Method and composition for treating pulmonary fibrosis

Abstract

To provide a composition and a dry powder inhaler for the treatment of fibrotic lung disease.SOLUTION: An inhalable pharmaceutical composition is provided comprising a dry powder comprising: diketopiperazine particles and a therapeutically effective dose of a compound having the formula in the figure and optionally a pharmaceutically acceptable carrier and / or excipient.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 the patient by oral inhalation. [Background technology]

[0002] Idiopathic pulmonary fibrosis (IPF) is a chronic lung disease of unknown cause that has no known cure. 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 become enlarged and cannot 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. The most common symptom of IPF is 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 Scarring in the lungs increases over time until they can no longer provide sufficient 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 scarring in the lungs, which is associated with the disease. However, it does not necessarily reduce the associated symptoms of coughing and shortness of breath. The oral tablet treatment has been shown to slow the progression of IPF. However, some patients side effects make it difficult to tolerate these drugs at the doses needed to slow progression. The repeated high doses required to slow disease progression can have gastrointestinal effects. Adverse effects, e.g. nausea, diarrhea, abdominal pain, vomiting; hepatobiliary, nervous system, 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 drugs are, for example, antacids to prevent gastroesophageal reflux and steroids to relieve shortness of breath. Oxygen therapy and exercise training to increase oxygen levels and their use to provide pulmonary rehabilitation for people with chronic conditions. Population-directed education and support is recommended for individuals with IPF. One major and invasive procedure is to provide the patient with a lung transplant. To improve or provide alternative and novel methods of treatment for patients with IPF. It is necessary to provide.

[0005] Drug delivery to pulmonary tissue is accomplished using a variety of methods and routes of administration, for example, oral. Drug delivery or enteral, such as tablets and capsules containing drugs and Parenteral, which involves the 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 have been developed for pulmonary delivery with success 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 administering medication, and These include inconsistency in the powder, equipment problems and poor powder deagglomeration. Some devices limit treatment by requiring the use of hazardous propellants to deliver the dose. However, high manufacturing costs and / or lack of patient compliance have hindered their production. Thus, the inventors have developed a powder formulation that provides consistent or improved powder delivery characteristics and is easy to use. and a novel formulation having a separate configuration that allows for better patient compliance. and identified the need to design and manufacture an inhaler. [Means for solving the problem]

[0007] Compositions and methods for using compositions in the treatment of interstitial lung diseases such as idiopathic pulmonary fibrosis - Patents.com In embodiments thereof, the composition is delivered locally to the pulmonary circulation or is an interchangeable formulation containing a dry powder pharmaceutical formulation for inhalation to be delivered to the lungs for systemic delivery. The present invention relates to a dry powder inhaler comprising a cartridge or capsule having a composition for use in administering the present invention thereto. 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 pharmaceuticals to the lungs and the systemic circulation thereof. A breath actuated inhaler including a system.

[0008] In certain embodiments, the method of treating idiopathic pulmonary fibrosis comprises delivering to lung tissue and administering to the alveoli and A drug delivery system for rapid delivery of active agents to the systemic circulation and onset of action in the lungs. systems, including drug delivery systems designed for pulmonary drug delivery by oral inhalation. In this manner, the active agent is delivered in a therapeutically effective manner with fewer adverse effects. In certain embodiments, the method of treatment includes 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 one or more of the compounds to treat a disease. In one embodiment, the method further comprises administering to the patient a dry powder formulation comprising the active agent or agents. A dose of dry powder is delivered to the lungs using a dry powder inhaler, and the active agent is delivered to the deep lungs. The pharmaceutical composition can be administered as a breath-actuated dry powder inhaler for oral or nasal inhalation. The drug is self-administered by the patient in one or more breaths using a delivery system. The drug may cause adverse gastrointestinal effects, such as nausea, diarrhea, abdominal pain, vomiting; hepatic, biliary, nervous, vascular, metabolic, and metabolic effects. The authors report that the adverse effects of 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 pulmonary stimulatory agent for delivery to pulmonary tissue. or administering a stable pharmaceutical composition comprising multiple active agents, , 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. The present invention also includes a formulation for inhalation comprising a therapeutically effective dose of a dry powder comprising 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 coactivator 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, The pharmaceutical composition may optionally further comprise one or more pharma- ceutically acceptable additives. In this and other embodiments, the pharmaceutical composition comprises an agent and / or a carrier. In use, the composition is provided to the patient in a container, capsule or cartridge for inhalation.

