FIELD

This disclosure concerns formulations including submicron particles comprising an active agent and a cationic surface-active material, wherein the submicron particles are dispersed within a matrix material. This disclosure also includes methods of making the formulations. SUMMARY

Embodiments of submicron particle formulations are disclosed. The disclosed compositions comprise a plurality of submicron particles comprising (i) 60-99.5 wt% of an amorphous active agent and (ii) a cationic surface-active material, wherein the cationic surface- active material is cationic over at least a portion of a pH range < 5; and a matrix material comprising a reverse enteric polymer or a pharmaceutically acceptable salt thereof, wherein the submicron particles are dispersed within the matrix material.

In some embodiments, the amorphous active agent has (i) a molecular weight > 500 daltons, (ii) a logD at pH 5-7 of > 3, (iii) an aqueous solubility at pH 5-7 of < 10 μg/mL, (iv) a T _g > 50 °C, or (v) any combination of (i), (ii), (iii), and (iv). In certain embodiments, the amorphous active agent is an antiviral agent. In any or all of the foregoing embodiments, the amorphous active agent may be present in an amount of from 20 wt% to 80 wt% of the composition.

In any or all of the above embodiments, the cationic surface-active agent may be cationic over a pH range from 2 to 8. In any or all of the above embodiments, the cationic surface-active material may comprise ionizable amino groups. In some embodiments, the cationic surface-active material comprises an amine-functionalized methacrylate copolymer.

In any or all of the above embodiments, the matrix material may have a weight average molecular weight within a range of from 5-250 kDa, an aqueous solubility of at least 10 mg/mL at pH < 4, or a combination thereof. In some embodiments, the matrix material comprises a reverse enteric amine-functionalized methacrylate or acrylate polymer or copolymer, chitosan, a pharmaceutically acceptable salt thereof, or any combination thereof.

In certain embodiments, (a) the submicron particles comprise (i) an amorphous active agent having a molecular weight > 500 daltons, and (ii) a 1 :2:0.2 copolymer of ethyl acrylate, methyl methacrylate, and trimethylaminoethyl-methacrylate chloride, the copolymer having a weight average molecular weight within a range of 125-175 kDa; and (b) the matrix material comprises a copolymer of methyl methacrylate and diethylaminoethyl methacrylate, or a pharmaceutically acceptable salt thereof, having a weight average molecular weight within a range of 175-225 kDa and a monomer ratio within a range of from 6:4 to 7:3.

In any or all of the above embodiments, the submicron particles may consist essentially of the amorphous active agent and the cationic surface-active material. In any or all of the above embodiments, the submicron particles may have a Z-average diameter of from 50 nm to 400 nm as determined by dynamic light scattering. In any or all of the above embodiments, the submicron particles may be positively charged with a calculated charge density within a range of from 0.005-0.075 mol/100 g, based on a mass of the submicron particles and the calculated charge density of the cationic surface-active material.

In any or all of the above embodiments, the composition may comprise 30-80 wt% of the plurality of submicron particles and 20-70 wt% of the matrix material. In any or all of the above embodiments, the composition may have a filter potency of at least 50% in an aqueous medium having a pH of 2 as determined with a 1-μιη filter after mixing the composition in the aqueous medium for a time period of from 5 minutes to 2 hours.

In some embodiments, a composition as disclosed herein comprises (a) a plurality of submicron particles comprising (i) 60-99.5 wt% of an amorphous active agent, and (ii) a quaternary amine-functionalized methacrylate copolymer; and (b) a matrix material comprising a reverse enteric amine-functionalized methacrylate or acrylate polymer or copolymer, chitosan, a pharmaceutically acceptable salt thereof, or any combination thereof. In certain embodiments, the amorphous active agent has (i) a molecular weight > 500 daltons, (ii) a logD at pH 5-7 of > 3, (iii) an aqueous solubility at pH 5-7 of < 10 μg/mL, (iv) a T _g > 50 °C, or (v) any combination of (i), (ii), (iii), and (iv). In any or all of the foregoing embodiments, the quaternary amine- functionalized methacrylate copolymer may be a 1 :2:0.2 copolymer of ethyl acrylate, methyl methacrylate, and trimethylaminoethyl-methacrylate chloride, the copolymer having a weight average molecular weight within a range of 125-175 kDa.

