Applications of powder discharge process to prepare pharmaceutical compositions

Abstract

The present disclosure provides pharmaceutical compositions comprising an active agent which are formulated using a high energy mixing process without melting the pharmaceutical composition. Therefore, the present methods are useful for formulating, for example, thermally labile or shear sensitive active agents.

Description

[0001] DESCRIPTION

[0002] APPLICATIONS OF POWDER DISCHARGE PROCESS TO PREPARE PHARMACEUTICAL COMPOSITIONS

[0003] REFERENCE TO RELATED APPLICATIONS

[0004] The present application claims the priority benefit of United States provisional application number 63 / 754,365 filed February 5, 2025, the entire contents of which are incorporated herein by reference.

[0005] BACKGROUND

[0006] 1. Field

[0007] The present invention relates generally to the field of pharmaceutical preparation and manufacturing, and more particularly, pharmaceutical formulations of compounds that lack heat tolerance.

[0008] 2. Description of Related Art

[0009] Compounds of therapeutic interest, for example benzimidazole-carbamate anthelmintics (also called benzimidazole carbamates or more generally benzimidazoles), may have low solubility, which may in turn correspond to low or variable oral bioavailability (Sutar et al., 2021), which reduces the therapeutic utility of pharmaceutical compositions thereof.

[0010] A strategy to improve the dissolution properties of poorly water-soluble drugs (or active pharmaceutical ingredients, API) involves the generation of an amorphous solid dispersion (ASD) (Schittny et al., 2020). In an ASD, the API is molecularly dissolved in a solid matrix, which is usually an amorphous polymer (Qian et al., 2010; Van den Mooter, 2012). The amorphous nature of these compositions eliminates the need for energy to disrupt crystal lattices during dissolution, thereby increasing apparent solubility and dissolution rate (Bhujbal et al., 2021).

[0011] There are two main pathways to preparing an ASD: solvent-based and thermal-based manufacturing methods (Mendonsa et al., 2020). In each type of manufacturing, the API has to interact molecularly with the polymer. For solvent-based methods, the polymer and API are dissolved in a common solvent to facilitate their molecular interaction. This is followed by the evaporation or sublimation of the solvent to generate an ASD. Spray drying is a preferredsolvent-based method for preparing ASDs in the initial stages of drug development because it can generate small batches and process thermolabile materials and high melting point compounds (Singh and Van den Mooter, 2016). However, a major limitation of the solventbased method is the solubility of the API and polymer in the selected solvent or co-solvent system. In the case of thermal-based methods, the materials are melted to a liquid state, allowing for an intimate interaction between the API and polymer. The molten mass is then quickly quenched to generate an ASD (Thiry et al., 2016). Among thermal-based methods, hot-melt extrusion (HME) is the most common manufacturing process. During HME, the barrel is set at high temperatures while the screws rotate, applying mechanical and thermal energy to the polymer-API blends (Haser et al., 2017). Consequently, the API particles are dissolved in the molten polymer during the HME processing, generating an ASD (Patil et al., 2015). Solvent-based methods are generally less preferred due to the requirement for large volumes of organic solvents, elevated manufacturing costs, and residual solvent traces that can lead to physical stability issues (Hermeling et al., 2022; Huang and Williams, 2018). Additionally, environmental and safety considerations emerge from the use of large amounts of organic solvents (He and Ho, 2015). Consequently, manufacturers have been transitioning from solvent-based to thermal-based methods for producing ASDs (Tambe et al., 2022).

[0012] In the last decade, the KinetiSol™ processing technology has emerged as another solvent-less, thermal-based, and scalable manufacturing process for preparing ASDs. KinetiSol™ employs protruding blades to apply shear to drug-polymer combinations at high RPM. Inside the KinetiSol™ chamber, these blades cause the powder particles to collide with each other and with the blades and chamber walls. This generates significant friction and heat (Tan et al., 2020). The intense mixing raises the temperature, leading to the formation of a molten mass. This mass is then discharged from the processing chamber and cooled, resulting in an ASD.

[0013] In KinetiSol™, the operator determines the processing RPMs, the duration of processing, and the ejection or discharge temperature. The process continues until either the set processing time or the discharge temperature is achieved, whichever comes first. In the formulation design space of ASDs, KinetiSol™ enables the manufacturing of high melting point APIs, thermally labile materials, and viscous polymers without adding plasticizers, all within a few seconds of manufacturing (Ellenberger et al., 2018). Additionally, KinetiSol™ processing provides an alternative method for ASD formulation of compounds with lowsolubility in organic solvents that are not suitable for spray-drying due to cost and environmental factors (Miller et al., 2014). Research on KinetiSol™ processing to date has primarily focused on the manufacturing of ASDs obtained as molten discharges (Ellenberger et al., 2018; Tan et al., 2020). Despite this, KinetiSol™ has demonstrated its capability to reduce the chemical degradation of APIs and excipients, especially when compared to HME (DiNunzio et al., 2010; Hughey et al., 2010, 2011, 2012).

[0014] However, there are exceptions to this. Davis Jr. et al. (2020) highlighted that there is a small subset of drugs that have heat tolerance properties that correspond with a difficulty in formulating such compounds using KinetiSol™ processing or any other thermal-based manufacturing process. Non-limiting examples of drugs with no heat tolerance that are difficult to formulate using KinetiSol™ processing include mebendazole and albendazole. Additionally, Ellenberger et al. considered molecules with zero heat tolerance outside the formulation space of KinetiSol™ (Ellenberger et al., 2018). Therefore, new methods for formulating compounds, particularly methods that facilitate KinetiSol™ processing of compounds that lack heat tolerance, are needed.SUMMARY

[0015] In one aspect, the present disclosure provides methods of forming a powder-discharge pharmaceutical composition comprising

[0016] a. obtaining an active agent and one or more pharmaceutically acceptable excipients;

[0017] b. subjecting the active agent and one or more pharmaceutically acceptable excipients to a compounding process in a thermokinetic chamber to form a compounded material; and

[0018] c. discharging the compounded material from the thermokinetic chamber at a discharge temperature to form the powder-discharge pharmaceutical composition.

[0019] In some embodiments, the discharge temperature is about 20 °C, about 21 °C, about 22 °C, about 23 °C, about 24 °C, about 25 °C, about 26 °C, about 27 °C, about 28 °C, about 29 °C, about 30 °C, about 31 °C, about 32 °C, about 33 °C, about 34 °C, about 35 °C, about 36 °C, about 37 °C, about 38 °C, about 39 °C, about 40 °C, about 41 °C, about 42 °C, about 43 °C, about 44 °C, about 45 °C, about 46 °C, about 47 °C, about 48 °C, about 49 °C, about 50 °C, about 51 °C, about 52 °C, about 53 °C, about 54 °C, about 55 °C, about 56 °C, about 57 °C, about 58 °C, about 59 °C, about 60 °C, about 61 °C, about 62 °C, about 63 °C, about 64 °C, about 65 °C, about 66 °C, about 67 °C, about 68 °C, about 69 °C, about 70 °C, about 71 °C, about 72 °C, about 73 °C, about 74 °C, about 75 °C, about 76 °C, about 77 °C, about 78 °C, about 79 °C, about 80 °C, about 81 °C, about 82 °C, about 83 °C, about 84 °C, about 85 °C, about 86 °C, about 87 °C, about 88 °C, about 89 °C, about 90 °C, about 91 °C, about 92 °C, about 93 °C, about 94 °C, about 95 °C, about 96 °C, about 97 °C, about 98 °C, or about 99 °C. In some embodiments, the discharge temperature is 20 °C, 21 °C, 22 °C, 23 °C, 24 °C, 25 °C, 26 °C, 27 °C, 28 °C, 29 °C, 30 °C, 31 °C, 32 °C, 33 °C, 34 °C, 35 °C, 36 °C. 37 °C, 38 °C, 39 °C, 40 °C, 41 °C, 42 °C, 43 °C, 44 °C, 45 °C, 46 °C, 47 °C, 48 °C, 49 °C, 50 °C, 51 °C, 52 °C, 53 °C, 54 °C, 55 °C, 56 °C, 57 °C, 58 °C, 59 °C, 60 °C, 61 °C, 62 °C, 63 °C, 64 °C, 65 °C, 66 °C, 67 °C, 68 °C, 69 °C, 70 °C, 71 °C, 72 °C, 73 °C, 74 °C, 75 °C, 76 °C, 77 °C, 78 °C, 79 °C, 80 °C, 81 °C, 82 °C, 83 °C, 84 °C, 85 °C, 86 °C, 87 °C. 88 °C, 89 °C, 90 °C, 91 °C, 92 °C, 93 °C, 94 °C, 95 °C, 96 °C, 97 °C, 98 °C, or 99 °C.In some embodiments, the discharge temperature is lower than the glass transition temperature of the one or more pharmaceutically acceptable excipients. In some embodiments, the temperature measured in the thermokinetic chamber during the method does not exceed the glass transition temperature of the one or more pharmaceutically acceptable excipients. In some embodiments, the operating temperature measured during the method does not exceed the glass transition temperature of the one or more pharmaceutically acceptable excipients.

[0020] Therefore, the present disclosure provides, in some embodiments:

[0021] methods of forming a powder-discharge pharmaceutical composition comprising

[0022] a. obtaining an active agent and one or more pharmaceutically acceptable excipients;

[0023] b. subjecting the active agent and one or more pharmaceutically acceptable excipients to a compounding process in a thermokinetic chamber to form a compounded material; and

[0024] c. discharging the compounded material from the thermokinetic chamber at a discharge temperature to form the powder-discharge pharmaceutical composition, wherein the discharge temperature is less than about 80 °C;

[0025] methods of forming a powder-discharge pharmaceutical composition comprising

[0026] a. obtaining an active agent and one or more pharmaceutically acceptable excipients;

[0027] b. subjecting the active agent and one or more pharmaceutically acceptable excipients to a compounding process in a thermokinetic chamber to form a compounded material; and

[0028] c. discharging the compounded material from the thermokinetic chamber at a discharge temperature to form the powder-discharge pharmaceutical composition, wherein the discharge temperature is less than about 65 °C;

[0029] methods of forming a powder-discharge pharmaceutical composition comprisinga. obtaining an active agent and one or more pharmaceutically acceptable excipients;

[0030] b. subjecting the active agent and one or more pharmaceutically acceptable excipients to a compounding process in a thermokinetic chamber to form a compounded material; and

[0031] c. discharging the compounded material from the thermokinetic chamber at a discharge temperature to form the powder-discharge pharmaceutical composition, wherein the discharge temperature is less than about 40 °C;

[0032] methods of forming a powder-discharge pharmaceutical composition comprising

[0033] a. obtaining an active agent and one or more pharmaceutically acceptable excipients;

[0034] b. subjecting the active agent and one or more pharmaceutically acceptable excipients to a compounding process in a thermokinetic chamber to form a compounded material; and

[0035] c. discharging the compounded material from the thermokinetic chamber at a discharge temperature to form the powder-discharge pharmaceutical composition, wherein the discharge temperature is between about 20 °C and 40 °C;

[0036] methods of forming a powder-discharge pharmaceutical composition comprising

[0037] a. obtaining an active agent and one or more pharmaceutically acceptable excipients;

[0038] b. subjecting the active agent and one or more pharmaceutically acceptable excipients to a compounding process in a thermokinetic chamber to form a compounded material; and

[0039] c. discharging the compounded material from the thermokinetic chamber at a discharge temperature to form the powder-discharge pharmaceuticalcomposition, wherein the discharge temperature is between about 30 °C and 40 °C; and

[0040] methods of forming a powder-discharge pharmaceutical composition comprising

[0041] a. obtaining an active agent and one or more pharmaceutically acceptable excipients;

[0042] b. subjecting the active agent and one or more pharmaceutically acceptable excipients to a compounding process in a thermokinetic chamber to form a compounded material; and

[0043] c. discharging the compounded material from the thermokinetic chamber at a discharge temperature to form the powder-discharge pharmaceutical composition, wherein the discharge temperature is about 36 °C.

[0044] In some embodiments, the powder-discharge pharmaceutical composition is not a melt agglomeration. In some embodiments, the powder-discharge pharmaceutical composition is not an amorphous solid dispersion. In some embodiments, the powder-discharge pharmaceutical composition comprises partially amorphous particles of the active agent. In some embodiments, the powder-discharge pharmaceutical composition comprises crystalline particles of the active agent. In some embodiments, the crystalline particles are microcrystalline. In some embodiments, the crystalline particles are nanocrystalline. In some embodiments, the crystalline particles are microcrystalline or nanocrystalline.

[0045] In some embodiments, the active agent comprises an agent which undergoes degradation at an elevated temperature in a formulation process, such as a temperature at or above the glass transition temperature of an excipient used in the formulation process. In some embodiments, the active agent is chemically sensitive to temperature. In some embodiments, the active agent is chemically sensitive to shear. In some embodiments, the active agent degrades at elevated temperature, such as a temperature above room temperature. In some embodiments, the active agent degrades when exposed to shearing forces. In some embodiments, the active agent does not undergo degradation during the compounding process.

[0046] In some embodiments, the active agent comprises a compound that is poorly soluble. In some embodiments, the active agent comprises a compound that is poorly soluble in water. In someembodiments, wherein the active agent comprises a compound that is poorly soluble in an organic solvent. In some embodiments, the active agent comprises a compound that undergoes degradation at an elevated temperature in a formulation process and is a poorly soluble compound.

[0047] In some embodiments, the active agent comprises a benzimidazole. In some embodiments, the active agent comprises albendazole, ricobendazole, mebendazole, flubendazole, parbendazole, oxibendazole, oxfendazole, or fenbendazole. In further embodiments, the active agent comprises fenbendazole.

[0048] In some embodiments, the active agent 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, antiarrhythmic 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, 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, keratolytics, lipid regulating agents, leukotriene inhibitors, macrolides, muscle relaxants, neuroleptics, nutritional agents, opioid analgesics, protease inhibitors, or sedatives.

[0049] In some embodiments, the pharmaceutical composition comprises from about 1 % w / w to about 20% w / w of the active agent. In further embodiments, the pharmaceutical composition comprises from about 5% w / w to about 15% w / w of the active agent. In some embodiments, the pharmaceutical composition comprises about 5% of the active agent. In other embodiments, the pharmaceutical composition comprises about 10% of the active agent.

[0050] In some embodiments, the one or more pharmaceutically acceptable excipients comprises lactose. In some embodiments, the one or more pharmaceutically acceptable excipients comprises leucine. In some embodiments, the one or more pharmaceutically acceptableexcipients comprises a P-Cyclodextrin, such as hydroxypropyl P-Cyclodextrin or sulfobutylether P-cyclodextrin, or salts thereof.

[0051] In some embodiments, the one or more pharmaceutically acceptable excipients comprises a pharmaceutically acceptable polymer. In some embodiments, the pharmaceutically acceptable polymer is a neutral non-cellulosic polymer. In further embodiments, neutral non-cellulosic polymer comprises a poly(vinyl acetate), polyvinyl caprolactam, poly(vinylpyrrolidone), poly(ethylene glycol), poly(ethylene oxide), poly(vinyl alcohol), or methacrylate unit.

[0052] In some embodiments, the pharmaceutically acceptable polymer comprises a poly(vinyl acetate) or a methacrylate unit. In some embodiments, the pharmaceutically acceptable polymer is a poly(vinyl acetate)-co-poly(vinylpyrrolidone) copolymer, dimethylaminoethyl methacrylate-methacrylic acid ester copolymer, ethylacrylate-methylmethacrylate copolymer, poly(vinyl acetate) phthalate, poly(methacrylate ethylacrylate) (1:1) copolymer, poly (methacrylate methylmethacrylate) (1:1) copolymer, poly(methacrylate methylmethacrylate) (1 :2) copolymer, or polyvinyl caprolactam-polyvinyl acetatepolyethylene glycol graft copolymer sodium dodecyl sulfate.

[0053] In some embodiments, the compounding process is a high energy mixing process. In some embodiments, the compounding process does not comprise an external heat input. In some embodiments, the compounding process comprises subjecting the active agent and one or more pharmaceutically acceptable excipients to a combination of frictional energy and shear energy. In some embodiments, the compounding process comprises a first set speed of between about 500 rpm and about 6000 rpm. In further embodiments, the first set speed is between about 500 rpm and about 1500 rpm. In still further embodiments, the first set speed is about 1000 rpm. In some embodiments, the compounding process comprises mixing the active agent and one or more pharmaceutically acceptable excipients at two or more set speeds. In some embodiments, the compounding process comprises mixing the active agent and one or more pharmaceutically acceptable excipients at two speeds. In some embodiments, the second set speed is between about 500 rpm and about 6000 rpm. In further embodiments, the second set speed is between about 3000 rpm to about 5000 rpm. In still further embodiments, the second set speed is from about 4000 rpm.

