JP2021527058A - Compositions and methods for inhalation - Google Patents

Abstract

The prostaglandin composition and methods for treating pulmonary arterial hypertension are disclosed. This composition is based on diketopiperazine for pulmonary inhalation.
[Selection diagram] None

Description

(Cross-reference of related applications)
This application claims priority under US Provisional Patent Application No. 62 / 682,109 filed June 7, 2018, the entire contents of which are incorporated herein by reference in its entirety.

(Technical field)
Compositions and methods for the treatment of pulmonary arterial hypertension disclose disclosure.

Pulmonary arterial hypertension (PAH) is a complex, characterized by a persistent increase in pulmonary arterial pressure and pulmonary vascular resistance (PVR), which causes an increase in afterload of the right ventricle and ultimately leads to right heart failure. It is a multifactorial progressive syndrome. Right ventricular insufficiency limits cardiac output during exertion. The most common symptoms are shortness of breath, fatigue, sore throat, syncope, and abdominal distension, which is characterized by decreased athletic performance.

The symptoms of PAH are non-specific. Resting symptoms have been reported only in very advanced cases due to the nonspecificity of the symptoms, with a significant delay of more than 2 years in the diagnosis of pulmonary hypertension (PH). Unfortunately, approximately 70% of PH patients are diagnosed after entering the advanced stages of the disease (World Health Organization (WHO) Functional Classification III and IV). Early detection and treatment of pulmonary hypertension (PH) is generally recommended because progressive diseases may be less responsive to treatment. Treatment begins with a basic assessment of disease severity followed by first-line treatment.

Assessment of patients with pulmonary hypertension includes assessment of disease severity using various clinical assessments, exercise tests, detection of specific biochemical markers, echocardiography and hemodynamic assessment. Patient clinical evaluation plays an important role in the choice of initial treatment, the assessment of response to treatment, and the potential for gradual expansion of treatment as needed.

PAHs are divided into 5 groups (1-5) according to the severity of the disease. In Group 1, for example, the disease is hereditary and is generally induced by drugs and toxins. PAH includes idiopathic pulmonary arterial hypertension (IPAH, formerly known as primary pulmonary hypertension), hereditary PAH, or connective tissue disease, HIV infection, portal hypertension, congenital heart disease, Includes other diseases such as pulmonary hypertension, and PAH due to exposure to drugs or toxins (eg, appetite suppressors). In the United States and Europe, the estimated prevalence is 15-50 cases per million. However, in certain high-risk groups, the prevalence of PAHs is substantially even higher. For example, the prevalence of PAH is 0.5% in HIV-infected patients, 7-12% in patients with collagenous vasculature, and 2-2 in patients with sickle cell disease. It is around 3.75%. 5% of patients with hepatosplenic schistosomiasis can be PAH. It is estimated that 10% of adult patients with congenital heart disease (CHD) also have PAHs. PAH in newborns is known as persistent pulmonary hypertension in newborns and is estimated to occur in 0.2% of postnatal infants.

Patients in Group 2 with PH due to left heart disease, especially left ventricular systolic dysfunction, left ventricular diastolic dysfunction, valvular disease, or congenital / acquired left ventricular inflow / outflow obstruction, and congenital cardiomyopathy. It is a patient who has become. In Group 3, PH was associated with chronic lung disease and / or obstructive lung disease with hypoxia, interstitial lung disease, other lung diseases with mixed restraint and obstructive patterns, sleep respiratory disorders, lungs. Due to vesicle hypoventilation, chronic high-altitude exposure and developmental lung disease. In Group 4, PH is due to chronic thromboembolic pulmonary hypertension, and patients in Group 5 have blood disorders such as chronic hemolytic anemia, myeloproliferative disease, splenectomy; sarcoidosis, pulmonary histocytoproliferative disease, lymph. Systemic diseases such as vascular myomatosis; metabolic disorders including sarcoidosis, Gaucher's disease and thyroid disorders; and other disorders such as tumor / mass obstruction, mediastinal fibrosis, chronic renal failure, partial PH PH is shown by an unclear multifactorial mechanism including.

First-line treatment is directed to the root cause of PH and is guaranteed for almost all PH patients. The severity of the disease should be reassessed after first-line treatment to determine if advanced treatment is needed. Advanced treatment is directed towards pulmonary hypertension itself rather than the root cause of PH. Advanced treatment is widely accepted by many patients with Group 1 pulmonary arterial hypertension (PAH). In contrast, group 3 PH patients, group 4 PH patients, or group 5 PH patients should be given on a case-by-case basis, with careful consideration of benefits and risks. Advanced treatment should not be given to most Group 2 PH patients.

Until 2001, the only drug available to treat PAH was epoprostenol (Floran, GlaxoSmithKline Pharmaceuticals), most of which was used as a bridge to transplantation. Since then, other therapies have evolved, resulting in a significant improvement in the prognosis of PAH patients.

Patient clinical evaluation plays an important role in the choice of initial treatment, the assessment of response to treatment, and the potential for gradual expansion of treatment as needed. As mentioned above, assessment of patients with pulmonary hypertension includes assessment of disease severity using various clinical assessments, exercise tests, identification of biochemical markers, echocardiography and hemodynamic assessment.

The clinical severity of PAH is classified by a system originally created by the New York Heart Association (NYHA) for heart failure and modified by WHO for PH patients. The functional classification (I-IV) system associates symptoms with activities to be restricted, allowing clinicians to accelerate disease progression and prognosis, and the need for specific treatment regimens, regardless of the underlying cause of PAH. Can be judged. Patients of Category I show PH, but physical activity is not restricted and normal physical activity does not cause dyspnea or fatigue, chest pain, or on the verge of fainting. Patients with Category II show pulmonary hypertension and have some limited physical activity. They are comfortable at rest and normal physical activity causes excessive dyspnea or fatigue, chest pain, or fainting. Category III is a patient with pulmonary hypertension and has severely restricted physical activity. They are comfortable at rest and are on the verge of excessive dyspnea or fatigue, chest pain, or fainting due to less than normal physical activity. Category IV is a patient with pulmonary hypertension who is unable to perform any physical activity without symptoms. These patients show signs of right heart failure. There may be dyspnea and / or fatigue at rest, and any physical activity increases discomfort.

The pathogenesis of PH is complex and many biochemical pathways and cell tumors have been identified or proposed as contributing to this vasoconstriction and vascular remodeling. These include nitric oxide (NO), prostacycline (PGI) and endothelin (ET-1) synthesis abnormalities, impaired potassium channel and growth factor receptor dysfunction, serotonin transport dysregulation, increased oxidative stress, and blood vessels. Includes activator matrix production, calcium signaling molecules, inflammatory mediators, growth factors, and enhancement of bone morphogenetic protein receptor 2 (BMPR2) variants. However, the relative importance of each of these processes is unclear.

In clinical and preclinical studies, pulmonary vascular endothelium plays an important role, and the interaction of pulmonary endothelial cells and pulmonary arterial smooth muscle cells with pulmonary pericytes initiates and / or progressive pulmonary artery occlusion characteristic of PAH. It strongly shows that there is an important role in sustainability. Pulmonary endothelial cells include growth factors (fibroblast growth factor [EGF] -2, serotonin [5-HT], angiotensin II, and vasoactive peptides (NO, PGI2, ET-1), cytokines (IL-1, 1, IL-6, Macrophage Growth Inhibitor [MIF]), and key mediators of several key mediators for vascular remodeling, including chemokine (monosphere-migrating protein [MCP] -1), adipokine (Leptin) A local source. Endothelial dysfunction occurs early in the disease, which is linked to overexpression of vasoconstrictors and growth factors such as thromboxane A2 and endoserin-1 and vasodilators such as NO and prostacyclin. And is thought to induce a chronic decline in anti-growth substances. Excessive parasecretion of ET-1, 5-HT, angiotensin II, and FGF-2 is the proliferation, survival, migration, and differentiation of lung endothelial cells. Many of these abnormalities increase vascular tone, promote the proliferation of endothelial and smooth muscle cells, followed by structural changes or remodeling of the pulmonary vascular bed, resulting in pulmonary vascular resistance. In addition, the adrenal gland increases the production of extracellular substrates, including collagen, elastin, fibronectin, and angiotensin.

