KR20200063078A - Method for producing inhalant formulation with enhanced inhalation efficiency of pirfenidone using excipient for treatment of pulmonary disease - Google Patents

Abstract

The present invention relates to a method for manufacturing an inhalation formulation for treating pulmonary diseases with enhanced inhalation efficiency of pirfenidone using an excipient. When using the inhalation formulation for pirfenidone by adding leucine among the types of excipients of the present invention, the inhalation efficiency of pirfenidone is significantly increased, so that it is possible to be usefully used as the method for manufacturing the inhalation formulation containing pirfenidone for treating pulmonary diseases, especially idiopathic pulmonary fibrosis.

Description

Method for producing inhalant formulation with enhanced inhalation efficiency of pirfenidone using excipient for treatment of pulmonary disease}

The present invention relates to a method for preparing an inhalation formulation for treating lung diseases with improved inhalation efficiency of pirfenidone using an excipient.

Pirfenidone is the first FDA-approved active ingredient for the treatment of idiopathic pulmonary fibrosis. To suppress the progress of fibrosis. Currently, pirfenidone is used as a solid preparation for oral administration. However, when it is administered orally, the amount of pirfenidone transferred to the gastrointestinal tract and the whole body increases, and there is a problem that side effects such as gastrointestinal disorders and skin light sensitization occur. In addition, the oral pirfenidone formulation is complicated and the dosage increases by 3 tablets 3 times a day, depending on the reaction and tolerability of the patient, thereby increasing patient convenience and frequency of side effects.

In the case of an inhaled dosage form administered to the lung, the drug is capable of local action in the lung, and it can increase bioavailability and reduce the single dose by taking advantage of the liver first-pass effect and large absorption surface area. There is an advantage that can be made. However, in the case of an inhalation formulation, the particle size should be about 4 μm in order to be delivered to the lungs.

Since pirfenidone is a therapeutic agent for lung disease, it is thought that when administered to the lung, the amount of reaching the target tissue, the lung, increases, and the bioavailability increases, so that it can exhibit efficacy in a small amount. In addition, since the proportion and absolute amount of systemic circulation decrease, side effects such as skin light sensitization are reduced, and gastrointestinal disorders are also expected to decrease because they do not go through the gastrointestinal tract. However, pirfenidone is difficult to manufacture into small particles due to its high crystallinity and static electricity, and due to its high cohesiveness, the rate at which it is delivered to the deep lung during inhalation is low.

Accordingly, the present invention is to develop a dry powder inhaler containing pirfenidone for improving the treatment efficiency and side effects of idiopathic pulmonary fibrosis, and taking pirfeni as an excipient in consideration of the high crystallinity and electrostatic properties of pirfenidone. We wanted to stabilize the dry powder inhalation formulation containing money.

On the other hand, Korean Patent Publication No. 2018-0100869 discloses a "pharmaceutical composition with improved tableting properties according to particle size control of pirfenidone and a method for manufacturing the same", and Korean Patent No. 1734858 discloses "Pirfeni Improved method for synthesizing money. However, there has not been disclosed a method for preparing an inhalation formulation for treating lung diseases with improved inhalation efficiency of pirfenidone using the excipients of the present invention.

The present invention has been derived by the above-described needs, in the present invention to stabilize the dry powder inhalation formulation containing pirfenidone in consideration of the high crystallinity and electrostatic properties of pirfenidone, by excipient type, solvent composition After preparing each composition containing pirfenidone according to the ratio of stars and excipients and spray-drying them, after measuring their microparticle size and inhalation efficiency, leucine was used as an excipient, and pirfenidone and leucine When added in a weight ratio of 1:1, and dissolved in distilled water and spray dried, the particle size Dv50 (50% cumulative volume distribution) of the dry powder formulation containing pirfenidone was 4.28 μm. It was confirmed that the intake efficiency is significantly increased compared to other conditions. In addition, when performing a pharmacokinetic and pharmacodynamic analysis of a dry powder inhalation formulation containing pirfenidone in a mouse animal model in which lung fibrosis is induced by bleomycin, pirfeni produced by the production method of the present invention The present invention was completed by confirming that when the dry powder formulation containing money was administered to the lungs at a dose of 15-30 mg/kg, the absorption efficiency of pirfenidone was increased and the lung fibrosis was also reduced compared to oral administration. .