[0054] In some embodiments, the compounding process comprises subjecting the active agent and one or more pharmaceutically acceptable excipients to the first speed for a first amount of time. Insome embodiments, the first amount of time is less than 60 seconds. In further embodiments, the first amount of time is between about 1 second and about 30 seconds. In still further embodiments, the first amount of time is between about 5 seconds and about 20 seconds. In yet further embodiments, the first amount of time is about 5 seconds.

[0055] In some embodiments, wherein the compounding process comprises subjecting the active agent and one or more pharmaceutically acceptable excipients to the second speed for a second amount of time. In some embodiments, the second amount of time is less than 120 seconds. In further embodiments, the second amount of time is between about 5 seconds and about 60 seconds. In still further embodiments, the second amount of time is about 45 seconds. In other embodiments, the second amount of time is about 30 seconds. In still other embodiments, the second amount of time is about 20 seconds. In yet other embodiments, the second amount of time is about 15 seconds.

[0056] In some embodiments, the compounding process further comprises subjecting the active agent and one or more pharmaceutically acceptable excipients to the first speed for a third amount of time. In some embodiments, the third amount of time is less than 60 seconds. In further embodiments, the third amount of time is between about 1 second and about 30 seconds. In still further embodiments, the third amount of time is between about 5 seconds and about 20 seconds. In yet further embodiments, the third amount of time is about 5 seconds. In some embodiments, neither the first speed nor the second speed is above 4000 rpm.

[0057] In some embodiments, the thermokinetic chamber has a chamber temperature that does not change by more than 15 °C during the compounding process. In further embodiments, the chamber temperature does not change by more than 10 °C. In still further embodiments, the chamber temperature does not change by more than 5 °C. In yet further embodiments, the chamber temperature does not change by more than 1 °C. In some embodiments, the chamber temperature does not exceed 40 °C during the compounding process.

[0058] In some embodiments, discharge temperature is between about 20 °C and about 40 °C. In further embodiments, the discharge temperature is between about 30 °C and about 40 °C. In still further embodiments, the discharge temperature is about 36 °C.

[0059] In some embodiments, the method does not comprise a milling step. In some embodiments, the method does not comprise a micronization step.In some embodiments, the method further comprises formulating the pharmaceutical composition into a unit dose. In some embodiments, the unit dose is formulated for oral, pulmonary, nasal, topical, transdermal, or parenteral delivery. In some embodiments, the unit dose is formulated for oral delivery. In further embodiments, the oral delivery is formulated as a tablet, capsule, or suspension. In some embodiments, the unit dose is formulated for pulmonary delivery. In some embodiments, the unit dose is formulated for topical delivery. In further embodiments, the topical delivery is an emulsion, ointment, or cream. In some embodiments, the unit dose is formulated for parenteral delivery. In further embodiments, the parenteral delivery is a suspension, microemulsion, or depot.

[0060] In another aspect, the present disclosure provides powder-discharge pharmaceutical compositions formed according to any one of the embodiments of the methods disclosed herein.

[0061] In another aspect, the present disclosure provides methods of treating a disease or disorder comprising administering to the patient a therapeutically effective amount of a powderdischarge pharmaceutical composition formed according to any one of the methods disclosed herein, wherein the active agent is effective to treat the disease or disorder. In some embodiments, the present disclosure provides powder-discharge pharmaceutical compositions formed according to any combination of embodiments of the methods disclosed herein for use in treating or preventing a disease or disorder. In some embodiments, the present disclosure provides use of a powder-discharge pharmaceutical composition formed according to any combination of embodiments of the methods disclosed herein in the manufacture of a medicament for treating or preventing a disease or disorder. In some embodiments, the disease or disorder is any disease or disorder treatable or preventable by an active agent disclosed herein.BRIEF DESCRIPTION OF DRAWINGS

[0062] The following drawings form part of the present specification and are included to further demonstrate certain aspects of the present invention. The invention may be better understood by reference to one or more of these drawings in combination with the detailed description of specific embodiments presented herein.

[0063] FIG. 1 shows the thermogravimetric analysis of fenbendazole (FBZ), Soluplus (SOL), and FBZ-SOL physical mixture (PM) at 1 : 1 w / w ratio. Additionally, the predicted weight loss of physical mixtures was added. It was considered the average of the FBZ and SOL curves. The traces from top to bottom over the temperature range 85C-135C are FBZ, FBZ-SOL (predicted), FBZ-SOL PM, and SOL.

[0064] FIG.2 - SEM images of the FBZ-SOL extrudates.

[0065] FIG. 3 illustrates the main degradation pathway of FBZ after undergoing thermal degradation during hot-melt extrusion (HME) according to LC-MS measurements. Considering that FBZ and the degradation product fenbendazoleamine have similar UV spectra, the chromatogram shown in FIG. 3 clearly illustrates the presence of both compounds in the sample.

[0066] FIG. 4 shows the wide-angle X-ray diffractogram of crystalline FBZ, SOL, FBZ-SOL physical mixture, and FBZ-SOL SD sample. The traces from top to bottom are FBZ-SOL SD, FBZ-SOL PM, SOL, and Neat FBZ.

[0067] FIG.5 - SEM images of the FBZ-SOL SD sample.

[0068] FIG. 6 - Chromatogram of a FBZ sample using the LC-MS method described in the Examples section below.

[0069] FIG. 7 shows the SEM image of the melt agglomerated mKSD sample. See Example 4. The bar shows a size of 50 pm.

[0070] FIGS. 8A & 8B - FIG. 8A shows the wide-angle X-ray diffractogram of crystalline FBZ, SOL, FBZ-SOL physical mixture, and mKSD sample. FIG. 8B shows a close-up of the mKSD WAXS diffractogram. For FIG. 8 A, the traces from top to bottom are mKSD, FBZ-SOL PM, SOL, and Neat FBZ.FIGS. 9A & 9B - FIG. 9A shows the wide-angle X-ray diffractogram of crystalline FBZ, SOL, FBZ-SOL physical mixture, and pKSD samples. FIG. 9B shows a close-up of the pKSD WAXS diffractograms. For FIG. 9A, the traces from top to bottom are 30s-pKSD, 20s-pKSD, 15s-pKSD, FBZ-SOL PM, SOL, and Neat FBZ. For FIG. 9B, the traces from top to bottom are 30s-pKSD, 20s-pKSD, and 15s-pKSD.

[0071] FIGS. 10A-10F show SEM images of pKSD samples prepared after KSD processing at 4000 RPMs. FIG. 10A and FIG. 10B: 15s-pKSD; FIG. 10C and FIG. 10D: 20s-pKSD; FIG.

[0072] 10E and FIG. 10F: 30s-pKSD.

[0073] FIG. 11 - SEM images of fenbendazole raw material.

[0074] FIG.12 - SEM images of SOL raw material.

[0075] FIG.13 shows the dissolution profile of neat crystalline FBZ, physical mixture of FBZ-SOL (FBZ-SOL PM), mKSD, and pKSD samples. The traces from top to bottom at 180 min are mKSD, 20s-pKSD, 30s-pKSD, 15s-pKSD, FBZ-SOL PM, and Neat crystalline FBZ.

[0076] FIGS.14A-14S show SEM images of fenbendazole (FBZ) and various excipients both alone and in compositions formed through the methods disclosed herein (unless noted otherwise). FIGS. 14A & 14B show SEM images of fenbendazole. FIGS. 14C & 14D show SEM images of Soluplus. FIG. 14E shows an SEM image of an FBZ-Soluplus composition formed through KinetiSol™ techniques known in the art; that is, through molten mass discharge techniques instead of the powder discharge techniques disclosed herein. SEM images of FBZ-Soluplus compositions formed according to presently disclosed methods may be found in FIG. 10. FIGS. 14F & 14G show SEM images of polyvinyl alcohol (PVA). FIGS. 14H-14K show SEM images of FBZ-PVA compositions prepared according to presently disclosed methods. FIGS. 14L-14O show SEM images of hydroxypropylmethylcellulose (HPMC). FIGS. 14P-14S show SEM images of FBZ-HPMC compositions prepared according to presently disclosed methods.

[0077] FIGS. 15A-15D show data related to dissolution tests of fenbendazole (FBZ) compositions comprising various amorphous excipients that were prepared according to methods disclosed herein. FIG. 15A provides dissolution data for a Kleptose®-FBZ composition. The composition formed according to the present methods has improved dissolution performance of FBZ. FIG. 15B provides dissolution data for a Captisol®-FBZcomposition. This data supports improved dissolution rates of compositions comprising a cyclodextrin excipient. FIG. 15C provides dissolution data for a leucine-FBZ composition. FIG. 15D provides dissolution data for a LactoHale® 300-FBZ composition. PM means a physical mixture of the components that have not been processed according to the presently disclosed formulation methods. For FIGS. 15A and 15B, the FBZ-SBECD PM is the bottom trace. For FIG. 15C at 150 min the top trace is Leucine-FBZ KSD and the bottom trace is Leucine-FBZ PM. For FIG. 15D at 150 min the top trace is Leucine-FBZ PM and the bottom trace is Leucine-FBZ KSD.

[0078] FIGS. 16A-16H show SEM images of fenbendazole (FBZ) compositions comprising amorphous excipients. An SEM image of fenbendazole is provided in FIG. 14A and FIG. 14B. FIG. 16A and FIG. 16B each show an SEM image of Captisol® Research Grade. Captisol® comprises P-Cyclodextrin Sulfobutyl Ethers, Sodium Salts. FIG. 16C and FIG. 16D each show an SEM image of Captisol®- 10% FBZ composition prepared according to the presently disclosed methods. The compositions shown in FIG. 16C and FIG. 16D have similar shape and particle size distribution after being processed according to the presently disclosed methods. FIG. 16E and FIG. 16F each show an SEM image of Kleptose® HP Parenteral grade. Kleptose® HP Parenteral grade comprises hydroxypropyl P-cyclodextrin. FIG. 16G and FIG.

[0079] 16H each show an SEM image of Kleptose®-FBZ composition prepared according to the presently disclosed methods.

[0080] FIGS. 17A & 17B show WAXS data for FBZ compositions comprising amorphous excipients. FIG. 17A shows WAXS data for Captisol®, Captisol® and FBZ physical mixture (PM), and a composition formed according to the present methods comprising Captisol® and FBZ. The composition formed according to the present methods is shown to have the FBZ peak at 6.7° (red arrow). FIG. 17B shows WAXS data for Kleptose® , Kleptose® and FBZ physical mixture (PM), and a composition formed according to the present methods comprising Kleptose® and FBZ. The composition formed according to the present methods is shown to have the FBZ peak at 6.7° (red arrow). For FIG. 17 A, the top trace is Captisol-FBZ PM, the center trace is Captisol-FBZ KSD, and the bottom trace is Captisol. For FIG. 17B, the top trace is Kleptose-FBZ PM, the center trace is Kleptose -FBZ KSD, and the bottom trace is Kleptose.

[0081] FIGS. 18A-18N show SEM images related to fenbendazole (FBZ) compositions comprising crystalline excipient Respitose® SV003 (which may also be referenced herein as SV003 or coarse lactose). FIGS. 18A- 18D are SEM images of Respitose® SV003. FIGS. 18E-18J are SEM images of an FBZ-Respitose® composition prepared according to a presently disclosed method wherein the processing time was 30 seconds. FIGS. 18K-18N are SEM images of an FBZ-Respitose® composition prepared according to a presently disclosed method wherein the processing time was 90 seconds.

[0082] FIGS. 19A-19J show SEM images related to fenbendazole (FBZ) compositions comprising crystalline excipient Lactohale® 300 (which may also be referenced herein as LH300 or fine lactose). FIGS. 19A-19D are SEM images of LH300. FIGS. 19E-19H are SEM images of an FBZ-LH300 composition prepared according to a presently disclosed method wherein the processing time was 30 seconds. FIG. 191 and FIG. 19J are SEM images of an FBZ-LH300 composition prepared according to a presently disclosed method wherein the processing time was 45 seconds.

[0083] FIGS. 20A-20L show SEM images related to fenbendazole (FBZ) compositions comprising crystalline excipient L-Leucine (which may also be referenced herein as Leucine). FIGS. 20A-20D are SEM images of L-Leucine. FIGS. 18E-18H are SEM images of an FBZ-Leucine composition prepared according to a presently disclosed method wherein the processing time was 30 seconds. FIGS. 18I-18L are SEM images of an FBZ-Leucine composition prepared according to a presently disclosed method wherein the processing time was 45 seconds.

[0084] FIGS. 21A & 21B illustrate the differences between amorphous and crystalline excipients when used to formulate compositions according to the presently disclosed methods. FIG. 21A, which is which is an SEM image of a composition that was formed according to methods disclosed herein comprising fenbendazole and an illustrative amorphous excipient Captisol®, has consistently shaped micro- and nano- crystals of fenbendazole embedded on the surface of the excipient. FIG. 2 IB, which is an SEM image of a composition that was formed according to methods disclosed herein comprising fenbendazole and an illustrative crystalline excipient Respitose® SV003, shows that particles of FBZ are on the surface of the excipient but do not have the shape characteristics that are present in FBZ particles of corresponding compositions comprising an amorphous excipient as shown in FIG. 21 A.

[0085] FIGS. 22A-22C show the wide-angle X-ray diffractograms related to compositions prepared according to methods disclosed herein comprising fenbendazole (FBZ) and illustrative crystalline excipients. FIG. 22A provides the wide-angle X-ray diffractograms ofFBZ and a composition prepared according to methods disclosed herein comprising FBZ and Leucine. As noted with the black arrow in FIG. 22B, the FBZ peak is present in the diffractogram of the composition with a slight overlap with the leucine peaks. FIG. 22B provides the wide-angle X-ray diffractograms of FBZ and a composition prepared according to methods disclosed herein comprising FBZ and coarse lactose. As noted with the black arrow in FIG. 22B, small traces of FBZ were detected in a composition prepared according to the presently disclosed methods comprising FBZ and coarse lactose. FIG. 22C provides the wide-angle X-ray diffractograms of fine lactose and a composition prepared according to methods disclosed herein comprising FBZ and fine lactose. As noted by the black arrow in FIG. 22C, small traces of FBZ were detected in in a composition prepared according to the presently disclosed methods comprising FBZ and fine lactose. The FBZ peak may, without being bound by theory, be broadened due to the decreased particle size of FBZ in this composition.

[0086] FIG. 23 provides evidence that compositions formed according to the presently disclosed methods have enhanced aerosol performance. The bars from left to right are in the same order as the figure legends.

[0087] FIGS. 24A-24G show SEM images of excipients formed without and API (in particular, FBZ) according to the presently disclosed pKSD-forming methods. FIG. 24A) Kleptose®; FIG. 24B) Captisol®; FIG. 24C) Respitose SV010; FIG. 24D) Respitose SV003; FIG. 24E) Lactohale 230; FIG. 24F) Lactohale 300; FIG. 24G) L-Leucine.

[0088] FIGS. 25A-25F show the wide-angle X-ray diffractograms related to illustrative excipients and compositions comprising such excipients and fenbendazole, each processed according to pKSD-forming methods disclosed herein. (FIG. 25A) Wide-angle X-ray diffractogram of crystalline FBZ, Respitose SV003, and FBZ-SV003 pKSD. (FIG. 25B) Closeup of the FBZ-SV003 pKSD WAXS diffractogram. (FIG. 25C) WAXS diffractogram of crystalline FBZ, LactoHale 300, and FBZ-LH300 pKSD. (FIG. 25D) Close-up of the FBZ-LH300 pKSD WAXS diffractogram. (FIG. 25E) WAXS diffractogram of crystalline FBZ, L-Leucine, and FBZ-Leu pKSD. (FIG. 25F) Close-up of the FBZ-Leu pKSD WAXS diffractogram. For FIG. 25A when 2-Theta is 35°, coarse lactose-FBZ pKSD is the top trace, coarse lactose is the middle trace, and FBZ is the bottom trace. For FIG. 25C at when 2-Theta is 35°, fine lactose is the top trace, fine lactose-FBZ pKSD is the middle trace, and FBZ is the bottom trace. For FIG. 25E at when 2-Theta is 35°, leucine-FBZ pKSD is the top trace, FBZ is the middle trace, and leucine is the bottom trace.DETAILED DESCRIPTION

[0089] The issue of bioavailability of drags that exhibit unacceptable (e.g., low) drag loading in amorphous solid dispersions remains a significant problem in pharmaceutical formulation. The present disclosure provides, in some embodiments, methods involving KinetiSol™ processing using Soluplus (SOL), Polyvinyl Alcohol (PVA), sulfobutylether-P-cyclodextrin (SBECD), and Hydroxypropyl [3-cyclodextrin (HPBCD) to enhance the solubility of active pharmaceutical ingredients (APIs), for example benzimidazoles. In some embodiments, the present invention provides methods for increasing the fine particle fraction. The inventors demonstrate that compositions formed according to presently disclosed methods may have higher bulk density than similar compositions known in the art. Therefore, the present invention is advantageous in facilitating higher dosages for administration of APIs. At least because the presently disclosed methods involve lower temperatures than corresponding methods known in the art, they are suitable for preparing formulations comprising thermolabile compounds. Especially, this invention is advantageous with drags that have high melting points, are thermally or shear sensitive, and exhibit low and pH dependent solubility by thermal and / or high energy mixing processing.

