INHALABLE FORMULATIONS OF IMATINIB, IMATINIB METABOLITES, IMATINIB SALTS, THEIR MANUFACTURE, AND USES THEREOF

Abstract

The invention generally relates to inhalable formulations of imatinib, imatinib metabolites, imatinib salts, their manufacture, and uses thereof.

Description

CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims the benefit of, and priority to, U.S. Provisional Application Nos. 62/849,054, filed May 16, 2019; 62/849,056, filed May 16, 2019; 62/849,058, filed May 16, 2019; 62/849,059, filed May 16, 2019; 62/877,575, filed Jul. 23, 2019; 62/942,408, filed Dec. 2, 2019; 62/984,037, filed Mar. 2, 2020; and 62/958,481, filed Jan. 8, 2020; the content of each of which is hereby incorporated by reference herein in its entirety.

FIELD OF THE INVENTION

[0002] The invention generally relates to inhalable formulations of imatinib, imatinib metabolites, imatinib salts, their manufacture, and uses thereof.

BACKGROUND

[0003] Pulmonary arterial hypertension (PAH) is a condition involving elevated blood pressure in the arteries of the lungs with unknown causes and is differentiated from systemic hypertension. PAH is a progressive disease where resistance to blood flow increases in the lungs causing damage to the lungs, the pulmonary vasculature and the heart that can eventually lead to death. While symptoms are treatable with vasodilators and other medications, there is no known disease modifying therapy or cure and advanced cases can eventually require lung transplants.

[0004] Imatinib, especially the mesylate salt thereof, is a tyrosine kinase inhibitor approved for use in treating certain types of cancer. Imatinib's potential to inhibit the tyrosine kinase PDGFR (platelet-derived growth factor receptor) which is highly upregulated in the pulmonary arteries in cases of PAH, led to interest in its use in treating PAH. See, Olschewski, H, 2015, Imatinib for Pulmonary Arterial Hypertension--Wonder Drug or Killer Drug? Respiration, 89:513-514, incorporated herein by reference. To that end, studies have been conducted to determine the potential of imatinib in treating PAH and patients have been found to respond favorably to said treatment. Unfortunately, an unacceptable amount of severe adverse events including subdural hematoma blunted enthusiasm for the drug. Frost, et al., 2015, Long-term safety and efficacy of imatinib in pulmonary arterial hypertension, J Heart Lung Transplant, 34(11):1366-75, incorporated herein by reference.

SUMMARY

[0005] Compositions and methods of the invention address problems with imatinib-based PAH treatments through the use of specialized formulations and delivery mechanisms. Particularly, inhalable formulations of molded imatinib particles (or salts or metabolites thereof) provide a uniform size and shape (including aerodynamically advantageous, non-naturally occurring shapes) in order to achieve predictable and efficient uptake of imatinib (or salts or metabolites thereof) in target lung tissue, especially for the treatment of PAH and other disorders of the pulmonary or cardiovascular systems.

[0006] The invention recognizes that direct delivery to the lung tissues through inhalation can offer greater lung exposure than equivalent doses of imatinib administered through conventional oral routes or by IV. Accordingly, a relatively high oral dose of imatinib, imatinib metabolites, or imatinib salts would be required to achieve the same target lung exposure as achieved by inhalation of the inventive formulations. Therefore, the use of inhalable formulations of the invention allows for therapeutic amounts of imatinib, its active metabolite, or salts thereof to reach the lungs for treatment of PAH and other conditions of the pulmonary cardiovascular system without the adverse events experienced with prolonged oral administration of imatinib mesylate.

[0007] In drug delivery and particularly that of inhalable formulations, particle geometry plays an important role in pharmacokinetics. Particle aerodynamics as determined by their size and shape can have significant effects on lung penetration via inhalation. Particle engineering also allows for more efficient deagglomeration, for example as inhalable powder is delivered from a device and as it transits through the oropharynx. Effective PAH treatment with imatinib without unwanted adverse events requires targeted delivery to reach therapeutic concentrations in the lung without systemic concentrations that might result in adverse events such as subdural hematoma. To achieve predictable and consistent levels of target lung concentrations with the desired low levels of systemic absorption, inhalable imatinib formulations should ideally be made up of micro or sub-micron particles of uniform geometry.

