CN115919813A - Pirfenidone powder inhalation and preparation method thereof - Google Patents

Pirfenidone powder inhalation and preparation method thereof Download PDF

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CN115919813A
CN115919813A CN202211483815.0A CN202211483815A CN115919813A CN 115919813 A CN115919813 A CN 115919813A CN 202211483815 A CN202211483815 A CN 202211483815A CN 115919813 A CN115919813 A CN 115919813A
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pirfenidone
leucine
precursor solution
spray drying
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石靖宇
佟振博
缪浩
李韧杰
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Southeast University
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Abstract

The invention relates to a pirfenidone powder inhalation and a preparation method thereof, wherein a precursor solution is prepared by a spray drying mode, and the precursor solution is prepared by taking pirfenidone as a raw material, polyvinyl alcohol and L-leucine as surface active substances and water as a solvent. Also relates to a preparation method of the pirfenidone powder inhalation, which comprises the following steps: weighing polyvinyl alcohol according to the prescription amount, heating and stirring at a certain temperature, and dissolving in water to obtain a polymer solution; weighing the pirfenidone according to the prescription amount, adding the pirfenidone into the prepared polymer solution, and stirring the mixture until the pirfenidone is completely dissolved; weighing the L-leucine with the prescription amount, adding the L-leucine into the solution prepared in the last step, and continuously stirring until the L-leucine is completely dissolved to obtain a precursor solution; and (3) introducing the precursor solution into a feeding device of a spray drying tower for spray drying to obtain the pirfenidone dry powder preparation. The invention solves the problem of potential safety hazard caused by dissolving and preparing the precursor solution by using the organic solvent ethanol, and the prepared aerosol particles have good aerodynamic characteristics.

Description

Pirfenidone powder inhalation and preparation method thereof
Technical Field
The invention relates to the technical field of pirfenidone preparation, in particular to a pirfenidone powder inhalation and a preparation method thereof.
Background
Pirfenidone (PFD), chemical name is 5-methyl-1-phenyl-2- (1H) pyridone, is a new pyridone compound with broad-spectrum anti-fibrosis effect, and can prevent and reverse fibrosis and scar formation. Pirfenidone is a low potency drug and currently, the only dosage forms on the market for pirfenidone are oral dosage forms, although an upper safety threshold for pirfenidone (801 mg TID, i.e., 801mg, 3 times per day) has been established, but the pulmonary doses that can be delivered by oral administration are too low, slow to take effect, requiring very large oral doses to provide efficient pulmonary levels. Furthermore, blood concentration safety limitations and poor compliance due to adverse effects associated with oral dosing also reduce the benefits of oral products, and it is not possible to continue to increase oral dosing to achieve optimal Idiopathic Pulmonary Fibrosis (IPF) treatment. Thus, the oral dosage form cannot achieve the optimum therapeutic effect.
The powder inhalation preparation is still in the development stage, and the existing powder inhalation preparation method has single auxiliary material and poor aerodynamic performance. And because pirfenidone is poor in water solubility, an organic solvent ethanol is mostly adopted for dissolving to prepare a precursor solution, certain potential safety hazards exist in the production and preparation processes, and organic solvent residues may also have certain harm to patients.
Disclosure of Invention
Aiming at the defects of the prior art, the invention provides a pirfenidone inhalation aerosol powder and a preparation method thereof, which solve the problem of potential safety hazard caused by dissolving and preparing a precursor solution by using an organic solvent ethanol.
The technical scheme adopted by the invention is as follows:
the application provides a pirfenidone powder inhalation, which is prepared by spray drying a precursor solution, wherein the precursor solution is prepared by taking pirfenidone as a raw material, polyvinyl alcohol and L-leucine as surface active substances and water as a solvent.
The mass ratio of the pirfenidone to the surface active substance is (1-3): 1.
the mass ratio of polyvinyl alcohol to L-leucine in the surface active substance is (1-3): 1.
the solid content of the precursor solution is not less than 1wt%.