[0010] In one embodiment, a pharma- ceutically acceptable compound comprising a diketopiperazine having the ability to form particles is and a therapeutically effective dose of the compound of the formula: [ka] and optionally one or more pharma- ceutically 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 formulated to contain a dose of one or more active agents for delivery by an inhaler. and can be formulated as follows: in a powder and optionally containing one or more drugs including nintedanib esylate The present invention includes a pharmaceutical composition comprising the compound of the present invention and a pharma- ceutically acceptable salt thereof, and a pharma- ceutically acceptable carrier and / or excipient. 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 one 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 pharma- ceutically acceptable carriers and / or excipients that 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 particulate 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 In the dry powder composition, the amount is in the range of about 1 mg to about 50 mg.

[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 also includes dry powders containing one or more pharma- ceutically acceptable carriers and / or excipients.

[0015] In another embodiment, 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 also includes dry powders comprising one or more pharma- ceutically 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-diaminetetraacetate having a specific surface area of ​​1.0 mm or less. In one embodiment, the microcrystalline particles are from about 23 nm to about 25 nm. 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 diketopiperazine particles by oral inhalation, 1 mg to 10 mg per inhalation session; 10mg~20mg;20mg~30mg, 30mg~50mg;50mg~100mg 100-150 mg; or 150-300 mg of the formula: [ka] a compound of the formula (I), a pharma- ceutically acceptable salt thereof, a derivative thereof, and optionally a pharma- ceutically acceptable carrier. and / or an excipient, The composition is provided in a single dose cartridge in a dry powder inhaler. The cartridges are then 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 is administered a therapeutically effective dose of dried A powder composition is administered, which may be fitted with one or more preservatives for compatibility with a dry powder inhaler prior to use. 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 dose per day is up to 500 mg per day; up to 7 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 performed 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 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 The composition may include one or more pharma- ceutically 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 pharma- tically effective amount of pirfenidone (5-methyl-1-phenyl-2- -(1H)-pyridone), or 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 of treatment a diketopy Perazine and the formula: [ka] or a pharma- ceutically acceptable salt thereof, such as an esylate salt, and optionally one or more and a pharma- ceutical 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] 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 dosing arrangement when loaded onto the inhaler. The dry powder inhaler is used to inject pirfenidone or nintedanib into the body. administering by oral inhalation an inhalable pharmaceutical dry powder comprising the The container comprises a dry powder composition to be inhaled. In one embodiment, the dry powder composition comprises a cap and a container. 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 providing one or more cartridges containing a dry powder composition to a patient. and aspirating one or more cartridge contents from each of the 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 the formula 3,6-bis(N-fumaryl-4 PHARMACEUTICALLY ACCEPTABLE EXcipient PARTICLES HAVING (-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. A high resistance dry powder inhaler with a resistance value of 0.01 to 0.01 mmHg is used to inhale at least 4 to 100 ng / l. This includes inhaling for 0 seconds or for 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 a The subject is administered a pharmaceutical composition comprising pirfenidone and / or nintedanib separately and sequentially. or in combination with one or more vasodilatory compounds. In an embodiment, the method comprises administering to the patient sildenafil, tadalafil, vardenafil, prostaglandin A, or a combination thereof. prostaglandins, their prodrugs, prostaglandin derivatives, treprostinil and other prostaglandins Medicinal compounds such as treprostinil analogues or pharma- ceuticals containing these compounds, such as treprostinil sodium. The present invention relates to a combination therapy comprising administering to a subject a vasodilator comprising 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 comprising pirfenidone and / or nintedanib. Dry Powder Formulation and / or Treprostinil, Treprostinil or Treprostinil These compounds include pharma- ceutically acceptable salts thereof, such as sodium, 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. or administered separately as its own formulation and administered to the patient at different intervals or sequentially during a dosing session. The information may be provided to persons.

[0026] In one embodiment, the drug delivery system is, for example, pirfenidone, nintedanib, prostaglandin E, Small molecules such as taglandins or their analogs such as treprostinil, as well as pulmonary A method for delivering protein-based products to treat 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 The Company will realize advantages over intravenous and subcutaneous injectable / infusion drug products.

