Pharmaceutical compositions for respiratory administration and methods of treating inflammatory diseases of the lungs

Abstract

The present disclosure describes pharmaceutical compositions including a therapeutically effective amount of the compounds described herein or a pharmaceutically acceptable salt thereof or pharmaceutically acceptable cocrystal thereof and one or more pharmaceutically acceptable excipients. Methods of preparing such pharmaceutical compositions, and methods of treating an inflammatory diseases of the lungs, the nose and the nervous system using the same, are also provided. The pharmaceutical compositions of the present disclosure may be administered by oral inhalation and may be used for the treatment of diseases such as asthma.

Description

Attorney Docket No. 143989.005602PHARMACEUTICAL COMPOSITIONS FOR RESPIRATORY ADMINISTRATION AND METHODS OF TREATING INFLAMMATORY DISEASES OF THE LUNGS,THE NOSE AND THE NERVOUS SYSTEMCROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims priority to and benefit of U.S. Provisional Patent Application No. 63 / 709,089 filed October 18, 2024, the entire contents of which are incorporated by reference.BACKGROUND

[0002] The aryl hydrocarbon receptor (AhR), a member of the bHLH-PAS family of transcription factors, is a cytosolic ligand-activated transcription factor that senses diverse endogenous and exogenous molecules mediating multiple biological activities. It is best known for mediating the toxic effects of environmental contaminants such as TCDD (dioxin) and a range of other xenobiotic substances. Recent evidence points to AhR as a highly-conserved pathway that can modulate inflammatory responses, thus the AhR pathway could be an important target for treating inflammatory diseases of the lungs, the nose and the nervous systems.

[0003] There is a wide expression of AhR in several cell types. Additionally, it has been shown that AhR plays a critical role as a regulator of both innate and adaptive immune responses by impacting the balance of Thl7 and Treg T cells. Thl7-associated cytokines, including IL- 17, contribute to the immunopathogenesis of inflammatory diseases of the lungs, the nose and the nervous system. Therefore, attention has recently been drawn to AhR as a target for the treatment or prevention of inflammatory diseases of the lungs, the nose and the nervous system.

[0004] Compounds such as those described herein, that bind and activate the Aryl hydrocarbon Receptor (AhR), provide for a novel class of anti-inflammatory compounds with AhR-dependent cytokine modulation useful for the treatment of inflammatory diseases of the lungs, the nose and the nervous systems. Thus, the beneficial effects of AhR activation provide for new therapeutic interventions in the treatment of such inflammatory diseases. The need exists for better treatment of inflammatory diseases of the lungs (including asthma), the nose (including allergic rhinitis), and the nervous systems (including multiple sclerosis). Suitably, a compound which binds and activates the Aryl hydrocarbon Receptor (AhR) in multiple cellAttorney Docket No. 143989.005602 types may provide a novel and useful treatment for such inflammatory' diseases. The present invention thus provides pharmaceutical compositions which include isoquinoline compounds or salts thereof, along with methods of making such compositions and methods of treating inflammatory' diseases of the lungs, the nose and the nervous system with the same.

[0005] Oral administration of pharmaceutical compositions containing various active compounds to treat respiratory disorder may result in delayed onset of action and reduced efficacy due to the need for systemic absorption and metabolism of the drug before reaching the target respiratory' system. Additionally', oral administration may lead to systemic side effects due to the distribution of the drug throughout the body.SUMMARY

[0006] Some embodiments provide a method of treating a respiratory disease or disorder in a patient in need thereof, the method including: respiratory administration to the patient a pharmaceutical composition including a therapeutically effective amount of a compound of Formula I:Formula I

[0007] or a pharmaceutically acceptable salt thereof or pharmaceutically acceptable cocrystal thereof, thereby treating the respiratory disease or disorder.

[0008] Some embodiments provide a method, wherein the inflammatory diseases of the lungs are steroid responsive asthma, steroid unresponsive asthma, chronic obstructive pulmonary disease, hereditary emphysema, emphysema or pulmonary fibrosis or combinations thereof.

[0009] Some embodiments provide a method wherein the pharmaceutical composition is in the form of a dry powder inhaler, a pressurized metered dose inhaler, a solution for nebulization or a soft mist inhaler.Attorney Docket No. 143989.005602

[0010] Some embodiments provide a method, wherein the therapeutically effective amount is about 5 pg to about 50 mg.

[0011] Some embodiments provide a method, wherein the compound of Formula I is in the form of a free base or a salt or cocrystal of hydrochloric acid, citric acid, maleic acid, tartaric acid, sulfuric acid, or combinations thereof.

[0012] Some embodiments provide a method, wherein the compound of Formula I is in the form of a hydrochloride salt.

[0013] Some embodiments provide a method, wherein the compound of Formula I is in the form of a citrate salt.

[0014] Some embodiments provide a method, wherein the compound of Formula I is in the form of a cocrystal with citric acid.

[0015] Some embodiments provide a method, wherein the compound of Formula I is in the form of a maleate salt.

[0016] Some embodiments provide a method, wherein the compound of Formula I is in the form of a tartrate salt.

[0017] Some embodiments provide a method, wherein the compound of Formula I is in the form of a cocrystal with tartaric acid.

[0018] Some embodiments provide a method, wherein the pharmaceutical composition delivers the compound of Formula I to the patient's lungs.

[0019] Some embodiments provide a pharmaceutical composition for delivery' by inhalation, including: a therapeutically effective amount of a compound of Formula I:Attorney Docket No. 143989.005602

[0020] or a pharmaceutically acceptable salt thereof or pharmaceutically acceptable cocrystal thereof, and one or more pharmaceutically acceptable excipients.

[0021] Some embodiments provide a pharmaceutical composition, wherein the compound of Formula I is in the form of a free base or a salt or cocrystal of hydrochloric acid, citric acid, maleic acid, tartaric acid, sulfuric acid, or combinations thereof.

[0022] Some embodiments provide a pharmaceutical composition, wherein the compound of Formula I is in the form of a hydrochloride salt.

[0023] Some embodiments provide a pharmaceutical composition, wherein the compound of Formula I is in the form of a citrate salt.

[0024] Some embodiments provide a pharmaceutical composition, wherein the compound of Formula I is in the form of a cocrystal with citric acid.

[0025] Some embodiments provide a pharmaceutical composition, wherein the compound of Formula I is in the form of a maleate salt.

[0026] Some embodiments provide a pharmaceutical composition, wherein the compound of Formula I is in the form of a tartrate salt.

[0027] Some embodiments provide a pharmaceutical composition, wherein the compound of Formula I is in the form of a cocrystal with tartaric acid.

[0028] Some embodiments provide a pharmaceutical composition, wherein the pharmaceutical composition is suitable for delivery via a dry powder inhaler, a pressurized metered dose inhaler, a nebulizer or a soft mist inhaler.

[0029] Some embodiments provide a pharmaceutical composition, wherein the pharmaceutical composition includes particles having a median aerodynamic particle size of from about 1 pm to about 10 pm.

[0030] Some embodiments provide a pharmaceutical composition, wherein the pharmaceutical composition includes a spray dried particles having a median aerodynamic particle size of from about 1 pm to about 10 pm.Atorney Docket No. 143989.005602

[0031] Some embodiments provide a pharmaceutical composition, wherein the pharmaceutical composition includes a solution or suspension formulation with or without propellant producing a median aerodynamic droplet size of from about 1 pm to about 10 pm.

[0032] Some embodiments provide a pharmaceutical composition, wherein the therapeutically effective amount is about 5 pg to about 50 mg.

[0033] Some embodiments provide the pharmaceutical composition, wherein the one or more pharmaceutically acceptable excipients includes a diluent, a stabilizer, a force control agent, a lubricant, a solubiliser, a co-solvent, a surfactant, a pH-adjusting agent, a buffer, a liquified propellant gas. a non-volatile solvent, a preservative, an antioxidant, a tonicity adjusting agent, a suspending agent or combinations thereof.

[0034] Some embodiments provide a method of making a pharmaceutical composition, including: a respirable particle including a compound of Formula I:Formula I

[0035] or a pharmaceutically acceptable salt thereof or pharmaceutically acceptable cocrystal thereof and forming the respirable particle into an inhaled dosage form with one or more pharmaceutical excipients.

[0036] Some embodiments provide a method, wherein the respirable particle is prepared by micromzing methods including jet-milling of formula I to a desired aerodynamic particle size.

[0037] Some embodiments provide a method, wherein the desired aerodynamic particle size is about 1 pm to about 10 pm.

[0038] Some embodiments provide a method, wherein the pharmaceutical composition is prepared by spray drying methods, including: dissolving the compound of Formula I and the one or more pharmaceutical excipient in a solvent to yield a solution; subjecting the solution to spray drying techniques to yield a dry powder.Attorney Docket No. 143989.005602

[0039] Some embodiments provide a method, wherein the solvent is ethanol or an ethanol and water solution.

[0040] Some embodiments provide a method wherein the one or more pharmaceutical excipient is L-leucine, mannitol, sugar, or a combination thereof.

[0041] Some embodiments provide a method, wherein the compound of formula I is present at about 2-10% by weight of the solute.

[0042] Some embodiments provide a method, wherein the one or more pharmaceutical excipients includes one or more of mannitol, L-leucine, sugar, and combinations thereof.

[0043] Some embodiments provide a method, wherein the one or more pharmaceutical excipient is present at about 90 to 98% by weight of the solute.

[0044] Some embodiments provide a method, wherein the solvent is a 60 / 40 water / ethanol solution.

[0045] Some embodiments provide a method of treating a respiratory disease or disorder in a patient in need thereof, the method including: administering intra-nasally to the patient a pharmaceutical composition including a therapeutically effective amount of a compound of Formula I:Formula I

[0046] or a pharmaceutically acceptable salt thereof or pharmaceutically acceptable cocrystal thereof, thereby treating the respiratory disease or disorder.

[0047] Some embodiments provide a method, wherein the inflammatory diseases of the nose are allergic rhinitis or nonallergic rhinitis or combinations thereof.Attorney Docket No. 143989.005602

[0048] Some embodiments provide a method, wherein the pharmaceutical composition is suitable for delivery intra-nasally via solution, suspension, powder inhalation, powder insufflation, a pressurized metered dose inhaler.

[0049] Some embodiments provide a pharmaceutical composition, wherein the therapeutically effective amount is about 5 pg to about 30 mg.

[0050] Some embodiments provide a method, wherein the compound of Formula I is in the form of a free base or a salt or cocrystal of hydrochloric acid, citric acid, maleic acid, tartaric acid, sulfuric acid, or combinations thereof.

[0051] Some embodiments provide a method, wherein the compound of Formula I is in the form of a hydrochloride salt.

[0052] Some embodiments provide a method, wherein the compound of Formula I is in the form of a citrate salt.

[0053] Some embodiments provide a method, wherein the compound of Formula I is in the form of a cocrystal with citric acid.

[0054] Some embodiments provide a method, wherein the compound of Formula I is in the form of a maleate salt.

[0055] Some embodiments provide a method, wherein the compound of Formula I is in the form of a tartrate salt.

[0056] Some embodiments provide a method, wherein the compound of Formula I is in the form of a cocrystal with tartaric acid.