The application also provides a preparation method of the pirfenidone powder inhalation, which comprises the following steps:
(1) Weighing polyvinyl alcohol according to the prescription amount, heating and stirring at a certain temperature, and dissolving in water to obtain a polymer solution;
(2) Weighing a prescription amount of pirfenidone, adding the pirfenidone into the polymer solution prepared in the step (1), and stirring until the pirfenidone is completely dissolved;
(3) Weighing the L-leucine with the formula amount, adding the L-leucine into the solution prepared in the step (2), and continuously stirring until the L-leucine is completely dissolved to obtain a precursor solution;
(4) And (3) introducing the precursor solution into a feeding device of a spray drying tower for spray drying to obtain the pirfenidone dry powder preparation.
In the step (1), the weighed polyvinyl alcohol with the prescription amount is heated, stirred and dissolved in water at the temperature of 60 ℃.
In the step (4), spray drying is carried out under the condition of circulating air in the atmosphere of air or nitrogen, and the circulating air and the feeding matte downstream mode are adopted for mixing, wherein the inlet temperature of the circulating air is 130 ℃, and the flow rate of the circulating air is 160L/min.
In the step (4), during spray drying, the precursor solution is injected into a spray drying tower through an ultrasonic nozzle at the speed of 3-5 ml/min.
The ultrasonic nozzle frequency was 120kHz and the ultrasonic dispersion pressure was 2bar.
The invention has the following beneficial effects:
the invention uses the subsidiary material high molecular polymer polyvinyl alcohol (1788 low viscosity) to cooperate with L-leucine for synergy. On one hand, the characteristic of polyvinyl alcohol as a surfactant is utilized, the dissolving difficulty of pirfenidone in water is reduced, the dissolving amount is increased, the use of an organic solvent can be avoided, and the safety risk is reduced; on the other hand, the pirfenidone forms micelle with polyvinyl alcohol when being dissolved, and when the drug is delivered to the lung, the drug component is wrapped by the high molecular polymer, so that the slow release effect of the lung can be realized, and the drug effect is improved. The polyvinyl alcohol has larger molecular weight and certain viscosity, so that the particle size of the aerosol powder is increased, the aerodynamic characteristics of the particles are improved through the L-leucine, and the negative effect brought by adding the polyvinyl alcohol is reduced.
The invention does not need to use organic solvent to prepare the precursor solution, thereby improving the safety of the preparation in the production and eating processes.
Additional features and advantages of the invention will be set forth in the description which follows, and in part will be obvious from the description, or may be learned by practice of the invention.
Drawings
FIG. 1 shows the dry powder formulation of pirfenidone in BREEZHAER obtained in example 1 of the present invention TM Particle size analysis results under the suction apparatus.
FIG. 2 is a particle morphology chart of the dry powder of example 3 of the present invention.
FIG. 3 is a distribution diagram of the deposition of the powder at each disc level in the lung obtained in the first set of experiments in Experimental example 4 of the present invention.
FIG. 4 is a graph showing the distribution of the deposition in each disc level in the lungs of the powder obtained in the second set of experiments in Experimental example 4 of the present invention.
FIG. 5 is a graph showing the distribution of the deposition in each disc level in the lungs of the powder obtained in the third set of experiments in Experimental example 4 of the present invention.
FIG. 6 is a graph showing the deposition profiles at each level in the lungs of the powder obtained in the fourth set of experiments in Experimental example 4 of the present invention.
Detailed Description
The following describes embodiments of the present invention with reference to the drawings.
The application provides a pirfenidone powder inhalation which is prepared from a precursor solution in a spray drying mode, wherein the precursor solution is prepared from pirfenidone serving as a raw material, polyvinyl alcohol and L-leucine serving as surface active substances and water serving as a solvent.