[0090] Enhancement of the solubility, in particular the solubility in water, of an API has, in some embodiments, the benefit of increasing bioavailability, such as oral bioavailability, of the API and / or making the bioavailability, such as oral bioavailability, more consistent across time. In this way, the present invention provides methods of forming compositions comprising APIs that are difficult to formulate into ASDs through other methods known in the art, such as APIs that lack heat tolerance. Non-limiting examples of APIs that lack heat tolerance include mebendazole, albendazole, and fenbendazole. Present KinetiSol™ techniques known in the art provide uniform ASDs, whereas the inventors have discovered methods of preparing compositions, particularly compositions of thermolabile compounds, wherein nanocrystals or microcrystals of the API are arranged on the surface of substrate or carrier. The API crystals of the present compositions have, in some embodiments, reduced particle size over corresponding formulations known in the art; in this manner, the present disclosure in some embodiments, provides methods resulting in increased solubility of the API compound. Moreover, the powder discharge pharmaceutical compositions disclosed herein are suitable for numerous routes of administration, such as by inhalation or by nasal delivery.The present disclosure provides methods for the preparation of compositions which in some embodiments comprise thermolabile compounds or thermolabile APIs. The presently disclosed methods are in some embodiments favorable over similar methods known in the art in that they are carried out under milder conditions. For example, in some embodiments the present disclosure provides methods that may be carried out at about room temperature. In some embodiments, the presently disclosed methods are improved over similar methods known in the art due to the reduced period of time required to form the compositions. In some embodiments, the presently disclosed methods are improved over similar methods known in the art because they do not require organic solvents. In some embodiments, the presently disclosed methods are improved over similar methods known in the art because they do not require a milling step. In some embodiments, the presently disclosed methods are improved over similar methods known in the art because they do not require a micronization step. In some embodiments, the presently disclosed methods are improved over similar methods known in the art because the compositions formed according to the methods have reduced particle size. In some embodiments, the present methods facilitate generation of nanocrystalline or microcrystalline APIs. In some embodiments, the present methods facilitate generation of nanocrystalline APIs. In some embodiments, the present methods facilitate generation of microcrystalline APIs. In some embodiments, the presently disclosed methods are improved over similar methods known in the art because adherence to the methods disclosed herein results in the generation of less impurities. Details on these aspects and more are found below and in the sections that follow.

[0091] Other objects, features and advantages of the present invention will become apparent from the following detailed description. It should be understood, however, that the detailed description and the specific examples, while indicating preferred embodiments of the invention, are given by way of illustration only, since various changes and modifications within the spirit and scope of the invention will become apparent to those skilled in the art from this detailed description.

[0092] I. Definitions

[0093] All publications and patent applications mentioned in the specification are indicative of the level of skill of those skilled in the art to which this disclosure pertains. All publications and patent applications are herein incorporated by reference to the same extent as if eachindividual publication or patent application was specifically and individually indicated to be incorporated by reference.

[0094] As used herein, “essentially free,” in terms of a specified component, is used herein to mean that none of the specified component has been purposefully formulated into a composition and / or is present only as a contaminant or in trace amounts. The total amount of the specified component resulting from any unintended contamination of a composition is therefore well below 0.05%, preferably below 0.01 %. Most preferred is a composition in which no amount of the specified component can be detected with standard analytical methods.

[0095] As used herein the specification, “a” or “an” may mean one or more. The use of the word "a" or "an" when used in conjunction with the term "comprising" in the claims and / or the specification may mean "one," but it is also consistent with the meaning of "one or more," "at least one," and "one or more than one." The use of the term "or" in the claims is used to mean "and / or" unless explicitly indicated to refer to alternatives only or the alternatives are mutually exclusive, although the disclosure supports a definition that refers to only alternatives and "and / or." Throughout this application, the term "about" is used to indicate that a value includes the inherent variation of error for the device, the method being employed to determine the value, or the variation that exists among the study subjects.

[0096] Throughout this application, the term “about” is used to indicate that a value includes the inherent variation of error for the device, the inherent variation in the method being employed to determine the value, the variation that exists among the study subjects, or a value that is within 10% of a stated value. In the present disclosure, each of the variously stated ranges is intended to be continuous so as to include each numerical parameter between the stated minimum and maximum value of each range. For example, a range of about 1 to about 4 includes about 1, 1, about 2, 2, about 3, 3, about 4, and 4. The terminology herein is used to describe specific embodiments of the disclosure, but their usage does not delimit the disclosure, except as outlined in the claims.

[0097] As used in this specification and claims, the words "comprising" (and any form of comprising, such as "comprise" and "comprises"), "having" (and any form of having, such as "have" and "has"), "including" (and any form of including, such as "includes" and "include") or "containing" (and any form of containing, such as "contains" and "contain") are inclusive or open-ended and do not exclude additional, unrecited elements or method steps.The term "or combinations thereof" as used herein refers to all pemmtations and combinations of the listed items preceding the term. For example, "A, B, C, or combinations thereof" is intended to include at least one of: A, B, C, AB, AC, BC, or ABC, and if order is important in a particular context, also BA, CA, CB, CBA, BCA, ACB, BAC, or CAB. Continuing with this example, expressly included are combinations that contain repeats of one or more item or term, such as BB, AAA, MB, BBC, AAABCCCC, CBBAAA, CAB ABB, and so forth. The skilled artisan will understand that typically there is no limit on the number of items or terms in any combination, unless otherwise apparent from the context.

[0098] As used herein, the terms “drug”, “pharmaceutical”, “active agent”, “therapeutic agent”, and “therapeutically active agent” are used interchangeably to represent a compound which invokes a therapeutic or pharmacological effect in a human or animal and is used to treat a disease, disorder, or other condition. In some embodiments, these compounds have undergone and received regulatory approval for administration to a living creature.

[0099] The terms “compositions,” “pharmaceutical compositions,” “formulations,” “pharmaceutical formulations,” “preparations”, and “pharmaceutical preparations” are used synonymously and interchangeably herein.

[0100] “Treating” or “treatment of a disease or condition” refers to executing a protocol, which may include administering one or more drugs to a patient, in an effort to alleviate signs or symptoms of the disease. Desirable effects of treatment include decreasing the rate of disease progression, ameliorating or palliating the disease state, and remission or improved prognosis. Alleviation can occur prior to signs or symptoms of the disease or condition appearing, as well as after their appearance. Thus, “treating” or “treatment” may include “preventing” or “prevention” of disease or undesirable condition. In addition, “treating” or “treatment” does not require complete alleviation of signs or symptoms, does not require a cure, and specifically includes protocols that have only a marginal effect on the patient.

[0101] The term “therapeutic benefit” or “therapeutically effective” as used throughout this application refers to anything that promotes or enhances the well-being of the subject with respect to the medical treatment of this condition. This includes, but is not limited to, a reduction in the frequency or severity of the signs or symptoms of a disease. For example, treatment of cancer may involve, for example, a reduction in the size of a tumor, a reduction inthe invasiveness of a tumor, reduction in the growth rate of the cancer, or prevention of metastasis. Treatment of cancer may also refer to prolonging survival of a subject with cancer.

[0102] “Subject’’ and “patient” refer to either a human or non-human, such as primates, mammals, and vertebrates. In particular embodiments, the subject is a human. In some embodiments, the subject is an animal.

[0103] As generally used herein “pharmaceutically acceptable” refers to those compounds, materials, compositions, and / or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues, organs, and / or bodily fluids of human beings and animals without excessive toxicity, irritation, allergic response, or other problems or complications commensurate with a reasonable benefit / risk ratio.

[0104] “Pharmaceutically acceptable salts” means salts of compounds disclosed herein which are pharmaceutically acceptable, as defined above, and which possess the desired pharmacological activity. Such salts include acid addition salts formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like; or with organic acids such as 1,2-ethanedisulfonic acid, 2-hydroxyethanesulfonic acid, 2-naphthalenesulfonic acid, 3 -phenylpropionic acid, 4,4'-methylenebis(3-hydroxy-2-ene- 1 -carboxylic acid), 4-methylbicyclo[2.2.2]oct-2-ene-l -carboxylic acid, acetic acid, aliphatic mono- and dicarboxylic acids, aliphatic sulfuric acids, aromatic sulfuric acids, benzenesulfonic acid, benzoic acid, camphorsulfonic acid, carbonic acid, cinnamic acid, citric acid, cyclopentanepropionic acid, ethanesulfonic acid, fumaric acid, glucoheptonic acid, gluconic acid, glutamic acid, glycolic acid, heptanoic acid, hexanoic acid, hydroxynaphthoic acid, lactic acid, laurylsulfuric acid, maleic acid, malic acid, malonic acid, mandelic acid, methanesulfonic acid, muconic acid, o-(4-hydroxybenzoyl)benzoic acid, oxalic acid, / 2-chlorobenzenesulfonic acid, phenyl-substituted alkanoic acids, propionic acid, p-toluenesulfonic acid, pyruvic acid, salicylic acid, stearic acid, succinic acid, tartaric acid, tertiarybutylacetic acid, trimethylacetic acid, and the like. Pharmaceutically acceptable salts also include base addition salts which may be formed when acidic protons present are capable of reacting with inorganic or organic bases. Acceptable inorganic bases include sodium hydroxide, sodium carbonate, potassium hydroxide, aluminum hydroxide and calcium hydroxide. Acceptable organic bases include ethanolamine, diethanolamine, triethanolamine, tromethamine, A-methylglucamine and the like. It should be recognized that the particular anion or cation forming a part of any salt of this invention is not critical, so long as the salt, as a whole, is pharmacologically acceptable.Additional examples of pharmaceutically acceptable salts and their methods of preparation and use are presented in Handbook of Pharmaceutical Salts: Properties, and Use (P. H. Stahl & C. G. Wermuth eds., Verlag Helvetica Chimica Acta, 2002).

[0105] A “high energy mixing process” refers to a formulation process that uses mixing blades rotating at a high speed, measured in revolutions per minute, generally at a minimum speed of 500 RPM, depending on the size of the processing unit and the composition being processed. This process may further comprise no heat applied from an external source.

[0106] The term “degradation” or “chemically sensitive” refers to a compound that is destroyed or rendered inactive and unacceptable for use. Degradation may include breaking one or more one or more chemical bonds in a reference undegraded compound.

[0107] The term “dissolution” as used herein refers to a process by which a solid substance, such as the active ingredients or one or more excipients, is dispersed in molecular form in a medium. The dissolution rate of the active ingredients of the pharmaceutical dose of the invention is defined by the amount of drug substance that goes in solution per unit time under standardized conditions of liquid / solid interface, temperature and solvent composition.

[0108] The term “amorphous” refers to a noncrystalline solid wherein the molecules are not organized in a definite lattice pattern. Alternatively, the term “crystalline” refers to a solid wherein the molecules in the solid have a definite lattice pattern. The crystallinity of the active agent in the composition is measured by powder x-ray diffraction.

[0109] A “poorly soluble drug” refers to a drug which meets the requires of the USP and BP solubility criteria of at least a sparingly soluble drug. The poorly soluble drug may be sparingly soluble, slightly soluble, very slightly soluble or practically insoluble. In a preferred embodiment, the drug is at least slightly soluble. In a more preferred embodiment, the dmg is at least very slightly soluble. As defined by the USP and BP, a soluble dmg is a dmg which is dissolved from 10 to 30 part of solvent required per part of solute, a sparingly soluble dmg is a dmg which is dissolved from 30 to 100 part of solvent required per part of solute, a slightly soluble drag is a drag which is dissolved from 100 to 1,000 part of solvent required per part of solute, a very slightly soluble dmg is a dmg which is dissolved from 1,000 to 10,000 part of solvent required per part of solute, and a practically insoluble dmg is a dmg which is dissolved from 10,000 part of solvent required per part of solute. The solvent may be water that is at a pH from 1-7.5, preferably physiological pH.As used in this specification, the term “significant” (and any form of significant such as “significantly”) is not meant to imply statistical differences between two values but only to imply importance or the scope of difference of the parameter.

[0110] As used herein, the term “substantially free of’ or “substantially free” in terms of a specified component, is used herein to mean that none of the specified component has been purposefully formulated into a composition and / or is present only as a contaminant or in trace amounts. The total amount of all containments, by-products, and other material is present in that composition in an amount less than 2%. The term “essentially free of’ or “essentially free” is used to represent that the composition contains less than 1% of the specific component. The term “entirely free of’ or “entirely free” contains less than 0.1% of the specific component.

[0111] As used herein, the term “substantially intact” in terms of a specified component, is used herein to mean that the specified component has not been degraded or rendered inactive in an amount less than 5%. The term “essentially intact” is used to represent that less than 2% of the specific component has been degraded or rendered inactive. The term “entirely intact” contains less than 0.1% of the specific component has been degraded or rendered inactive.

[0112] The term “homogenous” is used to mean a composition in which the components are mixed in such a way that the components are uniformly distributed amongst the composition. In a preferred embodiment, the composition is uniformly distributed in such a manner that there are no regions of a single component that are greater than 1 pm or more preferable less than 0.1 pm. In one embodiment, the composition is so homogeneously mixed in such a manner that there are no atoms of the thermally conductive excipient are adjacent to another atom of the thermally conductive excipient.

[0113] The terms “substantially” or “approximately” as used herein may be applied to modify any quantitative comparison, value, measurement, or other representation that could permissibly vary without resulting in a change in the basic function to which it is related.

[0114] A temperature, when used without any other modifier, refers to room temperature, preferably 23 °C, unless otherwise noted. An elevated temperature is a temperature which is more than 5 °C greater than room temperature; preferably more than 10 °C greater than room temperature.The term “unit dose” refers to a formulation of the pharmaceutical composition such that the formulation is prepared in a manner sufficient to provide a single therapeutically effective dose of the active agent to a patient in a single administration. Such unit dose formulations that may be used include but are not limited to a single tablet, capsule, or other oral formulations, or a single vial with a syringeable liquid or other injectable formulations. The resulting product can then undergo further downstream processing to create an intermediate product, such as granules, that can then be further formulated into an unit dose such as one prepared for oral delivery as tablets, capsules, three dimensionally printed selective laser sintered (3DPSLS) or suspensions; pulmonary7and nasal delivery7; topical delivery7as emulsions, ointments or creams; transdermal delivery; and parenteral delivery as suspensions, microemulsions or depot. In some forms, the final pharmaceutical composition that is produced is no longer a powder and is further produced as a homogenous final product. This final product has the capability of being processed into granules and being compressed or 3DPSLS into a final pharmaceutical unit dose form.

[0115] Notwithstanding that the numerical ranges and parameters setting forth the broad scope of the invention are approximations, the numerical values set forth in the specific examples are reported as precisely as possible. Any numerical value, however, inherently contain certain errors necessarily resulting from the standard deviation found in their respective testing measurements and parameters.

[0116] Other objects, features and advantages of the present disclosure will become apparent from the following detailed description. It should be understood, however, that the detailed description and the specific examples, while indicating preferred embodiments of the disclosure, are given by way of illustration only, since various changes and modifications within the spirit and scope of the disclosure will become apparent to those skilled in the art from this detailed description.

[0117] As used herein, the term “thermally labile API” refers to an API that degrades at its crystalline melting point, or one that degrades at temperatures below the crystalline melting point when in a non-crystalline (amorphous) form. As used herein, the term “thermolabile polymer” refers to a polymer that degrades at or below about 200 °C.

[0118] As used herein, the terms “lacking in heat tolerance”, “zero heat tolerance”, “no heat tolerance”, or any equivalent phrase or term, when used to describe an API refers to an APIthat is difficult to formulate and exhibits chemical degradation under KinetiSol™ processing known in the art.

[0119] As used herein, "thermally processed" or "processed thermally" means that components are processed by hot melt extrusion, thermokinetic compounding, melt granulation, compression molding, tablet compression, capsule filling, film-coating, or injection molding.

[0120] As used herein, the terms “discharge temperature” or “ejection temperature” refers to the temperature recorded by a probe of a chamber, such as an infrared (IR) probe recording the temperature of a thermokinetic chamber, just before a sample is discharged or ejected from said chamber.

