THIN FILM FREEZING METHODS AND COMPOSITIONS FORMULATED FROM DISPERSED ACTIVE AGENTS

CROSS-REFERENCE TO RELATED APPLICATIONS

[001] This application claims the benefit of priority to U.S. Provisional Patent Application No. 63/393,059, which was filed on July 28, 2022, and is incorporated herein by reference in its entirety.

FIELD OF THE INVENTION

[002] The invention generally encompasses compositions and methods for obtaining pharmaceutical compositions by dispersing micron and nano-sized particles of active pharmaceutical ingredients in a non-solvent to form a dispersion and subjecting the dispersion to a thin film freezing process.

BACKGROUND OF THE INVENTION

[003] The general method of delivery of drugs to the lungs for the treatment of numerous pulmonary disorders is through inhalation of the drug particles. The drug particles are generally in the form of an aerosol of respirable sized particles (e.g., in the range of microns or nanometers) incorporated into a colloidal dispersion containing either a propellant, as a pressurized metered dose inhaler (pMDI) or air such as is the case with a dry powder inhaler (DPI).

[004] It is of the upmost importance in the aerosol formulation that the composition is stable and the dose discharged from the metered dose valve is reproducible; however, there are numerous factors that influence these features, e.g., creaming, or settling, after agitation are common sources of dose irreproducibility in suspension formulations. Another concern is the flocculation of the composition after agitation. This flocculation often results in dose irreproducibility and as such, it is an undesirable process and composition and is often seen in aerosol formulations containing only medicament and propellant. Surfactants and other inactive excipients are often included in the formulations to serve as suspending aids to stabilize the suspension or as lubricants to reduce valve sticking which also causes dose irreproducibility. Drug absorption into the subject from the airway depends on numerous factors, e.g., the composition of the formulation, type of solute, the method of drug delivery, and the site of deposition. Dry powder presentations of active ingredients present unique opportunities in formulations, which do not occur in liquid presentations such as MDIs and nebulized solutions, and avoid many of the issues associated with liquid-based formulations [005] Within DPI drug delivery there is an additional subset of formulations that aim to address the delivery of crystalline and poorly water-soluble APIs. In many cases to improve the bioavailability of these poorly soluble compounds particle engineering technologies like jet milling, wet grinding, and antisolvent precipitation methods are utilized to prepare engineered API particles of micron or sub-micron size. However, these pre-engineered particles alone typically do not have good aerosol properties and therefore need to be blended with larger course carrier particles like lactose to improve their aerosol performance through a process called dry blending. This can improve the aerosol performance of these pre-engineered API particles but typically only to a certain extent and at the expense of adding additional excipients to the formulation.

[006] In contrast to this dry blending approach, the inventors have surprisingly found that by dispersing micron and nano-sized APIs into a non-solvent along with dissolved excipients a brittle matrix powder can be generated in the TFF process that obtains much higher fine particle fractions with even higher API to excipient ratios than can be achieved using traditional dry blending. This invention has broad applicability to delivering micron and nano-sized active ingredients to the deep lung and can offer advantages for poorly soluble active pharmaceutical ingredients. SUMMARY OF THE INVENTION

[007] The invention generally encompasses compositions and methods for obtaining excellent aerosol properties from micron and sub-micron sized particles of active pharmaceutical ingredients by dispersing one or more pre-engineered active ingredients in a non-solvent along with dissolved excipients and subjecting the resulting dispersion to a thin film freezing process.

[008] In embodiments, the active agent has been pre-engineered to have an average particle size of less than about 10 microns, for example, about 1 to about 5 microns. In other embodiments, the active agent has been pre-engineered to include particles having an average particle size of less than about 500 nm, for example, about 50 nm to about 250 nm.

[009] In embodiments, the pre-engineered active agent is included in the methods of the invention and retains its structure when combined with an excipient in the methods disclosed herein while providing higher delivery and increased drug load than methods in the art.

[010] In some embodiments, the invention encompasses methods of preparing a pharmaceutical composition comprising:

[Oil] (i) obtaining a solution including an excipient dissolved in a liquid phase;

[012] (ii) adding one or more pre-engineered active agents having a micron or sub-micron particle size to the liquid phase to obtain a dispersion (which includes the excipient and dispersed active agent); and

[013] (iii) depositing the dispersion on a reduced temperature surface such that the dispersion freezes on the surface to obtain a frozen dispersion.

[014] In certain embodiments the method comprises an additional step (D) comprising subjecting the frozen dispersion to a drying process to obtain a pharmaceutical composition.

[015] In some embodiments, the active agent is sparingly soluble in the liquid phase. In some embodiments, the active agent is slightly soluble in the liquid phase. In some embodiments, the active agent is very slightly soluble in the liquid phase. In some embodiments, the active agent is practically insoluble in the liquid phase. In some embodiments, the dispersion is a suspension in the liquid phase. In some embodiments, the liquid phase is a non-solvent for the active agent. In each of the above embodiments, the active agent in the liquid phase is referred to as a dispersion.

[016] In some embodiments, the excipient is an amino acid such as a hydrophobic amino acid. In some embodiments, the amino acid is histidine, leucine, trileucine, and/or glycine.

[017] In some embodiments, the pharmaceutical composition comprises from about 0.01% w/w to about 99% w/w of the excipient. In some embodiments, the pharmaceutical composition comprises from about 1% w/w to about 90% w/w of the excipient. In some embodiments, the pharmaceutical composition comprises from about 2.5% w/w to about 80% w/w of the excipient. In some embodiments, the excipient is a sugar or sugar alcohol such as a polysaccharide or mannitol. In some embodiments, the polysaccharide is lactose, trehalose, sucrose, lactose, maltose, or dextrose.

[018] In some embodiments, the pharmaceutical composition comprises from about 50% w/w to about 99% w/w of the active agent. In some embodiments, the pharmaceutical composition comprises from about 60% w/w to about 95% w/w of the active agent. In some embodiments, the pharmaceutical composition comprises from about 65% w/w to about 90% w/w of the active agent.

[019] In some embodiments, the dispersion further comprises a pharmaceutically acceptable polymer. In some embodiments, the pharmaceutically acceptable polymer is a nonionic triblock copolymers composed of a central hydrophobic chain of polyoxypropylene flanked by two hydrophilic chains of polyoxyethylene. In some embodiments, the pharmaceutically acceptable polymer is a polyethoxylated castor oil. In some embodiments, the pharmaceutically acceptable polymer is a linear ABA block polymers of ethylene oxide (EO) and propylene oxide (PO). In some embodiments, the pharmaceutically acceptable polymer is pol oxamer 188 or polysorbate 80. In some embodiments, the pharmaceutically acceptable polymer is a non-cellulosic non-ionizable polymer. In some embodiments, the non-cellulosic non-ionizable polymer is a polyvinylpyrrolidone. In some embodiments, the pharmaceutically acceptable polymer has a molecular weight from about 5,000 to about 100,000. In some embodiments, the molecular weight is from about 10,000 to about 50,000. In some embodiments, the molecular weight is from about 20,000 to about 30,000. In some embodiments, the pharmaceutical composition comprises from about 0.5% w/w to about 20% w/w of the pharmaceutically acceptable polymer. In some embodiments, the pharmaceutical composition comprises from about 1% w/w to about 15% w/w of the pharmaceutically acceptable polymer. In some embodiments, the pharmaceutical composition comprises from about 2.5% w/w to about 10% w/w of the pharmaceutically acceptable polymer.

[020] In some embodiments, the solvent is an organic solvent. In some embodiments, the organic solvent is a polar aprotic solvent. In some embodiments, the organic solvent is acetonitrile, tert-butanol, or 1,4-di oxane. In some embodiments, the solvent is 1,4-di oxane or acetonitrile. In some embodiments, the solvent is a mixture of 1,4-di oxane and acetonitrile. In some embodiments, the solvent is a mixture of /-butanol and acetonitrile.

[021] In some embodiments, the active pharmaceutical ingredient is selected from anticancer agents, antifungal agents, psychiatric agents such as analgesics, consciousness level-altering agents such as anesthetic agents or hypnotics, nonsteroidal anti-inflammatory agents (NSAIDs), anthelmintics, antiacne agents, antianginal agents, anti arrhythmic agents, antiasthma agents, antibacterial agents, anti-benign prostate hypertrophy agents, anticoagulants, antidepressants, antidiabetics, antiemetics, antiepileptics, antigout agents, antihypertensive agents, anti-inflammatory agents, antimalarials, antimigraine agents, antimuscarinic agents, antineoplastic agents, anti-obesity agents, antiosteoporosis agents, antiparkinsonian agents, antiproliferative agents, antiprotozoal agents, antithyroid agents, antitussive agent, anti-urinary incontinence agents, antiviral agents, anxiolytic agents, appetite suppressants, beta-blockers, cardiac inotropic agents, chemotherapeutic drugs, cognition enhancers, contraceptives, corticosteroids, Cox-2 inhibitors, diuretics, erectile dysfunction improvement agents, expectorants, gastrointestinal agents, histamine receptor antagonists, immunosuppressants, keratolytic, lipid regulating agents, leukotriene inhibitors, macrolides, muscle relaxants, neuroleptics, nutritional agents, opioid analgesics, protease inhibitors, or sedatives. In some embodiments, the active pharmaceutical ingredient is antifungal agent. In some embodiments, the antifungal agent is an azole antifungal agent such as voriconazole. In other embodiments, the active pharmaceutical ingredient is immunomodulating drug. In some embodiments, the immunomodulating drug is an immunosuppressing drug such as tacrolimus. In some embodiments, the active pharmaceutical ingredient is anthelmintic agent such as niclosamide. [022] In some embodiments, the pharmaceutical composition comprises at least 60% of the active pharmaceutical ingredient that is in the amorphous form. In some embodiments, the pharmaceutical composition comprises at least 80% of the active pharmaceutical ingredient that is in the amorphous form. In some embodiments, the pharmaceutical composition comprises at least 90% of the active pharmaceutical ingredient that is in the amorphous form. In some embodiments, the pharmaceutical composition comprises at least 95% of the active pharmaceutical ingredient that is in the amorphous form. In some embodiments, the pharmaceutical composition comprises at least 98% of the active pharmaceutical ingredient that is in the amorphous form. In some embodiments, the pharmaceutical composition comprises at least 99% of the active pharmaceutical ingredient that is in the amorphous form. In some embodiments, the pharmaceutical composition comprises at least 60% of the active pharmaceutical ingredient that is in the crystalline form. In some embodiments, the pharmaceutical composition comprises at least 80% of the active pharmaceutical ingredient that is in the crystalline form. In some embodiments, the pharmaceutical composition comprises at least 90% of the active pharmaceutical ingredient that is in the crystalline form. In some embodiments, the pharmaceutical composition comprises at least 95% of the active pharmaceutical ingredient that is in the crystalline form. In some embodiments, the pharmaceutical composition comprises at least 98% of the active pharmaceutical ingredient that is in the crystalline form. In some embodiments, the pharmaceutical composition comprises at least 99% of the active pharmaceutical ingredient that is in the crystalline form.

[023] In some embodiments, the pharmaceutical composition comprises from about 1% w/w to about 99% w/w of the active pharmaceutical ingredient. In some embodiments, the pharmaceutical composition comprises from about 2.5% w/w to about 90% w/w of the active pharmaceutical ingredient. In some embodiments, the pharmaceutical composition comprises from about 5% w/w to about 80% w/w of the active pharmaceutical ingredient.

[024] In some embodiments, the method further comprises using a surface that has been cooled to a first reduced temperature. In some embodiments, the first reduced temperature is from about -25 °C to about -190 °C. In some embodiments, the first reduced temperature is from about -20 °C to about -120 °C. In some embodiments, the first reduced temperature is from about from about -60 °C to about -90 °C.

[025] In some embodiments, the surface rotates at a speed. In some embodiments, the speed is from about 5 rpm to about 500 rpm. In some embodiments, the speed is from about 50 rpm to about 250 rpm. In some embodiments, the speed is from about 50 rpm to about 150 rpm.

[026] In some embodiments, the dispersion is deposited on the surface from a height from about 1 cm to about 250 cm. In some embodiments, the height is from about 2.5 cm to about 100 cm. In some embodiments, the height is from about 5 cm to about 50 cm.

[027] In some embodiments, the dry process comprises lyophilization. In some embodiments, the drying process comprises two drying cycles. In some embodiments, the first drying cycle comprises drying at a first temperature from about 0 °C to about -120 °C. In some embodiments, the first temperature is a temperature from about -10 °C to about -80 °C. In some embodiments, the first temperature is a temperature from about -20 °C to about -60 °C.

[028] In some embodiments, the first drying cycle comprises drying at a reduced pressure. In some embodiments, the reduced pressure is a first pressure from about 10 mTorr to about 500 mTorr. In some embodiments, the first pressure is from about 25 mTorr to about 250 mTorr. In some embodiments, the first pressure is from about 50 mTorr to about 150 mTorr.