The auxiliary material high molecular polymer polyvinyl alcohol for the aerosol powder is matched with L-leucine synergistic effect, on one hand, the characteristic that the polyvinyl alcohol is used as a surfactant is utilized, the dissolving difficulty of pirfenidone in water is reduced, the dissolving amount is improved, the use of an organic solvent can be avoided, the safety risk is reduced, on the other hand, pirfenidone forms micelles with the polyvinyl alcohol when being dissolved, and when lung delivery is carried out, the lung slow release effect can be realized by utilizing the characteristic that the high molecular polymer wraps a medicine component, and the medicine effect is improved. However, the polyvinyl alcohol has larger molecular weight and certain viscosity, so that the particle size of the aerosol powder is increased, and the L-leucine can improve the aerodynamic characteristics of the particles and reduce the negative effect brought by adding the polyvinyl alcohol.
Wherein the mass ratio of the pirfenidone to the surface active substance is (1-3): 1.
wherein the mass ratio of polyvinyl alcohol to L-leucine in the surface active substance is (1-3): 1.
wherein the solid content of the precursor solution is not less than 1wt%.
The polyvinyl alcohol is a low-viscosity polyvinyl alcohol 1788 type.
The application also provides a preparation method of the pirfenidone powder inhalation, which comprises the following steps:
(1) Weighing polyvinyl alcohol according to the prescription amount, heating and stirring at a certain temperature, and dissolving in water to obtain a polymer solution;
(2) Weighing a prescription amount of pirfenidone, adding the pirfenidone into the polymer solution prepared in the step (1), and stirring until the pirfenidone is completely dissolved;
(3) Weighing the prescription amountL-leucineAdding the solution prepared in the step (2), and continuously stirring until the solution is completely dissolved to obtain a precursor solution;
(4) And (3) introducing the precursor solution into a feeding device of a spray drying tower for spray drying to obtain the pirfenidone dry powder preparation.
The preparation method can improve the delivery efficiency of the pirfenidone entering deep lung and improve the deposition effect of the pirfenidone in lung by strictly controlling the dosage of the pirfenidone raw material medicine, the selection and improvement of the solvent, the technological parameters of spray drying and the like.
On the basis of ensuring the high proportion of the active ingredients in the dry powder preparation, the preparation process is improved to ensure that the preparation is safer and more efficient and is suitable for industrial expanded production.
The following specific examples further illustrate the preparation of pirfenidone powder inhalation formulations of the present application.
1. Examples 1 to 9
The preparation of each example followed the following steps:
(1) Weighing polyvinyl alcohol according to the formula amount, heating and stirring at the temperature of 60 ℃, and dissolving in water to obtain a polymer solution;
(2) Weighing a prescription amount of pirfenidone, adding the pirfenidone into the polymer solution prepared in the step (1), and performing ultrasonic stirring for assistance until the pirfenidone is completely dissolved;
(3) Weighing the L-leucine with the prescription amount, adding the L-leucine into the solution prepared in the step (2), and continuously performing ultrasonic stirring until the L-leucine is completely dissolved to obtain a spray-dried precursor solution;
(4) And (4) carrying out spray drying on the precursor solution obtained in the step (3) by using a spray drying tower, and collecting to obtain the pirfenidone dry powder preparation.
Specifically, during spray drying, the spray drying is carried out under the condition of circulating air in the air or nitrogen atmosphere, the circulating air and the feeding fog surface are mixed in a forward flow mode, the inlet temperature of the circulating air is 130 ℃, the flow rate of the circulating air is 160L/min, the precursor liquid is injected into a spray drying tower through an ultrasonic nozzle at the speed of 3-5ml/min, the frequency of the ultrasonic nozzle is 120kHz, and the ultrasonic dispersion pressure is 2bar.
The specific amounts of Pirfenidone (PFD), polyvinyl alcohol (PVA), and L-leucine (L) in the precursor solutions prepared in each example are shown in table 1.