[0057] Some embodiments provide a method, wherein the pharmaceutical composition delivers the compound of Formula I to the cavities within the patient's nose.

[0058] Some embodiments provide a method of treating inflammatory' diseases of the nervous system or disorder in a patient in need thereof, the method including: administering intra-nasally to the patient a pharmaceutical composition including a therapeutically effective amount of a compound of Formula I:Attorney Docket No. 143989.005602Formula I

[0060] or a pharmaceutically acceptable salt thereof or pharmaceutically acceptable cocrystal thereof, thereby treating the inflammatory diseases of the nervous system.

[0061] Some embodiments provide a method, wherein the inflammatory' diseases of the nervous system are multiple sclerosis, Parkinson's disease, Alzheimer's disease, neuromyelitis optica, anti-myelin oligodendrocyte glycoprotein antibody disorder, autoimmune encephalitis, acute disseminated encephalomyelitis, transverse myelitis, neurosarcoidosis, or combinations thereof.

[0062] Some embodiments provide a method, wherein the pharmaceutical composition is suitable for delivery intra-nasally via solution, suspension, powder inhalation, powder insufflation, a pressurized metered dose inhaler.

[0063] Some embodiments provide a method, wherein the therapeutically effective amount is about 5 pg to about 30 mg.

[0064] Some embodiments provide a method, wherein the compound of Formula I is in the form of a free base or a salt or cocrystal of hydrochloric acid, citric acid, maleic acid, tartaric acid, sulfuric acid, or combinations thereof.

[0065] Some embodiments provide a method, wherein the compound of Formula I is in the form of a hydrochloride salt.

[0066] Some embodiments provide a method, wherein the compound of Formula I is in the form of a citrate salt.

[0067] Some embodiments provide a method, wherein the compound of Formula I is in the form of a cocrystal with citric acid.Attorney Docket No. 143989.005602

[0068] Some embodiments provide a method, wherein the compound of Formula I is in the form of a maleate salt.

[0069] Some embodiments provide a method, wherein the compound of Formula I is in the form of a tartrate salt.

[0070] Some embodiments provide a method, wherein the compound of Formula I is in the form of a cocrystal with tartaric acid.

[0071] Some embodiments provide a method, wherein the pharmaceutical composition delivers the compound of Formula I to the cavities within the patient's nose.

[0072] Some embodiments provide a pharmaceutical composition for delivery by intranasal administration, including: a therapeutically effective amount of a compound of Formula I:Formula I

[0073] or a pharmaceutically acceptable salt thereof or pharmaceutically acceptable cocrystal thereof, and one or more pharmaceutically acceptable excipients.

[0074] Some embodiments provide a pharmaceutical composition, wherein the compound of Formula I is in the form of a free base or a salt or cocrystal of hydrochloric acid, citric acid, maleic acid, tartaric acid, sulfuric acid, or combinations thereof.

[0075] Some embodiments provide a pharmaceutical composition, wherein the compound of Formula I is in the form of a hydrochloride salt.

[0076] Some embodiments provide a pharmaceutical composition, wherein the compound of Formula I is in the form of a citrate salt.

[0077] Some embodiments provide a pharmaceutical composition, wherein the compound of Formula I is in the form of a cocrystal with citric acid.Attorney Docket No. 143989.005602

[0078] Some embodiments provide a pharmaceutical composition, wherein the compound of Formula I is in the form of a maleate salt.

[0079] Some embodiments provide a pharmaceutical composition, wherein the compound of Formula I is in the form of a tartrate salt.

[0080] Some embodiments provide a pharmaceutical composition, wherein the compound of Formula I is in the form of a cocrystal with tartaric acid.

[0081] Some embodiments provide a pharmaceutical composition, wherein the pharmaceutical composition is suitable for delivery via solution, suspension, powder inhalation, powder insufflation, a pressurized metered dose inhaler.

[0082] Some embodiments provide a pharmaceutical composition, wherein the pharmaceutical composition is suitable for delivery via a pressurized metered dose inhaler, a nebulizer, an atomization device, an insufflator, a nasal spray.

[0083] Some embodiments provide a pharmaceutical composition, wherein the pharmaceutical composition includes particles having a median particle size of from about 1 pm to about 10 pm or about 10 pm to about 200 pm based on the delivery technology platform.

[0084] Some embodiments provide a pharmaceutical composition, wherein the pharmaceutical composition includes droplets having a median size of from about 10 pm to about 200 pm.

[0085] Some embodiments provide a pharmaceutical composition, wherein the pharmaceutical composition includes a spray dried formulation, wherein the one or more pharmaceutical excipients includes one or more of mannitol, L-leucine, sugar, and combinations thereof.

[0086] Some embodiments provide a pharmaceutical composition, wherein the therapeutically effective amount is about 5 pg to about 30 mg.

[0087] Some embodiments provide a pharmaceutical composition, wherein the one or more pharmaceutically acceptable excipients includes a diluent, a stabilizer, a force control agent, a lubricant, a solubiliser, a co-solvent, an antisolvent, a surfactant, a pH-adjusting agent, a buffer, a liquified propellant gas, a non-volatile solvent, a preservative, lipid nanoparticles,Attorney Docket No. 143989.005602 an antioxidant, a tonicity adjusting agent, a suspending agent, a humectant or combinations thereof.BRIEF DESCRIPTION OF THE DRAWINGS

[0088] Aspects, features, benefits, and advantages of the embodiments described herein will be apparent with regard to the following description, appended claims, and accompanying drawings where:

[0089] Figure 1 is a formulation map for DMVT-506 based on Tm / Tg and Log P values.

[0090] Figure 2 is a graph depicting DMVT-506 solubility (wt.%) as a function of ethanol content (wt.%).

[0091] Figure 3 Particle size distributions after different milled batches / number of passes

[0092] Figure 4 is an SEM image of as-received DMVT-506, 5,000x magnification.

[0093] Figure 5 is an SEM image of micronized DMVT-506, 5,000x magnification.

[0094] Figure 6 is a graphic overlay of PXRD diffractograms from the as-received and jet milled DMVT-506.

[0095] Figure 7 is a graphic overlay of DSC thermograms from the as-received and jet milled DMVT-506.

[0096] Figure 8 is a graph depicting dynamic vapor sorption vs time comparison for jet milled DMVT-506.

[0097] Figure 9 is a graph depicting dynamic vapor sorption vs relative humidity comparison for as-received and jet milled DMVT-506.

[0098] Figure 10 is a graph depicting particle size distributions of Formulation I A-C (Formulation I A (2 / 48 / 40 DMVT-506 / Mannitol / Leucine), Formulation I B (10 / 40 / 40 DMVT- 506 / Mannitol / Leucine), Formulation I C (10 / 90 DMVT-506 / Mannitol)).Attorney Docket No. 143989.005602

[0099] Figure 11 is a graph depicting aerodynamic particle size distributions ofFormulation I A (2 / 48 / 40 DMVT-506 / Mannitol / Leucine), Formulation I B (10 / 40 / 40 DMVT- 506 / Mannitol / Leucine), Formulation I C (10 / 90 DMVT-506 / Mannitol).

[0100] Figure 12 is a graph depicting DVS isotherms for each SDL

[0101] Figure 13 depicts PXRD patterns for each SDI before / after DVS

[0102] Figure 14 depicts example thermograms for each SDI.

[0103] Figure 15 is a representative image of Formulation I A (2 / 48 / 40 DMVT- 506 / Mannitol / Leucine.

[0104] Figure 16 is a representative image of Formulation I B (10 / 40 / 40 DMVT- 506 / Mannitol / Leucine).

[0105] Figure 17 is a representative image of Formulation I C (10 / 90 DMVT-506 / Mannitol).

[0106] Figure 18 is a representative image of Formulation I D.

[0107] Figure 19 is a graph depicting potency vs time plot for formulation A stability samples.

[0108] Figure 20 is a graph depicting potency vs time plot for formulation B stability samples.

[0109] Figure 21 is a graph depicting Purity vs time for spray dried formulations.

[0110] Figure 22 is a chromatogram overlay of formulation A stability samples.

[0111] Figure 23 is a chromatogram overlay of formulation B stability samples.

[0112] Figure 24 is a graphic overlay of primary leucine peaks for samples after 4 weeks on stability.

[0113] Figure 25 is a chromatogram overlay of LOQ and blank injections to demonstrate specificity.

[0114] Figure 26 is a chromatogram overlay for lactose blend stability samples.Attorney Docket No. 143989.005602

[0115] Figure 27 is a graph depicting particle size distribution of ingoing & micronized DMVT-506 salt forms.

[0116] Figure 28 is a Diffractogram overlay of ingoing & micronized DMVT-506 salt forms.

[0117] Figure 29 depicts representative images of Formulation II.

[0118] Figure 30 depicts representative images of Formulation IV.

[0119] Figure 31 Depicts representative images of Ingoing Citric acid cocrystal (Formulation II-B).

[0120] Figure 32 Depicts representative Images of Formulation III.

[0121] Figure 33 is an isotherm overlay for the ingoing and micronized DMVT-506 salt forms.DETAILED DESCRIPTION

[0122] Before compounds, compositions and methods are described in detail, it is to be understood that this disclosure is not limited to the particular processes, compositions, or methodologies described, as these may vary. It is also to be understood that the terminology used in the description is for the purpose of describing the particular versions or embodiments only, and is not intended to limit the scope of the disclosure which will be limited only by the appended claims. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art. Although any methods and materials similar or equivalent to those described herein can be used in the practice or testing of embodiments of the disclosure, the preferred methods, devices, and materials are now described.

[0123] It is further appreciated that certain features of the disclosure, which are, for clarity, described in the context of separate embodiments, can also be provided in combination in a single embodiment. Conversely, various features of the disclosure which are, for brevity', described in the context of a single embodiment, can also be provided separately or in any suitable subcombination.Attorney Docket No. 143989.005602

[0124] As used in this document, the singular forms “a,” “an,” and “the” include plural references unless the context clearly dictates otherwise. Unless defined otherwise, all technical and scientific terms used herein have the same meanings as commonly understood by one of ordinary skill in the art. Nothing in this disclosure is to be construed as an admission that the embodiments described in this disclosure are not entitled to antedate such disclosure by virtue of prior invention. As used in this document, the term ‘‘comprising” means “including, but not limited to.”

[0125] As used herein, the term “about” means plus or minus up to 10% of the numerical value of the number with which it is being used. For example, “about 50%” means in the range of 45-55% and also includes exactly 50%.

[0126] "Administering," when used in conjunction with the compounds of the disclosure, means to administer a compound directly into or onto a target tissue or to administer a compound systemically or locally to a patient or other subject.

[0127] The term "animal" as used herein includes, but is not limited to, humans and non-human vertebrates such as wild, experimental, domestic, and farm animals, and pets. As used herein, the terms "subject," "individual." and "patient," are used interchangeably and refer to any animal, including mammals, mice, rats, other rodents, rabbits, dogs, cats, swine, cattle, sheep, horses, primates, non-human primates, humans, and the like.

[0128] The term "improves" is used to convey that the disclosure changes either the characteristics and / or the physical attributes of the tissue to which it is being provided, applied or administered. The term "improves" may also be used in conjunction with a disease state such that when a disease state is "improved" the symptoms or physical characteristics associated with the disease state are diminished, reduced, eliminated, delayed, or averted.