[0121] As used herein, “drug loading” means that the API is miscible with the polymer composition, i.e., not suspended, and refers to the amount of API relative to the total amount of the composition including inactive ingredients. For example, drug loading of 30% means that the composition contains API at 30% by weight relative to the entire composition that includes inactive ingredients.

[0122] 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 a drug that is not highly soluble.

[0123] As used herein, “poorly water soluble” or “PWS” means an API that has a solubility such that more than 30 parts of solvent are required to dissolve one part of the API. A POSA would understand that “poorly water soluble” means sparingly soluble, slightly soluble, very slightly soluble and practically insoluble. These are USP descriptive solubility terms defined in the USP; see United States Pharmacopoeia (2021), section titled “Description and Relative Solubility.”

[0124] As used herein, “water soluble” means that less than 30 parts of water are required to dissolve one part of solute (from USP, same as above).

[0125] The use of the term “or” in the claims is used to mean “and / or” unless explicitly indicated to refer to alternatives only or the alternatives are mutually exclusive, although thedisclosure supports a definition that refers to only alternatives and “and / or.” As used herein “another” may mean at least a second or more.

[0126] III. Methods of Formulating

[0127] A. Powder-discharge KinetiSol™

[0128] The KinetiSol™ process known in the art are high energy, fusion-based processes that utilize frictional and shear energies to rapidly transition drug-polymer blends into a molten state. APIs that lack the heat tolerance to withstand the molten state are therefore generally recognized as not suitable for formulation using KinetiSol™ methods known in the art, or any other thermal-based formulation process, such as hot melt extrusion (HME). For example, some APIs degrade over the course of formulation methods known in the art. The present disclosure is related to modifications to the KinetiSol™ formulation methods known in the art, particularly modifications that facilitate the formulation of pharmaceutical compositions comprising APIs that are unsuitable for formulation via methods known in the art. The present methods retain certain advantages of the KinetiSol™ methods known in the art, while broadening the utility of these methods such that they are useful with additional APIs.

[0129] The modified KinetiSol™ methods disclosed herein employ thermokinetic compounding that may be carried out in a thermokinetic chamber using one or multiple speeds during a single, compounding operation on a batch of components to form a pharmaceutical formulation of the present disclosure. A thermokinetic chamber includes a chamber having an inside surface and a shaft extending into or through the chamber. Extensions extend from the shaft into the chamber and may extend to near the inside surface of the chamber. The extensions are often rectangular in cross-section, such as in the shape of blades, and have facial portions. During thermokinetic compounding, the shaft is rotated causing the components being compounded, such as particles of the components being compounded, to impinge upon the inside surface of the chamber and upon facial portions of the extensions. The shear of this impingement causes comminution, frictional heating, or both of the components and translates the rotational shaft energy into heating energy. Any heating energy generated during thermokinetic compounding is evolved from the mechanical energy input. Thermokinetic compounding is carried out without an external heat source. The thermokinetic chamber and components to be compounded are not pre-heated prior to commencement of thermokinetic compounding. The thermokinetic chamber may include a temperature sensor to measure the temperature of the components or otherwise within the thermokinetic chamber.Instead of discharging a melt-agglomeration or a molten mass as in known KinetiSol™ methods, the present disclosure relates methods that involve discharging a powder from the thermokinetic chamber. Therefore, the presently disclosed modified KinetiSol™ methods are referenced herein as powder discharge-based KinetiSol™ . Where known methods provide in an amorphous solid dispersion (KSD), the present invention provides a composition wherein API nanocrystals or microcrystals are located on the surface of the composition. Compositions formed according to the present methods are referenced herein as pKSDs. Where known methods provide in an amorphous solid dispersion of excipient and API, pKSDs have, in some embodiments, API nanocrystals or microcrystals located on the surface of the composition. The present methods do not involve melting of the excipient or API. In this manner, therefore, the present methods are more suitable for formulation of compounds that lack heat tolerance than similar methods known in the art. Further details on this aspect are provided in the Examples section below.

[0130] As mentioned above, the thermokinetic chamber may include a temperature sensor to measure the temperature of the components or otherwise within the thermokinetic chamber. For KinetiSol™ methods known in the art. the real-time temperature of the composition within the KinetiSol™ chamber is monitored by a computer-control module, and upon reaching the user defined endpoint (also referenced herein as the discharge temperature), molten material is immediately discharged from the process. Total processing times for KinetiSol™ methods known in the art are generally less than 20 seconds, and elevated temperatures are observed for typically less than 5 seconds before discharge and cooling.

[0131] The present methods do not involve melting of the excipient or API. Therefore, the methods of the present disclosure have a discharge temperature that is lower than the discharge temperature of similar methods known in the art. In this manner, therefore, the present methods are more suitable for formulation of compounds that lack heat tolerance than similar methods known in the art. Accordingly, the modified KinetiSol™ methods disclosed herein may be carried out at room temperature. In some embodiments, the discharge temperature of the presently disclosed methods is room temperature. In some embodiments, the discharge temperature of the presently disclosed methods is about 20 °C, about 21 °C, about 22 °C, about 23 °C, about 24 °C, about 25 °C, about 26 °C, about 27 °C, about 28 °C, about 29 °C, about 30 °C, about 31 °C, about 32 °C, about 33 °C, about 34 °C, about 35 °C, about 36 °C, about 37 °C, about 38 °C, about 39 °C, about 40 °C, about 41 °C, about 42 °C, about 43 °C, about 44 °C, about 45 °C, about 46 °C, about 47 °C, about 48 °C, about 49 °C, about 50 °C, about 51 °C, about 52 °C, about 53 °C, about 54 °C, about 55 °C, about 56 °C, about 57 °C, about 58°C, about 59 °C, about 60 °C, about 61 °C, about 62 °C, about 63 °C, about 64 °C, about 65 °C, about 66 °C, about 67 °C, about 68 °C, about 69 °C, about 70 °C, about 71 °C, about 72 °C, about 73 °C, about 74 °C, about 75 °C, about 76 °C, about 77 °C, about 78 °C, about 79 °C, about 80 °C, about 81 °C, about 82 °C, about 83 °C, about 84 °C, about 85 °C, about 86 °C, about 87 °C, about 88 °C, about 89 °C, about 90 °C, about 91 °C, about 92 °C, about 93 °C, about 94 °C, about 95 °C, about 96 °C, about 97 °C, about 98 °C, about 99 °C, or any range derivable therein. In some embodiments, the discharge temperature of the presently disclosed methods is about 20 °C, about 21 °C, about 22 °C, about 23 °C, about 24 °C, about 25 °C, about 26 °C, about 27 °C, about 28 °C, about 29 °C, about 30 °C, about 31 °C, about 32 °C, about 33 °C, about 34 °C, about 35 °C, about 36 °C, about 37 °C, about 38 °C, about 39 °C, about 40 °C, about 41 °C, about 42 °C, about 43 °C, about 44 °C, about 45 °C, about 46 °C, about 47 °C, about 48 °C, about 49 °C, about 50 °C, about 51 °C, about 52 °C, about 53 °C, about 54 °C, about 55 °C, about 56 °C, about 57 °C, about 58 °C, about 59 °C, about 60 °C, about 61 °C, about 62 °C, about 63 °C, about 64 °C, about 65 °C, or any range derivable therein. In some embodiments, the discharge temperature of the presently disclosed methods is about 20 °C, about 21 °C, about 22 °C, about 23 °C, about 24 °C, about 25 °C, about 26 °C, about 27 °C, about 28 °C, about 29 °C, about 30 °C, about 31 °C, about 32 °C, about 33 °C, about 34 °C, about 35 °C, about 36 °C, about 37 °C, about 38 °C, about 39 °C, about 40 °C, or any range derivable therein. In some embodiments, the discharge temperature is less than about 100 °C. In some embodiments, the discharge temperature is less than about 75 °C. In some embodiments, the discharge temperature is less than about 65 °C. In some embodiments, the discharge temperature is less than about 40 °C. In some embodiments, the discharge temperature of the presently disclosed methods is between about 60 °C and about 70 °C. In some embodiments, the discharge temperature of the presently disclosed methods is between about 50 °C and about 60 °C. In some embodiments, the discharge temperature of the presently disclosed methods is between about 40 °C and about 50 °C. In some embodiments, the discharge temperature of the presently disclosed methods is between about 30 °C and about 40 °C. In some embodiments, the discharge temperature of the presently disclosed methods is between about 20 °C and about 30 °C. In some embodiments, the discharge temperature of the presently disclosed methods is between about 20 °C and about 25 °C or between about 25 °C and about 30 °C. In some embodiments, the discharge temperature of the presently disclosed methods is between about 22 °C and about 24 °C. In some embodiments, the discharge temperature of the presently disclosed methods is about 23 °C. Therefore, in someembodiments the present methods have the advantage of a lower maximum processing temperature than other methods known in the art.

[0132] Variations of thermokinetic compounding may be used depending on the pKSD and its components. For example, the thermokinetic chamber may be operated at a first speed for a defined period to achieve a first process parameter, then operated at a second speed for a defined time period in the same thermokinetic compounding process to achieve a final process parameter. In other examples, the thermokinetic chamber may be operated at more than two speeds, or at only two speeds, but in more than two time intervals, such as at a first speed for a defined time period, then at a second speed for a defined time period, then again at the first speed for a defined time period. Alternatively, the thermokinetic chamber may be operated at more than two speeds and in more than two time intervals, such as at a first speed for a defined time period, then at a second speed for a defined time period, then at a third speed for a defined time period, and then again at the first speed for a defined time period. In all examples, the defined time period is independently selected.

[0133] In some embodiments, the speed(s) of the present methods may be lower speeds used in than similar methods known in the art. For example, the first speed to achieve a first process parameter of the present methods may be lower than the first speed of similar methods known in the art. In some embodiments, the first speed of the present methods is lower than 4000 RPM. In some embodiments, the first speed is about 500 RPM, about 600 RPM, about 700 RPM, about 800 RPM, about 900 RPM, about 1000 RPM, about 1100 RPM, about 1200 RPM, about 1300 RPM, about 1400 RPM, about 1500 RPM, about 1600 RPM, about 1700 RPM, about 1800 RPM, about 1900 RPM, about 2000 RPM, about 2100 RPM, about 2200 RPM, about 2300 RPM, about 2400 RPM, about 2500 RPM, about 2600 RPM, about 2700 RPM, about 2800 RPM, about 2900 RPM, about 3000 RPM, about 3100 RPM, about 3200 RPM, about 3300 RPM, about 3400 RPM, about 3500 RPM, about 3600 RPM, about 3700 RPM, about 3800 RPM, about 3900 RPM, or any range derivable therein. In some embodiments, the first speed is between about 500 RPM and about 1500 RPM. In some embodiments, the first speed is about 1000 RPM. As mentioned above, the present methods may comprise operation of the thermokinetic chamber at more than one independently selected speed. In some embodiments, none of the speeds is above 6000 RPM. In some embodiments, none of the speeds is above 4000 RPM. Therefore, in some embodiments the present methods have the advantage of a lower maximum processing speed than other methods known in the art. In some embodiments, the present methods may comprise operation of the thermokinetic chamber at a first speed and a second speed. In some embodiments, the second speed is about 1000 RPM,about 1500 RPM, about 2000 RPM, about 2500 RPM, about 3000 RPM, about 3500 RPM, or about 4000 RPM, about 4500 RPM, about 5000 RPM, about 5500 RPM, or about 6000 RPM. In some embodiments, the second speed is between about 3500 RPM and about 4500 RPM. In some embodiments, the second speed is about 4000 RPM.

[0134] Thermokinetic compounding may be performed in batches or in a semi-continuous fashion, depending on the product volume. On a lab-scale, the process is designed to operate in batch mode, whereas in commercial processing, it is operated semi-continuously, achieving product throughput as high as 1,000 kg / hr. When performed in a batch, semi -continuous, or continuous manufacturing process, each thermokinetic compounding step (that is, operation at a speed for a time period to achieve a processing parameter) may occur for less than 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 70, 100, 120, 240, or 300 seconds, inclusive, or for an interval between any of these time points, inclusive, or for an interval between 1 second and any of these time points, inclusive. In some embodiments, the sum total of the time periods of all thermokinetic compounding steps is less than the corresponding sum total of all thermokinetic compounding steps for methods known in the art. In some embodiments, the sum total of the time periods of all thermokinetic compounding steps is less than 60 seconds. In some embodiments, the sum total of the time periods of all thermokinetic compounding steps is about 15 seconds, about 16 seconds, about 17 seconds, about 18 seconds, about 19 seconds, about 20 seconds, about 21 seconds, about 22 seconds, about 23 seconds, about 24 seconds, about 25 seconds, about 26 seconds, about 27 seconds, about 28 seconds, about 29 seconds, about 30 seconds, about 31 second, about 32 seconds, about 33 seconds, about 34 seconds, about 35 seconds, about 36 seconds, about 37 seconds, about 38 seconds, about 39 seconds, about 40 seconds, about 41 second, about 42 seconds, about 43 seconds, about 44 seconds, about 45 seconds, about 46 seconds, about 47 seconds, about 48 seconds, about 49 seconds, about 50 seconds, about 51 second, about 52 seconds, about 53 seconds, about 54 seconds, about 55 seconds, about 56 seconds, about 57 seconds, about 58 seconds, about 59 seconds, or any range derivable therein. In some embodiments, the sum total of the time periods of all thermokinetic compounding steps is about 20 seconds, about 21 seconds, about 22 seconds, about 23 seconds, about 24 seconds, about 25 seconds, about 26 seconds, about 27 seconds, about 28 seconds, about 29 seconds, about 30 seconds, about 31 second, about 32 seconds, about 33 seconds, about 34 seconds, about 35 seconds, about 36 seconds, about 37 seconds, about 38 seconds, about 39 seconds, or about 40 seconds. In some embodiments, the sum total of the time periods of all thermokinetic compounding steps is about 25 seconds. In other embodiments, the sum total of the time periods of all thermokinetic compounding steps is about 30 seconds. In stillembodiments, the sum total of the time periods of all thermokinetic compounding steps is about 40 seconds. Therefore, in some embodiments the present methods have the advantage of a shorter total processing time than other methods known in the art.

[0135] In some embodiments, the duration of a first step to achieve a first processing parameter is less than 30 seconds. In some embodiments, the duration of a first step to achieve a first processing parameter is about 1 second, about 2 seconds, about 3 seconds, about 4 seconds, about 5 seconds, about 6 seconds, about 7 seconds, about 8 seconds, about 9 seconds, about 10 seconds, about 11 seconds, about 12 seconds, about 13 seconds, about 14 seconds, about 15 seconds, about 16 seconds, about 17 seconds, about 18 seconds, about 19 seconds, about 20 seconds, about 21 seconds, about 22 seconds, about 23 seconds, about 24 seconds, about 25 seconds, about 26 seconds, about 27 seconds, about 28 seconds, about 29 seconds, or any range derivable therein. In some embodiments, the duration of a first step to achieve a first processing parameter is between about 1 second and about 10 seconds. In some embodiments, the duration of a first step to achieve a first processing parameter is about 5 seconds.

[0136] In some embodiments, the present methods comprise a second step at a second speed to achieve a second processing parameter. In some embodiments, the duration of a second step to achieve a second processing parameter is about 30 seconds. In other embodiments, the duration of a second step to achieve a second processing parameter is less than 30 seconds. In some embodiments, the duration of a second step to achieve a second processing parameter is about 1 second, about 2 seconds, about 3 seconds, about 4 seconds, about 5 seconds, about 6 seconds, about 7 seconds, about 8 seconds, about 9 seconds, about 10 seconds, about 11 seconds, about 12 seconds, about 13 seconds, about 14 seconds, about 15 seconds, about 16 seconds, about 17 seconds, about 18 seconds, about 19 seconds, about 20 seconds, about 21 seconds, about 22 seconds, about 23 seconds, about 24 seconds, about 25 seconds, about 26 seconds, about 27 seconds, about 28 seconds, about 29 seconds, or any range derivable therein. In some embodiments, the duration of a second step to achieve a second processing parameter is between about 10 seconds and about 30 seconds. In some embodiments, the duration of a second step to achieve a second processing parameter is about 20 seconds. In other embodiments, the duration of a second step to achieve a second processing parameter is about 15 seconds.

