EP3801552A1 - Composition et procédé d'inhalation - Google Patents

Composition et procédé d'inhalation

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Publication number
EP3801552A1
EP3801552A1 EP19815062.5A EP19815062A EP3801552A1 EP 3801552 A1 EP3801552 A1 EP 3801552A1 EP 19815062 A EP19815062 A EP 19815062A EP 3801552 A1 EP3801552 A1 EP 3801552A1
Authority
EP
European Patent Office
Prior art keywords
dry powder
powder composition
pharmaceutically acceptable
acceptable carrier
inhaler
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Pending
Application number
EP19815062.5A
Other languages
German (de)
English (en)
Other versions
EP3801552A4 (fr
Inventor
Joseph J. Guarneri
Nikhil AMIN
Marshall L. Grant
John J. Freeman
Kelly S. Kraft
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Mannkind Corp
Original Assignee
Mannkind Corp
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Mannkind Corp filed Critical Mannkind Corp
Publication of EP3801552A1 publication Critical patent/EP3801552A1/fr
Publication of EP3801552A4 publication Critical patent/EP3801552A4/fr
Pending legal-status Critical Current

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/007—Pulmonary tract; Aromatherapy
    • A61K9/0073—Sprays or powders for inhalation; Aerolised or nebulised preparations generated by other means than thermal energy
    • A61K9/0075—Sprays or powders for inhalation; Aerolised or nebulised preparations generated by other means than thermal energy for inhalation via a dry powder inhaler [DPI], e.g. comprising micronized drug mixed with lactose carrier particles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/557—Eicosanoids, e.g. leukotrienes or prostaglandins
    • A61K31/5575—Eicosanoids, e.g. leukotrienes or prostaglandins having a cyclopentane, e.g. prostaglandin E2, prostaglandin F2-alpha
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1605—Excipients; Inactive ingredients
    • A61K9/1617—Organic compounds, e.g. phospholipids, fats
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1605—Excipients; Inactive ingredients
    • A61K9/1617—Organic compounds, e.g. phospholipids, fats
    • A61K9/1623—Sugars or sugar alcohols, e.g. lactose; Derivatives thereof; Homeopathic globules
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
    • A61M15/00—Inhalators
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
    • A61M2202/00—Special media to be introduced, removed or treated
    • A61M2202/06—Solids
    • A61M2202/064—Powder

Definitions

  • compositions and methods for treating pulmonary arterial hypertension are disclosed.
  • Pulmonary arterial hypertension is a complex, multifactorial, progressive syndrome characterized by persistent elevation of pulmonary artery pressure and pulmonary vascular resistance (PVR) that leads to increase in right ventricular afterload and eventually culminates in right heart failure.
  • PVR pulmonary vascular resistance
  • Right ventricular failure limits cardiac output during exertion.
  • the most common symptom at presentation is breathlessness, fatigue, angina, syncope, and abdominal distension, with impaired exercise capacity as a hallmark of the disease.
  • Assessing patients with pulmonary' hypertension involves evaluating the severity' of their disease using a range of clinical assessments, exercise tests, detection of specific biochemical markers, and echocardiographic and hemodynamic assessments.
  • the clinical assessment of the patient has a pivotal role in the choice of the initial treatment, the evaluation of the response to therapy, and the possible escalation of therapy if needed.
  • PAH is classified into five groups (1-5) depending on the severity of the disease.
  • group 1 for example, the disease is heritable and commonly induced by drugs and toxins.
  • PAH includes idiopathic pulmonary arterial hypertension (IPAH, formerly called primary pulmonary hypertension), hereditary PAH, or PAH due to diseases such as connective tissue diseases, HIV infection, portal hypertension, congenital heart disease, schistosomiasis, and drug or toxin exposure (e.g. anorexigens).
  • IPH idiopathic pulmonary arterial hypertension
  • PAH due to diseases such as connective tissue diseases, HIV infection, portal hypertension, congenital heart disease, schistosomiasis, and drug or toxin exposure (e.g. anorexigens).
  • IPH idiopathic pulmonary arterial hypertension
  • PAH due to diseases such as connective tissue diseases, HIV infection, portal hypertension, congenital heart disease, schistosomiasis, and drug or toxin exposure (
  • PAH congenital heart disease
  • Group 2 patients develop PH due to left heart disease from, inter alia, left ventricular systolic dysfunction, left ventricular diastolic dysfunction, valvular disease, or congenital/acquired left heart inflow/outflow tract obstruction, and congenital car di omy op athi es .
  • the PH is due to chronic lung disease and/or hypoxia exhibiting chronic obstructive pulmonary disease, interstitial lung disease, other pulmonary' diseases with mixed restrictive and obstructive pattern, sleep-disordered breathing, alveolar hypoventilation disorders, chronic exposure to high altitude and developmental lung diseases.
  • PH is due to chronic thromboembolic pulmonary hypertension and group 5 patients exhibit PH due to unclear multifactorial mechanisms, including hematologic disorders such as chronic hemolytic anemia, myeloproliferative disorders, splenectomy; systemic disorders such as sarcoidosis, pulmonary histiocytosis, lymphangioleiomyomatosis; metabolic disorders, including glycogen storage disease, Gaucher’s disease and thyroid disorders; and other disorders such as tumor/mass obstruction, fibrosing mediastinitis, chronic renal failure, segmental PH.
  • hematologic disorders such as chronic hemolytic anemia, myeloproliferative disorders, splenectomy
  • systemic disorders such as sarcoidosis, pulmonary histiocytosis, lymphangioleiomyomatosis
  • metabolic disorders including glycogen storage disease, Gaucher’s disease and thyroid disorders
  • other disorders such as tumor/mass obstruction, fibrosing mediastinitis, chronic renal failure, segmental PH.
