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
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
  • A61K31/50—Pyridazines; Hydrogenated pyridazines
  • A61K31/501—Pyridazines; Hydrogenated pyridazines not condensed and containing further heterocyclic rings
• • 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
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
  • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
  • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K38/00—Medicinal preparations containing peptides
  • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
  • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
  • A61K38/18—Growth factors; Growth regulators
  • A61K38/1858—Platelet-derived growth factor [PDGF]
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K38/00—Medicinal preparations containing peptides
  • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
  • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
  • A61K38/19—Cytokines; Lymphokines; Interferons
  • A61K38/193—Colony stimulating factors [CSF]
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
  • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
  • A61K47/26—Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
• • 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
• • 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
  • A61K9/0078—Sprays or powders for inhalation; Aerolised or nebulised preparations generated by other means than thermal energy for inhalation via a nebulizer such as a jet nebulizer, ultrasonic nebulizer, e.g. in the form of aqueous drug solutions or dispersions
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P11/00—Drugs for disorders of the respiratory system
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P9/00—Drugs for disorders of the cardiovascular system
  • A61P9/12—Antihypertensives
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
  • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
  • C07B2200/13—Crystalline forms, e.g. polymorphs

Definitions

• the invention generally relates to inhalable formulations of imatinib, imatinib
• Pulmonary arterial hypertension is a condition involving elevated blood pressure in the arteries of the lungs with unknown causes and is differentiated from systemic
• PAH hypertension
• Imatinib 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.
• PDGFR platelet-derived growth factor receptor
• compositions and methods of the invention address problems with imatinib-based PAH treatments through the use of specialized formulations and delivery mechanisms.
• the invention recognizes that crystalline form and polymorph composition of drugs like imatinib and salts thereof can have significant effects on drug solubility, delivery, absorption, and metabolism. Accordingly, crystal form can be important for determining dosage and predicting patient response.
• the invention provides a formulation of inhalable imatinib with a higher ratio of API (active pharmaceutical ingredient) than found in conventional formulations.
• formulations comprising 50% or more imatinib or imatinib salts are provided.
• compositions and methods of the invention recognize that large volumes may be difficult or dangerous for patients to inhale and that, therefore, minimizing the amount of non- API components in the formulation can improve patient comfort, safety, and compliance by reducing the overall amount of compound that is inhaled while still providing a therapeutically effective API concentration in target tissue.
• compositions and methods of the invention can provide the load- reducing benefits discussed above while still delivering therapeutic results and avoiding the severe adverse events associated with other drug delivery routes.
• compositions of the invention offer greater lung exposure than equivalent doses of imatinib or imatinib mesylate administered through conventional oral routes or by IV. While a relatively high oral dose of imatinib or imatinib mesylate would be required to achieve the same target lung exposure as achieved by inhalation of the inventive formulations, significantly lower dosages can be delivered using the inventive compositions and methods.
• the imatinib or salts thereof used in compositions and methods of the invention can consist of entirely or almost entirely a single crystal form (e.g., greater than 80%, 85%, 90%, 95%, 99% or 100% of a single crystal form), thereby allowing for controlled and predictable dosing and patient response.
• greater than 95% of imatinib or a salt thereof in the inhalable formulation may be present in a single crystal form.
• the primary active metabolite of imatinib is N-desmethyl imatinib and has been found to exhibit the same potency as the imatinib parent compound. N-desmethyl imatinib also exhibits an increased half-life relative to the parent imatinib compound. Compounds and methods of the invention take advantage of this characteristic by providing inhalable
• formulations of N-desmethyl imatinib in the absence of the parent compound 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.
• This combination can allow for fewer doses with lower concentrations of active pharmaceutical ingredient relative to conventional oral or IV administration of imatinib mesylate.
• inhalable imatinib compounds may be micronized through wet or dry milling (e.g., jet milling) to achieve the desired particle size for dry powder formulations for inhalation.
• Imatinib or appropriate salts thereof may be micronized to particle sizes of about 0.5 pm to about 5 pm mass median aerodynamic diameter (MMAD) for desired deep lung penetration.
• MMAD mass median aerodynamic diameter
• Inhaled products can be limited in terms of mass of powder that can be administered and certain imatinib salts will contribute significantly to the molecular weight of the inhaled compound. Accordingly, in certain embodiments, the imatinib free base may be preferred for efficient delivery of the active moiety to lung tissue.
• various excipients or carriers can be added to imatinib or salts thereof before or after micronization depending on application while maintaining a relatively high (e.g., 50% or greater) ratio of the API.
• 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,
• DSPC distearylphosphatidylcholine
• APLcarrier ratios may be greater than 50:50, 75:25, or 90:10. Additional ratios are contemplated as discussed below.
• 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.
• inhalable imatinib formulations should ideally be made up of micro or sub-micron particles of uniform geometry.
• 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, NC) and described in U.S. Pat. Nos. 8,812,393; 9,444,907; 8,685,461,
• 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.
• 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.
• inhalable imatinib formulations e.g., efficient uptake in the target tissue with lower off-target concentrations, consistent dosing, and predictable modeling of pharmacokinetics
• PVOD pulmonary veno-occlusive disease
• HFpEF preserved ejection fraction
• compositions and methods of the present invention provide a new approach for treating the above conditions without the risks associated with systemic imatinib treatments.
• Another advantage of the compounds and methods of the invention is the ability to exclude all or most amorphous imatinib from the formulation, even after micronization.
• crystal form can be important to drug pharmacokinetics and dosing, as well as physicochemical stability and avoiding amorphous content can therefore be important to providing predictable and efficient therapy.
• formulations of the invention can be used to treat various conditions of the pulmonary cardiovascular system 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.
• 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 twice to four times per day schedule.
• compositions of the invention can have relatively high concentrations of API (e.g., 50% or greater), the above doses can be achieved with less overall volume of inhalable compared to conventional formulations having 1% - 3% API.
• formulations of the invention can include processing and administration of imatinib in free base form.
• Free base imatinib formulations of the invention can retain crystallinity after micronization and are less hygroscopic than certain imatinib salts.
• compounds and methods of the invention include inhalable formulations of free base imatinib.
• Methods and formulations of the invention may include spray-dried imatinib or salts thereof for inhalation. While carriers such as lactose may be used after micronization to aid in delivery via inhalation, those carriers may generally comprise larger diameter particles and complication in the separation of the active imatinib compound may result in lower amounts of the inhaled compound reaching the lungs.
• spray-dried methods may be used wherein imatinib or salts thereof along with various excipients or other additives may be micronized to a desired particle size and suspended or solubilized for spray-drying and inhalation.
• formulations with a higher (e.g., 50% or more) ratio of API can also help achieve more predictable drug concentrations in the target tissue.
• the micronized imatinib may be suspended in a feedstock for the purposes of spray-drying to avoid the creation of amorphous or polymorphic imatinib content that may occur if dissolved in a solution (e.g. in an appropriate organic solvent or within an acidified aqueous solution) upon spray-drying.
• a solution e.g. in an appropriate organic solvent or within an acidified aqueous solution
• the inhalable formulation can retain the desired crystal structure, particle size, and low levels of amorphous content obtained before the micronization process.
• Stable suspensions for spray-drying may be obtained through manipulation of factors affecting imatinib solubility such as pH, ionic strength, and dispersing agents or surfactants.
• Excipients that may be used before micronization in the spray-drying methods described above include, for example, leucine, dileucine, trileucine, bulking agents such as trehalose or mannitol, lecithin, DSPC or other lipid-based carriers, citrate, or acetate.
• inhalable imatinib solutions and suspensions may be provided along with methods of delivering such formulations through inhalation via a nebulizer.
• Nebulizers are drug delivery devices that aerosolize solutions and suspensions for inhalation using compressed gas. By providing imatinib directly to the lungs through nebulized formula, treatment of pulmonary and cardiovascular diseases become feasible without the high-systemic concentrations of imatinib found to be associated with subdural hematoma or other adverse events. Accordingly, systems and methods of the invention provide new means of treating PAH and other diseases without the compromises and risks of prior attempts.
• Formulations for nebulization may be provided in solution or suspension form. Imatinib formulations may be used with any type of nebulizer. For example, commercially available nebulizers from Vectura Group pic (UK) including jet nebulizers such as the Akita jet nebulizer and the FOX vibrating mesh nebulizer.
• nebulizers contemplated for use with formulations and methods of the invention include soft mist inhalers and ultrasonic wave nebulizers.
• Methods and kits of the invention may include dehydration and reconstitution agents for dehydrating and reconstituting liquid formulations of the invention in a sterile manner for nebulization.
• aspects of the invention include an inhalable formulation comprising imatinib or a salt thereof, wherein greater than 95% of the imatinib or salt thereof in the inhalable formulation is present in a single crystal form, with the proviso that the salt is not mesylate.
• the single crystal form may be type A as defined herein. In certain embodiments, the single crystal form may be type B as defined herein.
