Method and composition for treating pulmonary fibrosis

Abstract

To provide a system and a composition for the treatment of fibrotic pulmonary disease.SOLUTION: An inhalation system comprises a dry powder inhaler and a cartridge, wherein the cartridge comprises a pharmaceutical composition containing a dry powder comprising diketopiperazine particles and a therapeutically effective amount of a compound having the formula below.SELECTED DRAWING: None

Description

[Technical Field]

[0001] The present disclosure relates to methods, compositions and kits for the therapeutic treatment of idiopathic pulmonary fibrosis. The methods, compositions and kits include a combination product comprising a dry powder and an inhaler, The powder is intended to be administered to a patient by oral inhalation. [Background technology]

[0002] Idiopathic pulmonary fibrosis (IPF) is a chronic lung disease of unknown cause, and there is no cure for IPF. There is no healing. The disease is progressive and irreversible, causing scar tissue (fibrosis) to build up in the lungs. This causes the lungs to be unable to transport oxygen effectively into the bloodstream. It affects people between the ages of 50 and 70. It is a condition called interstitial lung disease (ILD). It belongs to the group of lung diseases that describe inflammation or scarring in the lungs. Signs and symptoms include shortness of breath and a persistent, dry cough. Subjects with IPF may experience difficulty eating or drinking. They may also experience loss of appetite and gradual weight loss. In individuals with IPF, the lungs become the organs and systems of the body. Scarring in the lungs increases over time until they can no longer provide enough oxygen to the tissues. do.

[0003] Currently, there are no surgical procedures or medications that can remove the progressive scarring of lung tissue. Therefore, it is important to learn good coping skills and educate patients about the disease. In particular, the treatment is designed to slow the progression of scar formation in the lungs, which is associated with the disease. However, these drugs may not necessarily reduce the associated symptoms of cough and shortness of breath. The oral tablet treatment has been shown to slow the progression of IPF. However, some patients Because of side effects, patients may be unable to tolerate these drugs at the doses needed to slow progression. The repeated high doses required to slow disease progression can cause gastrointestinal Adverse effects, such as nausea, diarrhea, abdominal pain, vomiting; hepatobiliary, nervous, vascular, metabolic and nutritional effects There are too many harmful effects, including disability.

[0004] There are several additional medications available that are useful for improving the symptoms of IPF, including shortness of breath and cough. Some of these medications include, for example, antacids to prevent gastroesophageal reflux and antihistamines to relieve shortness of breath. Oxygen therapy and exercise training to increase oxygen levels are also included. and their use to provide pulmonary rehabilitation for people with chronic conditions. Population education and support is recommended for subjects with IPF. One major and invasive procedure is to provide the patient with a lung transplant. To improve or offer alternative and novel methods of treatment to patients with IPF. It is necessary to provide

[0005] Drug delivery to pulmonary tissue is achieved using a variety of methods and routes of administration, including oral administration. Drug delivery or enteral, such as tablets and capsules containing medications and for the treatment of diseases or illnesses Parenteral, which involves injection of targeted drugs to treat the symptoms of a disease; Nebulizers and inhalers, e.g., metered dose inhalers, for treating airway or lung diseases or disorders Devices including inhalers and dry powder inhalers are also used. Summary of the Invention [Problem to be solved by the invention]

[0006] Several dry powder inhaler products developed for pulmonary delivery have been successful to date. However, there is room for improvement due to lack of practicality for use and / or manufacturing costs. Some of the persistent problems observed with prior art inhalers include lack of device durability, difficulty in dispensing medication, and These include inconsistencies in the powder, poor equipment and poor powder deagglomeration. In some devices, the need to use hazardous propellants to deliver the dose limits treatment. However, high manufacturing costs and / or lack of patient compliance hinder its production. Thus, the inventors have developed a powder delivery system that provides consistent or improved powder delivery characteristics and is easy to use. and a novel formulation with a discrete location that allows for better patient compliance. and identified the need to design and manufacture inhalers. [Means for solving the problem]

[0007] Compositions and methods for using compositions in the treatment of interstitial lung diseases such as idiopathic pulmonary fibrosis In embodiments thereof, the composition is delivered locally to the pulmonary circulation or interchangeable, including dry powder pharmaceutical formulations for inhalation, for delivery to the lungs for systemic delivery. and a dry powder inhaler containing the cartridge or capsule. are compact, reusable or disposable, and come in a variety of shapes and sizes; and an airflow conduit path for effective and rapid delivery of powdered medication to the lungs and their systemic circulation. A breath-actuated inhaler including a system.

[0008] In certain embodiments, the method of treating idiopathic pulmonary fibrosis comprises delivering to lung tissue and pulmonary alveoli and Drug delivery systems for rapid delivery and onset of action of active agents reaching the systemic circulation and the lungs. systems, including drug delivery systems designed for pulmonary drug delivery by oral inhalation. In this way, the active agent is delivered in a therapeutically effective manner with fewer adverse effects. In certain embodiments, the method of treatment is for treating idiopathic pulmonary disease. diagnosed with a pulmonary fibrotic and / or inflammatory disease, such as idiopathic pulmonary fibrosis, and treating a patient in need of treatment, or administering a therapeutic dose of 1 to treat a disease. In one embodiment, administering to the patient a dry powder formulation containing one or more active agents. In this study, a dry powder dose was delivered to the lungs using a dry powder inhaler, and the active agent was released deep into the lungs. The pharmaceutical composition can be administered as a breath-actuated dry powder inhaler for oral or nasal inhalation. It is self-administered by the patient using a device in one or more breaths. The drug may cause adverse gastrointestinal effects, such as nausea, diarrhea, abdominal pain, and vomiting; hepatobiliary, nervous, vascular, and metabolic effects. adverse effects caused by oral tablets or capsules, including metabolic and nutritional disorders It can be reduced.

[0009] In one embodiment, the method comprises administering to a subject in need of treatment a type 2 pulmonary stimulatory agent for delivery to lung tissue. or administering a stable pharmaceutical composition comprising multiple active agents, wherein the multiple active agents are , which may be formulated together or separately and administered separately and at different intervals during treatment. In certain embodiments, the pharmaceutical composition comprises a small molecule, such as pirfenidone, pyridone, analogs, nintedanib, its derivatives or analogs; and / or combinations thereof. and a formulation for inhalation comprising a therapeutically effective dose of a dry powder containing one or more active agents, including In certain embodiments, the pharmaceutical composition is suitable for treating an idiopathic pulmonary disease, and alone or in combination with deoxyribonuclease I (Dnase I) and granulocyte-macrophage coagulation Ronnie's stimulating factor (GM-CSF), kinase inhibitors, e.g., tyrosine kinase inhibitor molecules Any molecule or chemical that may be present in the composition in combination with other active agents, including anti-inflammatory agents, including The pharmaceutical composition may optionally further comprise one or more pharmaceutically acceptable additives. In this and other embodiments, the pharmaceutical composition comprises an agent and / or a carrier. The composition is provided to the patient in a container, capsule or cartridge for inhalation.

[0010] In one embodiment, a pharmaceutically acceptable carrier comprising a diketopiperazine having the ability to form particles is provided. and a therapeutically effective dose of an additive of the formula: [ka] and optionally one or more pharmaceutically acceptable carriers and / or excipients. In this and other embodiments, an inhalable pharmaceutical composition is disclosed comprising a dry powder comprising: Inhalable pharmaceutical compositions are designed to contain a dose of one or more active agents for delivery by inhaler. and can be formulated as follows: in a powder and optionally containing one or more drugs including nintedanib esylate and pharmaceutically acceptable salts thereof, and pharmaceutically acceptable carriers and / or excipients. The cartridges can be administered in dosing sessions as needed by the patient, with a maximum of 300 mg of active agent, which may be administered once or twice or more times per day. In embodiments and depending on the needs of the patient, dosing may be two, three or more times daily. A number of additional doses may be administered.