[029] In some embodiments, the second drying cycle comprises drying at a second temperature from about 0 °C to about 80 °C. In some embodiments, the second temperature is a temperature from about 10 °C to about 60 °C. In some embodiments, the second temperature is a temperature from about 20 °C to about 50 °C. In some embodiments, the second drying cycle comprises drying at a reduced pressure. In some embodiments, the reduced pressure is a second pressure from about 10 mTorr to about 500 mTorr. In some embodiments, the second pressure is from about 25 mTorr to about 250 mTorr. In some embodiments, the second pressure is from about 50 mTorr to about 150 mTorr.

[030] In some embodiments, an engineered API particle has a D50 particle size distribution measured by laser diffractometer from about 0.01 pm to about 150 pm and is incorporated into brittle matrix powder. In some embodiments, the D50 particle size distribution is from about 0.05 pm to about 100 pm. In some embodiments, the D50 particle size distribution is from about 0.1 pm to about 50 pm. In some embodiments, the excipient has a D50 particle size distribution measured by laser diffractometer from about 30 pm to about 150 pm. In some embodiments, the D50 particle size distribution is from about 40 pm to about 125 pm. In some embodiments, the D50 particle size distribution is from about 70 pm to about 100 pm. In some embodiments, the D50 particle size distribution is from about 40 pm to about 70 pm. [031] In some embodiments, the pharmaceutical composition comprises a brittle matrix powder wherein one or more of the API could be agglomerated. In some embodiments, the pharmaceutical composition comprises particles exhibiting two different forms. In some embodiments, the first form is one or more particles of the active pharmaceutical ingredient and the excipient are agglomerated. In some embodiments, the second form is one or more excipient particles which comprise one or more discrete domains of the active pharmaceutical ingredient deposited on the surface of the excipient. In some embodiments, the active pharmaceutical ingredient in the discrete domains is present as a nanostructured aggregate.

[032] In some embodiments, the pharmaceutical composition has a specific surface area of greater than 2 m ² /g. In some embodiments, the specific surface area is from about 2 m ² /g to about 100 m ² /g. In some embodiments, the specific surface area is from about 2.5 m ² /g to about 50 m ² /g. In some embodiments, the specific surface area is from about 2.5 m ² /g to about 25 m ² /g. In some embodiments, the specific surface area is from about 2.5 m ² /g to about 10 m ² /g. In some embodiments, the pharmaceutical composition has a specific surface area that is 50% greater than the specific surface area of the excipient. In some embodiments, the pharmaceutical composition has a specific surface area that is 75% greater than the specific surface area of the excipient. In some embodiments, the pharmaceutical composition has a specific surface area that is 100% greater than the specific surface area of the excipient.

[033] In some embodiments, the pharmaceutical composition has a mass median aerodynamic diameter (MMAD) from about 1.0 pm to about 10.0 pm. In some embodiments, the MMAD is from about 1.5 pm to about 8.0 pm. In some embodiments, the MMAD is from about 2.0 pm to about 6.0 pm. In some embodiments, the MMAD of the pharmaceutical composition is 10% less than the MMAD of an identical composition prepared using another method. In some embodiments, the MMAD of the pharmaceutical composition is 25% less. In some embodiments, the MMAD of the pharmaceutical composition is 50% less. In some embodiments, the MMAD of the pharmaceutical composition is 100% less.

[034] In some embodiments, the pharmaceutical composition has a geometric standard deviation (GSD) from about 1.0 to about 10.0. In some embodiments, the GSD is from about 1.25 to about 8.0. In some embodiments, the GSD is from about 1.5 to about 6.0.

[035] In some embodiments, the pharmaceutical composition has a fine powder fraction of the recovered dose that is 10% greater than the fine powder fraction of the recovered dose of a pharmaceutical composition prepared according to any other method. In some embodiments, the fine powder fraction of the recovered dose of the pharmaceutical composition is 15% greater. In some embodiments, the fine powder fraction of the recovered dose of the pharmaceutical composition is 20% greater. In some embodiments, the fine powder fraction of the recovered dose of the pharmaceutical composition is 25% greater. In some embodiments, the pharmaceutical composition has a fine powder fraction of the recovered dose of greater than 30%. In some embodiments, the fine powder fraction of the recovered dose is greater than 40%. In some embodiments, the fine powder fraction of the recovered dose is greater than 50%.

[036] In some embodiments, the pharmaceutical composition has an emitted dose of the recovered dose of greater than 70%. In some embodiments, the emitted dose of the recovered dose is greater than 80%. In some embodiments, the emitted dose of the recovered dose is greater than 90%.

[037] In some embodiments, the pharmaceutical composition has a relative standard deviation (RSD) of the homogeneity of the pharmaceutical composition is less than 8%. In some embodiments, the relative standard deviation of the homogeneity of less than 6%. In some embodiments, the relative standard deviation of the homogeneity of less than 4%. In some embodiments, the relative standard deviation of the homogeneity of the pharmaceutical composition is 50% less than the relative standard deviation of the homogeneity of a pharmaceutical composition prepared using other means. In some embodiments, the relative standard deviation of the homogeneity of the pharmaceutical composition is 100% less. In some embodiments, the relative standard deviation of the homogeneity of the pharmaceutical composition is 150% less. In some embodiments, the relative standard deviation of the homogeneity of the pharmaceutical composition is 200% less. In some embodiments, the pharmaceutical composition has a homogeneity from about 95% to about 105%. In some embodiments, the homogeneity is from about 97% to about 103%. In some embodiments, the homogeneity is from about 98% to about 102%. In some embodiments, the relative standard deviation (RSD) of the homogeneity of the pharmaceutical composition is less than 5%. In some embodiments, the relative standard deviation (RSD) of the homogeneity is less than 3%. In some embodiments, the relative standard deviation (RSD) of the homogeneity is less than 1%.

[038] In some embodiments, the excipient has a Carr’s Index of less than 25%. In some embodiments, the Carr’s index is less than 20%. In some embodiments, the Carr’s index is less than 15%. In some embodiments, the excipient has a tapped density of greater than 250 g/L. In some embodiments, the tapped density is greater than 400 g/L. In some embodiments, the tapped density is greater than 500 g/L. In some embodiments, the excipient has a tapped density from about 250 g/L to about 1500 g/L. In some embodiments, the tapped density is from about 400 g/L to about 1250 g/L. In some embodiments, the tapped density is from about 500 g/L to about 1000 g/L. In some embodiments, the excipient has a poured density of greater than 100 g/L. In some embodiments, the poured density is greater than 150 g/L. In some embodiments, the poured density is greater than 250 g/L. In some embodiments, the excipient has a poured density from about 100 g/L to about 1500 g/L. In some embodiments, the poured density is from about 200 g/L to about 1250 g/L. In some embodiments, the poured density is from about 250 g/L to about 1000 g/L.

[039] In various embodiments, the invention encompasses methods of preparing particles of one or more active agents dispersed within an excipient matrix including:

[040] (i) preparing a liquid phase comprising a dissolved excipient;

[041] (ii) adding an active agent to the liquid phase to obtain a liquid dispersion comprising an active agent dispersed in the liquid phase;

[042] (iii) subjecting the liquid dispersion to a reduced temperature surface such that the dispersion freezes to obtain a frozen dispersion; and

[043] (iv) subjecting the frozen dispersion to a drying process to obtain a pharmaceutical composition.

[044] In certain embodiments, the liquid phase comprises a non-solvent in which at least one of the one or more active agents is not dissolvable in the solvent and remains dispersed in the liquid phase.

[045] In certain embodiments, the active agent is engineered prior to addition in step (ii) above, for example, using a milling, grinding, anti-solvent precipitation, super critical CO2, or other appropriate engineering technology, to create a nano- or micron sized active particle.

[046] In certain embodiments, the active agent has a particle size of 10 micron or less.

[047] In certain embodiments, the method includes more than one active and at least one active is dispersed in the solvent and one or more of the additional actives are dissolved in the solvent .

[048] In certain embodiments, the liquid phase acts as a non-solvent to the dispersed active agent or agents.

[049] In certain embodiments, the non-solvent is an aqueous liquid, an organic liquid, or a combination thereof. [050] In certain embodiments, the liquid phase includes water, buffer salts, organic solvents, alcohols, ethers, halocarbons, hydrocarbons, halogenated hydrocarbons, aromatic hydrocarbons, esters, acetates, organic acids, amines, ketones, sulfones, nitriles, carbonates, or combinations thereof.

[051] In other embodiments, the organic solvent includes acetonitrile, tert-butanol, or 1,4- dioxane, or a combination thereof.

[052] In certain embodiments, the excipient is a sugar, a sugar alcohol, an amino acid, a flow enhancing agent, a polymer, or a combination thereof.

[053] In certain embodiments, the sugar is lactose, sucrose, maltose, trehalose, or a combination thereof.

[054] In certain embodiments, the sugar alcohol is mannitol.

[055] In certain embodiments, the amino acid is leucine, glycine, or a combination thereof.

[056] In certain embodiments, the flow enhancing agent is magnesium stearate.

[057] In certain embodiments, the polymer is polyvinylpyrrolidone having a molecular weight from about 10,000 to about 40,000.

[058] In certain embodiments, the active agent is small molecule active agent or a biologic active agent.

[059] In certain embodiments, the reduced temperature surface is maintained at a temperature below about -50 °C.

[060] In certain embodiments, the invention includes a porous matrix of engineered primary particles wherein the primary particles have a particle size of about 0.1 to about 500 micrometers (pm), of about 5 to about 100 pm, of less than 50 pm, of less than 20 pm.

[061] In certain embodiments, upon pulmonary delivery a sub-micron matrix of primary particles are fractured to release primary particles or aggregates of said primary particles. [062] In other embodiments, the invention encompasses compositions formulated using the methods disclosed herein including, for example, sub-micron particles, which are desirable for drug delivery because smaller particles provide a larger surface area/mass ratio for dissolution. [063] The present invention also provides a unit-dose delivery system used as a template for use in a dry powder inhaler including the composition formulated using the methods disclosed herein. The invention includes a unit-dose delivery system comprising one or more concave indentations; a cover positioned to sealed the one or more concave indentations; and a brittle matrix medicinal formulation appropriate for pulmonary delivery in at least one of the one or more concave indentations, wherein the brittle matrix medicinal formulation comprises a non- tightly packed porous flocculated web matrix comprising one or more brittle-matrix particles of one or more active agents, wherein a portion of the one or more brittle-matrix particles is delivered and templated by the formation of one or more particles upon atomization from the unit-dose delivery system using a dry powder inhaler to form a respirable porous particle for deep lung delivery.

[064] In other embodiments, the invention includes a formulation for use in a dry powder inhaler having a non-tightly packed porous flocculated web composition comprising one or more brittle-matrix particles of one or more active agents, wherein a portion of the one or more brittle-matrix particles is templated by a patient and/or device induced shearing energy to form a porous particle for deep lung delivery.

[065] In embodiments, the invention encompasses a thin film freezing method of preparing powders of one or more active agents dispersed within an excipient matrix comprising: [066] (i) preparing a liquid phase comprising an excipient;

[067] (ii) adding a pre-engineered active agent to the liquid phase to obtain a liquid dispersion comprising an active agent dispersed in the liquid phase; [068] (iii) subjecting the liquid dispersion to a reduced temperature surface such that the dispersion freezes to obtain a frozen dispersion; and

[069] (iv) subjecting the frozen dispersion to a drying process to obtain a pharmaceutical composition.

[070] In certain embodiments, the powder includes one or more pre-engineered microparticle or nano-particle active agents.

[071] In certain embodiments, the powder comprises pre-engineered active agent particles having an average particle size (D50) of from about 0.1 nm to about 900 microns.

[072] In certain embodiments, the powder comprises pre-engineered active agent particles having an average particle size (D50) of from about 1 nm to about 500 microns.

[073] In certain embodiments, the powder comprises pre-engineered active agent particles having an average particle size (D50) of from about 10 nm to about 100 microns.

[074] In certain embodiments, the powder comprises pre-engineered active agent particles having an average particle size (D50) of from about 25 nm to about 75 microns.

[075] In certain embodiments, the dispersion is a suspension in the liquid phase.

[076] In certain embodiments, the liquid phase is a non-solvent for the active agent.

[077] In certain embodiments, the pharmaceutical composition comprises from about 1% w/w to about 99% w/w of the active agent.

[078] In certain embodiments, the active agent has been pre-engineered to comprise an average particle size (D50) of about 10 microns to about 50 microns.

[079] In certain embodiments, the active agent has been pre-engineered to comprise an average particle size (D50) of about 50 nm to about 250 nm.

[080] In certain embodiments, the pharmaceutical composition comprises a drug load of from about 10% w/w to about 90% w/w of the active agent. [081] In certain embodiments, the pharmaceutical composition comprises a drug load of from about 5% w/w to about 20% w/w of the active agent and an FPF of about greater than 50%.

[082] In certain embodiments, the pharmaceutical composition comprises from about 2.5% w/w to about 80% w/w of the excipient.