• Inhalable formulations of the invention may include greater than 99% of the imatinib in a single crystal form. In various embodiments, 100% of the imatinib in the inhalable formulation may be present in a single crystal form.
• the inhalable formulation may be in a dry powder.
• the inhalable formulation may be a suspension of crystalline imatinib.
• the imatinib may be present in a therapeutically effective amount to treat a condition of the pulmonary cardiovascular system, such as pulmonary arterial hypertension (PAH).
• PAH pulmonary arterial hypertension
• the salt may be at least one selected from the group consisting of glycollate, isethionate, xinafoate, furoate, trifenatate, HC1, sulfate, phosphate, lactate, maleate, malate, fumarate, tartrate, succinate, adipate, citrate, and malonate.
• the salt may be glycolate, malate, tartrate, malonate, isethionate, or citrate.
• the inhalable formulation may further include one or more carrier agents.
• Certain aspects of the invention may include methods of treating a condition of the pulmonary cardiovascular system including providing to a subject an inhalable formulation comprising imatinib or a salt thereof, wherein greater than 95% of the imatinib or salt thereof in the inhalable formulation is present in a single crystal form, with the proviso that the salt is not mesylate.
• methods of the invention may include preparing an inhalable formulation by micronizing imatinib particles, suspending the micronized imatinib particles in a solution, and spray drying the suspended micronized imatinib particles.
• inhalable micronized particles are modified such that they can be delivered more readily from an inhaler device and show better lung deposition, while retaining the original form of the API to allow for modulation of residence time in the lungs (i.e. slowed dissolution rate relative to amorphous drug).
• the micronized particles may comprise a MMAD in the range of 0.5-5um.
• one or more excipients is included in the suspending step.
• the excipient may be a water soluble excipient, such as leucine, dileucine, trileucine, trehalose, mannitol, citrate, or acetate.
• the excipient may be a water insoluble excipient, such as lecithin, DSPC or limonene.
• insoluble excipients may be dissolved in a non-aqueous medium that is miscible or immiscible with water, thereby creating an emulsion.
• a liposomal dispersion could be created into which the suspended imatinib could be added and homogenized or where it could be spray dried in separate feedstocks.
• the inhalable formulation may contain a therapeutically effective amount of imatinib particles for treating a condition of the pulmonary cardiovascular system.
• the condition of the pulmonary cardiovascular system can be pulmonary arterial hypertension (PAH).
• the inhalable formulation may comprise less than about 3% amorphous imatinib particles by mass.
• the inhalable formulation can comprise less than about 1% amorphous imatinib particles.
• the inhalable formulation may include less than 5% water or, in certain embodiments, less than 1% water by mass.
• the invention may include an inhalable formulation produced by the above methods.
• aspects of the invention can include an inhalable formulation comprising micronized particles of imatinib, wherein the imatinib retains its crystal structure in the particles and the inhalable formulation comprises less than 5% amorphous imatinib particles by mass.
• the particles can comprise a size of about 0.5 to about 5 pm mass median aerodynamic diameter (MMAD).
• MMAD mass median aerodynamic diameter
• the inhalable formulation may further comprise one or more carrier agents.
• the one or more carrier agents include lactose.
• Imatinib may be present in a therapeutically effective amount to treat a condition of the pulmonary cardiovascular system.
• the condition of the pulmonary cardiovascular system can be pulmonary arterial hypertension (PAH).
• PAH pulmonary arterial hypertension
• the inhalable formulation can comprise less than 3% amorphous imatinib particles.
• the inhalable formulation may comprise less than 1% amorphous imatinib particles.
• the inhalable formulation can include less than 5% water. In some embodiments, the inhalable formulation may comprise less than 1% water.
• the invention can include methods of treating a condition of the pulmonary cardiovascular system including providing to a subject an inhalable formulation comprising micronized particles of imatinib, wherein the imatinib retains its crystal structure in the particles and the inhalable formulation comprises less than 5% amorphous imatinib particles.
• the subject may be a human.
• aspects of the invention include an inhalable formulation consisting of at least about 50% imatinib or a salt thereof.
• the inhalable formulation may include one or more carrier agents.
• the imatinib or salt thereof may be about 50% of the formulation and the carrier agents may make up the remainder of the formulation.
• the one or more carrier agents can comprise lactose.
• the inhalable formulation may be a dry powder.
• the imatinib or salt thereof can be present in a therapeutically effective amount to treat a condition of the pulmonary cardiovascular system.
• the condition of the pulmonary cardiovascular system may be pulmonary arterial hypertension (PAH).
• PAH pulmonary arterial hypertension
• Greater than 80% of the imatinib or salt thereof in the inhalable formulation can be present in a single crystal form.
• the single crystal form can be type A.
• the salt may be at least one selected from the group consisting of glycolate, malate, tartrate, malonate, isethionate, and citrate.
• methods of the invention may include treating a condition of the pulmonary cardiovascular system by providing to a subject an inhalable formulation consisting of at least about 50% imatinib or a salt thereof.
• the subject may be a human.
• aspects of the invention include an inhalable formulation comprising N-desmethyl imatinib or a salt thereof, wherein the formulation does not include imatinib.
• the N-desmethyl imatinib may be present in a therapeutically effective amount to treat a condition of the pulmonary cardiovascular system which may be pulmonary arterial hypertension (PAH).
• PAH pulmonary arterial hypertension
• the inhalable formulation can be a dry powder and can include micronized particles comprising a mass median aerodynamic diameter in the range of 0.5-5pm.
• the salt may be selected from mesylate, glycollate, isethionate, xinafoate, furoate, trifenatate, HC1, sulfate, phosphate, lactate, maleate, malate, fumarate.
• the inhalable formulation can include one or more carrier agents.
• the carrier agent can be selected from lactose, magnesium stearate, leucine, isoleucine, dileucine, trileucine, lecithin, and distearylphosphatidylcholine (DSPC).
• the invention can include methods of treating a condition of the pulmonary cardiovascular system by providing to a subject an inhalable formulation comprising N-desmethyl imatinib or a salt thereof, wherein the formulation does not include imatinib.
• the subject may be a human and the condition of the pulmonary cardiovascular system can be pulmonary arterial hypertension (PAH).
• PAH pulmonary arterial hypertension
• 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 0.5-5pm.
• 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.
• the excipient can be a water insoluble excipient selected from the group consisting of lecithin,
• DSPC distearylphosphatidylcholine
• limonene distearylphosphatidylcholine
• 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.
• the salt can be at least one selected from the group consisting of glycollate, isethionate, mesylate, xinafoate, furoate, trifenatate, HC1, sulfate, phosphate, lactate, maleate, malate, fumarate, tartrate, succinate, adipate, citrate, and malonate.
• the salt may be glycolate, malate, tartrate, malonate, isethionate, or citrate.
• the imatinib may be present in a crystal form.
• 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.
• aspects of the invention include methods of treating a condition of the pulmonary cardiovascular system. Methods may include providing to a subject a nebulized formulation of imatinib or a salt thereof.
• the formulation can include droplets that comprise imatinib or a salt thereof. The droplets may be sized between about 0.5 to about 5 pm.
• formulations may further comprise one or more excipients.
• nebulized formulations may comprise solubilized imatinib or a salt thereof in solution.
• the subject can be a mammal and, in preferred embodiments, a human.
• the condition of the pulmonary cardiovascular system may be pulmonary arterial hypertension (PAH).
• PAH pulmonary arterial hypertension
• the formulation may be nebulized using a jet nebulizer.
• the formulation may be nebulized using a vibrating mesh nebulizer.
• the invention may include a kit for treating a condition of the pulmonary cardiovascular system, comprising a liquid formulation of imatinib or a salt thereof and a nebulizer.
• the liquid formulation may be a sterile liquid formulation.
• the imatinib or a salt thereof may be a dry composition or a salt thereof and the kit may comprise one or more liquids for reconstituting the imatinib or salt thereof.
• the nebulizer may be a jet nebulizer, a vibrating mesh nebulizer, a soft mist inhaler, or an ultrasonic wave nebulizer.
• the dry composition of the imatinib or a salt thereof may include particles of imatinib or a salt thereof.
• the particles of imatinib or a salt thereof may have been micronized.
• the micronized particles may be sized about 0.5 to about 5 pm.
• the formulation may further include one or more excipients.
• the nebulizer can be operable to generate droplets of the liquid formulation sized between about 0.5pm and about 5 pm.
• the imatinib or a salt thereof may be partitioned into two or more volumes, each of the two or more volumes corresponding to a therapeutically effective individual dose for treating the condition of the pulmonary cardiovascular system.
• Each volume the imatinib or a salt thereof can be a sterile liquid formulation.
• Kits of the invention may further include a first set of one or more agents to dehydrate the liquid formulation to produce a dried composition of the imatinib or a salt thereof and a second set of one or more agents to reconstitute the dried composition as a sterile liquid formulation of the imatinib or a salt thereof.