[0137] In some embodiments, the present methods comprise a third step to achieve a third processing parameter. In some embodiments, the speed of the third step is the first speed. In other embodiments, the speed of the third step is a third speed. In some embodiments, the duration of a third step to achieve a third processing parameter is less than 30 seconds. In someembodiments, the duration of a third step to achieve a third processing parameter is about 1 second, about 2 seconds, about 3 seconds, about 4 seconds, about 5 seconds, about 6 seconds, about 7 seconds, about 8 seconds, about 9 seconds, about 10 seconds, about 11 seconds, about 12 seconds, about 13 seconds, about 14 seconds, about 15 seconds, about 16 seconds, about 17 seconds, about 18 seconds, about 19 seconds, about 20 seconds, about 21 seconds, about 22 seconds, about 23 seconds, about 24 seconds, about 25 seconds, about 26 seconds, about 27 seconds, about 28 seconds, about 29 seconds, or any range derivable therein. In some embodiments, the duration of a third step to achieve a third processing parameter is between about 1 second and about 10 seconds. In some embodiments, the duration of a third step to achieve a third processing parameter is about 5 seconds.

[0138] As mentioned above, KinetiSol™ methods known in the art may involve formation of a molten mass (also referenced herein as a melt-agglomeration), followed by quenching and milling to form amorphous solid dispersions. Amoiphous solid dispersions formed according to melt-agglomeration-based KinetiSol™ methods are referenced herein as KSDs. KSDs may have impurity levels, particularly when comprising APIs that are not suitable for formulation with known KinetiSol™ methods, of about 2%, about 3%, about 4%, about 5%, about 6%, about 7%, about 8%, about 9%, about 10%, about 11%, about 12%, about 13%, about 14%, about 15%, about 16%, about 17%, about 18%, about 19%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, about 100%, or any range derivable therein. KSDs may have impurity levels of above about 10%, above about 20%, above about 30%, above about 40%, above about 50%, above about 60%, above about 70%, above about 80%, or above about 90%. KSDs may have impurity levels that vary based upon the discharge temperature of the method. Impurities may, for example, include degradation products of the APIs that form a part of the KSD. In some embodiments, the present disclosure provides compositions with less impurities than corresponding KSDs which were formed according to known KinetiSol™ processes.

[0139] Variations of themiokinetic compounding may be used depending on the pharmaceutical composition and its components. For example, the themiokinetic chamber may be operated at a first speed to achieve a first process parameter, then operated at a second speed in the same themiokinetic compounding process to achieve a final process parameter. In other examples, the themiokinetic chamber may be operated at more than two speeds, or at only two speeds, but in more than two-time internals, such as at a first speed, then at a second speed, then again at the first speed. In some embodiments, the themiokinetic chamberPressure, duration of thermokinetic compounding, and other environmental conditions such as pH, moisture, buffers, ionic strength of the components being mixed, and exposure to gasses, such as oxygen, may also be such that degradation of any APIs present, one or all excipients, or one or all other components is avoided or minimized. Thermokinetic compounding may be performed in batches or in a semi-continuous fashion, depending on the product volume. When performed in a batch, semi-continuous, or continuous manufacturing process, each thermokinetic compounding step may occur for less than 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 70, 100, 120, 240, or 300 seconds, inclusive, or for an interval between any of these time points, inclusive, or for an interval between 1 second any any of these time points, inclusive.

[0140] The very brief processing times of KinetiSol™ enable production of compositions comprising thermally sensitive APIs and excipients. The high rates of shear inherent to KinetiSol™ accelerate solubilization kinetics of drug compounds, which typically results in processing temperatures that are well below the melting point of the API. Consequently, the production of compositions comprising compounds that degrade at elevated temperatures is achievable with the modified KinetiSol™ methods disclosed herein. The present methods are shown to be an improvement over known KinetiSol™ methods in that they provide compositions with less impurities, such as degradation products, than traditional KinetiSol™ methods that involve thermokinetic compounding processes occurring at temperatures above room temperature.

[0141] The KinetiSol™ process is not torque limited, and hence processing of highly viscous / non-thermoplastic / high molecular weight polymers can be easily accomplished without the use of plasticizers. The capabilities of KinetiSol™ enable the use of unique drug / excipient combinations to create solubility-enhanced compositions that cannot be reproduced or manufactured at large scales by other technologies.

[0142] IV. Pharmaceutical Compositions

[0143] In some aspects, the present disclosure provides pharmaceutical compositions containing an active agent such as an active pharmaceutical ingredient or a pharmaceutically acceptable salt, ester, derivative, analog, pro-drug, or solvates thereof, a pharmaceutically acceptable polymer including polymeric excipients, and a thermally conductive excipient (TCE) such as an inorganic or organic compound which promotes heat transfer. These compositions may be formulated as a powder-discharge solid dispersion. In some aspects, the pharmaceutically acceptable polymer and the excipient may be processed includingthrough a high energy process to obtain a compound excipient which is then formulated with the active agent. In some embodiments, the pharmaceutical composition is substantially, essentially, or entirely free of any other compound.

[0144] A. Active Agent

[0145] The pharmaceutical compositions described herein comprise an active agent. The pharmaceutical compositions described herein contain an active agent in an amount between about 10% to about 90% w / w, between about 20% to about 80% w / w, between about 20% to about 70% w / w, or between about 25% to about 50% w / w of the total composition. In some embodiments, the amount of the active agent is from about 10%, 20%, 22%, 24%, 25%, 26%, 28%, 30%, 32%, 34%, 35%, 36%, 38%, 40%, 42%, 44%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, to about 90% w / w or any range derivable therein. In some embodiments, the pharmaceutical composition is substantially, essentially, or entirely free of any other active agent.

[0146] In some embodiments, the active agent is classified using the Biopharmaceutical Classification System (BCS), originally developed by G. Amidon, which separates pharmaceuticals for oral administration into four classes depending on their aqueous solubility and their permeability through the intestinal cell layer. According to the BCS, drug substances are classified as follows: Class I — High Permeability, High Solubility ; Class II — High Permeability. Low Solubility; Class III — Low Permeability, High Solubility; and Class IV — Low Permeability, Low Solubility.

[0147] In particular, typical BCS Class II that may be incorporated into the present pharmaceutical compositions include but are not limited to anti-infectious drugs such as Albendazole, Acyclovir, Azithromycin, Cefdinir, Cefuroxime axetil, Chloroquine, Clarithromycin, Clofazimine, Diloxanide, Efavirenz, Fluconazole, Griseofulvin, Indinavir, Itraconazole, Ketoconazole, Lopinavir, Mebendazole, Nelfinavir, Nevirapine, Niclosamide, Praziquantel, Pyrantel, Pyrimethamine, Quinine, and Ritonavir. Antineoplasic drags such as Bicalutamide, Cyproterone, Gefitinib, Imatinib, and Tamoxifen. Biologic and Immunologic Agents such as Cyclosporine, Mycophenolate mofetil, Tacrolimus. Cardiovascular Agents such as Acetazolamide, Atorvastatin, Benidipine, Candesartan cilexetil, Carvedilol, Cilostazol, Clopidogrel, Ethylicosapentate, Ezetimibe, Fenofibrate, Irbesartan, Manidipine, Nifedipine, Nilvadipine, Nisoldipine, Simvastatin, Spironolactone, Telmisartan, Ticlopidine, Valsartan, Verapamil, Warfarin. Central Nervous System Agents such as Acetaminophen, Amisulpride, Aripiprazole, Carbamazepine, Celecoxib, Chlorpromazine, Clozapine, Diazepam, Diclofenac, Flurbiprofen, Haloperidol, Ibuprofen, Ketoprofen, Lamotrigine,Levodopa, Lorazepam, Meloxicam, Metaxalone, Methylphenidate, Metoclopramide, Nicergoline, Naproxen, Olanzapine, Oxcarbazepine, Phenytoin, Quetiapine Risperidone, Rofecoxib, and Valproic acid. Dermatological Agents such as Isotretinoin - Endocrine and Metabolic Agents such as Dexamethasone, Danazol, Epalrestat, Gliclazide, Glimepiride, Glipizide, Glyburide (glibenclamide), levothyroxine sodium, Medroxyprogesterone, Pioglitazone, and Raloxifene. Gastrointestinal Agents such as Mosapride, Orlistat, Cisapride, Rebamipide, Sulfasalazine, Teprenone, and Ursodeoxycholic Acid. Respiratory Agents such as Ebastine, Hydroxyzine, Loratadine, and Pranlukast. However, the skilled person will be well aware of other BCS class II drugs which can be used with the pharmaceutical compositions described herein.

[0148] Additionally, BCS class III drugs that may be incorporated into the present pharmaceutical compositions include but are not limited to cimetidine, acyclovir, atenolol, ranitidine, abacavir, captopril, chloramphenicol, codeine, colchicine, dapsone, ergotamine, kanamycin, tobramycin, tigecycline, zanamivir, hydralazine, hydrochlorothiazide, levothyroxine, methyldopa, paracetamol, propylthiouracil, pyrodostigmine, sodium cloxacillin, thiamine, benzidazole, didanosine, ethambutol, ethosuximide, folic acid, nicotinamide, nifurtimox, and salbutamol sulfate. However, the skilled person will be well aware of other BCS class III drugs which can be used with the pharmaceutical compositions described herein.

[0149] Additionally, BCS class IV drugs that may be incorporated into the present pharmaceutical compositions include but are not limited to hydrochlorothiazide, furosemide, cyclosporin A, itraconazole, indinavir, nelfinavir, ritonavir, saquinavir, nitrofurantoin, albendazole, acetazolamide, azithromycin, senna, azathioprine, chlorthalidone, BI-639667, rifabutin, paclitaxel, curcumin, etoposide, neomycin, methotrexate, atazanavir sulfate, Aprepitant, amphotericin B, amiodarone hydrochloride, or mesalamine. However, the skilled person will be well aware of other BCS class IV drugs which can be used with the pharmaceutical compositions described herein.

[0150] While the pharmaceutical compositions and methods described herein can be applied to any BCS class of drugs, BCS class II and IV are of interest for the pharmaceutical compositions described herein. Additionally, other active agents that are of specific consideration are those are those that are high melting point drugs such as a drug that has a melting point of greater than 200 °C. Alternatively, the active agents used herein may have a melting point from about 25 °C to about 1,000 °C, from about 100 °C to about 750 °C, or from about 200 °C to about 500 °C. In particular, the melting point may be greater than200 °C, 250 °C, 300 °C, 400 °C, 500 °C, 300 °C, 700 °C, 750 °C, 800 °C, 900 °C, or 1,000 °C.

[0151] In some aspects, the present methods may be used to formulate one or more poorly soluble and / or thermolabile active agents such as albendazole, ricobendazole, mebendazole, flubendazole, parbendazole, oxibendazole, oxfendazole, and fenbendazole.

[0152] Suitable active agents may be any poorly water-soluble, biologically active agents or a salt, isomer, ester, ether or other derivative 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, antiarrhythmic agents, anti-asthma agents, antibacterial agents, anti-benign prostate hypertrophy agents, anticoagulants, antidepressants, antidiabetics, antiemetics, antiepileptics, antigout agents, antihypertensive agents, antiinflammatory 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-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.

[0153] Non-limiting examples of the active agents may include 7-Methoxypteridine, 7-Methylpteridine, abacavir, abafungin, abarelix, acebutolol, acenaphthene, acetaminophen, acetanilide, acetazolamide, acetohexamide, acetretin, acrivastine, adenine, adenosine, alatrofloxacin, 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, bendroflumethi azide, 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, fenticonazole, 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, itraconazole, 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, 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, norethisterone, norfloxacin, norgestrel, nortriptyline HC1, nystatin, oestradiol, ofloxacin, olanzapine, omeprazole, omoconazole, ondansetron HC1, oprelvekin, ornidazole, oxaliplatin, oxamniquine, oxantelembonate, oxaprozin, oxatomide, oxazepam, oxcarbazepine, oxfendazole, oxiconazole, oxprenolol, oxyphenbutazone, oxyphencyclimine HC1, paclitaxel, palifermin, pamidronate, p-aminosalicylic acid, pantoprazole, paramethadione, paroxetine HC1, pegademase, pegaspargase, pegfilgrastim, pemetrexeddisodium, penicillamine, pentaerythritol tetranitrate, pentazocin, pentazocine, pentobarbital, pentobarbitone, pentostatin, pentoxifylline, perphenazine, perphenazine pimozide, perylene, phenacemide, phenacetin, phenanthrene, phenindione, phenobarbital, phenolbarbitone, phenolphthalein, phenoxybenzamine, pheno xybenzamine 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 -methylthiol, pteridine-7-thiol, pyrantelembonate, 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, sulphadi azine, 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.

[0154] In particular aspects, the active agents may be albendazole, ricobendazole, mebendazole, flubendazole, parbendazole, oxibendazole, oxfendazole, and fenbendazole, other members of the general class of benzimidazole-carbamates. Other active agents 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 agents 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 active agents may also include a psychiatric agent such as an antipsychotic, anti-depressive agent, or analgesic and / or tranquilizing agents such as benzodiazepines. The active 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 apharmaceutical composition with the appropriate pharmacokinetic properties for use as therapeutics.

[0155] In some aspects, the method may be mostly used with active agents which undergo degradation at an elevated temperature or pressure / shear. The active agents that may be used include those which decompose at a temperature above about 50 °C. In some embodiments, the active agent decomposes above a temperature of 80 °C. In some embodiments, the active agent decomposes above a temperature of 100 °C. In some embodiments, the active agent decomposes above a temperature of 150 °C. The active agent that may be used include therein which decompose at a temperature of greater than about 50 °C, 55 °C, 60 °C, 65 °C, 70 °C, 75 °C, 80 °C, 85 °C, 90 °C, 95 °C, 100 °C, 105 °C, 110 °C, 115 °C, 120 °C, 125 °C, 130 °C, 135 °C, 140 °C, 145 °C, or 150 °C.

[0156] Alternatively, the compound may be one that is sensitive to shear. These compounds are compounds for which the chemical and / or physical properties may change due to friction resulting from the manufacturing process itself, including chemical degradation of a drug or the loss of molecular weight of a polymer as non-limiting examples. The degree of loss of the chemical or physical properties of a compound due to shear is often seen as a function of the degree of mixing (e.g., blade RPM, rotation speed) and the properties of the polymer carrier (e.g. rheological properties).

[0157] B. Excipients

[0158] In some aspects, the present disclosure comprises one or more excipients formulated into powder-discharge pharmaceutical compositions. An “excipient” refers to pharmaceutically acceptable earners that 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. Non-limiting examples of excipients include polymer carriers, stabilizing agents, surfactants, surface modifiers, solubility enhancers, buffers, encapsulating agents, antioxidants, preservatives, nonionic wetting or clarifying agents, viscosity increasing agents, and absorption-enhancing agents. In some embodiments, the pharmaceutical composition is substantially, essentially, or entirely free of any other excipient.

[0159] Any pharmaceutically acceptable excipient known to those of skill in the art may be used to produce the composites and compositions disclosed herein. Examples of excipients for use with the present disclosure include, but are not limited to, e.g., lactose, glucose, starch, calcium carbonate, kaoline, crystalline cellulose, silicic acid, water, simple syrup, glucosesolution, starch solution, gelatin solution, carboxymethyl cellulose, shellac, methyl cellulose, polyvinyl pyrrolidone, dried starch, sodium alginate, powdered agar, calcium or sodium croscarmellose, a mixture of starch and lactose, sucrose, butter, hydrogenated oil, a mixture of a quaternary ammonium base and sodium lauryl sulfate, glycerine and starch, lactose, bentonite, colloidal silicic acid, talc, and stearates.

[0160] Excipients may be used to enhance the efficacy and efficiency of the API. Additional non-limiting examples of compounds that can be included are binders, carriers, cryoprotectants, lyoprotectants, fillers, stabilizers, protease inhibitors, antioxidants, bioavailability enhancers and absorption enhancers. The excipients may be chosen to modify the intended function of the active ingredient by improving flow, or bioavailability, or to control or delay the release of the API. Specific nonlimiting examples include sucrose, trehalose, Span 80, Span 20, Tween 80, Brij 35, Brij 98, Pluronic, sucroester 7, sucroester 11, sucroester 15, sodium lauryl sulfate (SLS, sodium dodecyl sulfate. SDS), dioctyl sodium sulphosuccinate (DSS, DOSS, dioctyl docusate sodium), oleic acid, laureth-9, laureth-8, lauric acid, vitaminETPGS, Cremophor® EL, Cremophor® RH, Gelucire® 50 / 13, Gelucire® 53 / 10, Gelucire® 44 / 14, Labrafil®, Solutol® HS, dipalmitoyl phosphadityl choline, glycolic acid and salts, deoxycholic acid and salts, sodium fusidate, cyclodextrins, Labrasol®, polyvinyl alcohols, polyvinyl pyrrolidones and tyloxapol.