[0008] Compositions and methods of the invention leverage particle molding technologies to create such imatinib particles specifically for inhalable formulations. Molds are preferably prepared from an elastomeric material and can be created by pouring the material, in liquid form, over a patterned object before curing the material. Mold-based preparation of pharmaceuticals include PRINT technology available from Liquidia Technologies, Inc. (Morrisville, N.C.) and described in U.S. Pat. Nos. 8,812,393; 9,444,907; 8,685,461, 7,976,759; and 8,944,804, the content of each of which is incorporated herein by reference.

[0009] Microfabrication techniques such as etching of a substrate (e.g., a silicon wafer) are well known in the semiconductor field and can be used to create a pattern consisting of repeated raised features consistent with the desired size and shape of the final imatinib particles for the inhalable formulation. The liquid mold material can then be laid over the patterned substrate and allowed to harden to produce a mold consisting of repeated reliefs that are the negative of the desired size and shape of the final imatinib particles of the inhalable formulation. Liquid imatinib solutions or suspensions can then be poured into the reliefs in the mold and hardened. The final imatinib particles having the desired size and shape can then be released from the mold for inclusion in the inhalable formulation.

[0010] In certain embodiments, compositions and methods of the invention use the advantages afforded by engineered, uniform micro and sub-micron imatinib particles for inhalable formulations (e.g., efficient uptake in the target tissue with lower off-target concentrations, consistent dosing, and predictable modeling of pharmacokinetics), particularly in treating conditions such as PAH, lung transplant rejection, pulmonary veno-occlusive disease (PVOD) and pulmonary hypertension, heart failure with preserved ejection fraction (HFpEF) and schistosomiasis. By combining the specific factors of inhalable imatinib formulations with the unique capabilities of molded pharmaceutical technology, the compositions and methods of the present invention provide a new approach for treating the above conditions without the risks associated with systemic imatinib treatments.

[0011] As mentioned above, certain embodiments of the invention use an active metabolite of imatinib. The primary active metabolite of imatinib is N-desmethyl imatinib and has been found to exhibit similar potency to the imatinib parent compound. Additionally, N-desmethyl imatinib exhibits an increased half-life relative to the parent imatinib compound. Accordingly, formulations that include N-desmethyl imatinib can provide therapeutic benefits in treating PAH and other conditions with more efficient delivery to and longer residence in the effected tissue due to the increased half-life of the metabolite. In certain embodiments, inhalable formulations of the invention may comprise an active metabolite of imatinib such as N-desmethyl imatinib. Additionally, various imatinib salts may be used in molded inhalable formulations as described herein. The salt may be at least one selected from the group consisting of glycollate, mesylate, isethionate, xinafoate, furoate, trifenatate, HCl, sulfate, phosphate, lactate, maleate, malate, fumarate, tartrate, succinate, adipate, citrate, and malonate.

[0012] Molded particles may be prepared with a size of about 0.5 .mu.m to about 5 .mu.m mass median aerodynamic diameter (MMAD) for desired deep lung penetration. If required, various excipients or carriers can be added to the imatinib, its metabolite, or salts of either before or after molding. For example, carriers, excipients, conditioners, and force control agents, such as lactose (which when used as a carrier may be conditioned with various solvents to increase separation of imatinib during inhalation), magnesium stearate, leucine, isoleucine, dileucine, trileucine, lecithin, distearylphosphatidylcholine (DSPC) or other lipid-based carriers, or various hydrophilic polymers where they exhibit appropriate physico-chemical properties may be included. The skilled artisan will appreciate that excipients or carriers are optional and that many embodiments of the invention do not require excipients or carriers.

[0013] Because the inhalable formulations described herein can modulate the uptake of imatinib in the target tissue of the lungs or microvasculature, formulations of the invention can be used to treat various conditions of the pulmonary and cardiovascular systems while avoiding the adverse events associated with higher doses that are administered by other routes of administration that introduce the drug systemically prior to reaching the target tissue. For example, compounds and methods of the invention can be used to treat PAH as well as lung transplant rejection, pulmonary veno-occlusive disease (PVOD) and pulmonary hypertension secondary to other diseases like heart failure with preserved ejection fraction (HFpEF) or schistosomiasis. Dose ranges can include between about 10 mg to about 100 mg per dose for inhalation on a single to four times per day schedule. From 0.1 mg to about 80 mg of imatinib may then be deposited within the lungs after inhalation per dose with up to about 70% to about 80% delivery efficiency achieved using engineered particle geometries.

