ADMINISTRATION OF PIRFENIDONE VIA INHALATION

Abstract

This invention relates to the administration of pirfenidon via entrainment from pirfenidon solution through electronic nicotine delivery systems and the use of pirfenidon administered via this route in the treatment of idiopathic pulmonary fibrosis.

Description

INHALATION ROUTE TLE PTRFENTDON ADMINISTRATION Technical Area This invention relates to the administration of pirfenidone via entrainment from pirfenidone solution through electronic nicotine delivery systems and the use of pirfenidone administered via this route in the treatment of idiopathic pulmonary fibrosis. State of the Art Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive, interstitial pneumonia of unknown etiology characterized by fibrosis, occurring in adults and limited to the lungs. The predominant pathological findings in IPF are fibroblastic foci and collagen deposition; inflammation is minimal, increasing the likelihood that antifibrotic drugs may slow the rate of disease progression. Pirfenidone, an antifibrotic drug, inhibits transforming growth factor beta (TGF-β)-stimulated collagen synthesis; it reduces the extracellular matrix and blocks fibroblast proliferation in vitro. Pirfenidone and its synthesis were first described in patent document number US3839346, while its anti-fibrotic activity was described in patent document number EP0458861. Its chemical name is... 5-Methyl-l-phenyl-lH-pyridin-2-one has the structural formula shown below. The first product containing the active ingredient pirfenidon, in 200 mg tablet form, was approved in Japan in 2008. A capsule version containing 267 mg of pirfenidon was approved in Europe in 2011 for use in patients with mild to moderate IPF, and in the United States in 2014 for the treatment of IPF of any severity. Purpose of the Invention Ideally, delivery methods that allow drugs to reach the target site directly and quickly, resulting in lower doses and thus minimizing and / or eliminating side effects, are preferred for the delivery of therapeutic drugs to the patient. Pirfenidone treatment begins with oral administration of 1 capsule three times a day (total 801 mg / day) and continues with 3 capsules three times a day (2403 mg / day) for a period of 14 days. Doses above 2403 mg / day are not recommended for any patient. In clinical studies, pirfenidon reduced the risk of death by 48% in the first year compared to placebo. However, patients using pirfenidon experienced side effects such as nausea (36%), rash (32%), dyspepsia (19%), dizziness (18%), vomiting (14%), photosensitivity (12%), anorexia (11%), abdominal pain, upper respiratory tract infection, diarrhea, fatigue, headache, gastroesophageal reflux, sinusitis, insomnia, weight loss, and arthralgia. Elevated liver enzymes, photosensitivity reactions, and gastrointestinal disturbances have also been reported. These effects appear to be dose-dependent. These side effects associated with pirfenidon treatment are exacerbated when pirfenidon is administered orally in high doses. If individuals experience one or more of the aforementioned side effects, close monitoring and dose reduction or discontinuation of the medication are recommended. In a recent study, the dose was gradually reduced for side effects rated as grade 2 or worse. However, if the side effects persisted or worsened despite dose reduction, the medication was discontinued. Reducing or completely discontinuing the medication eliminates the possibility of treatment and / or prolonging the lifespan of the patients. Inhalation of pirfenidone offers several advantages compared to oral administration. Specifically, pirfenidone is a low-potency drug, requiring high doses for oral administration. However, inhalation allows for the desired effect to be achieved at lower doses. While oral administration results in high toxicity at high doses, inhalation reduces toxicity at low doses. Gastrointestinal side effects are severe with oral administration, while they are either absent or reduced with inhalation. Whether the patient is fasting or not affects pirfenidone absorption and the severity of side effects with oral administration, whereas this variable is not present with inhalation. Patient tolerance is higher with inhalation than with oral administration, therefore dose adjustment is not necessary at the start of treatment. Patent applications W02015106150, WO2012106382 and WO2014018668 describe the administration of pirfenidone formulations via nebulizers, dry powder and pressurized gas inhalers. Nebulizers are devices that convert liquid medications into vapor using methods such as sound waves or compressed air, allowing them to be inhaled. However, due to the generally large size of nebulizers and their use in hospital settings, patient compliance is difficult with this treatment method. Although portable nebulizers have been developed in recent years thanks to advancements in technology, these devices cannot achieve the particle size necessary for effective treatment. Pressurized gas inhalers are more advantageous than nebulizers due to their portability, but they have a disadvantage in terms of ease of use