Over the last two decades, three major mechanisms of action, the endothelin, nitric oxide, and prostacyclin (prostaglandin (PG) I2) pathways, have been targeted for PAH-specific therapy. PAH-specific drug classification includes endothelin receptor antagonists, phosphodiesterase type 5 inhibitors (PDE-5i), including bosentan, citaxcentan and ambrisentan, and other agents such as sildenafil, tadalafil or soluble guanylate cyclase stimulants. ), And prostanoids. These "targeted" treatments have both long-term and short-term benefits for many patients. All currently approved PAH drugs belong to one of these categories. These agents have been first approved as monotherapy for major indications by improving 6-minute walking distance (6 MWD). Most of these Phase III trials include additional endpoints such as PAH functional classification, hemodynamics, and clinical deterioration. In these enrollment studies, these categories of drugs have universally shown improved motor performance and hemodynamics in PAH patients. In addition, some of these agents have been shown to be associated with improved outcomes in PAH patients when compared to historical data.

All currently approved PAH drugs belong to one of these categories, including protenoids, such as epoprostenol (Floran® and Veleri® IV infusion), treprostinil (Registered). Subcutaneous / IV infusion); Tyvaso® (registered trademark) (inhaled 4 times daily), Iloprost® (registered trademark) (6-9 inhalations daily). These agents have been first approved as monotherapy for major signs by improving 6-minute walking distance (6 MWD). Most of these Phase III trials include additional endpoints such as PAH functional classification, hemodynamics, and clinical deterioration. In these enrollment studies, these categories of drugs have universally shown improved motor performance and hemodynamics in PAH patients. In addition, some of these agents have been shown to be associated with improved outcomes in PAH patients when compared to historical data.

Parenteral prostacyclin analogs are the most widely studied. Intravenous epoprostenol is the first US Food and Drug Administration (FDA) approved treatment for PAH (approved in 1995). However, due to the extremely short half-life (3-5 minutes), epoprostenol needs to be delivered through an indwelling catheter as a continuous IV with risk of rebound PAH and acute right heart failure during fluid discontinuation. In addition, due to the inherent chemical stability of epoprostenol at room temperature and neutral pH (room temperature stability of less than 8 hours), an ice pack is required to delay degradation during the infusion period. A heat-stable epoprostenol injectable preparation (Veletri®) that does not require cooling has been approved by the FDA for use. However, serious adverse events related to the delivery system include pump failure, local infections, catheter blockages, and sepsis, which continue to be barriers to use.

Treprostinil is an epoprostenol analog of a long-acting tricyclic benzidine with an elimination half-life of approximately 2-4 hours and a distributed phase half-life of approximately 40 minutes. Unlike epoprostenol, treprostinil is scientifically stable at room temperature, can be administered at ambient temperature, and can overcome some of the limitations associated with treatment with epoprostenol. Treprostinil causes vasodilation of the venous vascular bed of the lungs and systemic, and inhibits platelet aggregation by binding to prostacyclin IP receptors on the surface of vascular smooth muscle cells and platelets. Treprostinil (Remodulin®) was first approved by the FDA in 2002 for continuous subcutaneous injections of WHO Group 1 PAH and functional classifications II-IV for adults and by United Therapeutics (Silver Spring, MD). It is commercially available. In a 12-week pivotal randomized controlled trial of 470 patients, subcutaneous treprostinil significantly improved athletic performance compared to placebo. The most common adverse event in patients treated with treprostinil subcutaneous injection was pain at the injection site.

Currently, oral sustained release tablets of treprostinyldiolamine (Orenitran®) are also available. However, with oral delivery therapy, treprostinil absorption may not be constant, especially when taken with food. Due to the pharmacological or physiochemical properties of treprostinil, it can be modified to intermittent administration of this drug via the inhalation pathway. Tyvaso® and Iloprost (Ventavis®) are solvents for inhalation and need to be administered many times over a long period of time in a doctor's office using a dedicated spray inhaler. A Tyvaso® inhalation system [Opti-Neb ultrasonic spray inhaler (NebuTech, Elsenfeld, Germany)] is used. The system is complex to assemble and use, cumbersome to administer doses (patients need to reset the device three times for every three breaths during treatment), and high error rates are human factors. I know from research. There is a clear risk of underdose, as the patient needs to breathe 9 times within the 90 second time limit. In addition, the mechanism of respiratory measurement is a time-based (time-correlated) trigger rather than inspiration, or expiratory airflow or exertion (respiratory correlation), thus allowing the patient to breathe (dose) within a 90-second time limit. ) May result in overdose or underdose by breathing more or less. The system also requires four different cleaning schedules (daily, weekly, monthly, and yearly). Therefore, new treatments for PHA are needed to facilitate patient administration of these products.

Drug delivery to lung tissue uses a variety of devices for inhalation, including spray inhalers and inhalers, such as metered dose inhalers and dry powder inhalers for treating local diseases or disorders. Has been achieved. The dry powder inhaler used to deliver the drug to the lungs contains a powdered formulation administration system and is usually bulk fed or stored in unit dose sachets such as hard gelatin capsules or blister packs. It is quantified in individual doses. The bulk container is equipped with a patient-operated measurement system to quickly separate a single dose from the powder prior to inhalation.

The reproducibility of administration in the inhaler requires that the drug formulation be uniform and that the administration be delivered to the subject for consistent and reproducible results. Therefore, the dosing system should ideally operate to efficiently and completely release all the formulations during the inhalation operation when the patient ingests his / her dose. However, it is not necessary to completely release the powder from the inhaler as long as reproducible administration can be achieved. In this respect, the flow properties of the powdered formulation, as well as the long-term physical and mechanical stability, are more important for bulk containers than for single-dose sachets. Good moisture protection to prevent product deterioration is easier with single dose sachets such as blister packs. However, the material used to make the blister allows air to enter the drug package, after which the product loses its potency on long-term storage, especially if the delivered product is hygroscopic. The ambient air that permeates through the blisters carries humidity that destabilizes the active ingredient. In addition, dry powder inhalers that use blister for drug delivery by inhalation suffer from inconsistent delivery doses to the lungs due to changes in air conduit structure due to puncture or peeling of the blister film. there is a possibility.

The powder inhaler and the like described in US Pat. Nos. 7,305,986, 7,464,706, 8,499,757, and 8,636,001. The powder inhaler can generate primary drug particles or a suitable inhalation plume during the inhalation operation by deagglomerating the powder formulation within a capsule or cartridge containing a single dose. The amount of fine powder discharged from the inhaler's mouthpiece during inhalation depends largely on, for example, the interparticle force in the powder formulation and the efficiency of the inhaler to separate those particles so that the force is suitable for inhalation. .. The advantages of drug delivery via the pulmonary circulation are numerous, including rapid entry into the arterial circulation, avoidance of drug degradation by hepatic metabolism, and ease of use without discomfort.