[0161] Polymer carriers that may or may not require a plasticizer include, for example, Respitose® SV003 (Lactose monohydrate and anhydrous lactose), LactoHale® 300 (Lactose monohydrate and anhydrous lactose), Eudragit® RS PO, Eudragit® SI 00, Kollidon® SR (poly(vinyl acetate)-co-poly(vinylpyrrolidone) copolymer), Ethocel® (ethylcellulose), HPC (hydroxypropylcellulose), cellulose acetate butyrate, poly(vinylpyrrolidone) (PVP), polyethylene glycol) (PEG), polyethylene oxide) (PEO), poly(vinyl alcohol) (PVA), hydroxypropyl methylcellulose (HPMC), ethylcellulose (EC), hydroxyethylcellulose (HEC), sodium carboxymethyl-cellulose (CMC), dimethylaminoethyl methacrylate-methacrylic acid ester copolymer, ethylacrylate-methylmethacrylate copolymer (GA-MMA), C-5 or 60 SH-50 (Shin-Etsu Chemical Corp.), cellulose acetate phthalate (CAP), cellulose acetate trimelletate (CAT), poly(vinyl acetate) phthalate (PVAP), hydroxypropylmethylcellulose phthalate (HPMCP), poly(methacrylate ethylacrylate) (1:1) copolymer (MA-EA), poly(methacrylate methylmethacrylate) (1:1) copolymer (MA-MMA), poly (methacrylate methylmethacrylate) (1:2) copolymer, Eudragit® L-30-D (MA-EA, 1:1), Eudragit® L100-55 (MA-EA, 1:1), Eudragit® EPO (poly(butyl methacylate-co-(2-dimethylaminoethyl) methacrylate-co-methyl methacrylate) 1:2:1), hydroxypropylmethylcellulose acetate succinate (HPMCAS), Coateric®(PVAP), Aquateric® (CAP), and AQUACOAT® (HPMCAS), Soluplus® (polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer, BASF), Luvitec® K 30 (polyvinylpyrrolidone, PVP), Kollidon® (polyvinylpyrrolidone, PVP), polycaprolactone, starches, pectins; polysaccharides such as tragacanth, gum arabic, guar gum, and xanthan gum.

[0162] Water soluble polymers include Soluplus®, methylcellulose, ethylcellulose, hydroxymethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, hydroxybutylcellulose, hydroxyethyl methylcellulose, hydroxypropyl methylcellulose, carboxymethylcellulose, hydroxypropyl methylcellulose acetate succinate, cellulose acetate phthalate, cellulose acetate trimellate, hydroxypropyl methylcellulose phthalate, cellulose acetate butyrate, polyvinylpyrrolidones, polyacrylates, polymethacrylates, polyvinyl alcohols, polyethylene glycols, polyvinyl acetate polyvinylpyrrolidone copolymers, polyethylene oxides, dimethylaminoethyl methacrylate-methacrylic acid ester copolymers, ethylacrylatemethylmethacrylate copolymers, poly(methyacrylate ethylacrylate) copolymers, poly(methacrylate methylmethacrylate) copolymers, starches, pectins, polysaccharides, gum arabic, guar gum, and xanthan gum.

[0163] The carrier may also contain various functional excipients, such as an antioxidant, super-disintegrant, surfactant including amphiphilic molecules, wetting agent, stabilizing agent, retardant, similar functional excipient, or combination thereof, plasticizers including citrate esters, polyethylene glycols, PG, triacetin, diethylphthalate, castor oil, and others known to those or ordinary skill in the art. Extruded material may also include an acidifying agent, adsorbent, alkalizing agent, buffering agent, colorant, flavorant, sweetening agent, diluent, opaquant, complexing agent, fragrance, preservative or a combination thereof.

[0164] Compositions with enhanced solubility may comprise a mixture of an API and an additive that enhances the solubility of the API. Examples of such additives include but are not limited to surfactants, polymer carriers, pharmaceutical carriers, thermal binders or other excipients. A particular example may be a mixture of an API with a surfactant or surfactants, an API with a polymer or polymers, or an API with a combination of a surfactant and polymer carrier or surfactants and polymer carriers.

[0165] Surfactants that can be used in the disclosed compositions to enhance solubility have been previously presented. Particular examples of such surfactants include but are not limited to sodium dodecyl sulfate, dioctyl docusate sodium, Tween 80, Span 20, Cremophor® EL or Vitamin E TPGS. Polymer carriers that can be used in the disclosed composition to enhance solubility have been previously presented. Particular examples of such polymer carriers include but are not limited to Soluplus®, Respitose® SV003 (Lactose monohydrate and anhydrouslactose), LactoHale® 300 (Lactose monohydrate and anhydrous lactose) Eudragit® L100-55, Eudragit® EPO, Kollidon® VA 64, Luvitec®. K 30, Kollidon®, AQOAT®-HF, and AQOAT®-LF. The composition of the present disclosure can thus be any combination of one or more of the APIs, zero, one or more of surfactants or zero, one or more of polymers presented herein.

[0166] Solubility can be indicated by peak solubility, which is the highest concentration reached of a species of interest over time during a solubility experiment conducted in a specified medium. The enhanced solubility can be represented as the ratio of peak solubility of the agent in a pharmaceutical composition of the present disclosure compared to peak solubility of the reference standard agent under the same conditions. Preferable, an aqueous buffer with a pH in the range of from about pH 4 to pH 8, about pH 5 to pH 8, about pH 6 to pH 7, about pH 6 to pH 8, or about pH 7 to pH 8, such as, for example, pH 4.0, 4.5, 5.0, 5.5, 6.0, 6.2, 6.4, 6.6, 6.7, 6.8, 6.9, 7.0, 7.1, 7.2, 7.4, 7.6, 7.8, or 8.0, may be used for determining peak solubility. This peak solubility ratio can be about 2:1, 3:1, 4:1, 5:1, 6:1, 7:1, 8:1, 9:1, 10:1, 12:1, 15:1, 20:1, 25:1, 30:1, 35:1, 40:1, 45:1, 50:1, 55:1 or higher.

[0167] C. Pharmaceutically Acceptable Polymers

[0168] In some aspects, the present disclosure provides compositions which may further comprise a pharmaceutically acceptable polymer. In some embodiments, the polymer (polymer carrier) has been approved for use in a pharmaceutical formulation and is known to undergo softening or increased pliability when raised above a specific temperature without substantially degrading.

[0169] When a pharmaceutically acceptable polymer is present in the composition, the pharmaceutically acceptable polymer is present in the composition at a level between 1% to 90% w / w, between 10% to 80% w / w, between 20% to 70% w / w, between 30% to 70% w / w, between 40% to 60% w / w. In some embodiments, the amount of the pharmaceutically acceptable polymer is from about 5%, 10%, 15%, 50%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 61%, 62%. 63%, 64%, 65%, 66%, 67%, 68%, 69%, 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, to about 90% w / w or any range derivable therein. In some embodiments, the pharmaceutical composition is substantially, essentially, or entirely free of any other pharmaceutically acceptable polymer.

[0170] Within the compositions described herein, a single polymer or a combination of multiple polymers may be used. In some embodiments, the polymers used herein may fall within two classes: cellulosic and non-cellulosic. These classes may be further defined by their respective charge into neutral and ionizable. Ionizable polymers have been functionalized withone or more groups which are charged at a physiologically relevant pH. Some non-limiting examples of neutral non-cellulosic polymers include polyvinyl pyrrolidone, polyvinyl alcohol, copovidone, and poloxamer. Within this class, in some embodiments, pyrrolidone containing polymers are particularly useful. Some non-limiting examples of charged cellulosic polymers include cellulose acetate phthalate and hydroxypropyl methyl cellulose acetate succinate. Finally, some non-limiting examples of neutral cellulosic polymers include hydroxypropyl cellulose, hydroxypropyl methyl cellulose, hydroxyethyl cellulose, and hydroxymethyl cellulose.

[0171] Some specific pharmaceutically acceptable polymers which may be used include, for example, Respitose® SV003 (Lactose monohydrate and anhydrous lactose), LactoHale® 300 (Lactose monohydrate and anhydrous lactose), Eudragit™ RS PO, Eudragit™ S100, Kollidon SR (poly(vinyl acetate)-co-poly(vinylpyrrolidone) copolymer), Ethocel™ (ethylcellulose), HPC (hydroxypropylcellulose), cellulose acetate butyrate, poly(vinylpyrrolidone) (PVP), polyethylene glycol) (PEG), poly(ethylene oxide) (PEG), poly(vinyl alcohol) (PVA), hydroxypropyl methylcellulose (HPMC), ethylcellulose (EC), hydroxyethylcellulose (HEC), carboxymethyl cellulose and alkali metal salts thereof, such as sodium salts sodium carboxymethyl-cellulose (CMC), dimethylaminoethyl methacrylate — methacrylic acid ester copolymer, carboxymethylethyl cellulose, carboxymethyl cellulose butyrate, carboxymethyl cellulose propionate, carboxymethyl cellulose acetate butyrate, carboxymethyl cellulose acetate propionateethylacrylate — methylmethacrylate copolymer (GA-MMA), C-5 or 60 SH-50 (Shin-Etsu Chemical Corp.), cellulose acetate phthalate (CAP), cellulose acetate trimelletate (CAT), poly(vinyl acetate) phthalate (PVAP), hydroxypropylmethylcellulose phthalate (HPMCP), poly(methacrylate ethylacrylate) (LI) copolymer (MA-EA), poly(methacrylate methylmethacrylate) (1:1) copolymer (MA-MMA), poly (methacrylate methylmethacrylate) (1 :2) copolymer, poly(methacylic acid-co-methyl methacrylate 1 :2), poly(methacrylic acid-co-methyl methacrylate 1:1), Poly (methyl acrylate-co-methyl methacrylate-co-methacrylic acid 7:3:1), poly (butyl methacrylate-co-(2-dimethylaminoethyl) methacrylate-co-methyl methacrylate 1:2:1), poly(ethyl acrylate-co-methyl methacrylate 2:1), poly(ethyl acrylate-co-methyl methacrylate 2:1), poly(ethyl acrylate-co-methyl methacrylate-co-trimethylammonioethyl methacrylate chloride l:2:0.2), poly(ethyl acrylate-co-methyl methacrylate-co-trimethylammonioethyl methacrylate chloride 1:2:0.1), Eudragit L-30-D™ (MA-EA, 1:1), Eudragit L-100-55™ (MA-EA, 1:1), hydroxypropyhnethylcellulose acetate succinate (HPMCAS), polyvinyl caprolactam-poly vinyl acetate-PEG graft copolymer such as SoluPlus® (PEG 6000 / vinylcaprolactam / vinyl acetate (13:57:30)), polyvinyl alcohol / acrylicacid / methyl methacrylate copolymer, polyalkylene oxide, Coateric™ (PVAP), Aquateric™ (CAP), and AQUACOAT™ (HPMCAS), polycaprolactone, starches, pectins, chitosan or chitin and copolymers and mixtures thereof, and polysaccharides such as tragacanth, gum arabic, guar gum, and xanthan gum.

[0172] Additional pharmaceutically acceptable polymers that may be used in the presently disclosed pharmaceutical compositions include but are not limited to polyethylene oxide; polypropylene oxide; polyvinylpyrrolidone; polyvinylpyrrolidone-co-vinylacetate; acrylate and methacrylate copolymers; polyethylene; polycaprolactone; polyethylene-co-polypropylene; alkylcelluloses such as methylcellulose; hydroxyalkydcelluloses such as hydroxymethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, and hydroxybutylcellulose; hydroxy alkyl alkylcelluloses such as hydroxy ethyl methylcellulose and hydroxypropyl methylcellulose; starches, pectins; polysaccharides such as tragacanth, gum arabic, guar gum, and xanthan gum. One embodiment of the pharmaceutically acceptable polymer is polyethylene oxide) (PEO), which can be purchased commercially from companies such as the Dow Chemical Company, which markets PEO under the POLY OX® exemplary grades of which can include WSR N80 having an average molecular weight of about 200,000; 1,000,000; and 2,000,000.

[0173] D. Other Excipients

[0174] In some aspects, the present disclosure provides pharmaceutical compositions that may further comprise one or more additional excipients. The excipients (also called adjuvants) that may be used in the presently disclosed compositions and composites, while potentially having some activity in their own right, for example, antioxidants, are generally defined for this application as compounds that enhance the efficiency and / or efficacy of the active pharmaceutical ingredient. It is also possible to have more than one active agent in a given solution, so that the particles formed contain more than one active agent.

[0175] Any pharmaceutically acceptable excipient known to those of skill in the art may be used to produce the pharmaceutical compositions disclosed herein. Examples of excipients for use with the present disclosure include, lactose, glucose, starch, calcium carbonate, kaolin, crystalline cellulose, silicic acid, water, simple syrup, glucose solution, starch solution, gelatin solution, carboxymethyl cellulose, shellac, methyl cellulose, polyvinyl pyrrolidone, dried starch, sodium alginate, powdered agar, calcium carmelose, a mixture of starch and lactose, sucrose, butter, hydrogenated oil, a mixture of a quaternary ammonium base and sodium lauryl sulfate, glycerine and starch, lactose, bentonite, colloidal silicic acid, talc, stearates, and polyethylene glycol, sorbitan esters, polyoxyethylene sorbitan fatty acid esters,polyoxyethylene alkyl ethers, poloxamers (polyethylene-polypropylene glycol block copolymers), sucrose esters, sodium lauryl sulfate, oleic acid, lauric acid, vitamin E TPGS, polyoxyethylated glycolysed glycerides, dipalmitoyl phosphadityl choline, glycolic acid and salts, deoxycholic acid and salts, sodium fusidate, cyclodextrins, polyethylene glycols, polyglycolyzed glycerides, polyvinyl alcohols, poly acrylates, poly methacrylates, polyvinylpyrrolidones, phosphatidyl choline derivatives, cellulose derivatives, biocompatible polymers selected from poly (lactides), poly(glycolides), poly(lactide-co-glycolides), poly(lactic acid)s, poly(glycolic acid)s, poly(lactic acid-co-glycolic acid)s and blends, combinations, and copolymers thereof.

[0176] As stated, excipients and adjuvants may be used in the pharmaceutical composition to enhance the efficacy and efficiency of the active agent in the pharmaceutical composition. Additional non-limiting examples of compounds that can be included are binders, earners, cryoprotectants, lyoprotectants, surfactants, fillers, stabilizers, polymers, protease inhibitors, antioxidants, bioavailability enhancers and absorption enhancers. The excipients may be chosen to modify the intended function of the active ingredient by improving flow, or bioavailability, or to control or delay the release of the API. Specific nonlimiting examples include: sucrose, trehaolose, Span 80, Span 20, Tween 80, Brij 35, Brij 98, Pluronic, sucroester 7, sucroester 11, sucroester 15, sodium lauryl sulfate (SLS, sodium dodecyl sulfate. SDS), dioctyl sodium sulphosuccinate (DSS, DOSS, dioctyl docusate sodium), oleic acid, laureth-9, laureth-8, lauric acid, vitamin E TPGS, Cremophor® EL, Cremophor® RH, Gelucire® 50 / 13, Gelucire® 53 / 10, Gelucire® 44 / 14, Labrafil®, Solutol® HS, dipalmitoyl phosphadityl choline, glycolic acid and salts, deoxycholic acid and salts, sodium fusidate, cyclodextrins, polyethylene glycols, Labrasol®, polyvinyl alcohols, polyvinyl pyrrolidones and tyloxapol.

[0177] The stabilizing carrier may also contain various functional excipients, such as: hydrophilic polymer, antioxidant, super-disintegrant, surfactant including amphiphilic molecules, wetting agent, stabilizing agent, retardant, similar functional excipient, or combination thereof, and plasticizers including citrate esters, polyethylene glycols, PG, triacetin, diethylphthalate, castor oil, and others known to those or ordinary skill in the art. Extruded material may also include an acidifying agent, adsorbent, alkalizing agent, buffering agent, colorant, flavorant, sweetening agent, diluent, opaquant, complexing agent, fragrance, preservative or a combination thereof.

[0178] Compositions with enhanced solubility may comprise a mixture of the active pharmaceutical ingredient and an additive that enhances the solubility of the active pharmaceutical ingredient. Examples of such additives include but are not limited tosurfactants, polymer carriers, pharmaceutical earners, thermal binders or other excipients. A particular example may be a mixture of the active pharmaceutical ingredient with a surfactant or surfactants, the active pharmaceutical ingredient with a polymer or polymers, or the active pharmaceutical ingredient with a combination of a surfactant and polymer carrier or surfactants and polymer carriers. A further example is a composition where the active pharmaceutical ingredient is a derivative or analog thereof.

[0179] In some embodiments, the pharmaceutical compositions may further comprise one or more surfactants. Surfactants that can be used in the disclosed pharmaceutical compositions to enhance solubility include those known to a person of ordinary skill. Some particular nonlimiting examples of such surfactants include but are not limited to sodium dodecyl sulfate, dioctyl docusate sodium, Tween 80, Span 20, Cremophor® EL or Vitamin E TPGS.

