5-50% of the total weight of the composition, preferably 10-30%.
The medicinal auxiliary materials in the dry powder inhalant comprise a dispersing auxiliary agent and a large-particle-size carrier according to functional division.
The dispersing auxiliary agent can make the granules have proper dispersity, and can prevent the granules from agglomerating and adhering, and is selected from one or more of sugar and sugar alcohol compounds, including but not limited to lactose, mannitol, sorbitol and the like, preferably mannitol.
The dispersibility aid is small molecular amino acids, and can be one or more selected from alanine, valine, leucine, isoleucine and phenylalanine, preferably leucine.
The large particle size carrier serves to aid in the transport of the drug particles from the site of administration to the throat. Lopinavir dry powder inhalants are suitable for delivery from the throat area to the lungs through the respiratory tract when the particles are small in size and highly dispersible, but are not suitable for delivery from the administration site to the throat area, and it is desirable to add a carrier of large particle size.
The carrier with large particle size is selected from one or more of saccharides and sugar alcohols, preferably one or more of lactose, mannitol, trehalose, sucrose, sorbitol, glucose, β -cyclodextrin, dimethyl β -cyclodextrin, erythritol and the like, and preferably one or more of lactose monohydrate or lactose.
The carrier with large particle size is characterized in that the particle size of more than 50 percent of particles is 25-300 mu m, preferably the particle size of more than 70 percent of particles is 50-200 mu m, and more preferably the particle size of more than 90 percent of particles is 50-100 mu m. The mixing ratio of the drug particles and the large-particle-size carrier is 100: 1-1: 100, preferably 50: 1-1: 50, and more preferably 20: 1-1: 20 by weight.
It is another object of the present invention to provide a process for the preparation of a dry powder pharmaceutical composition for inhalation comprising the steps of:
(a) dissolving lopinavir serving as a medicinal active ingredient and a dispersing auxiliary agent into an organic solvent, and performing spray drying to prepare amorphous medicinal granules;
(b) shearing and mixing the drug particles obtained in the step (a) and the large-particle-size carrier to obtain the drug.
The amorphous lopinavir particles have the particle size of more than 50 percent of particles between 0.1 and 10 mu m, preferably more than 70 percent of particles between 1 and 5 mu m, and more preferably more than 90 percent of particles between 2 and 4 mu m. Typically, the particle size of a particle is determined quantitatively by measuring the characteristic equivalent sphere diameter (referred to as the volume diameter) by laser diffraction, for example by a laser particle size tester.
The amorphous lopinavir particles can be prepared by one or more of spray drying, hot-melt extrusion, grinding method, coprecipitation method and the like, and the spray drying method is preferred. When the lopinavir particles are prepared by adopting a spray drying method, a solution for spray drying is firstly prepared, namely, the active ingredients and the dispersing auxiliary are respectively dissolved and then combined or uniformly dissolved into a solution state, and then the solution is used for subsequent spray drying. According to the lopinavir dissolution characteristics, the solvent is selected from ethanol, methanol, propylene glycol or an aqueous solution thereof, preferably an aqueous ethanol solution, more preferably a 50% ethanol solution.
The solids content of the solution for spray drying affects the efficiency of spray drying and the particle size and properties of the spray-dried particles and should generally be between 0.5 and 10% (w/v), preferably between 1 and 5% (w/v), more preferably between 1 and 3% (w/v).
In spray drying, the main process parameters that affect the performance of the produced particles include the spray drying gas inlet temperature, the spray gas flow rate, the spray liquid flow rate, and the like. The higher the inlet temperature of the spray drying gas is, the faster the drying speed is, the higher the material processing capacity is, but the more easily the main drug and the pharmaceutical excipients are chemically degraded/reacted, so the suitable inlet temperature is 80-140 ℃, preferably 90-130 ℃, and more preferably 100-120 ℃.
The higher the spray gas flow is, the faster the drying speed is, the higher the material processing capacity is, but the higher the power consumption is, the more easily the main medicine and the pharmaceutic adjuvant are subjected to chemical degradation/reaction, so that the suitable gas flow is 0.2-1.0 m3Min, preferably 0.3-0.8 m3Min, and more preferably 0.5 to 0.7 m3/min。
The lower the liquid spraying flow is, the higher the gas-liquid flow ratio is, the faster the drying speed is, the smaller the particle size of the obtained particles is, but the treatment amount can be obviously reduced, the treatment time can be obviously prolonged, and the longer the treatment time is, the more easily the main drug and the pharmaceutic adjuvant are caused to be chemically degraded/reacted, so the suitable liquid spraying flow is 1-10ml/min, preferably 2-8ml/min, and more preferably 5-7 ml/min.