• aspects of the invention may include methods of treating a condition of the pulmonary cardiovascular system. Such methods may include providing imatinib or a salt thereof, reconstituting the imatinib or a salt thereof in a sterile solvent to prepare a reconstituted solution of imatinib or salt thereof, and nebulizing the reconstituted solution.
• the reconstituted solution may include one or more excipients.
• the imatinib or a salt thereof may be a liquid formulation of the imatinib or a salt thereof, and the method can first include dehydrating the liquid formulation to produce a dried composition of the imatinib or a salt thereof. Dehydrating may be
• the reconstituting step can include transferring the sterile solvent from a first to sealed container to a second sealed container comprising the imatinib or salt thereof using a needle or dispensing pin.
• Nebulizing may include coupling the second sealed container to a nebulizer.
• nebulizing can include transferring the reconstituted solution from the second sealed container to the nebulizer using a needle or a dispensing pin.
• FIG. 1 shows an x-ray powder diffraction diagram of the type A crystal form of imatinib.
• FIG. 2 shows an x-ray powder diffraction diagram of the type B crystal form of imatinib.
• FIG. 3 diagrams steps of an exemplary method of preparing an inhalable formulation of imatinib.
• FIG. 4 shows imatinib lung levels over time for various doses of imatinib solutions and suspensions delivered via various administration routes.
• FIG. 5 shows an imatinib lung concentration comparison between 1 mg/kg of imatinib suspension or solution delivered by intratracheal instillation and 1 mg/kg of imatinib delivered by IV.
• FIG. 6 diagrams exemplary processing steps for inhalable imatinib preparations.
• FIG. 7 shows particle size distribution (PSD) analysis of unmicronized imatinib.
• FIG. 8 shows PSD analysis of micronized imatinib at 1 bar.
• FIG. 9 shows PSD analysis of micronized imatinib at 2 bar.
• FIG. 10 shows PSD analysis of micronized imatinib at 3 bar.
• FIG. 11 shows thermalgravimetric analysis (TGA) of imatinib Free Base, pre- micronization.
• TGA thermalgravimetric analysis
• DSC differential scanning calorimeter
• FIG. 13 shows a DSC thermogram of micronized imatinib.
• FIG. 14 shows a DSC thermogram of co-spray-dried imatinib with leucine.
• FIG. 15 shows PSD analysis of various carrier-based imatinib samples discussed in Example 2.
• FIG. 16 shows an exemplary manufacturing scheme for a 50:50 Imatinib: Lactose blend.
• FIG. 17 shows an exemplary sampling strategy for BCU testing.
• FIG. 18 shows an APSD profile for batch NP- 106- 18104-002 in Example 3.
• FIG. 19 shows Metrics Results for batch NP- 106- 18104-002 in Example 3.
• FIG. 20 shows an APSD profile for a 75:25 Imatinib:Lactose Spray-Dried formulation.
• FIG. 21 shows Metrics Results for a 75:25 Imatinib: Lactose Spray-Dried formulation.
• FIG. 22 shows an APSD profile for a 90:10 Imatinib:Lactose Spray-Dried formulation.
• FIG. 23 shows Metrics Results for a 90:10 Imatinib: Lactose Spray-Dried formulation.
• FIG. 24 shows an APSD profile for a 50:50 Imatinib:Lactose Spray-Dried formulation.
• FIG. 25 shows Metrics Results for a 50:50 Imatinib: Lactose Spray-Dried formulation.
• FIG. 26 shows an APSD Comparison profile for various Spray-Dried and Carrier Based DPI (Dry Powder Inhaler) Formulations.
• FIG. 27 shows an APSD Comparison profile for batch NP- 106- 18104-002 at Time Zero and Time 1 Month under two storage conditions as detailed in Example 3.
• FIG. 28 shows an APSD Comparison profile for a 75:25 Imatinib:Lactose Spray-Dried formulation at Time Zero and Time 1 Month under two storage conditions as detailed in Example 3.
• FIG. 29 shows an APSD Comparison profile for a 90:10 Imatinib:Lactose Spray-Dried formulation at Time Zero and Time 1 Month under two storage conditions as detailed in Example 3.
• FIG. 30 shows an APSD Comparison profile for a 50:50 Imatinib:Lactose Spray-Dried formulation at Time Zero and Time 1 Month under two storage conditions as detailed in Example 3.
• FIG. 31 shows a DSC thermogram of un-micronized material (Lot. lKg) from Example
• FIG. 31 shows a DSC thermogram of the micronized sub-lot #1 material (50g) from Example 4.
• FIG. 33 shows a DSC thermogram of the micronized bulk material (463.38g) from Example 4.
• FIG. 34 shows a DVS isotherm plot of the unmicronized Lot. lKg from Example 4.
• FIG. 35 shows a DVS isotherm plot of the micronized sub-lot #1 material (50g) from Example 4.
• FIG. 36 shows a DVS isotherm plot of the micronized sub-lot #2 material (50g)from Example 4.
• FIG. 37 shows a DVS isotherm plot of the micronized material (463.38g) from Example 4.
• FIG. 38 shows an XRPD overlay of Imatinib Free Base pre and post micronization from Example 4.
• FIG. 39 shows an XRPD isotherm plot of the micronized material (463.38g) from
• FIG. 40 shows a TGA thermogram of Carrier Based Formulation NP- 106- 18104-002 from Example 4.
• FIG. 41 shows a TGA thermogram of Spray-Dried formulation 119#008C (50:50
• FIG. 42 shows a TGA thermogram of Spray-Dried formulation 119#008A (75:25
• FIG. 43 shows a TGA thermogram of Spray-Dried formulation 119#008B (90:10
• FIG. 44 shows a sorption/desorption trace of batch 119#008A from Example 4.
• FIG. 45 shows a sorption/desorption trace of batch 119#008B from Example 4.
• FIG. 46 shows a sorption/desorption trace of batch 119#008C from Example 4.
• FIG. 47 shows a sorption/desorption trace of batch NP- 106- 18104-002 from Example 4.
• FIG. 48 shows a background subtracted XRPD trace of batch 119#008A from Example 4.
• FIG. 49 shows a background subtracted XRPD trace of batch 119#008B from Example 4.
• FIG. 50 shows a background subtracted XRPD trace of batch 119#008C from Example 4.
• FIG. 51 shows a background trace of Leucine.
• FIG. 52 shows overlaid, background subtracted, XRPD traces of batches 119#008A, B and C from Example 4.
• FIG. 53 shows a background subtracted XRPD trace of batch NP- 106- 18104-002 from Example 4.
• FIG. 54 shows adsorption & desorption for batch NP- 106- 18104-002 from Example 4.
• FIG. 55 shows adsorption & desorption for a 50:50 APLLeucine spray-dried formulation from Example 4.
• FIG. 56 shows adsorption & desorption for a 75:25 APLLeucine spray-dried formulation from Example 4.
• FIG. 57 shows adsorption & desorption for a 90:10 APLLeucine spray-dried formulation from Example 4.
• FIG. 58 shows adsorption & desorption for NP-106-104-M2 after one month of conditioning at 25°C/60%RH from Example 4.
• FIG. 59 shows adsorption & desorption for NP-106-104-M2 after one month of conditioning at 40°C/75%RH from Example 4.
• FIG. 60 shows adsorption & desorption for 119#008A(75:25) after one month of conditioning at 25°C/60%RH from Example 4.
• FIG. 61 shows adsorption & desorption for 119#008B(90:10) after one month of conditioning at 25°C/60%RH from Example 4.
• FIG. 62 shows adsorption & desorption for 119#008C(50:50) after one month of conditioning at 25°C/60%RH from Example 4.
• FIG. 63 shows adsorption & desorption for NP- 106- 104-002 after one month of conditioning at 25°C/60%RH from Example 4.
• FIG. 64 shows an overlaid DSC thermogram of the first heat cycle for batch NP- 106- 104- M2 after one month conditioning at 25°C/60 %RH and at 40°C/75%RH from Example 4.
• FIG. 65 shows an overlaid DSC thermogram of the magnified first heat cycle for batch NP-106-104-M2 after conditioning at 25°C/60 %RH and at 40°C/75%RH (1M) from Example 4.
• FIG. 66 shows an overlaid DSC thermogram of the second heat cycle for batch NP-106- 104-M2 after conditioning at 25°C/60 %RH and at 40°C/75%RH (1M) from Example 4.
• FIG. 67 shows overlaid DSC traces of the first heat cycle for batches 119#008A-C, NP- 106-104-002 after conditioning at 25°C/60 %RH from Example 4.
• FIG. 68 shows overlaid DSC traces of the second heat cycle for batches 119#008A-C, NP- 106- 104-002 after conditioning at 25°C/60 %RH from Example 4.
• FIG. 69 shows overlaid DSC traces of the first heat cycle for batches 119#008A-C, NP- 106-104-002, after conditioning at 40°C/75%RH from Example 4.