This disclosure also concerns monolithic dosage forms comprising an embodiment of a composition as set forth above.

A method for making a composition as disclosed herein includes (a) preparing submicron particles comprising (i) 60-99.5 wt% of an amorphous active agent and (ii) a cationic surface-active material, wherein the cationic surface-active material is cationic over at least a portion of a pH range < 5; and (b) dispersing the submicron particles in a matrix material comprising a reverse enteric polymer or a pharmaceutically acceptable salt thereof to provide a composition comprising the preforming submicron particles dispersed within the matrix material, wherein the matrix material has a different composition than the cationic surface-active material. In some embodiments, preparing the submicron particles includes preparing an emulsion comprising a water-immiscible organic solvent, water, the amorphous active agent, and the cationic surface-active material; and evaporating the water-immiscible organic solvent to provide the submicron particles. In any or all of the foregoing embodiments, dispersing the submicron particles in the matrix material may include combining the submicron particles and the matrix material to form an aqueous suspension; and drying the aqueous suspension to provide the composition comprising the submicron particles dispersed within the matrix material. In any or all of the above embodiments, the method may further include compacting the composition to produce a monolithic dosage form.

The foregoing and other objects, features, and advantages of the invention will become more apparent from the following detailed description, which proceeds with reference to the accompanying figures.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a schematic drawing of one embodiment of the disclosed submicron particle formulations showing submicron particles dispersed within a matrix material.

FIG. 2 is a schematic drawing showing dissolution of a conventional monolithic dosage form including an active agent, a soluble neutral polymer, and a surfactant.

FIG. 3 is schematic drawing showing dissolution of a monolithic dosage form comprising an embodiment of a submicron particle formulation as disclosed herein.

FIG. 4 is a graph of submicron particle size as a function of Eudragit ^® RL polymer content in itraconazole/Eudragit ^® RL polymer submicron particles.

FIG. 5 is a graph of filter potency as a function of Eudragit ^® RL polymer content in itraconazole/Eudragit ^® RL polymer submicron particles.

FIG. 6 is a graph of submicron particle size as a function of Ethocel™ 4 polymer content in itraconazole/Ethocel™ 4 polymer submicron particles.

FIG. 7 is a graph of filter potency as a function of Ethocel™ 4 polymer content in itraconazole/Ethocel™ 4 polymer submicron particles.

FIG. 8 is a graph of submicron particle size as a function of Eudragit ^® RL polymer content in itraconazole/Eudragit ^® RL polymer submicron particles after 3 days' storage.

FIG. 9 is a graph of filter potency as a function of Eudragit ^® RL polymer content in itraconazole/Eudragit ^® RL polymer submicron particles after 3 days' storage and filtration through a 0.45-micron PTFE filter.

FIG. 10 is a graph of filter potency at pH 2 (0.45-micron filter) as a function of polyvinylpyrrolidone concentration for 80 wt% itraconazole/20 wt% Eudragit ^® RL polymer submicron particles (A, solid circles) or 80 wt% itraconazole/ 10 wt% Eudragit ^® RL polymer/10 wt% Kollicoat ^® Smartseal 30D polymer submicron particles (B, open squares) dispersed in a matrix material comprising varying amounts of polyvinylpyrrolidone and Kollicoat ^® Smartseal 30D polymer.

FIG. 1 1 is a graph of submicron particle size at pH 2 as a function of

polyvinylpyrrolidone concentration for 80 wt% itraconazole/20 wt% Eudragit ^® RL polymer submicron particles (A, solid circles) or 80 wt% itraconazole/ 10 wt% Eudragit ^® RL polymer/

10 wt% Kollicoat ^® Smartseal 30D polymer submicron particles (B, open squares) dispersed in a matrix material comprising varying amounts of polyvinylpyrrolidone and Kollicoat ^® Smartseal 30D polymer.