  • Advanced therapy is directed at the underlying cause of the PH and is warranted in nearly all patients with PH.
  • the disease severity should be reassessed following primary therapy, in order to determine whether advanced therapy is indicated.
  • Advanced therapy is directed at the pulmonary hypertension itself, rather than the underlying cause of the PH.
  • Advanced therapy is widely accepted for many patients with group 1 pulmonary arterial hypertension (PAH). In contrast, it should only be administered on a case-by-case basis for patients with group 3 PH, group 4 PH, or group 5 PH, after carefully weighing the risks versus the benefits. Advanced therapy should not be administered to most patients with group 2 PH.
  • PAH pulmonary arterial hypertension
  • the clinical assessment of the patient has a pivotal role in the choice of the initial treatment, the evaluation of the response to therapy, and the possible escalation of therapy if needed.
  • diagnosing patients with pulmonary hypertension involves evaluating the severity of their disease using a range of clinical assessments, exercise tests, identification of biochemical markers, echocardiographic and hemodynamic assessments.
  • the clinical severity of PAH is classified according to a system originally developed for heart failure by the New York Heart Association (NYHA) and then modified by WHO for patients with PH.
  • This functional classification (I-IV) system links symptoms with activity limitations, and allows clinicians to quickly predict disease progression and prognosis, as well as the need for specific treatment regimens, irrespective of the underlying etiology of PAH.
  • Class I patients exhibit PH, but without resulting limitation of physical activity, and ordinary physical activity does not cause dyspnea or fatigue, chest pain, or near syncope.
  • Class IT patients exhibit pulmonary hypertension resulting in slight limitation of physical activity. They are comfortable at rest and ordinary physical activity causes undue dyspnea or fatigue, chest pain, or near syncope.
  • Class HI are patients with pulmonary hypertension resulting in marked limitation of physical activity, they are comfortable at rest and less than ordinary activity causes undue dyspnea or fatigue, chest pain, or near syncope.
  • Class IV are patients with pulmonary hypertension with inability to carry out any physical activity without symptoms. These patients manifest signs of light heart failure. Dyspnea and/or fatigue may even be present at rest, and discomfort is increased by any physical activity.
  • PH nitric oxide
  • PGI prostacyclin
  • ET-l endothelin
  • impaired potassium channel and growth factor receptor function impaired potassium channel and growth factor receptor function
  • serotonin transporter regulation increased oxidant stress
  • enhanced matrix production of vasoactive factors calcium signaling molecules, inflammatory mediators, growth factors, bone morphogenetic protein receptor 2 (BMPR2) mutations.
  • BMPR2 bone morphogenetic protein receptor 2
  • Pulmonary vascular endothelium is a critical local source of several key mediators for vascular remodeling, including growth factors (fibroblast growth factor [FGF]-2, serotonin [5- HT], angiotensin II, and vasoactive peptides (NO, PGI2, ET-l), cytokines (IL-l, IL-6, macrophage migration inhibitory factor [MIF]), and chemokines (monocyte chemoattractant protein [MCP]-l), adipokines (leptin).
  • growth factors fibroblast growth factor [FGF]-2, serotonin [5- HT], angiotensin II, and vasoactive peptides (NO, PGI2, ET-l
  • cytokines IL-l, IL-6, macrophage migration inhibitory factor [MIF]
  • MCP macrophage migration inhibitory factor
  • chemokines monocyte chemoattractant protein [MCP]-l
  • MCP monocyte chemoattractant protein
  • Endothelial dysfunction is believed to occur early in disease and this leads to chronically impaired production of vasodilator and antiproliferative agents such as NO and prostacyclin, along with overexpression of vasoconstrictor and proliferative substances such as thromboxane A2 and endothelin-l.
  • vasodilator and antiproliferative agents such as NO and prostacyclin
  • vasoconstrictor and proliferative substances such as thromboxane A2 and endothelin-l.
  • Paracrine overproduction of ET-l, 5-HT, angiotensin II, and FGF-2 contributes to an increased pulmonary vascular cell proliferation, survival, migration, and differentiation.
  • Many of these abnormalities both elevate vascular tone and promote endothelial and smooth muscle cell proliferation followed by structural changes or remodeling of the pulmonary vascular bed, which in turn results in an increase in pulmonary vascular resistance.
  • extracellular matrix including collagen, elastin, fibronectin, and ten
  • PAH-specific drugs include the endothelin receptor antagonists, phosphodiesterase type-5 inhibitors (PDE-5i), including bosentan, sitaxsentan and ambrisentan and others such as sildenafil, tadalafil, or soluble guanylate cyclase stimulators and prostanoids.
  • PDE-5i phosphodiesterase type-5 inhibitors
  • PAH drugs belong to one of these classes, including, protenoids, for example, epoprostenol (Flolan® and Veletri® intravenous infusions), treprostinil (Remodulin® subcutaneous/IV infusion); Tyvaso® (inhaled X4 time day) , Iloprost ® (inhaled 6-9 times/day).
  • protenoids for example, epoprostenol (Flolan® and Veletri® intravenous infusions), treprostinil (Remodulin® subcutaneous/IV infusion); Tyvaso® (inhaled X4 time day) , Iloprost ® (inhaled 6-9 times/day).
