Methods and compositions for treating pulmonary disease

Abstract

Methods, compositions and kits are disclosed for the treatment of fibrotic lung disease.The methods utilize a combination product for inhalation, which comprises a therapeutic amount of a dry powder formulation provided in an inhaler for administration to a subject in need by oral inhalation.The composition comprises diketopiperazine particles and a kinase inhibitor for oral inhalation.Methods and compositions for the treatment of lung disease and / or disorders, including interstitial lung disease, such as idiopathic pulmonary fibrosis, are disclosed herein.

Description

[Technical field]

[0001] Technical Field The present disclosure relates to methods, compositions, and kits for the therapeutic treatment of pulmonary diseases or disorders, including interstitial lung disease (e.g., idiopathic pulmonary fibrosis). In particular, the methods, compositions, and kits include combination products that include a dry powder contained in a cartridge for use with an inhaler, the dry powder being for administration to a patient by oral inhalation. [Background technology]

[0002] background Idiopathic pulmonary fibrosis (IPF) is a chronic lung disease of still unknown cause, and there is no cure for IPF. 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 belongs to a group of conditions called interstitial lung disease (ILD), which describes lung diseases that involve inflammation and scarring in the lungs. The most common signs and symptoms of IPF are shortness of breath and a persistent dry cough. Subjects affected by IPF also experience loss of appetite and gradual weight loss. In individuals with IPF, lung scarring increases over time until the lungs can no longer provide enough oxygen to the body's organs and tissues.

[0003] Currently, there are no procedures or drugs that can eliminate the progressive scarring of lung tissue. Therefore, it is important to learn good coping skills and educate patients about the disease. In general, treatments are designed to slow the progression of scarring in the lungs, and they may not necessarily reduce the symptoms of coughing and shortness of breath associated with the disease. Oral tablets of pirfenidone and nintedanib treatment have been shown to slow the progression of IPF; however, some patients cannot tolerate these drugs due to side effects at the dosages required to slow the progression. Because high doses are repeated and required to slow the disease progression, there are too many adverse effects, including gastrointestinal such as nausea, diarrhea, abdominal pain, vomiting; hepatobiliary system, nervous system, vascular system, metabolism and nutrition disorders.

[0004] There are some additional drugs that are useful for improving the symptoms of IPF, including shortness of breath and cough. Some of these drugs include, for example, antacids to prevent gastroesophageal reflux and opioids to treat shortness of breath. Oxygen therapy and exercise training to increase oxygen levels are recommended for patients with IPF, as well as education and support for people with chronic conditions to provide them with pulmonary rehabilitation. In addition, one major and invasive treatment is to provide the patient with a lung transplant. Therefore, there is a need to improve or provide patients with IPF with alternative new treatment methods to treat the disease.

[0005] Drug delivery to lung tissue is achieved using various methods and administration routes.For example, oral drug delivery, or enteral (e.g., tablets and capsules containing the above-mentioned drugs) and parenteral (including targeted drug injection) to treat the above-mentioned diseases or symptoms of the above-mentioned diseases.Devices for inhalation (including nebulizers and inhalers, such as metered dose inhalers and dry powder inhalers) are also used to treat local respiratory or pulmonary diseases or disorders.

[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 of use and / or manufacturing costs. Some of the persistent problems observed with prior art inhalers include lack of device durability, inconsistency in dosing, inconvenience of the equipment, and poor deagglomeration of the powder. In some devices, treatment is limited by the need to use harmful propellants to deliver the dose, and high manufacturing costs and / or lack of patient compliance discourage their production. Furthermore, delivering the active ingredient directly to the target organ may reduce the dose and cause fewer side effects than other routes of administration. Thus, the inventors have identified a need to design and manufacture new formulations and inhalers that provide consistent or improved powder delivery characteristics, have separate configurations that are easy to use and allow good patient compliance. Summary of the Invention [Means for solving the problem]

[0007] Abstract Disclosed herein are methods and compositions for the treatment of pulmonary diseases and / or disorders, including interstitial lung diseases, such as idiopathic pulmonary fibrosis.

[0008] In the present embodiment, the dry powder composition is provided in a dry powder inhaler, which comprises a replaceable cartridge or capsule that contains a pharmaceutical dry powder formulation for inhalation for delivery to the lungs, for local or systemic delivery to the pulmonary circulation.The pharmaceutical formulation comprises a dry powder for inhalation that contains a protein kinase inhibitor, for example, an organic small molecule and diketopiperazine particles for pulmonary delivery.A dry powder inhaler is also provided, which is a small, reusable or disposable breath-powered inhaler for use in the effective and rapid delivery of powdered medicine to the lungs and systemic circulation of an individual.

[0009] In certain embodiments, the method of treating idiopathic pulmonary fibrosis comprises providing a drug delivery system designed for pulmonary drug delivery by oral inhalation for rapid delivery and onset of action of the active agent delivered to lung tissue to reach the alveoli and systemic circulation in the lungs. In the method, the active agent molecule can reach its target site in a therapeutically effective manner and with fewer adverse effects. In one embodiment, the method of treatment comprises treating or administering to a patient diagnosed with a pulmonary disease or disorder, particularly a pulmonary fibrotic and / or inflammatory disease (including idiopathic pulmonary disease, e.g., idiopathic pulmonary fibrosis), and in need of treatment, a therapeutic dose of a dry powder formulation comprising one or more kinase inhibitors for treating the disease. In one embodiment, the dose of dry powder is delivered to the lungs using a dry powder inhaler, where the kinase inhibitor can reach the deep lung. In one embodiment, the pharmaceutical composition is self-administered by the patient with one or more breaths using a breath-actuated dry powder inhaler for inhalation from the mouth or nose. The delivery system may reduce the adverse effects caused by oral tablets or capsules, including gastrointestinal side effects such as nausea, diarrhea, abdominal pain, vomiting; hepatobiliary, neurological, vascular, metabolic and nutritional disorders. In one embodiment, the method further comprises administering to the subject in need of treatment a stable pharmaceutical composition comprising one or more active agents for delivery to lung tissue, wherein the one or more active agents can be formulated together or can be formulated separately to be administered separately and at different intervals during treatment.In certain embodiments, the pharmaceutical composition comprises a formulation for inhalation comprising a therapeutically effective dose of dry powder comprising one or more active agents, including small molecules (e.g., nintedanib, imatinib, pirfenidone, analogs thereof, and / or derivatives thereof (including prodrugs)), which inhibits the mechanism of scar formation in the lungs of patients being treated for such conditions.

[0010] In an exemplary embodiment, a dry powder formulation for inhalation is provided that includes a small molecule, including an inhibitor of scar formation in the lung for treating fibrotic disease. In one embodiment, the kinase inhibitor prevents scarring or inflammatory cascade reaction by binding to membrane receptors with kinase activity on the surface of cells, which results in the inhibition of scar formation in lung tissue. In one embodiment, a dry powder formulation is provided that includes a diketopiperazine and a kinase inhibitor compound that is targeted against key protein kinases in cells to regulate abnormal gene expression and inhibit phosphorylation of certain cell signaling pathways that cause fibrotic disease, especially in the lung. In an embodiment, the kinase inhibitor compound is targeted against kinase molecules, including kinases that transfer γ-phosphate groups from adenosine triphosphate (ATP) to serine, threonine, or tyrosine amino acid residues. In a particular embodiment, the pharmaceutical composition for treating pulmonary disease includes a kinase inhibitor that is classified as a type I inhibitor.

[0011] In one embodiment, the inhalable pharmaceutical composition may include one or more pharma- ceutically acceptable carriers and / or excipients, which are surfactants, amino acids, and / or phospholipids, or combinations thereof.

[0012] In a preferred embodiment, the inhalable pharmaceutical composition for treating ILD (including IPF) comprises one or more active agents and a compound of the formula: [ka] In one embodiment, the inhalable pharmaceutical composition comprises a diketopiperazine having the formula: [ka] wherein the Compound I content in the dosage form ranges from about 1 mg to about 100 mg, or up to about 150 mg (w / w) in the dry powder composition, and wherein the dosage is administered once or more per day. In another embodiment, the dosage may comprise a Compound I content in a therapeutic dosage that may include about 0.5 mg to about 9 mg, about 1 mg to about 7.5 mg, about 15 mg to about 50 mg, about 20 mg to about 60 mg, or about 1 mg to about 20 mg.

[0013] In some embodiments, the inhalable pharmaceutical composition comprises a dry powder comprising one or more pharma- ceutically acceptable carriers and / or excipients selected from 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, microcrystalline cellulose, polyvinylpyrrolidone, and polysorbate 80, or combinations thereof.

[0014] In other embodiments, the inhalable pharmaceutical composition comprises a dry powder comprising one or more pharma- ceutically acceptable carriers and / or excipients selected from the group consisting of sodium citrate, sodium chloride, leucine or isoleucine, and trehalose, or combinations thereof.

[0015] In certain embodiments, the inhalable pharmaceutical composition is administered in an amount of about 20 ml. 2 / g ~ approx. 63m 2 / g, approx. 10m 2 / g ~ approx. 35m 2 / g; approx. 15m 2 / g ~ approx. 30m 2The microcrystalline particles of 3,6-bis(N-fumaryl-4-aminobutyl)-2,5-diketopiperazine having a specific surface area ranging from about 23 nm to about 30 nm.