[083] In other embodiments, the invention encompasses a method of preparing a pharmaceutical composition comprising:

[084] (i) obtaining a solution comprising an excipient in a liquid phase;

[085] (ii) adding one or more pre-engineered active agents to the liquid phase to obtain a dispersion (which includes the excipient and dispersed active agent );

[086] (iii) depositing the dispersion on a reduced temperature thin film freezing surface such that the dispersion freezes on the surface to obtain a frozen dispersion; and

[087] (iv) subjecting the frozen dispersion to a drying process to obtain a pharmaceutical composition.

[088] In certain embodiments, the pre-engineered API particles retain their particle size following completion of step (iv) to create a distribution of pre-engineered API particles within the a brittle matrix powder.

[089] In certain embodiments, the powder of one or more active agents is a pre-engineered micro-particle or nano-particle comprising an average particle size (D50) of from about 0.1 nm to about 900 microns.

[090] In certain embodiments, the pharmaceutical composition comprises from about 1% w/w to about 99% w/w of the active agent.

[091] In certain embodiments, the active agent has been pre-engineered to comprise an average particle size (D50) of about 10 microns to about 250 nm.

[092] In certain embodiments, the pharmaceutical composition comprises a drug load of from about 10% w/w to about 90% w/w of the active agent. [093] In certain embodiments, the pharmaceutical composition comprises a drug load of from about 5% w/w to about 20% w/w of the active agent and an FPF of about greater than 50%.

BRIEF DESCRIPTION OF THE FIGURES

[094] FIG. 1A-1C illustrates the appearance of exemplary micronized niclosamide suspensions.

[095] FIG. 2 illustrates the appearance of exemplary nanosized niclosamide suspensions.

[096] FIG. 3 illustrates aerodynamic particle size distribution of exemplary micronized niclosamide formulations that contained 10% drug loading.

[097] FIG. 4 illustrates aerodynamic particle size distribution of exemplary micronized niclosamide formulations that contained 20% drug loading.

[098] FIG. 5 illustrates aerodynamic particle size distribution of exemplary micronized niclosamide blend powder.

[099] FIG. 6 illustrates aerodynamic particle size distribution of exemplary nanosized niclosamide formulations than contained 10% drug loading.

[0100] FIG. 7 illustrates aerodynamic particle size distribution of exemplary nanosized niclosamide formulations that contained 20% drug loading

[0101] FIG. 8 illustrates aerodynamic particle size distribution of exemplary nanosized niclosamide formulations that contained higher than 20% drug loading.

[0102] FIG. 9 illustrates aerodynamic particle size distribution of exemplary nanosized niclosamide blended powder.

DETAILED DESCRIPTION OF THE INVENTION [0103] For a more complete understanding of the features and advantages of the present invention, reference is now made to the detailed description of the invention along with the examples and claims.

[0104] While the making and using of various embodiments of the present invention are discussed in detail below, it should be appreciated that the present invention provides many applicable inventive concepts that can be embodied in a wide variety of specific contexts. The specific embodiments discussed herein are merely illustrative of specific ways to make and use the invention and do not limit the scope of the invention.

[0105] To facilitate the understanding of this invention, a number of terms are defined below. Terms defined herein have meanings as commonly understood by a person of ordinary skill in the areas relevant to the present invention.

DEFINITIONS

[0106] Terms such as “a”, “an” and “the” are not intended to refer to only a singular entity, but include the general class of which a specific example may be used for illustration. The terminology herein is used to describe specific embodiments of the invention, but their usage does not delimit the invention, except as outlined in the claims.

[0107] As used herein, the term “about” when referring to a value includes the stated value +/- 10% of the stated value. For example, about 50% includes a range of from 45% to 55%, while about 20 molar equivalents includes a range of from 18 to 22 molar equivalents. Accordingly, when referring to a range, “about” refers to each of the stated values +/- 10% of the stated value of each end of the range. For instance, a ratio of from about 1 to about 3 (weight/weight) includes a range of from 0.9 to 3.3.

[0108] As used herein, the term “active pharmaceutical ingredient” and “active agent,” are used interchangeably and refer to a substance that can used in a finished pharmaceutical product (FPP), intended to furnish pharmacological activity or to otherwise have a direct effect in the diagnosis, cure, mitigation, treatment or prevention of disease, or to have a direct effect in restoring, correcting or modifying physiological functions in human beings. The “active pharmaceutical ingredient” and “active agent” may be a small molecule (e.g., an antibiotic or antifungal) or biologic (e.g., a protein, antibody, or mRNA) and can be used alone in the methods of compositions of the invention or may be included in an aqueous or organic solvent or a pharmaceutically acceptable excipient. It will be further appreciated that it is possible for one compound to be included in more than one class of active agents, for example, peptides and proteins.

[0109] As used herein, the term “administering” refers to administration of the composition of the present invention to a subject.

[0110] As used herein, the term “antisolvent precipitation” is an approach to produce nanoparticles of poorly water-soluble drugs by mixing a drug solution and an antisolvent.

[OHl] As used herein, “bioavailability” is a term meaning the degree to which a drug becomes available to the target tissue after being administered to the body. Poor bioavailability is a significant problem encountered in the development of pharmaceutical compositions, particularly those containing an active ingredient that is not highly soluble in water. In certain embodiments, the active agent may be water soluble, poorly soluble, not highly soluble or not soluble. The skilled artisan will recognize that various methodologies may be used to increase the solubility of the active agents (e.g., use of different solvents, excipients, excipients, glycosylation, lipidation, degradation, combination with one or more salts and the addition of various salts).

[0112] As used herein, the term “brittle matrix” refers to a non-tightly packed porous flocculated web matrix comprising one or more particles of one or more active agents. Brittle matrix formulations of the invention can, for example, be delivered and templated by the formation of the particles upon atomization from a dose-delivery system using a dry powder inhaler to form a respirable porous particle for deep lung delivery.

[0113] As used herein, the term “composition” as used herein is intended to encompass a product that includes one or more active pharmaceutical ingredients, and optionally one or more pharmaceutically acceptable excipients, excipients or diluents as described herein, such as in specified amounts defined throughout the originally filed disclosure, which results from combination of specific components, such as specified ingredients in the specified amounts as described herein.

[0114] As used herein, the term “cryogenic” means the system or process is maintained for a period of time (e.g., 1, 5, 15, 30, 60 minutes, or 1, 2, 3, 4, 5, 6, etc. hours) at a very low temperature, for example, a temperature of less than about -50°C. For example, a cryogenic source is a source that can initiate and/or maintain a temperature of at least -50 °C or lower.

[0115] As used herein, the term “fine particle fraction” is defined to mean is the portion of the delivered material (i.e., a formulation that contains respirable aggregates and particles, either drops, dry powder, or the like) that actually is delivered to the lung. The fine particle fraction depends not only upon the performance of the particles and respirable aggregates, but also on the performance of the delivery device. This fine particle fraction will generally comprise respirable aggregates having a mass median aerodynamic diameter of between about 1 and about 5 pm. This is the desired size for the drops that are delivered for a nebulizer or pressurized metered dose inhaler (pMDI), or dry powder for a dry powder inhaler (DPI), such drops or powder comprising the aggregates and particles.

[0116] As used herein, the term “cryomilling” or cryogenic grinding, also known as freezer milling, and freezer grinding is the act of cooling or chilling a material and then reducing it into a small particle size. [0117] As used herein, the term “drug load” or “drug loading” refers to the ratio of the amount of active agent to the excipient(s) included in the pharmaceutical formulation or the percentage (w/w) of active agent compared to all other components in the pharmaceutical composition.

[0118] As used herein, the term “fine particle fraction” or “FPF” refers to the fraction or percentage of the active agent or active pharmaceutical ingredient mass contained in an aerosol cloud that may be small enough to enter the lungs and exert a clinical effect.

[0119] As used herein, the term “maintained” means to keep about the same for a period of time (e.g., about 1, 5, 15, 30, 60 minutes, or 1, 2, 3, 4, 5, 6, etc. hours). For example, maintained at a temperature below -50°C means the temperature is kept below about -50°C for a period of time including, but not limited to, about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 20, 25, 30, 35, 40, 45, 50, 55, or 60 minutes or 1, 2, 3, 4, 5, 6, 8, 10, 12, 24 hours or all time intervals in between.

[0120] As used herein, the term “milling” or “pharmaceutically acceptable milling” refers to any technique including applying energy through mechanical forces to break down particles into smaller sizes. This can be accomplished by using grinding media, screens, pegs, pebbles, or rods; the process may also be described as grinding, granulation, size reduction, comminution, or pulverization. As particles are forced through the mill, they are torn or crushed, thus reducing their size. Milling is used for mechanical size reduction used to control the size of APIs, reagents, and excipients to optimize a drug’s delivery and performance. Whether wet or dry, milling increases the surface area of a solid, which increases its dissolution rate and, in turn, its bioavailability. It ensures that formulations are consistent from one batch to the next, and it can improve an API’s ability to mix with excipients. Milling is one of the most common techniques used to address poor solubility in a new drug compound, not only because it’s effective, but also because it’s inexpensive compared to other methods. For example, jet milling accelerates particles to supersonic speeds to achieve sub-micron particle distributions. Typically a compressed gas source is used for accelerating API particles in a tornado-like flow path within the grinding chamber of the jet mill. As particles travel in the circular path, particle-on-particle attrition is affected and particle size reduction occurs. Large particles continually migrate to the outside of the mill via centrifugal force, while micronized particles migrate to the center mill outlet via drag force. Another exemplary milling process includes ball milling, which operates on the principle of impact and attrition. Impact occurs between fast moving balls and the powder material while the attrition mode comes in action when the hollow cylinder rotates on its longitudinal axis. Wet Grinding, also known as wet milling, is a process of taking materials in a liquid form or slurry and reducing particles, such as agglomerates, by breaking them apart or shearing them down in size.

[0121] As used herein, the term “nanomilling” is the process by which the particle size of an API is reduced in a liquid vehicle (typically aqueous) via grinding using polymeric or ceramic media.

[0122] As used herein, the term “particle” is used to describe a particle comprising an active agent, such active agents being described below in more detail. The particles form individual units within a respirable aggregate, such that the respirable aggregate comprises one or more particles comprising the active agent, dispersed throughout the respirable aggregate.

[0123] As used herein, “precipitation” refers to methods to pre-engineer active particles. Precipitation techniques include anti-solvent precipitation, which is also sometimes referred to as desolvation, which comprises drawing-out precipitation or solvent displacement and is achieved by decreasing the quality of the solvent in which a solute (the active ingredient in this case) is dissolved. Another exemplary technique is the use of super critical CO2, in which the substance proposed to convert to a nanoparticle is dissolved in the supercritical carbon dioxide. The mixture is then sprayed through a nozzle for rapid expansion of carbon dioxide solutions. This leads to quick evaporation of carbon dioxide and generation of nanoparticles. [0124] As used herein, the term “pre-engineered” or “pre-engineered API” refers to an active agent or active pharmaceutical ingredient that has been generated in a particular particle size for a particular administrative route or for the treatment of a particular indication. For example, pre-engineered API (or active agent) can be micron or nano-sized particle. As used herein, the term “nano” includes an active agent having an average particle size (i.e., D50) of from about 0.1 nm to about 999.9 nm. As used herein, the terms “micro” or “micron” includes an active agent having an average particle size (z.e., D50) of from about 1 micron (i.e., micrometer) to about 999.9 microns. Pre-engineering of the API or active agent can be achieved by various techniques including pharmaceutically accepted milling (e.g., jet milling, ball milling, etc.), grinding (e.g., wet grinding, etc.), and precipitation (e.g., anti-solvent, super critical CO2, etc.) methods.

[0125] As used herein the term “respirable aggregate” is used to describe an aggregate of one or more particles, the aggregate having a surface area (when in dry form) of greater than 1 m ² /g. More preferably, the surface area of the respirable aggregate is greater than about 5 m ² /g, even more preferably greater than about 10 m ² /g, and yet even more preferably greater than about 20 m ² /g. A respirable aggregate may also comprise smaller engineered active agent particles, each active agent particle having a particle size of less than about 1 pm. A respirable aggregate may be, for example a dry powder or a dry powder dispersed in liquid, forming one or more droplets. The respirable aggregates of the present invention are also easily wettable, as demonstrated by contact angle measurements for disks formed by pressing the respirable aggregates into tablet form. Such contact angle measurements are less than about 50 degrees, preferably less than 40 degrees, more preferably less than about 30 degrees, and even more preferably less than 20 degrees. Furthermore, the respirable aggregates of the present invention, when dry, have a porosity of at least about 10 percent, more preferably at least 25 percent, even more preferably at least about 40%, still more preferably at least 60% and up to about 80%. The respirable aggregates of the present invention demonstrate a density of from about 0.1 g/mL to about 5 g/mL.