because their operation requires attention, hand and breath coordination. Furthermore, the likelihood of effective and sufficient delivery of the medication to the target area is low with these devices. It has been determined that, due to the insufficiently small particle size in these devices, a very large portion of the dose accumulates at different points and enters the systemic circulation without reaching the lungs. Dry powder inhalers stand out due to their ease of use. Unlike pressurized gas inhalers, they do not require hand-breath coordination, playing a significant role in enabling patients to take their medication effectively. However, a problem remains with these devices: the inability to achieve the necessary particle size for effective treatment, and consequently, the inability to deliver the medication precisely to the desired area in the lungs. As explained in detail above, the current state of the technology for drug delivery via inhalation has certain shortcomings. Therefore, there is a need to develop different inhalation drug delivery methods and formulations that overcome these shortcomings. These methods and formulations should be economically viable, efficient, easily compliant with patient requirements, and suitable for generating small aerosol particles. Explanation of the Figures Figure 1 - Chromatogram showing the absence of combustion product formation. Description of the Invention The inventors, as a result of their research, surprisingly found that electronic nicotine delivery systems could be used for pirfenidone delivery with higher specificity. The inventors have found that pirfenidon can be 100% ejected from pirfenidon solution in electronic nicotine delivery systems. The inventors have shown through their studies that oral administration of pirfenidon and inhalation via electronic nicotine delivery system have the same effect on fibrosis. However, the dose required to achieve the same effect is 20 times higher with oral administration compared to inhalation. Therefore, it is thought that inhalation of pirfenidon via electronic nicotine delivery system will be effective in the treatment of fibrosis, and that the side effects encountered with oral administration will be less severe or absent. In electronic nicotine delivery systems, pirfenidone is administered in aerosolized form. Aerosolized pirfenidone has been shown to result in lower doses, more homogeneous and optimized drug delivery, and therefore fewer adverse side effects. Electronic nicotine delivery systems, compared to the aerosol particles produced in nebulizer devices, allow for more efficient and homogeneous drug delivery to the lung alveoli thanks to the production of smaller particles. Water is generally used as a solvent in nebulizers. However, the low solubility of the active substance in water when administering pirfenidon results in the inability to deliver the desired dose. The solubility of pirfenidon in water is 10 mg / ml. In the electronic nicotine delivery systems that are the subject of this invention, the solubility of pirfenidon in the propylene glycol solution is 300 mg / ml. Therefore, the desired dose of the active substance is delivered. From this perspective, pirfenidone delivery via electronic nicotine delivery systems is more advantageous than both oral and other inhalation methods currently available. Another advantage of electronic nicotine delivery systems is their suitability for use in different patient groups. The daily dose required by patients can be easily adjusted by changing the puffing time, number of puffs, or the amount of dose administered. Electronic nicotine delivery systems do not encounter the problem of incomplete / dead dose delivery that is experienced with nebulizers. While only 5-40% of the initially administered dose reaches the patient's target area in nebulizers, this rate is 100% in electronic nicotine delivery systems. The term pirfenidone encompasses all salts, hydrates, anhydrous forms, sol vats, amorphous and crystalline forms of pirfenidone. The formulation described in this invention contains, in addition to pirfenidone, at least one pharmaceutically suitable excipient. The term pharmaceutically suitable excipient means any pharmaceutical excipient that can be administered without undesirable toxicity. The excipients used in the formulation described in this invention may consist of a solvent and a humectant, or a mixture thereof. The solvents and humectants used in the formulation subject to this invention may be selected from propylene glycol and / or glycerol and / or water or a mixture thereof. The solubility of pirfenidon in these mixtures is as shown in Table 1. Solution Composition Solubility Propylene Glycol 300 mg / ml Propylene Glycol: Glycerin (1:1) 300 mg / ml Propylene Glycol: Glycerin: Water (1:1:1) 300 mg / ml Propylene Glycol: Water (1:1) 300 mg / ml Table 1 - Solubility of pirfenidone in solutions to be used in ENDS. The propylene glycol:glycerin mixing ratio in the formulations subject to the present invention may be in the range of 1:10 to 10:1. The propylene glycol:water mixing ratio in the formulations subject to the present invention