[0011] In one embodiment, the inhalable pharmaceutical composition comprises a surfactant, an amino acid and / or a phosphorus one or more pharmaceutically acceptable carriers and / or excipients which are lipids or combinations thereof may include:

[0012] In a preferred embodiment, the inhalable pharmaceutical composition for treating an ILD such as IPF comprises: one or more active agents and a compound of the formula: [ka] and a diketopiperazine having an amorphous powder, a crystalline form, or microcrystalline particle morphology, or a combination thereof.

[0013] In one embodiment, the inhalable pharmaceutical composition comprises a therapeutically effective dose of a compound of the formula: [ka] and the compound content in the dosage form is The range is about 1 mg to about 50 mg in the dry powder composition.

[0014] In some embodiments, the inhalable pharmaceutical composition contains lactose, mannose, sucrose, , mannitol, trehalose, sodium citrate, trisodium citrate, citric acid Zinc, Glycine, L-Leucine, Isoleucine, Trileucine, Sodium Tartrate, Tartar Zinc acetate, methionine, vitamin A, vitamin E, sodium chloride, zinc chloride, microcrystalline selenite cellulose, polyvinylpyrrolidone, and polysorbate 80, or a combination thereof. The present invention relates to a dry powder containing one or more pharmaceutically acceptable carriers and / or excipients.

[0015] In other embodiments, the inhalable pharmaceutical composition comprises sodium citrate, sodium chloride, Selected from the group consisting of leucine or isoleucine and trehalose or a combination thereof The present invention relates to a dry powder containing one or more pharmaceutically acceptable carriers and / or excipients.

[0016] In certain embodiments, the inhalable pharmaceutical composition is about 20 ml 2 / g ~ approx. 63m 2 / g range 3,6-bis(N-fumaryl-4-aminobutyl)-2,5-diamine having a specific surface area of In one embodiment, the microcrystalline particles comprise ketopiperazine. It has pore sizes in the range of about 30 nm.

[0017] A method of treating an interstitial lung disease, such as idiopathic pulmonary fibrosis, comprising administering to a patient in need of treatment to oral inhalation with diketopiperazine particles, 1 mg to 10 mg per inhalation session; 10mg~20mg;20mg~30mg, 30mg~50mg;50mg~100mg 100 to 150 mg; or 150 to 300 mg of the formula: [ka] a compound of the formula (I), a pharmaceutically acceptable salt thereof, a derivative thereof, and optionally a pharmaceutically acceptable carrier and / or an excipient, The composition is provided in a single dose cartridge in a dry powder inhaler. , multiple cartridges are provided to the patient for predetermined doses according to the patient's needs. It can be done.

[0018] In embodiments where the method includes pirfenidone, the patient receives a therapeutically effective dose of pirfenidone. A powder composition is administered, which, prior to use, is fitted with one or more tubes for fitting into a dry powder inhaler. Provided to the patient separately in blisters or pouches with multiple capsules or cartridges Each capsule or cartridge may contain up to 30 mg or 50 mg of the compound. In one embodiment, the therapeutically effective daily dose is up to 500 mg per day; up to 7 50 mg; up to 1,000 mg or up to 2,500 mg of the compound, which It is provided in multiple cartridges for inhalation by a dry powder inhaler. The administration may be carried out in one or multiple dosing sessions.

[0019] In this and other aspects, the method comprises the step of: , sucrose, mannitol, trehalose, sodium citrate, trisodium citrate Ingredients: Calcium carbonate, zinc citrate, glycine, L-leucine, isoleucine, trileucine, sodium tartrate Sodium, Zinc Tartrate, Methionine, Vitamin A, Vitamin E, Sodium Chloride, Zinc Chloride , polyvinylpyrrolidone and surfactants, such as polysorbate 80 Use a composition containing one or more pharmaceutically acceptable carriers and / or excipients. .

[0020] In another embodiment, the method for treating an interstitial lung disease, such as idiopathic pulmonary fibrosis, comprises administering the treatment A subject in need thereof is administered a pharmaceutically effective amount of pirfenidone (5-methyl-1-phenyl-2 or administering a dry powder containing one or more Pharmaceutically acceptable carriers and / or excipients include sodium citrate, sodium chloride, isine or isoleucine or trehalose.

[0021] In one embodiment, the method for treating pulmonary fibrosis comprises administering to a patient in need thereof a diketopy Perazine and the formula: [ka] or a pharmaceutically acceptable salt thereof, such as an esylate salt, and optionally one or more and a pharmaceutically acceptable carrier and / or excipient. The diketopiperazine may be in an amorphous form, a crystalline form, or a crystalline complex. or a combination thereof, wherein the diketopiperazine has the formula: [ka] It has.

[0022] In an exemplary embodiment, a method for treating interstitial lung disease and in particular for treating idiopathic pulmonary fibrosis is provided. The method involves administering to a patient in need of treatment a cartridge or capsule containing a dose of dry powder. a movable member for mounting the capsule and for achieving a dose placement when loaded onto the inhaler; and administering pirfenidone or nintedanib using a dry powder inhaler having a container capable of administering pirfenidone or nintedanib. administering by oral inhalation an inhalable pharmaceutical dry powder containing the The dry powder container comprises a lid and a container containing a dry powder composition to be inhaled. The inhaler cartridge and the dry powder dose are provided separately prior to use.

[0023] In certain embodiments, the method of treating IPF comprises administering to a patient in need of treatment an inhaler and one or more cartridges containing the dry powder composition; and administering to the patient Inhaling one or more cartridge contents from each of one or more cartridges. and wherein the one or more cartridges contain up to 300 mg per dosing session. An effective dose of the formula: [ka] The dry powder composition can deliver a compound of formula 3,6-bis(N-fumaryl-4 PHARMACEUTICALLY ACCEPTABLE EXcipient PARTICLES CONTAINING (-AMINOBUTYL)-2,5-DIKETOPIPERAZINE - Patent application In one embodiment, the method comprises a pressure of about 0.05 to about 0.200 (kPa) / liter / minute. Use a high resistance dry powder inhaler with a resistance of at least 4-1 / 2 times per inhalation. This includes inhaling for 0 seconds or 2 to 6 seconds.

[0024] In some embodiments, the method of treating an interstitial lung disease, such as pulmonary fibrosis, comprises administering to a subject in need of treatment: The subject is administered a pharmaceutical composition containing pirfenidone and / or nintedanib separately and sequentially. or in combination with one or more vasodilatory compounds. In embodiments, the method includes administering to a subject a drug selected from the group consisting of sildenafil, tadalafil, vardenafil, prostaglandins, and the like. prostaglandins, their prodrugs, prostaglandin derivatives, prostaglandins such as treprostinil lanzin analogues or pharmaceutically acceptable salts of these compounds, such as treprostinil sodium and administering to a subject a vasodilator containing a salt thereof or a prodrug thereof. In certain embodiments, the method includes simultaneously treating interstitial lung disease and pulmonary arterial hypertension. and administering to the patient's lungs a dry eye treatment comprising pirfenidone and / or nintedanib. Dry powder formulation and / or treprostinil, treprostinil or treprostinil These compounds include pharmaceutically acceptable salts thereof, such as sodium salts, or prodrugs thereof. A combination therapy comprising a dry powder composition comprising a vasodilator compound and using a dry powder inhaler. This includes delivery to the subject's systemic circulation by pulmonary inhalation.

[0025] In one embodiment, the method comprises administering to a patient in need of treatment an active ingredient in a stable dry powder formulation. a dry powder inhaler containing an agent (e.g., nintedanib, pirfenidone, or treprostinil) and administering the active agent by oral inhalation. Vasodilators may be formulated together with pirfenidone and nintedanib in the same formulation or separately. , administered separately as their own formulations, at different intervals during a dosing session or sequentially can be provided to the

[0026] In one embodiment, the drug delivery system is a drug delivery system for, for example, pirfenidone, nintedanib, prostaglandin E, Small molecules such as taglandins or their analogs such as treprostinil, as well as pulmonary and a method for delivering protein-based products for treating fibrosis and PAH. The method includes dissolving and dissolving a ketopiperazine-based drug formulation in a dry powder inhaler. and / or typical methods of drug delivery that are sensitive to enzymatic inactivation, such as oral tablets and and subcutaneous and intravenous injectable / infusion drug products.