[0014] The inhalable formulation may be in a dry powder of molded imatinib particles. In some embodiments, the inhalable formulation may be a suspension of molded imatinib. The molded imatinib may be present in a therapeutically effective amount to treat a condition of the pulmonary cardiovascular system, such as pulmonary arterial hypertension (PAH). The inhalable formulation may further include one or more carrier agents.

[0015] Aspects of the invention include an inhalable formulation comprising molded particles of imatinib or a salt thereof. The molded particles can be hardened in a mold from a liquid composition. The molded particles can have a mass median aerodynamic diameter in the range of 0.5-5 .mu.m. The molded particles can further comprise one or more excipients. The excipient may be a water soluble excipient selected from the group consisting of leucine, dileucine, trileucine, trehalose, mannitol, citrate, and acetate. In certain embodiments, the excipient can be a water insoluble excipient selected from the group consisting of lecithin, distearylphosphatidylcholine (DSPC) and limonene.

[0016] Inhalable formulations of the invention can include one or more carrier agents. The inhalable formulation can be a dry powder or a suspension of the molded particles. The imatinib of salt thereof may be present in a therapeutically effective amount to treating a condition of the pulmonary cardiovascular system.

[0017] In various embodiments, the salt can be at least one selected from the group consisting of glycollate, isethionate, mesylate, xinafoate, furoate, trifenatate, HCl, sulfate, phosphate, lactate, maleate, malate, fumarate, tartrate, succinate, adipate, citrate, and malonate. In preferred embodiments, the salt may be glycolate, malate, tartrate, malonate, isethionate, or citrate. The imatinib may be present in a crystal form.

[0018] Aspects of the invention include methods of preparing an inhalable formulation of imatinib or a salt thereof including applying a liquid composition comprising imatinib or a salt thereof to a mold, hardening the liquid composition within cavities in the mold to form particles within the cavities, and releasing the particles from the cavities in the mold, thereby preparing an inhalable formulation of imatinib or a salt thereof.

DETAILED DESCRIPTION

[0019] The invention relates to inhalable formulations of molded particles of imatinib, an imatinib metabolite such as N-desmethyl imatinib, or salts of either. Through the use of engineered molds, large quantities of uniform imatinib particles can be prepared having a size and shape tailored for inhalation and treatment of pulmonary and cardiovascular conditions.

[0020] References to imatinib formulations made herein, unless otherwise specified, should be understood to contemplate free base imatinib, imatinib metabolites including N-desmethyl imatinib, and salts of either including imatinib mesylate, sold under the trade name Gleevec. Imatinib as the free base has the structure as shown below.

##STR00001##

[0021] N-desmethyl imatinib is the primary active metabolite of imatinib formed when imatinib undergoes demethylation by the cytochrome P450 (CYP) isomer CYP3A4. N-desmethyl imatinib has the following structure:

##STR00002##

[0022] The methods and compositions described herein provide consistent particles of imatinib suited in size and shape for inhalable formulations to achieve efficient and predictable uptake in the target lung tissue. Greater concentrations of imatinib in target lung tissue can thereby be obtained than with equivalent doses administered orally or through IV. Accordingly, the invention provides improved treatment methods for life threatening diseases that were heretofore too risky for practical application.

[0023] In certain embodiments, compounds of the invention include formulations of imatinib, imatinib metabolites or salts thereof. In preferred embodiments the imatinib particles are used in a formulation (either in dry powder or suspension) for inhalation to treat a condition of the pulmonary cardiovascular system such as PAH. Certain salt forms are also contemplated. In various embodiments, salts contemplated herein include glycollate, isethionate, malonate, tartrate, and malate. Other salt forms contemplated herein are xinafoate, mesylate, furoate, trifenatate, HCl, sulfate, phosphate, lactate, maleate, fumarate, succinate, adipate, and citrate.