[0129] The term "inhibiting" includes the blockade, aversion of a certain result or process, or the restoration of the converse result or process. In terms of treatment by administration of a compound of the disclosure, "inhibiting" includes protecting against (partially or wholly) or delaying the onset of symptoms, alleviating symptoms, or protecting against, diminishing or eliminating a disease, condition, or disorder.

[0130] As used herein, the term “free base” refers to a non-salt form of a compound as described herein.Attorney Docket No. 143989.005602

[0131] The term “salts” can include acid addition salts or addition salts of free bases.The salts as described herein may be pharmaceutically acceptable. Examples of acids which may be employed to form pharmaceutically acceptable acid addition salts include but are not limited to salts derived from nontoxic inorganic acids such as nitric, phosphoric, sulfuric, hydrobromic, hydroiodic, hydrofluoric, or phosphorus acids, as well as salts derived from nontoxic organic acids such as aliphatic mono- and dicarboxylic acids, phenyl-substituted alkanoic acids, hydroxyl alkanoic acids, alkanedioic acids, aromatic acids, aliphatic and aromatic sulfonic acids, and acetic, maleic, succinic, or citric acids. Non-limiting examples of such salts include napadisylate, besylate, sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, nitrate, phosphate, monohydrogenphosphate, dihydrogenphosphate, metaphosphate, pyrophosphate, chloride, hydrochloride, bromide, iodide, acetate, trifluoroacetate, propionate, caprylate, isobutyrate, oxalate, malonate, succinate, suberate, sebacate, fumarate, maleate, mandelate, benzoate, chlorobenzoate, methylbenzoate, dinitrobenzoate, phthalate, benzenesulfonate, toluenesulfonate, phenylacetate, citrate, lactate, maleate, tartrate, methanesulfonate, and the like. Salts of amino acids are also contemplated, such as arginate, gluconate, galacturonate, and the like.

[0132] Those skilled in the art of organic chemistry will appreciate that many organic compounds can form complexes with solvents in which they are reacted or from which they are precipitated or crystallized. For example, a complex with water is known as a “hydrate.” Solvates of the compounds of the present disclosure are within the scope of this disclosure. The salts of the compound of any of the formulae described herein may form solvates (e.g., hydrates) and the present disclosure includes all such solvates. The meaning of the word “solvates” is well known to those skilled in the art as a compound formed by interaction of a solvent and a solute (i.e., solvation). Techniques for the preparation of solvates are well established in the art.

[0133] As used herein, unless specifically indicated, the term “active ingredient” refers to a compound of any of the formulae as described herein. The terms “active ingredient” and “active pharmaceutical ingredient” may be used interchangeably.

[0134] The phrase "pharmaceutically acceptable" refers to molecular entities and compositions that are generally regarded as safe and nontoxic. In particular, pharmaceutically acceptable carriers, diluents or other excipients used in the pharmaceutical compositions of this disclosure are physiologically tolerable, compatible with other ingredients, and do not typicallyAttorney Docket No. 143989.005602 produce an allergic or similar untoward reaction (for example, gastric upset, dizziness and the like) when administered to a subject. In some embodiments, as used herein, the term "pharmaceutically acceptable" means approved by a regulatory agency of the Federal or a state government or listed in the U.S. Pharmacopoeia or other generally recognized pharmacopoeia for use in animals, and more particularly in humans. The phrase "pharmaceutically acceptable salt(s)", as used herein, includes those salts of compounds of the disclosure that are safe and effective for use in mammals and that possess the desired biological activity. Pharmaceutically acceptable salts include salts of acidic or basic groups present in compounds of the disclosure or in compounds identified pursuant to the methods of the disclosure. Pharmaceutically acceptable acid addition salts include, but are not limited to, hydrochloride, hydrobromide, hydroiodide, nitrate, sulfate, bisulfate, phosphate, acid phosphate, isonicotinate, acetate, lactate, salicylate, citrate, tartrate, pantothenate, bitartrate, ascorbate, succinate, maleate, gentisinate, fumarate, gluconate, glucaronate, saccharate, formate, benzoate, glutamate, methanesulfonate, ethanesulfonate, benzensulfonate, p-toluenesulfonate, and pamoate (i.e., l,T-methylene-bis-(2-hydroxy-3-naphthoate)) salts. Certain compounds of the disclosure can form pharmaceutically acceptable salts with various amino acids. Suitable base salts include, but are not limited to, aluminum, calcium, lithium, magnesium, potassium, sodium, zinc, iron and diethanolamine salts. Pharmaceutically acceptable base addition salts are also formed with amines, such as organic amines. Examples of suitable amines are N.N'- dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, dicyclohexylamine, ethylenediamine, N-methylglucamine, and procaine.

[0135] As used herein, ‘‘respiratory administration"’ includes intranasal and inhalation administration. “Intranasal” administration is through the nose, and may be used for delivery to the nasal cavity, brain, respiratory tract, including the lungs, etc. “Inhalation” is used to indicate the treatment is delivered to the lungs; deliver}' may be through the nose, the mouth, or via the trachea, or intubation or other means.

[0136] As used herein, the term "therapeutic" means an agent utilized to treat, combat, ameliorate, protect against, or improve an unwanted condition or disease of a subject.

[0137] A "therapeutically effective amount" or "effective amount" of a compound or composition of the disclosure is a predetermined amount which confers a therapeutic effect on the treated subject, at a reasonable benefit / risk ratio applicable to any medical treatment. The therapeutic effect may be objective (i.e., measurable by some test or marker) or subjective (i.e.,Attorney Docket No. 143989.005602 subject gives an indication of or feels an effect or physician observes a change). The effect contemplated herein includes medical therapeutic treatment, as appropriate. The specific dose of a compound administered according to this disclosure to obtain therapeutic effects will, of course, be determined by the particular circumstances surrounding the case, including, for example, the compound administered, the route of administration, the co-administration of other active ingredients, the condition being treated, the activity of the specific compound employed, the specific composition employed, the age. body weight, general health, sex and diet of the subject; the time of administration, route of administration, and rate of excretion of the specific compound employed and the duration of the treatment. The effective amount administered will be determined by the physician in the light of the foregoing relevant circumstances and the exercise of sound medical judgment. A therapeutically effective amount of a compound of this disclosure is typically an amount such that when it is administered in a physiologically tolerable excipient composition, it is sufficient to achieve an effective systemic concentration or local concentration in the tissue.

[0138] The terms "treat", "treated", or "treating" as used herein refers to therapeutic treatment measures, wherein the object is to protect against (partially or wholly) or slow down (e.g, lessen or postpone the onset of) an undesired physiological condition, disorder or disease, or to obtain beneficial or desired clinical results such as partial or total restoration or inhibition in decline of a parameter, value, function or result that had or would become abnormal. For the purposes of this disclosure, beneficial or desired clinical results include, but are not limited to, alleviation of symptoms; diminishment of the extent or vigor or rate of development of the condition, disorder or disease; stabilization (i.e., not worsening) of the state of the condition, disorder or disease; delay in onset or slowing of the progression of the condition, disorder or disease; amelioration of the condition, disorder or disease state; and remission (whether partial or total), whether or not it translates to immediate lessening of actual clinical symptoms, or enhancement or improvement of the condition, disorder or disease. Treatment seeks to elicit a clinically significant response without excessive levels of side effects. Treatment also includes prolonging survival as compared to expected survival if not receiving treatment.

[0139] Some embodiments provide a pharmaceutical composition for delivery' by respiratory administration, including a therapeutically effective amount of a compound of Formula I:Attorney Docket No. 143989.005602Formula I or a pharmaceutically acceptable salt or a pharmaceutically acceptable cocrystal thereof, and one or more pharmaceutically acceptable excipients; wherein the pharmaceutical composition is a dry powder, a suspension or a solution. The compound of Formula I may be referred to herein as DMVT-506.

[0140] Some embodiments provide a pharmaceutical composition, wherein the pharmaceutical composition includes API particles having a median aerodynamic particle size suitable for respiratory treatment. In some embodiments, the aerodynamic particle size is from about 1 pm to about 10 pm. In some embodiments, the aerodynamic particle size is about 5 pm to about 10 pm. In some embodiments, the aerodynamic particle size is about 5 pm. In some embodiments, the aerodynamic particle size is about 10 pm. In some embodiments, the aerodynamic particle size is greater than 10 pm. As described further below, these aerodynamic particle sizes may be achieved by processes including but not limited to micronization, spray drying and molding technology.

[0141] Some embodiments provide a pharmaceutical composition, wherein the pharmaceutical composition includes a spray dried particle, wherein the one or more pharmaceutical excipients includes one or more of mannitol, L-leucine, sugar, and combinations thereof. In some embodiments, the compound of formula I is present at about 2- 10% by weight. In some embodiments, the one or more pharmaceutical excipient is present at about 90 to 98% by weight. In some embodiments, L-leucine is present at about 50% by weight. In some embodiments, mannitol is preset at 40-90% by weight. In some embodiments, a combination of L-leucine and mannitol amount to about 90% to about 98% by weight of the composition.

[0142] Some embodiments provide a pharmaceutical composition, wherein the compound of Formula I, regardless of manufacturing technique is in the form of a free base, a hydrochloride salt, a citrate salt, citrate cocrystal, a maleate salt, a tartrate salt, tartrate cocrystal, a sulfate salt, or combinations thereof. Some embodiments provide a pharmaceuticalAttorney Docket No. 143989.005602 composition, including the compound of Formula I as a free base. Some embodiments provide a pharmaceutical composition, including the compound of Formula I as a hydrochloride salt. Some embodiments provide a pharmaceutical composition, including the compound of Formula I as a citrate cocrystal. Some embodiments provide a pharmaceutical composition, including the compound of Formula I as a maleate salt.

[0143] Some embodiments provide a pharmaceutical composition, wherein the pharmaceutical composition is suitable for delivery via a dry powder inhaler (DPI).

[0144] Some embodiments provide a pharmaceutical composition, wherein the therapeutically effective amount is about 5 pg to about 50 mg.

[0145] In some embodiments, the therapeutically effective amount of the compound of Formula I refers to the free base equivalent, in embodiments wherein the compound of Formula I is in the form of a salt or cocrystal.

[0146] The pharmaceutical composition of the disclosure may be formulated for respiratory administration in any convenient way for use in human or veterinary medicine. Such compositions may be presented for use in a conventional manner with the aid of one or more suitable excipients. Acceptable excipients for therapeutic use are well-known in the pharmaceutical art, and are described, for example, in Remington's Pharmaceutical Sciences, Mack Publishing Co. (A. R. Gennaro edit. 1985). The choice of pharmaceutical excipient can be selected with regard to the intended route of administration and standard pharmaceutical practice. The pharmaceutical compositions may include a carrier, lubricant(s), and additional excipients, such as surfactants, buffers, solvents, cosolvents, antisolvents, preservative, antioxidant, tonicity7adjusting agent, penetration enhancer, suspending agent, humectant or a combination thereof, as may be appropriate for respiratory formulations. One suitable carrier is lactose. Some embodiments may7include a force control agent, for example, magnesium stearate.