[0016] A method for treating interstitial lung disease (including idiopathic pulmonary fibrosis) comprises administering to a subject in need of treatment, per inhalation session, diketopiperazine particles and 1 mg to 10 mg; 10 mg to 20 mg; 20 mg to 30 mg, 30 mg to 50 mg; 50 mg to 100 mg; 100 to 150 mg; or 150 to 300 mg of a formula: [ka] The present invention includes administering by oral inhalation a dry powder composition comprising a compound of the formula (I), a pharma- ceutically acceptable salt thereof, a derivative thereof, and optionally a pharma- ceutically acceptable carrier and / or excipient, wherein the dry powder composition is provided in a single-dose cartridge in a dry powder inhaler. In one embodiment, multiple cartridges can be provided to the patient for a given dose, depending on the patient's needs.

[0017] In the embodiment herein, where the method comprises pirfenidone, the patient is administered a therapeutically effective dose of the dry powder composition, which is provided to the patient separately in a blister or pouch with one or more capsules or cartridges for fitting into a dry powder inhaler before use, where each capsule or cartridge contains up to 30mg or 50mg of the compound.In one embodiment, the therapeutically effective dose per day can include up to 500mg; up to 750mg; up to 1,000mg or up to 2,500mg wt% of the compound per day, which is provided in multiple cartridges for inhalation with a dry powder inhaler.The administration can be performed in one or more dosing sessions.

[0018] In this and other aspects, the methods utilize compositions comprising one or more pharma- ceutically acceptable carriers and / or excipients selected from the group consisting of fumaryl diketopiperazine, 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 surfactants (e.g., polysorbate 80).

[0019] In an alternative embodiment, the method for treating interstitial lung disease (including idiopathic pulmonary fibrosis) comprises administering to a subject in need of treatment a pharma- ceutically effective amount of a dry powder comprising compound I of formula 2[4-methyl-1-(6-methylpyridin-2yl)-1H-pyrazol-5-yl]thieno-[3,2 c]pyridine, a pharma- ceutically acceptable salt thereof, an analog thereof, and / or a prodrug thereof, wherein the one or more pharma- ceutically acceptable carriers and / or excipients are sodium citrate, sodium chloride, leucine or isoleucine, or trehalose.

[0020] In one embodiment, the method of treating pulmonary fibrosis comprises administering to a patient in need of treatment a diketopiperazine and Compound I, optionally a compound of the formula: [ka] or a pharma- ceutically acceptable salt thereof (including esylate), and optionally one or more pharma- ceutically acceptable carriers and / or excipients; wherein said diketopiperazine is in amorphous, crystalline, or crystalline multiparticulate form, or a combination thereof, and said diketopiperazine has the formula: [ka] has.

[0021] In an exemplary embodiment, a method for treating interstitial lung disease and, in particular, idiopathic pulmonary fibrosis, comprises administering to a patient in need of treatment an inhalable pharmaceutical dry powder comprising a compound of formula I, or compound II (nintedanib), by oral inhalation using a dry powder inhaler having a cartridge containing a dose of said dry powder, or a container that includes a movable member for attaching a capsule and that can obtain a dosing configuration upon loading into the inhaler, wherein said cartridge contains the dry powder composition to be inhaled. In one embodiment, said dry powder inhaler cartridge consists of a cap and a container, and a dry powder dose provided separately prior to use. In one embodiment, nintedanib or another kinase inhibitor provided to a patient is in an amount of 1 mg, 3 mg, 5 mg, 7 mg, 8 mg, 9 mg, 10 mg, 15 mg, 20 mg of powder, which constitutes 1% to about 40% (w / w), about 5% to 10%, about 10% to about 20%, 20 to 30%, or 30% to about 40% or more. In some embodiments, the amount of kinase inhibitor in the dry powder is about 5%, 10%, 15%, 20%, 25%, 30%, 35% or 40% (w / w) nintedanib in the composition. In another embodiment, the amount of nintedanib to be administered to a patient comprises one or more cartridges containing a dry powder composition of nintedanib per dose session, where the disease is pulmonary fibrosis. In another embodiment, the dry powder containing nintedanib or other kinase inhibitor compounds is stable at room temperature (25°C / 60% relative humidity) for a period of at least one year. In this and other embodiments, the kinase inhibitor dry powder composition can be stored at room temperature for up to one year, two years, three years or longer. In this embodiment, the dry powder containing nintedanib can be stored in a blister package. The dry powder is also stable for use at higher temperatures, eg, in warm climates, due to its stability, eg, at temperatures of 40° C. and 70% relative humidity, for up to about 10-12 weeks.In one embodiment, the dry powder comprises a kinase inhibitor, for example, Compound I may comprise about 1 wt% to about 65 wt%, 1 wt% to about 60 wt%, or about 25 wt% to about 60 wt% in the composition.

[0022] In certain embodiments, a method of treating IPF comprises providing to a patient in need of treatment an inhaler and one or more cartridges containing a dose of a dry powder composition, and having the patient inhale the contents of the one or more cartridges from each of the one or more cartridges, wherein the one or more cartridges contain a dose of the formula: [ka] wherein the dry powder composition comprises particles of a pharma- ceutical acceptable excipient having the formula 3,6-bis(N-fumaryl-4-aminobutyl)-2,5-diketopiperazine. In one embodiment, the method includes having the patient inhale for at least 4 to 10 seconds, or 2 to 6 seconds, per inhalation using a high resistance dry powder inhaler having a resistance value of about 0.05 to about 0.200 (kPa) / liter / min.

[0023] In some embodiments, a method of treating interstitial lung disease (including pulmonary fibrosis) comprises administering to a subject in need of treatment a pharmaceutical composition comprising Compound I and / or Nintedanib (Compound II) separately, sequentially, or in combination with one or more of the following vasodilator compounds. In one embodiment, the method comprises a combination therapy comprising administering to the subject a vasodilator comprising one or more of the following: sildenafil, tadalafil, vardenafil, prostaglandins, prodrugs thereof, prostaglandin derivatives, prostaglandin analogs (e.g., treprostinil), or pharma- ceutically acceptable salts of these compounds (including treprostinil sodium), or prodrugs thereof. In certain embodiments, the method comprises simultaneously treating interstitial lung disease and pulmonary arterial hypertension by delivering a combination therapy comprising a dry powder formulation comprising Compound I and / or Nintedanib (Compound II) and / or a dry powder composition comprising a vasodilator compound (including treprostinil), or a pharma- ceutically acceptable salt of these compounds (including treprostinil sodium, or one or more of their prodrugs) to the patient's lungs and into the subject's circulatory system by pulmonary inhalation using a dry powder inhaler.

[0024] In one embodiment, the method includes providing a patient in need of treatment with a dry powder inhaler containing the active agent, such as compound I, nintedanib (compound II), pirfenidone, or treprostinil, in a stable dry powder formulation, and administering the active agent by oral inhalation.In one embodiment, the vasodilator can be formulated together with pirfenidone, nintedanib in the same formulation, or can be formulated separately, administered separately in its own formulation, and provided to the patient at different intervals during a dosing session, or sequentially.

[0025] In one embodiment, the drug delivery system comprises a dry powder inhaler containing a diketopiperazine-based drug formulation for delivering small molecules (e.g., Compound I, pirfenidone, nintedanib (Compound II), prostaglandins, or pharma- ceutically acceptable salts, prodrugs, or analogs thereof, including treprostinil) and a protein-based product for treating pulmonary fibrosis and PAH. The method offers advantages over typical methods for drug delivery (e.g., oral tablets and subcutaneous and intravenous injection / infusion drug products that are susceptible to degradation and / or enzymatic inactivation).

[0026] In certain embodiments disclosed herein, a method for treatment is provided, which comprises providing prostaglandin, treprostinil, or the pharmacologic acceptable salt of these compounds (including treprostinil sodium), or its prodrug or its derivative, in dry powder formulation to the patient with pulmonary fibrosis and PAH.The method comprises the steps of selecting the patient to be treated for PAH and interstitial lung disease, and administering to the patient a dry powder formulation comprising compound I, nintedanib, pirfenidone, or treprostinil or treprostinil salt or its derivative; wherein the treprostinil is combined with diketopiperazine microcrystalline particles to produce a pharmaceutical formulation or composition suitable for pulmonary inhalation, and having the patient inhale from an inhaler comprising the composition, and using a breath-actuated dry powder inhaler to deliver the treprostinil formulation. In this and other embodiments, the dry powder formulation is provided in a reconfigurable cartridge containing about 1 μg to about 200 μg of treprostinil or a salt thereof in the dry powder formulation per dose. In certain embodiments, the dry powder formulation may contain about 10 μg to about 300 μg of treprostinil per dose in a cartridge or capsule. In one embodiment, a cartridge for single use may contain about 10 μg to about 90 μg of treprostinil for at least one inhalation. In some embodiments, the dry powder formulation is delivered using at least one inhalation per use. In this and other embodiments, the dry powder formulation is delivered to a patient in less than 10 seconds, less than 8 seconds, or less than 6 seconds per inhalation or breath. In one embodiment, the pharmaceutical dry powder composition comprises microcrystalline particles of fumaryl diketopiperazine, wherein the particles are about 59 μg to about 90 μg of treprostinil. 2 / g ~ approx. 63m 2 / g and has a pore size ranging from about 23 nm to about 30 nm.