• FIG. 70 shows overlaid DSC traces of the second heat cycle for batches 119#008A-C, NP- 106- 104-002, after conditioning at 40°C/75%RH from Example 4.
• FIG. 71 shows a TGA thermogram of NP-106-104-M2 after conditioning at
• FIG. 72 shows a TGA thermogram of NP-106-104-M2 after conditioning at
• FIG. 73 shows overlaid hysteresis plots for batch NP-106-104-M2 after conditioning at 25°C/60%RH and 40°C/75%RH from Example 4.
• FIG. 74 shows overlaid hysteresis plots for batch 119#008A (75:25) after conditioning at 25°C/60%RH and 40°C/75%RH from Example 4.
• FIG. 75 shows overlaid hysteresis plots for batch 119#008B (90:10) after conditioning at 25°C/60%RH and 40°C/75%RH from Example 4.
• FIG. 76 shows overlaid hysteresis plots for batch 119#008C (50:50) after conditioning at 25°C/60%RH and 40°C/75%RH from Example 4.
• FIG. 77 shows overlaid hysteresis plots for batch NP- 106- 104-002 after conditioning at 25°C/60%RH and 40°C/75%RH from Example 4.
• FIG. 78 shows a background subtracted XRPD trace of batch NP-106-104-M2 after conditioning for 1 month at 25°C/60%RH from Example 4.
• FIG. 79 shows a background subtracted XRPD trace of batch NP-106-104-M2 after conditioning for 1 month at 40°C/75%RH from Example 4.
• FIG. 80 shows a background subtracted XRPD trace of batch 119#008A (75:25) after conditioning at 25°C/60%RH from Example 4.
• FIG. 81 shows a background subtracted XRPD trace of batch 119#008A (75:25) after conditioning at 40°C/75%RH from Example 4.
• FIG. 82 shows a background subtracted XRPD trace of batch 119#008B (90:10) after conditioning at 25°C/60%RH from Example 4.
• FIG. 83 shows a background subtracted XRPD trace of batch 119#008B (90:10) after conditioning at 40°C/75%RH from Example 4.
• FIG. 84 shows a background subtracted XRPD trace of batch 119#008C (50:50) after conditioning at 25°C/60%RH from Example 4.
• FIG. 85 shows a background subtracted XRPD trace of batch 119#008C (50:50) after conditioning at 40°C/75%RH from Example 4.
• FIG. 86 shows a background subtracted XRPD trace of NP- 106- 104-002 after
• FIG. 87 shows a background subtracted XRPD trace of NP- 106- 104-002 after
• the invention relates to inhalable formulations of imatinib and salts thereof. Specifically, inhalable formulations having high ratios of imatinib or salts thereof (e.g., 50% or more) relative to other components are described herein.
• Imatinib as used throughout the application, refers to the free base compound unless a salt thereof is recited. Imatinib as the free base has the below structure.
• compositions described herein provide greater concentrations of imatinib in target lung tissue than obtained with equivalent doses administered orally or through IV. Furthermore, those doses, comprising a high percentage of the overall formulation, are deliverable in lower volume formulations than conventional formulations of between 1% and 3% API. Reducing the volume a patient must inhale can increase patient comfort and compliance, thereby improving results. Additionally, a higher percentage of API content can improve the API distribution and blend uniformity.
• compositions of the invention allow for treatment of conditions of the pulmonary cardiovascular system (e.g., PAH) with lower doses and less inhalable volume than would be required in systemic administration, thereby lowering the risk of adverse events including subdural hematoma (See, Frost et ah).
• PAH pulmonary cardiovascular system
• the invention provides viable treatment methods for life threatening diseases that were heretofore too risky for practical application.
• compounds of the invention include formulations of imatinib or salts thereof.
• the free base imatinib is 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.
• imatinib salts that were found to exhibit suitable thermal stability and few or single polymorphic forms include glycollate, isethionate, malonate, tartrate, and malate.
• salt forms contemplated herein are xinafoate, furoate, trifenatate, HC1, sulfate, phosphate, lactate, maleate, fumarate, succinate, adipate, mesylate, and citrate.
• formulations can comprise at least 50% imatinib or a salt thereof.
• 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 micronized 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.
• leucine can be used as a force-control agent including different forms of leucine (e.g. isoleucine) along with dileucine and even trileucine.
• Lecithin phospholipids such as DSPC may be used as an excipient for dry powder inhalation.
• 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.
• inhalable formulations may have APLcarrier ratios of 50:50, 55:45, 60:40, 65:35, 70:30, 75:25, 80:20, 85:15, 90:10, or 95:5.
• Certain inhalable formulations may be pure API with no additional components.
• formulations may include imatinib or salts thereof as the API in amounts greater than 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, or 45%.
• API ratios refer to %w/w.
• micronized imatinib and salts thereof retain crystallinity, even after micronization and spray drying (as discussed in detail below).
• imatinib formulations of the invention can include less than 50%, less than 25%, less than 20%, less than 10%, less than 9%, less than 8%, less than 7%, less than 6%, less than 5%, less than 4%, less than 3%, less than 2%, or less than 1% amorphous imatinib by mass.
• formulations of the invention include no observable amorphous imatinib content.
• the desired crystalline form and low amorphous content obtained during micronization is carried through to the spray-dried inhalable powder because the imatinib crystals are not dissolved in the solution to a significant degree.
• imatinib formulations of the invention are significantly less hygroscopic than conventional imatinib mesylate compounds. Accordingly, the imatinib formulations of the invention are better suited for dry powder inhalation and can comprise less than 5% water content, less than 4%, less than 3%, less than 2%, or, in preferred embodiments, less than 1% water content.
• inhalable formulations of the invention include imatinib or a salt thereof present in a single crystal form.
• imatinib or a salt thereof may be present at greater than 75%, 80%, 85%, 90%, 95%, or, in preferred embodiments, greater than 99% in a single crystal form by mass.
• the single crystal form may be, for example, type A or type B in various embodiments.
• Crystalline purity can be estimated using any known method including, for example, x- ray powder diffraction (XRPD).
• XRPD x- ray powder diffraction
• FIG. 1 An XRPD diagram for the type A crystal form of free base imatinib is shown in FIG. 1.
• An XRPD diagram for the type B crystal form of free base imatinib is shown in FIG. 2.
• imatinib or salts thereof are provided in dry powder
• Dry powder can be administered via, for example, dry powder inhalers such as described in Berkenfeld, et ah, 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.
• imatinib suspensions having the characteristics described herein can be delivered via inhalation using, for example, a nebulizer.
• Imatinib suspensions may offer advantages over solutions as discussed below.
• micronization and particle diameter may be of particular importance for efficient delivery and imatinib may be preferably micronized to a mass median diameter of 2pm or less.
• the suspension solution for nebulizer inhalation can be aqueous and doses may be divided into individual containers or compartments for sterile storage prior to use.
• Micronized imatinib particle size can range from about 0.5pm to about 5 pm depending on application (e.g., dry powder or suspension for inhalation). In preferred embodiments the size range is about 1pm to about 3pm in dry powder formulations to achieve deep lung penetration.
• the imatinib formulations of the invention may be any suitable imatinib formulations of the invention.
• compositions of the invention may be used to treat any disease or disorder that involves inhibition of PDGFR or other kinases sensitive to imatinib.
• the compositions of the invention may be used to treat PAH.
• a therapeutically effective amount of a pharmaceutical composition of imatinib for treatment of PAH or other disorders, 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.
• inhalation e.g., via dry powder inhaler or nebulizer
• 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 on once, twice or three times per day schedule.
• About 0.1 mg to about 80 mg of the imatinib of salt thereof may then be deposited within the lung after inhalation.
• about 10 mg to 30 mg of imatinib may be given in a capsule for a single dry-powder inhalation dose with about 5 mg to about 10 mg of the compound to be expected to reach the lungs.
• imatinib may be present at about 0.1 to about 1 mg/kg in a dose and may be administered one to four times a day to obtain the desired therapeutic results.
• 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 ah, 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.
• Imatinib pharmaceutical compositions of the invention may be used to treat lung transplant recipients to prevent organ rejection. See, Keil, et ah, 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.
• LTx chronic lung allograft rejection after lung transplantation
• compositions described herein can be used to treat pulmonary veno-occlusive disease (PVOD).
• PVOD pulmonary veno-occlusive disease
• 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 afforded by low polymorphism and amorphous content.
• 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.
• Methods of the invention can include preparation of imatinib formulations.
• imatinib or salts thereof may be administered via inhalation in suspension or dry powder form.
• Dry powder formulations may be obtained via any known method including, in preferred embodiments, jet milling. Jet milling can be used to grind imatinib and, potentially, various additives (e.g., excipients) using a jet (or jets) of compressed air or gas to force collisions between the particles as they transit at near sonic velocity around the perimeter of a toroidal chamber. The size reduction is the result of the high-velocity collisions between particles of the process material.
• Outputs of the jet mill may allow particles to exit the apparatus once a desired size has been reached.