In order to solve the above problems, the present invention is a step of dissolving the lung disease treatment and excipients by adding the same amount to the water; And by spray drying the lysate to obtain a powder form of a formulation; provides a method for producing a pulmonary disease inhalation formulation for treating lung disease with improved inhalation efficiency of a therapeutic agent for lung disease.

In addition, the present invention provides an inhalation formulation for treating lung diseases with improved inhalation efficiency prepared by the above method.

In addition, the present invention provides a pharmaceutical composition for preventing or treating lung diseases containing the inhalation formulation for treating lung diseases as an active ingredient.

According to the present invention, when the inhalation formulation of pirfenidone is prepared by adding leucine among the excipient types, it has been confirmed that the inhalation efficiency of pirfenidone is significantly increased, so pir for treatment of lung diseases, especially idiopathic pulmonary fibrosis It can be usefully used as a method for preparing an inhalation formulation containing phenidone.

1 is a scanning electron microscope in the form of a dry powder inhalation formulation containing pirfenidone prepared through a spray drying process by mixing the pirfenidone and leucine of the present invention in a weight ratio of 1:1 and dissolved in tertiary distilled water. This is the picture I checked through.
2 is a schematic diagram of an animal experiment for confirming the efficacy of treating lung fibrosis. Pirfenidone was administered by varying the formulation, dose, or route of administration from 7 to 14 days of bleomycin administration, a pulmonary fibrosis-inducing agent.
3 is a result of measuring the concentration of pirfenidone in the plasma of animal model mice according to the dosage of the dry powder inhalant formulation containing pirfenidone. Oral: 30 mg/kg of pirfenidone orally administered; SDH (Spray dried-H): a group in which a dry powder inhalation formulation containing 30 mg/kg of pirfenidone was administered to the lungs using an insufflator; SDM (Spray dried-M): a group in which a dry powder inhalation formulation containing 15 mg/kg of pirfenidone was administered to the lungs using an injector; And SDL (Spray dried-L): A group in which a dry powder inhalation formulation containing 7.5 mg/kg of pirfenidone was administered to the lungs using an injector.
Figure 4 is a micrograph (microscopic magnification: × magnification: microscopic magnification: ×) performed by trichrome staining by excising the lung tissue of an animal model mouse administered with a dry powder inhalant formulation containing pirfenidone; 200). NC: normal group; PC: Pulmonary fibrosis-induced group treated with bleomycin; Oral: 30 mg/kg of pirfenidone orally administered; SDH: group in which a dry powder inhalation type containing 30 mg/kg of pirfenidone was administered to the lungs using an insufflator; SDM: a group in which a dry powder inhalation formulation containing 15 mg/kg of pirfenidone was administered to the lungs using an injector; And SDL: a group in which a dry powder inhalation formulation containing 7.5 mg/kg of pirfenidone was administered to the lungs using an injector.
5 is a result of evaluating the degree of improvement of pulmonary fibrosis according to the dosage of the dry powder inhalation formulation containing pirfenidone with an Ashcroft score. **, ## and $$ are ANOVA; Analysis compared to the normal group (NC), pulmonary fibrosis-induced bleomycin-induced group (PC), and 30 mg/kg pirfenidone oral administration group (Oral), respectively. Of Variance), and **, ## and $$ mean P value <0.005.

In order to achieve the object of the present invention, the present invention comprises the steps of adding and dissolving the lung disease treatment agent and excipient in the same amount of water; And by spray drying the lysate to obtain a powder form of a formulation; provides a method for producing a pulmonary disease inhalation formulation for treating lung disease with improved inhalation efficiency of a therapeutic agent for lung disease.