[0027] In certain embodiments disclosed herein, a patient with pulmonary fibrosis and PAH is administered a dry powder In the powdered preparation, prostaglandin, treprostinil, or treprostinilna The pharmacy acceptable salts or prodrugs of these compounds, such as thorium, The method further comprises providing a derivative thereof. selecting a patient to be treated for interstitial lung disease and administering nintedanib, pills, A dry drug containing phenidone, treprostinil, a treprostinil salt, or a derivative thereof. A dry powder formulation, in which treprostinil is combined with diketopiperazine microcrystalline particles. dry powder formulations which are combined to produce a pharmaceutical formulation or composition suitable for pulmonary inhalation; and having the patient inhale from an inhaler containing the composition; and administering a breath-actuated 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 per dose in the dry powder formulation. It is provided in a reconstitutable cartridge containing reprostinil or a salt thereof. In embodiments, the dry powder formulation comprises about 10 μl per dose in a cartridge or capsule. In one embodiment, the dosage form for a single use may contain from about 100 μg to about 300 μg of treprostinil. 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 / kg / day inhalation or breath-by-breath technique. In one embodiment, the pharmaceutical composition 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 an average particle size of about 59 μm. 2 / g ~ approx. 63m 2 / g and fine particles having a diameter of about 23 nm to about 30 nm. The pore size is

[0028] A method for treating pulmonary fibrosis concomitantly with a pulmonary arterial hypertension disease or disorder, comprising administering to the patient treprostin le, epoprostenol, bosentan, ambrisentan, macitentan, sildenafil and / or combinations thereof. Patients being treated for pulmonary arterial hypertension or patients with PAH, which may be amenable to treatment. Therefore, it is necessary to select patients who are to be treated only by oral or injectable administration, and to carry out the above treatment. 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 therapy 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 administered in amounts up to 200 μg per dose, e.g., 1 μg, 5 μg, 10 μg, 15 μg, 20 μg, 30μg, 60μg, 90μg, 100μg, 120μg, 150μg, 180μg Each dose contains treprostinil or its salt in an amount of 100μg, 200μg, or 300μg. Or more than one pharma- ceutically acceptable carrier and / or excipient is administered to the subject. In the present invention, the pharma- ceutically acceptable carrier and / or excipient may be formulated for oral inhalation, can form diketopiperazines such as fumaryl diketopiperazine, sugars such as Mannitol, xylitol, sorbitol and trehalose; glycine, leucine, isocyanate Amino acids such as soleucine 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 combination of excipients. a dry powder comprising an amino acid, the sugar being 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. The present invention also includes 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. The drug is administered using a dry powder inhaler for oral inhalation. Rostinil inhalation powder dose is for those suffering from pulmonary arterial hypertension and in need of treatment The dry powder inhaler is provided to a 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 six-month period. Treprostinil contains a dry powder and has functional class II early in the disease process. 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, sildenafil, and other salts. It may be formulated with one or more active agents.

[0032] In an embodiment according to this, the method of treating interstitial lung disease in a patient who also has PAH includes In patients with moderate to severe PAH, active agents such as treprostinil and diketopiperidine are used. and administering a dry powder formulation comprising a pharma- ceutical carrier and / or excipient such as ginseng. and a maximum of 200 μg of treprostinil per dose per session; is administered once or multiple 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 adapted to cause airflow through the inhaler during an inhalation operation and to move the inhaler within the container. The container is allowed to enter the airflow passage so that more than 60% of the dry powder dose in the container can be 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 at 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 1 to 4 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 PREFERRED EMBODIMENTS

[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 pulmonary fibrosis. administering one or more dry powder compositions to a patient suffering from A dry powder composition comprising nintedanib, pirfenidone and / or treprostinil is and delivery to the pulmonary tract and deep lungs.

[0036] In an exemplary embodiment, the dry powder delivery system comprises a dry powder containing a pharmaceutical agent and an oral A dry, single-use container or cartridge for delivery by inhalation containing a pharmaceutical dose. In one embodiment, the dry powder inhaler is a breath actuated dry powder inhaler. The container or cartridge may contain an active ingredient, including, but not limited to, a pharmaceutical active. and, optionally, one or more pharma- ceutically 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 It can be produced in high volumes in simple steps using materials that are readily available. Dry Powder Various embodiments of the inhaler 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 embodiment, the inhalation system is configured to include a single-use cart that contains pre-metered doses of the dry powder formulation. The present invention provides a reusable miniature breath-actuated inhaler in combination with a cartridge. Pulmonary artery hypertension for less than 10 seconds, or less than 6 seconds, or less than 4 seconds per Ridge session A dry powder dose is delivered in a single inhalation 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, It is possible to deliver more than 60% of the powder dose in less than 100 rpm and in less than 2 seconds.