[0027] Also disclosed herein is a method of treating pulmonary fibrosis concurrent with a pulmonary arterial hypertension disease or disorder, comprising the steps of selecting a patient to be treated having pulmonary arterial hypertension or having PAH (which exhibits a condition treatable with an active agent (including treprostinil, epoprostenol, bosentan, ambrisentan, macitentan, sildenafil, tadalafil, riociguat, etc., analogs thereof, or combinations thereof)), wherein the patient is treated exclusively by oral or injection administration, and replacing the aforementioned treatment with an inhalation therapy comprising providing the patient with an inhaler comprising the active agent in a stable dry powder composition to treat the disease or disorder, wherein the stable dry powder composition comprises the active agent and a diketopiperazine; and administering the stable dry powder composition to the patient by pulmonary inhalation; thereby treating the disease or condition.

[0028] In an exemplary embodiment, a formulation for treating pulmonary arterial hypertension and / or interstitial lung disease comprises treprostinil or a salt thereof in an amount of up to 200 μg per dose, e.g., 1 μg, 5 μg, 10 μg, 15 μg, 20 μg, 30 μg, 60 μg, 90 μg, 100 μg, 120 μg, 150 μg, 180 μg, 200 μg, or 300 μg, and one or more pharma- ceutically acceptable carriers and / or excipients per dose are administered to a subject. In this embodiment, the pharma- ceutically acceptable carrier and / or excipient may be formulated for oral inhalation, may form particles, and may include one or more of diketopiperazines (including fumaryl diketopiperazine), sugars (e.g., mannitol, xylitol, sorbitol, and trehalose); amino acids (including glycine, leucine, isoleucine, methionine); surfactants (including polysorbate 80); cationic salts (including mono-, di-, and trivalent salts including sodium chloride, potassium chloride, magnesium chloride, and zinc chloride); buffers (e.g., citrate and tartrate), or a combination of one or more carriers and / or excipients, and the like. In certain embodiments, the formulation comprises a dry powder comprising treprostinil, a sugar, and an amino acid, where the sugar is mannitol or trehalose; and the amino acid is leucine or isoleucine and a cationic salt. In certain embodiments, the formulation may further comprise sodium chloride, potassium chloride, magnesium or zinc chloride, sodium citrate, sodium tartrate, or a combination thereof.

[0029] In an exemplary embodiment, the combination therapy comprises a method for treating interstitial lung disease, comprising administering a dose of nintedanib or treprostinil to a patient, wherein the nintedanib dose is administered in the same inhaler provided in different cartridges, or from a different inhaler provided in its own cartridge, wherein the treprostinil dose or the nintedanib dose is administered using a dry powder inhaler for oral inhalation.In this embodiment, a treprostinil inhalation powder dose is provided to a patient suffering from pulmonary arterial hypertension and in need of treatment; wherein the dry powder inhaler comprises a container containing a cartridge, the container or cartridge comprises a dry powder containing treprostinil, and the treprostinil is administered in multiple daily doses over a period of 6 months, and the treprostinil is administered by oral inhalation to a patient with functional class II as a first-line monotherapy earlier in the course of the disease.

[0030] In alternative embodiments, dry powders for inhalation may be formulated with other carriers and / or excipients other than the diketopiperazine, such as sugars (including trehalose); buffers (including sodium citrate); salts (including sodium chloride and zinc chloride), and one or more active agents (including treprostinil, vardenafil, and sildenafil).

[0031] In embodiments herein, a method of treating interstitial lung disease in a patient who also has PAH includes administering to a patient with moderate to severe PAH a dry powder formulation comprising an active agent (including treprostinil) and a pharma- ceutically acceptable carrier and / or excipient (including a diketopiperazine), wherein the treprostinil is in an amount of up to 200 μg per dose per dosing session, and wherein the formulation is administered once or more daily using a dry powder inhaler.

[0032] In one embodiment, the dry powder inhaler includes a movable member for loading a container containing the pharmaceutical composition, the movable member may configure the container to obtain a dosing configuration from a container-loaded configuration such that the inhaler creates an airflow through the inhaler during an inhalation maneuver to allow the contents of the container to enter an airflow path, and more than 60% of the dry powder dose in the container is delivered to the lung in one inhalation. In one embodiment, the method includes administering a second dry powder composition comprising one or more of the aforementioned active agents.

[0033] In some embodiments, the treatment regimen using inhaled dry powder depends on the patient's needs and can be one inhalation to replace each of the nebulization sessions performed with standard treatment (including at least 1-4 inhalations per day depending on the severity of the disease). [Brief description of the drawings]

[0034] [Figure 1] 1 shows a graphical representation of data from room temperature stability studies collected from a composition of the present invention comprising T powder formulated with nintedanib at a loading of 20% in the composition. Samples were assayed at various times after incubation at 25° C., 60% RH for a period of one year.

[0035] [Diagram 2] Figure 2 shows a graphical representation of data obtained from room temperature stability studies collected from compositions of the invention containing nintedanib free base as a control for the samples in Figure 1. Samples were assayed at various times after incubation at 25°C, 60% RH for a period of one year.

[0036] [Diagram 3]3 shows a graphical representation of data obtained from room temperature stability studies collected from compositions of the present invention comprising T powder formulated with nintedanib at a loading of 20% in the composition. Samples were assayed at various times after incubation at 40° C., 75% RH for a period of 12 weeks.

[0037] [Figure 4] Figure 4 shows a graphical representation of data obtained from room temperature stability studies collected from compositions of the invention containing nintedanib free base as a control for the samples in Figure 1. Samples were assayed at various times after incubation at 40°C, 75% RH over a 12 week period.

[0038] [Diagram 5] Figure 5 shows a graphical representation of data obtained from a pharmacokinetic study carried out in Sprague Dawley rats using an exemplary dry powder comprising Compound I as described herein. The dry powder of the present invention was administered by insufflation in the circles on the graph. For comparison, data also shows samples from animals administered Compound I via IV injection (squares). DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0039] Detailed Description In an embodiment, disclosed herein is a method for treating interstitial lung disease, particularly pulmonary fibrosis, in a patient with disease (including pulmonary fibrosis).In one embodiment, the method comprises administering one or more dry powder compositions to a patient in need of treatment using a dry powder inhaler, and delivering the dry powder composition comprising compound I, nintedanib, pirfenidone, and / or treprostinil to airways and deep lung.

[0040] In an exemplary embodiment, the dry powder delivery system comprises a dry powder inhaler for single use of a pharmaceutical dose in a container or cartridge for delivering the dry powder (including pharmaceutical medicament) to a subject by oral inhalation. In one embodiment, the dry powder inhaler is a breath-actuated dry powder inhaler, and the container or cartridge is designed to contain an inhalable dry powder (including but not limited to a pharmaceutical formulation including an active ingredient (including a pharmacologic active substance) and optionally one or more pharmacologic acceptable carriers and / or excipients). In particular, the dry powder inhaler containing the pharmaceutical composition is for the treatment of pulmonary fibrosis and / or pulmonary arterial hypertension.

[0041] The dry powder inhaler is provided in various embodiments of shapes and sizes, and can be reusable, easy to use, inexpensive to manufacture, and / or can be produced in large quantities in simple steps using plastic or other acceptable materials. Various embodiments of the dry powder inhaler are provided herein, and generally, the inhalation system includes an inhaler, a powder-filled cartridge, and an empty cartridge. The inhalation system of the present invention can be designed to be used with any type of dry powder. In one embodiment, the dry powder is a relatively cohesive powder that requires optimal deagglomeration conditions. In one embodiment, the inhalation system provides a reusable, compact, breath-actuated inhaler in combination with a single-use cartridge containing a pre-metered dose of dry powder formulation. The inhaler can deliver a dry powder dose in less than 10 seconds, or less than 6 seconds, or less than 4 seconds per cartridge session, in a single inhalation per use in treating interstitial lung disease with or without pulmonary arterial hypertension. In certain embodiments, oral inhalation via an inhaler can deliver greater than 60% of the powder dose in less than 6 seconds, in less than 4 seconds, and in less than 2 seconds.

[0042] As used herein, the term "unit dose inhaler" refers to an inhaler adapted to receive a single enclosure, cartridge or container containing a dry powder formulation and delivers a single dose of the dry powder formulation from the single container to a user by inhalation. In some cases, multiple unit doses are required to provide a specific dosage to the user and to provide that the same inhaler can be used for multiple unit dose deliveries and in multiple dose sessions for a given number of use sessions.

[0043] As used herein, a "cartridge" is a powder-containing enclosure having an enclosure, cup or container and a lid configured to hold or contain a dry powder formulation. The cartridge is made of a rigid material and the cup or container can be moved relative to the lid in a translational motion (or vice versa) to acquire a closed configuration to hold the dry powder and dosing composition for use with an inhaler.

[0044] As used herein, "powder mass" refers to an agglomeration of powder particles or agglomerates having irregular geometric shapes (eg, width, diameter, and length).