[0027] In certain embodiments disclosed herein, patients with pulmonary fibrosis and PAH are administered a dry powder In the powdered formulation, prostaglandin, treprostinil, or treprostinina thorium, etc., and pharmaceutically acceptable salts thereof or prodrugs thereof or The method further comprises providing a derivative thereof. selecting a patient to be treated for interstitial lung disease and administering nintedanib, pills, Phenidone or treprostinil or treprostinil salts or derivatives thereof A dry powder formulation, wherein treprostinil is combined with diketopiperazine microcrystalline particles. dry powder formulations which are combined to form pharmaceutical formulations or compositions suitable for pulmonary inhalation; and having the patient inhale from an inhaler containing the composition; and and delivering the treprostinil formulation using a dry powder inhaler. In embodiments, the dry powder formulation contains from about 1 μg to about 200 μg of tocopherol in the dry powder formulation per dose. It is provided in a reconstitutable cartridge containing reprostinil or a salt thereof. In embodiments, the dry powder formulation is in a cartridge or capsule containing about 10 μg of powder per dose. In one embodiment, a single dose of treprostinil may be administered. The cartridge contains about 10 μg to about 90 μg of treprostaglandin E for at least one inhalation. In some embodiments, the dry powder formulation may comprise at least one inhalation per use. In this and other embodiments, the dry powder formulation is delivered using a 1000 mg dose per inhalation or breath. In one embodiment, the pharmaceutical dryer is delivered to the patient in less than 10 seconds, or less than 8 seconds, or less than 6 seconds. The dry powder composition comprises microcrystalline particles of fumaryl diketopiperazine, the particles having a diameter of about 59 mm. 2 / g ~ approx. 63m 2 / g and has a fine particle size of about 23 nm to about 30 nm. It has a pore size.

[0028] A method of treating pulmonary fibrosis concomitantly with a pulmonary arterial hypertension disease or disorder, comprising administering treprostin to a subject. epoprostenol, bosentan, ambrisentan, macitentan, sildenafil and the like, including tadalafil, riociguat, and their analogs or combinations thereof. Patients being treated for pulmonary arterial hypertension or patients with PAH, which present a potentially treatable condition. Therefore, it is necessary to select patients who will be treated only by oral or injectable administration and to Stable dry powder compositions comprising an active agent and a diketopiperazine for treating a disease or disorder - Patents.com and replacing the active agent in the composition with an inhalation treatment comprising providing the patient with an inhaler containing the active agent in the composition; and administering the stable dry powder composition to a patient by pulmonary inhalation; thereby treating the disease or Also disclosed herein are methods of treating the conditions.

[0029] In an exemplary embodiment, a formulation for treating pulmonary arterial hypertension and / or interstitial lung disease may be used in amounts up to 200 μg per dose, e.g., 1 μg, 5 μg, 10 μg, 15 μg, 20 μg, μg, 30μg, 60μg, 90μg, 100μg, 120μg, 150μg, 180μg treprostinil or its salts in an amount of 100µg, 200µg, or 300µg, with one per dose. Or multiple pharmaceutically acceptable carriers and / or excipients are administered to the subject. In the present invention, the pharmaceutically acceptable carrier and / or excipient may be formulated for oral inhalation, diketopiperazines such as fumaryl diketopiperazine, sugars such as Mannitol, xylitol, sorbitol and trehalose; glycine, leucine, iododecane Amino acids such as soleusine and methionine; surfactants such as polysorbate 80; sodium chloride monovalent, divalent and trivalent salts such as ammonium chloride, potassium chloride, magnesium chloride and zinc chloride cationic salts; buffers (e.g., citric acid and tartaric acid) or one or more carriers and / or In certain embodiments, the formulation comprises treprostinil, a sugar, and A dry powder containing an amino acid, wherein the sugar is mannitol or trehalose; is leucine or isoleucine and a cationic salt. In certain embodiments, the formulation comprises a salt Sodium chloride, potassium chloride, magnesium chloride or zinc chloride, sodium citrate , sodium tartrate, or a combination thereof.

[0030] In an exemplary embodiment, the combination therapy comprises a dose of nintedanib or treprostinil. and a method of treating interstitial lung disease comprising administering to a patient a nintedanib dose of: In the same inhaler provided with different cartridges or with its own cartridge The doses of treprostinil and nintedanib are administered from different inhalers provided together. is administered using a dry powder inhaler for oral inhalation. Rostinil inhalation powder dose is for patients suffering from pulmonary arterial hypertension and in need of treatment The dry powder inhaler is provided to the patient; the dry powder inhaler includes a container containing a cartridge, and the container or cartridge The drug is a dry drug containing treprostinil administered in multiple daily doses over a 6-month period. Contains a dry powder, treprostinil has functional class II early in the course of the disease It is administered to patients by oral inhalation as first-line monotherapy.

[0031] In an alternative embodiment, the dry powder for inhalation may contain other carriers and / or other than the diketopiperazine. or additives, for example, sugars such as trehalose; buffers such as sodium citrate; sodium chloride; and zinc chloride, and treprostinil, vardenafil, and sildenafil, It may be formulated with one or more active agents.

[0032] In embodiments according to this, the method of treating interstitial lung disease in a patient who also has PAH comprises: In patients with moderate to severe PAH, an active agent such as treprostinil and a diketopiperazine are used. and administering a dry powder formulation containing a pharmaceutically acceptable carrier and / or excipient, such as a medicament. treprostinil in an amount of up to 200 μg per dose per session, is administered one or more times daily using a dry powder inhaler.

[0033] In one embodiment, the dry powder inhaler comprises a movable member for loading a container containing the pharmaceutical composition. The movable member is configured to cause airflow through the inhaler during an inhalation operation and to move the inhaler through the container. The container is allowed to enter the airflow passage so that more than 60% of the dry powder dose in the container is delivered in a single inhalation. The container may be arranged to achieve a dosing configuration from a container loading configuration so that the drug is delivered to the lungs via In one embodiment, the method comprises providing a second dry powder composition comprising one or more of the active agents described above. The method includes administering

[0034] In some embodiments, the inhaled dry powder treatment regimen is determined by the needs of the patient. , with standard treatment, which includes at least one to four inhalations per day, depending on the severity of the disease. There may be one inhalation replacing each nebulization session that takes place. DETAILED DESCRIPTION OF THE INVENTION

[0035] The embodiments disclosed herein are directed to the treatment of interstitial lung disease in patients with diseases involving pulmonary fibrosis. In one embodiment, the method comprises administering to a subject in need of treatment a method for treating a disease, particularly pulmonary fibrosis. administering one or more dry powder compositions to a patient suffering from rheumatoid arthritis using a dry powder inhaler; A dry powder composition comprising nintedanib, pirfenidone and / or treprostinil is administered. and deep lung delivery.

[0036] In an exemplary embodiment, the dry powder delivery system is configured to deliver a dry powder containing a pharmaceutical agent to an oral Single-use dry pharmaceutical doses in containers or cartridges for delivery by inhalation In one embodiment, the dry powder inhaler is a breath-actuated dry powder inhaler. The container or cartridge may contain active ingredients, including but not limited to pharmaceutical active substances. and optionally one or more pharmaceutically acceptable carriers and / or excipients. In particular, the dry powder containing the pharmaceutical composition is designed to contain an inhalable dry powder containing the pharmaceutical composition. Dry powder inhalers are for the treatment of pulmonary fibrosis and / or pulmonary arterial hypertension.