[0180] Solubility can be indicated by peak solubility, which is the highest concentration reached of a species of interest over time during a solubility experiment conducted in a specified medium at a given temperature. The enhanced solubility can be represented as the ratio of peak solubility of the agent in a pharmaceutical composition of the present disclosure compared to peak solubility of the reference standard agent under the same conditions. Preferable, an aqueous buffer with a pH in the range of from about pH 4 to pH 8, about pH 5 to pH 8, about pH 6 to pH 7, about pH 6 to pH 8, or about pH 7 to pH 8, such as, for example, pH 4.0, 4.5, 5.0, 5.5, 6.0, 6.2, 6.4, 6.6, 6.7, 6.8, 6.9, 7.0, 7.1, 7.2, 7.4, 7.6, 7.8, or 8.0, may be used for determining peak solubility. This peak solubility ratio can be about 2:1, 3:1, 4:1, 5:1, 6:1, 7:1, 8:1, 9:1, 10:1, 12:1, 15:1, 20:1, 25:1, 30:1, 35:1, 40:1, 45:1, 50:1, 55:1 or higher.

[0181] Compositions of the active pharmaceutical ingredient that enhance bioavailability may comprise a mixture of the active pharmaceutical ingredient and one or more pharmaceutically acceptable adjuvants that enhance the bioavailability of the active pharmaceutical ingredient. Examples of such adjuvants include but are not limited to enzymes inhibitors. Particular examples are such enzyme inhibitors include but are not limited to inhibitors that inhibit cytochrome P-450 enzyme and inhibitors that inhibit monoamine oxidase enzyme. Bioavailability can be indicated by the Cmax or the AUC of the active pharmaceutical ingredient as determined during in vivo testing, where Cmax is the highest reached blood level concentration of the active pharmaceutical ingredient over time of monitoring and AUC is the area under the plasma-time curve. Enhanced bioavailability can be represented as the ratio of Cmax or the AUC of the active pharmaceutical ingredient in a pharmaceutical composition of the present disclosure compared to Cmax or the AUC of the reference standard the active pharmaceutical ingredient under the same conditions. This Cmax or AUC ratio reflectingenhanced bioavailability can be about 5:1, 6:1, 7:1, 8:1, 9:1, 10:1, 12:1, 15:1, 20:1, 25:1, 30:1, 35:1, 40:1, 45:1, 50:1, 55:1, 60:1, 65:1, 70:1, 75:1, 80:1, 85:1, 90:1, 95:1, 98:1, 99:1, 100:1 or higher.

[0182] In some aspects, the amount of the excipient in the pharmaceutical composition is from about 0.5% to about 20% w / w, from about 1% to about 10% w / w, from about 2% to about 8% w / w, or from about 3% to about 7% w / w. The amount of the excipient in the pharmaceutical composition comprises from about 0.5%, 1%, 1.5%, 2%, 2.5%, 3%, 3.5%, 4%, 4.5%, 5%, 5.5%, 6%, 6.5%, 7%, 7.5%, 8%, 9%, to about 10% w / w, or any range derivable therein, of the total pharmaceutical composition. In one embodiment, the amount of the excipient in the pharmaceutical composition is at 4% to 6% w / w of the total weight of the pharmaceutical composition.

[0183] E. Delivery

[0184] A variety of administration routes are available for delivering APIs to a patient in need. The particular route selected will depend upon the particular drug selected, the weight and age of the patient, and the dosage required for therapeutic effect. The pharmaceutical compositions may conveniently be presented in unit dosage form. APIs suitable for use in accordance with the present disclosure, and its pharmaceutically acceptable salts, derivatives, analogs, prodrugs, and solvates thereof, can be administered alone, but will generally be administered in admixture with a suitable pharmaceutical excipient, adjuvant, diluent, or earner selected with regard to the intended route of administration and standard pharmaceutical practice, and can in certain instances be administered with one or more additional API(s), preferably in the same unit dosage form.

[0185] An API may be used in a variety of application modalities, including oral delivery as tablets, capsules or suspensions; pulmonary and nasal delivery; topical delivery as emulsions, ointments or creams; transdermal delivery; and parenteral delivery as suspensions, microemulsions or depot. As used herein, the term “parenteral” includes subcutaneous, intravenous, intramuscular, or infusion routes of administration.

[0186] V. Examples

[0187] The following examples are included to demonstrate preferred embodiments of the invention. It should be appreciated by those of skill in the art that the techniques disclosed in the examples which follow represent techniques discovered by the inventor to function well in the practice of the invention, and thus can be considered to constitute preferred modes for its practice. However, those of skill in the art should, in light of the present disclosure, appreciatethat many changes can be made in the specific embodiments which are disclosed and still obtain a like or similar result without departing from the spirit and scope of the invention.

[0188] Example 1 - Materials and Methods

[0189] (i) Materials

[0190] Fenbendazole (FBZ; T able 1 ) , a benzimidazole-carbamate anth elmintic with poor water solubility and low and inconsistent oral bioavailability, was purchased from Shenzhen Nexconn Pharmatechs LTD (Shenzhen, China). Soluplus ® (SOL) was kindly donated by BASF (Ludwigshafen, Germany). Dimethylformamide (DMF), ethyl acetate, and acetonitrile (ACN) were purchased from Sigma Aldrich (Saint Louis, MO, USA). Methanol (MeOH), ethanol (EtOH), and 1.4-dioxane were obtained from Fisher Scientific (Pittsburgh, PA, USA). Dichloromethane (DCM) was acquired from Acros Organics (Morris Plains, NJ, USA). Magnesium stearate was obtained from Spectrum Chemical (New Brunswick, NJ, USA).

[0191] Table 1 - Chemical structure and some relevant physicochemical properties of fenbendazole reported in the literature.

[0192]

[0193]

[0194] A : https: / / pubchem.ncbi.nlm.nih.gov / compound / 3334.

[0195] B. https: / / go.drugbank.com / drugs / DB 11410

[0196] ( ii) Hot-melt extrusion (HME)

[0197] The FBZ-SOL blends, at a 5:95 w / w ratio, were admixed using a mortar and pestle. Subsequently, the blend was processed with a HAAKE miniLab II Micro Compounder (Thermo Electron Corporation, Waltham, MA, USA), operating at 100 rpm and 120 °C.

[0198] ( Hi ) Spray drying

[0199] Before performing spray drying, the solubility of FBZ was determined in the following solvents: DMSO, DMF, 1,4-dioxane, acetone, DCM, MeOH, ethyl acetate, EtOH, ACN, 0.1 N HC1 in water. Additionally, the solubility of FBZ was determined in DCM: MeOH compositions. For this purpose, an excess of FBZ (500 mg) was added into 10 mL of the solvents and kept for 4 days. Then, the samples were filtered using 0.2 pm PTFE syringe filters (Sigma Aldrich, Saint Louis, MO, USA).

[0200] For spray drying, an FBZ- SOL solution in a DCM: MeOH mixture at 80:20 v / v ratio was prepared (1 mg / mL of FBZ and 19 mg / mL SOL). This solution was spray-dried using a Buchi mini B290 (Buchi, Flawil, Switzerland). The inlet temperature was set at 70 °C, the atomization pressure was set at 473 L / h, and the feed rate was set at 5 mL / min. The condenser temperature was set at - 20 °C.

[0201] ( iv) KinetiSol™ processing

[0202] The FBZ-SOL blends were admixed using a mortar and pestle at a 5:95 w / w ratio. Then, magnesium stearate was added at 0.5 % w / w of the mixture’s total weight. The powder blend was subsequently added into the KinetiSol™ chamber (KinetiSol™ research formulator, KBC20, AustinPx, LLC, Georgetown, TX) to undergo conventional or modified processing conditions.

[0203] A) Melt agglomeration-based KinetiSol®:The powder blend underwent an initial processing phase at 4000 RPM for 30 s. This was followed by a secondary processing phase at 6000 RPM, during which the discharge temperatures were varied (Table 2). Immediately after discharge, the melt agglomerate was quenched using two blocks of aluminum. Then, the quenched samples were milled using an IKA Tube Mill (IKA-Werke, Stuafen, Germany) at 20000 RPM for 45 s pulses.

[0204] Table 2. Parameters employed for melt agglomeration-based KinetiSol™ processing.

[0205]

[0206] B) Powder discharge-based KinetiSol™

[0207] The powder blend underwent an initial processing phase at 1000 RPM for 5 s. This was followed by a secondary processing phase at 4000 RPM, during which the processing times were varied. To mitigate dust generation, a final processing phase was incorporated at 1000 RPM for 5 s (Table 3). Under these processing conditions, the KBC20 formulator’s sensors do not detect changes in the chamber temperature, resulting in the final product being a powder mixture rather than a melt agglomerated mass.

[0208] Table 3. Parameters employed for powder discharge-based KinetiSol™ processing.

[0209]

[0210] (v) Wide-angle X-ray Scattering (WAXS)

[0211] Samples were introduced into 1 mm Glass Number 50 (Glass 0500, borosilicate) capillaries (Hampton Research, Aliso Viejo, CA, USA) and analyzed for 1200 s using a SAXSLab instrument (WAXSLab, Northampton, MA, USA) equipped with a PILATUS3 R300 K detector (DECTRIS Ltd., Philadelphia, PA, USA). The instrument was operated using the Ganesha instrument software (SAXSLab, Northampton, MA, USA) in 2 apertures WAXS mode. WAXS was chosen to assess the solid state of the samples due to its demonstrated higher sensitivity in detecting crystalline traces, as evidenced by previous studies using the SAXLAB instrument (Davis et al., 2021; Jara et al., 2022).

[0212] ( vi ) Thermogravimetric analysis (TGA )

[0213] TGA was performed using a Mettler Thermogravimetric Analyzer, Model TGA / DSC 1 (Mettler Toledo, Columbus, OH). FBZ, SOL, and a physical mixture at a 1:1 FBZ:SOL ratio were evaluated. The samples were analyzed from 35 °C to 250 °C, using a heat rate of 10 °C / min under air at 50 L / min.

[0214] ( vii ) Liquid chromatography-mass spectrometry ( LC-MS )

[0215] Samples were analyzed using an Agilent 6125B Single Quadrupole LC / MS coupled to an Agilent 1260 LC stack (Agilent Technologies Co., Santa Clara, CA). The mobile phases consisted of A (water / 0.1 % formic acid) and B (MeOH), starting at 95% A at time 0 and finishing at 5% A at 20 min. The column was a ZORBAX Eclipse Plus C18 (2.1 mm x 50 mm; 5 pm). Additionally, this system had a diode-array (UV-Vis) detector that was used to quantify the FBZ concentrations.

[0216] (viii) Dissolution tests

[0217] The dissolution tests were performed in a Hanson SR8-Plus apparatus (Hanson Research Co., Chatsworth, CA, USA) using 200 mL vessels, using 100 RPM paddle speed and at 37 °C. 200 mg of the FBZ-SOL compositions were added into 120 mL of 0.1 N HC1. Sample points were collected after 5, 10, 15, 30, 60, 120, and 180 min, and filtered using 0.2 pm polyethersulfone (PES) syringe filters (Thermo Fisher Scientific Inc., Sunnyvale, CA, USA) and diluted in a 2:1 ratio with DMSO for HPLC analysis. The samples were measured at 295 nm using a Dionex HPLC system (Thermo Fisher Scientific Inc., Sunnyvale, CA, USA) with a VARIAN Lichrospher 100-5 RP18 250 x 4.6 mm column at a flow rate of 1 mL / min. Two mobile phases were used: mobile phase A was a trifluoroacetic acid (TFA) aqueous solution at 0.3%, and mobile phase B was MeOH (Thermo Fisher Scientific Inc.). The HPLC gradient is detailed in Table 4.

[0218] Table 4 HPLC gradient conditions for quantification of fenbendazole

[0219] | Time (min) | %B |

[0220]

[0221] Example 2 - Hot-melt extrusion led to almost complete degradation of FBZ TGA was initially performed to evaluate the thermal stability of FBZ, SOL, and their blend (FBZ-SOL), as shown in FIG. 1. As anticipated, the SOL sample exhibited an initial mass loss attributable to surface moisture, a phenomenon commonly observed in TGA of polymers at lower temperatures (Alshahrouri et al., 2021; Terife et al., 2012). Under the experimental conditions, FBZ showed mass loss at 158 °C, achieving a 13% mass loss at 250 °C. Notably, the FBZ-SOL blend in a 1 : 1 ratio demonstrated higher mass losses, deviating from the predicted curve, which was the average of the FBZ and SOL curves.

[0222] The above-mentioned TGA results are in concordance with those documented in the literature. In this study, TGA was conducted in an air atmosphere, contrasting with the nitrogen atmosphere used by Bezerra et al. (2022b). Bezerra et al. (2022b) reported that FBZ began to lose mass at 164 °C and experienced a 13% mass loss between 164 °C and 269 °C when analyzed at a heating rate of 10 °C / min in a nitrogen atmosphere.

[0223] Considering the TGA results, HME was performed at 120 °C to balance melt viscosity and potential thermal degradation. The resulting extrudates were milled (FIG. 2), and LC-MS was conducted to confirm the chemical stability of FBZ after HME. Unfortunately, 94% of impurities were observed, and the main degradation product was fenbendazoleamine (FIG. 3).

[0224] Typically, TGA is performed to justify that a certain API will be thermally stable when exposed to a thermal-based manufacturing method, as shown in reports from amorphous solid dispersion, twin screw extrusion, and 3D printing research fields (Goyanes et al., 2015; Moseson et al., 2020; Vo et al., 2020; Zhang et al., 2021).

[0225] However, solely relying on TGA data led to almost complete chemical degradation of FBZ when conducting HME. Attempts were made to reduce the processing temperature, but the FBZ-SOL blend was considered unextrudable at reduced temperatures due to prolonged residence times within the barrel of the HAAKE miniLab II. Additionally, HME was performedat higher temperatures, resulting in foam-like extrudates. These foam-like extrudes are usually related to the off-gassing due to chemical degradation and the release of volatiles (Hughey et al., 2010).

[0226] These results demonstrate, without being bound, that relying only on TGA to test the thermal stability of compositions before conducting thermal-based processing is misleading. DiNunzio et al. (2010) discussed that TGA is useful to indicate chemical degradation when the degradation products are volatile and show actual weight loss during the measurement. These observations have been further corroborated as the actual loss of API potency tends to be significantly higher than the weight loss observed in TGA experiments (Moseson et al., 2020;. Huang et al., 2017).

[0227] The present disclosure therefore shows that HME was not successful in preparing an ASD of FBZ employing SOL as polymeric matrix. However, the literature includes examples of benzimidazole-carbamate ASDs prepared by HME, such as albendazole (Hengsawas Surasarang et al., 2017; Martinez-Marcos et al., 2016), mebendazole (Kallai-Szabd et al., 2014), flubendazole (de Assis et al., 2022), and FBZ itself (Bezerra et al., 2022; Bezerra et al., 2023a; Bezerra et al., 2023b). Notably, Hengsawas Surasarang et al. (2017) reported that albendazole underwent chemical degradation when extruded at 120 °C.

[0228] Example 3: Spray drying was constrained by the low solubility of FBZ in organic solvents

[0229] Before conducting spray drying, the solubility of FBZ in different solvents was screened. Unfortunately, FBZ has low solubility in the organic solvents commonly used for spray drying (Table 5). FBZ had higher solubility in DMSO and DMF; both solvents have high boiling points and reduced vapor pressures, making them challenging for spray drying and requiring modified processing conditions (SaB and Fee, 2014). Additionally, FBZ was soluble in 1,4-dioxane. However, when the solvent was tested, FBZ was oxidized FBZ (299.3 g / mol) and generated the molecule oxfendazole (315.3 g / mol) as determined by EC-MS. Ethyl acetate and acetone were also tested as solvents, but the solubility of FBZ was reduced. Finally, a mixture of 20% MeOH and 80% DCM was employed for spray drying. The resulting spray-dried FBZ-SOE composition (FBZ-SOE SD) was amorphous, according to WAXS (FIG. 4) and the particles had a raisin-like morphology (FIG. 5). EC-MS showed that the ASD did not undergo chemical degradation, nor were fenbendazoleamine nor oxfendazole detected (FIG.

[0230] 6).Table 5: Solubility of FBZ in different solvent and cosolvent systems.

[0231]

[0232] These results demonstrate, without being bound, that the generation of a FBZ ASD by spray drying is feasible but limited in utility because of the low solid loads in the feedstock solution. In addition to the poor solubility of FBZ in organic solvents, the best solvent composition tested (80% DCM, 20% MeOH) allows a maximum amount of approximately 0.4% w / v solids load, which is low for sustainable and commercially viable spray drying that usually requires solid loads in the range of 5-50% w / w (Miller et al., 2022). Another limitation was the low yields obtained during spray drying, where most of the material got stuck in the cyclone. These problems are quite common in laboratory-scale spray dryers; however, theliterature mentions that at larger scales, these inefficiencies are reduced (Sosnik and Seremeta, 2015).