Some of the dry powder inhaler products developed for pulmonary delivery have been reasonably successful. However, there is room for improvement due to lack of practicality and / or manufacturing costs. Some of the persistent problems with prior art inhalers include device durability, dosing variations, device inconvenience, inadequate deagglomeration, and delivery problems in the light of separation from the propellant used. Includes high manufacturing costs and / or lack of patient compliance. Therefore, the inventors have found the need to design and manufacture novel formulations and inhalers with homogeneously improved powder delivery properties, ease of use, and separation configurations for good patient compliance. ..

The present disclosure relates to compositions and methods of using the compositions in the treatment of pulmonary hypertension. In embodiments herein, the composition comprising a dry powder for inhalation for delivery to the lungs comprises a replaceable cartridge for delivery to the pulmonary circulation locally or systemically, a dry powder inhaler. Provided within. Dry powder inhalers are small, reusable or disposable, come in a variety of shapes and sizes, and are equipped with an airflow conduit pathway system for effective and rapid delivery of powdered drugs to the lungs and systemic circulation. It is a respiratory inhaler.

In certain embodiments, the method of treating pulmonary arterial hypertension involves inhalation delivery for rapid delivery and manifestation of action of the activator delivered to the target tissue utilizing the arterial circulation of the pulmonary. Utilize a drug delivery system designed for drug delivery to the lungs, including. In this method, the activator can reach the target site in a therapeutically effective manner.

In certain embodiments, the method comprises one or more vasodilators comprising sildenafil, tadalafil, vardenafil, prostaglandins or analogs thereof, eg, treprostinil or a pharmaceutically acceptable salt thereof, including treprostinil sodium. A stable pharmaceutical composition comprising the active agent of is administered to treat PAH and treprostinil is delivered to the subject's body circulation by pulmonary inhalation using a dry powder inhaler. In certain embodiments, the method comprises providing a dry powder inhaler containing treprostinil in a stable dry powder formulation to a patient in need of treatment and administering the activator by oral inhalation.

In certain embodiments, the drug delivery system is a diketopiperazine-based drug for delivering small molecules, such as prostaglandins, or analogs thereof, including treprostinil and protein-based products for treating PAH. Includes a dry powder inhaler containing the formulation of. This method provides advantages over typical methods of drug delivery, such as oral tablets and subcutaneous and intravenous injectable / infused drug products, which are sensitive to degradation and / or enzyme inactivation.

In one embodiment disclosed herein, a method of providing a prostaglandin preparation to a patient in need of treatment is disclosed, the method of selecting a patient to be treated with PAH, and to the patient. It involves administering a pharmaceutical formulation or a formulation containing treprostinil that produces a pharmaceutical formulation or composition suitable for lung inhalation in combination with ketopiperazine, and delivering the treprostinil formulation using a breathable dry powder inhaler. In this embodiment and other embodiments, the dry powder formulation containing about 1 μg to about 200 μg of treprostinil in the dry powder formulation per dose is provided in a reconstituteable cartridge. In certain embodiments, the dry powder formulation may contain from about 10 μg to about 300 μg of treprostinil per dose, placed in a cartridge or capsule. In certain embodiments, the single-use cartridge may contain from about 10 μg to about 90 μg of treprostinil for at least one inhalation. In some embodiments, the dry powder formulation is delivered by at least one inhalation per use. In this embodiment and other embodiments, the dry powder formulation is delivered to the patient in less than 10 seconds, or less than 8 seconds or less than 6 seconds per inhalation or respiration. In certain embodiments, the dry powder pharmaceutical compositions, include microcrystalline grains of fumaryl diketopiperazine, said particles have a surface area ranging from about 59m 2 / ^{g to} about 63m 2 / ^g, about 23nm It has a pore size of ~ about 30 nm.

Also disclosed herein are patients treated for pulmonary arterial hypertension, or activities that include treprostinyl, epoprostenol, bosentan, ambricentan, macitentan, sildenafil, tadalafil, riosiguato, etc., or combinations thereof. Select PAH patients with symptoms that are treatable by the agent, typically treated only by oral or injectable administration; the above treatments, activators and active agents for the treatment of diseases or disorders. Replacing inhalation therapy with providing the patient with an inhaler containing the activator in a stable dry powder composition containing diketopiperazin; administering the stable dry powder composition to the patient by pulmonary inhalation; A method of treating pulmonary arterial hypertension disease or disorder, which comprises treating the disease or symptom by means of.

In an exemplary embodiment, the formulation for treating pulmonary arterial hypertension comprises an amount of treprostinil up to 200 μg per dose, eg, 1 μg, 5 μg, 10 μg, 15 μg, 20 μg, 30 μg, 60 μg, 90 μg per dose. , 100 μg, 120 μg, 150 μg, 180 μg, or 200 μg of treprostinil, and one or more pharmaceutically acceptable carriers and / or additives are administered to the subject. In this embodiment, the pharmaceutically acceptable carrier and / or additive may be formulated for oral inhalation and can form particles, eg, di, including fumaryldiketopipelazin. Sugars such as ketopiperazine, mannitol, xylitol, sorbitol, and trehalose; amino acids containing glycine, leucine, isoleucine, methionine; surfactants containing polysolvate 80; monovalents containing sodium chloride, potassium chloride, magnesium chloride, and zinc chloride Cationic salts containing divalent and trivalent salts; buffers such as citrates, tartrates, or combinations of one or more carriers and / or additives. In certain embodiments, the formulation comprises a dry powder containing treprostinil, a sugar that is mannitol or trehalose, an amino acid that is leucine or isoleucine, and a cationic salt. In certain embodiments, the formulation may further include sodium chloride, potassium chloride, magnesium chloride, zinc chloride, sodium citrate, sodium citrate, or a combination thereof.

In an exemplary embodiment, the treprostinil agent is administered using a dry powder inhaler for oral inhalation. In this embodiment, the treprostinil inhalation powder is provided to a patient suffering from pulmonary arterial hypertension and in need of treatment, the dry powder inhaler comprises a container containing a cartridge, and the container or cartridge contains treprostinil. Containing dry powder containing, treprostinil is administered multiple times daily for 6 months, and treprostinil is administered to patients with functional classification II as the first monotherapy by oral inhalation earlier in the disease. NS.

In certain embodiments, inhalable dry powder containing treprostinyl and a pharmaceutically acceptable carrier and / or additives was used by oral inhalation using a dry powder inhaler and a container containing the inhalable dry powder. Pulmonary arterial pulmonary hypertension fumalyl diketopipelazin particles comprising providing monotherapy to patients in need of treatment and administering the dry powder formulation to patients in need of treatment.

In some embodiments, the combination therapy with inhalable dry powder containing treprostinyl and fumaryldiketopiperazin is provided to patients in need of treatment, and prostacyclin analogs, bocentan, ambrisentan, and Administered separately in combination with an orally selected agent selected from endoserin receptor antagonists (ERA) containing macitentan, soluble guanylate cyclase agonists / stimulants such as Riosiguato, and PDE-5 inhibitors including sildenafil, vardenafil and tadalafil. Methods for treating pulmonary arterial hypertension, including that, are provided.

In an alternative embodiment, a dry powder containing treprostinil and fumaryldiketopiperazine can also be administered as part of upfront combination therapy with oral preparations. In another embodiment, an inhalable treprostinil composition comprising fumaryldiketopiperazine and treprostinil powder, wherein treprostinil is in an amount of about 1 μg to about 200 μg of a PDE-5 inhibitor or endothelin receptor antagonist. Administered in combination with such oral agents and / or combination therapies may also be administered in place of continuous parenteral infusion of prostacyclin analogs in critically ill patients classified in WHO Functional Classification IV. Phosphodiesterase inhibitors, including PDE-5 inhibitors, can also be formulated for inhalation, either alone or in combination with treprostinil, and when administered alone, can be administered after treprostinil as a combination therapy. ..