In the method of preparing an inhalation formulation for treating lung diseases with improved inhalation efficiency of a lung disease therapeutic agent of the present invention, the lung disease therapeutic agent may be pirfenidone, but is not limited thereto.

In addition, the excipient may be leucine, but is not limited thereto.

The term'excipient' refers to a substance that is added for the purpose of giving the drug a suitable form or increasing the amount to facilitate use.

In addition, the lung disease may be idiopathic pulmonary fibrosis, but is not limited thereto.

The present invention also provides an inhalation formulation for treating lung diseases with improved inhalation efficiency prepared by the above method.

The inhalation formulation for treatment of lung disease with improved inhalation efficiency according to the present invention may include pirfenidone, a therapeutic agent for lung disease.

The inhalation formulation of the present invention may have a particle size of 4-5㎛, but is not limited thereto.

The present invention also provides a pharmaceutical composition for the prevention or treatment of lung diseases containing the inhalation formulation for treating lung diseases as an active ingredient.

In the pharmaceutical composition of the present invention, the dose of the inhalation formulation for the treatment of lung disease may be 10-30 mg per kg body weight of the mouse, preferably 15-30 mg, and most preferably 30 mg. , But is not limited to this. When the administration dose of the inhalation formulation is less than 15 mg/kg of the mouse body weight, the therapeutic effect on pulmonary fibrosis is reduced compared to the oral administration, and 30 mg is the concentration that increases the therapeutic effect of pulmonary fibrosis upon oral administration and has no side effects. (Satomi Onoue et al., 2013, Pharm Res., 30:1586-1596). When converting 10 to 30 mg per kg body weight of the mouse, which is the dose, the product is multiplied by 0.081 (mouse → human conversion factor) (J Basic Clin Pharma 2016; 7:27-31). It is 0.81~2.43mg/kg body weight.

The pharmaceutical dosage form of the composition according to the present invention can be used alone or in combination with other pharmaceutically active compounds as well as in a suitable collection.

The pharmaceutical composition of the present invention may be administered in a pharmaceutically effective amount, the term "pharmaceutically effective amount" of the present invention to prevent or treat the disease at a reasonable benefit/risk ratio applicable to medical prevention or treatment Means sufficient amount, and effective dose level is the severity of the disease, the activity of the drug, the patient's age, weight, health, sex, the patient's sensitivity to the drug, the time of administration, the route of administration and rate of discharge, the duration of treatment, the combination or simultaneous It can be determined by factors including the drugs used and other factors well known in the medical field. The pharmaceutical composition of the present invention may be administered as an individual therapeutic agent or in combination with other therapeutic agents, and may be administered sequentially or simultaneously with conventional therapeutic agents. And it can be administered single or multiple. Considering all of the above factors, it is important to administer an amount that can achieve the maximum effect in a minimal amount without side effects.

Hereinafter, the present invention will be described in more detail using examples. It is obvious to those skilled in the art that these examples are only intended to illustrate the present invention more specifically and that the scope of the present invention is not limited by them.

Manufacturing example 1 to 3. By excipient type Pirfenidone Fine particle production

Microparticles containing pirfenidone were prepared by spray drying according to the composition of Table 1 below. Specifically, sodium chloride (NaCl), leucine and mannitol were used as excipients, and tertiary distilled water was used as the solvent. A spray drying solution was prepared by dissolving pirfenidone and excipients in tertiary distilled water, and then spray drying was performed using a spray dryer (SD-1000 manufactured by EYELA).

By excipient type Spray Drying Composition Preparation Example 1 Preparation Example 2 Preparation Example 3 Pirfenidone (%, w/v) One One One NaCl (%, w/v) One - - Leucine (%, w/v) - One - Mannitol (%, w/v) - - One menstruum Tertiary distilled water

Manufacturing example 4 to 6. By solvent type Pirfenidone Fine particle production

Microparticles containing pirfenidone were prepared by spray drying according to the composition of Table 2 below. Sodium chloride (NaCl) was used as an excipient, and the composition of the solvent was prepared by mixing with the ratio of tertiary distilled water and ethanol. After dissolving pirfenidone and excipients in the mixed solution to prepare a spray drying solution, a spray drying process was performed using a spray dryer. It was compared with Preparation Example 1 using 100% tertiary distilled water as a solvent.