[0024] Solutions or suspensions of imatinib can be poured into molds featuring recesses of a desired size and shape for final particles for the inhalable formulation. Molded drug particles and techniques for forming such particles are disclosed in U.S. Pat. Nos. 8,812,393; 9,444,907; 8,685,461, 7,976,759; and 8,944,804.

[0025] As described therein patterns can be prepared from which elastomeric molds can be obtained. The pattern should be created with a repeating array of raised features having the desired size and shape of the imatinib particles to be formed. The pattern can be prepared using known microfabrication techniques including etching, chemical vapor deposition, lithographic techniques, and other methods. Semiconductor fabrication and silicon wafer processing techniques are well suited to preparing patterns.

[0026] The size and structure of the features, matching those of the desired inhalable imatinib particles, can be engineered to achieve the desired disposition and therapeutic levels in the target tissue. For example, aerodynamic features of the size and shape can be modelled using known techniques to determine and maximize lung penetration. After obtaining a shape and size having the desired aerodynamic profile, the above processing techniques can be used to prepare a patterned surface with features corresponding to the modeled particle. Particle sizes can range from about 0.5 .mu.m to about 5 .mu.m depending on the application (e.g., dry powder or suspension for inhalation). In preferred embodiments the size range is about 1 .mu.m to about 3 .mu.m in dry powder formulations to achieve deep lung penetration. In certain embodiments, engineered particle shapes may include spheres or spheroids, cylinders, or various polyhedrons. See Mack, et al., 2012, Particle Engineering for Inhalation Formulation and Delivery of Biotherapeutics, Inhalation, August 2012, incorporated herein by reference.

[0027] A liquid material can be poured over the pattern and hardened to create a mold including, negative spaces corresponding to the features of the patterned surface. Mold materials that can be selected are preferably low surface energy polymeric materials such as silicone, perfluoropolyether, fluoropolymers, fluorinated elastomer-based materials, fluoropolyether, perfluoropolyether (PFPE), or PFPE-based materials.

[0028] Upon removal of the hardened mold from the patterned surface, the mold will retain the recesses left by the features on the patterned surfaces. Because those recesses correspond to the desired shape and size of the imatinib particles for the inhalable formulations, imatinib solutions or suspensions poured into the mold and hardened will result in uniform imatinib particles for inhalable formulations of the invention.

[0029] In various embodiments the imatinib particles are comprised of imatinib crystals. In certain embodiments, the molded particles are featured in dry powder formulations for inhalation. Dry powder can be administered via, for example, dry powder inhalers such as described in Berkenfeld, et al., 2015, Devices for Dry Powder Drug Delivery to the Lung, AAPS PharmaSciTech, 16(3):479-490, incorporated herein by reference. Dry powder compounds may be divided into single doses for single, twice daily, three times daily, or four times daily inhalation to treat disorders such as PAH or other conditions of the pulmonary cardiovascular system. The single doses may be divided into individual capsules or other formats compatible with the dry powder inhaler to be used.

[0030] In other embodiments, molded imatinib particle suspensions can be delivered via inhalation using, for example, a nebulizer. For nebulized suspensions, particle diameter may be of particular importance for efficient delivery and imatinib may be preferably molded in particles of a mass median diameter of 2 .mu.m or less. The suspension for nebulizer inhalation can be aqueous and doses may be divided into individual containers or compartments for sterile storage prior to use.

[0031] In certain embodiments, molded imatinib formulations of the invention may include one or more excipients. Excipients may include, for example, lactose in various forms (e.g., roller dried or spray dried). Larger lactose particles can be used as a carrier for inhalation of molded imatinib formulations. The carrier particles, with their larger size, can be used to increase aerodynamic forces on the combined imatinib/carrier in order to aid in delivery through inhalation. Solvents may be used to condition the lactose surface such that the active component can be effectively separated from the lactose as it leaves the inhaler device and within the oral cavity when being used as a carrier. Magnesium stearate can be used as a force-control agent or conditioning agent in various embodiments. In some embodiments, leucine can be used as a force-control agent including different forms of leucine (e.g. isoleucine) along with dileucine and even trileucine.

[0032] Lecithin phospholipids such as DSPC may be used as an excipient for dry powder inhalation. In certain embodiments, excipients may include various hydrophilic polymers. See, for example, Karolewicz, B., 2016, A review of polymers as multifunctional excipients in drug dosage form technology, Saudi Pharm J., 24(5):525-536, incorporated herein by reference.