FIG. 12 is a graph of filter potency (0.45-μιη filter) as a function of polyvinylpyrrolidone concentration for 80 wt% telaprevir/20 wt% Eudragit ^® RL polymer submicron particles or 90 wt% telaprevir/10 wt% Eudragit ^® RL polymer submicron particles dispersed in a matrix material comprising varying amounts of polyvinylpyrrolidone and Kollicoat ^® Smartseal 30D polymer.

FIG. 13 is a series of photographs showing dispersion over time in gastric buffer of a compact comprising 80 wt% itraconazole/20 wt% Eudragit ^® RL polymer submicron particles dispersed in a chloride salt of Kollicoat ^® Smartseal 30D polymer with a loading of 45 wt% itraconazole in the compact.

FIG. 14 is a series of photographs showing dispersion over time in gastric buffer of a compact comprising 70 wt% itraconazole/30 wt% Eudragit ^® RL polymer submicron particles dispersed in a chloride salt of Kollicoat ^® Smartseal 30D polymer with a loading of 45 wt% itraconazole in the compact.

FIG. 15 is a series of photographs showing dispersion over time in gastric buffer of a compact comprising 70 wt% itraconazole/30 wt% Eudragit ^® RL polymer submicron particles dispersed in polyvinylpyrrolidone with a loading of 45 wt% itraconazole in the compact.

FIG. 16 is a graph of filter potency (1-μιη filter) as a function of percent active agent in a spray-dried powder comprising 80 wt% itraconazole/20 wt% Eudragit ^® RL polymer submicron particles dispersed in a chloride salt of Kollicoat ^® Smartseal 30D polymer.

DETAILED DESCRIPTION

This disclosure concerns embodiments of compositions comprising a plurality of submicron particles dispersed in a matrix material comprising a reverse enteric polymer or a pharmaceutically acceptable salt thereof. In some embodiments, the submicron particles comprise 60-99.5 wt% of an amorphous active agent and a cationic surface-active material. In certain embodiments, the composition is compacted into a monolithic dosage form. I. Definitions

The following explanations of terms and abbreviations are provided to better describe the present disclosure and to guide those of ordinary skill in the art in the practice of the present disclosure. As used herein, "comprising" means "including" and the singular forms "a" or "an" or "the" include plural references unless the context clearly dictates otherwise. The term "or" refers to a single element of stated alternative elements or a combination of two or more elements, unless the context clearly indicates otherwise.

Unless explained otherwise, all technical and scientific terms used herein have the same meaning as commonly understood to one of ordinary skill in the art to which this disclosure belongs. Although methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present disclosure, suitable methods and materials are described below. The materials, methods, and examples are illustrative only and not intended to be limiting. Other features of the disclosure are apparent from the following detailed description and the claims.

Unless otherwise indicated, all numbers expressing quantities of components, molecular weights, percentages, temperatures, times, and so forth, as used in the specification or claims are to be understood as being modified by the term "about." Accordingly, unless otherwise implicitly or explicitly indicated, or unless the context is properly understood by a person of ordinary skill in the art to have a more definitive construction, the numerical parameters set forth are approximations that may depend on the desired properties sought and/or limits of detection under standard test conditions/methods as known to those of ordinary skill in the art. When directly and explicitly distinguishing embodiments from discussed prior art, the embodiment numbers are not approximates unless the word "about" is recited.

Although there are alternatives for various components, parameters, operating conditions, etc. set forth herein, that does not mean that those alternatives are necessarily equivalent and/or perform equally well. Nor does it mean that the alternatives are listed in a preferred order unless stated otherwise.

Definitions of common terms in chemistry may be found in Richard J. Lewis, Sr. (ed.), Hawley's Condensed Chemical Dictionary, published by John Wiley & Sons, Inc., 1997 (ISBN 0- 471 -29205-2).