[0038] As used herein, the term "unit dose inhaler" refers to a single container that contains a dry powder formulation. adapted to receive an inlet receptacle, cartridge or container and adapted to receive aspiration 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 dosage to the user, and the same inhaler can be used for multiple units. Multiple dose sessions for dose delivery and for a pre-determined number of use sessions. It should be understood that the present invention can be used in

[0039] As used herein, a "cartridge" refers to a cartridge configured to hold or contain a dry powder formulation. The container (powder-containing container) is arranged as follows: The cartridge is made of a rigid 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 for holding dry powder and an inhaler. It is possible to achieve a dosage regimen 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 via inhalation. The container may be a single enclosure containing a container with a single dose 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 within the bounds of the device or is used to indicate that it includes the standard deviation of error for the method.

[0043] As used herein, the term "particulate" refers to any particulate material, regardless of its exact external or internal structure. Particles having a diameter of about 0.5 to about 1000 μm. Particles having a diameter of about 0.5 to about 10 microns Microparticles with a molecular weight of about 1.5 or less can easily pass through most of the natural barriers and reach the lungs. A diameter of less than 10 microns is needed to navigate the curvature of the throat and avoid being exhaled. A diameter of about 0.5 μm or greater is required for the most efficient absorption. Aerodynamic diameter of about 0.5 to about 6 μm to reach the deep lung (or alveolar region) where The particles contained in the "respirable fraction" (RF) are generally accepted to be those having It is preferable to maximize the proportion of particles that are in contact with the substrate, but several references, for example Ande Somewhat different from measurements using standard techniques with a rson cascade impactor Other impactors, such as NEXT GENERATION IM Using PACTOR™ (NGI™, MSP Corporation) , the aerodynamic particle size can be measured, and thus the inhalable fraction can be determined by measuring the aerodynamic particle size of the inhaled gas. In some embodiments, the laser diffraction is used to determine the size of the target particle, e.g., <6.4 μm. The disclosure of which is incorporated herein by reference for its relevant teachings relating to instrumentation, such as laser diffraction. No. 8,508,732, which is incorporated herein by reference in its entirety. 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 the airflow rate of 80% or more, 85% or more, or more. or more than 90% empty cartridge and <12.5μm, <7.0μm or The VMGD for emitted particles <4.8 μm may indicate progressively better aerodynamic performance. do.

[0044] The respirable fraction per dose (RF / fill) is the fraction of powder that is filled to be used as a dose. The percentage of powder in the respirable dose that is expelled from the inhaler by the release of the contents (% ), i.e., the percentage of particles from the filled dose that are emitted with a size suitable for pulmonary delivery. It stands for "aerodynamic performance of a particle," which is a measure of the aerodynamic performance of a particle. RF / filling values ​​of greater than 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 loading can be up to about 80%, and about 80% of the loading is the standard Using standard techniques, particles are discharged with a particle size of <5.8μm.

[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 imply.

[0046] As used herein, "amorphous powder" refers specifically to any powder that is non-crystalline. "Dry powder" refers to a dry powder that lacks any distinct repeating form, shape or structure.

[0047] The present disclosure relates to improved powders, compositions, methods of making particles, and methods for preparing particles comprising microcrystalline particles. Therapies enabling improved delivery of drugs to the lungs for treating diseases and disorders in elephants - Patents.com Methods are also provided to reduce the adverse effects caused by 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 particles containing microcrystalline diketopiperazine particles yielding powders having multiple active agents. By providing a piperazine composition, improved delivery is achieved. The co-produced powders were able to deliver increased drug loading in a smaller powder dose. Depending on the starting material, the powder can be: by a variety of methods, including those utilizing surfactant-free or surfactant-containing solutions. It can be produced by the above method.

[0048] In an alternative embodiment disclosed herein, the drug delivery system comprises a plurality of substantially uniform microparticles. The dry powder for inhalation may include crystalline particles, the microcrystalline particles being substantially hollow spheres. The present invention relates to a method for preparing a diketopiperazine crystallite having a crystallite-like structure and which does not self-assemble in suspension or solution. In certain embodiments, the microcrystalline particles may include a shell, which may be porous. Depending on the drug and / or drug content being used and other factors in the process of making the powder, The diketopiperazine crystallites may be substantially hollow spheres or substantially solid particles. 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 about 0.43 cm 3 / g and an average pore volume of about 23 Phases having average pore sizes ranging from about 23.8 nm to about 30 nm or from about 23.8 nm to about 26.2 nm The particles include those that are relatively porous.