[0045] As used herein, "unit dose" refers to a dry powder formulation that is pre-metered for inhalation. Alternatively, a unit dose may be a single enclosure that contains a container with a single dose or multiple doses of the formulation that can be delivered by inhalation as a single metered amount. A unit dose enclosure / cartridge / container contains a single dose. Alternatively, it may contain multiple individually accessible compartments (each containing a unit dose).

[0046] As used herein, the term "about" is used to indicate that a value includes the standard deviation of error for the device or method being employed to determine the value.

[0047] As used herein, the term "microparticle" refers to a particle having a diameter of about 0.5 to about 1000 μm, regardless of the exact external or internal structure. Microparticles having a diameter between about 0.5 and about 10 microns can successfully pass through most of the natural barriers to reach the lungs. A diameter of less than about 10 microns is necessary to successfully pass through the bends of the throat, and a diameter of about 0.5 μm or larger is necessary to avoid being exhaled. It is generally accepted that particles with an aerodynamic diameter of about 0.5 to about 6 μm, as measured using standard techniques (e.g., with an Anderson Cascade Impactor), are preferred to reach the deep lung (or alveolar region), where most efficient absorption is believed to occur, although some references use somewhat different ranges. Other impactors can be used to measure aerodynamic particle size (e.g., the NEXT GENERATION IMPACTOR). TM (NGI TM MSP Corporation), where the respirable fraction is defined by a similar aerodynamic size, e.g., <6.4 μm. In some embodiments, a laser diffraction device is used to determine particle size (e.g., a laser diffraction device disclosed in U.S. Pat. No. 8,508,732, the disclosure of which is incorporated herein by reference in its entirety for its related art relating to laser diffraction). Here, the volumetric median geometric diameter (VMGD) of the particles is measured to evaluate the performance of the inhalation system. For example, in various embodiments, a cartridge emptying of ≧80%, 85%, or 90% and a VMGD of emitted particles of <12.5 μm, <7.0 μm, or <4.8 μm may indicate progressively better aerodynamic performance.

[0048] Respirable fraction at fill (RF / fill) represents the percentage (%) of powder emitted from the inhaler upon expulsion of the powder content filled for use as a dose that is suitable for respiration, i.e., the percentage of particles from the emitted filled dose that have a suitable size for pulmonary delivery, which is a measure of the aerodynamic performance of microparticles. As described herein, RF / fill values ​​of 40% or more reflect acceptable aerodynamic performance characteristics. In certain embodiments disclosed herein, the respirable fraction at fill can be greater than 50%. In exemplary embodiments, the respirable fraction at fill can be up to about 80%, where about 80% of the fill is emitted at a particle size of <5.8 μm, as measured using standard techniques.

[0049] As used herein, the term "dry powder" refers to a finely divided particulate composition that is not suspended or dissolved in a spray or other liquid. It does not necessarily mean that it is completely free of all water molecules.

[0050] As used herein, "amorphous powder" refers to a dry powder lacking a distinct repeating form, shape, or structure, including all non-crystalline powders.

[0051] The present disclosure also provides improved powders, compositions, methods of making the particles, and methods of treatment comprising microcrystalline particles that allow improved delivery of drugs to the lungs to treat diseases or disorders in subjects and reduce adverse effects caused by enteral or intravenous therapy.The embodiments disclosed herein achieve improved delivery by providing crystalline diketopiperazine compositions comprising microcrystalline diketopiperazine particles with high capacity for drug adsorption, resulting in powders with high drug loading of one or more active agents.The powders made with the microcrystalline particles of the present invention can deliver increased drug loading in smaller powder dose amounts, which can facilitate drug delivery to patients.The powders can be made by various methods, including methods utilizing surfactant-free or surfactant-containing solutions, depending on the starting material.

[0052] In an alternative embodiment disclosed herein, the drug delivery system may comprise a dry powder for inhalation comprising a plurality of substantially uniform microcrystalline particles, wherein the microcrystalline particles may have a substantially hollow spherical structure and may comprise a shell that may be porous and comprises crystallites of diketopiperazine that do not self-assemble in suspension or in solution.In certain embodiments, the microcrystalline particles may be substantially hollow spherical and substantially solid particles comprising crystallites of diketopiperazine, depending on the drug and / or drug content provided, as well as other factors in the process of making the powder.In one embodiment, the microcrystalline particles are relatively porous and have a diameter of about 0.43 cm. 3 / g average pore volume (approximately 0.4 cm 3 / g ~ approx. 0.45cm 3 / g) and particles having average pore sizes ranging from about 23 nm to about 30 nm, or from about 23.8 nm to 26.2 nm, as determined by BJH adsorption.

[0053] Certain embodiments disclosed herein include dry powders comprising a plurality of substantially uniform microcrystalline particles, wherein the particles have a substantially spherical structure including a shell that may be porous, the particles do not self-assemble in suspension or solution, have a volume median geometric diameter of less than 5 μm; or less than 2.5 μm, and comprise crystallites of a diketopiperazine that comprises an active agent.

[0054] In certain embodiments herein, up to about 92% of the microcrystalline particles have a volume median geometric diameter of 5.8 μm. In one embodiment, the shell of the particle is constructed from interlocking diketopiperazine microcrystals with one or more drugs adsorbed on their surface. In some embodiments, the particles may entrap the drug in their internal void volume, and / or there may be a combination of drug adsorbed on the surface of the crystallites and drug entrapped in the internal void volume of the spheroids.

[0055] In certain embodiments, a diketopiperazine composition is provided that includes a plurality of substantially uniformly formed microcrystalline particles, the particles having a substantially hollow spherical structure and including a shell containing crystallites of non-self-assembled diketopiperazine; the particles are formed by a method that includes the steps of combining a solution of diketopiperazine having a trans-isomer content ranging from about 45% to 65% in solution and a surfactant-free acetic acid, simultaneously homogenizing in a high shear mixer at a high pressure of up to 2,000 psi to form a precipitate; washing the precipitate in suspension with deionized water; concentrating the suspension and drying the suspension in a spray dryer. The microcrystalline particles can be preformed without the active agent for later use or can be combined with the active agent in suspension before spray drying.

[0056] The method may further comprise adding a solution containing an active agent or active ingredient (e.g., a drug or bioactive agent) with other pharma- ceutically acceptable carriers and / or excipients before drying, e.g., spray drying, the solution or suspension with mixing. In this manner, the active agent or active ingredient is adsorbed and / or entrapped on or within the particles. The particles produced by this process may be in the submicron size range before spray drying.

[0057] In certain embodiments, a diketopiperazine composition is provided comprising a plurality of substantially uniformly formed microcrystalline particles, wherein the particles have a substantially hollow spherical structure and include a shell comprising crystallites of non-self-assembled diketopiperazine, the particles having a volumetric mean geometric diameter of less than or equal to 5 μm; wherein the particles are formed by a process comprising combining diketopiperazine in solution and a solution of surfactant-free acetic acid and simultaneously homogenizing in a high shear mixer at high pressure up to 2,000 psi to form a precipitate; washing the precipitate in suspension with deionized water; concentrating the suspension and drying the suspension in a spray dryer.

[0058] The method may further include adding a solution containing an active agent or ingredient (e.g., a drug or bioactive agent) with mixing prior to spray drying, such that the active agent or ingredient is adsorbed and / or entrapped on or within the particles. The particles produced by this process may be in the submicron size range prior to spray drying.

[0059] In certain embodiments, a diketopiperazine composition is provided comprising a plurality of substantially uniformly formed microcrystalline particles, wherein the microcrystalline particles have a substantially hollow spherical structure and include a shell comprising crystallites of non-self-assembled diketopiperazine, the particles having a volume average geometric diameter of less than or equal to 5 μm; wherein the particles are formed by a process comprising combining diketopiperazine in solution and a solution of acetic acid in the absence of surfactant and in the absence of active agent, simultaneously homogenizing in a high shear mixer at high pressure up to 2,000 psi to form a precipitate; washing the precipitate in suspension with deionized water; concentrating the suspension and drying the suspension in a spray dryer.

[0060] In certain embodiments where the starting material containing the active ingredient is an extract exhibiting a high degree of viscosity or a material having a honey-like viscous appearance, the microcrystalline particles are formed as described above and by washing them in water using tangential flow filtration before combining with the extract or viscous material. After washing in water, the resulting particle suspension is freeze-dried to remove water and resuspended in an alcohol solution (including ethanol or methanol), or suspension, or solution, before adding the active ingredient as a solid. In one embodiment, the method of making the composition optionally includes adding an optional additional excipient, such as one or more amino acids (e.g., leucine, isoleucine, norleucine, methionine) or one or more phospholipids (e.g., 1,2 dipalmitoyl-sn-glycero-3-phosphocholine (DPPC) or 1,2-distearoyl-sn-glycero-3-phosphocholine (DSPC)) simultaneously with the active ingredient or after adding the active ingredient and prior to spray drying. In certain embodiments, forming the composition includes filtering or winterizing the extract containing the desired active agent, as required, to separate and remove layers of unwanted materials such as lipids to increase its solubility.