may be in the range of 1:10 to 10:1. The propylene glycol:glycerin:water mixing ratios in the formulations subject to the present invention may be in the range of 1:1:10 to 1:10:1 to 10:1:1. The D90 value of pirfenidone used in the formulation of the present invention ranges from 1 pm to 150 pm. The particle size distribution of pirfenidone was measured using the laser diffraction method. The basis of the laser diffraction method relies on the inverse relationship between the size of the particles and the angle of refraction of the light rays. In the laser diffraction method, laser beams are directed onto the particles, and the rays that strike the particles, are refracted, and reflected forward, passing through a lens before falling onto a detector. The rays falling on the detector are digitized by means of a transducer, and the particle size and percentage are calculated by means of a computer. The particle size of pirfenidone used in the present invention was measured using a Malvem Mastersizer 2000 device. The wet method (25°C, 2000 rpm, 30 sec.) was preferred, in which the active substance particles are dispersed in a dispersion agent for measurement. For use in ENDS, the stability of the pirfenidon-containing solution, more specifically its thermal stability, is important. Within the scope of this invention, the pirfenidon solution prepared for use in END systems has been found to be stable. The inventors have determined that pirfenidon is thermally stable and is therefore a candidate active substance for use in END systems. Studies have shown that pirfenidon is thermally stable, does not undergo any degradation during administration via electronic nicotine delivery systems, and does not produce combustion products. Electronic nicotine delivery systems are essentially personal vaporizers powered by a power source. Different electronic nicotine delivery systems (ENDS) can be used within the scope of this invention. In general, an ENDS consists of 4 main components; • A cartridge or reservoir in which the solution will be stored • A heating element (atomizer) • A power source (battery) • A mouthpiece. In electronic nicotine delivery systems, a puff activates a battery-powered heating element. This activation causes the solution inside the chamber to aerosolize / vaporize. Users then inhale the resulting aerosol or vapor. The inventors have demonstrated that electronic nicotine delivery systems can be used as electronic drug delivery systems for the active ingredient pirfenidone. Electronic cigarettes are battery-powered electronic nicotine delivery systems. Currently, there are approximately 500 different types of electronic cigarettes on the market. See Shu-Hong Zhu and etc., "Four hundred and sixty brands of e-cigarettes and counting: implications for product regulation," BMJ Journals, Volume 23, Issue suppl 3. Although the Joyetech eVic-VTC Mini and Joyetech CUBIS Atomizer were used in the studies covered by this invention, all devices on the market are applicable within the scope of this invention. The formulation subject to this invention contains, in addition to the active ingredient pirfenidone, steroids (including but not limited to prednisolone), corticosteroids, nintedanib, cytotoxic agents (including but not limited to azathioprine and cyclophosphamide), bardoxolone, LPA antagonists, e.g., LPAIs (including but not limited to AM152); torisel (temsirolimus); PI3K inhibitors; pentraxin (including but not limited to Pentraxin-2 (PTX-2 or PRM-151)); MEK inhibitors (including but not limited to ARRY-162 and ARRY-300); p38 inhibitors; PAI-1 inhibitors (including but not limited to tiplaxtine); Agents that reduce the activity of transforming growth factor beta (TGF-β) (including, but not limited to, TGF-β neutralizing antibodies such as GC-1008 (Genzyme / Medlmmune)); anti-TGF-β2 mAbTars such as lerdelimumab (CAT-152; Trabio, Cambridge Antibody); anti-TGF-β1 antibodies such as metelimumab (CAT-192, Cambridge Antibody);Small molecule TGF-β inhibitors such as LY-2157299 (Eli Lilly); ACU-HTR-028 (Opko Health); antibodies targeting one or more TGF-β isoforms; inhibitors of TGF-β receptor kinases TGFBR1 (ALK5) and TGFBR2 and modulators of postsensor signaling pathways; chemokine receptor signaling modulators; Inhibitors targeting both endothelin receptor A and B, and inhibitors selectively targeting endothelin receptor A (including but not limited to ambrisentan; avosentan; bosentan; klazosentan; darusentan; BQ-153; FR-139317, L-744453; masitentan; PD-145065; PD-156252; PD163610; PS-433540; S-0139; sitaxentan sodium; TBC-3711; zibotentan); agents that reduce the activity of connective tissue growth factor (CTGF) 7 (including but not limited to FG-3019) and also agents containing other CTGF-neutralizing antibodies such as FG-3019;Matrix metalloproteinase (MMP) inhibitors (including, but not limited to, MMPI-12, PUP-1, and tigapotide triflutate; and doxycycline, marimastat, and sipemastat); epidermal growth factor receptor (EGFR) activity-reducing agents such as erlotinib, gefitinib, BMS-690514, and cetuximab; EGF receptor-targeting antibodies; EGF receptor kinase inhibitors and modulators of post-receptor