[0037] The dry powder inhaler comes in various shape and size embodiments and is reusable; Easy to use, inexpensive to manufacture, and / or made of plastic or other tolerable materials Dry powders can be produced in high volumes in simple steps using materials that are readily available. Various embodiments of inhalers are provided herein, and generally, the inhalation system includes an inhaler, a powder The inhalation system includes both filled and empty cartridges. In one embodiment, the dry powder is , a relatively sticky powder that requires optimal deagglomeration conditions. In this configuration, the inhalation system is configured to deliver a single-use cart containing pre-metered doses of the dry powder formulation. The present invention provides a reusable miniature breath-actuated inhaler in combination with a cartridge. Pulmonary arterial hypertension in less than 10 seconds, less than 6 seconds, or less than 4 seconds per ridge session A single inhalation dry powder dose is delivered per use for the treatment of interstitial lung disease with or without pulmonary embolism. In certain embodiments, oral inhalation through an inhaler can be achieved in less than 6 seconds, 4 seconds, or It is possible to deliver more than 60% of the powder dose in less than 10 seconds and in less than 2 seconds.

[0038] As used herein, the term "unit dose inhaler" refers to a single sealed inhaler containing a dry powder formulation. adapted to receive a receptacle, cartridge, or container and capable of inhaling from a single container refers to an inhaler that delivers a single dose of a dry powder formulation to the user via A unit dose must provide a specific dose to the user, and the same inhaler can be used for multiple units. Multiple dose sessions for volume delivery and for a predetermined number of use sessions It should be understood that it can be used in

[0039] As used herein, a "cartridge" refers to a device adapted to hold or contain a dry powder formulation. The enclosed container (powder-containing enclosed container) is arranged as follows: The cartridge is made of a strong material and the cup or container is attached to the lid in a translational motion. The device is movable relative to the inhaler or vice versa and is used with a closed arrangement that holds dry powder and an inhaler. The dosage regimen can be achieved using

[0040] As used herein, a "powder agglomerate" refers to an agglomeration or irregular geometric shape of powder particles. , for example, refers to an aggregate having a width, diameter and length.

[0041] As used herein, a "unit dose" refers to a pre-measured dry powder formulation for inhalation. Alternatively, a unit dose refers to a single metered amount delivered by inhalation. The container may be a single enclosure containing containers with single or multiple doses of the formulation. A unit dose enclosure / cartridge / container contains a single dose. The container may comprise a plurality of individually accessible compartments, each containing a unit dose.

[0042] As used herein, the term "about" means that a value is relative to the device or is used to indicate that it includes the standard deviation of the error for the method.

[0043] As used herein, the term "microparticle" refers to any particle, regardless of its exact external or internal structure. Refers to particles having a diameter of about 0.5 to about 1000 μm. Diameter of about 0.5 to about 10 microns Microparticles with a particle size of approximately 100 nm can easily pass through most natural barriers and reach the lungs. A diameter of less than 10 microns is required to navigate the curvature of the throat and avoid being exhaled. A diameter of approximately 0.5 μm or greater is required for efficient absorption. Aerodynamic diameter of about 0.5 to about 6 μm to reach the deep lung (or alveolar region) The particles contained in the "respirable fraction" (RF) are generally accepted to be those particles having It is preferable to maximize the proportion of particles that are oriented in the direction of the grain size. measured using standard techniques with a rson cascade impactor. Other impactors, such as NEXT GENERATION IM, are using the same range. Using PACTOR™ (NGI™, MSP Corporation) , the aerodynamic particle size can be measured, and thus the inspirable fraction can be calculated using similar aerodynamic In some embodiments, the laser diffraction The disclosure of which is incorporated herein by reference for its relevant teachings relating to instruments such as laser diffraction. No. 8,508,732, which is incorporated in its entirety by reference herein. Particle size is determined using a diffraction instrument to measure the volume median geometric diameter (VMGD) of the particle. For example, in various embodiments, the performance of the inhalation system is evaluated by measuring 80% or more, 85% or more. Empty the cartridge by more than 90% and use <12.5μm, <7.0μm or VMGD for emitted particles <4.8 μm may indicate progressively better aerodynamic performance. do.

[0044] The respirable fraction of the filled dose (RF / filled) is the powder that is filled to be used as a dose. The percentage of powder in the respirable dose that is expelled from the inhaler upon discharge of the contents (% ), i.e., the percentage of particles from the filled dose that are emitted at a size suitable for pulmonary delivery. represents the aerodynamic performance of a particle, which is a measure of the aerodynamic performance of the particle. RF / fill values above 40% reflect acceptable aerodynamic performance characteristics. In certain embodiments, the respirable fraction relative to the fill may be greater than 50%. In this form, the respirable fraction relative to the load can be up to about 80%, and about 80% of the load is It is discharged with a particle size of <5.8μm as measured using standard techniques.

[0045] As used herein, the term "dry powder" refers to a powder that is suspended or dissolved in a propellant or other liquid. This refers to a microparticulate composition that is completely free of all water molecules. It is not necessarily meant to be implied.

[0046] As used herein, "amorphous powder" refers to any powder that is specifically defined and includes all non-crystalline powders. refers to a dry powder that lacks any repetitive form, shape or structure.

[0047] The present disclosure provides improved powders, compositions, methods of making particles, and methods for preparing particles containing microcrystalline particles. Therapies enabling improved delivery of drugs to the lungs for treating diseases and disorders in elephants - Patents.com The present invention also provides a method for reducing the adverse effects of enteral or intravenous therapy. The embodiments disclosed herein have high performance for drug adsorption and can be used to provide one or more high-drug content Crystalline diketopiperazine containing microcrystalline diketopiperazine particles yielding powders with multiple active agents. Improved delivery is achieved by providing a piperazine composition. The co-produced powders can deliver increased drug content in a smaller powder dose. Depending on the starting material, the powder may be: by a variety of methods, including those utilizing surfactant-free or surfactant-containing solutions. It can be made by

[0048] In an alternative embodiment disclosed herein, the drug delivery system comprises a plurality of substantially uniform microparticles. The dry powder for inhalation may comprise crystalline particles, the microcrystalline particles being substantially hollow spheres. The diketopiperazine crystallites have a crystalline structure and do not self-assemble in suspension or solution. In certain embodiments, the microcrystalline particles may comprise a shell, which may be porous, including a porous shell. Depending on the drug and / or drug content being used and other factors in the process of making the powder, They can be substantially hollow spheres and substantially solid particles containing crystallites of diketopiperazine. In one embodiment, the microcrystalline particles have a diameter of about 0.4 cm as determined by BJH adsorption. 3 / g ~ approx. 0.45cm 3 / g range of approximately 0.43 cm 3 / g and an average pore volume of about 23 Phases having an average pore size ranging from about 23.8 nm to about 30 nm or from about 23.8 nm to 26.2 nm It includes particles that are relatively porous.

[0049] Certain embodiments disclosed herein provide a dried product comprising a plurality of substantially uniform microcrystalline particles. powder, the particles having a substantially spherical structure including a shell which may be porous, , containing crystallites of diketopiperazine that do not self-assemble in suspension or solution, less than 5 μm or has a volume median geometric diameter of less than 2.5 μm and contains an active agent.

[0050] In certain embodiments herein, up to about 92% of the microcrystalline particles are 5.8 μm In one embodiment, the shell of the particle has a volume median geometric diameter of The present invention is composed of intertwined diketopiperazine microcrystals with one or more drugs attached thereto. In some embodiments, the particles entrap the drug in their internal void volume and / or crystallize. The combination of drug adsorbed on the surface of the sphere and drug trapped in the void volume inside the sphere was investigated. It is possible.

[0051] In certain embodiments, a diketopiper comprising a plurality of substantially uniformly formed microcrystalline particles is provided. A rhodium composition is provided, wherein the particles have a substantially hollow spherical structure and do not self-assemble. the particles comprise a shell containing crystallites of a diketopiperazine; the particles are prepared by the following method: Trans isomer content in the range of approximately 45% to 65% in solution without the presence of surfactants and combining a solution of diketopiperazine having the formula: and concurrently homogenizing under high pressure up to 2,000 psi to form a precipitate. washing the precipitate in a suspension with deionized water; concentrating the suspension and suspending and drying the liquid in a spray drying apparatus. The formulation may be preformed for later use or may be combined with the active agent in a suspension prior to spray drying. It is possible.