[0147] In some embodiments, the one or more pharmaceutically acceptable excipients comprise a diluent, a stabilizer, a force control agent, a lubricant, a solubiliser, a co-solvent, a surfactant, a pH-adjusting agent, a buffer, a liquified propellant gas, a non volatile solvent, a preservative, an antioxidant, a tonicity adjusting agent, a penetration enhancer, a suspending agent, a humectant or combinations thereof.Attorney Docket No. 143989.005602

[0148] In some embodiments, the one or more pulmonary' excipient is mannitol, L- leucine, sugar or a combination thereof.

[0149] In some embodiments, the solid dispersion contains less than about 5% total impurities as measured by assay and related substances testing. For example, the solid dispersion may contain less than about 5%, less than about 4%, less than about 3%, less than about 2%, less than about 1%, less than about 0.5%, or any range or value contained therein, of total impurities. Without wishing to be bound by theory, the dispersion agent which is used in the solid dispersion may contribute to one or more decomposition pathways of the compound of Formula I. One of ordinary skill in the art may, accordingly, select a dispersion agent which minimizes the degradation of the compound of Formula I and thus allows a solid dispersion with fewer impurities to be obtained. It is desirable to minimize the impurities in the solid dispersion, so as to similarly minimize the impurities in the pharmaceutical composition.

[0150] In some embodiments, the solid dispersion is stable for at least three months at 25 °C / 60%RH in open packaging, and 40 °C / 75%RH in open and closed packaging. Stability may be evaluated by comparing an initial characterization of the solid dispersion to characterization after one, two, or three months. Characterization may include but is not limited to differential scanning calorimetry’ (DSC), X-ray powder diffraction (XRPD), assay and related substances testing, or any other characterization method known to those skilled in the art. In some embodiments, the amount of total impurities in the solid dispersion after 4 weeks does not increase substantially, relative to the initial amount of total impurities, when stored at 25°C / 60%RH or 40°C / 75%RH.

[0151] The pharmaceutical composition or unit dosage form of the disclosure may be administered according to a dosage and administration regimen defined by routine testing in the light of the guidelines given above in order to obtain optimal activity while minimizing toxicity or side effects for a particular subject. The dosing regimen of the pharmaceutical composition of the disclosure is not particularly limited and may be determined by one of skill in the art.

[0152] The dosage of the compounds of the disclosure may vary according to a variety of factors such as underlying disease conditions, the individual's condition, weight, sex and age, and the mode of administration. An effective amount for treating a disorder can easily be determined by empirical methods know n to those of ordinary’ skill in the art, for example byAttorney Docket No. 143989.005602 establishing a matrix of dosages and frequencies of administration and comparing a group of experimental units or subjects at each point in the matrix. The exact amount to be administered to a subject will vary depending on the state and severity of the disorder and the physical condition of the subject. A measurable amelioration of any symptom or parameter can be determined by a person skilled in the art or reported by the subject to the physician. It will be understood that any clinically or statistically significant attenuation or amelioration of any symptom or parameter of urinary tract disorders is within the scope of the disclosure. Clinically significant attenuation or amelioration means perceptible to the subject and / or to the physician. It will be understood that the pharmaceutical formulations of the disclosure need not necessarily contain the entire amount of the compound that is effective in treating the disorder, as such effective amounts can be reached by administration of a plurality of divided doses of such pharmaceutical formulations.

[0153] Some embodiments provide a method of making a pharmaceutical composition, including preparing a dry powder composition including a compound of Formula I or a pharmaceutically acceptable salt thereof or pharmaceutically acceptable cocrystal thereof with or without one or more pharmaceutically acceptable excipients via micronization, or spray drying or molding technology7. In some embodiments, the active ingredient itself is micronized, while the excipients are not.

[0154] It should be noted, that some embodiments provide a pharmaceutical composition comprising particles that together make up a complete pharmaceutical composition. In other embodiments, a particle itself may not be the complete pharmaceutical composition.

[0155] Some embodiments provide a method, wherein the compound of Formula I is in the form of a free base, a hydrochloride salt, a citrate salt, citrate cocrystal, a maleate salt, a tartrate salt, tartrate cocrystal, a sulfate salt, or combinations thereof.

[0156] Some embodiments provide a method, wherein the pharmaceutical composition is prepared by micronization methods including, but not limited to jet-milling the compound of formula I to a desired aerodynamic particle size. In some instances, the desired aerodynamic particle size is aerodynamic particle size suitable for respiratory7treatment. In some embodiments, the aerodynamic particle size is from about 3 pm to about 10 pm. In some embodiments, the aerodynamic particle size is about 5 pm to about 10 pm. In someAttorney Docket No. 143989.005602 embodiments, the aerodynamic particle size is about 5 pm. In some embodiments, the aerodynamic particle size is about 10 pm.

[0157] In some embodiments, the pharmaceutical composition is prepared by spray drying methods, including dissolving the compound of formula I and the one or more pharmaceutical excipient in a solvent to yield a solution; and subjecting the solution to spray drying techniques to yield a dry powder. Spray drying techniques are well known in the art and generally involve dissolving the desired substance(s) in a solvent and feeding the solution through a nozzle to atomize the solution, which is then quickly dried to yield a dry’ powder. In some embodiments, the solvent is ethanol or an ethanol and water solution. A 60 / 40 water / ethanol solution appears well-suited for this application. In some embodiments, one or more pharmaceutical excipient can be dissolved along with the active ingredient. In particular, pulmonary excipients such as but not limited to, L-leucine, mannitol, sugar, and combinations thereof, may be used in various amounts. In some embodiments, up to 98% by weight of the solute may be made up of such excipients, with about 2% to about 10% of the solute being the active (i.e. the compound of Formula I, or a pharmaceutically acceptable salt thereof or pharmaceutically acceptable cocrystal thereof).

[0158] Some embodiments provide a method of treating inflammatory diseases of the lungs in a patient in need thereof, the method including respiratory administration to the patient a pharmaceutical composition including a therapeutically effective amount of a compound of Formula I or a pharmaceutically acceptable salt thereof or pharmaceutically acceptable cocrystal thereof, thereby treating inflammatory diseases of the lungs. In some instances, the inflammatory’ diseases of the lungs are steroid responsive asthma, steroid unresponsive asthma, chronic obstructive pulmonary disease, hereditary^ emphysema, emphysema or pulmonary fibrosis or combinations thereof. In some embodiments the pharmaceutical composition is a dry powder suitable for administration as a dry powder, for example, and not limitation, for administration by a dry powder inhaler. Some embodiments provide a method, wherein the therapeutically effective amount is about 5 pg to about 50 mg.

[0159] Some embodiments provide a method of treating inflammatory diseases of the nervous system in a patient in need thereof, the method including respiratory administration to the patient a pharmaceutical composition including a therapeutically effective amount of a compound of Formula I or a pharmaceutically acceptable salt thereof or pharmaceutically acceptable cocrystal thereof, thereby treating inflammatory’ diseases of the nervous system. InAttorney Docket No. 143989.005602 some instances, the inflammatory' diseases of the nervous system are multiple sclerosis, Parkinson’s disease, Alzheimer’s disease, neuromyelitis optica, anti-myelin oligodendrocyte glycoprotein antibody disorder, autoimmune encephalitis, acute disseminated encephalomyelitis, transverse myelitis, neurosarcoidosis, or combinations thereof. In some embodiments the pharmaceutical composition is a dry' powder suitable for administration as a dry powder, for example, and not limitation, for administration by a dry pow der inhaler. Some embodiments provide a method, wherein the therapeutically effective amount is about 5 pg to about 30 mg.

[0160] Some embodiments provide a method of treating inflammatory diseases of the nose in a patient in need thereof, the method including respiratory administration to the patient a pharmaceutical composition including a therapeutically effective amount of a compound of Formula I or a pharmaceutically acceptable salt thereof or pharmaceutically acceptable cocrystal thereof, thereby treating inflammatory diseases of the nose. In some instances, the inflammatory’ diseases of the nose are allergic rhinitis or nonallergic rhinitis or combinations thereof. In some embodiments the pharmaceutical composition is a dry powder suitable for administration as a dry pow der, for example, and not limitation, for administration by a dry pow der inhaler. Some embodiments provide a method, wherein the therapeutically effective amount is about 5 pg to about 30 mg.

[0161] Some embodiments provide a method, wherein the compound of Formula I is in the form of a free base, a hydrochloride salt, a citrate salt, citrate cocrystal, a maleate salt, a tartrate salt, tartrate cocrystal, a sulfate salt, or combinations thereof. Some embodiments provide a method, wherein the compound of Formula I is in the form of a hydrochloride salt. Some embodiments provide a method, wherein the compound of Formula I is in the form of a citrate cocrystal. Some embodiments provide a method, wherein the compound of Formula I is in the form of a maleate salt.

[0162] Some embodiments provide a method, wherein the compound of Formula I is in the form of a free base, a hydrochloride salt, a citrate salt, citrate cocrystal, a maleate salt, a tartrate salt, tartrate cocrystal, a sulfate salt, or combinations thereof. Some embodiments provide a method, wherein the compound of Formula I is in the form of a hydrochloride salt. Some embodiments provide a method, wherein the compound of Formula I is in the form of a citrate cocrystal. Some embodiments provide a method, w herein the compound of Formula I is in the form of a maleate salt.Attorney Docket No. 143989.005602

[0163] The methods and compositions of the present disclosure may be employed in the disclosed embodiments, which may be combined as appropriate to form new embodiments.EXAMPLES

[0164] The following examples were carried out according to embodiments of the present disclosure.

[0165] Amorphous Form Evaluation

[0166] As part of formulation selection for spray drying, Tm, Tg, and the log of the octanol / water partition coefficient (Log P) are used to place the compound on a formulation selection map. The formulation selection map can guide decisions regarding active loading as well as excipient selection (see Figure 1). The vertical axis for the formulation selection map is the ratio of melting point and glass transition (Tm / Tg) in Kelvin. This ratio is related to the tendency of a compound to crystal lize as a higher difference in the two temperatures indicates a larger difference in free energy' between the cry stalline and amorphous form. For compounds with a high propensity to cry stallize (e.g. high Tm / Tg ratio), low loading SDDs are typically selected and nanocrystal formulations may also be considered as an alternative in some cases. The horizontal axis is Log P, which is a measure of lipophilicity7. At very high Log P, lower loading is typically needed to ensure adequate dissolution rate. Additionally, lipid-based formulations may be considered for certain high Log P compounds. For DMVT-506, the Tm / Tg ratio is about 1.28, which indicates a relatively low driving force for crystallization and that moderate drug loading in an amorphous material can be targeted. The glass transition temperature was measured to be 95.4 °C, so under dry conditions with minimal residual solvent, DMVT-506 is expected to maintain an amorphous form. This glass transition temperature also compares favorably to typical elevated stability temperatures, such as 40 °C.

[0167] These thermal properties also suggest that high energy salt forms may offer increased dissolved drug levels for enhanced bioavailability7relative to the cry stalline free base.