signaling pathways; platelet-derived growth factor (PDGF) activity-reducing agents (including, but not limited to, imatinib mesylate (Novartis)); and also PDGF neutralizing antibodies; PDGF receptor-targeting antibodies (PDGFR), PDGFR kinase activity inhibitors, and inhibitors of post-receptor signaling pathways; Agents that reduce vascular endothelial growth factor (VEGF) activity (including but not limited to axitinib, bevacizumab, BIBF-1120, CDP-791, CT-322, IMC-18F1, PTC-299 and ramusirumab);and also VEGF-neutralizing antibodies; antibodies targeting VEGF receptor 1 (VEGFR1, Flt-1) and VEGF receptor 2 (VEGFR2, KDR) and the soluble form of VEGFR (sFlt) and its derivatives that neutralize VEGF; multiple receptor kinase inhibitors such as BIBF-1120 that inhibit receptor kinases for vascular endothelial growth factor, fibroblast growth factor and platelet-derived growth factor; agents interfering with integrin function (including but not limited to STX-100 and IMGN-388) and also agents containing integrin-targeted antibodies;Agents that interfere with the pro-fibrotic activities of IL-4 (including but not limited to AER-001, AMG-317, APG-201, and sIL-4Ra) and IL-3 (including but not limited to AER-001, AMG317, anrukinzumab, CAT-354, sintredekine besudotox, MK-6105, QAX-576, SB-313, SL-102, and TNX-650), as well as antibodies that neutralize both cytokines and antibodies, antibodies targeting IL-4 and IL-13 receptors, soluble forms of the IL-4 receptor, agents that bind to and neutralize both IL-4 and IL-3, chimeric proteins containing part or all of IL-13, and especially pseudomonas endotoxin, JAK-STAT kinase pathway signaling domains. Agents that inhibit epithelial-mesenchymal transition, including mTor inhibitors (including but not limited to AP-23573 or rapamycin); copper-lowering agents such as tetrathiomolybdate; and oxidative stress-reducing agents including α-acetylcysteine ​​and tetrathiomolybdate;and may include interferon gamma or a combination thereof. Also included are agents that are phosphodiesterase 4 (PDE4) inhibitors (including but not limited to roflumilast); phosphodiesterase 5 inhibitors (PDE5) (including but not limited to mirodenafil, PF-4480682, sildenafil citrate, SLx-2101, tadalafil, udenafil, UK-369003, vardenafil and zaprinast) or cyclooxygenase inhibitors; These may include modifiers of the arachidonic acid pathway, including (but not limited to) 5-lipoxogenase inhibitors (Zileuton), or combinations thereof. They may also include compounds that reduce tissue remodeling or fibrosis, including prolyl hydrolase inhibitors (including but not limited to 1016548, CG-0089, FG-2216, FG-4497, FG-5615, FG-6513, fibrostatin A (Takeda), lufironil, P-1894B, and safironil), and peroxisome proliferator-activated receptor (PPAR)-gamma agonists (including but not limited to pioglitazone and rosiglitazone) or combinations thereof.Agents also include BG-12, chemokine activity modulators (including but not limited to CNTO 888, an antibody targeting CCL2), Lysl oxidase inhibitors (including but not limited to AB0024 / GS-6624, antibodies targeting human lysis oxidase-2), NOX4 inhibitors (including but not limited to GKT137831, a selective NOX 1 / 4 inhibitor), angiotensin II receptor antagonists (including but not limited to lorsartan), or Wnt-beta catenin signaling agents (including but not limited to ICG-001); JNK inhibitors (including but not limited to CC930); IL-4 / IL-13 antibody / soluble receptors (including but not limited to SARİ56597), and a deuterated pirfenidone (as described in W02009035598, for example). pirfenidone can be substituted with one to fourteen deuterium atoms, replacing one hydrogen atom, or a combination thereof. Driftability Test: The driftability of pirfenidone in electronic nicotine delivery systems and the amount of pirfenidone drifted have been measured. In summary, this test involved applying pirfenidone solutions at concentrations of 2 mg / ml, 4 mg / ml, 8 mg / ml, 25 mg / ml, 50 mg / ml, and 100 mg / ml at power levels of 8, 10, and 12 Watts. Each concentration was applied as three separate puffs, each lasting 3 seconds, at 8, 10, and 12 Watts. The waiting time between puffs was set at 30 seconds. A total of 60 ml of aerosol was collected for each different concentration. The collected aerosol was then re-liquefied, and the amount of pirfenidone it contained was measured. The solutions used for comparison were prepared without the active ingredient pirfenidon, while all conditions were kept the same as those for solutions containing pirfenidon. The stability of pirfenidon within the device and the loss of active substance due to its adhesion to surfaces were measured. As a result, it was proven that pirfenidon was 100% dispersed from the device, remained stable, and no combustion products were formed. Table 2 relates to the results of the pirfenidon dispersibility test. The details of the driftability test and analysis study are as follows. Pirfenidone Solution Concentrations and Atomizer Parameters Solution Name Solution Concentration Atomizer Parameters Puff Time (Seconds) Solution A 2 mg / ml 8-10-12 Watt 3 Solution B 4 mg / ml 8-10-12 Watt 3 Solution