[0052] The method may further comprise the step of adding an active agent or active agent to the solution or suspension prior to drying, e.g., prior to the spray drying step. a solution containing a pharmaceutically acceptable component, e.g., a drug or bioactive agent, in a pharmaceutically acceptable carrier and / or The step of adding the active agent or active ingredient together with the additives while mixing may further be included. The active component is adsorbed and / or entrapped on or within the particle. The particles obtained may be in the submicron size range before spray drying.

[0053] In certain embodiments, a diketopiper comprising a plurality of substantially uniformly formed microcrystalline particles is provided. A rhodium composition is provided, wherein the particles have a substantially hollow spherical structure and do not self-assemble. and a shell comprising crystallites of diketopiperazine, said particles having a volume average diameter of 5 μm or less. the particles have a geometric diameter; the particles can be dispersed in the following manner: The method also includes the steps of combining a solution of diketopiperazine and acetic acid in a high shear mixer. The process involves a simultaneous homogenization step under high pressure of up to 2,000 psi to form a precipitate. washing the precipitate in a suspension with deionized water; concentrating the suspension; and drying the suspension in a spray drying apparatus.

[0054] The method may further comprise the step of spray drying wherein the active agent or active ingredient is adsorbed onto or within the particles. or to be entrapped, a solution containing an active agent or active ingredient, such as a drug or bioactive agent, is mixed. The particles produced by this process may further comprise the step of: Can be in the submicron size range before spray drying.

[0055] In certain embodiments, a diketopiper comprising a plurality of substantially uniformly formed microcrystalline particles is provided. A lathane composition is provided, wherein the microcrystalline particles have a substantially hollow spherical structure and are self-assembled. and a shell comprising crystallites of diketopiperazine that do not adhere to the surface of the particle, the crystallites having a volume average diameter of 5 μm or less. the particles have a mean geometric diameter; the particles can be dispersed in the following manner: A solution of diketopiperazine and acetic acid in solution was combined without the presence of an activator. This is done in parallel with the mixing step in a high shear mixer under high pressures of up to 2,000 psi. homogenizing to form a precipitate; and washing the precipitate in suspension with deionized water. concentrating the suspension and drying the suspension in a spray drying apparatus. Formed by the method.

[0056] The starting material containing the active ingredient is a highly viscous extract or a honey-like consistency. In certain embodiments, the microcrystalline particles are substances having a certain appearance, as described above, and Washing the extract or viscous material in water using tangential flow filtration before combining them After washing in water, the resulting particle suspension is freeze-dried to form a The active ingredient is removed and resuspended in an alcohol solution containing ethanol or methanol. In one embodiment, the composition is optionally The method of production involves the addition of one or more amino acids (e.g., leucine, isoleucine, isine, methionine) or one or more phospholipids (e.g., 1,2-dipalmitoyl -sn-glycero-3-phosphocholine (DPPC) or 1,2-distearoyl Any further additions, such as dimethyl-sn-glycero-3-phosphocholine (DSPC) The method includes adding an agent simultaneously with or after the active ingredient and before spray drying. In certain embodiments, forming the composition comprises optionally extracting the desired active agent. The solution is then filtered or winterized to separate and remove undesirable materials, such as the lipid layer. The method includes increasing the decomposition rate.

[0057] The method may further comprise adding the solution to the mixture while mixing, the mixing being performed under high shear. This may be done with or without homogenization in a mixer, and the active agent or active ingredient may be mixed with the granules. The solution is activated prior to the spray drying step so that it is adsorbed and / or captured in or on the surface of the polymer. The process may include a therapeutic agent or active ingredient, such as a drug or bioactive agent. The particles may be in the submicron size range before spray drying, or the particles may be in the submicron size range during spray drying. It may be formed from a solution.

[0058] Thus, in some embodiments, the drug content is delivered in a crystalline powder using FDKP. This can be up to about 10%, or about 20%, or about 30%, or more. The FDKP or FDKP disodium salt is freeze-dried or spray-dried at a content exceeding 100%. The particles do not self-assemble, but form submicron-sized particles. In embodiments that include it, the drug content may typically be greater than 0.01% (w / w). In embodiments, from about 0.01% (w / w) to about 75% (w / w), depending on the drug being delivered; About 1% to about 50% (w / w), about 10% (w / w) to about 25% (w / w), or about 10 % to about 20% (w / w) or 5% to about 30% or more than 25% of the drug-containing microcrystalline particles In an example embodiment where the drug is nintedanib, the amount of nintedanib or The percentage of pirfenidone may comprise about 1% to about 50% (w / w) of the dry powder content. In certain embodiments, the drug content may be greater in dry powder compositions, The shape and size of the drug particles achieved may vary.

[0059] In an exemplary embodiment, the method for treating interstitial lung disease comprises administering a compound selected from the group consisting of fumaryl diketopiperazine, A dry powder composition comprising microcrystalline particles, Treprostinil is adsorbed onto the particles, and the content of treprostinil in the composition is up to About 20% (w / w) or up to about 30% (w / w), about 0.5% (w / w) to about 20% (w / w) or about 1% (w / w) to about 10% (w / w) or about 1% to about 5% (w / w) In one embodiment, the compositions herein contain methionine, histidine, iodopropanol, methylparaben ... It may contain one or more additives suitable for inhalation, such as amino acids such as soleucine and leucine. In this embodiment, for example, treprostinil, nintedanib, pirfenidone composition The product contains microcrystalline particles of fumaryl diketopiperazine and treprostinil in a single inhalation. The patient self-administers an effective dose containing about 1 mg to 15 mg of the dry powder composition. and can be used in the prevention and treatment of pulmonary fibrosis or pulmonary hypertension and interstitial lung disease. In this embodiment, the treprostinil content in the formulation may be about 1 μg to about 200 μg. In embodiments, the dry powder content of the cartridge containing treprostinil is 20μg, 30μg, 60μg, 90μg, 120μg, 150μg, 180μg, 2 The dose may be 00 μg, 300 μg or 500 μg.

[0060] In an alternative embodiment, the pharmaceutically acceptable carrier for making the dry powder is The composition may include any carrier or additive useful for making and suitable for pulmonary delivery. Examples of particularly suitable carriers and additives are sugars such as sugars and polysaccharides, e.g., lactose, mannose, sugar, sucrose, mannitol, trehalose; citrate, amino acids such as glycine , L-Leucine, Isoleucine, Trileucine, Tartrate, Methionine, Vitamin A , Vitamin E, Zinc Citrate, Sodium Citrate, Trisodium Citrate, Sodium Tartrate Sodium, Sodium Chloride, Zinc Chloride, Zinc Tartrate, Polyvinylpyrrolidone, Polysorbate Phospholipids containing phosphate 80 and diphosphatidylcholine are also included.

[0061] In one embodiment, a dry powder formulation is self-administered to a person's lungs by a dry powder inhalation system. A method is also provided, which includes obtaining a dry powder inhaler in a closed position and having a mouthpiece. a cartridge containing a pre-metered dose of the dry powder formulation in a storage arrangement, The dry powder contains nintedanib, pirfenidone, or treprostinil. and opening the dry powder inhaler and placing the cartridge or capsule. and; closing the inhaler and moving the cartridge to the dispensing position; and; closing the mouthpiece. Place in the human mouth and deliver the dry powder formulation to the lungs in less than 6 seconds with a single deep inhalation Includes.

[0062] In another embodiment, diketopiperazine-based microparticles are used as carriers or additives. A method for treating interstitial lung diseases, such as idiopathic pulmonary fibrosis, is disclosed. For example, the compound of formula 2,5-diketo-3,6-di(4-X-aminobutyl)piperazine, where X is (selected from the group consisting of succinyl, glutaryl, maleyl and fumaryl) This embodiment involves administering an inhalable dry powder composition or formulation comprising ketopiperazine. Alternatively, the dry powder composition may include a diketopiperazine salt to create an amorphous powder. In yet another embodiment, a dry powder composition or formulation is provided, wherein the diketopiperazine , 2,5-diketo-3,6-di-(4-fumaryl-aminobutyl)piperazine, with or without a physiologically acceptable carrier or excipient and an active agent.