In another embodiment, the inhalation system includes a breathable dry powder inhaler, a container or cartridge containing a dry powder containing the drug for delivering the activator to the airway or lung, and the drug includes, for example, Includes diketopiperazine in crystalline powder form that self-assembles in suspension, amorphous powder form, and / or microcrystalline powder form containing crystals that do not self-assemble in suspension, or a combination thereof. Included are inhalable formulations for pulmonary delivery, such as compositions, or combinations thereof, and compositions containing treprostinyl, sildenafil, valdenafil, tadalafil, or activators containing combinations thereof.

In an alternative embodiment, the dry powder for inhalation is another carrier and / or additive other than diketopiperazine, such as sugars containing trehalose, buffers containing sodium citrate, sodium chloride and chloride. It is formulated with a salt containing zinc and one or more active agents including treprostinyl, valdenafil, and sildenafil.

In embodiments herein, the method of treating PAH is a pharmaceutical composition comprising a dry powder formulation containing treprostinyl and a pharmaceutically acceptable carrier and / or additive for moderate to severe PAH patients. Containing to administer in an amount of treprostinyl up to 200 μg using a dry powder inhaler with a movable member for loading the container containing the movable member, the movable member so that the contents of the container enter the airflow path. Containers from container loading configuration to dosing configuration so that the inhaler creates airflow through the inhaler during the inhalation operation and more than 60% of the dry powder dose in the container is delivered to the lungs in a single inhalation. Can be configured.

In some embodiments, the treatment regimen by inhalation of dry powder is according to the patient's needs and is performed with standard treatment including at least 1 to 4 inhalations daily, depending on the severity of the disease. The spray session can be replaced with a single inhalation.

In the embodiments disclosed herein, a dry powder composition and a dry powder inhaler comprising a container or cartridge for delivering a dry powder containing a pharmaceutical to a subject by oral inhalation are disclosed. In certain embodiments, the dry powder inhaler is a breathable dry powder inhaler, the container or cartridge containing, but not limited to, an active ingredient, including a pharmaceutically active substance, and optionally a pharmaceutically acceptable carrier. Designed to contain inhalable dry powders, including pharmaceutical formulations. In particular, dry powder inhalers are for the treatment of pulmonary arterial hypertension.

Dry powder inhalers are offered in various shapes and sizes of embodiments, are reusable, easy to use, inexpensive to manufacture, and / or simple using plastic or other acceptable materials. It can be mass-produced in various processes. Various embodiments of a dry powder inhaler are provided herein, and inhalation systems generally include an inhaler, a powder-filled cartridge, and an empty cartridge. The inhalation system can be designed to use any type of dry powder. In certain embodiments, the dry powder is a relatively highly cohesive powder that requires optimal deagglomeration conditions. In one embodiment, the inhalation system is a reusable, compact respiratory inhaler combined with a single-use cartridge containing a pre-weighed dose of powdered formulation. The inhaler delivers dry powder in a single inhalation to a patient being treated for pulmonary arterial hypertension in less than 10 seconds. In certain embodiments, oral inhalation can deliver more than 60% powder in less than 6 seconds, less than 4 seconds, and less than 2 seconds.

As used herein, the term "unit dose inhaler" is adapted to accept a single sachet, cartridge or container containing a dry powder formulation, which is inhaled into a single dose of dry powder formulation. An inhaler that delivers to the user from a single container. It should be understood that in some cases multiple unit doses are required to provide the specified dose to the user.

As used herein, the term "cartridge" is a powder containment enclosure configured to hold or contain a dry powder formulation, and refers to an enclosure having a cup or container and a lid. The cartridge is made of a hard material and the cup or container is movable relative to the lid and vice versa.

As used herein, the term "powder mass" refers to the agglomeration of powder particles or the irregular agglomeration of width, diameter, length, etc.

As used herein, the term "unit dose" refers to a pre-measured dry powder formulation for inhalation. Alternatively, a unit dose can refer to a single enclosure containing a container containing a single dose or multiple doses of a formulation that can be delivered by inhalation as a single measured dose. Unit dose sachets / cartridges / containers contain single doses. Alternatively, it may have multiple compartments that are individually accessible, each containing a unit dose.

The term "about" as used herein is used to indicate that a value includes the standard deviation of the error of the device or method used to determine the value.

As used herein, the term "fine particles" refers to particles with a diameter of about 0.5 μm to about 1000 μm, regardless of the exact external or internal structure. Particles with diameters between about 0.5 micron and about 10 microns can successfully pass through most natural barriers and reach the lungs. It must be less than about 10 microns in diameter to pass through the bends of the throat and must be about 0.5 microns or more in diameter to avoid exhalation. To reach the deep (or alveoli) part of the lung, where the most efficient absorption is believed to occur, some literature uses standard techniques, such as the Anderson Cascade Impactor. Although a slightly different range is used when measured using, it is preferable to maximize the proportion of particles contained in the "breathable proportion" (RF), generally from about 0.5 to about. It is recognized as a particle with an aerodynamic diameter of 6 μm. Other impactors can be used to measure aerodynamic particle size, such as NEXT GENERATION IMPACTOR ^TM (NGI ^TM , MSP), with similar aerodynamic particle size, eg less than 6.4 μm. The rate of breathability is defined. In some embodiments, a laser diffractometer, eg, the volume center geometric diameter (VMGD) of a particle, is measured to assess the performance of an inhalation system, its entire size for teachings related to laser diffraction. The particle size is measured using the laser diffractometer disclosed in US Pat. No. 8,508,732, which is incorporated herein by reference. For example, in various embodiments, the empty filling factor of the cartridge is 80% or more, 85% or more, or 90% or more, and the VMGD of the emitted particles is less than 12.5 μm, less than 7.0 μm, or 4.8 μm. Since it is less than, it is possible to gradually show good aerodynamic performance.

Respirable Percentage (RF / fill) on Fill is the percentage of powder in the dose released from the inhaler upon discharge of the filled powder content for use as a dose and is suitable for breathing. That is, the proportion of particles from the filled dose released in a size suitable for lung delivery, which is an indicator of the aerodynamic performance of the microparticles. As described herein, an RF / fill value of 40% or higher reflects acceptable aerodynamic performance. In certain embodiments disclosed herein, the breathable rate at filling can be greater than 50%. In an exemplary embodiment, the breathable percentage on filling is up to about 80% and about 80% of the filling is released with a particle size of less than 5.8 μm as measured using standard techniques. ..

As used herein, the term "dry powder" refers to a particulate composition that is not suspended or dissolved in a propellant or other liquid. This does not necessarily mean that all water molecules are completely absent.

As used herein, the term "amorphous powder" refers to a dry powder that lacks a well-defined repeating form, shape, or structure, including all non-crystalline powders.

The present disclosure also makes it possible to improve improved powders, compositions, methods of producing particles, including microcrystalline particles, and therapeutic methods that make it possible to improve the delivery of agents to the lungs for treating a disease or disorder of interest. To disclose. The embodiments disclosed herein are crystalline diketopiperazines comprising microcrystalline diketopiperazine particles with high drug adsorption capacity in order to obtain a powder with a high drug content of one or more activators. By providing the composition, improved delivery is achieved. The powder produced using the microcrystalline particles of the present invention can deliver an increased drug content with a smaller amount of powder dose, facilitating drug delivery to a patient. The powder can be produced by various methods, including a surfactant-free solution or a surfactant-containing solution, depending on the starting material.