By solvent type Spray dry liquid composition Preparation Example 1 Preparation Example 4 Preparation Example 5 Preparation Example 6 Pirfenidone (%, w/v) One One One One NaCl (%, w/v) One One One One menstruum
(Third distilled water: ethanol) 100:0 80:20 50:50 20:80

Manufacturing example 7 to 9. Sodium chloride (NaCl) by usage Pirfenidone Fine particle production

Microparticles containing pirfenidone were prepared by spray drying according to the composition of Table 3 below. Different amounts of sodium chloride were used as excipients, and a spray drying solution was prepared by dissolving pirfenidone and excipients in tertiary distilled water, and then spray drying was performed using a spray dryer. The mixing ratio of pirfenidone and sodium chloride was evaluated in comparison with Preparation Example 1 using 1:1.

By sodium chloride usage Spray Drying Composition Preparation Example 1 Preparation Example 7 Preparation Example 8 Preparation Example 9 Pirfenidone (%, w/v) One One One One NaCl (%, w/v) One 0.5 0.3 0.1 menstruum Tertiary distilled water

Manufacturing example 10 to 13. Leucine ( Leucine ) By usage Pirfenidone Fine particle production

Microparticles containing pirfenidone were prepared by spray drying according to the composition of Table 4 below. Different amounts of leucine were used as excipients. A spray drying solution was prepared by dissolving pirfenidone and excipients in tertiary distilled water, and then spray drying was performed using a spray dryer. It was evaluated in comparison with Preparation Example 2 using a mixing ratio of perpinidone and leucine 1:1.

By leucine usage Spray Drying Composition Preparation Example 2 Preparation Example 10 Preparation Example 11 Preparation Example 12 Preparation Example 13 Pirfenidone (%, w/v) One One One One One Leucine (%, w/v) One 0.5 0.3 0.1 2 menstruum Tertiary distilled water

Comparative example 1 and 2. Pirfenidone Preparation of raw materials and single component microparticles

Pyrphenidone raw material itself was used as Comparative Example 1, and Comparative Example 2 was prepared by dissolving pirfenidone in tertiary distilled water to prepare a 1% pirfenidone (w/v) spray drying solution and spraying using a spray dryer. The drying process was performed.

Example One. Pirfenidone Containing dry powder Inhalant Check particle size distribution

For the dry powder inhalation formulation containing each pirfenidone prepared by the method of Preparation Examples 1 to 13, its microparticle size was measured using a Malvern particle size analyzer (mastersizer 3000). As a result, when compared with Comparative Examples 1 and 2, as shown in Table 5, the drying method containing pirfenidone in the method of Preparation Example 1, Preparation Example 2, Preparation Examples 4 to 8, Preparation Examples 10 to 13 When the powder inhaler formulation was prepared, the particle size was significantly reduced. In particular, pirfeni of Preparation Example 2 prepared through a spray drying process by mixing pirfenidone and leucine in a 1:1 weight ratio and dissolving in tertiary distilled water. It was confirmed that the dry powder inhaler type containing money had the smallest particle size. In addition, in order to observe the morphological characteristics of the dry powder inhalation formulation containing pirfenidone prepared by the method of Preparation Example 2 using a Zeiss Ultra Plus Scanning Electron Microscope, as a result, it was found in a circular shape as shown in FIG. 1. It was confirmed to show a close shape.