[0061] The method may further include adding a solution to the mixture with mixing, where the mixing may be performed with or without homogenization in a high shear mixer, as appropriate, where the solution contains an active agent or ingredient (e.g., a drug or bioactive agent) prior to spray drying, such that the active agent or ingredient is adsorbed and / or entrapped within or on the surface of the particles. The particles produced by this process may be in the submicron size range prior to spray drying, or the particles may be formed from the solution during spray drying.

[0062] In some embodiments herein, the drug content can be delivered on lyophilized or spray-dried crystalline powders using FDKP and with a content of about 10%, or about 20%, or about 30% or more. In embodiments using microcrystalline particles formed from FDKP or FDKP disodium salt, where the particles are not self-assembled and include submicron sized particles, the drug content can typically be greater than 0.01% (w / w). In one embodiment, the drug content to be delivered with the microcrystalline particles is about 0.01% (w / w) to about 75% (w / w); 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% depending on the drug to be delivered. In exemplary embodiments where the drug is nintedanib, the percentage of Compound I, nintedanib or pirfenidone in the composition may comprise about 1% to about 50% (w / w) of the dry powder content. In certain embodiments, the drug content may be greater in the dry powder composition and may vary depending on the morphology and size of the drug particles to be delivered.

[0063] In an exemplary embodiment, the method of treating interstitial lung disease includes a dry powder composition comprising microcrystalline particles of fumaryl diketopiperazine, wherein the compound I, nintedanib, pirfenidone, or treprostinil is adsorbed to the particles, and wherein the content of treprostinil in the composition comprises up to about 20% (w / w), or about 30% (w / w), ranging from about 0.5% (w / w) to about 20% (w / w), or from about 1% (w / w) to about 10% (w / w), or from about 1% (w / w) to about 5% (w / w) of the dry powder. In one embodiment, the compositions herein may include one or more excipients suitable for inhalation, including amino acids including methionine, histidine, isoleucine, and leucine. In this embodiment, for example, the composition of treprostinil, nintedanib, pirfenidone or compound I may be used in the prevention and treatment of pulmonary fibrosis or pulmonary hypertension and interstitial lung disease by having a patient self-administer an effective dose comprising about 1 mg to 15 mg of a dry powder composition comprising fumaryl diketopiperazine and microcrystalline particles of treprostinil in one inhalation. In certain embodiments, the treprostinil content in the formulation may be about 1 μg to about 200 μg. In one embodiment, the dry powder content of a cartridge containing treprostinil may be between 20 μg to 500 μg (e.g., 20 μg, 30 μg, 60 μg, 90 μg, 120 μg, 150 μg, 180 μg, 200 μg, 300 μg, or 500 μg) per dose regimen.

[0064] In alternative embodiments, the pharma- ceutically acceptable carrier for making dry powder can include any carrier or excipient that is useful for making dry powder and suitable for pulmonary delivery.Exemplary pharma-ceutically suitable carriers and excipients include sugars, including saccharides and polysaccharides (e.g., lactose, mannose, sucrose, mannitol, trehalose); citrate, amino acids (e.g., glycine, L-leucine, isoleucine, trileucine), tartrate, methionine, vitamin A, vitamin E, zinc citrate, sodium citrate, trisodium citrate, sodium tartrate, sodium chloride, zinc chloride, zinc tartrate, polyvinylpyrrolidone, polysorbate 80, phospholipids (including diphosphatidylcholine), etc.

[0065] In one embodiment, the method of self-administering dry powder formulation to lungs using dry powder inhalation system is also provided.The method includes the steps of: obtaining a dry powder inhaler in a closed position and having a mouthpiece; obtaining a cartridge containing a pre-metered dose of dry powder formulation in a confined configuration, wherein the dry powder comprises Compound I, nintedanib, or pirfenidone, or treprostinil; opening the dry powder inhaler and attaching the cartridge or capsule; closing the inhaler and moving the cartridge to dose position; placing the mouthpiece in mouth and inhaling deeply once, delivering the dry powder formulation to lungs in less than 6 seconds.

[0066] In another embodiment, a method for treating interstitial lung disease, including idiopathic pulmonary fibrosis, using diketopiperazine-based microparticles as a carrier or excipient is disclosed.The method includes, for example, administering an inhalable dry powder composition or formulation that includes a diketopiperazine having the 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 dry powder composition can include a diketopiperazine salt to create an amorphous powder.In yet another embodiment, a dry powder composition or formulation is provided in which the diketopiperazine is 2,5-diketo-3,6-di(4-fumaryl-aminobutyl)piperazine, with or without a pharmaceutically acceptable carrier or excipient and the active agent.

[0067] An inhalation system for delivering a dry powder formulation to the lungs of a patient is provided, the system comprising a 0.05 to about 0.200

number

[0068] In one embodiment, a dry powder inhalation kit is provided comprising a dry powder inhaler as described above and one or more pharmaceutical cartridges containing a dry powder formulation for treating disorders or diseases such as airway and lung diseases (including pulmonary fibrosis, pulmonary arterial hypertension, cystic fibrosis, respiratory infections), cancer, and other systemic diseases (including endocrine diseases including diabetes and obesity).

[0069] Also provided is a method of treating a disease or disorder in a patient with the dry powder inhaler embodiment disclosed herein. The method of treatment includes providing a patient in need of treatment with a dry powder inhaler including a cartridge containing a dose of an inhalable formulation comprising an active ingredient selected from the group as described above and a pharma- ceutically acceptable carrier and / or excipient; and having the patient inhale deeply through the dry powder inhaler for about 3-4 seconds or less than 6 seconds to deliver the dose to the patient's lungs. In the method, the patient may resume normal breathing patterns thereafter. Treatment of interstitial lung disease may be sustained for periods of 1 week, 2 weeks, 3 weeks, and up to 2 months; where, for example, administration of nintedanib to the patient may be performed once or twice daily at up to 300 mg while monitoring the patient for any adverse side effects.

[0070] Dry powder pharmaceutical compositions provided herein include kinase inhibitor molecules targeting cellular proteins including platelet-derived growth factor receptor (PDGFR), fibroblast growth factor receptor (FGFR), vascular endothelial growth factor receptor (VEGFR), colony-stimulating factor-1 receptor (CSF1R), leukocyte-specific protein tyrosine kinase (Lck2), transforming growth factor beta (TGF-β) kinases (including activin receptors, e.g., TGF-β type I receptor kinases for activin, ALK-4, ALK-5 and ALK-7); epidermal growth factor receptor (EGFR) and derivatives thereof, analogs thereof; and / or combinations thereof, which are used in dry powder formulations delivered using an inhaler or nebulizer with a liquid diluent.

[0071] In alternative embodiments, the kinase inhibitor can be of any type. For example, type I inhibitors can be, but are not limited to, bosutinib, crizotinib, dasatinib, erlotinib, gefitinib, lapatinib, pazopanib, ruxolitinib, sunitinib, and vemurafenib. In some embodiments, the kinase inhibitor can be a type II inhibitor, including imatinib, sorafenib, axitinib, and nilotinib. In other embodiments, the kinase inhibitor is a type III inhibitor, such as trametinib and GnF2. In alternative embodiments, the kinase inhibitor is a type IV or type V inhibitor, such as afatinib, ibrutinib, and HK1-272. In some embodiments, dry powder pharmaceutical compositions for inhalation and for treating pulmonary diseases, including fibrotic lung diseases, may be formulated to include one or more of the above kinase inhibitors, as well as, and optionally, one or more pharma- ceutically acceptable carriers or excipients, including diketopiperazines.

[0072] In certain embodiments, the pharmaceutical composition may further comprise any molecule or compound suitable for treating idiopathic pulmonary disease and may be present in the composition either alone or in combination with other active agents. Examples of active agents include, but are not limited to, deoxyribonuclease I (DNase I) and granulocyte-macrophage colony-stimulating factor (GM-CSF), anti-inflammatory drugs, including tyrosine kinase inhibitor molecules and kinase inhibitors such as activin receptor-like kinase inhibitors. In the embodiments herein, the pharmaceutical formulation optionally comprises one or more pharma- ceutical acceptable excipients and / or carriers. In this and other embodiments, the pharmaceutical composition is provided to the patient in a container, capsule or cartridge for inhalation using a dry powder inhaler.

[0073] In one embodiment, an inhalable pharmaceutical formulation is disclosed that includes a dry powder containing a pharma- ceutically acceptable excipient (including a diketopiperazine having the ability to form particles) and a therapeutically effective dose of a compound that inhibits the enzymatic activity of a kinase-associated receptor protein molecule (e.g., a tyrosine kinase), thereby inhibiting the phosphorylation of an intracellular protein involved in a signal transduction pathway that results in the activation of scar formation.The inhalable pharmaceutical formulation may optionally include one or more pharma- ceutically acceptable carriers and / or excipients. In this and other embodiments, the inhalable pharmaceutical formulations may be formulated to contain a dose of one or more active agents in a formulation for delivery with an inhaler in an amount of up to 30 mg (e.g., 1 mg, 2 mg, 3 mg, 4 mg, 5 mg, 6 mg, 7 mg, 8 mg, 9 mg, 10 mg, 12 mg, 15 mg, 20 mg, 25 mg) of inhalable dry powder per cartridge or capsule, and optionally one or more pharma- ceutically acceptable salts thereof, including serine-kinase inhibitors, tyrosine kinase inhibitors (including Bruton's tyrosine kinase (BTK) inhibitors, inositol tyrosine kinase (ITK) inhibitors, Aurora kinase inhibitors, CDK kinase inhibitors, MAPP kinase inhibitors, activin receptor-like kinase inhibitors), pharma- ceutically acceptable carriers, and / or excipients thereof. Multiple cartridges can be administered up to 300 mg of active agent per dosing session and per day, which can be administered once or more than once per day, depending on the needs of the patient. In some embodiments, and depending on the needs of the patient, the dosage can be further administered two, three or more times per day.