In an alternative embodiment disclosed herein, the drug delivery system comprises a dry powder for inhalation containing a large number of substantially homogeneous microcrystalline particles, the microcrystalline particles being substantially hollow. Includes a shell that has a spherical structure and may be porous, containing crystallites of diketopiperazine that do not self-assemble in suspension or solution. In certain embodiments, depending on the drug and / or the drug content provided, and other factors in the process of making the powder, the microcrystalline particles are substantially hollow spherical, diketopiperazine crystallites. It can be a substantially solid particle containing. In some embodiments, the microcrystalline particles, as determined by BJH adsorption, about 0.43 cm ³ / g, an average pore volume in the range of about 0.4 cm ³ / g to about 0.45 cm ³ / g, and about Includes relatively porous particles with an average pore size in the range of 23 nm to about 30 nm, or about 23.8 nm to about 26.2 nm.

Certain embodiments disclosed herein include a dry powder containing a large number of substantially uniform microcrystalline particles, the particles having a substantially spherical structure including a shell that can be porous. The particles contain crystals of diketopiperazine that do not self-assemble in suspension or solution, have a median volume geometric diameter of less than 5 μm or less than 2.5 μm, and contain an activator.

In certain embodiments herein, up to about 92% of the microcrystalline particles have a median volume geometric diameter of 5.8 μm. In certain embodiments, the shell of the particles is composed of linked diketopiperazine crystallites with one or more agents adsorbed on the surface. In some embodiments, the particles are capable of trapping the drug in the internal voids and / or a combination of the drug adsorbed on the surface of the crystallite and the drug trapped in the internal voids of the sphere. ..

In certain embodiments, a diketopiperazine composition comprising a large number of substantially uniformly formed microcrystalline particles is provided, in which the particles have a substantially hollow spherical structure and are non-self-aggregating diketopiperazine crystals. Containing shells containing offspring, the particles are a high pressure of up to 2,000 psi when diketopiperazine solution with trans isomer content in the range of about 45% to 65% is combined with acetic acid solution in the absence of surfactant. Simultaneously homogenize in a high shear mixer to form a precipitate, wash the precipitate with deionized water, concentrate the suspension, and dry the suspension with a spray dryer. Formed by the method including. The microcrystalline particles can be formed in advance for later use or can be combined with the activator in suspension prior to spray drying.

This method uses a solution containing the active agent or active ingredient, such as a drug or physiologically active agent, prior to the spray drying step so that the active agent or active ingredient is adsorbed and / or captured on or in the particles. The step of adding in mixture with other pharmaceutically acceptable carriers and / or additives can be further included. The particles produced by this method can be in the submicron size range prior to spray drying.

In certain embodiments, a diketopiperazine composition comprising a large number of substantially uniformly formed microcrystalline particles is provided in which the particles have a substantially hollow spherical structure and are non-self-aggregating diketopiperazine crystals. Containing shells containing offspring, the particles have a volume average geometric diameter of 5 μm or less, and the particles are highly sheared at high pressures of up to 2,000 psi in diketopiperazine solution combined with acetic acid solution in the absence of surfactant. Formed by a method that includes the steps of simultaneously homogenizing with a mixer to form a precipitate, washing the precipitate in suspension with deionized water, concentrating the suspension, and drying the suspension with a spray dryer. Will be done.

This method mixes a solution containing the activator or active ingredient, such as a drug or bioactive agent, prior to the spray drying step so that the activator or active ingredient is adsorbed and / or captured on or in the particles. The step of adding the above can be further included. The particles produced by this method can be in the submicron size range prior to spray drying.

In certain embodiments, a diketopiperazine composition comprising a large number of substantially uniformly formed microcrystalline particles is provided, wherein the microcrystalline particles have a substantially hollow spherical structure and do not self-assemble. Containing shells containing crystallites, the particles have a volume average geometric diameter of 5 μm or less, and the particles are in diketopiperazine solution with acetic acid solution in the absence of surfactant and in the absence of activator. Combined, homogenize simultaneously in a high shear mixer at a high pressure of up to 2,000 psi to form a precipitate, wash the precipitate in suspension with deionized water, concentrate the suspension and in a spray dryer. It is formed by a method that includes the step of drying the suspension.

In certain embodiments, where the starting material containing the active ingredient has a viscous extract or honey-like viscous appearance, the microcrystalline particles tangent them in water before combining with the extract or viscous material, as described above. It is formed by washing with flow filtration. After washing in water, the resulting particle suspension is lyophilized to remove water and reconstituted in an alcohol solution containing ethanol or methanol before adding the active ingredient as a solid, suspension or solution. Suspended. In certain embodiments, the method of optionally producing the composition includes one or more of leucine, isoleucine, norleucine, methionine, etc. at the same time as the active ingredient or following the addition of the active ingredient and prior to spray drying. Contains amino acids, or one or more phospholipids, such as 1,2-dipalmitoyl-sn-glycero-3-phosphocholine (DPPC), or 1,2-distearoyl-sn-glycero-3-phosphocholine (DSPC). The step of adding additional additives is included. In certain embodiments, the preparation of the composition comprises optionally filtering or freezing the extract containing the desired activator to separate and remove layers of unwanted material such as lipids to increase solubility. Is done.

The method can further include adding the solution to the mixture while mixing prior to the spray drying step so that the activator or active ingredient is adsorbed and / or captured within or on the surface of the particles. Mixing can be done arbitrarily with or without homogenization in a high shear mixer and the solution contains an activator or active ingredient such as a drug or bioactive agent. The particles produced by this method are in the submicron size range prior to spray drying, or the particles can be formed from solution during spray drying.

In some embodiments herein, the drug content is lyophilized or spray dried at a content of about 10%, about 20%, or about 30% or more, a crystalline powder using FDKP. Can be delivered on. In embodiments using microcrystalline particles formed from FDKP, or disodium salts of FDKP, that contain non-self-assembled, submicron-sized particles, the drug content is typically 0.01% (w / w /). w) Can be super. In certain embodiments, the drug content delivered with the microcrystalline particles is from about 0.01% (w / w) to about 75% (w / w), about 1% (w), depending on the drug being delivered. / W) to about 50% (w / w), about 10% (w / w) to about 25% (w / w), about 10% (w / w) to about 20% (w / w), or It is about 5% (w / w) to about 30% (w / w), or more than 25% (w / w). In an example of an embodiment, the agent is a peptide such as insulin, typically approximately 10% (w / w) to 45% (w / w), or about 10% (w), for the microparticles of the invention. / W) to about 20% (w / w) of insulin is included. In certain embodiments, the drug content of the particles varies, depending on the form and size of the drug delivered.

In an exemplary embodiment, the composition comprises a dry powder containing microcrystalline particles of fumalyl diketopiperazine adsorbing treprostinil, the content of treprostinil in the composition being up to about 20% of the dry powder. (W / w) is included and ranges from about 0.5% to about 10% (w / w), or from about 1% to about 5% (w / w). In certain embodiments, the compositions herein include other additives suitable for inhalation, such as methionine, isoleucine, and amino acids containing leucine. In this embodiment, the treprostinil composition contains pulmonary hypertension due to self-administration in a single inhalation of an effective dose containing microcrystalline particles of fumaryldiketopiperazine and a dry powder composition of about 1 mg to 15 mg containing treprostinil. Can be used as a prophylaxis and treatment for. In certain embodiments, the content of treprostinil in the formulation can be from about 1 μg to about 200 μg. In certain embodiments, the dry powder content of the cartridge containing treprostinil can be 20 μg, 30 μg, 60 μg, 90 μg, 120 μg, 150 μg, 180 μg, or 200 μg.