[0168] Organic Solubility7

[0169] In addition to the solubility in methanol and acetone mentioned above,DMVT-506 solubility was measured in solvents which would support formulations for respiratory delivers7. While there are few approved excipients for respiratory delivery, a varietyAttorney Docket No. 143989.005602 of sugars and amino acids have been safely administered to humans and animals. While use of these excipients provides a safe foundation around which to formulate a product, organic solubility of sugars and amino acids is typically poor and water solubility is relatively high. Due to the need for significant water content to dissolve these excipients, aqueous / organic blends of ethanol and acetone were evaluated. Ethanol / water blends with as little as 20 wt.% ethanol demonstrated sufficient solubility to support spray drying of a dilute DMVT-506 formulation for respiratory delivery. The relationship between DMVT-506 and ethanol content from 0 to 40 wt.% in an aqueous mixture is plotted in Figure 2.

[0170] Milling Feasibility

[0171] Jet milling, or the process of micronization, is a continuous process in which the material for size reduction is co-fed with a high velocity gas stream into an annular region known as the milling chamber. Inside the chamber, the particles are driven to collide with themselves repeatedly resulting in the breakup of the material. The energy transfer to the particles can often result in the generation of amorphous content, which will be a key performance metric for the micronized material as there is driving force for crystallization.

[0172] Manufacturing

[0173] The screening process was essentially a trial-and-error process whereby the feeding pressure was set to 50 psig and the grind pressure was maximized to 19 psig so as the venturi nozzles could still pull a vacuum on the solid feeder. Material was fed in 2 g batches of API, denoted A, B and C. A was fed individually, whereas B and C were combined. Results of the particle size tests are shown in Figure 3 and Table 1.Attorney Docket No. 143989.005602

[0174] Characterization

[0175] Morphology via Scanning Electron Microscopy

[0176] The jet milled DMVT-506 was compared to the as-received API via scanning electron microscopy (SEM) as shown in Figure 4 and Figure 5. The SEM analysis qualitatively confirmed the particle size data. Particle size was reduced via jet milling to a size suitable for inhalation.

[0177] Crystallinity via PXRD, DSC, and DVS

[0178] The micronized DMVT-506 was compared to the as-received DMVT-506 byPXRD, DSC, and dynamic vapor sorption (DVS) using water vapor. PXRD showed the same diffraction pattern for the jet milled material as the as-received, demonstrating that any changes in crystallinity attributable to jet milling must be at a low level, if present (Figure 6). Similarly, the melt temperature and heat of fusion were measured to be the same for both materials by DSC (Figure 7, Table 2)

[0179] Since any amorphous material generated during milling is expected to be present at particle surfaces, a surface-sensitive technique like dynamic vapor sorption is more sensitive than PXRD and DSC to low-level amorphous content (< 1 wt.%). This technique is effective for detecting low level amorphous content because molecular reorganization to a lower energy state (such as crystallization) excludes vapors which might be otherwise associated with the material. During the DVS experiment, relative humidity was increased from 0 to 90 to 0% RH in steps of 10% RH with up to 10 hours for equilibration at each step. The time-series data (Figure 8) shows a small local maximum in the jet milled DMVT-506 mass signal during equilibration at 40% RH. This difference in starting and ending mass, and the increased noise in the desorption steps combine to suggest that there may be a very smallAttorney Docket No. 143989.005602 amount of amorphous material generated during micronization. The final equilibrated mass at each humidity step is then plotted in Figure 9, which also demonstrates slight change before and after humidity exposure. The overall larger vapor sorption signal for the jet milled DMVT- 506 also demonstrates the greater surface area of this material relative to the as-received material.

[0180] Spray Dry ing Feasibility

[0181] Initial Formulations

[0182] Based on API properties determined previously, four initial formulations were proposed for screening of performance, physical stability, and chemical stability. These formulations are outlined below in Table 3. In order to minimize the safety risk of introducing materials to the lung, precedented. soluble excipients including mannitol and L-leucine (Leu) were proposed, with leucine expected to provide a hydrophobic particle shell, which promotes consistent aerosol performance. By varying the level of leucine with mannitol as the bulking sugar, the sensitivity and extent of the leucine surface enrichment mechanism can be assessed. Mannitol is expected to crystallize during spray drying, providing a stable (though slightly more dense) physical form upon spray drying. While neither of these excipients are considered by the FDA to be "generally recognized as safe" for inhalation, mannitol is an API approved for inhalation at > 60 mg, and leucine is expected to have no pharmacological impact on pulmonary physiology.

[0183] Preliminary Manufacturing Summary'

[0184] The feasibility' of each of these formulations was evaluated by the manufacture and analysis of the resulting spray dried particles. A solvent system of ethanol and water was chosen as the spray solution. The spray dried particles were manufactured on a Lab Dryer with 35 kg / hr drying gas capacity (BLD-35). In the spray drying process, a solution containing spray solvent matrix and dissolved API and excipients is fed to a nozzle and atomized into dropletsAttorney Docket No. 143989.005602 that are rapidly dried into particles by a hot nitrogen gas stream. The particles are collected by a cyclone that separates them from the drying gas exhaust.

[0185] Thermodynamic process parameters were chosen based on a combination of modeled predictions of the dew point temperature and relative humidity of the outlet gas stream, as well as predictions based on historical data for the solution flow rate and outlet gas temperature. Atomization gas pressure was also chosen based on modeled predictions of particle size, with a target particle size distribution of 1-5 pm. In-process particle size checks were also conducted to ensure that the chosen atomization gas pressure resulted in the target particle sizes.

[0186] Due to solubility concerns, the organic and aqueous phases of the spray solution were prepared separately. Excipients were dissolved into water, and DMVT-506 was dissolved into ethanol. The flask containing DMVT-506 was wrapped in foil to minimize exposure to light. Once all solids were visually confirmed to be dissolved, the aqueous phase was added to the organic phase and stirred for 5-10 minutes to ensure that no precipitation occurred. Formulation D had no aqueous phase solution preparation step due to only containing DMVT- 506.

[0187] Formulations A and B were manufactured at typical yield and serve as a successful proof of concept for spray drying DMVT-506. Formulation C presented more challenges and resulted in very low yields, likely due to DMVT-506 retaining solvent and creating sticky particles.

[0188] The differences between these four formulations demonstrate the benefit of including leucine for particle surface enrichment, therefore avoiding agglomeration. A manufacturing summary that includes all process parameters is given below in Table 4.Attorney Docket No. 143989.005602

[0189] Characterization

[0190] Particle size Distribution Analysis via Laser Light Scattering

[0191] The geometric particle size distributions of these samples were measured using a Malvern Mastersizer 3000 unit with an Aero S dry disperser accessory and results are presented in Table 5 and Figure 10. Method parameters can be found in Geometric Particle Size Distribution, below. Formulations A and B are likely suitable for respiratory delivery, with 90% of particles by volume being approximately 5 pm and 50% of particles by volume being approximately 2 pm. The wide range of particle sizes found in Formulation C, with 90% of particles by volume being under 250 pm, indicate that this formulation is not suitable for respiratory delivery due to its significant agglomeration. Due to the low yield of Formulation D, there was not enough material collected to perform this analysis.

[0192] Aerodynamic Particle Size via Time-of-Flight / Laser Diffraction

[0193] The aerodynamic particle sizes of these samples were measured using a TSIAerodynamic Particle Sizer (APS) 3321 spectrometer configured with a Small Scale PowderAttorney Docket No. 143989.005602Disperser 3433 as well as an Aerosol Diluter 3302A. Method parameters can be found in Aerodynamic Particle Size. Average results are plotted in Figure 11 with summary statistics provided in Table 6. The volume-weighted mean particle size (D[4,3] measured by laser diffraction above) can be compared to the volume-weighted mean aerodynamic diameter (AD) reported below, which show s that the presence of leucine in these formulations results in better aerosol performance. In other words, aerosol performance is superior when the particles behave aerodynamically as if they are smaller than they are geometrically. These results suggest that this material will aerosolize effectively for respiratory delivery given an appropriate aerosol generation mechanism. This phenomenon appears to also occur in Formulation C, which has an AD of 3.5 pm compared to a D[4,3] of 80.4 pm. However, the APS can only aerosolize particles up to 20 pm in size, which gives an inaccurate distribution of aerodynamic diameters shown in Figure 1 1. Due to the low yield of Formulation D, there was not enough material collected to perform this analysis.

[0194] Water Sorption by DVS

[0195] The sorption and desorption isotherms for each material are overlaid in Figure 12. Formulation 1 A shows substantially higher water sorption (still <3% at 90% RH) compared with the other formulations (<1.5% at 90% RH).

[0196] Crystallinity via PXRD

[0197] While the general diffraction patterns remained the same after exposure to90% RH, 25 °C in the DVS, a more sensitive approach to characterizing subtle changes in crystallinity' is to analyze peak shape. Since the main leucine peak at 60is well-resolved from other peaks, it is a good candidate for peak shape analysis. The full-width at half max (FWHM) of this peak was calculated for each sample (Figure 13 and Table 7). For nano-scale crystalline domains, peak broadening occurs when smaller, less perfect crystals are present. If crystalAttorney Docket No. 143989.005602 perfection and / or growth occurs, the FWHM would decrease, as was observed for formulation A after DVS. Larger crystalline leucine domains at the time the material is produced also likely correlates with improved leucine surface enrichment, since the mechanism driving surface enrichment is the larger size and therefore slower diffusion of crystalline leucine relative to dissolved species.

[0198] Despite the identical leucine content for formulations A and B, formulation B exhibited a significantly sharper leucine peak. Further experimentation would be needed to determine whether the greater API content or lower mannitol content in formulation B is primarily responsible for this result. Changes in spray drying conditions which impact the thermodynamics in the spray div er can also influence excipient crystallization.

[0199] Thermal Properties via DSC

[0200] Similar to PXRD, evidence of mannitol was observed in all spray dried intermediates. Mannitol is expected to melt at approximately 166 °C. Crystalline leucine undergoes sublimation at temperatures above 200 °C, so analysis was limited to 200 °C to avoid over-pressurizing the crucibles used for analysis and contaminating the instrument. Based on previous analysis, crystalline DMVT-506 is expected to melt at 193 °C, and a dry glass transition temperature would be expected at approximately 95 °C. Perhaps due to the low level of API present in formulations A and B. no glass transition is detected (Figure 14). The material is believed to be amorphous in these samples because no API melt was observed. In formulations C and D, crystallization events are observed, and a melt peak at the expected temperature of the API is observed.

[0201] Particle Morphology by SEMAttorney Docket No. 143989.005602

[0202] Particle morphology' varied between lots of SDI with A consisting of collapsed spheres, B consisting of collapsed spheres with more plate-like / ridged features, C consisting of agglomerated spheres and collapsed spheres, and D consisting of a mixture of spheres (some of which burst) and collapsed spheres, also with agglomeration (Figure 15 - Figure 18).

[0203] Water Content by Karl Fischer Titration

[0204] Water content was characterized by a Coulometric (oven / headspace) technique in which samples were heated to 140 °C. Prior to running the experiment, a representative sample underwent a temperature ramp to determine an appropriate oven temperature to minimize degradation and maximize water release. This pre-check showed a degradation onset of about 160 °C therefore a temperature of 140 °C is recommend for future analysis. See Table 8 for results (based on analysis of three samples per lot). Lot D was not analyzed due to the lack of material available.