[0033] In various embodiments, the molded imatinib formulations of the invention may be pharmaceutical compositions for use in treating various conditions of the pulmonary cardiovascular system, such as PAH. For example, imatinib is a potent inhibitor of the platelet-derived growth factor receptor (PDGFR) and other signaling kinases. Accordingly, the compositions of the invention may be used to treat any disease or disorder that involves inhibition of PDGFR or other kinases sensitive to imatinib.

[0034] In certain embodiments, the compositions of the invention may be used to treat PAH. For treatment of PAH or other disorders, a therapeutically effective amount of a pharmaceutical composition of molded imatinib according to the various embodiments described herein can be delivered, via inhalation (e.g., via dry powder inhaler or nebulizer) to deliver the desired amount of imatinib compound to the target lung tissue. Imatinib particles can be molded to a desired size and shape to achieve the desired delivery characteristics.

[0035] Dosages for treating PAH and other conditions of the pulmonary cardiovascular system may be in the range of between about 10 mg to about 100 mg per dose for inhalation of once, twice daily, three times per day or four times per day schedule. From 0.1 mg to about 80 mg of imatinib may then be deposited within the lungs after inhalation per dose with up to about 70% to about 80% delivery efficiency achieved using engineered particle geometries. In certain embodiments about 10 mg to 30 mg of imatinib may be given in a capsule for a single dry-powder inhalation dose with a range of about 3 mg to about 25 mg of the compound to be expected to reach the lungs depending upon the physicochemical properties of the powder and delivery efficiencies obtained with the inhaler device. In inhalable suspension embodiments, imatinib may be present at about 0.01 to about 1 mg/kg in a dose and may be administered one to four times a day to obtain the desired therapeutic results.

[0036] In certain embodiments, imatinib formulations of the invention may be used to treat pulmonary hypertension as a result of schistosomiasis. See, for example, Li, et al., 2019, The ABL kinase inhibitor imatinib causes phenotypic changes and lethality in adult Schistosoma japonicum, Parasitol Res., 118(3):881-890; Graham, et al., 2010, Schistosomiasis-associated pulmonary hypertension: pulmonary vascular disease: the global perspective, Chest, 137(6 Suppl):20S-29S, the content of each of which is incorporated herein by reference.

[0037] Molded imatinib pharmaceutical compositions of the invention may be used to treat lung transplant recipients to prevent organ rejection. See, Keil, et al., 2019, Synergism of imatinib, vatalanib and everolimus in the prevention of chronic lung allograft rejection after lung transplantation (LTx) in rats, Histol Histopathol, 1:18088, incorporated herein by reference.

[0038] In certain embodiments, pharmaceutical compositions described herein can be used to treat pulmonary veno-occlusive disease (PVOD). See Sato, et al., 2019, Beneficial Effects of Imatinib in a Patient with Suspected Pulmonary Veno-Occlusive Disease, Tohoku J Exp Med. 2019 February; 247(2):69-73, incorporated herein by reference.

[0039] For treatment of any conditions of the pulmonary cardiovascular system for which imatinib may produce a therapeutic effect, compounds and methods of the invention may be used to provide greater concentration at the target lung tissue through inhalation along with consistent, predictable pharmacokinetics. The efficient localization of therapeutic compound at the target tissue allows for lower systemic exposure and avoidance of the adverse events associated with prolonged oral administration of imatinib mesylate.

[0040] Methods of the invention can include preparation of molded imatinib formulations. As noted above, molded particles of imatinib, imatinib metabolites, or salts of either may be administered via inhalation in suspension or dry powder form. Once released from the mold, in dry powder form, imatinib formulations of the invention can be prepared for inhalation. In certain embodiments, the dry powder imatinib can be combined with larger carrier particles such as lactose as discussed above. In some embodiments a suspension of molded imatinib particles can be formed. Imatinib suspensions of molded crystal forms may be used in nebulized inhalation treatment.