[0049] Certain embodiments disclosed herein provide a dried product comprising a plurality of substantially uniform microcrystalline particles. The powder comprises particles having a substantially spherical structure including a shell which may be porous, the particles being , 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 having one or more drugs attached thereto. In some embodiments, the particles entrap the drug in their interior void volume and / or form crystals. The combination of drug adsorbed on the surface of the sphere and drug trapped in the void volume inside the sphere was It is possible.

[0051] In certain embodiments, a diketopiper comprising a plurality of substantially uniformly formed microcrystalline particles. A radiant composition is provided, the particles having a substantially hollow spherical structure and not self-assembled. the particles comprise a shell containing crystallites of a diketopiperazine; the particles are formed by the following method: Trans isomer content in the range of approximately 45% to 65% in solution without the presence of surfactants and mixing the solution of diketopiperazine having the formula: and homogenizing the mixture 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 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. The solution containing the active ingredient, e.g., a drug or biologically active agent, is mixed with other pharma- ceutically acceptable carriers and / or The method may further include adding, while mixing, an active agent or an active ingredient. The active components are adsorbed and / or entrapped on or within the particles. The particles may be in the submicron size range prior to spray drying.

[0053] In certain embodiments, a diketopiper comprising a plurality of substantially uniformly formed microcrystalline particles. A radiant composition is provided, the particles having a substantially hollow spherical structure and not self-assembled. and a shell comprising crystallites of small diketopiperazine, said particles having a volume average geometric mean diameter of 5 μm or less. the particles have a geometrical diameter; the particles can be dispersed in the following manner: The method includes the steps of combining a solution of diketopiperazine and acetic acid in a high shear mixer. The process is then carried out in parallel with homogenization 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 drying the suspension in a spray drying apparatus.

[0054] The method further comprises the step of: adsorbing and / or dissolving the active agent or active ingredient on or within the particles prior to the spray drying step. or to be entrapped, a solution containing an active agent or active ingredient, such as a drug or bioactive agent, is mixed with the The particles produced by this process may further include adding, while mixing, 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. A lazin composition is provided, the microcrystalline particles having a substantially hollow spherical structure and self-assembled. and a shell comprising crystallites of diketopiperazine that do not form a crystallite, the particles 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 any additives and without the presence of an activator. The mixing step is carried out in parallel under high pressure up to 2,000 psi in a high shear mixer. 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 a material having a certain appearance, as described above and Washing them in water using tangential flow filtration before combining with the extract or viscous materials After washing in water, the resulting particle suspension is freeze-dried to remove water. The active ingredient is removed and resuspended in an alcohol solution containing ethanol or methanol. In one embodiment, the composition is optionally added as a solid or in a suspension or solution. The method of preparation includes the step of adding 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 Optional additional additions such as dimethyl-sn-glycero-3-phosphocholine (DSPC) The method includes adding a spray-drying agent either simultaneously with the active ingredient or after the active ingredient is added and before spray drying. In certain embodiments, forming the composition comprises optionally extracting the desired active agent. The mixture is then filtered or winterized to separate and remove undesirable materials, such as the lipid layer, and the solvent. The method includes increasing the hydrolysis rate.

[0057] The method may further include adding the solution to the mixture while mixing, the mixing being at high shear. The homogenization may be performed with or without homogenization in a mixer, and the active agent or active ingredient may be mixed with the granules. The solution is pre-sprayed prior to the spray drying step so that the active ingredient is adsorbed and / or captured within or on the surface of the polymer. The process includes a therapeutic agent or active ingredient, such as a drug or a bioactive agent. The particles may be in the submicron size range prior to 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 of more than 1000 mg / kg. The microcrystalline particles formed by the method are not self-organized, and the particles are submicron-sized. In embodiments that include 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% microcrystalline particles containing the drug In an exemplary embodiment in which 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 a dry powder composition, The morphology and size of the drug particles achieved may vary.