[0126] As used herein, the terms “therapeutically effective amount” or “effective amount” refers to an amount of an active pharmaceutical ingredient, active agent or drug substance useful for treating or ameliorating an identified disease or condition, or for exhibiting a detectable therapeutic or inhibitory effect. "Therapeutically effective amount" or “effective amount” further includes within its meaning a non-toxic but sufficient amount of the particular drug to which it is referring to provide the desired therapeutic effect. The exact amount required will vary from subject to subject depending on factors such as the subject’s general health, the patient's age, etc. The exact amounts will depend on the purpose of the treatment, and will be ascertainable by one skilled in the art using known techniques (see, e.g., Lieberman, Pharmaceutical Dosage Forms (vols. 1-3, 1992); Lloyd, The Art, Science and Technology of Pharmaceutical Compounding (1999); Pickar, Dosage Calculations (1999); and Remington: The Science andPractice of Pharmacy, 20th Edition, 2003, Gennaro, Ed., Lippincott, Williams & Wilkins).

[0127] As used herein, the terms “treat”, “treating” and “treatment” refer to any indicia of success in the treatment or amelioration of an injury, pathology or condition, including any objective or subjective parameter such as abatement; remission; diminishing of symptoms or making the injury, pathology or condition more tolerable to the patient; slowing in the rate of degeneration or decline; making the final point of degeneration less debilitating; improving a patient's physical or mental well-being. The treatment or amelioration of symptoms can be based on objective or subjective parameters; including the results of a physical examination, neuropsychiatric exams, and/or a psychiatric evaluation.

[0128] The abbreviation, “(w/w)” refers to the phrase “weight for weight”, i.e., the proportion of a particular substance within a mixture, as measured by weight or mass or a weight amount of a component of the composition disclosed herein relative to the total weight amount of the composition. Accordingly, the quantity is unit less and represents a weight percentage amount of a component relative to the total weight of the composition. For example, a 2% (w/w) solution means 2 grams of solute is dissolved in 100 grams of solution.

PHARMACEUTICAL COMPOSITIONS

[0129] In some embodiments, the present disclosure provides pharmaceutical compositions containing one or more particles wherein an active pharmaceutical ingredient has been deposited on the surface of the excipient and the pharmaceutical compositions comprise both the active pharmaceutical ingredient and the excipient as single particles. Additionally, these particles may be mixed with one or more additional excipients after the initial processing of the active pharmaceutical ingredient and the excipient. These pharmaceutical compositions may further comprise a pharmaceutical composition has been prepared in such a way that the particles may be agglomerated together. In another embodiment, the pharmaceutical compositions may further comprise a pharmaceutical composition has been prepared in such a way that the active pharmaceutical ingredient is present as a discrete domain on the excipient particles. These discrete domains may represent a nanostructured aggregate or other higher order structure to the pharmaceutical composition.

[0130] In some embodiments, the pharmaceutical composition may be defined by one or more favorable properties such as the specific surface area, mass median aerodynamic diameter (MMAD), the geometric standard deviation (GSD), fine particle fraction, emitted dose, homogeneity, critical primary pressure, Carr’s Index, tapped density, or poured density. The present pharmaceutical compositions prepared according to the methods described herein may have a specific surface area from about 2 m ² /g to about 100 m ² /g, from about 2.5 m ² /g to about 50 m ² /g, from about 2.5 m ² /g to about 25 m ² /g, or from about 2.5 m ² /g to about 10 m ² /g. The specific surface area of the composition may be from about 2 m ² /g, 2.5 m ² /g, 3 m ² /g, 4 m ² /g, 5 m ² /g, 6 m ² /g, 8 m ² /g, 10 m ² /g, 12.5 m ² /g, 15 m ² /g, 20 m ² /g, 25 m ² /g, 30 m ² /g, 40 m ² /g, 50 m ² /g, 75 m ² /g, to about 100 m ² /g, or any range derivable therein. The specific surface area may be determined by the single-point Braummer-Emmett-Teller (BET) method using a Monosorb rapid surface area analyzer. Furthermore, the specific surface area of the pharmaceutical compositions prepared using the methods described herein compared to a composition with the same components prepared using conventional powder blending may be 50% greater, 55% greater, 60% greater, 65% greater, 70% greater, 75% greater, 80% greater, 85% greater, 90% greater, 95% greater, 100% greater, or 125% greater.

[0131] Similarly, the present pharmaceutical compositions may have a MMAD that is from about from about 1.0 pm to about 10.0 pm, from about 1.5 pm to about 8.0 pm, or from about 2.0 pm to about 6.0 pm. The MMAD may be from about 0.5 pm, 1.0 pm, 1.5 pm, 2.0 pm, 2.5 pm, 3.0 pm, 3.5 pm, 4.0 pm, 4.5 pm, 5.0 pm, 6.0 pm, 7.5 pm, 8.0 pm, to about 10.0 pm, or any range derivable therein. The MMAD may be measured using laser diffraction as described in the Examples below. The MMAD of the pharmaceutical compositions prepared using the methods described herein compared to a composition with the same components prepared using conventional blending may be 20% less, 25% less, 30% less, 35% less, 40% less, 45% less, 50% less, 55% less, 60% less, 65% less, 70% less, 75% less, 80% less, 85% less, 90% less, 95% less, 100% less, or 125% less.

[0132] Additionally, the present pharmaceutical compositions may have a GSD that is from about 1.0 to about 10.0, from about 1.25 to about 8.0, or from about 1.5 to about 6.0. The GSD may be from about 0.5, 1.0, 1.5, 2.0, 2.5, 3.0, 3.5, 4.0, 4.5, 5.0, 6.0, 7.5, 8.0, to about 10.0, or any range derivable therein. The GSD may be measured using laser diffraction as described in the Examples below.

[0133] Similarly, the present pharmaceutical compositions prepared using the methods described herein may have a fine powder fraction that is 5% greater, 10% greater, 15% greater, 20% greater, 25% greater, 30% greater, 35% greater, 40% greater, 45% greater, 50% greater,

55% greater, 60% greater, 65% greater, 70% greater, 75% greater, 80% greater, or 90% greater. The fine particle fraction (FPF) of the recovered dose may be calculated as the total amount of drug collected with an aerodynamic diameter below 5 pm as a percentage of the total amount of drug collected. Similarly, the instant composition may have an emitted dose that is greater than 50%, greater than 60%, greater than 70%, greater than 80%, greater than 90%, greater than 95%, greater than 97%, or greater than 98%. The emitted fraction (EF) may be calculated as the total amount of drug emitted from the device as a percentage of total amount of drug collected.

[0134] Furthermore, the present compositions preferably have high degree of homogeneity compared to compositions prepared using other methods such conventional powder blending. The present compositions may have a homogeneity from about 95% to about 105%, from about 97% to about 103%, or from about 98% to about 102%. The homogeneity may be from about 90%, 92%, 95%, 96%, 97%, 98%, 99%, 100%, 101%, 102%, 103% 104%, 105%, 108%, or to about 110%, or any range derivable therein. Furthermore, the relative standard deviation of the homogeneity is less than 10%, less than 8%, less than 6%, less than 5%, less than 4%, less than 3%, less than 2%, or less than 1%. The homogeneity may be determined by performing the assay of drug in bulk powder and reported as the percentage of drug to the nominal dose. The relative standard deviation of the homogeneity may be calculated by the standard deviation of the drug percentage divided by the average of drug percentage. In some embodiments, the relative standard deviation of the homogeneity of the pharmaceutical compositions prepared using the present methods is less those prepared using conventional methods. The relative standard deviation of the homogeneity may be about 25% less, 30% less, 40% less, 50% less, 60% less, 75% less, 80% less, 100% less, 120% less, 125% less, 140% less, 150% less, 160% less, 175% less, 180% less, 200% less, or about 250% less. [0135] Furthermore, the pharmaceutical compositions when formulated into an inhaler or other similar device may have a critical primary pressure that is greater than a similar composition prepared by jet milling. The critical primary pressure represents a pressure that overcomes interparticulate forces and disperses powder to primary particles or smaller agglomerates. The critical primary pressure may be 5% greater, 10% greater, 15% greater, 20% greater, 25% greater, 30% greater, 40% greater, 50% greater, or 75% greater.

[0136] Finally, the present pharmaceutical compositions may have a Carr’s Index that is less than 30%, less than 25%, less than 20%, or less than 15%. Similarly, the composition may have a tapped density that is greater than 200 g/L, greater than 250 g/L, greater than 300 g/L, greater than 350 g/L, greater than 400 g/L, greater than 450 g/L, greater than 500 g/L, or greater than 750 g/L. The tapped density may be from about 250 g/L to about 1500 g/L, from about 400 g/L to about 1250 g/L, or from about 500 g/L to about 1000 g/L. The tapped density may be from about 200 g/L, 250 g/L, 300 g/L, 400 g/L, 450 g/L, 500 g/L, 550 g/L, 600 g/L, 700 g/L, 750 g/L, 800 g/L, 900 g/L, 1,000 g/L, 1,250 g/L, 1,400 g/L, 1,500 g/L, to about 1,600 g/L, or any range derivable therein. The poured density of the pharmaceutical composition may be from about 100 g/L to about 1500 g/L, from about 200 g/L to about 1250 g/L, or from about 250 g/L to about 1000 g/L. The poured density of the pharmaceutical composition may be from about 50 g/L, 100 g/L, 150 g/L, 200 g/L, 250 g/L, 300 g/L, 400 g/L, 450 g/L, 500 g/L, 550 g/L, 600 g/L, 700 g/L, 750 g/L, 800 g/L, 900 g/L, 1,000 g/L, 1,250 g/L, 1,400 g/L, 1,500 g/L, to about 1,600 g/L, or any range derivable therein. The poured density may be greater than about 100 g/L, 150 g/L, 200 g/L, 250 g/L, or 300 g/L. The poured and tapped density are measured according to a method modified from USP <616> method using a Tapped Density Tester and a 10-mL graduated cylinder. Carr’s (Compressibility) index are calculated based on USP General Chapter <616>.

Active Pharmaceutical Ingredient and Active Agents of the Invention [0137] The “active pharmaceutical ingredient” used in the present methods refers to any substance, compound, drug, medicament, or other primary active ingredient that provides a therapeutic or pharmacological effect when administered to a human or animal. In some embodiments, the pharmaceutical composition comprises from about 1% w/w to about 99% w/w, from about 2.5% w/w to about 90% w/w, from about 5% w/w to about 80% w/w, or from about 0.5% w/w, 1% w/w, 1.5% w/w, 2% w/w, 2.5% w/w, 5% w/w, 10% w/w, 15% w/w, 20% w/w, 30% w/w, 40% w/w, 50% w/w, 60% w/w, 70% w/w, 80% w/w, 90% w/w, 95% w/w, 98% w/w, to about 99% w/w of the active pharmaceutical ingredient, or any range derivable therein. In some embodiments, at least 60%, 80%, 85%, 90%, 95%, 97%, 98%, or 99% of the active pharmaceutical ingredient is in amorphous form. In other embodiments, at least 60%, 80%, 85%, 90%, 95%, 97%, 98%, or 99% of the active pharmaceutical ingredient is in crystalline form. In some embodiments, the active agent or active pharmaceutical ingredient has been pre-engineered to have a particular average diameter. In certain embodiments, the pre-engineered API (or active agent) can be micron or nano-sized particle. In certain embodiments, the active agent has an average diameter of about 0.1 nm to about 1000 microns, about 10 nm to about 500 microns; about 50 nm to about 250 microns, about 100 nm to about 100 microns. In certain embodiments, the active agent has an average particle size of about: 0.1 nm, 10 nm, 50 nm, 100 nm, 150 nm, 200 nm, 250 nm, 300 nm, 350 nm, 400 nm, 450 nm, 500 nm, 750 nm, 1 micron, 10 microns, 50 microns, 100 microns, 150 microns, 200 microns, 250 microns, 300 microns, 350 microns, 400 microns, 450 microns, 500 microns, 750 microns or 900 microns. In certain embodiments, the particles have an average particle size of less than about 10 microns, for example, about 1 to about 5 microns. In other embodiments, the particles have an average particle size of less than about 500 nm, for example, about 50 nm to about 250 nm. [0138] The pre-engineered active agents having a micro or nano scale particle size as disclosed herein can be generated, for example, by jet milling, wet milling, or antisolvent precipitation. The micro- or nano-sized particles when used in the methods of the invention have better loading and performance that active agents formulated using methods in the art.

[0139] Suitable active pharmaceutical ingredients may be any biologically active agents or a salt, isomer, ester, ether or other derivative, including prodrug, thereof, which include, but are not limited to, anticancer agents, antifungal agents, psychiatric agents such as analgesics, consciousness level-altering agents such as anesthetic agents or hypnotics, nonsteroidal antiinflammatory agents (NSAIDS), anthelminthics, antiacne agents, antianginal agents, anti arrhythmic agents, anti-asthma agents, antibacterial agents, anti-benign prostate hypertrophy agents, anticoagulants, antidepressants, antidiabetics, antiemetics, antiepileptics, antigout agents, antihypertensive agents, anti-inflammatory agents, antimalarials, antimigraine agents, antimuscarinic agents, antineoplastic agents, antiobesity agents, antiosteoporosis agents, antiparkinsonian agents, antiproliferative agents, antiprotozoal agents, antithyroid agents, antitussive agent, anti-urinary incontinence agents, antiviral agents, anxiolytic agents, appetite suppressants, beta agonists, beta-blockers, cardiac inotropic agents, chemotherapeutic drugs, cognition enhancers, contraceptives, corticosteroids, Cox-2 inhibitors, diuretics, erectile dysfunction improvement agents, expectorants, gastrointestinal agents, histamine receptor antagonists, immunosuppressants, keratolytics, lipid regulating agents, leukotriene inhibitors, macrolides, muscle relaxants, neuroleptics, nutritional agents, opioid analgesics, protease inhibitors, or sedatives.