[0074] In certain embodiments, methods are provided for treating pulmonary diseases, including interstitial lung diseases, such as idiopathic pulmonary fibrosis, comprising administering to a subject in need of treatment a kinase inhibitor molecule, including a tyrosine kinase inhibitor, and a compound having the formula: [ka] and optionally one or more pharmaceutical excipients or carriers as defined above for the formulation. In one embodiment, the kinase inhibitor molecule includes, but is not limited to, axitinib, afatinib, bosutinib, cabozantinib, crizotinib, ceritinib, alectinib, dasatinib, brigatinib, ibrutinib, bosutinib, dastinib, nilotinib, ponatinib, cabozantinib, erlotinib, gefitinib, imatinib, rapamycin ... Tinib, nilotinib, pazopanib, regorafenib, ruxolitinib, sorafenib, sunitinib, vandetanib, vemurafenib, sirolimus, fasudil, riboviclib, idelalisib, midostaurin, piceatannol, trametinib, ruxolitinib, lenvatinib, regorafenib, tofacitinib, osimertinib, erdafitinib, etc.

[0075] In certain embodiments, the kinase inhibitor molecule has the formula: [ka] or a pharma- ceutically acceptable salt, analog, or derivative thereof, which molecules inhibit the kinase activity associated with the TGF-β receptor.

[0076] In one embodiment, a dry powder for inhalation is provided comprising crystalline particles of a diketopiperazine comprising an ALK-5 kinase inhibitor having the formula 2[4-methyl-1-(6-methylpyridin-2-yl)-1H-pyrazol-5-yl]thieno-[3,2 c]pyridine, and / or a pharmaceutically acceptable salt, analog, or derivative thereof, and one or more pharmaceutically acceptable excipients. EXAMPLES

[0077] The following examples illustrate some of the processes for making dry powders suitable for use with the inhalers described herein, and data obtained from experiments using the dry powders.

[0078] Example 1 Preparation of crystalline composite nintedanib dry powder A 10% nintedanib solution (the concentration of nintedanib in this solution can range from 1% nintedanib to 35% (w / w) nintedanib) was prepared by adding nintedanib (0.025 g) to a 10% (w / w) acetic acid solution (0.225 g) (the concentration of the acetic acid solution can range from 10% to 100% acetic acid). The nintedanib solution was added to a suspension of 3,6-bis(N-fumaryl-4-aminobutyl)-2,5-diketopiperazine, or microcrystalline particles of fumaryl diketopiperazine (XC) (1.31% solids, 188.93 g) (the solids content of the XC suspension can range from 0.5% to 5% (w / w)). The nintedanib XC suspension was spray dried using a Buchi B-290 spray dryer under the conditions shown in Table 1 to produce 1% (w / w) nintedanib XC powder with a yield of approximately 2.5 g. [Table 1]

[0079] Preparation of 20% (w / w) Nintedanib Crystalline XC Powder A 10% nintedanib solution (the concentration of nintedanib in this solution can range from 1% nintedanib to 35% (w / w) nintedanib) was prepared by adding nintedanib (3.33 g) to a 20% acetic acid solution (29.97 g) (the concentration of the acetic acid solution can range from 10% to 100% acetic acid). Separately, an XC suspension was prepared by adding fumaryl diketopiperazine particles (11.67 g) to deionized water (705.03 g) (suspension solids = 1.63%) (the solids content of the XC suspension can range from 0.5% to 5%). The nintedanib solution was then 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 produce 20% nintedanib XC powder with a yield of approximately 15 g.

[0080] Preparation of crystalline nintedanib T dry powder A 10% nintedanib solution (the concentration of nintedanib in this solution can range from 1% nintedanib to 35% (w / w) nintedanib) was prepared, for example, by adding nintedanib (0.025 g) (the nintedanib charge can range from 0.025 g to 0.50 g) to a 10% acetic acid solution (0.225 g) (the concentration of the acetic acid solution can range from 10% to 100% acetic acid). The nintedanib solution was added to a suspension of preformed particles of 3,6-bis(N-fumaryl-4-aminobutyl)-2,5-diketopiperazine (T suspension; 8.11% solids, 30.52 g) as described below (the solids content of the T suspension can range from 0.5% to 20% (w / w)). The nintedanib T suspension was then dried by either spray drying or freeze drying to produce 1% nintedanib T powder. Spray dried powder was dried using a Buchi B-290 spray dryer with the conditions shown in Table 1. Freeze dried powder was prepared by first pelleting the nintedanib T suspension in liquid nitrogen followed by drying in a Virtis Genesis 25 XL shelf freeze dryer. The freeze dryer was run with a program that ramped the shelf temperature from -45°C to 25°C at 0.2°C / min and then maintained under vacuum at 25°C until the powder was completely dry, resulting in a yield of approximately 2.5g.

[0081] Preparation of spray-dried 20% (w / w) nintedanib crystalline T powder A 10% nintedanib solution (the concentration of nintedanib in this solution can range from 1% nintedanib to 35% nintedanib) was prepared by adding nintedanib (3.33 g) to a 20% (w / w) acetic acid solution (30.0 g) (the concentration of the acetic acid solution can range from 10% to 100% acetic acid). The nintedanib solution was added to a T suspension (8.99% solids, 129.81 g) (the solids content of the T suspension can range from 0.5% to 20 wt%). The nintedanib T suspension was then spray dried using a Buchi B-290 spray dryer under the conditions shown in Table 1. The resulting yield was about 15 g.

[0082] Preparation of lyophilized 20% Nintedanib T powder A 10% nintedanib solution (the concentration of nintedanib in this solution can range from 1% nintedanib to 35% (w / w) nintedanib) was prepared by adding nintedanib (2.63 g) to a 10% acetic acid solution (23.63 g) (the concentration of the acetic acid solution can range from 10% to 100% acetic acid). The nintedanib solution was added to a T suspension (8.99% solids, 104.23 g) (the solids content of the T suspension can range from 0.5% to 20 wt%). The nintedanib T suspension was lyophilized by first pelleting the nintedanib T suspension in liquid nitrogen followed by drying in a Virtis Genesis 25 XL tray freeze dryer. The freeze dryer was run on a program that ramped the shelf temperature from -45°C to 25°C at 0.2°C / min, then held under vacuum at 25°C until the powder was completely dry, resulting in a yield of approximately 12 g.

[0083] Preparation of freeze-dried 20% Nintedanib T powder with reduced solid content A 10% nintedanib solution (the concentration of nintedanib in this solution can range from 1% nintedanib to 35% (w / w) nintedanib) was added to 3.09 g of nintedanib. * ) to a 20% acetic acid solution (27.81 g) (the concentration of the acetic acid solution can range from 10% to 100% acetic acid). Separately, the T suspension (8.99% solids, 132.48 g) was prepared. *) was diluted with deionized water (136.62 g) (the solids content of the T suspension can range from 0.5% to 20% (w / w)). The nintedanib solution was added to the diluted T suspension resulting in a nintedanib T suspension with a solids content of 5.00%. The nintedanib T suspension was lyophilized by first pelleting it in liquid nitrogen followed by drying in a Virtis Genesis 25 XL shelf freeze dryer. The freeze dryer was run on a program that ramped the shelf temperature from -45°C to 25°C at 0.2°C / min and then maintained under vacuum at 25°C until the powder was completely dry, resulting in a yield of approximately 15 g.

[0084] Preparation of lyophilized 20% Nintedanib T powder with inverse addition of components A 10% nintedanib solution (the concentration of nintedanib in this solution can range from 1% nintedanib to 35% (w / w) nintedanib) was prepared by adding nintedanib (3.09 g) to a 20% acetic acid solution (27.81 g) (the concentration of the acetic acid solution can range from 10% to 100% acetic acid). The nintedanib solution was then diluted with deionized water (97.19 g). The lyophilized T particles (11.91 g) were then added to the 20% acetic acid solution (27.81 g). * ) was added in portions to the nintedanib solution over a period of 4 minutes. Deionized water (10.00 g) was used to wash the remaining lyophilized T particles into the nintedanib T suspension. The nintedanib T suspension was lyophilized by first pelleting it in liquid nitrogen and then drying in a Virtis Genesis 25 XL shelf freeze dryer. The freeze dryer was run on a program that ramped the shelf temperature from -45°C to 25°C at 0.2°C / min, then maintained under vacuum at 25°C until the powder was completely dry, resulting in a yield of approximately 15 g.