  • epoprostenol Flolan® and Veletri® intravenous infusions
  • treprostinil Remodulin® subcutaneous/IV infusion
  • Tyvaso® inhaled X4 time day
  • Iloprost ® inhaled 6-9 times/day
  • 6MWD six
  • Intravenous epoprostenol was the first US Food and Drug Administration (FDA)-approved treatment for PAH (approved in 1995).
  • FDA US Food and Drug Administration
  • epoprostenol needs to be delivered as a continuous intravenous infusion through an indwelling catheter, with the risk of rebound PAH and acute right heart failure in case of infusion interruption.
  • ice packs are needed to slow decomposition throughout the infusion period.
  • thermostable epoprostenol preparation for infusion (Veletri®), which does not require cooling, has been approved for use by the FDA.
  • serious adverse events related to the delivery' system include pump malfunction, local site infection, catheter obstruction, and sepsis continues to be a barrier for its use.
  • Treprostinil is a longer-acting tricyclic benzidine analogue of epoprostenol with a terminal elimination half-life of approximately 2 to 4 hours and a distribution half-life of approximately 40 minutes. Unlike epoprostenol, Treprostinil is chemically stable at room temperature allowing it to be administered at ambient temperature and overcomes some of the limitations associated with epoprostenol therapy. Treprostinil causes vasodilation of pulmonary and systemic arterial vascular beds, and inhibits platelet aggregation by binding to prostacyclin IP receptors located on the surface of vascular smooth muscle cells and platelets.
  • Treprostinil (Remodulin®) was first approved by the FDA in 2002 for adults with WHO group 1 PAH and functional class II to class IV status for continuous subcutaneous infusion and is marketed by United Therapeutics (Silver Spring, MD). In a pivotal 12 week randomized, controlled trial of 470 patients, subcutaneous Treprostinil significantly improved exercise capacity compared with placebo. The most common adverse events noted in subcutaneous infusion of Treprostinil-treated patients were infusion site pain.
  • treprostinil diolamine Orenitran®
  • Orenitran® an oral, extended release tablet of treprostinil diolamine
  • the absorption of treprostinil may be inconsistent particularly taken with food.
  • the pharmacological and physiochemical properties of treprostinil make this drug amenable to intermittent administration via the inhaled route.
  • Tyvaso® and Iloprost are solutions for inhalation, which need to be administered using a special nebulizer for a prolonged period of time and often times in a physician’s office.
  • Tyvaso® inhalation system Opti- Neb ultrasonic nebulizer (NebuTec, Elsenfeld, Germany)].
  • the inhalation system is complex to assemble and use, cumbersome to administer the dose (patient need to reset the device 3 times during a treatment session after every 3 breaths) and was found to have high error rates in human factor study.
  • breath counter mechanism is triggered by time (time related) and not by inspiration or expiration flow or effort (breath related) and thus patient can overdose or under dose themselves by taking more or less than prescribed breaths (dose) in the 90 seconds time limit.
  • the system also requires 4 different cleaning schedule (daily, weekly, monthly and yearly). Accordingly, new methods of PAH treatment are needed to facilitate the administration of these products to a patient.
  • Drug delivery to lung tissue has been achieved using a variety of devices for inhalation, including, nebulizers and inhalers, such as metered dose inhalers and dry powder inhalers to treat local disease or disorders.
  • Dry powder inhalers used to deliver medicaments to the lungs contain a dose system of a powder formulation usually either in bulk supply or quantified into individual doses stored in unit dose compartments such as hard gelatin capsules or blister packs.
  • Bulk containers are equipped with a measuring system operated by the patient in order to isolate a single dose from the powder immediately before inhalation.
  • Dosing reproducibility with inhalers requires that the drug formulation is uniform and that the dose be delivered to a subject with consistency and reproducible results. Therefore, the dosing system ideally should operate to completely discharge all of the formulation effectively during an inspiratory maneuver when the patient is taking his/her dose. However, complete powder discharge from the inhaler is not required as long as reproducible dosing can be achieved. Flow properties of the powder formulation, and long term physical and mechanical stability in this respect, are more critical for bulk containers than they are for single unit dose compartments. Good moisture protection for preventing product degradation can be achieved more easily for unit dose compartments such as blisters.
  • the materials used to manufacture the blisters allow air into the drug compartment and subsequently, the formulation loses viability with prolonged storage, particularly if the formulation to be delivered is hygroscopic.
  • the ambient air permeating through the blisters carries in humidity that destabilizes the active ingredient.
  • dry powder inhalers which use blisters to deliver a medicament by inhalation can suffer with inconsistency of dose delivery to the lungs due to variations in geometry of the air conduit architecture resulting from puncturing films or peeling films of the blisters.
  • Dry powder inhalers such as those described in U.S. Patents No. 7,305,986, 7,464,706, 8,499,757 and 8,636,001, which disclosures are incorporated herein by reference in their entirety, can generate primary drug particles, or suitable inhalation plumes during an inspiratory maneuver by deagglomerating the powder formulation within a capsule or cartridge comprising a single dose.
  • the amount of fine powder discharged from the inhaler's mouthpiece during inhalation is largely dependent on, for example, the inter-particulate forces in the powder formulation and the efficiency of the inhaler to separate those particles so that they are suitable for inhalation.
  • the benefits of delivering drugs via the pulmonary circulation are numerous and include rapid entry into the arterial circulation, avoidance of drug degradation by liver metabolism, and ease of use without discomfort.
  • a composition is provided in a dry powder inhaler comprising a replaceable cartridge comprising a dry powder for inhalation for delivery to the lungs for local or systemic delivery into the pulmonary circulation.