[0205] Ethanol Content by Head-space Gas ChromatographyEthanol content was characterized by a head-space gas chromatography (GC) measurement. Each lot was measured twice, with the average reported in Table 9, except lot D. All results were well below the ICH limit of 5000 ppm ethanol.

[0206] Assay and Related Substances by HPLCAttorney Docket No. 143989.005602

[0207] Assay and related substances were measured for each SDI, and the related substances profile was minimally changed from the ingoing API, demonstrating that the API was preserved throughout this spray drying process (Table 10). Samples were analyzed in duplicate, and lot A exhibited an additional related substance at RRT 1.33 in both replicates (Table 10). As has been revealed by previous analyses, lot D contained less than half of the 100% active content that was expected, with a label claim measured here of approximately 43%.

[0208] Lots A, B, and C were also below the target label claim, though greater than 90%. It is likely that batch cross-contamination also contributed to the substandard potency observed for lot D. In general, cross-contamination at a maximum accounts for about one to two percent of the entire yield which minimally effects the physical and chemical characteristics of a material. However, the total yield for lot D was three percent, meaning that this material is likely approximately half carry-over, which supports the lower than expected potency result, 43%.

[0209] * Both replicates had identical values for individual related substances; thus no range can be provided

[0210] SDI Stability

[0211] Stability Study OverviewAttorney Docket No. 143989.005602

[0212] Following initial characterization, SDI formulations A and B were placed at several conditions to assess the material's chemical and physical stability. Each sample is identified by a three character label, where the first capital letter refers to the formulation (A: 2 / 48 / 50 DMVT- 506 / Mannitol / Leucine and B: 10 / 40 / 50 DMVT-506 / Mannitol / Leucme). The second character, a number, represents the stability time; in this case, two and four weeks are represented by the numbers 1 and 2, respectively. The last character, a lowercase letter, refers to the stability condition, with parameters found in Table 11. Conditions a-c were chosen to amplify any material changes over two to four weeks. Control samples were held at condition d for four weeks; minimal change was expected at 5 °C. The same lot as the ingoing API was used as an HPLC standard.

[0213] Assay and Related Substances by HPLC

[0214] Both the assay and related substances of each sample were evaluated. Below in Table 12 is a summary of results for both SDIs. Each material was analyzed in duplicate and data between replicates appeared consistent.

[0215] The potency of both SD's was most significantly affected with storage at 70 °C (condition c). In Figure 19 through Figure 21, the average potency of each material is plotted versus time to visualize this result. Furthermore, compared to initial data, the % label claim of A decreased at all storage conditions except b (40°C / 75%RH. closed). In contrast, the % label claim of B was unchanged at all storage conditions except 70 °C. Storage of each formulation at 70 °C resulted in the largest decrease in both potency and purity. It should be noted that theAttorney Docket No. 143989.005602 purity and potency of each control sample (stored at 5 °C) was found to be identical, within error, to the initial data collected.

[0216] Overall, at each condition tested, formulation A showed an increased number of related substances compared to B. This result is shown in Figure 21. The impurity profile of both formulations was found to differ from the initial data collected. An overlay of chromatograms for each SDI, collected after four weeks on stability, is provided in Figure 22 and Figure 23. For formulation A, storage at condition b resulted in the least growth of related substances, likely due to the primary and secondary containment closure. This protection against moisture appeared beneficial after comparing the total level of impurities to condition a (25 °C / 60% RH, open). In general, the development of more than 10 impurities was observed for A at each condition, demonstrating the potential shelf-life risk of chemical instability7. For formulation B, only condition c was seen to have related substances growth on par with A. At both conditions a and b, only two additional related substances were found to develop at low levels. These results indicate a significantly lower risk associated with the stability of formulation B. Since formulation B has both more active content (10 wt.% vs. 2 wt.%) and less mannitol content (40 wf.% vs. 48 wt.%) relative to formulation A, it is not possible to attribute a causal relationship at this point. However, it is anticipated that the greater API content is the more determinative factor in the improved chemical stability.

[0217] Crystallinity via PXRDAttorney Docket No. 143989.005602

[0218] The crystallinity profile of each sample underwent minimal changes while on stability at conditions a, b, and d (condition c was excluded from all physical analyses). The alpha and beta mannitol phases previously identified in both SDI lot A and B remained constant at all conditions examined. Additionally, crystalline leucine was found in all samples. A summary' of each sample's leucine peak position and full w idth at half max (FWHM) can be found below in Table 13. Smaller FWHM means sharper crystalline peaks, which correlates with larger and / or more perfect nano-scale crystalline domains. For formulation B, at each condition tested, the calculated FWHM is similar to data previously summarized in Table 7. In contrast, the calculated FWHM of formulation A decreased at all conditions. Also, a visual comparison of samples A2a and A2d show ed slight sharpening of the leucine peak, shown below in Figure 24. The overall lower FWHM for each formulation B sample relative to formulation A implies larger crystalline leucine domains, which may result in superior physical stability and moisture resistance due to the hydrophobicity of leucine. The changes observed for formulation A are consistent with expectations given the change observed after exposure to high humidity via DVS (Table 7).

[0219] Thermal properties of each sample was analyzed via DSC in triplicates.Parameters and preparation of samples was equivalent to analysis of prior as-received and micronized DMVT- 506. However, interference was observed near the API melt region, around 196.6 to 198.3 °C, which resulted in decreased ability to resolve possible API crystallization while on stability'. To eliminate this interfering thermal event, replicates of each sample were equilibrated overnight in a controlled climate chamber set to approximately 22°C / 0%RH. After, each sample was sealed within the chamber before removal and subsequent analysis with lid piercing conducted immediately prior to analysis. The complete summary of the mannitol melt event for each sample is located below' in Table 14. For each SDI, no API melt peak or change in mannitol melt heat of fusion w as obser ed. No change to the physical state of either the excipient or API within formulation A or B was detected relative to initial data. Once dataAttorney Docket No. 143989.005602 was reviewed with proposed method changes to eliminate interference, the test method was revised for future SDI analysis, with parameters summarized below.Table 14. Mannitol melting point for samples after 4 weeks on stability.

[0220] Lactose Chemical Compatibility

[0221] Stability Study Overview

[0222] Lactose carriers are used in the delivery of inhalation therapies to enhance powder properties and / or enable the delivery of a low active dose, advantageous for small lipophilic active ingredients with poor solubility. In this body of work, micronized DMVT-506 was blended with Respitose ML003 via a LabRam 1 acoustic mixer to generate a homogeneous material. The mixed formulation was then placed on stability at multiple conditions to assess changes in chemical stability and component compatibility. Each sample is defined by a three character label present after the base lot number. All materials analyzed had the same composition, reflected in the capital letter A (A: 0.25 / 99.75 DMVT-506 / Lactose Monohydrate). The second character, numbers 1 and 2, represent aging time; either two or four weeks, respectively. The two-week samples were stored at 5°C after aging and analyzed simultaneously with the four week samples. The lower case letter refers to the stability condition of the sample. All conditions are defined below in Table 15. A control sample was held at condition a for four weeks; no significant change was expected at 5 °C. Conditions b and c were chosen to probe the effects of direct humidity exposure and elevated temperatures on chemical compatibility.Attorney Docket No. 143989.005602

[0223] Assay and Related Substances by HPLC

[0224] Both assay and related substances were evaluated for each sample; below inTable 16 is a summary of the results. Each material was analyzed in duplicate. Conclusions regarding the chemical compatibility of an API and excipient, such as lactose, can be assessed by evaluating either the purity or potency vs. time. It should be noted that these two evaluations are separate and do not influence one another. Overall, the purity between replicates was consistent. However, high variability was observed for potency and % label claim, suggesting that the acoustic mixer and the processing steps employed to mix the lactose and API were unsuccessful in generating a homogeneous blend. Therefore, potency and % label claim will not be the basis for sample comparisons. Instead, purity values have been used to comment on the compatibility of DMVT-506 and lactose at each monitored condition. A diluent and lactose blank were analyzed with the samples to identify potential chromatographic interference. The lactose blank had lactose monohydrate combined with diluent at the same concentration observed in each sample. Additionally, a limit of quantitation (LOQ) solution, with a theoretical DMVT-506 concentration of 0.04 pg / mL, was prepared to ensure the system achieved adequate signal-to-noise ratio. An overlay of these solutions can be seen below in Figure 25. The DMVT-506 peak detected in the LOQ solution was determined to have an area of about 4743 pV*sec. Interestingly, DMVT-506 was present in the lactose blank with a peak of 3122 pV*sec. However, there is no significant impact on the quantitation of DMVT-506 within each sample because the area and corresponding concentration within the blank is less than LOQ.

[0225] An overlay of chromatograms for each stability sample is provided in Figure26. The control Sample A2a, stored at 5°C, had a purity of 99.6% and an impurity profile similar to the working standard. Both samples stored open at 40°C / 75%RH, Alb and A2b, were found to have the same purity and profile as the control. Both samples Ale and A2c,Attorney Docket No. 143989.005602 stored closed at 60°C / l 1%RH, had a purity of 99.4% and were observed to have 2 additional related substances. The first, with a retention time ratio of 1.43, was found in all other materials tested below the limit of detection indicating that formation is not due to chemical incompatibility. The second, with a retention time ratio of 2.17, was detected in samples Ale and A2c suggesting that formation is a result of storage at elevated temperatures. Lastly, these impurities were present in both 2 and 10 wt% SDI stability samples further supporting that they are not a consequence of blending DMVT-506 with lactose. Overall, the constant purity value for each sample, regardless of time on stability, offers high confidence that there is low risk associated with the chemical stability of micronized DMVT-506 in lactose blends. By using a low ratio of API : lactose monohydrate, there should be ample lactose monohydrate surface area to interact with the API and allow any potential chemical reactions to occur. Additionally, compared to previous results for the 2 wt.% active content "A" SDI formulation, open exposure to humidity’ does not significantly impact the chemical stability of lactose blends.Table 16. Assay analysis of each lactose blend stability sample

[0226] Micronized Salt Form Feasibility

[0227] From the polymorph screening activities two candidates were selected, a maleate salt and a citric acid co-crystal. These were assessed similarly to the free base with a series of two gram batch sizes used to assess feasibility, prior to milling to a target of 5 g. Despite the wide ingoing size range (see Figure 27) both salts were able to be milled below the target D90 of 10 pm using the lowest energy condition of the 2" jet mill. The milling condition of each material and respective yield are presented in Table 17.Attorney Docket No. 143989.005602

[0228] Additionally, both the purity' and potency of each ingoing material were unchanged with micronization. Any residual solvents present had little to no effect on the potency of the maleate salt and citric acid co-crystal.

[0229] Particle Size Analysis via Laser Light Scattering

[0230] The size disparity between the ingoing (Formulation II A and Formulation IIB) and jet milled (Formulation III and Formulation IV) DMVT-506 maleate salt and citric acid co-crystal materials may be indicative of very fine native crystal size generated during the salt manufacturing process (Table 18 and Figure 27). Following this logic, larger particles would then be crystals with many crystalline grain boundaries.