[0059] In an exemplary embodiment, the method of treating interstitial lung disease comprises administering a 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, isoform, It may contain one or more excipients 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. By having the patient self-administer an effective dose containing about 1 mg to 15 mg of the dry powder composition. and may be used in the prevention and treatment of pulmonary fibrosis or pulmonary hypertension and interstitial lung disease. In this embodiment, the content of treprostinil in the formulation may be about 1 μg to about 200 μg. In an embodiment, 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 pharma- ceutically acceptable carrier for making the dry powder comprises 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, 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 Contains phospholipids including diphosphatidylcholine, etc.

[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, the method comprising 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 to place the cartridge or capsule. and closing the inhaler and moving the cartridge to the dosing position; and closing the mouthpiece. Delivering a dry powder formulation to the human lungs in less than six seconds via a single deep inhalation Includes.

[0062] In another embodiment, diketopiperazine-based microparticles are used as carriers or additives. A method for treating an interstitial lung disease, 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) In this embodiment, the method comprises administering an inhalable dry powder composition or formulation comprising ketopiperazine. 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, comprising a diketopiperazine. , 2,5-diketo-3,6-di-(4-fumaryl-aminobutyl)piperazine, The composition may be administered in the presence or absence of 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) per liter per minute. and a high resistance dry powder inhaler configured to have a flow conduit having a total resistance to flow. Dry powder inhalers include single-use dry powder inhalers that can be disposed of after use. The powder formulation may be provided in a powder formulation or may be provided as replaceable individual particles within a multi-use inhaler. and the individual dose enclosures or containers can be disposed of after use. Individual dose cartridges containing the powdered formulation may be provided in individual packages or Multiple cartridge doses may be provided in a blister package.

[0064] In one embodiment, the 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 mellitus and One or more of the dry powder formulations for treating other systemic diseases such as endocrine disorders such as obesity. A dry powder inhalation kit is provided that includes a plurality of medication cartridges.

[0065] The disclosed embodiments of the dry powder inhaler are intended to treat a disease or disorder in a patient. The method of treatment comprises administering to a patient in need of treatment a compound selected from the group as described above. and a pharma- ceutically acceptable carrier and / or excipient. providing a dry powder inhaler comprising 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 for 1 week, 2 weeks, 3 weeks, and up to administration of nintedanib to patients for a maximum period of 2 months; 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 quinine kinase inhibitor comprising a tyrosine kinase inhibitor. and a ribozyme inhibitor molecule of the formula: [ka] and optionally one or more pharmaceutical agents as defined above in relation to the formulation. and administering to the patient an inhalable composition comprising an excipient or carrier, the composition comprising an inhalant and a therapeutic agent for treating an 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, la Patinib, nilotinib, pazopanib, panatinib, regorafenib, ruxolitinib, so These include rafenib, sunitinib, vandetanib, and vemurafenib.

[0067] The following examples are examples of dry powder formulations 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: EXAMPLES

[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 0% nintedanib) is nintedanib (0.025 g) at 10% (w / w w) Acetic acid solution (0.225 g) (The concentration of the acetic acid solution is in the range of 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 A crystalline particle (XC) suspension (1.31% solids, 188.93 g) was added to the suspension (XC suspension The solids content of the liquid may 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% Nintedanib XC (w / w) 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 (3.33 g * ) dissolved in 20% acetic acid Add 29.97 g of acetic acid (the concentration of the acetic acid solution can range from 10% to 100% acetic acid). Separately, the XC suspension was prepared by mixing 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), for example, nintedanib (0.025 g) (nintedanib Tedanib charge can range from 0.025 g to 0.50 g) in 10% acetic acid solution (0 0.225 g) (the concentration of the acetic acid solution can range from 10% to 100% acetic acid). The nintedanib solution was prepared by dissolving 3,6-bis(N-fumaryl- added to a suspension of preformed particles of 4-aminobutyl-2,5-diketopiperazine. (T suspension; 8.11% solids, 30.52 g) (The solids content of the T suspension is 0.5% to 20 The nintedanib T suspension is then spray-dried or freeze-dried. The powder was dried by spray drying to produce 1% Nintedanib T powder. The powder was dried by spray drying 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 samples were 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 at 25°C under vacuum until it was 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 (3.33 g * ) 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 solutions were 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 freeze-dried 20% Nintedanib T powder 10% nintedanib solution (the concentration of nintedanib in this solution is 1% nintedanib to 1 0% nintedanib) is nintedanib (2.63 g * ) 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 mixing it with 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 first pelleted in liquid nitrogen, followed by V The freeze-dried samples were frozen by drying in an irtis Genesis 25XL shelf freeze dryer. The freeze-drier was operated according to a program, and the shelf temperature was changed from -45°C 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 (3.09 g * ) 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 * ) The solid content of the suspension was 0.5% to 20% (w The nintedanib solution was added to this diluted T suspension and diluted with water to a concentration of 5.00 mL / w. The Nintedanib T suspension was obtained having a solid content of: 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, and then the powder was The powder was kept at 25°C under vacuum until completely dry, resulting in a yield of approximately 15 g. there were.