  • the dry powder inhaler is a breath-powered inhaler which is compact, reusable or disposable, has various shapes and sizes, and comprises a system of airflow conduit pathways for the effective and rapid delivery of powder medicament to the lungs and the systemic circulation.
  • the method of treating pulmonary arterial hypertension utilizes a drug delivery system which is designed for drug delivery to the lungs, including by inhalation, for rapid delivery and onset of action of the active agent being delivered to target tissues using the arterial circulation in the lungs.
  • the active agent can reach its target site in a therapeutically effective manner.
  • the method comprises administering a stable pharmaceutical composition comprising, one or more active agents, including, a vasodilator, including, sildenafil, tadalafil, vardenafil, a prostaglandin or an analog thereof, for example, treprostinil or a pharmaceutically acceptable salt thereof, including treprostinil sodium, for treating PAH and delivering the treprostinil into the systemic circulation of a subject by pulmonary inhalation using a dry powder inhaler.
  • the method comprises providing to a patient in need of treatment a dry powder inhaler comprising treprostinil in a stable dry powder formulation, and administering the active agent by oral inhalation.
  • the drug delivery system comprises a dry powder inhaler comprising a diketopiperazine-based drug formulation for delivering small molecules, for example, a prostaglandin, or analogs thereof including, tresprostinil and protein-based products for treating PAH.
  • a dry powder inhaler comprising a diketopiperazine-based drug formulation for delivering small molecules, for example, a prostaglandin, or analogs thereof including, tresprostinil and protein-based products for treating PAH.
  • the method provides advantages over typical methods of drug delivery, such as, oral tablet and subcutaneous and intravenous injectable/infusion drug products that are sensitive to degradation and/or enzymatic deactivation.
  • a method for providing a prostaglandin formulation to a patient in need thereof comprising, selecting a patient to be treated for PAH patient, and administering to the patient a dry powder formulation comprising treprostinil; wherein the treprostinil is combined with a diketopiperazine to produce a pharmaceutical formulation or composition suitable for pulmonary inhalation, and delivering the trepostinil formulation using a breath-powered dry powder inhaler.
  • the dry powder formulations is provided in a reconfigurable cartridge comprising from about 1 pg to about 200 pg of treprostinil in the dry powder formulation per dose.
  • the dry powder formulation can comprise from about 10 pg to about 300 pg of treprostinil per dose in a cartridge or capsule.
  • a cartridge for single use can comprise from about 10 pg to about 90 pg of treprostinil for at least one inhalation.
  • 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, or less than 8 seconds or less than 6 seconds per inhalation or breath.
  • the pharmaceutical dry powder composition comprises microcrystalline particles of fumaryl diketopiperazine wherein the particles have a specific surface area ranging from about 59 m 2 /g to about 63 m 2 /g and have a pore size ranging from about 23 nm to about 30 nm.
  • an active agent including treprostinil, epoprostenol, bosentan, ambrisentan, macis
  • the formulation for treating pulmonary arterial hypertension comprises treprostinil in an amount up to 200 pg per dose, for example, amounts of 1 pg, 5 pg, 10 pg, 15 pg, 20 pg, 30 pg, 60 pg, 90 pg, 100 pg, 120 pg, 150 pg, 180 pg, or 200 pg, and one or more pharmaceutically acceptable carriers and/or excipients per dose are to be administered to a subject.
  • the pharmaceutically acceptable carrier and/or excipient can be formulated for oral inhalation and can form particles, for example, a diketopiperazine, including, fumaryl diketopiperazine, sugars such as mannitol, xylitol, sorbitol, and trehalose; amino acids, including, glycine, leucine, isoleucine, methionine; surfactants, including, polysorbate 80; cationic salts, including, monovalent, divalent and trivalent salts, including, sodium chloride, potassium chloride, magnesium chloride, and zinc chloride; buffers such as citrates and tartrates, or combination of one or more carriers and/or excipients and the like.
  • a diketopiperazine including, fumaryl diketopiperazine, sugars such as mannitol, xylitol, sorbitol, and trehalose
  • amino acids including, glycine, leucine, isole
  • the formulation comprises a dry powder comprising treprostinil, a sugar and an amino acid, wherein the sugar is mannitol or trehalose; and the amino acid is leucine or isoleucine and a cationic salt.
  • the formulation can further comprise sodium chloride, potassium chloride, magnesium chloride or zinc chloride, sodium citrate, sodium tartrate, or combinations thereof.
  • the treprostinil dose is administered using a dry powder inhaler for oral inhalation.
  • a treprostinil inhalation powder dose is provided to a patient suffering with pulmonary arterial hypertension and in need of treatment; wherein the a dry powder inhaler comprises a container including, a cartridge, and the container or cartridge comprises the dry powder comprising treprostinil is administered in multiple daily doses for a period of six months and the treprostinil is administered by oral inhalation at an earlier time in the course of the disease to patients with Functional Class II as a first line monotherapy.
  • a method for treating pulmonary arterial hypertension comprising providing a patient in need of treatment a monotherapy using an inhalable dry powder comprising treprostinil and a pharmaceutically acceptable carrier, and/or excipient by oral inhalation using a dry powder inhaler and a container comprising the inhalable dry powder and administering the dry powder formulation to the patient.
  • the treprostinil formulation comprises fumaryl diketopiperazine particles.
  • a method for treating pulmonary arterial hypertension comprising providing a patient in need of treatment a combination therapy using an inhalable dry powder comprising treprostinil and fumaryl diketopiperazine, and administering separately in combination with orally administered drugs selected from prostacyclin analogues, endothelin receptor antagonists (ERAs), including bosentran, ambrisentran and macitentan, soluble guanine cyclase agonists/stimulators such as riociguat, and PDE-5 inhibitors, including sildenafil, vardenafil and tadalafil.