Particle size of pirfenidone according to the preparation example Dv 50(㎛) Preparation Example 1 11.4 Manufacturing example 2 4.28 Preparation Example 3 64.2 Preparation Example 4 11.5 Preparation Example 5 9.09 Preparation Example 6 8.63 Preparation Example 7 21.3 Preparation Example 8 28.7 Preparation Example 9 62.8 Preparation Example 10 6.44 Preparation Example 11 5.18 Preparation Example 12 8.14 Preparation Example 13 7.91 Comparative Example 1 107 Comparative Example 2 54.3

Example 2. Pirfenidone Containing dry powder Inhalant Check suction efficiency

By excipient type (Preparation Examples 1 to 3), by solvent composition (Preparation Examples 4 to 6), by excipient sodium chloride ratio (Preparation Example 1, Production Examples 7 to 9) and by excipient leucine ratio (Preparation Example 2, Production Example For dry powder inhalation formulations containing each pirfenidone prepared in 10 to 13), Copley's AES (Andesren cascade impactor) was used to evaluate the delivery efficiency to the lungs. As a result, as shown in Table 6 below, when leucine was used as an excipient (Preparation Example 2, Preparation Examples 10 to 13), high inhalation efficiency was shown, and in particular, leucine was used as an excipient, and 100% tertiary distilled water was used. The dry powder inhalant formulation containing pirfenidone prepared after dissolving leucine and pirfenidone in a weight ratio of 1:1 after the spraying process (Preparation Example 2) showed the best suction efficiency.

Inhalation efficiency of pirfenidone according to the manufacturing example MMAD±SD(μm) GSD±SD ED±SD(%) FPF±SD(%) RF±SD(%) Preparation Example 1 6.96 ± 0.24 1.42 ± 0.06 97.96 ± 0.37 11.37 ± 0.26 41.93 ± 4.66 Manufacturing example 2 3.85 ± 0.21 1.46 ± 0.08 99.12 ± 0.08 23.37 ± 0.83 84.52 ± 5.33 Preparation Example 3 8.17 ± 0.28 1.14 ± 0.01 99.06 ± 0.40 2.89 ± 1.61 4.43 ± 1.22 Preparation Example 4 7.77 ± 0.44 1.38 ± 0.11 98.58 ± 0.41 4.38 ± 2.30 27.13 ± 10.44 Preparation Example 5 7.28 ± 0.47 1.50 ± 0.08 97.33 ± 0.01 5.74 ± 1.01 38.55 ± 6.85 Preparation Example 6 7.77 ± 0.43 1.39 ± 0.11 98.45 ± 0.39 4.92 ± 2.88 27.86 ± 10.10 Preparation Example 7 6.80 ± 0.56 1.39 ± 0.12 97.78 ± 0.46 6.76 ± 1.63 43.22 ± 12.27 Preparation Example 8 8.03 ±0 .12 1.18 ± 0.01 98.57 ± 0.09 2.81 ± 0.20 9.99 ± 1.86 Preparation Example 9 7.98 ± 0.05 1.14 ± 0.01 98.76 ± 0.70 2.56 ± 0.50 5.23 ± 0.89 Preparation Example 10 4.55 ± 0.25 1.60 ± 0.20 98.67 ± 0.04 38.12 ± 2.45 74.79 ± 3.11 Preparation Example 11 4.70 ± 0.10 1.64 ± 0.04 98.43 ± 0.58 29.25 ± 0.90 74.37 ± 2.17 Preparation Example 12 6.85 ± 0.16 1.46 ± 0.04 96.07 ± 0.28 32.50 ± 4.68 44.40 ± 2.96 Preparation Example 13 4.44 ± 0.27 1.49 ± 0.16 93.77 ± 0.73 44.24 ± 3.34 77.15 ± 4.08

MMAD: Mass median aerodynamic diameter; GSD: geometric standard deviation; ED: emitted dose; FPF: fine particle fraction; RF: respirable fraction

Example 3. Confirmation of treatment efficacy of pulmonary fibrosis according to the dosage amount of dry powder inhalation formulation containing pirfenidone

As confirmed in Examples 1 and 2, among the Preparation Examples 1 to 13, the particle size (Dv50) was the smallest, and the dry powder inhalation formulation containing pirfenidone of Preparation Example 2 with the highest inhalation efficiency was subjected to pharmacokinetics ( PK, pharmacokinetics (PD), and pharmacodynamics (PD) analysis were performed to analyze the efficiency in vivo .