[0231] Assay and Related Substances by HPLC

[0232] Both the assay and related substances of each DMVT-506 salt form were evaluated. Each material was analyzed in duplicate. A summary of the results for both the ingoing and micronized maleate salt and citric acid co-crystal is provided below in Table 19.Attorney Docket No. 143989.005602The ingoing (Formulation II-A) and micronized (Formulation IV) maleate salt samples were found to have identical impurity profiles. Additionally, both maleate salt samples had similar values for overall purity and potency. For the ingoing (Formulation II-B) and micronized (Formulation III) citric acid co-crystal, potency and purity were also similar. Overall, these results suggest that the ingoing materials did not undergo degradation during micronization. Furthermore, all materials had similar % label claim values.

[0233] Crystallinity by PXRD

[0234] The diffractogram of each ingoing and micronized DMVT-506 salt form(Formulation II through Formulation IV) displayed sharp peaks, indicating the samples are crystalline. An overlay of diffraction patterns can be found below in Figure 28. A comparison of the ingoing (Formulation II) and micronized (Formulation IV) DMVT-506 maleate salt diffractograms demonstrates that the crystalline form of the ingoing material is unaffected by jet-milling. Additionally, this same conclusion can be drawn from the ingoing (Formulation II- B) and micronized (Formulation 111) DMVT-506 citric acid co-crystal. Furthermore, the diffraction patterns of both the ingoing maleate salt and citric acid co-crystal are consistent with previous data collected.

[0235] Morphology by SEM

[0236] The micronized DMVT-506 salt forms were compared to the ingoing materials via scanning electron microscopy (SEM) as shown in Figure 29 through Figure 32. The SEM analysis qualitatively confirmed the particle size distribution data plotted in Figure 28 for all materials tested. Particles of both the ingoing (Formulation II) and micronized (Formulation IV) maleate salt were observed to be crystalline with jagged edges. The ingoingAttorney Docket No. 143989.005602 salt was found to have large agglomerates with diameters of about 40 gm, and micronization resulted in particles with a diameter mostly less than or equal to 5 pm. Aggregates in the ingoing material were composed of densely packed small crystalline domains. In contrast, no agglomerates were detected in the micronized salt sample. This demonstrates effective jet milling and supports the above hypothesis that micronization was effective at the lowest energy condition due to the presence of many crystalline grain boundaries in the starting particles.

[0237] Particles of both the ingoing (Formulation II -B) and micronized (FormulationIII) citric acid co-crystal had smoother domains than the maleate salt samples. For both cocrystal materials, agglomerates with diameters of about 15 pm were the most prominent species observed. The starting material aggregates were composed of loosely packed small crystalline domains. To clarify, loose packing was defined by the observed void areas present in the structure.

[0238] Thermal Properties by DSC

[0239] Each sample was analyzed in triplicate. Parameters and preparation of samples was equivalent to analysis of the prior micronized DMVT-506 materials. A summary of results can be found below in Table 20. No glass transition (Tg) or melt peak was observed for any of the ingoing or micronized DMVT-506 salt forms. Additionally, jet milling had little to no effect on the onset degradation temperature of the ingoing maleate salt (Formulation II) and citric acid co-crystal (Formulation II-B). The micronized (Formulation IV) maleate salt sample had an onset degradation temperature of about 190.4 °C. Also, the micronized citric acid co-crystal (Formulation III) had an onset degradation temperature of about 178 °C. Initial investigation of the maleate salt samples detected a small-scale thermal event at about 120° C. These samples underwent additional testing with a modulated method which analyzed the samples from 25 to 155 °C at a rate of 2.5 °C / min and a modulation of 1.5°C. The results suggested that this event was not a Tg due to variability in the associated energy and midpoint temperature of the transition. Likely, this thermal event is the result of residual volatiles present in both the ingoing and micronized maleate salt samples. This conclusion is supported by decomposition data collected for the ingoing salt, which depicts volatile loss at around 118 °C. Overall, the physical state of each material was consistent with historical data.Attorney Docket No. 143989.005602

[0240] Water Sorption by DVS

[0241] Both the ingoing maleate salt (Formulation II) and citric acid co-crystal(Formulation II-B) were exposed to a humidity cycle to confirm the physical state and classification of each material. Additionally, the micronized maleate salt (Formulation IV) and citric acid co-crystal (Formulation III) were analyzed in the same manner to evaluate the formation of low-level amorphous content post jet-milling. Figure 33 provides an isotherm overlay for all materials tested. With the current method, none of the materials underwent a crystallization event and counterpart materials had similar hysteresis observed at 50 %RH. Also, the maleate salt and citric acid co-crystal samples showed minimal water sorption until 80%RH, consistent with the hydrophobicity of these crystalline forms observed previously. However, the ingoing citric acid co-crystal experienced a greater change in mass than historically observed, likely due to the material being composed of smaller crystalline domains. It should be noted the ingoing maleate salt obtained a max sorption of about 1.23% which was double the micronized sample. This result is likely attributable to method variability (the sample with less sorption at 90% RH, Formulation IV, was held for approximately 130 minutes until equilibrium was detected and the instrument returned to 80% RH, while the sample with more sorption at 90% RH, Formulation II, was held for approximately 290 minutes until equilibrium was detected and the instrument returned to 80% RH).

[0242] For DMVT-506, it appears that chemical and physical stability risks are related. For instance, the spray dried, amorphous forms of DMVT-506 were more susceptible to both chemical degradation and to physical change over time. For example, spray dried composition C and D had thermal events corresponding to both the ciystallization and melt of DMVT-506. Thermal events associated with excipients were unaffected. Overall, the mannitol melt peak of C had an enthalpy similar to what was expected. Therefore, these physical changes are API specific. API crystallization would detract from the amorphous solubility benefit and potentially change particle morphology sufficiently to impact the aerosol performance. On the other hand, spray dried compositions A and B, containing 50 wt.% leucine exhibited physical stability . Based on the variety of chemical and physical stability- performance observed across spray dried forms, it may be possible to define a spray drying strategy to result in chemicallyAttorney Docket No. 143989.005602 and physically stable, amorphous API-containing particles, such as by considering mannitol / leucine / API formulation optimization, process parameter selection, or alternative processing approaches, such as the previously mentioned spray dried, API coated lactose cores.

[0243] By micronizing crystalline material, most of the physical stability risks associated with metastable amorphous forms can be avoided. Not all crystalline forms are stable to elevated temperature and humidity7, but solid forms of DMVT-506 crystallized with HC1, maleic acid, and citric acid all exhibit no change after two weeks at accelerated stability conditions as well as no form change before and after DVS analysis. The low level of vapor sorption for these forms also indicates a hydrophobic crystal structure which should be stable to a wide range of possible humid environments.

[0244] Methods

[0245] Analytical Methods

[0246] PXRD

[0247] A small amount of solid (up to 10 mg if available) is placed on a 0.2 mmSi(510) PXRD cup and analyzed on a Rigaku Miniflex 600 equipped with a DiteX Ultra detector and an ASC-6 autosampler with sample spinning.

[0248] TGA

[0249] 1- 10 mg of sample is placed in a 40 pL aluminum pan and analyzed on a TAInstruments TGA Discovery.Attorney Docket No. 143989.005602

[0250] DSC

[0251] In triplicate (n=3), transfer 1 - 5 mg of each sample into separate aluminum crucibles. Seal all crucibles with a press kit and analyze via a Mettler DSC.

[0252] NMR

[0253] Samples were prepared by dissolving the solids in de-DMSO before adding the solution to a standard NMR glass sample tube. All samples were analyzed on a Varian 600 MHz NMR instrument equipped with an autosampler. Spectra were referenced to the parent solvent peak and all integrations were calculated based on the aromatic peak in DMVT-506.Attorney Docket No. 143989.005602

[0254] FTIR

[0255] Infrared spectra are obtained on a Thermo iS-50 equipped with a single bounce attenuated total reflectance (ATR) attachment with a diamond cry stal a DTGS detector. 64 scans with 2 cm’1resolution are recorded for each spectrum.

[0256] Microscopy

[0257] Samples are prepared by creating a suspension of each sample in mineral oil and imaged on an Olympus BX53 with either plain polarized (PP), cross polarized (CP) light, or CP light with a 532 nm (magenta) compensator.

[0258] Geometric Particle Size Distribution

[0259] Aerodynamic Particle SizeTransfer about 5 mg of material onto the instrument for analysis. Analyze each sample in triplicate (n=3).Attorney Docket No. 143989.005602

[0260] DVS

[0261] Karl Fischer TitrationIn triplicate, prepare standard blanks, standard, sample blanks, and samples. Prepare one post bracketing standard. For blanks, empty KF vials are sealed throughout standard and sample prep.Attorney Docket No. 143989.005602

[0262] Gas Chromatography

[0263] In duplicate (n=2), transfer 40 -100 mg of each sample into separate headspace vials. Seal vials then added dimethyl acetamide (DMAC) through the septum via a syringe. Shake or vortex to break up larger agglomerates.Atorney Docket No. 143989.005602

[0264] Assay and Related Substances via HPLC

[0265] Amber volumetric flasks were used to combat the light sensitivity of DMVT-506 containing drug products. In duplicate, transfer 8 mg of the DMVT-506 reference standard into separate 200 mL flasks. Fill 3 / 4th full with diluent and sonicate for 10 minutes. Equilibrate standards for 1 hour at room temperature before filling to volume wi th diluent.

[0266] Transfer 1 mL of stock standard 1 to a 50 mL flask. Fill to volume with diluent and mix to generate an intermediate solution. Then transfer 1 mL of the intermediate solution into a 20 mL flask. Fill to volume with diluent and mix to generate LOQ.

[0267] For DMVT-506 Bulk Powder Samples SDIs & Micronized Materials:

[0268] Transfer enough material to achieve a theoretical working concentration of 40 pg API / mL into a 200 mL flask. Fill 3 / 4th full with diluent and vortex on high for 1 minute. Fill to volume with diluent after visual verification of dissolution. Sample in amber HPLC vial for analysis.

[0269] For DMVT-506 Lactose Blends:

[0270] Transfer enough material to achieve a theoretical working concentration of 40 pg API / mL into a 10 mL flask. Fill 3 / 4th full with diluent and vortex on high for 2 minutes. Fill to volume with diluent and invert 5x to mix. Directly transfer 5 mL of solution into a syringe and purge about 3 mL to waste. Atach PTFE syringe filter and collect sample in amber HPLC vial for analysis.Attorney Docket No. 143989.005602

Claims

Attorney Docket No. 143989.005602CLAIMSWhat is claimed is:

1. A method of treating a respiratory disease or disorder in a patient in need thereof the method comprising: respiratory administration to the patient a pharmaceutical composition comprising a therapeutically effective amount of a compound of Formula I:Formula I or a pharmaceutically acceptable salt thereof or pharmaceutically acceptable cocrystal thereof, thereby treating the respirator}' disease or disorder.

2. The method of claim 1, wherein the inflammatory diseases of the lungs are steroid responsive asthma, steroid unresponsive asthma, chronic obstructive pulmonary disease, hereditary emphysema, emphysema or pulmonary fibrosis or combinations thereof.

3. The method of claim 1 wherein the pharmaceutical composition is in the form of a dry powder inhaler, a pressurized metered dose inhaler, a solution for nebulization or a soft mist inhaler.