TABLE 1 specific amounts of PFD, PVA and L used in examples 1-9
Figure BDA0003961132830000031
2. Particle size analysis test
A dry powder formulation of pirfenidone from example 1 above was prepared in Breezhaler using a SYMPATEC laser particle size analyzer TM (Norwalk, described in U.S. Pat. No. 5, 8479730 (Ziegler et al) suction apparatus for particle size analysis, the results are shown in FIG. 1.
As can be seen from the attached figure 1, the particle size D10 (the particle size corresponding to the cumulative particle size distribution percentage of one sample reaching 10%) of the pirfenidone dry powder preparation prepared in example 1 is 4.09 μm, D50 (the particle size corresponding to the cumulative particle size distribution percentage of one sample reaching 50%) is 9.13 μm, and D90 (the particle size corresponding to the cumulative particle size distribution percentage of one sample reaching 90%) is 19.17 μm, which completely meet the inhalation standards of human body, and the particle size can be found to be uniform by combining frequency distribution.
3. Particle surface topography analysis test
The particle surface morphology of the pirfenidone dry powder preparation prepared in each example above is observed and analyzed by Scanning Electron Microscope (SEM), wherein the particle morphology of the pirfenidone dry powder preparation prepared in example 3 is shown in fig. 2.
As can be seen from figure 2, the polyvinyl alcohol and the leucine, which are taken as surface active substances, have surface active characteristics, are easily adsorbed on a gas-liquid interface in a drying process, and are finally enriched on the surfaces of particles, so that the shapes of the particles are changed, and depressions and folds are generated. The shape increases the surface roughness of the particles, reduces the aerodynamic diameter, and is beneficial to dry powder particles to enter the respiratory tract of a human body so as to increase the administration effect.
3. Pirfenidone dry powder preparation content detection experiment
The conditions (temperature, solid content, etc.) of spray drying and the precursor solution have certain influence on the content of Active Pharmaceutical Ingredients (API) in the dry powder preparation, and further influence the dosage and curative effect required by the preparation used by a patient. In order to verify the relationship between the content of Active Pharmaceutical Ingredients (API) and the conditions of spray drying and precursor solutions and to explore the technical scheme for improving the content of Active Pharmaceutical Ingredients (API), the following experiments were designed:
experimental example 1
In the case where 5 sets of experiments were set in experimental example 1 and the preparation steps and other conditions were the same as in examples 1 to 9, the content, solid content and theoretical content of powder API of Pirfenidone (PFD), polyvinyl alcohol (PVA), and L-leucine (L) in the precursor solution prepared in the 5 sets of experiments in experimental example 1 are shown in table 2.
TABLE 2 Experimental example 1 PFD, PVA, L contents, solid content and theoretical content of powder API in the precursor solution
Figure BDA0003961132830000041
The actual content of the Active Pharmaceutical Ingredient (API) in 5 experimental examples of experimental example 1 in the theoretical content was measured as follows: 37.8%, 38.4%, 73.7%, 68.2%, 70.2%.
The conclusion can be drawn: the deviation of the actual content of the API from the theoretical content is large, especially when the solid content is lower than the auxiliary content of the medicine.
Experimental example 2
4 sets of experiments were set up, and under the same conditions as in experimental example 1, precursor liquid and dry powder formulations were prepared using 20% methanol and water, respectively, as solvents, and the effect of the polyvinyl alcohol surfactant properties on the API content detection was examined.
The contents of Pirfenidone (PFD), polyvinyl alcohol (PVA), and L-leucine (L) in the precursor solutions in 4 experiments of experimental example 2 are shown in table 3.
TABLE 3 Experimental example 2 Each group of experimental precursor solutions had PFD, PVA, L contents, solid contents and theoretical powder API contents
Figure BDA0003961132830000051
Wherein, P1 and P2 are prepared dry powder preparations, S1 and S2 are respectively prepared precursor liquid used for preparing P1 and P2, the solvent used for S1 and P1 is water, and the solvent used for S2 and P2 is 20 percent methanol.