In other spray drying conditions, the type of spray drying gas is not particularly limited, and air may be used, but nitrogen or an inert gas may be selected as the spray drying gas in order to further reduce the chemical reaction.
Because the fluidity of the prepared particles is reduced due to too high moisture content, the stability is poor or/and the particle size of the particles is increased in the storage process, the particles are controlled by the operating parameters in the spray drying process, and it is noted that once the solution is sprayed, the inlet temperature is adjusted to keep the outlet temperature at 70-80 ℃ for about 10-15 min, so that the residual moisture of the obtained particles is further reduced by secondary drying. The water content in the granules is controlled to be 5% or less, preferably 3% or less, more preferably 2% or less.
The shearing mixing of the invention refers to that the particles in the material group are subjected to the external force from a cutter, a stirring paddle or a screen mesh, and the particles mutually form the sliding and collision action of a shearing surface, so that the local mixing is caused. The shear mixing means a device generally used for material dispersion and pulverization, and includes a disk mill, a knife mill, a ball mill, a high-speed mixer, a high-speed pulverizer, etc., preferably a high-speed mixer. The aggregate can be broken up by adopting high-speed shearing and mixing, so that the acting force between the main drug particles and the carrier is greater than that between the main drug particles, and a highly uniform drug composition is obtained, but the particle size distribution and stability of the mixed powder can be influenced by a high-energy shearing and mixing mode, poor sequence, overlong time and the like, so that all influencing factors are comprehensively considered, and a proper and time-saving shearing and mixing process is selected.
The dry powder formulations obtained by the process of the present invention, which are uniformly dispersed, can be administered by dosing in single-dose or multi-dose containers, which can be capsules or blisters, preferably capsules, more preferably HPMC capsules, by appropriate packaging to provide chemical and physical protection, by active or passive inhalation devices. The capsule can be used for inhalation preparation, and also can be used for oral administration.
The invention amorphizes the active ingredient by a spray drying technology, improves the dissolubility and bioavailability and reduces the administration dosage, in order to improve the inhalation characteristic of the particles obtained by spray drying, a dispersing auxiliary agent is added to ensure that the particles with proper particle size distribution have good dispersity and low hygroscopicity, and finally, the particles and a carrier with large particle size are sheared and mixed, thereby providing a preparation method of the dry powder pharmaceutical composition for inhalation. The composition can be administered to lung by dry powder inhalation device, has high aerodynamic Fine Particle Fraction (FPF), and has the advantages of good inhalation property, good stability and high safety.
The invention also provides application of the pharmaceutical composition in preparing medicaments for treating viral diseases, wherein the viral diseases comprise viral pneumonia and AIDS, and the viral pneumonia is pneumonia caused by viruses such as influenza virus, parainfluenza virus, cytomegalovirus, adenovirus, rhinovirus, coronavirus, 2019 novel coronavirus, coxsackie, echovirus, herpes simplex, varicella-zoster, rubella, measles and the like.
Detailed Description
Example 1: preparation of amorphous lopinavir
Dissolving lopinavir in 50% ethanol solution with solid content of 3% (w/v), spray drying according to the following process parameters, collecting the obtained particles, and calculating the yield.
Inlet temperature: 120 deg.C
Liquid spraying flow rate: 6ml/min
Atomization pressure: 180KPa
Flow rate of spray gas: 0.6 m3/min。
Example 2: preparation of amorphous lopinavir granules
Weighing lopinavir according to the ratio of 7:2:1 (w/w/w): mannitol: leucine was dissolved in 50% ethanol solution with a solid content of 3% (w/v), spray dried according to the process parameters in example 1 and the resulting particles were collected.
Example 3: preparation of amorphous lopinavir granules
Weighing lopinavir according to the ratio of 7:2:1 (w/w/w): lactose: leucine was dissolved in 50% ethanol solution with a solid content of 3% (w/v), spray dried according to the process parameters in example 1 and the resulting particles were collected.
Example 4: preparation of amorphous lopinavir granules
Weighing lopinavir according to the ratio of 5.5:3:1.5 (w/w): mannitol: leucine was dissolved in 50% ethanol solution with a solid content of 3% (w/v), spray dried according to the process parameters in example 1 and the resulting particles were collected.