C 8 mg / ml 8-10-12 Watt 3 Solution D 25 mg / ml 8-10-12 Watt 3 Solution E 50 mg / ml 8-10-12 Watt 3 Solution F 100 mg / ml 8-10-12 Watt 3 Amount of Solution and Blank to be Collected Number of Puffs: 3 Puff Duration (Seconds): 3 Total Liquid Volume (ml): Amount consumed to produce 3x60ml aerosol: 2 Time Between Puffs (Seconds): 30 Volume of Vapor Extraction Solution A 60 ml Solution B 60 ml Solution C 60 ml Solution D 60 ml Solution E 60 ml Solution F 60 ml Blank Solution 60 ml Analytical Method Requirements (HPLC Equipment Parameters) Standard Pirfenidone Working Standard to be Used Reagents to be Used Triethylamine Orthophosphoric Acid (85% TiC) Methanol Acetonitrile Distilled Water Method HPLC Detector UV-VIS Column PurospherSTAR RP-8 endcapped 250x4.6mm 5.0μ Wavelength 220 nm Flow Rate 1.0 ml / min Injection Volume 15 μΐ Column Temperature 40 °C Autosampler Temperature 25 °C Injection Time 20 minutes (isocratic system) Preparation of Solutions: Preparation of Diluted Ortho-Phosphoric Acid Solution: 20 ml of 85% ortho-phosphoric acid is placed in a 100 ml (5 ml) volumetric flask. The volume is then filled completely with distilled water. Preparation of the Buffer Solution: 0.9 ml of triethylamine is added to 650 ml of distilled water and mixed thoroughly. The pH is adjusted to 3.0 ± 0.05 with dilute orthophosphoric acid. Preparation of Mobile Phase Solution: The buffer solution, methanol, and acetonitrile are mixed in a ratio of 650:130:220 (v / v / v). It is filtered through a 0.45 μηι HV membrane filter and degassed. Dilution Solution: Propylene glycol:glycerin is prepared and mixed in a ratio of (80:20). Preparation of Pirfenidone Standard Solution: Weigh 30 mg of Pirfenidone into a 20 ml volumetric flask. Dissolve in a small amount of mobile phase solution. Complete the volume with mobile phase solution. (C Pirfenidone = 1-5 mg / ml) Preparation of Sample Solution: 500 mg of pirfenidon is weighed into a 25 ml volumetric flask. A small amount of dilution solution is added. It is left in an ultrasonic bath for 5 minutes and dissolved. The volume is completed with dilution solution. This solution is carried in an electronic device. The resulting vapor is condensed. Solutions A, B, C, D, E, and F are prepared from the resulting stock solution. Procedure • Baseline and pressure are conditioned by injection of dilution solution. • Once the system has reached equilibrium, one injection of the dilution solution is administered. • Six injections of Standard-1 solution are administered. • Two injections of Standard-2 solution are administered. • Three sample solutions are prepared, and two injections are administered from each. • Chromoatomic chromatography of the injections is recorded. • Six sample solution injections are followed by one control injection of standard-1 solution. • The mean, standard deviation, and relative standard deviation of the analysis results are calculated. Acceptance Criteria • The % RSD between the peak areas of pirfenidone obtained from 6 consecutive injections of Standard-1 solution must be less than 2.0. • The agreement between the average peak areas of pirfenidone obtained from standard-1 and standard-2 solutions should be in the range of 98.0% - 102.0%. Calculation Pirfenidone Percentage (%) at Fixed Volume = AN x CS x P ---------- x 100 AS x CN AN: Area of ​​Pirfenidone Peak in Sample Chromatogram AS: Area of ​​the Pirfenidone Peak in the Standard Chromatogram CS: Concentration of the Standard (mg / ml) CN: Sample Concentration (mg / ml) P: Potential of the Standard (as-is) Combustion Product Detection The amount of product burned during pirfenidone delivery in an electronic nicotine delivery system is determined. This is done by measuring the amount of pirfenidone delivered in 60 ml of solution over a 3-second period at different wattages. This process is applied to both a solution system without pirfenidone and a solution system containing pirfenidone. According to the analysis results, pirfenidone does not produce a combustion product while being carried through the electronic nicotine delivery system. The chromatogram showing the absence of combustion product formation is given in Figure 1. 8 Watt 10 Watt 12 Watt Concentration (mg / ml) Result (%) Concentration (mg / ml) Result (%) Concentration (mg / ml) Result (%) 2 mg / ml 0.001 100.2% 0.001 100.0% 0.001 99.9% 4 mg / ml 0.001 100.3% 0.001 99.8% 0.001 99.6% 8 mg / ml 0.001 101.1% 0.001 99.9% 0.001 100.0% 25 mg / ml 0.001 100.3% 0.001 99.7% 0.001 100.0% 50 mg / ml 0.001 100.4% 0.001 99.8% 0.001 101.2% 100 mg / ml 0.001 100.0% 0.001 99.5% 0.001 100.6% Table 2 - Driftability Test Results In vitro Study: The particle dispersion of aerosols generated via electronic nicotine delivery systems was measured using the Next Generation Impactor (NGI) and the Dekati Low Pressure Impactor (DLPI). The Dekati Low Pressure Impactor is a 13-step impactor that allows measurements between 30 nm and 10 pm. The measurements showed that the aerodynamic diameter of aerosol particles obtained via electronic nicotine delivery systems ranged from 500 nm to 1 pm. Particles of this size can be delivered to the lung alveoli. The inventors also