The actual content of the Active Pharmaceutical Ingredient (API) in the 4 experiments in experimental example 2 in the theoretical content was measured as follows: 94.8%, 97.0%, 68.2%, 72.5%.
The conclusion can be drawn by experimental example 2: the API content in the water-soluble and alcohol-soluble precursor liquid is normal, which proves that the PVA micelle system does not influence the property of the API in the solution state; after the water-soluble and alcohol-soluble precursor solutions are sprayed and dried, the API content is approximate and lower, and the fact that PVA does not influence the detection of the API content in the dry powder is proved.
Experimental example 3
4 sets of experiments are set, under the condition that other conditions are the same as those of experimental example 1, 20% methanol and water are respectively used as solvents, under the condition of the same drug auxiliary ratio, precursor liquid preparation is carried out, the spray drying temperature is reduced, the solid content is adjusted, dry powder preparation is carried out, and the influence of the temperature and the solid content is verified.
The spray drying conditions after adjustment are as follows:
inlet temperature of drying air: 120 deg.C (130 deg.C in examples 1-9);
cold air flow rate: 160L/min (also 160L/min in examples 1 to 9).
The contents and solid contents of Pirfenidone (PFD), polyvinyl alcohol (PVA), L-leucine (L) in the precursor solutions in 4 experiments in experimental example 3, and the API theoretical contents are shown in table 4.
TABLE 4 PFD, PVA and L contents and solid contents in each set of experimental precursor solutions in Experimental example 3, as well as the theoretical API content
Figure BDA0003961132830000052
Figure BDA0003961132830000061
Wherein, the dry powder 1-4 is powder prepared from the solution 1-4 (precursor solution).
The actual content of the Active Pharmaceutical Ingredient (API) in the 4 experiments in experimental example 3 in the theoretical content was measured as follows: 97%, 98%, 96%, 98%, 82%, 63%, 82%, 71%.
The conclusion can be drawn by experimental example 3: under the condition that the solution is still stable, the API content is obviously improved after the spray drying temperature is reduced. The temperature proves to be an important reason for the low content of the API in the dry powder sample, and the reduction of the temperature is helpful for increasing the content of the API in the sample. At lower solids (1% down to 0.5%), the API content decreased significantly. Therefore, the solid content in the precursor liquid is preferably not less than 1%.
4. FPF detection assay
Experimental example 4
The Fine Particle Fraction (FPF) is generally defined as the fraction or percentage of the mass of drug contained in the aerosol cloud, which may be small enough to enter the lungs and exert a clinical effect. FPF is a major measure of aerosol quality and widely predicts the amount of drug deposited in the lungs in an inhaler device.
Experimental example 4 were set up to 4 sets of experiments, and the content of Pirfenidone (PFD), polyvinyl alcohol (PVA), and leucine (L) in each set of experiments were shown in table 5, using 20% methanol and water as solvents, respectively, under the same conditions as in experimental example 1.
TABLE 5 contents of PFD, PVA and L in each set of experimental examples in Experimental example 4
Figure BDA0003961132830000062
The FPF of the new-generation medicinal disk impactor (NGI) is detected under the following conditions:
time: 4s of medicines: pirfenidone
Temperature: number of 28 ℃ sparging: 10 granules (Capsule)
Humidity: flow rate of 55%: 60L/min
The distribution of NGI disc fractions is shown in table 6 below:
table 6 distribution of NGI in each pan of 4 experiments in experimental example 4
Figure BDA0003961132830000063
Figure BDA0003961132830000071
Wherein S1-S8 refer to 8 disc levels, respectively.
The distribution of the deposition in the lung at each disc level for the 4 experimental groups is shown in FIGS. 3-6, respectively.
The overall FPF results for each set of experiments are shown in table 7:
TABLE 7 FPF Overall results for 4 sets of experiments in Experimental example 4
Serial number P1 P2 P3 P4
MMAD/μm 7.988 6.129 4.871 5.930
Total FPF/% 11.546 22.550 27.498 19.635
Emitted FPF/% 12.486 23.684 27.814 23.523
Wherein, MMAD, total FPF and Emitted FPF respectively represent the aerodynamic mass median diameter, absolute FPF (not considering the powder residue in the capsule) and relative FPF (considering the powder residue in the capsule).