In an alternative embodiment, the pharmaceutically acceptable carrier for producing the dry powder includes any carrier or additive that is useful in the production of the dry powder and is suitable for pulmonary delivery. Examples of pharmaceutically acceptable carriers or additives include sugars containing monosaccharides and polysaccharides such as lactose, mannose, sucrose, mannitol, trehalose, citrate, glycine, L-leucine, isoleucine, trileucine. Amino acids containing, tartrate, methionine, vitamin A, vitamin E, zinc citrate, sodium citrate, trisodium citrate, sodium tartrate, sodium chloride, zinc chloride, zinc tartrate, polyvinylpyrrolidone, polysorbate 80, diphosphotidyl Contains phospholipids including choline.

In certain embodiments, a method of self-administering a dry powder formulation to its own lungs by a dry powder inhalation system is also provided. This method involves obtaining a dry powder inhaler in a closed position with a mouthpiece, obtaining a cartridge containing a pre-measured dose of the dry powder formulation in a contained configuration, a dry powder inhaler. Includes opening and installing the cartridge, closing the inhaler to move the cartridge into the dosing configuration, putting the mouthpiece in its mouth, and inhaling once deep to deliver the dry powder formulation.

In yet another embodiment, methods of treating obesity, hyperglycemia, insulin resistance, pulmonary hypertension, anaphylaxis, and / or diabetes are disclosed. The method includes administration of an inhalable dry powder composition or formulation comprising diketopiperazine having, for example, diketopiperazine having the formula 2,5-diketo-3,6-di (4-X-aminobutyl) piperazine. X is selected from the group consisting of succinyl, glutalyl, maleyl, and fumaryl. In this embodiment, the dry powder composition can include a diketopiperazine salt. In yet another embodiment, the diketopiperazine is 2,5-diketo-3,6-di (4-fumalyl-aminobutyl) piperazine, which comprises or comprises a pharmaceutically acceptable carrier or additive. No dry powder composition or formulation is provided.

An inhalation system is provided for delivering the dry powder formulation to the patient's lungs, which system is dosed in the range of 0.065 to about 0.200 (√kPa) / liter per minute with respect to the flow. Includes a dry powder inhaler configured to have a flow path with total resistance. The dry powder inhaler can either contain a single-use dry powder formulation that can be discarded after use, or can be provided containing a replaceable individual dose in a multi-use inhaler and can be provided individually. Dose sachets or containers can be discarded after use.

In certain embodiments, the dry powder inhaler described above, respiratory organs including pulmonary arterial pulmonary hypertension, cystic fibrosis, respiratory infections, cancer, and other systemic diseases including endocrine diseases including diabetes and obesity or A dry powder inhalation kit containing one or more drug cartridges containing a dry powder formulation for treating disorders such as lung disease or disease is provided.

Also provided are methods of treating a patient's disease or disorder by embodiments of a dry powder inhaler disclosed herein. The method of treatment comprises a cartridge containing, for a patient in need of treatment, a dose of an inhalable formulation containing an active ingredient selected from the group described above and a pharmaceutically acceptable carrier and / or additive. Included in providing a dry powder inhaler and allowing the patient to inhale deeply through the dry powder inhaler in about 3-4 seconds to deliver the dose. This method allows the patient to then resume normal breathing patterns.

The following examples describe some methods of making dry powders suitable for use in the inhalers described herein and show data obtained from tests using dry powders.

(Example 1)
Preparation of Surfactant-Free Dry Powder Containing FDKP polycrystalline Powder for Use in Inhalers: In an exemplary embodiment, a surfactant-free dry powder containing FDKP polycrystalline particles is prepared. NS. Using a dual-feed high-shear mixer, approximately equal masses of acetic acid solution (Table 1) and FDKP solution (Table 2) maintained at about 25 ° C. ± 5 ° C. were ^{fed through a 0.001 in 2} opening at 2000 psi. , A precipitate was formed by homogenization. The precipitate was recovered in near isothermal deionized (DI) water. The weight% content of FDKP microcrystals in the suspension is about 2 to 3.5%. The FDKP concentration of the suspension can be assayed for solids by oven drying. The FDKP polycrystalline suspension can be optionally washed by tangential filtration using deionized water. FDKP microcrystals can be arbitrarily separated by filtration, centrifugation, spray drying, or lyophilization.

Dry powders (A, B, C and D) containing microcrystalline particles produced by the method described above were tested for various properties, including surface area, water content, and porosity measurements. Four different powders were used in this test. The residual water content of all the powders tested was 0.4%. Table 2a shows the data obtained from this test.

The data in Table 2a shows that the spray dried, the surface area of the majority of dry powder comprising fine crystal grains of the test sample was ^{59m 2} / ^g~63m 2 / g. The porosity data is that the microcrystalline particles are ^{relatively porous with an average pore volume of about 0.43 cm 3} / g and an average pore size in the range of about 23.8 nm to 26.2 nm as measured by BJH adsorption. Show that. The porosity measurement data differ from the prior art FDKP crystallites, which have been shown to have an average pore volume of about 0.36 ^{cm 3 / g and an average pore size of about 20 nm to 22 nm.} show.

(Example 2)
Preparation of dry powder containing microcrystalline FDKP particles containing treprostinil. A solution containing 0.2-1.0% by weight of treprostinil in ethyl alcohol was added to the suspension of FDKP crystallites obtained as described in Example 1. The mixture was spray dried using a Buchi B290 spray dryer equipped with a high efficiency cyclone. Nitrogen was used as the process gas (60 nm). The mixture was dried using a pump dose of 10-12% with a suction rate of 90-100% and an inlet temperature of 170-190 ° C. The weight% concentration of treprostinil in the obtained powder was 0.5 to 10%. Delivery efficiencies of these powders after being expelled from the dry powder inhaler ranged between approximately 50% and 70%.

(Example 3)
Use of the treprostinil-fumaryl diketopiperazine composition in healthy subjects. The study was an open-label, single-dose study in 36 healthy, normal volunteers sequentially assigned to 6 groups (30, 60, 90, 120, 150, and 180 μg) receiving a single dose of TreT. Met. The safety and tolerability of dry powder compositions containing treprostinil is each continuous using a powder dry inhaler system containing a single inhalation dose cartridge before increasing the dose for the next group. Evaluated in groups. Blood samples were drawn at selected times prior to administration of the composition and throughout 480 minutes after administration. Blood samples were analyzed for treprostinil using a validated analytical method and PK parameters were calculated using the non-compartment method.

A total of 36 individuals were randomly administered. There were no serious adverse events, serious adverse events, or deaths during the study period. There were no adverse events leading to early termination of the subject. The most frequently reported adverse events were cough (n = 11, 30.6%) and headache (n = 8, 22%). Biological analysis data indicate that plasma levels and exposures of treprostinil have achieved clinically relevant levels comparable to those observed in previous Tyvaso® single-dose clinical trials. confirmed. The C _max and AUC of treprostinil increased linearly with increasing dose. Overall, treprostinil is safe and well tolerated when inhaled as a dry powder, producing clinically appropriate concentrations of treprostinil.

The above disclosure is an exemplary embodiment. It should be acknowledged by those skilled in the art that the devices, techniques, and methods disclosed herein describe typical embodiments that work well in the practice of the present disclosure. However, one of ordinary skill in the art can make many changes in the particular embodiments disclosed in the light of the present disclosure and still obtain similar or similar results without departing from the spirit and scope of the invention. Should be understood.

Unless otherwise stated, all numbers representing quantities such as component weights, molecular weights, reaction conditions, etc. used in the specification and claims are understood to be moderated by the term "about" in all cases. Should be. Therefore, unless otherwise indicated, the numerical parameters shown herein and in the appended claims are approximations that may vary depending on the desired properties to be obtained. At the very least, it does not attempt to limit its application as an equivalent to the claims, and each numerical parameter is at least interpreted by applying conventional rounding means in the light of the number of significant figures reported. Should be. Although the numerical ranges and parameters that indicate the wide range are approximations, the numerical values shown in the particular embodiment are reported as accurately as possible. However, any number essentially contains the error that inevitably arises from the standard deviation seen in each test measurement.