measured the particle dispersion of aerosols generated via electronic nicotine delivery systems using a Malvern Mastersizer 2000 device. According to the measurement results, they found the average D50 value to be 1.5 pm. It is clear that the particle size distribution at this value is smaller than the particle size distribution obtained in all inhalation delivery methods currently available in the known state of the art. In vivo Study: Thirty-six male Wistar-Albino rats weighing 220-260 grams were maintained under normal laboratory conditions at 21-24 °C with a 12 / 12 hour light / dark cycle. A single dose of intratracheal bleomycin (10 mg / kg) was administered to induce pulmonary fibrosis. After fibrosis induction, the rats were randomly assigned to six experimental groups, with six rats in each group. • Control group: In this group, pulmonary fibrosis will be induced but no treatment will be given. • Group receiving oral pirfenidon treatment: Animals in this group will be administered 200 mg / kg / day of oral pirfenidon via gavage for 7 days. • Group receiving 10 mg / kg / day inhalation therapy: In this group, pirfenidone aerosol will be administered while the animals are kept in a closed area until the appropriate dose is given. • Group receiving 20 mg / kg / day inhalation therapy: In this group, pirfenidone aerosol will be administered while the animals are kept in a closed area until the appropriate dose is given. • Group receiving 40 mg / kg / day inhalation therapy: In this group, pirfenidone aerosol will be administered while the animals are kept in a closed area until the appropriate dose is given. • Group receiving only propylene glycol via inhalation: Animals in this group will be kept in a confined area and administered only propylene glycol. For inhalation administration, pirfenidone was dissolved in propylene glycol at a concentration of 100 mg / ml. Rats were exposed to a fixed dose of aerosolized pirfenidone once daily for 7 consecutive days via an electronic nicotine delivery system within their cages. For this application, the caged animals received 60 ml of aerosol in 3-second puffs at 30-second intervals for 7 days. The total dose delivered into the cages was calculated for each group. The cage was maintained under normoxic and normocapnic conditions and had a volume of approximately 0.5 L. The pirfenidon dose was selected according to the results of Poulin et al. and Rasooli et al. Inhalation of propylene glycol was performed similarly to pirfenidon administration. All rats were physically examined after the study, and the observations were as follows: In the treatment groups, the rats were active, had good appetites, and were in good mood. Their fur was smooth and shiny, and an increase in body weight was observed. However, in the control groups, both the rats' activity and appetite decreased. Their fur darkened, and a decrease in body weight was observed. Furthermore, cyanosis was observed on the rats' legs and the outer edges of their lips, as well as symptoms of coughing and shortness of breath. In the continuation of the study, on day 15, rats were anesthetized with intraperitoneal injections of ketamine (100 mg / kg) and xylazine (10 mg / kg), and their right and left lungs were resected. One lobe of the lung was placed in 10% buffered formalin solution for histopathological examination. The other lobe was frozen at -80 °C, and supermatants of the homogenates were prepared for cytokine analysis by ELISA. ELISA test results are given in Table 3. According to the results, TNF-κC (pg / ml / mg), IL-6 (pg / ml / mg), LPO (ng / ml / mg), SOD (U / ml / mg), TGF-β (pg / ml / mg), TIMP (ng / ml / mg), MMP-2 (ng / ml / mg), and hydroxyproline (pg / ml / mg) levels were significantly higher in the control groups compared to the treatment groups, but no difference was found between the 5 groups that received oral and inhalation pirfenidon. The results show that oral and inhalation pirfenidon treatment reduces inflammation and pulmonary fibrosis. Treatment Group Control Group P inhaler Oral inhaler No treatment 10 mg / kg / day 20 mg / kg / day 40 mg / kg / day 200 mg / kg / day Propylene glycol No treatment Baseline weight (g) 242.3 ± 13.4 236.3 ± 26.1 250.4 ± 29.9 242.3 ± 16.3 244 ± 24.32 255.6 ± 16.3 0.254 Post-administration weight (g) 273.5 ± 10.4 290.8 ± 18.5 317.8 ± 38.9 298.8 ± 9.7 206.9 ± 18.3 208.6 ± 12.6 0.001 TNF-α (pg / nL / mg) 200.7 ± 118 202 ± 80.5 178.3 ±95.4 120.6 ±42.6 285 ±48.9 295.7 ± 136.3 0.041 IL-6 (pg / ml / mg) 12.6 ±4.5 12.0 ±4.8 12.3 ±4.1 11.6 ± 1.8 24.2 ±9.1 25.5 ±6 0.003 LPO (ng / ml / mg) 23.2± 11.1 20.4 ±8.2 22.6 ±10.1 18.9 ±8.8 50.4 ± 17.3 62.5 ± 30.2 0.001 SOD (U / ml / mg) 86.4 ± 7.6 89.6 ±8 82.1 ± 13.6 75.7 ± 10 106.7 ±3.9 113.6 ±9.5 0.001 TGF-β (pg / ml / mg) 220.5 ±66.1 226.8 ± 191.1 219.8 ±65.3 253.7± 111.8 466.3 ± 181.3 442.7 ± 134.8 0.027 T1MP (ng / ml / mg) 13.7 ±4.2 12.3 ± 1.4 12.4 ±2.5 12.8 ± 1.8 17.3 ±0.6 17.8 ±6.3 0.020 MMP-2 (ng / ml / mg) 0.1 ±0.1 0.1 ±0.04 0.1 ±0.1 0.1 ±0.05 0.4 ±0.1 0.5 ±0.1 0.001 Hydroxyproline (pg / ml / mg) 10.3 ± 1.2 9.6 ± 1.3 9.9 ± 1.6 9.6 ± 1.1 14.3 ±3.3 15.1 ± 1.9 0.010. Table 3 - ELISA test results Histological examination results are given in Table 4. The presence and degree of inflammation and fibrosis were assessed as described in previous studies. See Sur S, Wild JS, Choudhury BK, Sur N, Alam R, and Klinman DM: Long term prevention of allergic lung inflammation in a mouse model of asthma by CpG oligodeoxynucleotides, J Immunol. 