[0063] An inhalation system for delivering a dry powder formulation to the lungs of a patient is provided, the system comprising: In the dosing configuration, values range from 0.05 to approximately 0.200 (vkPa) / liter per minute. a high resistance dry powder inhaler configured to have a flow conduit with a total resistance to flow; Dry powder inhalers are single-use dry powder inhalers that can be disposed of after use. The inhaler may be provided with a powder formulation or may be provided as replaceable individual tablets within a multi-use inhaler. and the individual dose enclosures or containers can be discarded after use. Individual dose cartridges containing the powder formulation may be provided in individual packages or Multiple cartridge doses may be provided in a blister package.

[0064] In one embodiment, a dry powder inhaler as described above is used to treat a respiratory disorder or disease, such as pulmonary fibrosis. diseases of the respiratory tract, lungs, pulmonary arterial hypertension, cystic fibrosis, respiratory tract infections, cancer, and diabetes and One or more dry powder formulations for treating other systemic diseases, such as endocrine disorders, including obesity. A dry powder inhalation kit is provided that includes a plurality of medication cartridges.

[0065] Embodiments of the dry powder inhaler disclosed herein may be used to treat a disease or disorder in a patient. The method of treatment comprises administering to a patient in need thereof a compound selected from the group described above. and a pharmaceutically acceptable carrier and / or excipient. providing a dry powder inhaler including a cartridge containing an inhalable formulation of the formula; is inhaled deeply through a dry powder inhaler for about 3-4 seconds or less than 6 seconds, and delivering the dose to the lungs. In this manner, the patient then breathes in a normal breathing pattern. Treatment for interstitial lung disease may be resumed at 1 week, 2 weeks, 3 weeks, and up to administration of e.g. nintedanib to patients for up to The maximum dose is 300 mg once or twice daily, and patients should be monitored for adverse side effects. It will be targeted.

[0066] In an alternative embodiment, a subject in need of treatment is administered a quinazolam containing a tyrosine kinase inhibitor. and a phosphodiesterase inhibitor molecule of the formula: [ka] and optionally one or more pharmaceutical agents as defined above with respect to the formulation. and administering an inhalable composition comprising an excipient or carrier to treat interstitial lung disease (e.g., In one embodiment, a method for treating a pulmonary disease, such as idiopathic pulmonary fibrosis, is provided. Kinase inhibitor molecules include, but are not limited to, axitanib, bosutinib, cabozantinib, Zantinib, crizotinib, dasatinib, erlotinib, gefitinib, imatinib, laparoscopic Patinib, nilotinib, pazopanib, panatinib, regorafenib, ruxolitinib, so These include rafenib, sunitinib, vandetanib, and vemurafenib.

[0067] The following examples are examples of dry powders suitable for use with the inhalers described herein. Some of the processes for making the powder and data from experiments using dry powders are presented. For example: [Example]

[0068] Example 1 Preparation of crystalline composite nintedanib dry powder 10% nintedanib solution (the concentration of nintedanib in this solution is 1% nintedanib to 1 nintedanib (0.025 g) at 10% (w / w) Acetic acid solution (0.225 g) (The concentration of the acetic acid solution ranges from 10% to 100% acetic acid. The nintedanib solution was prepared by adding 3,6-bis(N-fumaryl) (4-aminobutyl)-2,5-diketopiperazine or fumaryl diketopiperazine Crystalline particle (XC) suspension (1.31% solids, 188.93 g) was added to the suspension (XC suspension The solids content of the liquid can range from 0.5% to 5% (w / w). Nintedanib XC Suspension The solution was spray dried using a Buchi B-290 spray dryer under the conditions shown in Table 1 to obtain a 1% (w / w) Nintedanib XC powder was produced with a yield of approximately 2.5 g.

[0069] [Table 1]

[0070] Preparation of 20% (w / w) Nintedanib Crystalline XC Powder Preparation 10% nintedanib solution (the concentration of nintedanib in this solution is 1% nintedanib to 1 0% nintedanib) is nintedanib (3.33g * ) dissolved in 20% acetic acid Add 29.97 g of acetic acid solution (the concentration of the acetic acid solution can range from 10% to 100% acetic acid). Separately, the XC suspension was prepared by adding fumaryl diketopiperazine particles (11 .67g * ) in deionized water (705.03 g) (suspension solids = 1.63%) (XC suspension The solid content of the mixture can range from 0.5% to 5%. Then, the nintedanib solution was added to the XC suspension, and the resulting nintedanib XC suspension was spray dried using a Buchi B-290 spray dryer under the conditions shown in Table 1 to obtain a 20% Nintedanib XC powder was produced, resulting in a yield of approximately 15 g.

[0071] Preparation of crystalline nintedanib T dry powder 10% nintedanib solution (the concentration of nintedanib in this solution is 1% nintedanib to 1 0% nintedanib) can be, for example, nintedanib (0.025 g) (nintedanib Tedanib charge (which can range from 0.025 g to 0.50 g) in 10% acetic acid solution (0 0.225g) (the concentration of the acetic acid solution can range from 10% to 100% acetic acid) The nintedanib solution was prepared by the following procedure: added to a suspension of preformed particles of (4-aminobutyl)-2,5-diketopiperazine (T suspension; 8.11% solids, 30.52 g) (The solid content of the T suspension is 0.5% to 20 The nintedanib T suspension is then spray dried or freeze-dried. The spray dried powder was dried by evaporation to produce 1% nintedanib T powder. Dried using a Buchi B-290 spray dryer under the conditions indicated. Freeze-dried powder The nintedanib T suspension was first pelleted in liquid nitrogen, followed by Virtis G. The solution was prepared by drying in an Enesis 25XL shelf freeze dryer. The dryer was programmed to ramp the shelf temperature from -45°C to 25°C at 0.2°C / min. The powder was then kept under vacuum at 25°C until completely dry. The amount was about 2.5 g.

[0072] Preparation of spray-dried 20% (w / w) nintedanib crystalline T powder 10% nintedanib solution (the concentration of nintedanib in this solution is 1% nintedanib to 1 0% nintedanib) is nintedanib (3.33g * ) dissolved in 20% acetic acid solution (30.0 g) (the concentration of the acetic acid solution can range from 10% to 100% acetic acid) Nintedanib solution was prepared by dissolving in T suspension (8.99% solids, 129.81 g) (The solids content of the suspension can range from 0.5% to 20%). The ntedanib T suspension was prepared using a Buchi B-290 spray dryer under the conditions shown in Table 1. It was spray dried and the resulting yield was about 15 g.

[0073] Preparation of lyophilized 20% nintedanib T powder 10% nintedanib solution (the concentration of nintedanib in this solution is 1% nintedanib to 1 0% nintedanib) is nintedanib (2.63g * ) dissolved in 10% acetic acid Add 23.63 g of acetic acid (the concentration of the acetic acid solution can range from 10% to 100% acetic acid). The nintedanib solution was prepared by dissolving it in a T suspension (8.99% solids, 104.2 3g * ) (The solids content of the suspension can range from 0.5% to 20%). Nintedanib T suspension was prepared by first pelleting the nintedanib T suspension in liquid nitrogen, followed by V Freeze the cells by drying them in a irtis Genesis 25XL shelf freeze dryer. The freeze-drier was operated according to a program, and the shelf temperature was changed to -45°C at 0.2°C / min. ℃ to 25℃, then hold at 25℃ under vacuum until the powder is completely dry. A yield of approximately 12 g was obtained.