In order to facilitate review of the various embodiments of the disclosure, the following explanations of specific terms are provided:

Active agent: A drug, medicament, pharmaceutical, therapeutic agent, nutraceutical, or other compound that may be administered to a subject to effect a change, such as treatment, amelioration, or prevention of a disease, disorder, or condition, or at least one symptom associated therewith, or to effect a change in a subject's overall health or wellbeing. Average diameter: The average diameter of submicron particles is determined by dynamic light scattering (DLS), for example using a Zetasizer ZSP (Malvern Instruments™ Ltd). The reported size is the Z-average diameter, calculated from the technique of cumulants using the intensity based harmonic mean (2,3), where Si is the scattered intensity from particle / ^' and D/ ^' is the diameter of particle / ^' :

Charge density: A measurement of ionic charge per unit volume or mass. As used herein, charge density is expressed as moles of charge per 100 g of sample.

Copolymer: A polymer formed from polymerization of two or more different monomers. Filter potency: A test which measures the concentration of an active agent passing through a filter. A composition comprising submicron particles including the active agent is added to an aqueous solution. The concentration of the active agent in the resulting solution or suspension is determined using standard techniques, e.g. , high-performance liquid

chromatography. After a period of time, e.g. , between 5 minutes and 2 hours, the suspension is filtered through a filter having a defined pore size (e.g. , 1 μιη, 0.45 μιη, or 0.2 μιη), and a concentration of active agent in the filtrate is determined via standard techniques.

Friability: A measure of the mechanical stability of a monolithic dosage form, such as a tablet. Friability may be defined as the percent weight loss by the monolithic dosage form due to mechanical action. Friability testing typically is performed by placing sample including a plurality of monolithic dosage forms in a drum and rotating the drum a standard number of rotations, e.g. , 100 rotations, and loose dust is removed from the tumbled sample. The weight of the sample is measured before and after tumbling in the drum, and the percent weight loss, or friability, is measured. Friability testers are commercially available, e.g., from Agilent Technologies (Santa Clara, CA), Copley Scientific (Colwick, UK), and Sotax Corp.

(Westborough, MA).

Glass transition temperature, T _g : The temperature at which an amorphous solid , such as glass or a polymer, becomes brittle or strong on cooling , or soft or pliable on heating. T _g can be determined, for example, by differential scanning calorimetry (DSC). DSC measures the difference in the amount of heat required to raise the temperature of a sample and a reference as a function of temperature. During a phase transition, such as a change from an amorphous state to a crystalline state, the amount of heat required changes. For a solid that has no crystalline components, a single glass transition temperature indicates that the solid is homogeneous or a molecular dispersion. In general, when a sample of an amorphous active agent is tested by increasing the temperature of the sample at a constant rate, typically 1 to 10 °C/min, T _g will be observed as a relatively sharp increase in heat capacity.

LogD: The logarithm of the distribution coefficient - the ratio of the sum of the concentrations of all forms (ionized and un-ionized) of a compound in octanol and water.

Matrix material: As used herein, the term "matrix material" refers to a polymeric material in which submicron particles are mixed or dispersed.

Monolithic dosage form: A unitary solid dosage form, e.g., a tablet or lozenge.

Pharmaceutically acceptable salt: A biologically compatible salt of a compound, which salts are derived from a variety of organic and inorganic counter ions well known in the art. Pharmaceutically acceptable counter ions include, by way of example only, sodium, potassium, calcium, magnesium, ammonium, tetraalkylammonium, and the like; and when the molecule contains a basic functionality, salts of organic or inorganic acids, such as chloride, bromide, tartrate, mesylate, acetate, maleate, oxalate, and the like.

Polymer: A molecule of repeating structural units (e.g., monomers) formed via a chemical reaction, i.e., polymerization.