Example 5: lopinavir composition preparation for dry powder inhalation using lactose monohydrate as large particle size carrier
Lactose monohydrate was weighed according to the following table and mixed with the granulate of example 4 in a high speed mixer with shear for 10 min.
| Lactose monohydrate | 70.0g |
| Lopinavir granules | 30.0g |
| Total up to | 100.0g |
Drug particle saturation solubility determination
Adding excessive particles in the embodiments 1-4 into purified water, oscillating for 24 hours at the rotating speed of 200 rpm, centrifuging, taking supernate and determining the saturated solubility, wherein the results are as follows:
| raw material for non-treatment | Example 1 | Example 2 | Example 3 | Example 4 | |
| Saturated solubility (mg/ml) | 0.02 | 24.8 | 26.4 | 19.2 | 23.5 |
The lopinavir alone of example 1 had a greatly increased saturated solubility after spray drying compared to the untreated base.
Yield, angle of repose, particle size D90And evaluation of moisture absorption
"particle size (D90)" according to the invention: the laser particle size tester measures the percentage of particles with different particle sizes in the powder sample to the total amount of the particles, and D90 indicates the corresponding particle size when the cumulative particle size distribution percentage of one sample reaches 90%.
The angle of repose of the powder is measured by a fixed funnel method, also known as a residual cone method. Injecting sample powder into the center of a disc with a certain limited diameter through a funnel until the material on the inclined edge of the powder accumulation layer automatically flows out along the edge of the disc, stopping injecting, measuring the height of a cone formed on the disc, and comparing the height with the radius of the disc to obtain the tangent value of the repose angle, thereby obtaining the repose angle. It is considered that the smaller the angle of repose, the smaller the friction force, the better the fluidity, and the easier the filling.
The "hygroscopicity" of the present invention: the method is carried out according to the guideline of the drug hygroscopicity test in the appendix of the second part of Chinese pharmacopoeia 2015 edition.
| Yield (%) | Angle of repose: (。） | D90（μm） | Moisture absorption (%) | |
| Example 1 | 55 | 55.5 | 5.97 | 30.59 |
| Example 2 | 66 | 45.0 | 4.97 | 26.25 |
| Example 3 | 62 | 49.8 | 6.09 | 30.86 |
| Example 4 | 68 | 39.3 | 5.54 | 22.08 |
From the above results, it can be seen that the addition of the dispersion aid increases the yield of the drug granules, decreases the angle of repose, improves the flowability of the granules, and decreases the particle size of the granules, and that, in comparison with examples 2 and 3, smaller angles of repose and particle size were obtained compared with the granules obtained by adding lactose to mannitol, indicating that the granules had better flowability, more uniform particle size distribution, and less hygroscopicity. Comparing examples 2 and 4, the larger the amount of mannitol and leucine used, the smaller the angle of repose and hygroscopicity.
Stability study of the composition
The purpose of this study was to examine the effect of the dry powder composition of example 5 on stability.
The powder of example 5 was filled in capsules at 25 mg/capsule, placed under long-term conditions (25 ℃/RH 60%) and accelerated conditions (40 ℃/75% RH) for 1 month, and then samples were taken to measure the substances concerned, and the content of impurities was counted to determine the tendency of change of impurities.
The "fog particle distribution", namely the fine particle dose (FPF), is an important parameter for evaluating the quality of an inhaled preparation, and refers to the percentage of the fine drug particle dose of the inhaled powder aerosol in a labeled amount, which can be measured by an in vitro device (refer to "0951 inhalation preparation fine particle aerodynamic property measurement method" in the fourth part of the chinese pharmacopoeia 2015), and the numerical value of the "fog particle distribution", which can reflect the deposition rate of an active ingredient in the lung, for example, when the gas flow reaches 60L/min, the ratio of the fog particle distribution in 2-7 grades is equivalent to the deposition rate of the active ingredient in the lung.
The test instrument: the New Generation of Impactors (NGI) are equipment available from COPLEY, united kingdom.
The dry powder mixture of example 5 was loaded in an aliquot of 25mg into HPMC capsule # 3, the spray distribution and emitted dose of the dry powder in each capsule were measured using a New Generation Impactor (NGI) at a flow rate of 60L/min for 4s per inhalation time, and the amount of the 2 nd to 7 th (aerodynamic particle size range: 0.34 to 4.46 μm) collection pan was counted as the total spray distribution.
| At 0 time | Accelerated condition of 1 month | Long term conditions of 1 month | |
| Total impurities (%) | 0.18 | 0.26 | 0.20 |
| FPF value (%) | 42.5 | 45.8 | 46.4 |
Claims (10)
1. A lopinavir inhalation dry powder pharmaceutical composition comprises lopinavir and pharmaceutically acceptable auxiliary materials, wherein the auxiliary materials comprise:
(1) large particle size carrier selected from sugar and sugar alcohol compounds, including but not limited to lactose, mannitol, trehalose, sucrose, sorbitol, glucose, β -cyclodextrin and dimethyl β -cyclodextrin, erythritol and one or more of them, preferably lactose monohydrate or anhydrous lactose;
(2) the dispersing auxiliary agent can be selected from sugar and sugar alcohol compounds, including but not limited to lactose, mannitol, sorbitol and the like, and can also be selected from one or more of small molecular amino acids, alanine, valine, leucine, isoleucine, phenylalanine and the like, and mannitol and leucine are preferred.