4. The method of claim 1, wherein the therapeutically effective amount is about 5 pg to about 50 mg.

5. The method of claim 1, wherein the compound of Formula I is in the form of a free base or a salt or cocrystal of hydrochloric acid, citric acid, maleic acid, tartaric acid, sulfuric acid, or combinations thereof.

6. The method of claim 1, wherein the compound of Formula I is in the form of a hydrochloride salt.

7. The method of claim 1, wherein the compound of Formula I is in the form of a citrate salt.

8. The method of claim 1, wherein the compound of Formula I is in the form of a cocrystal with citric acid.

9. The method of claim 1, wherein the compound of Formula I is in the form of a maleate salt.Attorney Docket No. 143989.00560210. The method of claim 1, wherein the compound of Formula I is in the form of a tartrate salt.

11. The method of claim 1, wherein the compound of Formula I is in the form of a cocrystal with tartaric acid.

12. The method of claim 1, wherein the pharmaceutical composition delivers the compound of Formula I to the patient’s lungs.

13. A pharmaceutical composition for delivery by inhalation, comprising: a therapeutically effective amount of a compound of Formula I:Formula I or a pharmaceutically acceptable salt thereof or pharmaceutically acceptable cocrystal thereof, and one or more pharmaceutically acceptable excipients.

14. The pharmaceutical composition of claim 13, wherein the compound of Formula I is in the form of a free base or a salt or cocrystal of hydrochloric acid, citric acid, maleic acid, tartaric acid, sulfuric acid, or combinations thereof.

15. The pharmaceutical composition of claim 13, wherein the compound of Formula l is in the form of a hydrochloride salt.

16. The pharmaceutical composition of claim 13, wherein the compound of Formula I is in the form of a citrate salt.

17. The pharmaceutical composition of claim 13, wherein the compound of Formula l is in the form of a cocrystal with citric acid.

18. The pharmaceutical composition of claim 13, wherein the compound of Formula I is in the form of a maleate salt.

19. The pharmaceutical composition of claim 13, wherein the compound of Formula l is in the form of a tartrate salt.

20. The pharmaceutical composition of claim 13, wherein the compound of Formula I is in the form of a cocrystal with tartaric acid.Attorney Docket No. 143989.00560221. The pharmaceutical composition of claim 13, wherein the pharmaceutical composition is suitable for delivery via a dry powder inhaler, a pressurized metered dose inhaler, a nebulizer or a soft mist inhaler.

22. The pharmaceutical composition of claim 13, wherein the pharmaceutical composition includes particles having a median aerodynamic particle size of from about 1 pm to about 10 pm.

23. The pharmaceutical composition of claim 13, wherein the pharmaceutical composition comprises a spray dried particles having a median aerodynamic particle size of from about 1 pm to about 10 pm.

24. The pharmaceutical composition of claim 13, wherein the pharmaceutical composition includes a solution or suspension formulation with or without propellant producing a median aerodynamic droplet size of from about 1 pm to about 10 pm.

25. The pharmaceutical composition of claim 13, wherein the therapeutically effective amount is about 5 pg to about 50 mg.

26. The pharmaceutical composition of claim 13, wherein the one or more pharmaceutically acceptable excipients comprises a diluent, a stabilizer, a force control agent, a lubricant, a solubiliser, a co-solvent, a surfactant, a pH-adjusting agent, a buffer, a liquified propellant gas, a non volatile solvent, a preservative, an antioxidant, a tonicity adjusting agent, a suspending agent or combinations thereof.

27. A method of making a pharmaceutical composition, comprising: a respirable particle comprising a compound of Formula I:Formula I or a pharmaceutically acceptable salt thereof or pharmaceutically acceptable cocrystal thereof and forming the respirable particle into an inhaled dosage form with one or more pharmaceutical excipients.

28. The method of claim 27, wherein the respirable particle is prepared by micronizing methods comprising jet-milling of formula I to a desired aerodynamic particle size.Attorney Docket No. 143989.00560229. The method of claim 27, wherein the desired aerodynamic particle size is about 1 pm to about 10 pm.

30. The method of claim 27, wherein the pharmaceutical composition is prepared by spray drying methods comprising: dissolving the compound of Formula I and the one or more pharmaceutical excipient in a solvent to yield a solution; subjecting the solution to spray drying techniques to yield a dry powder.

31. The method of claim 30, wherein the solvent is ethanol or an ethanol and water solution.

32. The method of claim 27 wherein the one or more pharmaceutical excipient is L-leucine, mannitol, sugar, or a combination thereof.

33. The method of claim 27, wherein the compound of formula I is present at about 2-10% by weight of the solute.

34. The method of claim 27, wherein the one or more pharmaceutical excipients comprises one or more of mannitol, L-leucine, sugar, and combinations thereof.

35. The method of claim 27, wherein the one or more pharmaceutical excipient is present at about 90 to 98% by weight of the solute.

36. The method of claim 30, wherein the solvent is a 60 / 40 water / ethanol solution.

37. A method of treating a respiratory disease or disorder in a patient in need thereof, the method comprising: administering intra-nasally to the patient a pharmaceutical composition comprising a therapeutically effective amount of a compound of Formula I:Formula I or a pharmaceutically acceptable salt thereof or pharmaceutically acceptable cocrystal thereof, thereby treating the respiratory disease or disorder.

38. The method of claim 37, wherein the inflammatory diseases of the nose are allergic rhinitis or nonallergic rhinitis or combinations thereof.Attorney Docket No. 143989.00560239. The method of claim 37, wherein the pharmaceutical composition is suitable for delivery intra-nasally via solution, suspension, powder inhalation, powder insufflation, a pressurized metered dose inhaler.

40. The pharmaceutical composition of claim 37, wherein the therapeutically effective amount is about 5 pg to about 30 mg.

41. The method of claim 37, wherein the compound of Formula I is in the form of a free base or a salt or cocrystal of hydrochloric acid, citric acid, maleic acid, tartaric acid, sulfuric acid, or combinations thereof.

42. The method of claim 37, wherein the compound of Formula I is in the form of a hydrochloride salt.

43. The method of claim 37, wherein the compound of Formula I is in the form of a citrate salt.

44. The method of claim 37, wherein the compound of Formula I is in the form of a cocrystal with citric acid.

45. The method of claim 37, wherein the compound of Formula I is in the form of a maleate salt.

46. The method of claim 37, wherein the compound of Formula I is in the form of a tartrate salt.

47. The method of claim 37, wherein the compound of Formula I is in the form of a cocrystal with tartaric acid.

48. The method of claim 37, wherein the pharmaceutical composition delivers the compound of Formula I to the cavities within the patient’s nose.

49. A method of treating inflammatory diseases of the nervous system or disorder in a patient in need thereof, the method comprising: administering intra-nasally to the patient a pharmaceutical composition comprising a therapeutically effective amount of a compound of Formula I:Formula I or a pharmaceutically acceptable salt thereof or pharmaceutically acceptable cocrystal thereof,Attorney Docket No. 143989.005602 thereby treating the inflammatory diseases of the nervous system.

50. The method of claim 49, wherein the inflammatory diseases of the nervous system are multiple sclerosis, Parkinson’s disease, Alzheimer’s disease, neuromyelitis optica, antimyelin oligodendrocyte glycoprotein antibody disorder, autoimmune encephalitis, acute disseminated encephalomyelitis, transverse myelitis, neurosarcoidosis, or combinations thereof.

51. The method of claim 49. wherein the pharmaceutical composition is suitable for delivery intra-nasally via solution, suspension, powder inhalation, powder insufflation, a pressurized metered dose inhaler.

52. The method of claim 49, wherein the therapeutically effective amount is about 5 pg to about 30 mg.

53. The method of claim 49, wherein the compound of Formula I is in the form of a free base or a salt or cocrystal of hydrochloric acid, citric acid, maleic acid, tartaric acid, sulfuric acid, or combinations thereof.

54. The method of claim 49, wherein the compound of Formula I is in the form of a hydrochloride salt.

55. The method of claim 49, wherein the compound of Formula I is in the form of a citrate salt.

56. The method of claim 49, wherein the compound of Formula I is in the form of a cocrystal with citric acid.

57. The method of claim 49, wherein the compound of Formula I is in the form of a maleate salt.

58. The method of claim 49, wherein the compound of Formula I is in the form of a tartrate salt.

59. The method of claim 49, wherein the compound of Formula I is in the form of a cocrystal with tartaric acid.

60. The method of claim 49, wherein the pharmaceutical composition delivers the compound of Formula I to the cavities within the patient's nose.

61. A pharmaceutical composition for delivery by intranasal administration, comprising: a therapeutically effective amount of a compound of Formula I:Attorney Docket No. 143989.005602Formula I or a pharmaceutically acceptable salt thereof or pharmaceutically acceptable cocrystal thereof, and one or more pharmaceutically acceptable excipients.

62. The pharmaceutical composition of claim 61, wherein the compound of Formula I is in the form of a free base or a salt or cocrystal of hydrochloric acid, citric acid, maleic acid, tartaric acid, sulfuric acid, or combinations thereof.

63. The pharmaceutical composition of claim 61, wherein the compound of Formula I is in the form of a hydrochloride salt.

64. The pharmaceutical composition of claim 61, wherein the compound of Formula I is in the form of a citrate salt.

65. The pharmaceutical composition of claim 61, wherein the compound of Formula I is in the form of a cocrystal with citric acid.

66. The pharmaceutical composition of claim 61, wherein the compound of Formula I is in the form of a maleate salt.

67. The pharmaceutical composition of claim 61, wherein the compound of Formula I is in the form of a tartrate salt.

68. The pharmaceutical composition of claim 61, wherein the compound of Formula I is in the form of a cocrystal with tartaric acid.

69. The pharmaceutical composition of claim 61, wherein the pharmaceutical composition is suitable for delivery via solution, suspension, powder inhalation, powder insufflation, a pressurized metered dose inhaler.

70. The pharmaceutical composition of claim 61, wherein the pharmaceutical composition is suitable for delivery7via a pressurized metered dose inhaler, a nebulizer, an atomization device, an insufflator, a nasal spray.

71. The pharmaceutical composition of claim 61, wherein the pharmaceutical composition includes particles having a median particle size of from about 1 pm to about 10 pm or about 10 pm to about 200 pm based on the delivery7technology7platform.Attorney Docket No. 143989.005602'll. The pharmaceutical composition of claim 61, wherein the pharmaceutical composition includes droplets having a median size of from about 10 pm to about 200 pm.

73. The pharmaceutical composition of claim 61, wherein the pharmaceutical composition comprises a spray dried formulation, wherein the one or more pharmaceutical excipients comprises one or more of mannitol, L-leucine, sugar, and combinations thereof.

74. The pharmaceutical composition of claim 61, wherein the therapeutically effective amount is about 5 pg to about 30 mg.

75. The pharmaceutical composition of claim 61, wherein the one or more pharmaceutically acceptable excipients comprises a diluent, a stabilizer, a force control agent, a lubricant, a solubiliser, a co-solvent, an antisolvent, a surfactant, a pH-adjusting agent, a buffer, a liquified propellant gas, a non-volatile solvent, a preservative, lipid nanoparticles, an antioxidant, a tonicity adjusting agent, a suspending agent, a humectant or combinations thereof.

Images