Reverse enteric polymer: A polymer that is soluble at low pH (pH < 3) and is insoluble at high pH (pH > 7). By soluble is meant that the polymer has a solubility of at least 20 mg/mL in aqueous medium at the given pH. By insoluble is meant that the polymer has a solubility of less than 1 mg/mL in aqueous medium at the given pH.

Solution: A homogeneous mixture composed of two or more substances. A solute (minor component) is dissolved in a solvent (major component). A plurality of solutes and/or a plurality of solvents may be present in the solution.

Submicron particle: As used herein, the term submicron particle refers to particles having at least one dimension of less than one micron, particularly particles having a size of less than 500 nm in all dimensions. They can be dispersed in a solution or in a solid matrix.

Neutral polymer: A polymer that, overall, has a net neutral charge.

Surface-active material/surfactant: As defined by lUPAC, a surface-active agent or material is a substance which lowers the surface tension of the medium in which it is dissolved, and/or the interfacial tension with other phases, e.g., between two liquids or between a liquid and a solid. Surface-active materials may act as dispersants. A cationic surface-active material includes one or more cationic groups, e.g., ionizable amino groups.

Suspension: A heterogeneous mixture in which very small particles are dispersed substantially uniformly in a liquid or gaseous medium. A liquid suspension in which the dispersed particles have a diameter between about 1 -100 nm is considered to be a colloidal suspension. The particles in a colloidal suspension tend to remain in suspension. If the particles have a diameter larger than about 100 nm, they typically will settle if undisturbed and form a sediment.

Weight average molecular weight:

ΣΝ ²

Mw = where Mi is the molecular weight of a chain, and Ni is the number of chains of that molecular weight. Weight average molecular weight is determined by methods that are sensitive to molecular size, such as light-scattering techniques, small angle neutron scattering, X-ray scattering, and sedimentation velocity.

II. Submicron Particle Formulations

Disclosed herein are embodiments of submicron particle formulations. The formulation comprises a plurality of submicron particles dispersed in a matrix material. In some embodiments, the submicron particles comprise (i) 60-99.5 wt% of an amorphous active agent and (ii) a cationic surface-active material, wherein the cationic surface-active material is cationic over at least a portion of a pH range < 5. The matrix material comprises a reverse enteric polymer or a pharmaceutically acceptable salt thereof. In any or all of the above embodiments, the submicron particles may be dispersed within or substantially throughout the matrix material.

In any or all of the above embodiments, the submicron particles may comprise at least

60 wt%, at least 70 wt%, at least 80 wt%, at least 90 wt%, at least 92 wt%, at least 95 wt% , at least 97 wt%, or at least 99 wt% amorphous active agent, such as at least 60-99.5 wt%, 70-99 wt%, 75-99 wt%, 80-99 wt%, or 90-99wt% of an amorphous active agent. In some

embodiments, the amorphous active agent has a molecular weight > 500 daltons, > 600 daltons, > 700 daltons, > 800 daltons, or > 900 daltons, such as a molecular weight of 500-2000 daltons, 500-1500 daltons, 500-1000 daltons, or 600-1000 daltons. In any or all of the foregoing embodiments, the amorphous active agent may be poorly aqueous soluble with an aqueous solubility at pH 5-7 of < 10 μg/mL, < 5 μg/mL, < 1 μg/mL, or even < 0.1 μg/mL, such as an aqueous solubility of 0.0001 -10 μg/mL, 0.0001 -5 μg/mL, 0.001 -1 μg/mL, or 0.001 -0.1 μg/mL. In any or all of the foregoing embodiments, the amorphous active agent may have a logD at pH 5- 7 of > 3, > 4, or > 5, such as a logD at pH 5-7 within a range of 3-10, 4-10, 5-10, or 5-7. In any or all of the foregoing embodiments, the amorphous active agent may have a glass transition temperature T _g of > 50, > 75 °C, or > 100 °C, such as a T _g from 50-180 °C, 75-180 °C, or 100- 180 °C. In any or all of the foregoing embodiments, the active agent may be in a non-crystalline or crystalline form prior to forming the submicron particles. However, at least 90 wt% of the active agent in the submicron particles is in an amorphous form. In some embodiments, at least 95 wt% of the active agent in the submicron particles is in an amorphous form.