The terms "a", "an", "the", and similar references used in the context of describing the invention (especially in the context of the following claims) are apparent unless otherwise stated or by context. It should be construed to cover both the singular and the plural, unless inconsistent with. The enumeration of the range of values herein is intended to serve merely as an abbreviation for individually referring to each individual value contained within the range. Unless otherwise stated herein, individual values are incorporated herein as if they were individually listed herein. All methods described herein may be performed in any suitable order, unless otherwise stated herein or as clearly contradictory to the context. The use of any example, or exemplary description (eg, "etc.") provided herein is only intended to better articulate the invention and claim. It does not impose any particular restrictions on the range of. The statements herein should not be construed as indicating non-claims essential to the practice of the present invention.

The use of the term "or" in the claims is "and / or" unless it is explicitly stated that it means only alternatives or the alternatives are mutually exclusive. Although used to mean, the present disclosure supports alternatives only and the definition meaning "and / or".

The grouping of alternative elements or embodiments disclosed herein should not be construed as limiting. The components of each group may be referenced and claimed individually or in any combination with other components of the group or other elements found herein. For convenience and patentability reasons, it is expected that one or more components of a group will be included in or removed from the group. If such inclusion or deletion occurs, the specification is deemed to include the modified group and satisfies all statements of the Markush group used in the appended claims.

This specification describes preferred embodiments of the present invention, including the best embodiments known to the inventor for carrying out the present invention. Of course, variations of those described embodiments will be apparent to those skilled in the art by reading the above description. The inventor expects those skilled in the art to properly use such modifications, and the inventor intends to implement the invention in ways other than those specifically described herein. There is. Accordingly, the present invention includes any modification of the subject matter and equivalents set forth in the appended claims, as permitted by applicable law. Moreover, any combination of the above-mentioned elements in any conceivable variation is included in the present invention unless otherwise stated herein or as clearly contradictory to the context.

Some of the embodiments disclosed herein may be further limited in the claims by the use of the phrase "consisting of" or "consisting of essentially". When used in a claim, the transitional phrase "consisting of", whether at the time of filing or added by amendment, excludes elements, steps, or components not specified in the claim. The transition phrase "becomes essential" limits the scope of the claim to those that do not substantially affect a particular material or step and the basic and novel features (s). The embodiments so claimed are described and made possible essentially or explicitly herein.

In addition, numerous patents and printed publications are referenced throughout this specification. Each of the above cited references and printed publications is incorporated herein by reference in their entirety.

Furthermore, it should be understood that the embodiments disclosed herein exemplify the principles of the present invention. Other modifications that may be adopted are within the scope of the present invention. Therefore, the alternative configuration can be used as an embodiment without limitation according to the teachings of the present specification. Therefore, the present invention is not exactly limited as shown and described.

(Additional note)
(Appendix 1)
A pharmaceutical dry powder composition comprising an amount of up to 200 μg of a treprostinil agent and one or more of its pharmaceutically acceptable salts and a pharmaceutically acceptable carrier and / or additive.

(Appendix 2)
The pharmaceutical dry powder composition according to Appendix 1, wherein the one or more pharmaceutically acceptable carriers and / or additives are diketopiperazine.

(Appendix 3)
The pharmaceutical dry powder composition according to Appendix 2, wherein the diketopiperazine is fumalyl diketopiperazine, and the composition contains crystals of the diketopiperazine and microcrystalline particles containing the treprostinil.

(Appendix 4)
The pharmaceutical dry powder composition according to Appendix 1, wherein the treprostinil is present in the dry powder composition in an amount of about 1 μg to about 180 μg.

(Appendix 5)
The pharmaceutical dry powder composition according to Appendix 1, which is in a substantially crystalline form.

(Appendix 6)
The one or more pharmaceutically acceptable carriers and / or additives are lactose, mannose, sucrose, mannitol, trehalose, sodium citrate, trisodium citrate, zinc citrate, glycine, L-leucine, isoleucine. , Trileucine, sodium citrate, zinc tartrate, methionine, vitamin A, vitamin E, sodium chloride, zinc chloride, polyvinylpyrrolidone, or polysorbate 80, the pharmaceutical dry powder composition according to Appendix 1.

(Appendix 7)
The pharmaceutical dry powder composition according to Appendix 6, wherein the one or more pharmaceutically acceptable carriers and / or additives are sodium citrate, sodium chloride, leucine or isoleucine, and trehalose.

(Appendix 8)
The pharmaceutical dry powder composition according to Appendix 7, further comprising polysorbate 80.

(Appendix 9)
The microcrystalline particles have a specific surface area in the range of about ^59m 2 / g to about ^63m 2 / g, a pharmaceutical dry powder composition according to appendix 3.

(Appendix 10)
The pharmaceutical dry powder composition according to Appendix 3, wherein the polycrystalline particles have a pore size in the range of about 23 nm to about 30 nm.

(Appendix 11)
A dry powder inhaler comprising a moving member for loading an enclosure and configuring a container to achieve a dosing configuration, wherein the enclosure comprises a dry powder composition comprising the pharmaceutical dry powder composition according to Appendix 1. Inhaler.

(Appendix 12)
The dry powder inhaler according to Appendix 11, wherein the enclosure comprises a cartridge consisting of a lid and a container.

(Appendix 13)
Inhalation of dry powder containing up to 200 μg of treprostinil or a pharmaceutically acceptable salt thereof and / or a dry powder composition containing one or more pharmaceutically acceptable carriers or additives for patients in need of treatment. A method of treating pulmonary arterial hypertension, including administration by oral inhalation using a vessel.

(Appendix 14)
The one or more pharmaceutically acceptable carriers and / or additives are fumalyl diketopiperazin, lactose, mannose, sucrose, mannitol, trehalose, sodium citrate, trisodium citrate, zinc citrate, glycine. , L-leucine, isoleucine, trileucine, sodium citrate, zinc tartrate, methionine, vitamin A, vitamin E, sodium chloride, zinc chloride, polyvinylpyrrolidone, and polysorbate 80, the pulmonary artery according to Appendix 11. How to treat pulmonary hypertension.

(Appendix 15)
The method for treating pulmonary arterial hypertension according to Appendix 12, wherein the one or more pharmaceutically acceptable carriers and / or additives are sodium citrate, sodium chloride, leucine or isoleucine, and trehalose.

(Appendix 16)
The method for treating pulmonary arterial hypertension according to Appendix 11, wherein the one or more pharmaceutically acceptable carriers and / or additives are fumalyl diketopiperazine.

(Appendix 17)
The method for treating pulmonary arterial hypertension according to Appendix 11, wherein the dry powder composition is administered in less than 10 seconds with at least one inhalation.

(Appendix 18)
Through inhalation using a dry powder inhaler containing up to 200 μg of treprostinyl or a pharmaceutically acceptable salt thereof and / or a dry powder composition containing one or more pharmaceutically acceptable carriers and / or additives. A pharmaceutical dry powder composition for the treatment of pulmonary arterial hypertension, including oral administration.

(Appendix 19)
The one or more pharmaceutically acceptable carriers and / or additives are fumalyl diketopiperazin, lactose, mannose, sucrose, mannitol, trehalose, sodium citrate, trisodium citrate, zinc citrate, glycine. , L-leucine, isoleucine, trileucine, sodium citrate, zinc tartrate, methionine, vitamin A, vitamin E, sodium chloride, zinc chloride, polyvinylpyrrolidone, and polysolvate 80, according to Appendix 18. Dry powder composition.