• desired particle size for dry powder inhalation and other formulations may be in the range of about 0.5 pm to about 5 pm.
• bulk imatinib may be micronized to the desired size for inhalation via wet milling wherein the imatinib particles are suspended in a slurry and reduced through shearing or impact with a grinding media.
• An unexpected finding of the invention is that, once micronized, free base imatinib retains crystallinity and is considerably less hygroscopic than certain salt forms of imatinib (e.g., imatinib mesylate). Furthermore, micronized imatinib obtained using methods of the invention has been found to exhibit no apparent polymorphs other than the designated Type A and very low levels of amorphous content. Accordingly, this can result in improved stability of the drug substance and any drug product upon storage. Single crystal forms such as described may allow for more predictable in vivo behavior and appropriate dosing can be determined.
• imatinib formulations of the invention can be prepared for inhalation.
• imatinib formulations of the invention with their low polymorphic and amorphous content, can be prepared for inhalation.
• the dry powder imatinib can be combined with larger carrier particles such as lactose as discussed above.
• an imatinib suspension can be formed.
• the suspension may result from dry micronization followed by suspension of the resulting dry powder or can be obtained as the outcome of a wet milling procedure.
• Imatinib suspensions of micronized crystal forms may be used in nebulized inhalation treatment or may be spray dried for dry powder treatments.
• FIG. 3 diagrams a spray drying method for preparing a dry powder imatinib formulation for inhalation. First, bulk imatinib is micronized 303 as described above to obtain imatinib particles in a desired size range.
• micronized imatinib is suspended in a solution 305 such that they do not dissolve and instead retain the desired crystalline features (e.g., low polymorphism and amorphous content).
• the suspended particles can then be spray dried 307 using any known method. Spray drying techniques are well characterized and described, for example, in Ziaee, et ah, 2019, Spray drying of pharmaceuticals and biopharmaceuticals: Critical parameters and experimental process optimization approaches, Eur. J. Pharm. Sci., 127:300-318, and Weers et ah, 2019, AAPS PharmSciTech. 2019 Feb 7;20(3):103.
• Spray drying micronized imatinib or salts thereof provides for uniform and predictable crystallinity and particle size and can avoid the need for large carrier molecules that may adversely affect the amount of inhaled drug that reaches the target lung tissue.
• micronized drug particles may be suspended within a non- aqueous solvent or within an emulsion of a non-aqueous solvent which, in turn is emulsified or dispersed within an aqueous environment (e.g. oil in water) and spray-dried, resulting in crystalline drug particles.
• the non-aqueous component may or may not be fugitive and thus could be removed completely during spray drying or, it could be retained, depending on the desired properties required.
• each atomized droplet (mass median diameter ⁇ lOpm) contains dispersed drug crystals. During the initial moments of the drying process, the more volatile aqueous phase begins to evaporate.
• the rapidly receding atomized droplet interface drives enrichment of the slowly diffusing drug and emulsion particles at the interface. This leads to formation of a void space in the center of the drying droplet. As the drying process continues, the less volatile oil phase in the emulsion droplets evaporates, resulting in formation of hollow pores in their place. Overall, the resulting hollow spray-dried composite particles contain drug crystals.
• formulation methods include manipulation of the suspension to prevent dissolution of the imatinib.
• Aqueous solution factors such as pH, ionic strength and dispersing agents may be used to obtain a stable suspension for nebulized inhalation or spray drying.
• the pH of the aqueous solution may be adjusted to prevent dissolution.
• salt in the aqueous solution may be used to reduce solubility of the imatinib crystals in certain embodiments.
• a dispersing agent or surfactant e.g., Tween 20 or Tween 80
• Tween 20 or Tween 80 e.g., Tween 20 or Tween 80
• excipients can be added to the suspension before spray drying.
• the excipient may be a water-soluble excipient, such as leucine, dileucine, trileucine, trehalose, mannitol, citrate or acetate.
• the excipient may be a water insoluble excipient, such as lecithin, distearylphosphatidylcholine (DSPC) or limonene.
• DSPC distearylphosphatidylcholine
• limonene such insoluble excipients may be dissolved in a non-aqueous medium that is miscible or immiscible with water, thereby creating an emulsion.
• a liposomal dispersion could be created into which the suspended imatinib could be added and homogenized or where it could be spray dried in separate feedstocks.
• imatinib or salts thereof in the compositions and methods discussed herein may be substituted with imatinib metabolites such as N-desmethyl imatinib and salts thereof.
• imatinib metabolites such as N-desmethyl imatinib and salts thereof.
• N-desmethyl imatinib is the primary active metabolite of imatinib formed when imatinib undergoes demethylation by the cytochrome P450 (CYP) isomer CYP3A4.
• CYP cytochrome P450
• N- desmethyl imatinib has the following structure:
• N-desmethyl imatinib has been found to exhibit the same potency as the imatinib parent compound but exhibits an increased half-life relative to the parent imatinib compound. Accordingly, inhalable formulations of N-desmethyl imatinib as described herein provide therapeutic benefits with reduced risk of adverse events through more efficient delivery to and longer residence in the effected tissue relative to conventional oral or IV administration of imatinib mesylate.
• compounds of the invention include formulations of N- desmethyl imatinib or salts thereof.
• N-desmethyl imatinib is 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.
• salts contemplated herein include glycollate, isethionate, malonate, tartrate, and malate.
• Other salt forms contemplated herein are xinafoate, furoate, trifenatate,
• micronized N-desmethyl imatinib and salts thereof retain crystallinity, even after micronization and spray drying (as discussed in detail below).
• micronized N-desmethyl imatinib particles in a solution as opposed to solubilizing, the desired crystalline form and low amorphous content obtained during micronization is carried through to the spray-dried inhalable powder because the N-desmethyl imatinib crystals are not dissolved in the solution to a significant degree.
• particles of imatinib, imatinib metabolites, or salts thereof may be prepared using molding techniques. 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.
• 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.
• 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.
• aerodynamic features of the size and shape can be modelled using known techniques to determine and maximize lung penetration.
• 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 0.5pm to about 5 pm depending on the application (e.g., dry powder or suspension for inhalation). In preferred embodiments the size range is about 1pm to about 3pm in dry powder formulations to achieve deep lung penetration.
• engineered particle shapes may include spheres or spheroids, cylinders, or various polyhedrons. See Mack, et ah, 2012, Particle Engineering for Inhalation Formulation and Delivery of Bio therapeutics, Inhalation, August 2012, incorporated herein by reference.
• 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.
• the mold 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.
• compositions and methods of the invention may include imatinib, imatinib metabolites, or salts thereof for nebulized delivery.
• Nebulizers use oxygen, compressed air, or ultrasonic power to break up solutions and suspensions into small aerosol droplets that can be directly inhaled by a user in need of treatment.
• Formulations and methods of the invention may use any known type of nebulizer including soft mist inhalers, jet nebulizers, ultrasonic wave nebulizers, and vibrating mesh nebulizers. Jet nebulizers and vibrating mesh nebulizers, for example, are commercially available from Vectura Group pic (UK).
• Soft mist inhalers use mechanical energy stored in a spring by user-actuation to pressurize a liquid container, causing the contained-liquid to spray out of a nozzle for inhalation in the form of a soft mist.
• Soft mist inhalers do not rely on gas propellant or electrical power for operation.
• the average droplet size in soft mist inhalers is about 5.8 micrometers.
• Jet nebulizers are the most commonly used and may be referred to as atomizers. Jet nebulizers use a compressed gas (e.g., air or oxygen) to aerosolize a liquid medicine when released therethrough at high velocity. The resulting aerosolized droplets of therapeutic solution or suspension are then inhaled by a user for treatment.
• the compressed gas may be pre compressed in a storage container or may be compressed on-demand by a compressor in the nebulizer.
• Ultrasonic wave nebulizers rely on an electronic oscillator to generate a high frequency ultrasonic wave that, when directed through a reservoir of a therapeutic suspension of solution, aerosolized the medicine for inhalation.
• Vibrating mesh nebulizers use the vibration of a membrane having thousands of holes at the top of the liquid reservoir to aerosolize a fine-droplet mist for inhalation. Vibrating mesh nebulizers avoid some of the drawbacks of ultrasonic wave nebulizers, offering more efficient aerosolization with reduced treatment times and less heating of the liquid being nebulized.
• nebulizers used in the invention may include pulsed air flow as described in U.S. Pat. No. 7,866,317, mixed flow of aerosol and compressed gas as described in U.S. Pat. No. 8,181,644, or other nebulizer features as described in U.S. Pat. Nos. 7,647,928; 8,910,625; and 7,891,358; and U.S. Pat. Pub. No. 2015/0174343, the content of each of which is incorporated herein by reference.
• concentration of imatinib formulations may be achieved at various areas of the lung through manipulation of delayed release technology such as described in U.S. Pat. No. 8,534,277, incorporated herein by reference.