1999;162:6284-6293., Ashcroft T, Simpson JM, and Timbrell V: Simple method of estimating severity of pulmonary fibrosis on a numerical scale, J Clin Pathol. 1988;41:467^170., Chen M, Cheung FW, Chan MH, Hui PK, Ip SP, Ling YH, Che CT, and Liu WK: Protective roles of Cordyceps on lung fibrosis in cellular and rat models, J Ethnopharmacol. 2012;143:448-454. Histopathological examination results revealed that bleomycin exposure caused a significant inflammatory response and an increase in collagen deposition. Oral and inhaled pirfenidon treatment was observed to reduce the bleomycin-induced inflammatory response and collagen deposition. Furthermore, lower concentrations of inhaled pirfenidon reduced both the inflammatory response and collagen deposition. Alveolar hemorrhage Hemosiderin deposition Alveolar macrophages Interstitial inflammation Mucosal lymphoid tissue Peribronchial fibrosis Interstitial fibrosis Pirfenidon 10 mg / kg via inhalation None-Rare None None Mild-Moderate None None Mild Pirfenidon 20 mg / kg via inhalation None-Rare None None Mild-Moderate None None Mild Pirfenidon 40 mg / kg via inhalation None None None Mild None None None-Mild Pirfenidon 200 mg / kg via oral administration None None None Mild None None Mild Propylene glycol via inhalation Focal Rare Rare Moderate-Severe Moderate Moderate-Severe Moderate No application Focal Rare-Focal Rare Severe Moderate Severe Moderate Table 4 - Histopathological examination results How the invention can be applied to industry. The formulation described in this invention is used in the treatment of idiopathic pulmonary fibrosis. It may also be used in the treatment of pulmonary fibrosis, renal glomerular sclerosis, liver cirrhosis, benign prostatic hypertrophy, hypertrophic scarring (keloids), rheumatoid arthritis, and Hennansky-Pudlak Syndrome (HPS). Additionally, it may be used to prevent or remove scar tissue associated with fibrosis in damaged tissues of the lungs, skin, joints, kidneys, prostate gland, and liver. Studies have shown that pirfenidon can safely slow or halt the progressive growth of fibrotic lesions and prevent the formation of new fibrotic lesions following tissue injury. More specifically, the formulation in question is intended for the treatment of pulmonary fibrosis, idiopathic pulmonary fibrosis, idiopathic interstitial pneumonia, autoimmune lung diseases, benign prostatic hypertrophy, coronary or myocardial infarction, atrial fibrillation, cerebral infarction, myocardial fibrosis, musculoskeletal fibrosis, postoperative adhesions, liver cirrhosis, renal fibrotic disease, fibrotic vascular disease, scleroderma, Hennansky-Pudlak syndrome, neurofibromatosis, Alzheimer's disease, diabetic retinopathy and / or skin lesions, HIV-related lymph node fibrosis, chronic obstructive pulmonary disease (COPD), inflammatory pulmonary fibrosis, rheumatoid arthritis, rheumatoid spondylitis, osteoarthritis, gout; other arthritic conditions, sepsis, septic shock; endotoxic shock, gram-negative sepsis, toxic shock syndrome, myofascial pain syndrome (MPS); shigellosis; asthma; adult respiratory distress syndrome, inflammatory bowel disease, Crohn's disease, psoriasis, eczema, ulcerative colitis;Glomerular nephritis, scleroderma, chronic thyroiditis, Graves' disease; Ormond's disease, autoimmune gastritis; myasthenia gravis, autoimmune hemolytic anemia, autoimmune neutropenia; thrombocytopenia, pancreatic fibrosis; active hepatitis including hepatic fibrosis; acute and chronic kidney disease, renal fibrosis, diabetic nephropathy, irritable bowel syndrome, pyrexia, restenosis, cerebral malaria, stroke and ischemic damage, neural trauma, Alzheimer's disease, Huntington's disease, Parkinson's disease, acute and chronic pain, allergies including allergic rhinitis and allergic conjunctivitis, cardiac hypertrophy, chronic heart failure, acute coronary syndrome, cachexia, malaria, leprosy; leishmaniasis, Lyme disease, Reiter's syndrome, acute synovitis, muscle degeneration; Bursitis, tendinitis, tenosynovitis, herniated disc, rupture or prolapse of intervertebral disc syndrome, osteopetrosis, thrombosis, silicosis, pulmonary sarcoidosis, bone resorption, for example;Bone diseases associated with osteoporosis or multiple myeloma, cancer including but not limited to metastatic breast carcinoma, colorectal carcinoma, malignant melanoma, stomach cancer, and non-small cell lung cancer, graft-versus-host reaction, and autoimmune diseases, such as multiple sclerosis, lupus, and fibromyalgia, AIDS, and 5 other viral diseases, such as Herpes Zoster, Herpes Simplex I or II, influenza virus, Severe; This includes the treatment of Severe Acute Respiratory Syndrome (SARS), cytomegalovirus, and diabetes. Example 1 10% (weight / volume) pirfenidon solution in propylene glycol - Pirfenidon 10 g It contains 100 ml of propylene glycol (ym).