[0041] Maintaining a stable solution of molded imatinib particles (to retain the desired geometry thereof) is important in certain embodiments of the formulations and methods of the invention. Accordingly, formulation methods include manipulation of the suspension to prevent dissolution of the molded imatinib particles. Aqueous solution factors such as pH, ionic strength and dispersing agents may be used to obtain a stable suspension for nebulization. For example, the pH of the aqueous solution may be adjusted to minimize or prevent dissolution.

[0042] Additionally, the presence of ions in aqueous solution may tend to `salt out` the imatinib. The solubility of both imatinib and its salts may decrease with salinity. Accordingly, salt in the aqueous solution may be used to reduce solubility of the molded imatinib in certain embodiments. The solubility of both imatinib and its salts also depends on pH. Imatinib has maximal aqueous solubility in mildly acidic solutions. Increasing pH may be used to reduce the solubility of the molded imatinib in certain embodiments.

[0043] To promote dispersion and thoroughly deagglomerate the imatinib particles, a dispersing agent or surfactant (e.g., Tween 20 or Tween 80) may be added but should not enhance dissolution of the molded imatinib in suspension.

[0044] In certain embodiments, excipients can be added to the suspension. In various embodiments, the excipient may be a water-soluble excipient, such as leucine, dileucine, trileucine, trehalose, mannitol, citrate or acetate. In other embodiment, the excipient may be a water insoluble excipient, such as lecithin, distearylphosphatidylcholine (DSPC) or limonene. Such insoluble excipients may be dissolved in a non-aqueous medium that is miscible or immiscible with water, thereby creating an emulsion.

[0045] When the compounds of the present invention are administered as pharmaceuticals, to humans and mammals, they can be given per se or as a pharmaceutical composition containing, for example, 0.1 to 99.5% (more preferably, 0.5 to 90%) of active ingredient, i.e., at least one of a therapeutic compound of the invention and/or derivative thereof, in combination with a pharmaceutically acceptable carrier.

[0046] The effective dosage of each agent can readily be determined by the skilled person, having regard to typical factors such as the age, weight, sex and clinical history of the patient. In general, a suitable daily dose of a compound of the invention will be that amount of the compound which is the lowest dose effective to produce the desired therapeutic effect. Such an effective dose will generally depend upon the factors described above.

[0047] If desired, the effective daily dose of the active compound may be administered as one, two, three, four, five, six or more sub-doses administered separately at appropriate intervals throughout the day, optionally, in unit dosage forms.

[0048] The pharmaceutical compositions of the invention include a "therapeutically effective amount" or a "prophylactically effective amount" of one or more of the compounds of the present invention, or functional derivatives thereof. An "effective amount" refers to an amount effective, at dosages and for periods of time necessary, to achieve the desired therapeutic result, e.g., a diminishment or prevention of effects associated with PAH. A therapeutically effective amount of a compound of the present invention or functional derivatives thereof may vary according to factors such as the disease state, age, sex, and weight of the subject, and the ability of the therapeutic compound to elicit a desired response in the subject. A therapeutically effective amount is also one in which any toxic or detrimental effects of the therapeutic agent are outweighed by the therapeutically beneficial effects.

[0049] A "prophylactically effective amount" refers to an amount effective, at dosages and for periods of time necessary, to achieve the desired prophylactic result. Typically, since a prophylactic dose is used in subjects prior to, or at an earlier stage of disease, the prophylactically effective amount may be less than the therapeutically effective amount. A prophylactically or therapeutically effective amount is also one in which any toxic or detrimental effects of the compound are outweighed by the beneficial effects.

[0050] Dosage regimens may be adjusted to provide the optimum desired response (e.g. a therapeutic or prophylactic response). For example, a single inhalable bolus may be administered, several divided doses may be administered over time or the dose may be proportionally reduced or increased as indicated by the exigency of the therapeutic situation. Actual dosage levels of the active ingredients in the pharmaceutical compositions of this invention may be varied so as to obtain an amount of the active ingredient which is effective to achieve the desired therapeutic response for a particular subject, composition, and mode of administration, without being toxic to the patient.

[0051] The term "dosage unit" as used herein refers to physically discrete units suited as unitary dosages for the mammalian subjects to be treated; each unit containing a predetermined quantity of active compound calculated to produce the desired therapeutic effect in association with the required pharmaceutical carrier. The specification for the dosage unit forms of the invention are dictated by and directly dependent on (a) the unique characteristics of the compound, and (b) the limitations inherent in the art of compounding such an active compound for the treatment of sensitivity in individuals.