• nebulizer formulations may include particles sized and shaped as described in U.S. Pat. No. 8,101,160, or prepared using methods described in U.S. Pat. Pub. No. 2018/0257084, the content of each of which is incorporated herein by reference.
• Formulations and methods of the invention may include nebulized imatinib administered using techniques or in combination with other inhalable compounds as described in U.S. Pat. Nos. 7,928,089;
• Kits of the invention may include a nebulizer such as those described above along with an effective does of a solution or suspension of imatinib or salts thereof for treating a cardiovascular or pulmonary disease such as PAH.
• Kits may include additional materials for reconstituting dry ingredients including imatinib formulations for nebulization in a sterile manner.
• kits may include sealed containers of dry ingredients and sterile solvents (e.g., water) as well as syringes, needles, dispensing pins, mini-spikes, or other means of accessing the solvent within the sealed container and adding it to the dry ingredients.
• solutions can be reconstituted in a sterile manner and then nebulized by users as described herein.
• lyophilizers are available, for example, from SP Scientific, Warminster, PA.
• Dehydration of formulations of the invention for nebulizing may be performed using any known dehydration methods or agents such as critical point drying with CO2 under pressure, solvent substitution, vacuum, or blow drying (e.g., in a nitrogen atmosphere).
• 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.
• 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.
• 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.
• 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.
• 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 prophylactic dose is used in subjects prior to, or at an earlier stage of disease.
• 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.
• Dosage regimens may be adjusted to provide the optimum desired response (e.g. a therapeutic or prophylactic response).
• a single inhalable bolus may be
• 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.
• dosage unit 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.
• 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.
• 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.
• 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
• 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.
• 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.
• the aqueous suspension may contain the active material in admixture with excipients suitable for the manufacture of aqueous suspensions.
• 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.
• suspending agents dispersing or wetting agents
• a naturally occurring phosphatide for example lecithin
• condensation products of an alkylene oxide with fatty acids for example polyoxyethylene stearate
• 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.
• preservatives for example ethyl, or n-propyl p-hydroxybenzoate
• coloring agents for example ethyl, or n-propyl p-hydroxybenzoate
• flavoring agents such as sucrose, mannitol, or trehalose.
• sweetening agents such as sucrose, mannitol, or trehalose.
• 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.
• 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.
• pharmaceutically acceptable carriers 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.
• pharmaceutically acceptable carrier is used to mean any carrier, diluent, adjuvant, excipient, or vehicle, as described herein.
• 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.
• suitable carriers, diluents, solvents, or vehicles include water, ethanol, polyols, suitable mixtures thereof, vegetable oils (such as olive oil), and organic esters such as ethyl oleate.
• excipients include lactose, milk sugar, sodium citrate, calcium carbonate, and dicalcium phosphate.
• disintegrating agents include starch, alginic acids, and certain complex silicates.
• lubricants include magnesium stearate, sodium lauryl sulphate, talc, as well as high molecular weight polyethylene glycols.
• 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.
• TABLE 1 shows lung level comparisons in an animal model of various doses of imatinib and imatinib mesylate suspensions and solutions administered orally or via intratracheal instillation (IT) or intravenous (IV).
• FIG. 4 shows lung concentrations of imatinib over time of the various forms and routes described in TABLE 1.
• the suspensions administered via IT were found to maintain levels above IC50 long enough to allow for TID or even BID dosing for inhaled solutions.
• the plotted routes, forms, and doses are indicated in TABLE 1 above.
• FIG. 5 shows lung concentrations of imatinib solution and suspensions administered via IT compared to lung concentrations of an IV solution of imatinib at lmg/kb dose and illustrates a clear AUC advantage in the IT suspension over the IT solution and both over the IV solution.
• Imatinib Free Base was obtained as a dry powder.
• Micronized material was used to manufacture a 50 % drug load with inhalation grade lactose (Respitose ML001, available from DFE pharma, Germany). This formulation was manufactured at 4-gram total batch size using low shear blending. An STB-50 vessel was used for the manufacture. The processing steps are shown in the flow diagram in FIG. 6. This formulation equated to a 10 mg nominal dose per 20 mg of powder.
• formulations (20.0 ⁇ 0.2 mg) was filled into size 3 Hydroxypropyl methylcellulose (HPMC) capsules by hand. Filled capsules were tested for emitted dose by a Dosage Unit Sampling Apparatus (DUSA) and total lung dose using an OPC-standard anatomical throat.
• the inhaler used for this component of the study was a HR-RS01 (Plastiape, Italy) at 60 L/min.
• a feasibility batch was manufactured on small scale (2 g) using a Buchi B290 laboratory spray dryer (see Table 2 below). Micronized Imatinib was suspended in water at an APLLeucine ratio of 75:25 w/w. The aspiration rate was at the highest setting, maximum suitable atomisation pressure and feed rate of 2 - 4 mL/min. Spray drying conditions was checked by assessment of yield, powder appearance and PSD during the run.
• unmicronized imatinib was dispersed with compressed air (2 bar) and sized by laser diffraction (RODOS dry powder feeder; HELOS laser diffractometer, WINDOX 4.0 software; Sympatec GmbH, Germany).
• the 10, 50 and 90 % undersize particle size values (X10, X50 and X90, respectively) were obtained.
• SSA specific surface area
• XRPD X-ray powder diffraction
• thermal properties of all samples were investigated using a differential scanning calorimeter (DSC 8000, PerkinElmer, UK), calibrated with an indium standard. Approximately 3 mg of sample was accurately weighted into an aluminum pan and crimped with a lid to form a hermetic seal. The sample and reference pan were heated at a rate of 10°C/min from 20°C to 300°C. The calorimeter head was continuously flushed with dry nitrogen gas at 0.2 L/min during all measurements. Thermalgravimetric analysis was performed with a PerkinElmer Pyris 1 using aluminum vented pans in ceramic crucibles. The samples were heated at a rate of 10°C/min from 20°C to 400°C.
• Particle size distribution (PSD) analysis of the unmicronized material is shown in FIG. 7 and micronized material is shown at 1, 2, and 3 bar in FIGS. 8-10, respectively. These data are also summarized in Table 3. In addition, the specific surface area of unmicronized and micronized Imatinib free -base is shown in TABFE 4.
• Table 3 Particle size distribution of unmicronized, micronized and co-spray dried Imatinib.
• Unmicronized Imatinib had a median particle size of 10.4 pm and 10% and 90%- undersize of 2.38 and 28.68 pm, respectively.
• the span of the PSD of the unmicronized material was 2.53.
• the surface area of the unmicronized material was 0.88 m2/g.
• the median particle size of the micronized material when dispersed at 1, 2 and 3 bar was 1.95, 1.89 and 2.01 pm, respectively.
• the particle size in terms of dlO, d50 and d90 was 0.79, 3.02 and 8.04 pm, respectively. These data suggested that the spray-drying of suspended micronized Imatinib had a modestly larger particle size.
• the un-micronized sample was analyzed by thermogravimetric analysis (TGA) to determine the decomposition temperature prior to differential scanning calorimeter (DSC) analysis. It was concluded that the sample starts to decompose at approx. 300°C and therefore the DSC analysis was set for 20-300°C (FIG. 11).
• the DSC thermograms of unmicronized and micronized imatinib are shown in FIGS. 12 and 13, respectively.
• DSC of the Free Base suggested a large endothermic event with an onset of ca. 210°C (peak at ca. 212°C), which was most likely associated with material melting.
• the imatinib exhibited similar DSC thermograms for both the un-micronized and micronized material with a melt onset of approx. 210°C and peak enthalpies of approx. 119 J/g.
• the DSC trace of spray-dried Imatinib/leucine batch is shown in FIG. 14.
• the material shows a melting event at 211°C associated with Imatinib melting. There was no cold crystallization or Tg. This suggests that the material remained completely crystalline.
• the capsule content uniformity and preliminary aerosolization data using a coated OPC anatomical throat are shown in Tables 5 and 6, respectively.
• the single actuation content is shown in Table 7.
• the particle sizing of the formulation is summarized in Table 8 and shown in FIG. 15.
• Table 5 %Assay per 10 random capsules filled with carrier-based formulation.
• the emitted dose from the device was 6.6 mg and total lung dose was approximately 4.5 mg. These data suggest a high-payload of active was able to achieve high lung delivery. Single actuation content ranged from 63 - 71% delivered normalized to the nominal loaded dose. These data suggested good delivery efficiency of the formulation. Particle sizing of the formulation suggested a bimodal distribution. The volume weighted median diameter was 9.3 pm and the 90% undersize was 41 pm and is related to the coarser carrier in the formulation. These data suggest that the high-payload carrier formulation exhibited good aerosolization efficiency.
• the emitted dose from the device of the spray dried formulation was 8.3 mg and total lung dose was approximately 6.9 mg.
• the throat deposition was lower than the high payload carrier formulation and the delivery efficiency was better than the carrier-based formulation.
• Single actuation content ranged from 72 - 85% delivered normalized to the nominal loaded dose.