Pulmonary fibrosis induced by bleomycin is a commonly used model in animal experiments to test for therapeutic agents for potential idiopathic pulmonary fibrosis (IPF). Bleomycin induces pulmonary inflammation, followed by chronic progression of pulmonary fibrosis, and the fibrosis phase occurs around 7 days after bleomycin injection . For prophylactic treatment, antifibrotic drugs are suggested to be effective regardless of disease progression, especially when administered at the “fibrous” stage, but can actually diagnose lung fibrosis after respiratory symptoms and radiologic evidence are found. Therefore, treatment may start at the fibrosis stage. Therefore, considering the actual treatment period, from about 7 days after injection of bleomycin, pirfenidone and leucine of the present invention were mixed at a weight ratio of 1:1 and dissolved in tertiary distilled water to contain pirfenidone prepared through a spray drying process. A dry powder inhalation type was injected.

In the animal model of pulmonary fibrosis, 50 μl of a 5 mg/ml bleomycin solution, which is a pulmonary fibrosis-inducing substance, is injected directly into the lungs of an SD-mouse (250 weeks old, male, male) according to intratracheal instillation (ITI). A mouse animal model induced by pulmonary fibrosis by mycin was constructed, and all procedures were approved by the Animal Experimental Ethics Committee of Chungbuk National University. During the 7-14 day period with bleomycin injection, an injector (insufflator, DP-4, Penn-century, USA) was injected into the model mouse airway, thereby allowing the dry powder inhalation formulation containing pirfenidone of the present invention once daily. It was administered to the lungs, and the doses were 7.5 mg/kg, 15 mg/kg and 30 mg/kg, respectively, and a pirfenidone solution (10 mg/ml) was prepared as a comparative control and orally administered at 30 mg/kg (Table 7). ). The dose of 30 mg/kg is a therapeutic efficacy when administered orally and has no side effects (Satomi Onoue et al., 2013, Pharm Res., 30:1586-1596).

Experimental information for animal model mice Experimental group Method of administration Injection concentration Number of experimental animals (n) Normal group (NC) - - 6 Fibrosis-induced group (PC) - - 6 Oral administration group (Oral) Oral 30mg/kg 6 SDH(Spray dried-H) Insufflator 30mg/kg 6 SDM(Spray dried-M) Insufflator 15mg/kg 6 SDL(Spray dried-L) Insufflator 7.5mg/kg 6

SDH (Spray dried-H): 30 mg/kg of dry powder inhalation formulation containing pirfenidone; SDM (Spray dried-M): Dry powder inhalation formulation containing pirfenidone 15mg/kg administration group; And SDL (Spray dried-L): 7.5 kg of dry powder inhalation type containing pirfenidone.

Thereafter, blood was collected from the mouse animal model every 10 minutes, 20 minutes, 30 minutes, 1 hour, and 3 hours after the administration of the inhalation formulation by orbital blood collection method, and then centrifuged to recover plasma to give a liquid chromatography-mass spectrometer (LC The concentration of pirfenidone (PRF) in plasma was measured via -MS/MS (FIG. 2).

In addition, in order to evaluate the therapeutic efficacy of pulmonary fibrosis according to the dosages (30mg/kg, 15mg/kg and 7.5mg/kg) of the dry powder inhalation formulation containing pirfenidone in pharmacodynamics, bleomycin administration 14 On the first day, the lung animal tissue model was sacrificed to remove the lung tissue and the lung lobe tissue was excised, followed by Masson's trichrome stain to observe the degree of lung fibrosis under a microscope and Ashcroft scroe (Ashcroft scroe; Ashcroft et. al., 1988, J Clin Pathol., 41:467-470). Ashcroft scores indicate the severity of interstitial fibrosis (0: normal lung, 1: minimal fiber thickness in the alveoli or bronchial wall, 2-3: moderate thickness wall with no apparent damage to the structure of the lung, 4- 5: evaluation of increased fibrosis and fibrous bands or small fibrous masses with obvious damage to the lung structure, 6-7: severe lung structure damage and wide range of fiber areas, 8: full range of fiber occlusion) Was evaluated based on the Ashcroft Fibrosis Score System.