[0052] In some embodiments, therapeutically effective amount can be estimated initially either in cell culture assays or in animal models, usually rats, non-human primates, mice, rabbits, dogs, or pigs. The animal model is also used to achieve a desirable concentration range and route of administration. Such information can then be used to determine useful doses and routes for administration in other subjects. Generally, the therapeutically effective amount is sufficient to reduce PAH symptoms in a subject. In some embodiments, the therapeutically effective amount is sufficient to eliminate PAH symptoms in a subject.

[0053] Dosages for a particular patient can be determined by one of ordinary skill in the art using conventional considerations, (e.g. by means of an appropriate, conventional pharmacological protocol). A physician may, for example, prescribe a relatively low dose at first, subsequently increasing the dose until an appropriate response is obtained. The dose administered to a patient is sufficient to effect a beneficial therapeutic response in the patient over time, or, e.g., to reduce symptoms, or other appropriate activity, depending on the application. The dose is determined by the efficacy of the particular formulation, and the activity, stability, or half-life of the compounds of the invention or functional derivatives thereof, and the condition of the patient, as well as the body weight or surface area of the patient to be treated. The size of the dose is also determined by the existence, nature, and extent of any adverse side-effects that accompany the administration of a particular vector, formulation, or the like in a particular subject. Therapeutic compositions comprising one or more compounds of the invention or functional derivatives thereof are optionally tested in one or more appropriate in vitro and/or in vivo animal models of disease, such as models of PAH, to confirm efficacy, tissue metabolism, and to estimate dosages, according to methods well known in the art. In particular, dosages can be initially determined by activity, stability or other suitable measures of treatment vs. non-treatment (e.g., comparison of treated vs. untreated cells or animal models), in a relevant assay. Administration can be accomplished via single or divided doses.

[0054] In certain embodiments, in which an aqueous suspension is part of the manufacturing process, the aqueous suspension may contain the active material in admixture with excipients suitable for the manufacture of aqueous suspensions. Such excipients are suspending agents dispersing or wetting agents such as a naturally occurring phosphatide, for example lecithin, or condensation products of an alkylene oxide with fatty acids, for example polyoxyethylene stearate, or condensation products of ethylene oxide with long chain aliphatic alcohols, for example heptadecaethyleneoxycetanol, or condensation products of ethylene oxide with partial esters derived from fatty acids and a hexitol such a polyoxyethylene with partial esters derived from fatty acids and hexitol anhydrides, for example polyoxyethylene sorbitan monooleate. The aqueous suspensions may also contain one or more preservatives, for example ethyl, or n-propyl p-hydroxybenzoate, one or more coloring agents, one or more flavoring agents, and one or more sweetening agents, such as sucrose, mannitol, or trehalose.

[0055] Dispersible powders and granules suitable for preparation of an aqueous suspension by the addition of water provide the active ingredient in admixture with a dispersing or wetting agent, suspending agent and one or more preservatives.

[0056] The term "pharmaceutical composition" means a composition comprising a compound as described herein and at least one component comprising pharmaceutically acceptable carriers, diluents, adjuvants, excipients, or vehicles, such as preserving agents, taste-masking agents, fillers, disintegrating agents, wetting agents, emulsifying agents, suspending agents, sweetening agents, flavoring agents, perfuming agents, antibacterial agents, antifungal agents, lubricating agents and dispensing agents, depending on the nature of the mode of administration and dosage forms.

[0057] The term "pharmaceutically acceptable carrier" is used to mean any carrier, diluent, adjuvant, excipient, or vehicle, as described herein. Examples of suspending agents include ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar and tragacanth, or mixtures of these substances. Prevention of the action of microorganisms can be ensured by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, sorbic acid, and the like. It may also be desirable to include isotonic agents, for example sugars, sodium chloride, and the like. Examples of suitable carriers, diluents, solvents, or vehicles include water, ethanol, polyols, suitable mixtures thereof, vegetable oils (such as olive oil), and injectable organic esters such as ethyl oleate. Examples of excipients include lactose, milk sugar, sodium citrate, calcium carbonate, and dicalcium phosphate. Examples of disintegrating agents include starch, alginic acids, and certain complex silicates. Examples of lubricants include magnesium stearate, sodium lauryl sulphate, talc, as well as high molecular weight polyethylene glycols.