[0140] Non-limiting examples of the active pharmaceutical ingredients may include 7- Methoxypteridine, 7-Methylpteridine, abacavir, abafungin, abarelix, acebutolol, acenaphthene, acetaminophen, acetanilide, acetazolamide, acetohexamide, acetretin, acrivastine, adenine, adenosine, al atr ofloxacin, albendazole, albuterol, alclofenac, aldesleukin, alemtuzumab, alfuzosin, alitretinoin, allobarbital, allopurinol, all-transretinoic acid (ATRA), aloxiprin, alprazolam, alprenolol, altretamine, amifostine, amiloride, aminoglutethimide, aminopyrine, amiodarone HC1, amitriptyline, amlodipine, amobarbital, amodiaquine, amoxapine, amphetamine, amphotericin, amphotericin B, ampicillin, amprenavir, amsacrine, amylnitrate, amylobarbitone, anastrozole, anrinone, anthracene, anthracyclines, aprobarbital, arsenic trioxide, asparaginase, aspirin, astemizole, atenolol, atorvastatin, atovaquone, atrazine, atropine, atropine azathioprine, auranofin, azacitidine, azapropazone, azathioprine, azintamide, azithromycin, aztreonum, baclofen, barbitone, BCG live, beclamide, beclomethasone, bendroflumethiazide, benezepril, benidipine, benorylate, benperidol, bentazepam, benzamide, benzanthracene, benzathine penicillin, benzhexol HC1, benznidazole, benzodiazepines, benzoic acid, bephenium hydroxynaphthoate, betamethasone, bevacizumab (avastin), bexarotene, bezafibrate, bicalutamide, bifonazole, biperiden, bisacodyl, bisantrene, bleomycin, bleomycin, bortezomib, brinzolamide, bromazepam, bromocriptine mesylate, bromperidol, brotizolam, budesonide, bumetanide, bupropion, busulfan, butalbital, butamben, butenafine HC1, butobarbitone, butobarbitone (butethal), butoconazole, butoconazole nitrate, butylparaben, caffeine, calcifediol, calciprotriene, calcitriol, calusterone, cambendazole, camphor, camptothecin, camptothecin analogs, candesartan, capecitabine, capsaicin, captopril, carbamazepine, carbimazole, carbofuran, carboplatin, carbromal, carimazole, carmustine, cefamandole, cefazolin, cefixime, ceftazidime, cefuroxime axetil, celecoxib, cephradine, cerivastatin, cetrizine, cetuximab, chlorambucil, chloramphenicol, chlordiazepoxide, chlormethiazole, chloroquine, chlorothiazide, chlorpheniramine, chlorproguanil HC1, chlorpromazine, chlorpropamide, chlorprothixene, chlorpyrifos, chlortetracycline, chlorthalidone, chlorzoxazone, cholecalciferol, chrysene, cilostazol, cimetidine, cinnarizine, cinoxacin, ciprofibrate, ciprofloxacin HC1, cisapride, cisplatin, citalopram, cladribine, clarithromycin, clemastine fumarate, clioquinol, clobazam, clofarabine, clofazimine, clofibrate, clomiphene citrate, clomipramine, clonazepam, clopidogrel, clotiazepam, clotrimazole, clotrimazole, cioxacillin, clozapine, cocaine, codeine, colchicine, colistin, conjugated estrogens, corticosterone, cortisone, cortisone acetate, cyclizine, cyclobarbital, cyclobenzaprine, cyclobutane-spirobarbiturate, cycloethane-spirobarbiturate, cycloheptane- spirobarbiturate, cyclohexane-spirobarbiturate, cyclopentane-spirobarbiturate, cyclophosphamide, cyclopropane-spirobarbiturate, cycloserine, cyclosporin, cyproheptadine, cyproheptadine HC1, cytarabine, cytosine, dacarbazine, dactinomycin, danazol, danthron, dantrolene sodium, dapsone, darbepoetin alfa, darodipine, daunorubicin, decoquinate, dehydroepiandrosterone, delavirdine, demeclocycline, denileukin, deoxycorticosterone, desoxymethasone, dexamethasone, dexamphetamine, dexchlorpheniramine, dexfenfluramine, dexrazoxane, dextropropoxyphene, diamorphine, diatrizoicacid, diazepam, diazoxide, dichlorophen, dichlorprop, diclofenac, dicumarol, didanosine, diflunisal, digitoxin, digoxin, dihydrocodeine, dihydroequilin, dihydroergotamine mesylate, diiodohydroxyquinoline, diltiazem HC1, diloxamide furoate, dimenhydrinate, dimorpholamine, dinitolmide, diosgenin, diphenoxylate HC1, diphenyl, dipyridamole, dirithromycin, disopyramide, disulfiram, diuron, docetaxel, domperidone, donepezil, doxazosin, doxazosin HC1, doxorubicin (neutral), doxorubicin HC1, doxycycline, dromostanolone propionate, droperidol, dyphylline, echinocandins, econazole, econazole nitrate, efavirenz, ellipticine, enalapril, enlimomab, enoximone, epinephrine, epipodophyllotoxin derivatives, epirubicin, epoetinalfa, eposartan, equilenin, equilin, ergocalciferol, ergotamine tartrate, erlotinib, erythromycin, estradiol, estramustine, estriol, estrone, ethacrynic acid, ethambutol, ethinamate, ethionamide, ethopropazine HC1, ethyl-4-aminobenzoate (benzocaine), ethylparaben, ethinylestradiol, etodolac, etomidate, etoposide, etretinate, exemestane, felbamate, felodipine, fenbendazole, fenbuconazole, fenbufen, fenchlorphos, fenclofenac, fenfluramine, fenofibrate, fenoldepam, fenoprofen calcium, fenoxycarb, fenpiclonil, fentanyl, fenti conazole, fexofenadine, filgrastim, finasteride, flecamide acetate, floxuridine, fludarabine, fluconazole, fluconazole, flucytosine, fludioxonil, fludrocortisone, fludrocortisone acetate, flufenamic acid, flunanisone, flunarizine HC1, flunisolide, flunitrazepam, fluocortolone, fluometuron, fluorene, fluorouracil, fluoxetine HC1, fluoxymesterone, flupenthixol decanoate, fluphenthixol decanoate, flurazepam, flurbiprofen, fluticasone propionate, fluvastatin, folic acid, fosenopril, fosphenytoin sodium, frovatriptan, furosemide, fulvestrant, furazolidone, gabapentin, G-BHC (Lindane), gefitinib, gemcitabine, gemfibrozil, gemtuzumab, glafenine, glibenclamide, gliclazide, glimepiride, glipizide, glutethimide, glyburide, Glyceryltrinitrate (nitroglycerin), goserelin acetate, grepafloxacin, griseofulvin, guaifenesin, guanabenz acetate, guanine, halofantrine HC1, haloperidol, hydrochlorothiazide, heptabarbital, heroin, hesperetin, hexachlorobenzene, hexethal, histrelin acetate, hydrocortisone, hydroflumethiazide, hydroxyurea, hyoscyamine, hypoxanthine, ibritumomab, ibuprofen, idarubicin, idobutal, ifosfamide, ihydroequilenin, imatinib mesylate, imipenem, indapamide, indinavir, indomethacin, indoprofen, interferon alfa-2a, interferon alfa-2b, iodamide, iopanoic acid, iprodione, irbesartan, irinotecan, isavuconazole, isocarboxazid, isoconazole, isoguanine, isoniazid, isopropylbarbiturate, isoproturon, isosorbide dinitrate, isosorbide mononitrate, isradipine, itraconazole (Itra), ivermectin, ketoconazole, ketoprofen, ketorolac, khellin, labetalol, lamivudine, lamotrigine, lanatoside C, lanosprazole, L-DOPA, leflunomide, lenalidomide, letrozole, leucovorin, leuprolide acetate, levamisole, levofloxacin, lidocaine, linuron, lisinopril, lomefloxacin, lomustine, loperamide, loratadine, lorazepam, lorefloxacin, lormetazepam, losartan mesylate, lovastatin, lysuride maleate, Maprotiline HC1, mazindol, mebendazole, Meclizine HC1, meclofenamic acid, medazepam, medigoxin, medroxyprogesterone acetate, mefenamic acid, Mefloquine HC1, megestrol acetate, melphalan, mepenzolate bromide, meprobamate, meptazinol, mercaptopurine, mesalazine, mesna, mesoridazine, mestranol, methadone, methaqualone, methocarbamol, methoin, methotrexate, methoxsalen, methsuximide, methyclothiazide, methylphenidate, methylphenobarbitone, methyl-p-hydroxybenzoate, methylprednisolone, methyltestosterone, methyprylon, methysergide maleate, metoclopramide, metolazone, metoprolol, metronidazole, Mianserin HC1, miconazole, midazolam, mifepristone, miglitol, minocycline, minoxidil, mitomycin C, mitotane, mitoxantrone, mofetilmycophenolate, molindone, montelukast, morphine, Moxifloxacin HC1, nabumetone, nadolol, nalbuphine, nalidixic acid, nandrolone, naphthacene, naphthalene, naproxen, naratriptan HC1, natamycin, nelarabine, nelfinavir, nevirapine, nicardipine HC1, niclosamide, nicotin amide, nicotinic acid, nicoumalone, nifedipine, nilutamide, nimodipine, nimorazole, nisoldipine, nitrazepam, nitrofurantoin, nitrofurazone, nizatidine, nofetumomab, nor ethisterone, norfloxacin, norgestrel, nortriptyline HC1, nystatin, oestradiol, ofloxacin, olanzapine, omeprazole, omoconazole, ondansetron HC1, oprelvekin, ornidazole, oxaliplatin, oxamniquine, oxantel emb onate, oxaprozin, oxatomide, oxazepam, oxcarbazepine, oxfendazole, oxiconazole, oxprenolol, oxyphenbutazone, oxyphencyclimine HC1, paclitaxel, palifermin, pamidronate, p-aminosalicylic acid, pantoprazole, paramethadione, paroxetine HC1, pegademase, pegaspargase, pegfilgrastim, pern etrexeddi sodium, penicillamine, pentaerythritol tetranitrate, pentazocin, pentazocine, pentobarbital, pentobarbitone, pentostatin, pentoxifylline, perphenazine, perphenazine pimozide, perylene, phenacemide, phenacetin, phenanthrene, phenindione, phenobarbital, phenolbarbitone, phenolphthalein, phenoxybenzamine, phenoxybenzamine HC1, phenoxymethyl penicillin, phensuximide, phenylbutazone, phenytoin, pindolol, pioglitazone, pipobroman, piroxicam, pizotifen maleate, platinum compounds, plicamycin, polyenes, polymyxin B, porfimersodium, posaconazole (Posa), pramipexole, prasterone, pravastatin, praziquantel, prazosin, prazosin HC1, prednisolone, prednisone, primidone, probarbital, probenecid, probucol, procarbazine, prochlorperazine, progesterone, proguanil HC1, promethazine, propofol, propoxur, propranolol, propylparaben, propylthiouracil, prostaglandin, pseudoephedrine, pteridine-2- methyl-thiol, pteridine-2-thiol, pteridine-4-methyl-thiol, pteridine-4-thiol, pteridine-7-methyl- thiol, pteridine-7-thiol, pyrantel emb onate, pyrazinamide, pyrene, pyridostigmine, pyrimethamine, quetiapine, quinacrine, quinapril, quinidine, quinidine sulfate, quinine, quininesulfate, rabeprazole sodium, ranitidine HC1, rasburicase, ravuconazole, repaglinide, reposal, reserpine, retinoids, rifabutine, rifampicin, rifapentine, rimexolone, risperidone, ritonavir, rituximab, rizatriptan benzoate, rofecoxib, ropinirole HC1, rosiglitazone, saccharin, salbutamol, salicylamide, salicylic acid, saquinavir, sargramostim, secbutabarbital, secobarbital, sertaconazole, sertindole, sertraline HC1, simvastatin, sirolimus, sorafenib, sparfloxacin, spiramycin, spironolactone, stanolone, stanozolol, stavudine, stilbestrol, streptozocin, strychnine, sulconazole, sulconazole nitrate, sulfacetamide, sulfadiazine, sulfamerazine, sulfamethazine, sulfamethoxazole, sulfanilamide, sulfathiazole, sulindac, sulphabenzamide, sulphacetamide, sulphadiazine, sulphadoxine, sulphafurazole, sulphamerazine, sulpha-methoxazole, sulphapyridine, sulphasalazine, sulphinpyrazone, sulpiride, sulthiame, sumatriptan succinate, sunitinib maleate, tacrine, tacrolimus, talbutal, tamoxifen citrate, tamulosin, targretin, taxanes, tazarotene, telmisartan, temazepam, temozolomide, teniposide, tenoxicam, terazosin, terazosin HC1, terbinafine HC1, terbutaline sulfate, terconazole, terfenadine, testolactone, testosterone, tetracycline, tetrahydrocannabinol, tetroxoprim, thalidomide, thebaine, theobromine, theophylline, thiabendazole, thi amphenicol, thioguanine, thioridazine, thiotepa, thotoin, thymine, tiagabine HC1, tibolone, ticlopidine, tinidazole, tioconazole, tirofiban, tizanidine HC1, tolazamide, tolbutamide, tolcapone, topiramate, topotecan, toremifene, tositumomab, tramadol, trastuzumab, trazodone HC1, tretinoin, triamcinolone, triamterene, triazolam, triazoles, triflupromazine, trimethoprim, trimipramine maleate, triphenylene, troglitazone, tromethamine, tropicamide, trovafloxacin, tybamate, ubidecarenone (coenzyme Q10), undecenoic acid, uracil, uracil mustard, uric acid, valproic acid, valrubicin, valsartan, vancomycin, venlafaxine HC1, vigabatrin, vinbarbital, vinblastine, vincristine, vinorelbine, voriconazole, xanthine, zafirlukast, zidovudine, zileuton, zoledronate, zoledronic acid, zolmitriptan, zolpidem, and zopiclone.