[0074] Preparation of freeze-dried 20% nintedanib T powder with reduced solid content 10% nintedanib solution (the concentration of nintedanib in this solution is 1% nintedanib to 1 0% nintedanib) is nintedanib (3.09g * ) dissolved in 20% acetic acid Add 27.81 g of acetic acid (the concentration of the acetic acid solution can range from 10% to 100% acetic acid). Separately, T suspension (8.99% solids, 132.48 g) was prepared. * ) The solid content of the suspension was 0.5% to 20% (w / w). The nintedanib solution was added to this diluted T suspension and diluted to 5.00 % solids content. This was first pelleted in liquid nitrogen, followed by Virtis Genesis 25XL Lyophilization was performed by drying in a shelf freeze dryer. Program the freeze dryer The shelf temperature was ramped from -45°C to 25°C at 0.2°C / min, followed by the powder. The powder was kept under vacuum at 25°C until completely dry, resulting in a yield of approximately 15 g. there were.

[0075] Preparation of lyophilized 20% nintedanib T powder with reverse component addition 10% nintedanib solution (the concentration of nintedanib in this solution is 1% nintedanib to 1 0% nintedanib) is nintedanib (3.09g * ) dissolved in 20% acetic acid Add 27.81 g of acetic acid (the concentration of the acetic acid solution can range from 10% to 100% acetic acid). The nintedanib solution was diluted with deionized water (97.19 g). Then, freeze-dried T particles (11.91 g * ) into the nintedanib solution little by little for 4 minutes. Deionized water (10.00 g) was used to remove the remaining lyophilized T particles. The nintedanib T suspension was first washed in liquid nitrogen. First pelleted, then in a Virtis Genesis 25XL shelf freeze dryer. The freeze-drier was operated according to the program, and the shelf The temperature was ramped from -45°C to 25°C at 0.2°C / min, and then dried until the powder was completely dry. The resulting yield was approximately 15 g.

[0076] Preparation of freeze-dried 20% nintedanib esylate T powder 1% Nintedanib Esylate Solution (The concentration of Nintedanib Esylate in this solution is 1 % nintedanib esylate to 5% nintedanib esylate) Danib esylate (3.61g * ) into deionized water (357.39g) little by little. The nintedanib esylate solution was prepared by dissolving it in a T suspension (8.99% solids, 126 .70g * ) (The solids content of the suspension can range from 0.5% to 20%). The resulting nintedanib esylate T suspension was pelleted in liquid nitrogen and subsequently The samples were dried in a Virtis Genesis 25XL shelf freeze dryer. The shelf temperature was ramped from -45°C to 25°C at 0.2°C / min. The powder was then kept under vacuum at 25°C until completely dried, and the resulting yield was It was about 15g.

[0077] Powder Test The powders were dispersed in a Sympatec laser diffraction spectrometer equipped with a RODOS bulk powder dispersion system. The geometric particle size distribution was evaluated using the instrument. The bulk powder was subjected to pressures of 0.5 bar and 3. The powder was dispersed in an Andersen cascade impactor (ACI) at 0 bar. The aerodynamic particle size distribution was also evaluated using a Gen 2C compressor at 4 kPa. The drug was released from the cartridge (10 mg cartridge filling) through the ACI. Data for the powder are shown in Table 2.

[0078] [Table 2] [Table 3]

[0079] As can be seen in Table 2, the process product yields were 0.01 for the spray-dried or freeze-dried dry powder. For both compositions, the percentage was greater than about 67%. Furthermore, regardless of the method used to prepare the powder, The freeze-dried T powder and the 10% and 20% by weight of nintedanib in the composition It can be seen that the percent yield improved for all powders with The average amount of saturates delivered from the delivery system as measured by cartridge emptying (CE) measurements. Powders were greater than 75% for all XC powders and spray-dried T powders and all freeze-dried The results showed that the C value was 62% or more for the selected powders, and some powders had a C value of over 97%. The data show that the XC powder at higher concentrations (10 wt. % and 20 wt. %) , but appears to have more consistent cartridge emptying performance at lower concentrations. It also shows that the powder with the best CE performance was the spray-dried or freeze-dried 1% T powder.

[0080] Example 2 Preparation of crystalline composite pirfenidone dry powder 25% pirfenidone solution (the concentration of pirfenidone in this solution is 1% pirfenidone) pirfenidone (0.20 g) (which can range from 0.15 to 40% pirfenidone) The pirfenidone charge used to prepare these powders ranged from 0.2 g to 0.63 g. (varied) in ethanol (0.60 g) (when 25% pirfenidone solution was used, Add water to ethanol in a maximum 50:50 weight ratio of ethanol:water. The pirfenidone solution was prepared by mixing the microcrystalline (XC) suspension (1.31%) with 100 mL of ... The solid content of the XC suspension ranged from 0.5% to 5%. Pirfenidone XC suspension was sprayed with Buchi B-290 under the conditions shown in Table 1. A dryer was used to spray dry the powder to produce pirfenidone XC.

[0081] Preparation of crystalline pirfenidone powder 25% pirfenidone solution (the concentration of pirfenidone in this solution is 1% pirfenidone) pirfenidone (0.20 g) (which can range from 0.15 to 40% pirfenidone) The pirfenidone charge used to prepare these powders ranged from 0.2 g to 0.33 g. When ethanol (0.60 g) (25% pirfenidone solution) was used, water The pirfenidone solution was prepared by adding it to ethanol. The liquid was T suspension (8.11% solids, 22.19 g) (the solid content of T suspension is 0.5% to 2 The pirfenidone T suspension was then spray dried or frozen. The spray dried powder was dried to produce Pirfenidone T powder. Dried using a Buchi B-290 spray dryer under the conditions indicated. Freeze-dried powder The pirfenidone T suspension was first pelleted in liquid nitrogen, followed by Virtis Prepared by drying in a Genesis 25XL shelf freeze dryer. The dryer was programmed to ramp the shelf temperature from -45°C to 25°C at 0.2°C / min. The powder was then placed under vacuum at 25°C until it was completely dry.

[0082] Preparation of amorphous pirfenidone powder 25% pirfenidone solution (the concentration of pirfenidone in this solution is 40% pirfenidone) pirfenidone (0.20 g) (which can range from 1% pirfenidone to 1% pirfenidone) The pirfenidone charge used to prepare these powders ranged from 0.2 g to 0.22 g. When ethanol (0.60 g) (25% pirfenidone solution) was used, Add water to ethanol in a maximum 50:50 weight ratio of ethanol:water. Separately, a 10% FDKP disodium salt solution was prepared. Leucine (leucine charge ranged from 0 g to 0.45 g) and FDKP-dimethicone The sodium salt (1.80 g) was dissolved in deionized water (16.20 g). The concentration of KP-disodium salt can range from 5% to 20%.

[0083] The pirfenidone solution was added to the FDKP-disodium salt solution, and the resulting solution The mixture was sprayed using a Buchi B-290 spray dryer operated using the conditions shown in Table 1. After mist drying, pirfenidone amorphous powder was produced.

[0084] The above disclosure is an exemplary embodiment. Those skilled in the art will recognize that the present invention will reveal exemplary embodiments that work well in the practice of the present disclosure. However, those of ordinary skill in the art, in light of this disclosure, may experience some skepticism regarding the specific embodiments disclosed. Many modifications may be made to the same or similar embodiments without departing from the spirit and scope of the present invention. It should be recognized that similar results can be obtained.

[0085] Unless otherwise indicated, the terms used in this specification and elsewhere herein represent amounts, properties, e.g., molecular weight, reaction conditions, etc. of ingredients. All numbers used in the appended claims are modified in all instances by the term "about." Accordingly, unless indicated to the contrary, the following specification and accompanying patents The numerical parameters set forth in the claims may vary depending upon the desired properties sought to be obtained. At the very least, it is an approximation that may vary depending on the scope of the claims. Notwithstanding any attempt to approximate the accuracy of any numerical parameter, it is understood that the accuracy of any numerical parameter is based on the number of significant digits reported. and should at least be interpreted by applying normal rounding techniques. Numerical ranges and parameters indicating ranges are approximate, but are not intended to be limiting unless otherwise specified. The figures are reported as accurately as possible.