The conclusion obtained in experimental example 4 is as follows: under the condition of adopting PVA for solubilization, the FPF of the particles prepared by spray drying can reach or even exceed the FPF of the particles prepared by dissolving by adopting a methanol solvent, and the delivery quantity required by effective absorption of the lung is completely reached; a decrease in PVA content is beneficial for increasing FPF, but too low a content affects the extent of API dissolution.
A dry powder Fine Particle Fraction (FPF) of 15% or greater for each set of experiments, and wherein the particles have at least one or more of the following characteristics:
d50 diameter is 5-20 μm;
the aerodynamic diameter is 1-8 μm;
the aerodynamic mass median diameter (MMAD) is between 1 and 8 μm.
Those of ordinary skill in the art will understand that: although the present invention has been described in detail with reference to the foregoing embodiments, it will be apparent to those skilled in the art that changes may be made in the embodiments and/or equivalents thereof without departing from the spirit and scope of the invention. Any modification, equivalent replacement, or improvement made within the spirit and principle of the present invention should be included in the protection scope of the present invention.

Claims (9)

1. The pirfenidone powder inhalation is prepared by spray drying a precursor solution, and is characterized in that the precursor solution is prepared by taking pirfenidone as a raw material, polyvinyl alcohol and L-leucine as surface active substances and water as a solvent.
2. The dry powder inhalation of pirfenidone ear according to claim 1, wherein the mass ratio of pirfenidone to the surface active substance is (1-3): 1.
3. the dry powder inhalation of the ear pirfenidone according to claim 1 or 2, wherein the mass ratio of the polyvinyl alcohol to the L-leucine in the surface active substance is (1-3): 1.
4. the dry powder inhalation ear pirfenidone according to claim 1, wherein the solid content of the precursor solution is not less than 1wt%.
5. A method for preparing pirfenidone powder inhalation, which is characterized by comprising the following steps:
(1) Weighing polyvinyl alcohol according to the formula amount, heating, stirring and dissolving in water at a certain temperature to obtain a polymer solution;
(2) Weighing a prescription amount of pirfenidone, adding the pirfenidone into the polymer solution prepared in the step (1), and stirring until the pirfenidone is completely dissolved;
(3) Weighing the L-leucine with the formula amount, adding the L-leucine into the solution prepared in the step (2), and continuously stirring until the L-leucine is completely dissolved to obtain a precursor solution;
(4) And (3) introducing the precursor solution into a feeding device of a spray drying tower for spray drying to obtain the pirfenidone dry powder preparation.
6. The method for preparing pirfenidone powder for inhalation according to claim 5, wherein in step (1), the weighed and prescribed amount of polyvinyl alcohol is dissolved in water at 60 ℃ with heating and stirring.
7. The process for preparing pirfenidone powder for inhalation according to claim 5, wherein in the step (4), the spray drying is performed under the condition of circulating air in air or nitrogen atmosphere, and the circulating air is mixed with the feeding matte in a concurrent flow manner, wherein the inlet temperature of the circulating air is 130 ℃, and the flow rate of the circulating air is 160L/min.
8. The method for preparing pirfenidone powder for inhalation according to claim 5, wherein in the step (4), the precursor solution is injected into the spray drying tower through an ultrasonic nozzle at a speed of 3-5ml/min during spray drying.
9. The method for preparing pirfenidone aerosol powder for inhalation according to claim 8, wherein the ultrasonic nozzle frequency is 120kHz and the ultrasonic dispersion pressure is 2bar.
CN202211483815.0A 2022-11-24 2022-11-24 Pirfenidone powder inhalation and preparation method thereof Pending CN115919813A (en)

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