  • drugs selected from prostacyclin analogues, endothelin receptor antagonists (ERAs), including bosentran, ambrisentran and macitentan, soluble guanine cyclase agonists/stimulators such as riociguat, and PDE-5 inhibitors, including sildenafil, vardenafil and tadala
  • a dry powder comprising treprostinil and fumaryl diketopiperazine can also be administered as a part of up-front combination therapy with an oral agent.
  • an inhalable treprostinil composition comprising a dose of fumaryl diketopiperazine and treprostinil powder, wherein treprostinil is in an amount from about 1 pg to about 200 pg administered in combination with an oral agent such as a PDE-5 inhibitor, or an endothelin receptor antagonist and/or the combination therapy may also be administered to replace continuously parenteral infusion of prostacyclin analogs in patients with severe disease and classified in WHO Functional class IV.
  • Phosphodiesterase inhibitors, including PDE-5 inhibitors can also be formulated for inhalation alone, or in combination with the treprostinil and can be administered subsequently if administered alone, as a combination therapy.
  • the inhalation system comprises a breath-powered dry powder inhaler, a container or cartridge containing a dry powder, for delivering an active agent to the pulmonary tract and lungs, including a medicament
  • the medicament can comprise, for example, an inhalable drug formulation for pulmonary delivery such as a composition comprising a diketopiperazine in a crystalline powder form that self-assembles in a suspension, an amorphous powder form, and/or a microcrystalline powder form comprising crystallites that do not self-assemble in suspension, or combinations thereof, and an active agent, including, treprostinil, sildenafil, vardenafil, tadalafil, or combinations thereof.
  • the dry powder for inhalation may be formulated with other carriers and/or excipients other than diketopiperazines, for example a sugar, including trehalose; buffers, including sodium citrate; salts, including, sodium chloride and zinc chloride, and one or more active agents, including, treprostinil, vardenafil, and sildenafil.
  • a sugar including trehalose
  • buffers including sodium citrate
  • salts including, sodium chloride and zinc chloride
  • active agents including, treprostinil, vardenafil, and sildenafil.
  • the method of treating PAH comprises, administering to a patient with moderate to severe PAH a dry powder formulation comprising treprostinil and a pharmaceutically acceptable carrier and/or excipient in an amount up to 200 pg of treprostinil using a dry powder inhaler comprising a movable member for loading a container comprising the pharmaceutical composition and the movable member can configure a container to attain a dosing configuration from a container loading configuration so that inhaler creates an airflow through the inhaler during an inhalation maneuver to allow the contents of the container to enter the airflow path and greater than 60% of a dry powder dose in the container is delivered to the lungs in a single inhalation.
  • the treatment regimen with an inhalation dry powder depends on the patient’s need and can be one inhalation to replace each of a nebulization session performed with standard therapy, including, at least one to four inhalations per day depending on the severity of disease.
  • dry powder compositions and dry powder inhalers comprising a container or a cartridge for delivering dry powders including pharmaceutical medicaments to a subject by oral inhalation are described.
  • the dry powder inhaler is a breath-powered, dry powder inhaler
  • the container or cartridge is designed to contain an inhalable dry powder, including but not limited to pharmaceutical formulations comprising an active ingredient, including a pharmaceutically active substance, and optionally, a pharmaceutically acceptable carrier.
  • the dry powder inhalers are for the treatment of pulmonary arterial hypertension.
  • the dry powder inhalers are provided in various embodiments of shapes and sizes, and can be reusable, easy to use, inexpensive to manufacture and/or produced in high volumes in simple steps using plastics or other acceptable materials.
  • the inhalation systems comprise inhalers, powder-filled cartridges, and empty cartridges.
  • the present inhalation systems can be designed to be used with any type of dry powder.
  • the dry powder is a relatively cohesive powder which requires optimal deagglomeration conditions.
  • the inhalation system provides a re-useable, miniature breath-powered inhaler in combination with single-use cartridges containing pre-metered doses of a dry powder formulation.
  • the inhaler can deliver a dry powder dose in a single inhalation to a patient in treating pulmonary arterial hypertension in less than 10 seconds.
  • oral inhalation can deliver greater than 60% of a powder dose in less than 6 seconds, in less than 4 seconds and in less than 2 seconds.
  • a unit dose inhaler refers to an inhaler that is adapted to receive a single enclosure, cartridge or container comprising a dry powder formulation and delivers a single dose of a dry powder formulation by inhalation from a single container to a user. It should be understood that in some instances multiple unit doses will be required to provide a user with a specified dosage.
  • a“cartridge” is an enclosure configured to hold or contain a dry powder formulation, a powder containing enclosure, which has a cup or container and a lid.
  • the cartridge is made of rigid materials, and the cup or container is moveable relative to the lid in a translational motion or vice versa.
  • a“powder mass” is referred to an agglomeration of powder particles or agglomerate having irregular geometries such as width, diameter, and length.
  • a“unit dose” refers to a pre-metered dry powder formulation for inhalation.
  • a unit dose can be a single enclosure including a container having a single dose or multiple doses of formulation that can be delivered by inhalation as metered single amounts.
  • a unit dose enclosure/cartridge/container contains a single dose. Alternatively it can comprise multiple individually accessible compartments, each containing a unit dose.