[0233] Example 4: KinetiSol™ processing was able to reduce the chemical degradation of FBZ at reduced discharge temperatures

[0234] Due to the chemical degradation of FBZ during HME and the low yields obtained during spray drying, KinetiSol™ processing was evaluated as an alternative manufacturing method. KinetiSol™ has been marketed as a fusion-based, solvent-free processing method that utilizes frictional and shear energies in a fraction of the time of other ASD technologies (https: / / www.austinpx.com / kinetisol). In this regard, the thermal exposure of a KinetiSol™ sample is significantly lower than that of an HME sample (Ellenberger et al., 2018). KinetiSol™ utilizes protrading blades to strike the sample at variable RPMs. These continuous impacts and shear forces cause the sample to heat and melt, forming a melt agglomerate that is then discharged after a few seconds of processing based on the selected discharge temperature (Ellenberger et al., 2018). To date, all KinetiSol™ samples (KSD) reported in the literature have exclusively been melt agglomerates.

[0235] KinetiSol™ was also tested for the preparation of an ASD of FBZ. Interestingly, KinetiSol™, with a discharge temperature of 125.9 °C and a processing time of only 11.7 seconds at 6000 RPM, resulted in non-detectable concentrations of FBZ (Table 6). Fortunately, unlike HME, melt viscosity was not a limiting factor for KinetiSol™, and processing at temperatures below 120 °C was feasible. As shown in Table 6, several attempts were made to test lower discharge temperatures.

[0236] Table 6. FBZ impurities and solid-state after KinetiSol™ processing at different discharge temperatures. The samples were analyzed using LC-MS. The sample with the lowest level of impurities was employed for further testing (FBZ-KSD).

[0237]

[0238]

[0239] Interestingly, chemical degradation of FBZ was observed even at 63.9 °C, which was the lowest temperature at which it was possible to obtain a melt agglomerated material (this sample will be identified as mKSD in the discussions below).

[0240] The mKSD sample was further characterized using SEM and WAXS. SEM revealed that the sample’s morphology was similar to other KSD materials reported in the literature (FIG. 6) (Ellenberger et al., 2018). On the other hand, WAXS analysis showed that the sample was predominantly amorphous, but some crystalline traces were detected (FIG. 7). This is likely due, without being bound by theory, to the reduced processing time at 6000 RPM. Additionally, the mKSD sample showed the lowest amount of impurities (6.4%) after 3.4 seconds of processing at 6000 RPM (Table 6). Notably, this chemical degradation occurred at lower processing temperatures than those observed by TGA (FIG. 1). These results suggest, without being bound by theory, that the chemical degradation of FBZ at low processing temperatures occurs without weight loss and the generation of volatiles. This demonstrates the labile nature of FBZ and confirms the observations from Davis Jr. et al. (2020) and Ellenberger et al. (2018) regarding other benzimidazole carbamates (mebendazole and albendazole), which were considered outside the formulation space of KinetiSol™ (Ellenberger et al., 2018; Davis et al., 2020).

[0241] Example 5: Alternative KinetiSol™ parameters can improve the dissolution performance of FBZ without generating detectable impurities.

[0242] KinetiSol™ processing, as traditionally employed in the literature (melt agglomeration), was not able to completely avoid the generation of fenbendazoleamine. . HME at 120 °C led to almost complete degradation of FBZ, generating the degradation product fenbendazoleamine. On the other hand, Spray drying successfully generated an ASD, but its effectiveness was limited by the low concentration of FBZ in the cosolvent system. Therefore, manufacturing under mild conditions was explored. In this embodiment, preparation of a composition according to methods disclosed herein results in discharge of a powder blend from the KinetiSol™ chamber instead of a melt agglomerate. The samples were prepared using 15, 20, and 30 s of processing time at 4000 RPM, where the KinetiSol™ formulator sensor did notdetect an increase in temperature (Table 7). As described by Davis et al., the KinetiSol™ mixing chamber dissipates part of the heat that is generated by shearing (Davis et al., 2020).

[0243] Interestingly, these powder-discharged KinetiSol™ samples (pKSD) did not undergo chemical degradation. However, they showed crystalline traces, as indicated by WAXS (FIG.

[0244] 8). SEM revealed that the samples were fragments of SOL covered by nano- and microsized particles, as seen in FIG. 9 (FBZ and SOL are shown in FIG. 10 and FIG. 11, respectively). Interestingly, there were differences between the pKSD samples prepared at different processing times at 4000 RPM after 15, 20, and 30 s (15s-pKSD, 20s-pKSD, and 30s-pKSD, respectively). According to SEM images (FIG. 9), the 20s-pKSD and 30s-pKSD were more homogeneously dispersed than the 15s-pKSD sample.

[0245] It is uncertain whether FBZ is crystalline or partially amorphous. Regarding other solid-state characterization techniques, Dedroog et al. (2020) highlighted the complementary use of XRD and DSC for characterization. However, DSC was deemed unsuitable for our study due to the degradation of FBZ before reaching its melting point, which could lead to thermal decomposition, artifacts, and potential damage to the instrument (Hughey et al., 2011; Zainal et al., 2021). Regarding XRD, the samples were too diluted for effective analysis. Literature suggests that XRD has a detection limit of approximately 5% w / w, which can vary depending on the API (Dedroog et al., 2020).

[0246] The generation of nano- and micronized particles aligns with the initial findings on KinetiSol ™ processing that have been reported in the literature. Hughey et al. (2010) demonstrated that micronized API and / or plasticizers are not required for KinetiSol™ processing, unlike in hot-melt extrusion (HME). This particle size reduction mechanism has the advantage of rapidly generation of compositions by KinetiSol™ processing.

[0247] Table 7. FBZ impurities after KinetiSol™ at different processing times. The samples were analyzed using LC-MS.

[0248]

[0249] Example 6: pKSD samples improved the dissolution performance of FBZThe pKSD samples were compared to the conventionally prepared mKSD sample (melt aggregate KSD sample, 6.4% impurities). For this purpose, dissolution tests were performed using HPLC-UV to differentiate between FBZ and fenbendazoleamine. The pKSDs compositions successfully improved the dissolution performance of FBZ when compared to the physical mixture. Interestingly, the mKSD sample achieved higher FBZ concentrations within 3 hours of dissolution, which might be related to the higher degree of amorphization of the sample. Additionally, the 15s-pKSD sample had a lower dissolution performance and was more variable than the 20s-pKSD and 30s-pKSD samples, as seen in FIG. 13. The improvement in the dissolution rate is related to a reduction in particle size. In the literature, submicron particles enhance the apparent supersaturation due to the increase in particle curvature and dissolution pressure, improving the overall dissolution of an API (Malamatari et al., 2018). Additionally, the literature mentions that the increase in solubility is usually a combination of the effect of particle size reduction and solid state changes generated during processing (Mosch witzer, 2013).

[0250] As mentioned before, FBZ and fenbendazoleamine have a similar chromophore (Error! Reference source not found.). This similarity required the use of a chromatographic technique to differentiate them. The inventors used HPLC-UV for the tests to differentiate FBZ from fenbendazoleamine. Previous studies have shown that degradation products generated during HME can have UV spectra similar to the original drug, causing misleading results when UV spectrophotometry is employed. This has been observed with drugs like albendazole and gliclazide (Huang et al., 2017; Hengsawas Surasarang, 2017. Thus, without using HPLC-UV or LC-MS, the degradation of FBZ might have been missed.

[0251] Data presenting dissolution performance of FBZ compositions comprising amorphous and crystalline excipients is presented in FIG. 15.

[0252] Example 7: Pulmonary Delivery

[0253] In some embodiments, compositions prepared according to the methods disclosed herein may be useful for the delivery of APIs. In some embodiments, the presently disclosed methods provide compositions with improved characteristics for delivering APIs to the lungs, such as delivery of APIs by inhalation. Table 8 provides the initial particle size distribution of illustrative API fenbendazole (FBZ) and various illustrative excipients, some of which are crystalline (Respitose® SV003, LactoHale® 300, L-Leucine) and some of which are amorphous (Captisol®, Kleptose®). Initial particle size distribution was measured to monitorpossible changes after processing. The particle distribution size after processing is provided in Table 9 for certain illustrative excipients with the indicated processing times. As shown in Table 9, compositions comprising FBZ and Leucine or FBZ and Kleptose® had decreased the particle size after processsing, while compositions comprising FBZ and a lactose excipient (that is, Respitose® SV003 and LactoHale® 300) or FBZ and Captisol® did not exhibit a change in particle size after processing. Additional details of the particle size distribution of various excipient and processing time combinations are provided in Table 10.

[0254] Table 8. Initial particle size distribution of excipients and fenbendazole (FBZ)

[0255]

[0256] Table 9. Fenbendazole (FBZ) formulations for inhalation

[0257]

[0258] Captisol® and Kleptose® compositions were formulated with 10% FBZ and 90% excipient. Processing times varied as noted in the table. Formulation was carried out at room

[0259] temperature.Table 10. Particle size distribution (PSD) of fenbendazole (FBZ) formulations

[0260]

[0261] *Granule size of formulation SV003-FBZ 90s was measured to be 2.09 ± 0.41 mm by caliper (n=50).

[0262] SEM images of the illustrative amorphous excipients of the tables above and compositions thereof prepared according to the methods disclosed herein are provided in FIG.

[0263] 16. SEM images of the illustrative crystalline excipients of the tables above and compositions thereof prepared according to the methods disclosed herein are provided in FIGS 18-20. Wide-angle X-ray diffractograms for FBZ, each excipient, and compositions prepared according to the presently disclosed methods comprising FBZ and each illustrative excipient may be found as FIG. 17 (amorphous excipients) and FIG. 22 (crystalline excipients). In each case, the presence of peaks associated with FBZ are evident in the diffractogram of the composition prepared according to the presently disclosed methods. As shown in FIG. 21, compositions formed according to the present methods comprising an amorphous excipient have different characteristics than compositions comprising crystalline excipients. For example, compositions formed according to the present methods comprising an amorphous excipient are shown to have consistently shaped crystals of the drug on the surface. More particularly, the crystals of drug are micro-crystals or nano-crystals. The compositions formed according to the present application are embedded in the surface of the excipient.Table 11. Bulk density and Hausner ratio of exemplary excipients and compositions formed by methods disclosed herein.

[0264]

[0265] Method adapted from USP <616> using a 5 mL graduated cylinder. Tapped density was measured every 100 taps until there was less than a 1% change in volume.

[0266] The Hausner ratio of a sample is calculated as the tapped density divided by the bulk density and is a measure of the flowability of the sample. According to USP-NF 1174 Powder flow guidelines, samples may be classified by flow character based upon their Hausner ratio. A Hausner ratio of between 1.00 and 1.11 corresponds with Excellent flow character. A Hausner ratio of between 1.12 and 1.18 corresponds with Good flow character. A Hausner ratio of between 1.19 and 1.25 corresponds with Fair flow character. AHausner ratio of between 1.26 and 1.34 corresponds with Passable flow character. A Hausner ratio of between 1.35 and 1.45 corresponds with Poor flow character. A Hausner ratio of between 1.46 and 1.59 corresponds with Very poor flow character. A Hausner ratio of 1.60 or greater corresponds with Very, very poor flow character.Table 12. Aerosol performance of compositions formulated according to present methods.

[0267]

[0268] NG1 studies were carried out with High Resistance RS01 at 60 L / min, 4kPa, with 40 mg composition in two HPMC capsules with a solvent of DMSO.As shown in Table 11 above, the bulk density and Hausner ratio was determined for exemplary excipients useful in the methods disclosed herein as well as for exemplary formulations formed according to the present methods. Table 12 provides data related to the aerosol performance of compositions formed according to the present methods. In some embodiments, preparation of compounds in accordance with the presently disclosed methods results in compositions with higher bulk density than compositions formed according to methods known in the art. In this manner, the present disclosure provides an advantage of providing formulations with higher doses than similar formulations known in the art. In some embodiments, compositions of the present disclosure have improved properties for administration by inhalation.

[0269] Example 8 - Particle characterization for additional embodiments In some embodiments, the present methods may involve use of excipients with different particle sizes. The present methods may involve selecting an excipient based at least in part on its particle size for modulation of the properties of a composition comprising said excipient. As shown in the Tables below and elsewhere in the application, the particles formed according to the present methods may have advantageous uniformity.

[0270] Table 13: Particle Size of Excipients

[0271]

[0272] Jet-milling: 0.5 g / min at 75 and 70 psi grinding and pusher pressure. IKA-milling: two cycles of 20000 RPM for 45 s. Particle size distribution measured by Laser diffraction with a dry disperser.

[0273] Table 14. Bulk density and Hausner ratio of additional fenbendazole pKSD-processed samples

[0274]

[0275]

[0276] * * *

[0277] All of the methods disclosed and claimed herein can be made and executed without undue experimentation in light of the present disclosure. While the compositions and methods of this invention have been described in terms of preferred embodiments, it will be apparent to those of skill in the art that variations may be applied to the methods and in the steps or in the sequence of steps of the method described herein without departing from the concept, spirit and scope of the invention. More specifically, it will be apparent that certain agents which are both chemically and physiologically related may be substituted for the agents described herein while the same or similar results would be achieved. All such similar substitutes and modifications apparent to those skilled in the art are deemed to be within the spirit, scope and concept of the invention as defined by the appended claims.REFERENCES

[0278] The following references, to the extent that they provide exemplary procedural or other details supplementary to those set forth herein, are specifically incorporated herein by reference.

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Claims

CLAIMS1. A method of forming a powder-discharge pharmaceutical composition comprising: a. obtaining an active agent and one or more pharmaceutically acceptable excipients;b. subjecting the active agent and one or more pharmaceutically acceptable excipients to a compounding process in a thermokinetic chamber to form a compounded material; andc. discharging the compounded material from the thermokinetic chamber at a discharge temperature to form the powder-discharge pharmaceutical composition, wherein the discharge temperature is less than about 65 °C.

2. The method according to claim 1, wherein the powder-discharge pharmaceutical composition comprises partially amorphous particles of the active agent.

3. The method according to claim 1 or claim 2, wherein the powder-discharge pharmaceutical composition comprises crystalline particles of the active agent.

4. The method according to claim 3, wherein the crystalline particles are microcrystalline or nanocrystalline.

5. The method according to any one of claims 1-4, wherein the active agent comprises an agent which undergoes degradation at an elevated temperature in a formulation process.

6. The method according to any one of claims 1-5, wherein the active agent comprises an agent which undergoes degradation at or above the glass transition temperature of the excipient.

7. The method according to any one of claims 1-6, wherein the active agent is chemically sensitive to temperature or shear.

8. The method according to any one of claims 1-7, wherein the active agent comprises albendazole, ricobendazole, mebendazole, flubendazole, parbendazole, oxibendazole, oxfendazole, or fenbendazole.

9. The method according to any one of claims 1-8, wherein the compounding process is a high energy mixing process.

10. The method according to any one of claims 1-9, wherein the compounding process does not comprise an external heat input.

11. The method according to any one of claims 1-10, wherein the compounding process comprises mixing the active agent and one or more pharmaceutically acceptable excipients at two or more set speeds.

12. The method according to any one of claims 1-11, wherein the compounding process comprises subjecting the active agent and one or more pharmaceutically acceptable excipients to the first speed for a first amount of time.

13. The method according to any one of claims 1-12, wherein the compounding process comprises subjecting the active agent and one or more pharmaceutically acceptable excipients to the second speed for a second amount of time.

14. The method according to any one of claims 1-13, wherein the compounding process further comprises subjecting the active agent and one or more pharmaceutically acceptable excipients to the first speed for a third amount of time.

15. The method according to any one of claims 12-14, wherein neither the first speed nor the second speed is above 4000 rpm.

16. The method according to any one of claims 1-15, wherein the thermokinetic chamber has a chamber temperature that does not change by more than 15 °C during the compounding process.

17. The method according to any one of claims 1-16, wherein the chamber temperature does not exceed 40 °C during the compounding process.

18. The method according to any one of claims 1-17, wherein the method further comprises formulating the pharmaceutical composition into a unit dose.

19. The method of claim 18, wherein the unit dose is formulated for oral, pulmonary, nasal, topical, transdermal, or parenteral delivery.

0. A method of treating a disease or disorder comprising administering to the patient a therapeutically effective amount of a powder-discharge pharmaceutical composition formed according to any one of claims 1-19 wherein the active agent is effective to treat the disease or disorder.

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