[0141] In particular aspects, the active pharmaceutical ingredients may be voriconazole or other members of the general class of azole compounds. Exemplary antifungal azoles include a) imidazoles such as miconazole, ketoconazole, clotrimazole, econazole, omoconazole, bifonazole, butoconazole, fenti conazole, isoconazole, oxiconazole, sertaconazole, sulconazole and tioconazole, b) triazoles such as fluconazole, itraconazole, isavuconazole, ravuconazole, posaconazole, voriconazole, terconazole and c) thiazoles such as abafungin. Other drugs that may be used with this approach include, but are not limited to, hyperthyroid drugs such as carimazole, anticancer agents like cytotoxic agents such as epipodophyllotoxin derivatives, taxanes, bleomycin, anthracyclines, as well as platinum compounds and camptothecin analogs. The following active pharmaceutical ingredients may also include other antifungal antibiotics, such as poorly water-soluble echinocandins, polyenes (e.g., Amphotericin B and Natamycin) as well as antibacterial agents (e.g., polymyxin B and colistin), and anti-viral drugs. The agents may also include a psychiatric agent such as an antipsychotic, anti-depressive agent, or analgesic and/or tranquilizing agents such as benzodiazepines. The agents may also include a consciousness level-altering agent or an anesthetic agent, such as propofol. The present compositions and the methods of making them may be used to prepare pharmaceutical compositions with the appropriate pharmacokinetic properties for use as therapeutics.

[0142] In some aspects, the pharmaceutically active ingredient is an immune system modulating compound. The compound may be an immunosuppressive agent such as tacrolimus. Tacrolimus (TAC) is a widely used immunosuppressive agent isolated from Streptomyces tsukubaensis . It has proven to be a potent immunosuppressant in transplantation medicine for treatment of organ rejection and different immunological diseases such as pulmonary fibrosis and bronchiolar asthma. TAC was first introduced as rescue therapy when cyclosporin A (CsA) therapy failed to prevent graft rejection. It has a mechanism of action similar to that of CsA, but its immunosuppressive activity is 10- to 100-times more potent than CsA. TAC is currently available in both an intravenous and oral dosage form (commercially known as Prograf®). However, these current available dosage forms of the drug are poorly tolerated and provide a variable and/or low bioavailability. The oral formulations of TAC present a considerable challenge as the drugs are practically insoluble in water and extensively metabolized from both CYP3A4 metabolism and p-glycoprotein efflux transport within the intestinal epithelium. The oral bioavailability of TAC varies from 4% to 93%. Inefficient or erratic drug absorption is primarily the result of incomplete absorption from the gastrointestinal tract and first-pass metabolism, which is subject to considerable inter-individual variation.

[0143] In some embodiments, the active pharmaceutical ingredient is niclosamide. Niclosamide is a poorly water soluble, lipophilic molecule previously known to have poor and variable bioavailability which for its current approved indication for treating helminthic infections in the gastrointestinal tract is not a limiting factor. When attempting to repurpose the medication for the treatment of diseases such as prostate cancer or viral infections, which require systemic concentrations and/or lung concentrations of the drug, the challenges to overcome the bioavailability limitations become clear. As niclosamide is both poorly water soluble and lipophilic, the rate limiting step for the oral absorption of the drug is the dissolution of the molecule. This drug also has a number of other potential uses including as a treatment of viral infections such as SARS-CoV-2 and MERS.

[0144] Unfortunately, the majority of drugs that show pharmacological activity against cancers in vitro are poorly water-soluble and thus exhibit poor or no bioavailability. While often not a limitation for their currently approved indications, their usefulness in treating cancers often requires significantly better absorption of the drugs to achieve drug concentrations sufficient for tumor inhibition. These pharmaceutical compositions need mechanisms that may be used to overcome the limitations of solubility by the pharmaceutical industry in 19 commercial products approved by the Food & Drug Administration between 2007 and 2017.

Inhalation

[0145] In some embodiments, the present disclosure relates to respirable particles must be within a particular aerodynamic size range. In some embodiments, the pharmaceutical composition has a MMAD of from about 0.1 to 10.0 microns, from about or 1.5 to about 8 microns, from about 2.0 to about 6.0 microns, or from about 0.5 microns, 1.0 microns, 1.5 microns, 2.0 microns, 2.5 microns, 3.0 microns, 3.5 microns, 4.0 microns, 4.5 microns, 5.0 microns, 6.0 microns, 8.0 microns, 10.0 microns, to about 15.0 microns, or any range derivable therein. In some embodiments, the present disclosure provides methods for the administration of the inhalable pharmaceutical composition provided herein using a device. Administration may be, but is not limited, to inhalation of pharmaceutical using an inhaler. In some embodiments, an inhaler is a simple passive dry powder inhaler (DPI), such as a Plastiape RS01 monodose DPI. In a conventional dry powder inhaler, dry powder is stored in a capsule or reservoir and is delivered to the lungs by inhalation without the use of propellants.

[0146] In some embodiments, an inhaler is a single use, disposable inhaler such as a singledose DPI, such as a DoseOne™, Spinhaler, Rotohaler®, Aerolizer®, or Handihaler. These dry powder inhalers may be a passive DPI. In some embodiments, an inhaler is a multidose DPI, such as a Plastiape RS02, Turbuhaler®, Twisthaler™, Diskhaler®, Diskus®, or Ellipta™. In some embodiments, the inhaler is Twincer®, Orbital®, TwinCaps®, Powdair, Cipla Rotahaler, DP Haler, Revolizer, Multi -haler, Twister, Starhaler, or Flexhaler®. In some embodiments, an inhaler is a plurimonodose DPI for the concurrent delivery of single doses of multiple medications, such as a Plastiape RS04 plurimonodose DPI. Dry powder inhalers have medication stored in an internal reservoir, and medication is delivered by inhalation with or without the use of propellants. Dry powder inhalers may require an inspiratory flow rate greater than 30 L/min for effective delivery, such as between about 30-120 L/min.

[0147] In some embodiments, the inhaler may be a metered dose inhaler. Metered dose inhalers deliver a defined amount of medication to the lungs in a short burst of aerosolized medicine aided by the use of propellants. Metered dose inhalers comprise three major parts: a canister, a metering valve, and an actuator. The medication formulation, including propellants and any required excipients, are stored in the canister. The metering valve allows a defined quantity of the medication formulation to be dispensed. The actuator of the metered dose inhaler, or mouthpiece, contains the mating discharge nozzle and typically includes a dust cap to prevent contamination. In some embodiments, the inhalable pharmaceutical composition is delivered as a propellant formulation, such as HFA propellants.

[0148] In some embodiments, an inhaler is a nebulizer or a soft-mist inhaler such as those described in PCT Publication No. WO 1991/14468 and WO 1997/12687, which are incorporated herein by reference. A nebulizer is used to deliver medication in the form of an aerosolized mist inhaled into the lungs. The medication formulation be aerosolized by compressed gas, or by ultrasonic waves. A jet nebulizer is connected to a compressor. The compressor emits compressed gas through a liquid medication formulation at a high velocity, causing the medication formulation to aerosolize. Aerosolized medication is then inhaled by the patient. An ultrasonic wave nebulizer generates a high frequency ultrasonic wave, causing the vibration of an internal element in contact with a liquid reservoir of the medication formulation, which causes the medication formulation to aerosolize. Aerosolized medication is then inhaled by the patient. In some embodiments, the single use, disposable nebulizer may be used herein. A nebulizer may utilize a flow rate of between about 3-12 L/min, such as about 6 L/min. In some embodiments, the nebulizer is a dry powder nebulizer. [0149] In some embodiments, the composition may be administered on a routine schedule. As used herein, a routine schedule refers to a predetermined designated period of time. The routine schedule may encompass periods of time which are identical, or which differ in length, as long as the schedule is predetermined. For instance, the routine schedule may involve administration four times a day, three times a day, twice a day, every day, every two days, every three days, every four days, every five days, every six days, a weekly basis, a monthly basis or any set number of days or weeks there-b etween. Alternatively, the predetermined routine schedule may involve administration on a twice daily basis for the first week, followed by a daily basis for several months, etc. In some embodiments, the pharmaceutical composition is administered once per day. In preferred embodiments, the pharmaceutical composition is administered less than once per day, such as every other day, every third day, or once per week.

[0150] In some embodiments, the amount of the pharmaceutical composition of the nebulizer or inhaler may be provided in a unit dosage form, such as in a capsule, blister or a cartridge, wherein the unit dose comprises at least 0.05 mg of the pharmaceutical composition, such as at least 0.075 mg or 0.100 mg of the pharmaceutical composition per dose. In particular aspects, the unit dosage form does not comprise the administration or addition of any excipient and is merely used to hold the powder for inhalation (i.e., the capsule, blister, or cartridge is not administered). In some embodiments, the entire amount of the powder load may be administered in a high emitted dose, such as at least 1 mg, preferably at least 10 mg, even more preferably 50 mg. In some embodiments, administration of the powder load results in a high fine particle dose into the deep lung such as greater than 1 mg. Preferably, the fine particle dose into the deep lung is at least 5 mg, even more preferably at least 10 mg. In some embodiments, the dose may further comprise using a dose from a reservoir or non-unit dose form and the relevant dose is metered out from the device such as a Turbuhaler. Excipients

[0151] In some embodiments, the present disclosure comprises one or more excipients formulated into pharmaceutical compositions. An “excipient,” also commonly known as pharmaceutically acceptable excipients, diluents or bulking agents, are relatively inert substances used to facilitate administration or delivery of an API into a subject or used to facilitate processing of an API into drug formulations that can be used pharmaceutically for delivery to the site of action in a subject. Furthermore, these compounds may be used as diluents in order to obtain a dosage that can be readily measured or administered to a patient. Non-limiting examples of excipients include polymers, stabilizing agents, surfactants, surface modifiers, solubility enhancers, buffers, encapsulating agents, antioxidants, preservatives, nonionic, anionic and cationic wetting or clarifying agents, viscosity increasing agents, pH adjusting agents and absorption-enhancing agents. In some embodiments, the pharmaceutical composition comprises from about 1% w/w to about 99% w/w, from about 10% w/w to about 95% w/w, from about 15% w/w to about 90% w/w, or from about 1% w/w, 2.5% w/w, 5% w/w, 10% w/w, 15% w/w, 20% w/w, 25% w/w, 30% w/w, 35% w/w, 40% w/w, 45% w/w, 50% w/w, 55% w/w, 60% w/w, 65% w/w, 70% w/w, 75% w/w, 80% w/w, 85% w/w, 80% w/w, 92% w/w, 94% w/w, 95% w/w, 97% w/w, to about 99% w/w of the excipient, or any range derivable therein. In some embodiments, at least 60%, 80%, 85%, 90%, 95%, 97%, 98%, or 99% of the excipient is in amorphous form. In other embodiments, at least 60%, 80%, 85%, 90%, 95%, 97%, 98%, or 99% of the excipient is in crystalline form.

[0152] In some embodiments, the pharmaceutical compositions of the present disclosure may further comprise one or more excipients, such as a sugar or sugar alcohol. The compositions may also further comprise one or more additional excipients such as a lubricant, a glidant, or an amino acid. Furthermore, one or more flow enhancing agents such as magnesium salts may be used. A non-limiting example of a flow enhancing agent is magnesium stearate. In other embodiments, the compositions may further comprise one or more silicon dioxides or silicas. Such silica could be a fumed silica or another form of silica that is approved for use in inhalation treatments. In other aspects, larger molecules like amino acids, peptides and proteins are incorporated to facilitate inhalation delivery, including leucine, trileucine, histidine and others. Some non-limiting examples of amino acids include hydrophobic amino acids, such as leucine.