  • microparticle refers to a particle with a diameter of about 0.5 to about 1000 pm, irrespective of the precise exterior or interior structure. Microparticles having a diameter of between about 0.5 and about 10 microns can reach the lungs, successfully passing most of the natural barriers. A diameter of less than about 10 microns is required to navigate the turn of the throat and a diameter of about 0.5 pm or greater is required to avoid being exhaled.
  • RF respirable fraction
  • RF respirable fraction
  • a laser diffraction apparatus is used to determine particle size, for example, the laser diffraction apparatus disclosed in U.S. Patents No.
  • VMGD volumetric median geometric diameter
  • Respirable fraction on fill represents the percentage (%) of powder in a dose that is emitted from an inhaler upon discharge of the powder content filled for use as the dose, and that is suitable for respiration, i.e., the percent of particles from the filled dose that are emitted with sizes suitable for pulmonary delivery, which is a measure of microparticle aerodynamic performance.
  • a RF/fill value of 40% or greater than 40% reflects acceptable aerodynamic performance characteristics.
  • the respirable fraction on fill can be greater than 50%.
  • a respirable fraction on fill can be up to about 80%, wherein about 80% of the fill is emitted with particle sizes ⁇ 5.8 pm as measured using standard techniques.
  • dry powder refers to a fine particulate composition that is not suspended or dissolved in a propellant, or other liquid. It is not meant to necessarily imply a complete absence of all water molecules.
  • amorphous powder refers to dry powders lacking a definite repeating form, shape, or structure, including all non-crystalline powders.
  • the present disclosure also provides improved powders comprising microcrystalline particles, compositions, methods of making the particles, and therapeutic methods that allow for improved delivery of drugs to the lungs for treating diseases and disorders in a subject.
  • Embodiments disclosed herein achieve improved delivery by providing crystalline diketopiperazine compositions comprising microcrystalline diketopiperazine particles having high capacity for drug adsorption yielding powders having high drug content of one or more active agents.
  • Powders made with the present microcrystalline particles can deliver increased drug content in lesser amounts of powder dose, which can facilitate drug delivery to a patient.
  • the powders can be made by various methods including, methods utilizing surfactant-free solutions or solutions comprising surfactants depending on the starting materials.
  • the drug delivery system can comprise a dry powder for inhalation comprising a plurality of substantially uniform, microcrystalline particles, wherein the microcrystalline particles can have a substantially hollow spherical structure and comprise a shell which can be porous comprising crystallites of a diketopiperazine that do not self-assemble in a suspension or in solution.
  • the microcrystalline particles can be substantially hollow spherical and substantially solid particles comprising crystallites of the diketopiperazine depending on the drug and/or drug content provided and other factors in the process of making the powders.
  • the microcrystalline particles comprise particles that are relatively porous, having average pore volumes of about 0.43 cm 3 /g, ranging from about 0.4 cm 3 /g to about 0.45 cm 3 /g, and average pore size ranging from about 23 nm to about 30 nm, or from about 23.8 nm to 26.2 nm as determined by BJH adsorption.
  • Certain embodiments disclosed herein comprise dry powders comprising a plurality of substantially uniform, microcrystalline particles, wherein the particles have a substantially spherical structure comprising a shell which can be porous, and the particles comprise crystallites of a diketopiperazine that do not self-assemble in suspension or solution, and have a volumetric median geometric diameter less than 5 pm; or less than 2.5 pm and comprise an active agent.
  • the microcrystalline particles have a volumetric median geometric diameter of 5.8 pm.
  • the particle's shell is constructed from interlocking diketopiperazine microcrystals having one or more drugs adsorbed on their surfaces.
  • the particles can entrap the drug in their interior void volume and/or combinations of the drug adsorbed to the crystallites' surface and drug entrapped in the interior void volume of the spheres.
  • a diketopiperazine composition comprising a plurality of substantially uniformly formed, microcrystalline particles, wherein the particles have a substantially hollow spherical structure and comprise a shell comprising crystallites of a diketopiperazine that do not self-assemble; wherein the particles are formed by a method comprising the step of combining diketopiperazine having a trans isomer content ranging from about 45% to 65% in a solution and a solution of acetic acid without the presence of a surfactant and concurrently homogenizing in a high shear mixer at high pressures 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 drying apparatus.
  • the microcrystalline particles can be pre-formed without for later used, or combined with an active agent in suspension prior to spray drying.
  • the method can further comprise the steps of adding with mixing a solution comprising an active agent or an active ingredient such as a drug or bioactive agent along with other pharmaceutically acceptable carriers and/or excipients prior to the spray drying step so that the active agent or active ingredient is adsorbed and/or entrapped on or within the particles.
  • Particles made by this process can be in the submicron size range prior to spray-drying.
  • a diketopiperazine composition comprising a plurality of substantially uniformly formed, microcrystalline particles, wherein the particles have a substantially hollow spherical structure and comprise a shell comprising crystallites of a diketopiperazine that do not self-assemble, and the particles have a volumetric mean geometric diameter less than equal to 5 pm; wherein the particles are formed by a method comprising the step of combining diketopiperazine in a solution and a solution of acetic acid without the presence of a surfactant and concurrently homogenizing in a high shear mixer at high pressures 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 drying apparatus.
  • the method can further comprise the steps of adding with mixing a solution comprising an active agent or an active ingredient such as a drug or bioactive agent prior to the spray drying step so that the active agent or active ingredient is adsorbed and/or entrapped on or within the particles.
  • Particles made by this process can be in the submicron size range prior to spray-drying.