[0085] Preparation of freeze-dried 20% Nintedanib Essilate T powder A 1% nintedanib esylate solution (the concentration of nintedanib esylate in this solution can range from 1% nintedanib esylate to 5% nintedanib esylate) was added to 3.61 g of nintedanib esylate. * The nintedanib esylate solution was prepared by adding the T suspension (8.99% solids, 126.70 g) in portions to deionized water (357.39 g). * ) (the solids content of the T suspension can range from 0.5% to 20%) and the resulting Nintedanib esylate T suspension was pelleted in liquid nitrogen and subsequently dried in a Virtis Genesis 25 XL shelf freeze dryer. The freeze dryer was run with a program that ramped the shelf temperature from -45°C to 25°C at 0.2°C / min and then held under vacuum at 25°C until the powder was completely dry, resulting in a yield of approximately 15g.

[0086] Powder Testing The powders were evaluated for geometric particle size distribution using a Sympatec laser diffraction instrument fitted with a RODOS bulk powder dispensing system. The bulk powders were dispersed at 0.5 bar and 3.0 bar. The powders were also evaluated for aerodynamic particle size distribution using an Andersen Cascade impactor (ACI). The powders were ejected at 4 kPa from a Gen 2C cartridge (10 mg cartridge load) via the ACI. The data for the nintedanib powders are shown in Table 2. [Table 2]

[0087] Table 2 shows the target yields (g) for the process. Percent yield (%) shows the percent of the target yield recovered from the process. As can be seen in Table 2, the process product yields were greater than about 67% in the composition reactions for both spray-dried and lyophilized dry powders. Furthermore, it can be seen that the percent yields were improved for the lyophilized T powders and all powders containing 10 wt% and 20 wt% nintedanib in the composition, regardless of the method of making the powder. The data shows that the average powder delivered from the delivery system, as assessed by cartridge exhaust (CE) measurement, was greater than 75% for all XC powders and spray-dried T powders, greater than or equal to 62% for all lyophilized T powders, and some powders were greater than about 97% CE. The data above also demonstrate that the XC powders at the higher concentrations (10 wt% and 20 wt%) appear to have more consistent cartridge discharge performance than those at the lower concentrations, however the best CE performing powder was the 1% T powder, whether spray dried or freeze dried.

[0088] Sample powders were taken for room temperature stability at 25°C, 60% relative humidity (RH) testing over a one year period and also incubated at 40°C, 75% RH over a 12 week period. Test samples were taken at various time points from the start of the experiment and assayed for nintedanib content. Parallel samples were also run with nintedanib free base compound alone for comparison. Results from the experiment are illustrated in Figures 1, 2, 3, and 4. Figures 1 and 2 show the room temperature stability results of the experiment, where the stability of nintedanib formulated in crystalline (T powder) as described above was similar to the nintedanib free base (Figure 2) compound over the duration of the experiment, but with less variation in content in powder-formulated T powder (NinT) (Figure 1). Similarly, compared to the nintedanib free base compound (Figure 4), T powder formulated with nintedanib tested at extreme heat of 40°C, 75% RH for 12 weeks (Figure 3) appears to have a similar stability profile and is very stable or loses less than about 5% of the original content of nintedanib in the composition over an extended period of time.

[0089] Example 2 Preparation of crystalline composite pirfenidone dry powder A 25% pirfenidone solution (the concentration of pirfenidone in this solution can range from 1% pirfenidone to 40% pirfenidone) was prepared by adding pirfenidone (0.20 g) (the pirfenidone loading used to prepare these powders varied between 0.2 g to 0.63 g) to ethanol (0.60 g) (when a 25% pirfenidone solution was used, water can be added to the ethanol up to a 50:50 weight ratio of ethanol:water). The pirfenidone solution was added to a microcrystalline (XC) suspension (1.31% solids, 137.40 g) (the solids content of the XC suspension can range from 0.5% to 5%). The pirfenidone XC suspension was spray dried using a Buchi B-290 spray dryer at the conditions shown in Table 1 to produce pirfenidone XC powder.

[0090] Preparation of crystalline pirfenidone powder A 25% pirfenidone solution (the concentration of pirfenidone in this solution can range from 1% pirfenidone to 40% pirfenidone) was prepared by adding pirfenidone (0.20 g) (the pirfenidone loading used to prepare these powders varied between 0.2 g and 0.33 g) to ethanol (0.60 g) (when a 25% pirfenidone solution was used, water could be added to the ethanol up to a 50:50 weight ratio of ethanol:water). The pirfenidone solution was added to a T suspension (8.11% solids, 22.19 g) (the solids content of the T suspension can range from 0.5% to 20%). The pirfenidone T suspension was then dried by either spray drying or freeze drying to produce pirfenidone T powder. The spray dried powder was dried using a Buchi B-290 spray dryer at the conditions shown in Table 1. Lyophilized powder was prepared by first pelleting the pirfenidone T suspension in liquid nitrogen followed by drying in a Virtis Genesis 25 XL shelf freeze dryer, which was run with a shelf temperature ramp from -45°C to 25°C at 0.2°C / min and maintained under vacuum at 25°C until the powder was completely dry.

[0091] Preparation of amorphous pirfenidone powder A 25% pirfenidone solution (the concentration of pirfenidone in this solution can range from 1% pirfenidone to 40% pirfenidone) was prepared by adding pirfenidone (0.20 g) (the pirfenidone loading used to prepare these powders varied between 0.2 g to 0.22 g) to ethanol (0.60 g) (when a 25% pirfenidone solution was used, water could be added to the ethanol up to a 50:50 weight ratio of ethanol:water). Separately, a 10% FDKP-disodium salt solution was prepared. Leucine (the leucine loading ranged from 0 g to 0.45 g) and FDKP-disodium salt (1.80 g) were dissolved in deionized water (16.20 g) (the concentration of FDKP-disodium salt in this solution can range from 5% to 20%). The pirfenidone solution was added to the FDKP-disodium salt solution and the resulting solution was spray dried using a Buchi B-290 spray dryer operated using the conditions shown in Table 1 to produce pirfenidone amorphous powder.

[0092] Example 3 Preparation of crystalline composite (XC) dry powder using compound I A 15% (w / w) powder preparation for a target yield of 2.5 g was prepared. A 15% Compound I solution (the concentration of Compound I in this solution can range from 1% to 15%) was prepared by adding Compound I (0.125 g) (the Compound I loading can range from 0.025 g to 0.75 g) to a 50% acetic acid solution (0.708 g) (the concentration of the acetic acid solution can range from 50% to 100% acetic acid). The Compound I solution was added to a XC suspension (1.31% solids, 181.30 g) (the solids content of the XC suspension can range from 0.5% to 5%) (the suspension loading is adjusted to obtain the desired Compound I loading in the final powder). The Compound I XC suspension was spray dried using a Buchi B-290 spray dryer at the conditions shown in Table 3 to produce the desired Compound I XC powder.

[0093] 20% 9 w / w) for a target yield of 20 g XC powder preparation: A powder was prepared to contain 20% Compound I using XC powder particles for a target yield of 20 g. A 15% Compound I solution (the concentration of Compound I in this solution can range from 1% Compound I to 15% Compound I) was prepared by adding Compound I (4.00 g) to a 50% acetic acid solution (29.97 g) (the concentration of the acetic acid solution can range from 50% to 100% acetic acid). Separately, an XC suspension was prepared by adding crystalline FDKP particles (16.00 g) to deionized water (957.33 g) (suspended solids = 1.64%) (the solids content of the XC suspension can range from 0.5% to 5%). The Compound I solution was then added to the XC suspension and the resulting Compound I XC suspension was spray dried using a Buchi B-290 spray dryer under the conditions shown in Table 3 to produce a 20% Compound I XC powder.

[0094] Crystalline composite dry powder compositions were also made using similar process steps to make the formulations as described above at 40 wt% and 60 wt% Compound I. Data from these samples are also shown in Table 4 below.

[0095] Preparation of crystalline (T) dry powder using compound I A 15% powder preparation for a target yield of 2.5 g was prepared using a Compound I solution (the concentration of Compound I in this solution can range from 1% Compound I to 15% Compound I) prepared by adding Compound I (0.125 g) (Compound I loading can range from 0.025 g to 0.75 g) to a 50% acetic acid solution (0.708 g) (the concentration of the acetic acid solution can range from 50% to 100% acetic acid). The Compound I solution was added to a T suspension (11.04% solids, 21.51 g) (the solids content of the crystalline T suspension can range from 0.5% to 20%) (the suspension loading is adjusted to obtain the desired Compound I loading in the final powder). The Compound IT suspension was spray dried using a Buchi B-290 spray dryer at the conditions shown in Table 3 to produce the desired Compound IT powder. [Table 3]

[0096] Powder Testing The powders were evaluated for geometric particle size distribution using a Sympatec laser diffraction instrument equipped with a cuvette system. The powders were dispersed in aqueous acetic acid solution adjusted to pH 4.5 for evaluation. The powders were also evaluated for aerodynamic particle size distribution using an Alberta Idealized Throat Model (AIT). The powders were discharged at 4 kPa from a Gen 2C cartridge (10 mg cartridge loading) through the AIT model. The Compound I assay of these powders was determined using HPLC analysis. The data of Compound I powders prepared to date is shown in Table 4. [Table 4] N / A: Data not available

[0097] The data demonstrate that all XC and T powders, including Compound I, were suitable for pulmonary delivery or inhalation, as shown by the high percentage of cartridge exhaust (CE) and MtF / F data for the samples tested, indicating that the powders can be readily aerosolized and delivered to the airways at high concentrations.