2. Composition according to claim 1, characterized in that the active ingredient lopinavir is in amorphous form, representing between 5% and 50% of the total weight of the composition, preferably between 10% and 30%.
3. The pharmaceutical composition of claim 1 or 2, wherein the amorphous lopinavir has a particle size of 0.1 to 10 μm for more than 50%, preferably 1 to 5 μm for more than 70%, and more preferably 2 to 4 μm for more than 90%.
4. A dry powder pharmaceutical composition for inhalation according to claim 3, wherein said large particle size carrier comprises more than 50% of the particles having a size of between 25 and 300 μm, preferably more than 70% of the particles having a size of between 50 and 200 μm, more preferably more than 90% of the particles having a size of between 50 and 100 μm.
5. A process for the preparation of a dry powder pharmaceutical composition for inhalation according to claim 1 comprising the steps of:
(a) dissolving lopinavir and a dispersing auxiliary agent into an organic solvent, and performing spray drying to prepare amorphous drug particles;
(b) shearing and mixing the drug particles obtained in the step (a) and the large-particle-size carrier to obtain the drug.
6. The preparation method of claim 5, wherein the amorphous lopinavir is prepared by one or more of spray drying, hot-melt extrusion, milling, and coprecipitation, preferably spray drying.
7. The process according to claim 5 or 6, characterized in that the organic solvent is selected from ethanol, methanol, propylene glycol, and the like or aqueous solutions thereof, preferably aqueous ethanol solution; the solid content of the solution is 0.5-10% (w/v), preferably 1-5% (w/v), and more preferably 1-3% (w/v).
8. The method according to claim 5 or 6, wherein the step (b) is shear mixing using a disk mill, a knife mill, a ball mill, a high-speed pulverizer, and a high-speed mixer, preferably a high-speed mixer.
9. The dry powder pharmaceutical composition of claim 1, 2 or 4 for use in the preparation of a medicament for treating viral diseases, including viral pneumonia and aids, wherein the viral pneumonia is caused by viruses such as influenza virus, parainfluenza virus, cytomegalovirus, adenovirus, rhinovirus, coronavirus, 2019 novel coronavirus, coxsackie, echovirus, herpes simplex, varicella-zoster, rubella, measles and the like.
10. Use according to claim 9, characterized in that the medicament can be a dry powder inhalation formulation.
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| US20220378727A1 (en) * | 2021-05-14 | 2022-12-01 | The University Of Hong Kong | Dry powder formulations of tamibarotene for pulmonary and intranasal delivery |
| WO2023075714A1 (en) * | 2021-10-25 | 2023-05-04 | Arven Ilac Sanayi Ve Ticaret Anonim Sirketi | Dry powder compositions comprising anti-viral agents |
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| WO2021212183A1 (en) * | 2020-04-24 | 2021-10-28 | Centre For Digestive Diseases Pty Limited | Products of manufacture and methods for treating, ameliorating or preventing microbial infections |
| CN112206225A (en) * | 2020-07-16 | 2021-01-12 | 郑鉴忠 | Production method of anti-new coronavirus western medicine with monarch, minister, assistant and guide compatibility |
| WO2022029604A1 (en) | 2020-08-07 | 2022-02-10 | Council For Scientific And Industrial Research | Microemulsion drug delivery system for treatment of acute respiratory distress syndrome |
| US20220378727A1 (en) * | 2021-05-14 | 2022-12-01 | The University Of Hong Kong | Dry powder formulations of tamibarotene for pulmonary and intranasal delivery |
| WO2023075714A1 (en) * | 2021-10-25 | 2023-05-04 | Arven Ilac Sanayi Ve Ticaret Anonim Sirketi | Dry powder compositions comprising anti-viral agents |
| CN114053226A (en) * | 2021-11-18 | 2022-02-18 | 上海欣峰制药有限公司 | Pharmaceutical preparation of cefminox sodium compound and preparation method thereof |
| CN114209651A (en) * | 2021-11-18 | 2022-03-22 | 上海欣峰制药有限公司 | Pharmaceutical preparation of cefotaxime sodium compound and preparation method thereof |
| WO2023177367A1 (en) * | 2022-03-18 | 2023-09-21 | Pulmocures Ilac Egitim Danismanlik A.S. | Dosage forms of active substances used against viral diseases in dry powder inhaler device for symptoms caused by covid-19 and other viral lung diseases |
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