[0075] Preparation of freeze-dried 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 (3.09 g * ) 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 prepared by diluting it with deionized water (97.19 g). Then, the freeze-dried T particles (11.91 g * ) into the nintedanib solution in small portions for 4 minutes. Deionized water (10.00 g) was used to wash the remaining lyophilized T particles. The nintedanib T suspension was first washed in liquid nitrogen. First pelleted, then freeze-dried in a Virtis Genesis 25XL shelf freeze dryer. The freeze-drier was operated according to a program and the shelf temperature was 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 Essilate T powder 1% Nintedanib Essilate Solution (The concentration of Nintedanib Essilate in this solution is 1 % nintedanib esylate to 5% nintedanib esylate) Danib esylate (3.61g * ) into deionized water (357.39 g) little by little. The nintedanib esylate solution was prepared by dissolving in T suspension (8.99% solids, 126 .70g * ) (the solids content of the suspension may range from 0.5% to 20%), The nintedanib esilate T suspension obtained as above 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 at 25° C. under vacuum until it was completely dry. The resulting yield was It weighed about 15g.

[0077] Powder Testing The powders were analyzed using 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 pressurized at 0.5 bar and 3. The powders were dispersed in an Andersen Cascade Impactor (ACI) at 10 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 fill) through the ACI. Data for the powder is shown in Table 2.

[0078] [Table 2] [Table 3]

[0079] As can be seen in Table 2, the process product yields were 100% for the spray-dried or freeze-dried dry powder. For both, the composition reactants had a concentration of more than about 67%. Furthermore, regardless of the method for making the powder, The composition contains 10% and 20% nintedanib by weight of freeze-dried T powder and the composition. It can be seen that the percent yield improved for all powders with The average mass delivered from the delivery system as measured by cartridge emptying (CE) measurements. Powders were >75% for all XC powders and spray-dried T powders and >75% for all freeze-dried The results showed that the C value for the selected T powders was 62% or more, and some powders had a C value of more than about 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 is also shown 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 may range from 0.01% to 40% pirfenidone) The pirfenidone charges 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, Up to a 50:50 weight ratio of ethanol:water (water could be added to ethanol) The pirfenidone solution was prepared by mixing the microcrystalline (XC) suspension (1.31% The solid content of the XC suspension ranged from 0.5% to 5%. The pirfenidone XC suspension was sprayed with Buchi B-290 under the conditions shown in Table 1. A dryer was used for spray drying to produce pirfenidone XC powder.

[0081] Preparation of crystalline pirfenidone powder 25% pirfenidone solution (the concentration of pirfenidone in this solution is 1% pirfenidone pirfenidone (0.20 g) (which may range from 0.01% to 40% pirfenidone) The pirfenidone charges 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 100% ethanol to the ethanol solution. The liquid was dissolved in 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 freeze dried. The powder was dried by drying to produce Pirfenidone T powder. The spray dried powder had the following properties as shown in Table 1. 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 The samples were 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 cooled to room temperature and kept at 25° C. under vacuum 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 charges used to prepare these powders ranged from 0.2 g to 0.22 g. When ethanol (0.60 g) (25% pirfenidone solution) was used, Up to a 50:50 weight ratio of ethanol:water (water could be added to ethanol) Separately, a 10% FDKP disodium salt solution was prepared. isine (leucine charge ranged from 0 g to 0.45 g) and FDKP-dihydroxybenzoate The FD 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. It was fog dried to produce pirfenidone amorphous powder.

[0084] The above disclosure is an exemplary embodiment. Those skilled in the art will recognize that the present invention provides 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 Numerous modifications may be made to the present invention, including but not limited to the above, 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 following statements in this specification and elsewhere herein express the amounts, characteristics, 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 the accompanying patents The numerical parameters set forth in the claims may vary depending upon the desired properties sought to be obtained. These are approximations that may vary depending on the nature of the claims. And not as an attempt to approximate, each numerical parameter has been reported to the number of significant digits. 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. Figures are reported as accurately as possible.