As a result, when the dry powder inhalation formulation containing 15 mg/kg and 30 mg/kg of pirfenidone was administered to the lungs as shown in FIG. 3, pirfenidone absorption was compared to the oral administration group (Oral; 30 mg/kg). Not only was it excellent in efficiency, but the dose of pirfenidone in the animal model mouse body and the pharmacokinetic parameter C _max (maximum serum concentration) CUC (maximum serum concentration), AUC increased as the dosage of the dry powder inhaler formulation containing pirfenidone increased. (area under the curve) and the relative bioavailability (relative bioavailability) through the increase, it was confirmed that the amount of pirfenidone absorption shows dose responsiveness according to the dose (Table 8).

PK parameters (pharmacokinetic parameters) C _max (µg/ml) AUC _inf (hr ^* μg/ml) T _1/2
(hr) K Relative bioavailability
(%, based on 100% of Oral group) Oral 15.8±5.99 ^# 12.4±3.47 1.4±0.24 0.7±0.15 100.0 SDH 35.4±3.02 ^* 33.4±2.73 ^* 0.4±0.01 ^* 1.5±0.05 ^* 270.5 SDM 21.8±2.14 ^# 15.0±2.00 ^* 0.4±0.01 ^* 1.5±0.06 ^* 243.4 SDL 3.7±0.28 ^*,# 3.8±0.38 0.5±0.03 1.4±0.09 ^* 121.5

C _max : maximum or peak concentration of the drug observed after drug administration, AUC: area under the curve (total drug absorption), T _1/2 : half-life, K: loss constant. * Indicates statistical significance using ANOVA (Analysis Of Variance) compared to the oral administration group (Oral), and means that P value <0.05.

In addition, as a result of performing Masson's trichrome after resecting the left lobe tissue of the mouse animal model mouse, which was administered to the lungs with a dry powder inhalation formulation containing pirfenidone, normal as shown in FIG. 4. Compared to the group (NC), it was confirmed that bleomycin treatment in the lung fibrosis-induced group (PC) induced excessive collagen accumulation in the lung epilepsy. On the other hand, when the dry powder inhalation formulations containing pirfenidone (SDH, SDM and SDL) were administered to the lungs, the degree of pulmonary fibrosis was significantly reduced, similar to that of normal tissue (NC) lung tissue, and pirfenidone. It has been found that the effect of improving fibrosis also increases as the dose of the dry powder inhaler formulation containing the composition increases. As in the results of measuring the Ashcroft score, the dry powder inhalation-type administration group containing 15 mg/kg and 30 mg/kg of pirfenidone had a better Ashcroft score than the oral administration group (Oral; 30 mg/kg) as well as the normal group (NC). It was confirmed that it was evaluated at a similar level (Fig. 5).

Claims (8)

Dissolving the lung disease treatment agent and excipients by adding the same amount to water; And
Spray drying the lysate to obtain a powder form of a formulation; A method for producing a pulmonary disease treatment inhalation formulation with improved inhalation efficiency of a pulmonary disease treatment agent comprising a. The method of claim 1, wherein the treatment for pulmonary disease is pirfenidone. The method of claim 1, wherein the excipient is leucine (leucine). The method of claim 1, wherein the lung disease is idiopathic pulmonary fibrosis. An inhalation formulation for the treatment of lung diseases with improved inhalation efficiency prepared by the method of any one of claims 1 to 4. The inhalation formulation for treating lung diseases according to claim 5, wherein the inhalation formulation has a particle size of 4-5 μm. A pharmaceutical composition for preventing or treating lung disease, comprising the inhalation formulation for treating lung disease according to claim 5 or 6 as an active ingredient. [9] The pharmaceutical composition for preventing or treating lung disease according to claim 7, wherein the dose of the inhalation formulation is 10-30 mg per kg of mouse body weight.

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