• Table 9 %Assay per 10 through life capsules filled with carrier-based formulation.
• the objective for this evaluation was to further identify the performance of imatinib free base when included into both blended and spray dried formulations.
• Imatinib Free Base Particle size reduction of Imatinib Free Base was performed using a 2-inch air jet mill (Food Pharma Systems, PM-2, Italy). The system was operated under nitrogen at a venturi and ring pressure of 8 bar and 7 bar, respectively. A total of 700.00g of raw Imatinib Free Base material was micronized, twelve sub-lots of 50g each in order to obtain at least 550 g (yield) of micronized material.
• the rate at which the material was introduced into the mill was approximately 0.5 g/min. All samples were collected and stored in an amber glass jar, which was then sealed in an aluminium laminate pouch.
• Micronized material was then used for the manufacture of Spray-Dried formulations (50:50, 75:25, 90:10) and a Carrier- Based formulation, 50 API : 50 ML001, as described below.
• Spray-Dried formulations 50:50, 75:25, 90:10
• Carrier- Based formulation 50 API : 50 ML001
• lactose ML001 and Imatinib at a 50:50 ratio were evaluated positively so a larger scale of 30g blend size was evaluated.
• Part of the micronized material collected from the the air-jet micronization was used to manufacture the formulation described above, using low shear blending.
• the STB- 110 vessel was been used for the manufacture.
• the batch was NP- 106- 18104-002 and the process followed for the manufacture of this formulation is shown in FIG. 16.
• the blended formulation was manufactured to equate to a 10 mg nominal dose per 20 mg of powder inside each capsule.
• Filled capsules were tested for emitted dose by DUSA and APSD using an OPC anatomical throat.
• An HR-RS01 as-received high resistance device, Plastiape, Italy was used for testing at 60 L/min.
• a feasibility batch was manufactured on small scale (10 g) using a Buchi B290 laboratory spray dryer. Micronized Imatinib was suspended in water at an APLLeucine ratio of 75:25, 50:50 and 90:10 w/w. The aspiration rate was at the highest setting, maximum suitable atomisation pressure of 4.0 bar, feed rate of 2 - 4 mL/min and within outlet temperature of 75°C. Spray drying conditions were checked by assessment of yield, powder appearance and PSD during the run.
• Powders were collected under reduced humidity conditions and stored refrigerated at 2- 8°C, in sealed containers. All formulations were filled into size 3 HPMC capsules for evaluation, using the following fill weights:
• the aim of the second part of this study was to evaluate the combination of leucine for a formulation containing Imatinib with 75%, 50% and 90% drug loading. These preparations were manufactured by suspending the micronized Imatinib in an aqueous system with leucine and then spray drying the system. These formulations were tested in terms of Aerodynamic Particle Size Distribution (APSD) and Emitted Dose by DUSA, using the High Resistance RS01 Plastiape device. The target dose weight of the formulation in the capsule was equivalent to a nominal API dose of 10.00 mg.
• Feed solutions were prepared according to the details in Table 13 - Overview of Spray- Dried formulations. For each solution, leucine was initially dissolved under stirring into deionised water. Once the leucine had fully dissolved, the micronized imatinib was added to create an opaque white suspension. Addition of the API resulted in some formation of foam. This appeared to be worse in the batches spray dried at higher API concentration (119#008A/B).
• Blend content uniformity (BCU) testing was performed and results are summarized in the table below (Table 15) taken from ten sections (FIG. 17). These data suggest the formulation NP- 106- 18104-002 was homogenous and met USP ⁇ 905> acceptance criteria. Table 15 - Blend Content Uniformity Results post blend manufacture
• the emitted dose as determined from single actuation content measurements using the high-resistance RS01 are shown in Table .
• the average emitted dose of the formulation blended with lactose was approximately 7 mg and this resulted in 74% emitted fraction.
• the average emitted dose of the spray dried formulations was approximately 8.74 mg and this resulted in 87% emitted fraction.
• APSD analysis was carried out firstly using the standard High Resistance RS01 at 60L/min, using an OPC anatomical throat, and the results summary is shown in Table 19 and Error! Reference source not found, for the Carrier Based DPI formulation 50 ML001: 50 Imatinib.
• the emitted dose was 6 mg and fine particle mass less than 5 pm (FPM ⁇ 5 pm) was 2.6 mg.
• the MMAD was 3.1 pm and the GSD was 2 pm.
• the MMAD were 4.48-4.25 pm and the GSD was 1.76-2.18 pm.
• the emitted dose was determined from single actuation content measurements using the high-resistance RS01 and are shown in Table .
• the aim of this study was to perform initial physicochemical characterization of unmicronized Imatinib Free Base using an array of techniques.
• the unmicronized form of the drug was then processed by micronization and blended with lactose or spray dried and characterized after being placed into stability at 40°C/75%RH and @25°C/60%RH for 1 Month and 3 Months.
• Imatinib Free Base Particle size reduction of Imatinib Free Base was performed using a 2-inch air jet mill (Food Pharma Systems, PM-2, Italy). The system was operated under nitrogen at a venturi and ring pressure of 8 bar and 7 bar, respectively. A total of 600.00g of raw Imatinib Free Base material was micronized, twelve sub-lots of 50g each in order to obtain at least 550 g (yield) of micronized material.
• the rate at which the material was introduced into the mill was approximately 0.5 g/min. All samples were collected and stored in an amber glass jar, which was then sealed in an aluminium laminate pouch.
• a feasibility batch was manufactured on small scale (10 g) using a Buchi B290 laboratory spray dryer. Micronized Imatinib was suspended in water at APLLeucine ratios of 75:25, 50:50 and 90:10 w/w. The aspiration rate was at the highest setting, maximum suitable atomisation pressure of 4.0 bar, feed rate of 2 - 4 mL/min and within outlet temperature of 75°C. Spray drying conditions were checked by assessment of yield, powder appearance and PSD during the run.
• Powders were collected under reduced humidity conditions and stored refrigerated at 2- 8°C, in sealed containers.
• SSA specific surface area
• XRPD X-ray powder diffraction
• the samples were analysed in deep fill silicon sample holders. Each sample was packed into the well and levelled to ensure a flat surface without introducing possible preferred orientation.
• the samples were analysed using a PANalytical diffractometer set at 40 kV and 40 mA with a Cu source, using a 0.5 mm Ni filter to remove Kb interference. 0.6 mm divergence slits, 1 mm anti-scatter slits and 2.5° soller slits in the primary and secondary optics were used.
• the instrument was fitted with a Lynxeye detector and data was collected over a range of 10 - 80° 2Q, with a step size of 0.05°, a scan speed of 0.03°/sec and a step time of 494 sec/step.
• the samples were spun at a rate of 15 rpm to reduce any preferred orientation affects.
• a corundum standard was analysed to ensure instrument alignment.
• the calorimeter head was continuously flushed with dry nitrogen gas at 0.2 L/min during all measurements.
• Vapour sorption experiments were conducted isothermally at 25°C using a TA instruments Q5000 SA Dynamic Vapour Sorption analyser. Samples of spray dried formulation ( ⁇ 10mg) were subject to initial desorption from ambient to 0% RH, followed by sorption up to 90% RH and subsequent desorption to 0% RH. All step changes were performed in increments of 10% RH and the sample was allowed to equilibrate to a weight change ⁇ 0.01% / min for a minimum of 5 minutes (and maximum of 240 minutes) at each relative humidity before progressing with the next step.
• Imatinib Three samples of Imatinib (l x feed and 2 x micronized) were submitted for analysis by ICP-OES for chromium, nickel and iron content using the Thermo Fisher iCap 6500 ICP- OES.
• the instrument was used in solvent mode, with the Isomist module set at 5°C.
• the calibration range was 0 to 20ppm with respect to sample mass.
• the sample was prepared for analysis by dissolving 50mg ⁇ 5mg in methanol (25mL); a clear solution was obtained, free from particulates. All system suitability requirements were met (analytical quality control, drift, calibration linearity).
• a total of 600.00g of raw Imatinib Free Base material was micronized and 463.38g were collected from the Micronization of twelve sub-lots. The remaining 66.1 lg collected by last two sub-lots micronization was used for the manufacture of Spray-Drying formulations (50:50, 75:25, 90:10) and Carrier- Base Formulation 50 APL50 MF001.
• PSD particle size distribution
• the micronized 463.38g of bulk material (Imatinib) had a median particle size of 1.95pm and 10% undersize of 0.90pm and 90% - of 4.32pm.
• the span of the PSD of the micronized material was 1.75.
• the 100. lg of additional material micronized in a second moment had a median of particle size of 1.58pm and a span of 1.74.
• Table 26 Particle size distribution of unmicronized, micronized Imatinib.
• SSA Specif Surface Area Analysis
• the unmicronized material had a SSA of 0.88m g in line with a median partcile size of 10.42pm.
• a final analysis by BET was performed at the end for the ten micronized sub-lots blended together (463.38g) to ensure that the whole bulk lot Specific Surface Area was in line with the singular sub-lots manufactured and reported in table 27 below.