[0086] Any numerical values, however, necessarily vary from the standard deviation found in their 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 The terms "a," "an," and "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 The recitation of ranges of values ​​herein is intended to encompass each and every individual value falling within the range. They are merely intended to serve as a shorthand way of referring to individual values. Unless otherwise indicated, each individual value is as if it were individually listed herein. All methods described herein are incorporated herein by reference in their entirety. Unless otherwise indicated or 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 construed as limiting the scope of what is otherwise claimed. No limitation is imposed on the language in this specification that is essential to the practice of the invention. The accompanying drawings should not be construed as indicating any incompatibilities or limitations in the present specification or the accompanying drawings.

[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 that the terms are mutually exclusive. However, the present disclosure supports a definition that refers 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 any of the following for convenience: and / or may be included in or removed from a group for patentability reasons. When an inclusion or deletion occurs, the specification will be considered to include the group as amended herein. Therefore, the written description of all Markush groups used in the appended claims is is deemed 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 embodiments are possible. The embodiments will be apparent to those of skill in the art upon reading the above description. The inventors anticipate that such modifications may be used as necessary, and have made the following modifications as specifically described herein. It is intended that the invention be practiced otherwise than as described. As permitted by law, all of the subject matter recited in the claims appended hereto is intended to be included herein. Moreover, the above elements in all possible variations thereof are intended to be included within the scope of the present invention. Any combination of is intended to be used unless otherwise indicated herein or otherwise clearly contradicted by context. Insofar as this is the case, it is encompassed by the present invention.

[0091] Certain embodiments disclosed herein are described as "consisting of" or "consisting essentially of." The claims may be further defined using the following language: The transitional phrase "consisting of," whether added by application or by amendment, shall Exclude any element, step, or ingredient not specified in the claim. "becomes" refers to a claim that is substantially directed to specific materials or steps and basic, novel features. The embodiments as claimed herein are limited to those which do not affect the is 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] Moreover, it is to be understood that the embodiments disclosed herein are illustrative of the principles of the present invention. Other modifications that may be used are within the scope of the present invention. By way of example, and not of 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: 【Chemistry 1】 and optionally a pharma- ceutically acceptable carrier and / or excipient.

13. An inhalable pharmaceutical composition comprising:

2. The dose is in an amount of up to 50 mg and may contain one or more pharma- ceutically acceptable salts thereof. and a pharma- ceutical acceptable carrier and / or excipient. composition.

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

4. The diketopiperazine has 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 said compound.

6. 2. 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 be 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 pharma- ceutically acceptable carriers and / or excipients.

2. The inhalable pharmaceutical composition according to claim 1.

8. The dry powder may contain sodium citrate, sodium chloride, leucine or isoleucine, and and trehalose; and / or 8. 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 are approximately 25 m ２ / g ~ approx. 63m ２ / g range of specific surface area.

5. An inhalable pharmaceutical composition according to claim 4.

11. 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 that is capable of being administered by oral inhalation. and up to 50 mg of a compound of the formula: 【Chemistry 3】 and optionally a pharma- ceutically 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 dry powder inhaler prior to use. The patient is provided with one or more capsules or cartridges for administering the therapeutic agent to the patient, each capsule Or 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 said compound.

15. Fumaryl diketopiperazine, lactose, mannose, sucrose, mannitol, Rehalose, 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 pharma- ceutically acceptable carriers selected from the group consisting of The method of claim 12 further comprising:

16. The one or more pharma- ceutically acceptable carriers and / or excipients may be sodium citrate. , sodium chloride, leucine or isoleucine, or trehalose. The method described above.

17. The one or more pharma- ceutically acceptable carriers and / or excipients may be fumaryl diketopiperidine.

12. The method of claim 11, wherein the compound is radinidine.

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 a dosage arrangement.

13. A dry powder inhaler comprising:

13. A dry powder inhaler comprising:

20. The enclosure includes a cartridge consisting of a lid and a container, and the dry powder dose is comprised of a compound having 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 pharma- ceutically 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 that is capable of being administered by oral inhalation.

21. A method comprising administering an inhalable pharmaceutical composition according to claim 20.

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