[0153] Some compositions may further comprise a mixture of two or more excipients. In some embodiments, the amount of the further excipient may be from about 0.05% w/w to about 50% w/w, from about 1% w/w to about 15% w/w, or from about 2.5% w/w to about 10% w/w. In some embodiments, the amount of the additional excipient is from about 0.05% w/w, 0.1% w/w, 0.25% w/w, 0.5% w/w, 0.75% w/w, 1.0% w/w, 1.5% w/w, 2.0% w/w, 2.5% w/w, 3.0% w/w, 4.0% w/w, 5.0% w/w, 6.0% w/w, 8.0% w/w, 10% w/w, 15% w/w, 20% w/w, 25% w/w, 30% w/w, 40% w/w, to about 50% w/w, or any range derivable therein.

Saccharide Excipients

[0154] In some embodiments, the present disclosure comprises one or more excipients as excipients formulated into pharmaceutical compositions. These excipients include carbohydrates or saccharides such as disaccharides such as sucrose, trehalose, or lactose, a trisaccharide such as fructose, glucose, galactose comprising raffinose, polysaccharides such as starches or cellulose, or a sugar alcohol such as xylitol, sorbitol, or mannitol. In some embodiments, these excipients are solid at room temperature. Some non-limiting examples of sugar alcohols include erythritol, threitol, arabitol, xylitol, ribitol, mannitol, sorbitol, galactitol, fucitol, iditol, inositol, volemitol, isomalt, maltitol, lactitol, maltotritol, maltotetraitol, or a polyglycitol. In some aspects, the excipients used herein are soluble in the solvent used to prepare the pharmaceutical composition. The excipients may slightly soluble, very soluble, or completely soluble. The solubility of the excipient in the solvent system are described using the solubility standards established in the U.S. Pharmacopeia.

Polymers

[0155] In some embodiments, the excipient is a pharmaceutically acceptable polymer. In some embodiments, the excipient is a non-cellulosic polymer. In some embodiments, the excipient is a non-ionizable non cellulosic polymer, such as polyvinylpyrrolidone. In some embodiments, the polyvinylpyrrolidone has a molecular weight from about 10,000 to about 40,000 or from about 20,000 to about 30,000. In some embodiments, the polyvinylpyrrolidone has a molecular weight from about 10,000, 12,000, 14,000, 16,000, 18,000, 20,000, 22,000, 24,000, 26,000, 28,000, 30,000, 32,000, 34,000, 36,000, 38,000, to about 40,000, or any range derivable therein. In some embodiments the polyvinylpyrrolidone has a molecular weight of about 24,000.

MANUFACTURING METHODS

Thin-Film Freezing

[0156] Without wishing to be bound by any theory, it is believed that this process may be used to introduce the particles into a single particle containing one or more active pharmaceutical ingredients and the excipient into the same particle. In particular, if multiple therapeutic agents are present in the composition, the particles contain two or more of the active pharmaceutical ingredients. The particles obtained from this process may exhibit one or more beneficial properties for administration via inhalation such as a high surface area, a low tapped density, a low poured density, or improved flowability or compressibility such as a low Carr’s Index. The method comprises dissolving the excipient into a solvent then adding one or more active agents into the solvent containing the excipient to form a dispersion in which the active agent is not dissolved. The solvent may be an organic solvent such as acetonitrile, dioxane, or an alcohol such as isopropanol or butanol. The organic solvent is a polar aprotic solvent wherein the solvent lacks an acidic proton but contains one or more polar bonds. These solvents may also include tetrahydrofuran, dimethylformamide, or dimethylsulfoxide. In some embodiments, the solvent may be a mixture of two or more solvents.

[0157] In some embodiments, the method further comprises dropping the dispersion onto a surface that has been cooled to a first reduced temperature. In some embodiments, the first reduced temperature is from about -10 °C to about -120 °C, from about -20 °C to about -100 °C, from about -60 °C to about -90 °C, or from about -150 °C, -125 °C, -120 °C, -110 °C, -100 °C, -75 °C, -50 °C, -25 °C, or 0 °C, or any range derivable therein. In some embodiments, the dispersion is applied from a height from about 1 cm to about 250 cm, from about 2.5 cm to about 100 cm, from about 5 cm to about 50 cm, or from about 0.5 cm, 1 cm, 1.5 cm, 2 cm, 2.5 cm, 5 cm, 10 cm, 15 cm, 20 cm, 25 cm, 50 cm, 75 cm, 100 cm, 150 cm, 200 cm, 250 cm, to about 300 cm, or any range derivable therein. In some embodiments, the surface rotates at a speed. In some embodiments, the speed is from about 5 rpm to about 500 rpm, from about 25 rpm to about 400 rpm, from about 50 rpm to about 250 rpm, from about 50 rpm to about 150 rpm, or from about 5 rpm, 10 rpm, 15 rpm, 20 rpm, 25 rpm, 50 rpm, 75 rpm, 100 rpm, 150 rpm, 200 rpm, 250 rpm, 300 rpm, 400 rpm, to about 500 rpm, or any range derivable therein.

[0158] In some embodiments, the drying process comprises lyophilization. In some embodiments, the drying process comprises two drying cycles. In some embodiments, the first drying cycle comprises drying at a first temperature from about -120 °C to about 0 °C, from about -10 °C to about -80 °C, from about -20 °C to about -60 °C, or from about -150 °C, -125 °C, -120 °C, -110 °C, -100 °C, -90 °C, -80 °C, -70 °C, -60 °C, -50 °C, -40 °C, -30 °C, -20 °C, -10 °C, to about 0 °C, or any range derivable therein. In some embodiments, the pharmaceutical composition is dried at a first reduced pressure from about 10 mTorr to 500 mTorr, from about 25 mTorr to about 250 mTorr, from about 50 mTorr to about 150 mTorr, or from about 5 mTorr, 6 mTorr, 7 mTorr, 8 mTorr, 9 mTorr, 10 mTorr, 20 mTorr, 25 mTorr, 50 mTorr, 100 mTorr, 150 mTorr, 200 mTorr, 250 mTorr, 300 mTorr, 350 mTorr, 400 mTorr, 450 mTorr, to about 500 mTorr, or any range derivable therein.

[0159] In some embodiments, the second drying cycle comprises drying at a second temperature from about 0 °C to about 80 °C, from about 10 °C to about 60 °C, from about 20 °C to about 50 °C, or from about 0 °C, 10 °C, 20 °C, 30 °C, 40 °C, 50 °C, 60 °C, 70 °C, to about 80 °C, or any range derivable the rein. In some embodiments, the second drying cycle comprises drying at a reduced pressure. In some embodiments, the pharmaceutical composition is dried at a second reduced pressure from about 10 mTorr to 500 mTorr, from about 25 mTorr to about 250 mTorr, from about 50 mTorr to about 150 mTorr, or from about 10 mTorr, 15 mTorr, 20 mTorr, 25 mTorr, 50 mTorr, 75 mTorr, 100 mTorr, 150 mTorr, 200 mTorr, 250 mTorr, 300 mTorr, 350 mTorr, 400 mTorr, 450 mTorr, to about 500 mTorr, or any range derivable therein.

[0160] In other embodiments, the invention includes compositions and method for preparing micron-sized or submicron-sized particles by dispersing one or more active agents in a liquid phase comprising one or more excipients dissolved in one or more solvents to form an active agent dispersed in a solvent including a dissolved excipient; spraying or dripping droplets dispersion such that the active agent is exposed to an vapor-liquid interface of less than about 50, 100, 150, 200, 250, 300, 400 or even 500 cm ^-1 area/volume; and contacting or dispersing the droplet onto a freezing surface that has a temperature differential of at least 30° C between the droplet and the surface, wherein the surface freezes the droplet into a thin film with a thickness of less than 500 micrometers and a surface area to volume between about 25 to about 500 cm ^-1 .

[0161] In one embodiment, the method further includes the step of removing the solvent from the frozen material to form particles. In another embodiment, the droplets freeze upon contact with the surface in about 50, 75, 100, 125, 150, 175, 200, 250, 500, 1,000 and 2,000 milliseconds. In another aspect, the droplets freeze upon contact with the surface in about 50 and 150 milliseconds. In another aspect, the droplet has a diameter between 2 and 5 mm at room temperature. In another aspect, the droplet forms a thin film on the surface of between 50 and 500 micrometers in thickness. In another aspect, the droplets have a cooling rate of between 50-250 °C/s. In another aspect, the particles after solvent removal have a surface area of 10, 15, 25, 50, 75, 100, 125, 150 or 200 m ² /gr.

[0162] Another embodiment of the invention includes a method for preparing micron-sized or submicron-sized solvent particles including: engineering an active agent using, for example, nanomilling or cryomilling, preparing a liquid phase including one or more excipients dissolved in an aqueous or organic solvent or combination thereof, adding the engineered active agent to the liquid phase, and contacting the droplet with a freezing surface that has a temperature differential of at least 30 °C between the droplet and the surface, wherein the droplet freezes into a thin film with a thickness of less than 500 micrometers and a surface area to volume between 25 to 500 cm ^-1 . The method may further include the step of removing the solvent from the frozen material to form particles

[0163] In one embodiment, the invention includes a liquid dispersion with one or more dissolved excipients and one or more active agents that are micron-sized or submicron-sized: spraying or dripping droplets of an dispersed active agent and one or more excipients in a solvent or solvents, wherein the droplet is exposed to an vapor-liquid interface of less than 50 cm ^-1 area/volume; contacting the droplet with a freezing surface that has a temperature differential of at least 30 °C between the droplet and the surface, wherein the droplet freezes into a thin film with a thickness of less than 500 micrometers and a surface area to volume between 25 to 500 cm ^-1 . [0164] Yet another embodiment includes compositions and methods for preparing micronsized or submicron-sized particles by preparing an emulsion including a non-water soluble active agent; and contacting the droplet with a freezing surface that has a temperature differential of at least 30°C between the droplet and the surface, wherein the surface freezes the droplet into a thin film with a thickness of less than 500 micrometers and a surface area to volume between 25 to 500 cm-1.

[0165] Yet another embodiment includes a system for preparing a non-solvent including dispersed sub-micron or micron-particles that are included in a liquid phase including an excipient, wherein the solvent source is composed of one or more solvents. In one aspect, the solution source further includes water, at least one organic solvent, or a combination thereof. In one aspect, the organic solvent is elected from the group consisting of ethanol, methanol, tetrahydrofuran, acetonitrile, acetone, tert-butyl alcohol, dimethyl sulfoxide, N,N-dimethyl formamide, diethyl ether, methylene chloride, ethyl acetate, isopropyl acetate, butyl acetate, propyl acetate, toluene, hexanes, heptane, pentane, and combinations thereof.

[0166] In another embodiment, a method for spray freezing includes spraying a solvent including active agent dispersed in a non-solvent including one or more excipients through a nozzle, wherein the spray rapidly generates frozen solvent particles having a size range of 1 nm to 10 microns. In one aspect, the solvent particles produced have a particle size of less than 10 microns. In another aspect, the solvent particle has a surface area greater than 50 m ² /g. In another aspect, the one or more solvents comprises a first solvent that is less volatile than a second solvent, wherein the more volatile solvent is removed but not the second solvent. In yet another aspect, the one or more solvents comprises a first solvent that is less volatile than a second solvent, wherein the more volatile solvent is removed by evaporation, sublimation, lyophilization, vacuum, heat or chemically. [0167] Yet another embodiment of the invention includes a single-step, single-vial method for preparing micron-sized or submicron-sized particles by reducing the temperature of a vial wherein the vial has a temperature differential of at least 30° C. between the solvent and the vial and spraying or dripping droplets of an active agent dispersed in a liquid phase including one or more excipients dissolved or dispersed in a solvent or solvents directly into the vial such that the active agent is exposed to a vapor-liquid interface of less than 500 cm ^-1 area/volume, wherein the surface freezes the droplet into a thin film with a thickness of less than 500 micrometers and a surface area to volume between 25 to 500 cm ^-1 . The droplets freeze upon contact with the surface in about 50, 75, 100, 125, 150, 175, 200, 250, 500, 1,000 and 2,000 milliseconds, and may even freeze upon contact with the surface in about 50, 150 to 500 milliseconds. In one example, a droplet has a diameter between 0.1 and 5 mm at room temperature or even a diameter between 2 and 4 mm at room temperature. In another example, the droplet forms a thin film on the surface of between 50 and 500 micrometers in thickness. In one specific example the droplets will have a cooling rate of between about 50 and about 250 °C/s. The vial may be cooled by a cryogenic solid, a cryogenic gas, a cryogenic liquid, a freezing fluid, a freezing gas, a freezing solid, a heat exchanger, or a heat transfer fluid capable of reaching cryogenic temperatures or temperatures below the freezing point of the solvent. The vial may even be rotated as the spraying or droplets are delivered to permit the layering or one or more layers of the final particles. In one example, the vial, including the active agent and the one or more solvents are pre-sterilized prior to spraying or dripping. The method may also include the step of spraying or dripping is repeated to overlay one or more thin films on top of each other to fill the vial to any desired level up to totally full.