  • a diketopiperazine composition comprising a plurality of substantially uniformly formed, microcrystalbne particles, wherein the microcrystalline particles have a substantially hollow spherical structure and comprise a shell comprising crystallites of a diketopiperazine that do not self-assemble, and the particles have a volumetric mean geometric diameter less than equal to 5 pm; wherein the particles are formed by a method comprising the step of combining diketopiperazine in a solution and a solution of acetic acid without the presence of a surfactant and without the presence of an active agent, and concurrently homogenizing in a high shear mixer at high pressures 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 drying apparatus.
  • the microcrystalline particles are formed as above and by washing them in water using tangential flow filtration prior to combining with the extract or viscous material. After washing in water, the resultant particle suspension is lyophilized to remove the water and re suspended in an alcohol solution, including ethanol or methanol prior to adding the active ingredient as a solid, or in a suspension, or in solution.
  • the method of making the composition comprises the step of adding any additional excipient, including one or more, amino acid, such as leucine, isoleucine, norleucine, methionine or one or more phospholipids, for example, l,2-dipalmitoyl-sn-glycero-3-phosphocholine (DPPC) or l,2-distearoyl-sn-glycero-3-phosphocholine (DSPC), concurrently with the active ingredient or subsequent to adding the active ingredient, and prior to spray drying.
  • forming the composition comprises the step wherein the extract comprising desired active agents is optionally filtered or winterized to separate and remove layers of unwanted materials such as lipids to increase its solubility.
  • the method can further comprise the steps of adding a solution with mixing to the mixture, and wherein the mixing can optionally be performed with or without homogenization in a high shear mixer, wherein the solution comprises an active agent or an active ingredient such as a drug or bioactive agent prior to the spray drying step so that the active agent or active ingredient is adsorbed and/or entrapped within or on the surface of the particles.
  • Particles made by this process can be in the submicron size range prior to spray-drying, or the particles can be formed from the solution during spray-drying.
  • the drug content can be delivered on crystalline powders using FDKP and which are lyophilized or sprayed dried at contents to about 10%, or about 20%, or about 30% or higher.
  • drug content can typically be greater than 0.01 % (w/w).
  • the drug content to be delivered with the microcrystalline particles of from about 0.01 % (w/w) to about 75 % (w/w); from about 1 % to about 50 % (w/w), from about 10 % (w/w) to about 25 % (w/w), or from about 10 % to about 20% (w/w), or from 5% to about 30%, or greater than 25% depending on the drug to be delivered.
  • the drug is a peptide such as insulin
  • the present microparticles typically comprise approximately 10 % to 45% (w/w), or from about 10 % to about 20% (w/w) insulin.
  • the drug content of the particles can vary depending on the form and size of the drug to be delivered.
  • the composition comprises a dry powder comprising microcrystalline particles of fumaryl diketopiperazine, wherein the treprostinil is adsorbed to the particles and wherein the content of the treprostinil in the composition comprises up to about 20% (w/w) and ranges from about 0.5% to about 10% (w/w), or from about 1% to about 5% (w/w) of the dry powder.
  • the composition herein can comprise other excipients suitable for inhalation such as amino acids including methionine, isoleucine and leucine.
  • the treprostinil composition can be used in the prevention and treatment of pulmonary hypertension by self-administering an effective dose comprising about 1 mg to 15 mg of a dry powder composition comprising microcrystalline particles of fumaryl diketopiperazine and treprostinil in a single inhalation.
  • the treprostinil content in the formulation can be from about 1 pg to about 200 pg.
  • the dry powder content of the cartridges comprising treprostinil can be 20 pg, 30 pg, 60 pg, 90 pg, 120 pg, 150 pg, 180 pg, or 200 pg.
  • the pharmaceutically acceptable carrier for making dry powders can comprise any carriers or excipients useful for making dry powders and which are suitable for pulmonary delivery.
  • pharmaceutically suitable carriers and excipients include, sugars, including saccharides and polysaccharides, such as lactose, mannose, sucrose, mannitol, trehalose; citrates, amino acids such as glycine, L-leucine, isoleucine, trileucine, tartrates, methionine, vitamin A, vitamin E, zinc citrate, sodium citrate, trisodium citrate, sodium tartrate, sodium chloride, zinc chloride, zinc tartrate, polyvinylpyrrolidone, polysorbate 80, phospholipids including diphosphotidylcholine and the like.
  • a method of self-administering a dry powder formulation to one’s lung(s) with a dry powder inhalation system comprises: obtaining a dry powder inhaler in a closed position and having a mouthpiece; obtaining a cartridge comprising a pre-metered dose of a dry powder formulation in a containment configuration; opening the dry powder inhaler to install the cartridge; closing the inhaler to effectuate movement of the cartridge to a dose position; placing the mouthpiece in one’s mouth, and inhaling once deeply to deliver the dry powder formulation.
  • a method of treating obesity, hyperglycemia, insulin resistance, pulmonary hypertention, anaphylaxis, and/or diabetes comprises the administration of an inhalable dry powder composition or formulation comprising, for example, a diketopiperazine having the formula 2,5-diketo-3,6-di(4-X- aminobutyl)piperazine, wherein X is selected from the group consisting of succinyl, glutaryl, maleyl, and fumaryl.
  • the dry powder composition can comprise a diketopiperazine salt.
  • a dry powder composition or formulation wherein the diketopiperazine is 2,5-diketo-3,6-di-(4-fumaryl- aminobutyl)piperazine, with or without a pharmaceutically acceptable carrier, or excipient.
  • An inhalation system for delivering a dry powder formulation to a patient’s lung(s) comprising a dry powder inhaler configured to have flow conduits with a total resistance to flow in a dosing configuration ranging in value from 0.065 to about 0.200 (VkPa)/liter per minute.