Claims

1. This is a method for delivering pirfenidone via inhalation, characterized by the delivery of pirfenidone through entrainment from a pirfenidone solution via electronic nicotine delivery systems.

2. According to claim 1, a method for the delivery of pirfenidone via electronic nicotine delivery systems using a pirfenidone solution is the five-emission drift pathway, characterized by the pirfenidone solution containing propylene glycol, glycerol, water, or a mixture thereof.

3. It is a pirfenidone solution according to claim 2, and its characteristic feature is that the propylene glycol:glycerin mixture ratio is between 1:10 and 10:

1.

4. According to claim 2, it is a pirfenidone solution characterized by having a propylene glycol:water mixing ratio between 10 1:10 and 10:

1.

5. According to claim 2, it is a pirfenidone solution and its characteristic feature is that the propylene glycol:glycerin:water mixture ratios are in the range of 1:1:10 to 1:10:1 to 10:1:

1.

6. According to Claim 2, the solution is pirfenidone and its characteristic is that the D90 value of the pirfenidone it contains, as measured by laser diffraction, is in the range of 1 pm to 150 pm.

7. According to Claim 1, the method for the delivery of pirfenidone from pirfenidone solution via entrainment through electronic nicotine delivery systems is characterized by the use of 8, 10 or 12 Watts of power for delivery.

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