• the data show an increased SSA upon micronization of 7.43 m /g. That was in line with a median particle size reduction of 1.95pm comparing with the unmicronized material analysed at the beginning.
• the un-micronized sample was analysed on the TGA to determine the decomposition temperature prior to DSC analysis. It was concluded that the sample starts to decompose at approx. 300°C and therefore the DSC analysis was set for 20-300°C (FIG. 31).
• the DSC thermograms of un-micronized and micronized sub-lot #1 materials and the overlay of their respective thermograms are shown in FIGS. 31-32.
• DSC of the Free Base suggested a large endothermic event with an onset of ca. 210°C (peak at ca. 213.01°C and 212.23°C) was observed, which was most likely associated with material melting.
• the imatinib exhibited similar DSC thermograms for both the un-micronized and micronized sub-lot #1 materials with a melt onset of approx. 210°C and peak enthalpies of approx. 120J/g.
• the DSC thermogram for the 463.38g of material (ten sub-lots blended together) is shown in FIG. 33 with an observed peak at 212.52°C and peak enthalpy approx maintained at 120J/g like the un-micronized and first sub-lot.
• Sorption/Desorption Analysis (Dynamic 2.4. Vapour Sorption, DVS) for the various lots is shown in FIGS. 34-37.
• the pre and post micronized material XRPD diffractograms are shown in FIG. 38.
• Micronized Imatinib exhibited a similar diffraction pattern as observed before micronization.
• the peak positions remain the same after micronization, but the overall pattern intensity is lower post micronization, and in addition the intensity varied from peak to peak.
• the peak at 6.0°2theta and 19°2theta are significantly more intense for the pre-micronized sample than they are in the micronized sample and peaks at 17°2theta and 21°2theta have a higher intensity for the micronized sample than that of the un-micronized sample.
• the un-micronized sample does show a large, board single peak at 24°2theta, however, once micronized this peak appears to have split into two, less intense peaks.
• Imatinib l x feed and 2 x micronized
• ICP-OES Thermo Fisher iCap 6500 ICP- OES.
• the sample was prepared for analysis by dissolving 50mg ⁇ 5mg in methanol (25mL); a clear solution was obtained, free from particulates.
• the aim of the second part of this study was to evaluate the combination of leucine for a formulation containing Imatinib with 75%, 50% and 90% drug loading. These preparations were manufactured by suspending the micronized Imatinib in an aqueous system with leucine and then spray drying the system.
• Feed solutions were prepared according to the details in Table 30. For each solution, leucine was initially dissolved under stirring into deionised water. Once the leucine had fully dissolved, the micronized imatinib was added to create an opaque white suspension. Addition of the API resulted in some formation of foam. This appeared to be worse in the batches spray dried at higher API concentration (119#008A/B).
• the feed solutions were spray dried according to the conditions detailed in Table 31.
• the feed solutions were constantly stirred during spray drying to avoid sedimentation of the suspended API during the run.
• Table 32 reports the particle size of the spray dried formulations. All three formulations had particle size suitable for pulmonary delivery. Particle size also appeared to slightly increase with increasing leucine content.
• Table 33 below shows the specific surface area results analysed by BET according to the method described in the methods section above.
• the surface area of the 90:10, 75:25 and 50:50 preparation was 9.6, 14.0 and 22.0 m /g, respectively.
• Table 33 Specific surface area (SSA) analyzed by BET of unmicronized and micronized Imatinib.
• the four samples were analysed by DSC according to the method described in methods section.
• the first heating cycle displayed an event at - 210 - 211 °C which was related to the melting of imatinib.
• the temperature at which the melt occurred appeared to decrease very slightly with increasing leucine content.
• the second heating cycle displayed a glass transition for each of the formulations at a temperature of -70 - 80°C. This was a result of the API within the formulations being quench cooled during the cooling phase of the DSC method.
• the first heating cycle displayed two key endothermic events.
• the leucine showed a very weak endothermic event on both cycle 1 and 2 at ⁇ 76°C.
• the micronized API showed a melt on cycle 1 at 212°C and a weak glass transition in cycle 2 at 78°C, similar to what was observed in the spray dried formulations.
• TGA thermal gravimetry analysis
• the carrier-based formulation shows a TGA around 120 - 150 °C, which is related to the presence of lactose in this formulation preparation.
• Sorption/desorption (DVS) analysis was performed on spray dried formulations and carrier-based formulation. Traces for batches 119#008A/B/C and NP-106- 104-002 are shown in FIGS. 44-47, respectively.
• the spray dried formulations generally had very low hygroscopicity.
• Batch 119#008A 75:25 imatinib: leucine
• 119#008B 90:10 imatinib: leucine
• 119#008C 50:50 API: leucine
• the formulations released virtually all the moisture they had previously taken up.
• XRPD Analysis of Spray Dried Formulations was performed on the spray dried formulations according to the method described in the method section above.
• the background subtracted traces for 119#008A/B/C can be seen in FIGS. 48, 49, and 50 respectively. All three formulations appeared to be largely crystalline and an overlay of these XRD traces can be seen in FIG. 52.
• the subtracted background, which would be the trace for the leucine material can be seen in FIG. 51.
• the background subtracted traces for NP-106-18104-002 can be seen in FIG. 53.
• TAM analysis was performed all drug substance material. Analysis was conducted for 6 hours at 0 %RH and for 8 hrs at 90%RH. The system was brought back down to 0% RH for a final 8 hours. The wetting (adsorption) and drying (desorption) thermogram over time are shown in FIGS. 54-57 for the micronized, spray-dried 50:50, 75:25 and 90:10 with leucine.
• the area under the curve (AUC) of the wetting peak is representative of the enthalpy of re-crystallisation.
• the AUC of the wetting peak for the micronized, spray-dried 50:50, 75:25 and 90:10 with leucine ranged from 9.2 - 11.1 J/g.
• PSD particle size distribution
• Table 34 Particle size distribution of micronized Imatinib, Spray Dried Formulation and Carrier Based formulation after 1M at 40°C/75%RH and 25°C/60%RH
• SSA Specific surface area
• TAM analysis was performed all drug substance material. Analysis was conducted for 6 hours at 0 %RH and for 8 hrs at 90%RH. The system was brought back down to 0% RH for a final 8 hours. The wetting (adsorption) and drying (desorption) thermogram over time are shown in FIGS. 58-59 for the micronized material (NP-106-104-M2) after 1 Month of conditioning at 25°C/60%RH and 40°C/75%RH,
• the area under the curve (AUC) of the wetting peak is representative of the enthalpy of re-crystallisation.
• the AUC of the wetting peak for the micronized was similar. Further work using this method is advised with unmicronized material to determine the amount of amorphicity in these systems. Our current understanding is that the amorphous content is below the limit of quantification.
• the stability samples were analysed by DSC according to the method described in the method section above. Overlaid traces of the first heat cycle, magnified first heat cycle and second heat cycle can be seen in FIGS. 64-66 respectively.
• the first heat cycle for NP-106-104-M2 25/60 displayed a sharp melt event at 212°C relating to Imatinib. There also appeared to be a very small crystallisation event at 101.7°C which suggested that there was a small amount of amorphous material within the sample.
• the second heat cycle displayed a Tg at 78.0°C. This was a result of the imatinib being quench cooled during the cooling phase of the run.
• the first heat cycle for NP-106-104-M2 40/75 also displayed a sharp melt event at 212°C relating to imatinib.
• a series of very weak glass transitions at 42.3 & 67.2°C followed by equally small crystallisation events at 101.8, 121.5, 152.1 & 175.2°C were also observed in the first heat cycle. This again suggested there was a very small amount of amorphous material within the sample.
• the second heat cycle displayed a Tg at 78.0°C, which was a result of the NP-106 being quench cooled during the cooling phase of the run.
• the DSC thermograms for batches 119#008A-C, stored at 25°C/60 %RH (FIG. 67) and 40°C/75%RH (FIG. 69) displayed an event at - 211 - 212°C which was related to the melting of imatinib. Again, the temperature at which the melt occurred appeared to decrease subtly with increasing leucine content.
• the second heating cycle for these samples displayed a glass transition for each of the formulations at a temperature of -70 - 80°C. There appears to be little impact of storage on these samples. On close examination of the baseline, very small events are observed. These will be interpreted fully along 3-month data, but may indicate a very small amount of amorphous material.
• thermogram of NP-106-104-M2 at 40°C/75%RH shows degradation of the sample starts at Ca. 300°C with no prior mass loss.
• the thermogram for NP- 106-104-M2 at 25°C/60%RH shows an initial steady mass loss of Ca. 3% from 150- 300°C followed by degradation at Ca. 300°C.
• Micronized API XRPD analysis was performed on the bulk micronized material, labelled as NP- 106- 104- M2 and according to the method described in the method section above.

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• 2020
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• 2022
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• 2023
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