(Appendix 20)
The pharmaceutical dry powder composition according to Appendix 19, wherein the one or more pharmaceutically acceptable carriers and / or additives are sodium citrate, sodium chloride, leucine or isoleucine, and trehalose.

(Appendix 21)
The pharmaceutical dry powder composition according to Appendix 18, wherein the one or more pharmaceutically acceptable carriers and / or additives are fumalyl diketopiperazine.

(Appendix 22)
The pharmaceutical dry powder composition according to Appendix 18, wherein the dry powder composition is administered in less than 10 seconds with at least one inhalation.

(Appendix 23)
Pulmonary arterial lung, including oral administration of a dry powder composition containing up to 200 μg of treprostinil or a pharmaceutically acceptable salt thereof, and / or one or more pharmaceutically acceptable carriers and / or additives. An inhaler containing a pharmaceutical dry powder composition for the treatment of hypertension.

(Appendix 24)
The one or more pharmaceutically acceptable carriers and / or additives are fumalyl diketopiperazin, lactose, mannose, sucrose, mannitol, trehalose, sodium citrate, trisodium citrate, zinc citrate, glycine. , L-leucine, isoleucine, trileucine, sodium citrate, zinc tartrate, methionine, vitamin A, vitamin E, sodium chloride, zinc chloride, polyvinylpyrrolidone, and polysorbate 80, the inhalation according to Appendix 23. vessel.

(Appendix 25)
The inhaler according to Appendix 24, wherein the one or more pharmaceutically acceptable carriers and / or additives are sodium citrate, sodium chloride, leucine or isoleucine, and trehalose.

(Appendix 26)
23. The inhaler according to Appendix 23, wherein the one or more pharmaceutically acceptable carriers and / or additives are fumalyl diketopiperazine.

(Appendix 27)
23. The inhaler according to Appendix 23, wherein the dry powder composition is administered in less than 10 seconds with at least one inhalation.

Claims (27)

A pharmaceutical dry powder composition comprising an amount of up to 200 μg of a treprostinil agent and one or more of its pharmaceutically acceptable salts and a pharmaceutically acceptable carrier and / or additive. The pharmaceutical dry powder composition according to claim 1, wherein the one or more pharmaceutically acceptable carriers and / or additives are diketopiperazine. The pharmaceutical dry powder composition according to claim 2, wherein the diketopiperazine is fumalyl diketopiperazine, and the composition contains crystals of the diketopiperazine and microcrystalline particles containing the treprostinil. The pharmaceutical dry powder composition according to claim 1, wherein the treprostinil is present in the dry powder composition in an amount of about 1 μg to about 180 μg. The pharmaceutical dry powder composition according to claim 1, which is in a substantially crystalline form. The one or more pharmaceutically acceptable carriers and / or additives are lactose, mannose, sucrose, mannitol, trehalose, sodium citrate, trisodium citrate, zinc citrate, glycine, L-leucine, isoleucine. The pharmaceutical dry powder composition according to claim 1, which is selected from trisodium citrate, sodium citrate, zinc tartrate, methionine, vitamin A, vitamin E, sodium chloride, zinc chloride, polyvinylpyrrolidone, or polysolvate 80. The pharmaceutical dry powder composition according to claim 6, wherein the one or more pharmaceutically acceptable carriers and / or additives are sodium citrate, sodium chloride, leucine or isoleucine, and trehalose. The pharmaceutical dry powder composition according to claim 7, further comprising polysorbate 80. The microcrystalline particles have a specific surface area in the range of about ^59m 2 / g to about ^63m 2 / g, a pharmaceutical dry powder composition of claim 3. The pharmaceutical dry powder composition according to claim 3, wherein the polycrystalline particles have a pore size in the range of about 23 nm to about 30 nm. A dry powder inhaler comprising a moving member for loading an enclosure and for configuring a container to achieve a dosing configuration, wherein the enclosure comprises the pharmaceutical dry powder composition according to claim 1, dried. Powder inhaler. The dry powder inhaler according to claim 11, wherein the enclosure comprises a cartridge comprising a lid and a container. Inhalation of dry powder containing up to 200 μg of treprostinil or a pharmaceutically acceptable salt thereof and / or a dry powder composition containing one or more pharmaceutically acceptable carriers or additives for patients in need of treatment. A method of treating pulmonary arterial hypertension, including administration by oral inhalation using a vessel. The one or more pharmaceutically acceptable carriers and / or additives are fumalyl diketopiperazin, lactose, mannose, sucrose, mannitol, trehalose, sodium citrate, trisodium citrate, zinc citrate, glycine. , L-leucine, isoleucine, trileucine, sodium citrate, zinc tartrate, methionine, vitamin A, vitamin E, sodium chloride, zinc chloride, polyvinylpyrrolidone, and polysolvate 80, according to claim 11. How to treat pulmonary arterial hypertension. The method for treating pulmonary arterial hypertension according to claim 12, wherein the one or more pharmaceutically acceptable carriers and / or additives are sodium citrate, sodium chloride, leucine or isoleucine, and trehalose. .. The method for treating pulmonary arterial hypertension according to claim 11, wherein the one or more pharmaceutically acceptable carriers and / or additives are fumalyl diketopiperazine. The method for treating pulmonary arterial hypertension according to claim 11, wherein the dry powder composition is administered in less than 10 seconds with at least one inhalation. Through inhalation using a dry powder inhaler containing up to 200 μg of treprostinyl or a pharmaceutically acceptable salt thereof and / or a dry powder composition containing one or more pharmaceutically acceptable carriers and / or additives. A pharmaceutical dry powder composition for the treatment of pulmonary arterial hypertension, including oral administration. The one or more pharmaceutically acceptable carriers and / or additives are fumalyl diketopiperazin, lactose, mannose, sucrose, mannitol, trehalose, sodium citrate, trisodium citrate, zinc citrate, glycine. , L-leucine, isoleucine, trileucine, sodium citrate, zinc tartrate, methionine, vitamin A, vitamin E, sodium chloride, zinc chloride, polyvinylpyrrolidone, and polysolvate 80, according to claim 18. Pharmaceutical dry powder composition. The pharmaceutical dry powder composition according to claim 19, wherein the one or more pharmaceutically acceptable carriers and / or additives are sodium citrate, sodium chloride, leucine or isoleucine, and trehalose. The pharmaceutical dry powder composition according to claim 18, wherein the one or more pharmaceutically acceptable carriers and / or additives are fumalyl diketopiperazine. The pharmaceutical dry powder composition according to claim 18, wherein the dry powder composition is administered in less than 10 seconds with at least one inhalation. Pulmonary arterial lung, including oral administration of a dry powder composition containing up to 200 μg of treprostinil or a pharmaceutically acceptable salt thereof, and / or one or more pharmaceutically acceptable carriers and / or additives. An inhaler containing a pharmaceutical dry powder composition for the treatment of hypertension. The one or more pharmaceutically acceptable carriers and / or additives are fumalyl diketopiperazin, lactose, mannose, sucrose, mannitol, trehalose, sodium citrate, trisodium citrate, zinc citrate, glycine. 23, which is selected from the group consisting of L-leucine, isoleucine, trileucine, sodium citrate, zinc tartrate, methionine, vitamin A, vitamin E, sodium chloride, zinc chloride, polyvinylpyrrolidone, and polysolvate 80. Inhaler. 24. The inhaler of claim 24, wherein the one or more pharmaceutically acceptable carriers and / or additives are sodium citrate, sodium chloride, leucine or isoleucine, and trehalose. 23. The inhaler according to claim 23, wherein the one or more pharmaceutically acceptable carriers and / or additives are fumalyl diketopiperazine. 23. The inhaler according to claim 23, wherein the dry powder composition is administered in less than 10 seconds with at least one inhalation.