[0058] The term "pharmaceutically acceptable" means it is, within the scope of sound medical judgment, suitable for use in contact with the cells of humans and lower animals without undue toxicity, irritation, allergic response, and the like, and are commensurate with a reasonable benefit/risk ratio.

INCORPORATION BY REFERENCE

[0059] References and citations to other documents, such as patents, patent applications, patent publications, journals, books, papers, web contents, have been made throughout this disclosure. All such documents are hereby incorporated herein by reference in their entirety for all purposes.

EQUIVALENTS

[0060] Various modifications of the invention and many further embodiments thereof, in addition to those shown and described herein, will become apparent to those skilled in the art from the full contents of this document, including references to the scientific and patent literature cited herein. The subject matter herein contains important information, exemplification and guidance that can be adapted to the practice of this invention in its various embodiments and equivalents thereof.

Claims

1. An inhalable formulation comprising molded particles of imatinib or a salt thereof.

2. The inhalable formulation of claim 1 wherein the molded particles are hardened in a mold from a liquid composition.

3. The inhalable formulation of claim 1 wherein the molded particles comprise a mass median aerodynamic diameter in the range of 0.5-5 .mu.m.

4. The inhalable formulation of claim 1 wherein the molded particles further comprise one or more excipients.

5. The inhalable formulation of claim 4 wherein the excipient is a water soluble excipient selected from the group consisting of leucine, dileucine, trileucine, trehalose, mannitol, citrate, and acetate.

6. The inhalable formulation of claim 4 wherein the excipient is a water insoluble excipient selected from the group consisting of lecithin, distearylphosphatidylcholine (DSPC) or limonene.

7. The inhalable formulation of claim 1 further comprising one or more carrier agents.

8. The inhalable formulation of claim 1 wherein the inhalable formulation is a dry powder or a suspension of the molded particles.

9. The inhalable formulation of claim 1 wherein the imatinib or salt thereof is present in a therapeutically effective amount to treating a condition of the pulmonary cardiovascular system.

10. The inhalable formulation of claim 9 wherein the condition of the pulmonary cardiovascular system is pulmonary arterial hypertension (PAH).

11. The inhalable formulation of claim 1 wherein the salt is at least one selected from the group consisting of glycolate, malate, tartrate, malonate, isethionate, or citrate.

12. The inhalable formulation of claim 1 wherein the imatinib is present in a crystal form.

13. A method of preparing an inhalable formulation of imatinib or a salt thereof, the method comprising: applying a liquid composition comprising imatinib or a salt thereof to a mold; hardening the liquid composition within cavities in the mold to form particles within the cavities; and releasing the particles from the cavities in the mold, thereby preparing an inhalable formulation of imatinib or a salt thereof.

14. The method of claim 13 wherein the inhalable particles comprise a mass median aerodynamic diameter in the range of 0.5-5 .mu.m.

15. The method of claim 13 wherein the liquid composition further comprises one or more excipients.

16. The method of claim 15 wherein the excipient is a water soluble excipient selected from the group consisting of leucine, dileucine, trileucine, trehalose, mannitol, citrate, and acetate.

17. The method of claim 15 wherein the excipient is a water insoluble excipient selected from the group consisting of lecithin, distearylphosphatidylcholine (DSPC) and limonene.

18. The method of claim 13 further comprising mixing one or more carrier agents with the inhalable particles to prepare the inhalable formulation.

19. The method of claim 13 wherein the inhalable formulation is a dry powder.

20. The method of claim 13 wherein the inhalable formulation is a suspension of the inhalable particles.

21. The method of claim 13 wherein the inhalable formulation contains a therapeutically effective amount of imatinib for treating a condition of the pulmonary cardiovascular system.

22. The method of claim 21 wherein the condition of the pulmonary cardiovascular system is pulmonary arterial hypertension (PAH).

23. The method of claim 13 wherein the salt is at least one selected from the group consisting of glycolate, malate, tartrate, malonate, isethionate, or citrate.