[0098] Example 4 Pharmacokinetic Study in Rats with Compound I Crystalline Complex (XC) Dry Powder - Insufflation study was conducted in rats to deliver a dose of Compound I (protein kinase antagonist) dry powder. The study was conducted to determine the pharmacokinetic profile of Compound I dry powder made by the process as described above after pulmonary insufflation or intravenous injection of a single dose of the composition administered in solution to male Sprague Dawley (Charles River Laboratories) adult rats (weighing 200g-250g at the time of the study). Dry powder containing 22.1 wt% actual drug content was used, tested at 1 mg / ml in solution to deliver a dose of 0.8 mg / kg to 18 rats in each test group. Rats were habituated and anesthetized prior to the experiment. Lung and blood samples were taken from rats at 10, 20, 30, 120, and 240 minutes after drug administration. The samples were analyzed. The results are shown in Figure 5.

[0099] Figure 5 illustrates the lung and plasma concentrations of Compound I administered by insufflation (circle) and by IV injection. As shown in Figure 5, higher content of Compound I was detected in rat lungs after insufflation compared to IV injection for a longer period after administration, and much of Compound I remained in the lung tissue. The above data indicates that insufflation and inhalation of Compound I is more effective in treating disease than when delivered by other administration routes.

[0100] The foregoing disclosure is an illustrative embodiment. It should be understood by those skilled in the art that the devices, techniques and methods disclosed herein elucidate representative embodiments that function well in the practice of the present disclosure. However, those skilled in the art should, in light of the present disclosure, understand that many changes can be made in the specific embodiments disclosed and still obtain the same or similar results without departing from the spirit and scope of the present invention.

[0101] Unless otherwise indicated, all numbers expressing quantities of ingredients, properties (e.g., molecular weight, reaction conditions, and the like) used in the specification and claims should be understood in all instances to be modified by the term "about." Thus, unless indicated to the contrary, the numerical parameters set forth in the following specification and the appended claims are approximations that may vary depending on the desired properties sought to be obtained. At the very least, and without attempting to limit the application of the doctrine of equivalents to the scope of the claims, each numerical parameter should be construed in light of, at the very least, the number of reported significant digits and by applying ordinary rounding techniques. Notwithstanding that the numerical ranges and parameters setting forth broad ranges are approximations, the numerical values ​​set forth in the specific examples are reported as precisely as possible. Any numerical values, however, inherently contain certain errors necessarily resulting from the standard deviation found in their respective testing measurements.

[0102] The terms "a," "an," and "the," and similar referents used in the context of describing the present invention (especially in the context of the claims below) should be construed to cover both the singular and the plural, unless otherwise indicated herein or the context clearly contradicts. The recitation of ranges of values ​​herein is merely intended to serve as a shorthand method of individually referring to each separate value falling within the range. Unless otherwise indicated herein, each separate value is incorporated herein as if it were individually set forth herein. All methods described herein may be performed in any suitable order, unless otherwise indicated herein or otherwise clearly contradicted by context. The use of any and all examples or exemplary language (e.g., "such as") provided herein is intended only to better clarify the invention and does not pose a limitation on the scope of the claims as otherwise claimed. No language in the specification should be construed as indicating any non-claimed element essential to the practice of the invention.

[0103] Although use of the term "or" in the claims is used to mean "and / or" unless expressly indicated to refer to alternatives only or the alternatives are not mutually exclusive, the present disclosure supports a definition that refers only to alternatives and "and / or."

[0104] Grouping of alternative elements or embodiments disclosed herein should not be construed as limiting. Each group member may be referred to and claimed individually or in combination with other members of the group or other elements found herein. It will be understood that for reasons of convenience and / or patentability, one or more members of a group may be included in or deleted from a group. When any such inclusion or deletion occurs, the specification is hereby deemed to include the group as modified to satisfy all Markush group descriptions used in the appended claims.

[0105] Preferred embodiments are described herein, including the best mode known to the inventors for carrying out the invention. Of course, variations to those preferred embodiments will become apparent to those skilled in the art upon reading and understanding the foregoing description. The inventors expect that such variations will be adopted by those skilled in the art as appropriate, and the inventors intend the invention to be practiced otherwise than as specifically described herein. Accordingly, this invention includes all modifications and equivalents of the subject matter recited in the claims appended hereto as permitted by applicable law. Moreover, any combination of the above-described elements in all possible variations thereof is encompassed by the invention unless otherwise indicated herein or otherwise clearly contradicted by context.

[0106] Specific embodiments disclosed herein may be further limited in the claims using the language consisting of or consisting essentially of. When used in the claims, whether as filed or added by amendment, the transitional term "consisting of" excludes any element, step, or ingredient not specified in the claim. The transitional term "consisting essentially of" limits the scope of the claim to those specified materials or steps and which do not essentially affect its basic and novel characteristics. The embodiments so claimed are essentially or explicitly described and enabled herein.

[0107] Additionally, throughout this specification, there are numerous references to patents and printed publications. Each of the above cited references and printed publications is individually incorporated herein by reference in its entirety.

[0108] 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 employed are within the scope of the present invention. Thus, by way of illustration, but not of limitation, alternative configurations may be utilized in accordance with the teachings herein. Thus, the present invention is not limited to that precisely as shown and described.

Claims

1. Formula for diketopiperazine particles and therapeutically effective dose: 【Chemistry 9】 A dry powder containing a compound having or a pharmaceutically acceptable salt thereof, An inhalable pharmaceutical composition comprising, as necessary, one or more pharmaceutically acceptable carriers and / or excipients.

2. The inhalable pharmaceutical composition according to claim 1, wherein the therapeutically effective dose is an amount up to 50 mg and the pharmaceutically acceptable carrier and / or excipient.

3. The inhalable pharmaceutical composition according to claim 1, wherein the one or more pharmaceutically acceptable carriers and / or excipients are surfactants, amino acids, or phospholipids.

4. The diketopiperazine is in the form of crystalline or microcrystalline particles and has the formula: 【Chemistry 10】 The inhalable pharmaceutical composition according to claim 1.

5. The inhalable pharmaceutical composition according to claim 1, wherein the dried powder contains the compound in a therapeutically effective dose ranging from about 1 mg to about 50 mg in the dried powder composition.

6. The inhalable pharmaceutical composition according to claim 1, wherein the pharmaceutical dried powder composition is an amorphous powder.

7. The inhalable pharmaceutical composition according to claim 1, wherein the dried powder comprises one or more pharmaceutically acceptable carriers and / or excipients selected from 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.

8. The inhalable pharmaceutical composition according to claim 7, wherein the dried powder comprises one or more pharmaceutically acceptable carriers and / or excipients selected from the group consisting of sodium citrate, sodium chloride, leucine or isoleucine, and trehalose.

9. The inhalable pharmaceutical composition according to claim 3, wherein the surfactant is polysorbate 80.

10. Microcrystalline particles are approximately 25 m ２ / g ~ approx. 63m ２ The inhalable pharmaceutical composition according to claim 4, having a specific surface area in the range of / g.

11. The pharmaceutical dried powder composition according to claim 4, wherein the microcrystalline particles have a pore size in the range of about 23 nm to about 30 nm.

12. A dry powder composition for treating idiopathic pulmonary fibrosis, The aforementioned dried powder composition is characterized by being administered to patients requiring treatment by oral inhalation. The aforementioned dried powder composition comprises crystalline diketopiperazine particles and formula up to 50 mg: 【Chemistry 11】 The compound or a pharmaceutically acceptable salt thereof, and optionally one or more pharmaceutically acceptable carriers and / or excipients, The aforementioned dried powder composition is provided in a dried powder inhaler, Dry powder composition.

13. The dry powder composition according to claim 12, wherein a therapeutically effective dose of the dry powder composition is provided to the patient in one or more capsules or cartridges for fitting into the dry powder inhaler before use, each capsule or cartridge containing up to 30 mg of the compound.

14. The therapeutically effective dose is the dried powder composition according to claim 13, comprising up to 300 mg of the compound per day, provided in multiple cartridges.

15. The dry powder composition according to claim 12, comprising one or more pharmaceutically acceptable carriers and / or excipients selected from the group consisting of fumaryldiketopiperazine, 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.

16. The dried powder composition according to claim 12, wherein the one or more pharmaceutically acceptable carriers and / or excipients are sodium citrate, sodium chloride, leucine or isoleucine, or trehalose.

17. The dried powder composition according to claim 11, wherein the 1 or more pharmaceutically acceptable carriers and / or excipients are fumaryldiketopiperazine.

18. The dry powder composition according to claim 11, characterized in that it is administered in at least one inhalation of less than 10 seconds per cartridge.

19. A dry powder inhaler comprising a movable member for attaching a cartridge, wherein the container is configured to obtain a drug dispensing configuration, the cartridge comprising the dry powder composition described in claim 1.

20. An inhalable pharmaceutical composition according to claim 1 for treating idiopathic pulmonary fibrosis, wherein the inhalable pharmaceutical composition is administered to a patient requiring treatment by oral inhalation.

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