  • the dry powder inhaler can be provided comprising a dry powder formulation for single use that can be discarded after use, or with individual doses that are replaceable in a multiple use inhaler and the individual dose enclosures or containers can be discarded after use.
  • a dry powder inhalation kit comprising a dry powder inhaler as described above, one or more medicament cartridges comprising a dry powder formulation for treating a disorder or disease such as respiratory tract and lung disease, including pulmonary arterial hypertension, cystic fibrosis, respiratory infections, cancer, and other systemic diseases, including, endocrine disease, including, diabetes and obesity.
  • a disorder or disease such as respiratory tract and lung disease, including pulmonary arterial hypertension, cystic fibrosis, respiratory infections, cancer, and other systemic diseases, including, endocrine disease, including, diabetes and obesity.
  • Methods of treating a disease or disorder in a patient with the dry powder inhaler embodiments disclosed herewith comprises providing to a patient in need of treatment a dry powder inhaler comprising a cartridge containing a dose of an inhalable formulation comprising an active ingredient selected from the group as described above and a pharmaceutical acceptable carrier and/or excipient; and having the patient inhale through the dry powder inhaler deeply for about 3 to 4 seconds to deliver the dose.
  • the patient can resume normal breathing pattern thereafter.
  • surfactant-free dry powder comprising FDKP microcrystalline powder for use with inhalers:
  • surfactant free dry-powders comprising FDKP microcrystalline particles were prepared.
  • acetic acid solution Table 1
  • FDKP solution Table 2
  • the precipitate was collected in deionized (DI) water of about equal temperature.
  • DI deionized
  • the suspension FDKP concentration can be assayed for solids content by an oven drying method.
  • the FDKP microcrystallite suspension can be optionally washed by tangential flow filtration using deionized water.
  • the FDKP microcrystallites can be optionally isolated by filtration, centrifugation, spray drying or lyophilization.
  • Dry powders (A, B, C and D) comprising microcrystalline particles made by the methods described above were tested for various characteristics, including surface area, water content and porosity measurements. Four different powders were used in this experiments. All powders tested had a residual water content of 0.4%. Table 2a demonstrates data obtained from the experiments.
  • the data in Table 2a show that the surface area of spray ed-dried, bulk dry powder comprising the microcrystalline particles of the samples tested ranged from 59 m 2 /g to 63 m 2 /g.
  • the porosity data indicate that the microcrystalline particles are relatively porous, having average pore volumes of about 0.43 cm 3 /g and average pore size ranging from about 23.8 nm to 26.2 nm as determined by BJH adsorption.
  • the porosimetry data indicate that these particles differ from prior art FDKP microparticles which have been shown to have an average pore volume of about 0.36 cm 3 /g and average pore size from about 20 nm to about 22.6 nm.

Abstract

L'invention concerne une composition de prostaglandine et un procédé de traitement de l'hypertension artérielle pulmonaire. La composition est à base de dicétopipérazine pour inhalation pulmonaire.
EP19815062.5A 2018-06-07 2019-06-07 Composition et procédé d'inhalation Pending EP3801552A4 (fr)

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WO2015061720A2 (fr) 2013-10-25 2015-04-30 Insmed Incorporated Composés de prostacycline, compositions en contenant et leurs procédés d'utilisation
IL310250A (en) 2016-05-05 2024-03-01 Liquidia Tech Inc Terfostinil in dry powder form for the treatment of pulmonary hypertension
WO2020223237A1 (fr) 2019-04-29 2020-11-05 Insmed Incorporated Compositions de poudre sèche de promédicaments de tréprostinil et méthodes d'utilisation de celles-ci
JP2023523557A (ja) 2020-04-17 2023-06-06 ユナイテッド セラピューティクス コーポレイション 間質性肺疾患の治療における使用のためのトレプロスチニル
US11793780B2 (en) 2020-06-09 2023-10-24 United Therapeutics Corporation Prodrugs of treprosiinil
EP4236934A1 (fr) * 2020-10-28 2023-09-06 Insmed Incorporated Compositions de poudre sèche de promédicaments de tréprostinil et procédés d'utilisation associés
CA3199324A1 (fr) 2020-11-17 2022-05-27 Adam Marc Silverstein Imatinib inhale pour le domaine de l'hypertension pulmonaire
EP4301372A1 (fr) 2021-03-03 2024-01-10 United Therapeutics Corporation Composition de poudre sèche de treprostinil et son promédicament et comprenant en outre de l'(e)-3,6-bis[4-(n-carbonyl-2-propényl)amidobutyl]-2,5-dicétopipérazine (fdkp)
US20230263807A1 (en) 2022-02-08 2023-08-24 United Therapeutics Corporation Treprostinil iloprost combination therapy

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AU2006290870B2 (en) * 2005-09-14 2013-02-28 Mannkind Corporation Method of drug formulation based on increasing the affinity of active agents for crystalline microparticle surfaces
WO2012174472A1 (fr) * 2011-06-17 2012-12-20 Mannkind Corporation Microparticules de dicétopipérazine de capacité élevée
BR112015023168B1 (pt) * 2013-03-15 2021-08-10 Mannkind Corporation Composição de 3,6-bis(n-fumaril-4-aminobutil)-2,5-dicetopiperazina cristalina, método de produção de partículas de 3,6-bis(n-fumaril-4-aminobutil)-2,5-dicetopiperazina e uso de uma composição de dicetopiperazina cristalina
CN114904100A (zh) * 2016-01-29 2022-08-16 曼金德公司 干粉吸入器
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