[0168] The ability to produce high surface area stable submicron and micron-sized protein particles creates new opportunities for oral, depot, pulmonary, injectable, and transdermal delivery applications. In pulmonary delivery, high surface area porous particles with aerodynamic diameters between about 1 and about 3 pm may be deposited more efficiently in the deep lung compared to dense particles with similar aerodynamic diameters. In depot delivery, about 300 to about 500 nm submicron active agent particles have been encapsulated uniformly into about 10 to about 50 pm diameter microspheres to achieve high loadings.

EXAMPLES

Methods

Preparation of dry powder for inhalation using thin film freezing.

[0169] The formulation compositions and solvent ratios are shown the Table 1. The excipients were dissolved in water or organic solvent mixture mixtures (e.g., acetonitrile/water 80/20). The pre-engineered micronized or nanosized niclosamide particles were dispersed into the solutions as a suspension. The suspension was fed by a pump dropwise onto a rotating cryogenically cooled stainless steel drum. The processing temperature was controlled at -100 °C. The frozen samples were collected in a stainless-steel container and then transferred into a -80 ° freezer before drying in a lyophilizer. A typical drying cycle is shown in Table 2. Table 1. Compositions of formulations prepared by suspensions based thin film freezing.

Table 2. Drying cycle Preparation of micronized and nanosized niclosamide

[0170] The particle size of niclosamide was reduced to micron and nano-size by different methods. The micronized niclosamide was prepared by jet-milling using a fluid energy Jet-O- Mizer with a push pressure of 65 PSI and a grinder pressure of 75 PSI. A target feed rate of 1.192 g/min using nitrogen gas as the feed gas was achieved and powders were passed through the grinder 3 times to yield a final average particle size (D50) of 2.2 microns by laser diffraction.

[0171] The nanosized niclosamide was prepared by ball milling. Prior to nano milling, niclosamide was dispersed in surfactant solutions (e.g., pol oxamer 188 or tween 80), as described in Table 3. The niclosamide suspensions were diluted with water and passed through Dyno-Mill Research Lab (RL).

Table 3. Compositions of niclosamide suspensions before nano milling

[0172] NIC-Suspension 1 was tested first using tween-80 as a stabilizer and was not able to achieve a sub 1 micrometer average particle size. Several processing parameters were tested to help maintain flow and try to reach a particle size below Imicormeter with NIC-Suspension 1. The processing parameters tested included; 1) increased tip speed to 13.4 m/s, 2) added water to dilute solution, 3) upgraded from hand mixing the feed solution to using an overhead mixer, 4) added additional 0.2g of Tween80 and 5) smaller grinding media bead size (0.2 - 0.4mm). Despite these changes NIC-Suspension 1 using tween-80 was not able to reduce the average particle size below 1 micron. The learnings from the Suspension 1 testing were then applied to NIC-Suspension 2 including the usage of larger grinding media (0.4 - 0.6mm) bead size, more dilute drug loading, and the use of an overhead mixer to agitate the feed solution. With these process improvements and the usage of pol oxamer Pl 88 in place of tween-80 as the stabilizing surfactant NIC-Suspension 2 was able to achieve a sub 1 micrometer average particle size after only 1 hour of processing. Table 4 shows the final operating parameters and particles sizes achieved in these processes.

Table 4. Nanomilling Parameters and Results for NIC-Suspension 1 and 2 Preparation of micronized/ nano-sized niclosamide blends

[0173] Micronized (2.2 pm) or nanosized (158 nm) niclosamide was mixed with coarse lactose particles for inhalation (e.g., Inhalac 230®, DVso 70-110 microns) at different ratios including 10/90 w/w, and 20/80 w/w. The mixed powders were blended using a tubular mixer at 25 rpm for 10-20 minutes. Drug quantification by HPLC

[0174] The content of niclosamide from NGI analysis and the blend uniformity test was analyzed with an Agilent® HPLC 1260 Infinity II at a wavelength of 331 nm. The two mobile phases were designated as Phase A (0.3% formic acid in water) and Phase B (100% acetonitrile). A Waters Xbridge C18 column (4.6 * 150 mm, 3.5 pm) (Milford, MA) was used at 30 °C with a flow rate of 1.0 mL/min. The isocratic method was performed for 6 minutes at a mobile phase A:B ratio of 30:70. An Ultimate 3000 Autosampler was used to inject 15 pL samples. The retention time of tacrolimus was approximately 3.3 minutes. The standard curve of the tacrolimus at concentrations of 1-500 pg/mL were prepared. All analyses maintained linearity in the range tested. All chromatography data was processed by Agilent® OpenLab CDS software.

In-vitro aerosol dynamic testing

[0175] The aerodynamic properties of TFF niclosamide powders were evaluated by a Next Generation Pharmaceutical Impactor (NGI) (MSP Corp, Shoreview, MN), connected with a high-capacity pump (model HCP5, Copley Scientific, Nottingham, UK) and Critical Flow Controller (model TPK 2000, Copley Scientific, Nottingham, UK). Different inhalers including high-resistance RS00 (size #3) Plastiape® inhalers (Plastiape S.p.a, Osnago, Italy) were used in this test. The test powder (approximately 3-6 mg) was filled into Vcap® Plus DPI size 3 HPMC capsules. The inhaler was attached to the induction port by a molded silicon adapter. The pre-separator was not used in this test. Before the analysis, the NGI collection cups were coated with 1.5% w/v polysorbate 20 in methanol to prevent particle bounce and reentrainment. The measurements were set at the flow rate that produces a 4 kPa pressure drop across each inhaler and at a duration consistent with the withdrawal of 4 L of air from the adapter of the inhaler. For the device evaluation tests, the flow rate was set to provide 4 kPa pressure drops. The pressure drop across each inhaler and the flow rate were measured using a differential pressure manometer (Extech Instrument, Long Branch, NJ, USA), and a TSI flow meter model 4000 (TSI Incorporated, Shoreview, MN, USA), respectively. After aerosolization, the deposited powders from the capsule, inhaler, adapter, induction port, stages 1-7, and the micro-orifice collector (MOC) were extracted by diluting with known volumes of ACN/Water (80/20 v/v).

[0176] The content of niclosamide in the deposited powders was quantified using the HPLC method as described in section 2.2. Copley Inhaler Testing Data Analysis Software (CITDAS) version 3.10 (Copley Scientific, Nottingham, UK) was used to calculate mass median aerodynamic diameter (MMAD), geometric standard deviation (GSD), fine particle dose (FPD), and emitted dose (ED). The FPF of recovered dose (or nominal dose) was calculated as the percentage of FPD with respect to the total amount of drug collected from the capsule, inhaler, adapter, induction port, stages 1-7, MOC and external filter. The FPF of delivered dose was calculated as the percentage of FPD with respect to the total amount of drug deposited on the adapter, induction port, stages 1-7, MOC, and external filter. The EF was calculated as the percentage of the amount of drug emitted from the inhaler with respect to the total amount of drug collected from the capsule, inhaler, adapter, induction port, stages 1-7, MOC, and external filter.

Results

Appearance of micronized suspensions

[0177] Figure 1. shows the appearance of micronized niclosamide suspensions. The sedimentation of micronized niclosamide particles was observed in F7 and more obvious in Fl l because these formulations have no suspending agent (e.g., tween 80 or poloxamer 188). The formulation that contained 0.2% tween 80 (e.g., F8 and F 12) showed slower sedimentation rate, compared to F7 and Fl l. However, F12 still shows a faster rate of sedimentation than F8 due to higher drug loading. We found that the addition of tween 80 and poloxamer helped to disperse and suspend the micronized niclosamide particles in both 10% w/w and 20% w/w drug loading formulations (e.g., F9, F10, F13, and F14). Moreover, the ACN/water organic solvent mixture showed no difference in sedimentation rate, compared to water.

Aerodynamic properties

[0178] The aerodynamic properties of TFF micronized niclosamide formulations are shown in Figures 3, 4, and 5 and in Tables 5, 6, 7. Comparing Fl and F3, the leucine-based formulation exhibited higher aerosol performance than the mannitol-based formulation. F5 and F6 showed significantly higher FPF and smaller MMAD than Fl and F2, indicating the addition of leucine in the formulation helped to improve the aerodynamic properties of formulations. The different solid contents of feed solutions from 1% w/v to 4% w/v did not significantly affect the aerosol performance of formulations as F4, F5, and F6 showed no significant difference in FPF.

[0179] We found that the addition of suspending agent in the formulations did not negatively impact the aerosol performance. Although the aerosol performance of F8 was slightly lower than that of F7, no significant difference in aerosol performance was observed between Fl l and F12. Additionally, F9 and F10, which contained both tween 80 and poloxamer show similar FPF and MMAD, compared with F7 and Fl l.

[0180] Moreover, different solvent systems were also used to prepare the TFF powder. The in vitro aerodynamic testing demonstrated that the formulations prepared from acetonitrile/water systems and from an aqueous system showed no difference in aerodynamic properties.

[0181] The aerosol performance of micronized niclosamide blended with Inhalac® 230 was also evaluated. The NGI results are shown in Figure 5 and Table 7. Despite different drug loading, all micronized niclosamide blends showed <25% FPF of recovered dose and > 4 microns MMAD. This demonstrated that TFF niclosamide powder exhibited higher aerosol performance than micronized niclosamide blends.

Table 5. Aerosol performance of micronized niclosamide formulations that contained 10% drug loading.

Table 6. Aerosol performance of micronized niclosamide formulations that contained 20% drug loading.

Table 7. Aerosol performance of micronized niclosamide blended powder

[0182] The aerodynamic properties of TFF nanosized niclosamide formulations are shown in Figures 6-9 and in Tables 8-11. Overall, TFF nanosized niclosamide formulations than contained 10% and 20% dug loading showed high FPF (> 75% of recovered dose) and small MMAD (< 1.5 pm); however, more than 30% of drug particles are deposited on the external filter.

[0183] The drug loading, the amount of leucine, and type of sugar excipient appeared to have an effect on particle distribution and aerosolization. The higher drug loading formulations (e.g., F29 - 32) showed significantly lower drug deposition on the external filter, compared to 10% and 20% drug loading formulations. The formulations that have no leucine (e.g., F33 and F34) exhibited high capsule retention and poor aerodynamic properties, while the formulations that have leucine showed high aerosol performance. This indicates leucine helps to improve the aerosol performance of niclosamide particles. Additionally, at 40% and 60% drug loading, the lactose/leucine based formulation showed lower drug deposition on external filter than the mannitol/leucine based formulations.

[0184] The aerosol performance of nanosized niclosamide blended with Inhalac® 230 was also evaluated. The NGI results are shown in Figure 9 and Table 11. Despite different drug loading, all nanosized niclosamide blends showed poor aerosol performance (<11% FPF of recovered dose). This demonstrated that TFF nanosized niclosamide formulations exhibited higher aerosol performance than nanosized niclosamide/Inhalac blended powder.

Table 8. Aerosol performance of nanosized niclosamide formulations that contained 10% drug loading.

Table 9. Aerosol performance of nanosized niclosamide formulations that contained 20% drug loading

Table 10. Aerosol performance of nanosized niclosamide formulations that contained higher than 20% drug loading

Table 11. Aerosol performance of nanosized niclosamide blended powder

Conclusion

[0185] This study demonstrated that TFF slurry processing of pre-engineered API nano and micro particles can result in improved aerosol properties especially when compared to dry blending and pure API delivery. Micronized and nanosized drug particles that are deposited in the TFF produced brittle matrix excipients can be aerosolized and exhibited higher aerosol performance, compared with those same pre-engineer APIs deposited onto coarse lactose carrier particles as is more traditionally practiced in dry blending. For nanosized API’s at high drug loadings the improvement in aerosol performance was markedly enhanced by the TFF process. For example in formulation 42 with a niclosamide drug loading of 90% an FPF of 63% was achieved. When this same drug loading of 90.9% was tested using the nanosized niclosamide/P188 materials an FPF of only 12% was achieved. Additionally, in formulation 39 with a drug loading of 80% an FPF of 79.93% was achieved via TFF processing of the nanosized niclosamide. When this same 80% drug loading was tested using the dry blending approach with Inhalac® 230 as the carrier powder an FPF of only 16.8% was achieved. This clearly demonstrates the improvement in FPF that can be achieved when TFF processing preengineered APIs.

[0186] It is to be understood that, although prior art use and publications may be referred to herein, such reference does not constitute an admission that any of these form a part of the common general knowledge in the art

[0187] Numerous variations and modifications will suggest themselves to persons skilled in the relevant art, in addition to those already described, without departing from the basic inventive concepts. All such variations and modifications are to be considered within the scope of the present invention, the nature of which is to be determined from the foregoing description.