[0086] However, any numerical value will necessarily vary from the standard deviation found in its respective testing measurements. It inherently contains certain errors that are introduced.

[0087] As used in connection with the description of the present invention (and particularly in connection with the claims below), the term "1 "A," "an," "the," and similar references are used throughout this specification. Unless otherwise indicated in the document or clearly contradicted by context, both the singular and the plural are used. The recitation of ranges of values herein is intended to encompass each individual value falling within the range. It is merely intended to serve as a shorthand way of referring to different values individually. Unless otherwise indicated, each individual value is treated as if it were individually listed herein. All methods described herein are incorporated herein by reference in their entirety. Unless otherwise indicated or otherwise clearly contradicted by context, Any examples or exemplary language provided herein (e.g., "etc.") The use of is intended merely to better illustrate the invention and is not intended to be a substitute for the scope otherwise claimed. No language in this specification imposes any limitation on the claimed invention that is essential to the practice of the invention. should not be construed as indicating elements that are not

[0088] Use of the term "or" in the claims means only alternatives or alternatives. "and / or" is used to mean "and / or" unless expressly indicated to be mutually exclusive. However, the present disclosure supports definitions that refer to the alternative only and "and / or."

[0089] Groupings of alternative elements or embodiments disclosed herein are not to be construed as limitations Each group member may be used individually or in combination with other members of the group or other elements found herein. One or more members of a group may be referred to and claimed in any combination with and / or may be included in or deleted from a group for patentability reasons. When an inclusion or deletion occurs, the specification is considered to include the group as amended herein; Therefore, the written description of all Markush groups used in the appended claims is is considered to be fulfilled.

[0090] The preferred embodiments are the best mode known to the inventors for carrying out the invention. Of course, variations of the preferred embodiment are possible. The embodiments will be apparent to those skilled in the art upon reading the above description. The inventors anticipate that such modifications may be used as needed, and have provided the following specific examples: It is intended that the invention be practiced otherwise than as described. As permitted by usage, all of the subject matter recited in the claims appended hereto Moreover, the above elements in all possible variations thereof are intended to encompass all modifications and equivalents thereof. Any combination of the above is acceptable unless otherwise indicated herein or otherwise clearly contradicted by context. Insofar as they are not, they are encompassed by the present invention.

[0091] Certain embodiments disclosed herein may be referred to as "consisting of" or "consisting essentially of." The claims may be further defined using the following language: Whether added by application or amendment, the transitional phrase "consisting of" shall Excludes any element, step, or ingredient not specified in the claim. "becomes" refers to a claim that is substantially reduced to particular materials or steps and basic, novel features. The embodiments so claimed are limited to those which do not affect the are clearly or expressly stated and valid.

[0092] Additionally, numerous references to patents and publications are made throughout this specification. Each of the references and publications is individually incorporated by reference herein in its entirety.

[0093] It is further understood that the embodiments disclosed herein are illustrative of the principles of the present invention. Other modifications that may be employed are within the scope of the present invention. By way of example, but not limitation, alternative configurations may be utilized in accordance with the teachings herein. Accordingly, the present invention is not limited to that precisely as shown and described.

Claims

1. diketopiperazine particles and a therapeutically effective dose of a compound of the formula: 【Chemical 1】 and optionally a pharmaceutically acceptable carrier and / or excipient.

1. An inhalable pharmaceutical composition comprising:

2. The dose may be in an amount of up to 50 mg and may contain one or more pharmaceutically acceptable salts thereof. and a pharmaceutically acceptable carrier and / or excipient. composition.

3. The one or more pharmaceutically acceptable carriers and / or additives may be surfactants, amino 2. The inhalable pharmaceutical composition of claim 1, which is an acid or a phospholipid.

4. The diketopiperazine may be in crystalline or microcrystalline particulate form and have the formula: 【Chemistry 2】 2. The inhalable pharmaceutical composition of claim 1, wherein

5. The dry powder may be in the range of about 1 mg to about 50 mg of therapeutic agent in the dry powder composition.

10. The inhalable pharmaceutical composition of claim 1, comprising an effective dose of the compound.

6. 10. The inhalable pharmaceutical dry powder composition of claim 1, wherein the pharmaceutical dry powder composition is an amorphous powder. Pharmaceutical composition.

7. The dry powder may contain lactose, mannose, sucrose, mannitol, trehalose, , sodium citrate, trisodium citrate, zinc citrate, glycine, L-leucine , Isoleucine, Trileucine, Sodium Tartrate, Zinc Tartrate, Methionine, Vitamin A, Vitamin E, Sodium Chloride, Zinc Chloride, Polyvinylpyrrolidone and Polysorbate 80, comprising one or more pharmaceutically acceptable carriers and / or additives selected from 2. The inhalable pharmaceutical composition of claim 1.

8. The dry powder may contain sodium citrate, sodium chloride, leucine or isoleucine, and and trehalose, and / or one or more pharmaceutically acceptable carriers selected from the group consisting of The inhalable pharmaceutical composition according to claim 7, further comprising an additive.

9. 4. The inhalable pharmaceutical composition of claim 3, wherein the surfactant is polysorbate 80. thing.

10. The microcrystalline particles have a specific surface area in the range of about 25 m ２ / g to about 63 m ２ / g, Claim 5. The inhalable pharmaceutical composition according to claim 4.

11. The microcrystalline particles according to claim 4, wherein the microcrystalline particles have a pore size ranging from about 23 nm to about 30 nm. The pharmaceutical dry powder composition described above.

12. A method for treating idiopathic pulmonary fibrosis, comprising administering to a patient in need of treatment a compound by oral inhalation. and up to 50 mg of a compound of the formula: 【Chemistry 3】 and optionally a pharmaceutically acceptable carrier and / or excipient. wherein the dry powder composition is provided in a dry powder inhaler. Law.

13. A therapeutically effective dose of the dry powder composition is prepared by mixing the dry powder composition in a suitable solution with the dry powder inhaler prior to use. provided to said patient in one or more capsules or cartridges for Alternatively, the cartridge contains up to 30 mg of the compound.

14. The therapeutically effective dose may be up to 30 mg / day provided in multiple cartridges.

14. The method of claim 13, comprising 0 mg of the compound.

15. Fumaryl diketopiperazine, lactose, mannose, sucrose, mannitol, Lehalose, sodium citrate, trisodium citrate, zinc citrate, glycine, L -Leucine, isoleucine, trileucine, sodium tartrate, zinc tartrate, methionine , Vitamin A, Vitamin E, Sodium Chloride, Zinc Chloride, Polyvinylpyrrolidone and Poly sorbate 80 and / or one or more pharmaceutically acceptable carriers selected from the group consisting of The method of claim 12 further comprising:

16. The one or more pharmaceutically acceptable carriers and / or excipients may be sodium citrate. , sodium chloride, leucine or isoleucine, or trehalose. The method described below.

17. The one or more pharmaceutically acceptable carriers and / or excipients may be fumaryl diketopiperidine.

12. The method of treating pulmonary arterial hypertension according to claim 11, wherein the compound is thiazolidine.

18. The dry powder composition is administered in at least one inhalation per cartridge in less than 10 seconds. The method of claim 11 .

19. A movable member for mounting the cartridge and configuring the container to achieve dosage placement.

10. A dry powder inhaler comprising: a cartridge containing the dry powder composition of claim 1.

1. A dry powder inhaler comprising:

20. The enclosure includes a cartridge consisting of a lid and a container, and the dry powder dose is of the formula: 【Chemistry 4】 and a compound having the formula 3',6-bis(N-fumaryl-4-aminobutyl)-2,5-diketone 20. The dry formulation of claim 19, comprising particles of a pharmaceutically acceptable excipient having topiperazine. Dry powder inhaler.

21. A method for treating idiopathic pulmonary fibrosis, comprising administering to a patient in need of treatment a compound by oral inhalation.

21. A method comprising administering the inhalable pharmaceutical composition of claim 20.

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