In some embodiments, the amorphous active agent is an antiviral agent or an antifungal agent (e.g., itraconazole). In certain embodiments, the amorphous active agent is an antiviral agent (e.g. telaprevir). In certain examples, the amorphous active agent was itraconazole or telaprevir. Properties of two exemplary active agents are shown below in Table 1 .

Table 1

The submicron particles further comprise a cationic surface-active material wherein the cationic surface-active material is cationic over at least a portion of a pH range < 5. In some embodiments, the cationic surface-active material is cationic over a pH range of from 2 to 8. In any or all of the above embodiments, the cationic surface-active material may comprise ionizable amino groups, such as ionizable secondary, tertiary, and/or quaternary amino groups. In some embodiments, the cationic surface-active material comprises an amine-functionalized methacrylate copolymer. By "amine-functionalized" is meant that the methacrylate copolymer has at least one amine group. The amine group can be either a primary amine, a secondary amine, a tertiary amine, or a quaternary amine. By "methacrylate copolymer" is meant that the copolymer is made by polymerization of at least two methacrylate or acrylate monomers. In certain embodiments, at least one of the methacrylate or acrylate monomers is amine functionalized. The amine-functionalized methacrylate copolymer may have a weight average molecular weight within a range of 50-250 kDa, 75-225 kDa, 100-200 kDa, or 125-175 kDa. In certain embodiments, the amine-functionalized methacrylate copolymer is a copolymer of ethyl acrylate, methyl methacrylate, and trimethylaminoethyl-methacrylate chloride. One exemplary amine-functionalized methacrylate copolymer is Eudragit ^® RL, a 1 :2:0.2 copolymer of ethyl acrylate, methyl methacrylate, and trimethylaminoethyl-methacrylate chloride with a weight average molecular weight of 150 kDa (Evonik Industries AG, Essen, Germany). In any or all of the above embodiments, the submicron particles may consist essentially of, or consist of, the amorphous active agent and the cationic surface-active material. "Consist essentially of" means that the submicron particles do not comprise any additional components that materially affect the submicron particle properties, including, but not limited to, anionic or non-ionic surface- active materials, crystalline active agents, stabilizing polymers, or the like. However, the submicron particles may comprise trace amounts of components that do not materially affect the submicron particle properties, including, for example, trace amounts (< 1 wt%) of solvent(s) used to prepare the submicron particles. "Consist essentially of" also means that the particles may include small amounts (up to 5 wt%) of water, particularly if the system is in equilibrium with an environment having a relatively high relative humidity.

In any or all of the above embodiments, the submicron particles may comprise a solid solution of amorphous active agent distributed substantially homogeneously throughout the cationic surface-active material, domains of amorphous active agent dispersed throughout the cationic surface-active material, any combination of these states, or those states that lie between them.

In any or all of the above embodiments, the submicron particles may have a Z-average diameter, or effective cumulant diameter, of < 400 nm as determined by dynamic light scattering. The diameter refers to the diameter of spherical particles or the maximum diameter for non-spherical particles. In some embodiments, the submicron particles have an average diameter of < 300 nm, or < 200 nm, such as an average diameter within a range of 50-400 nm, 50-300 nm, or 50-200 nm. In any or all of the above embodiments, the submicron particles may have a net positive charge. In some embodiments, the submicron particles have a calculated charge density within a range of from 0.005-0.075 mol/100 g, based on a mass of the submicron particles and the calculated charge density of the cationic surface-active material, such as a calculated charge density within a range of from 0.005-0.06 mol/100 g, 0.005-0.05 mol/100 g, 0.005-0.04 mol/100 g, or 0.005-0.03 mol/100 g. For 100-nm submicron particles, a charge density of 0.005-0.075 mol/100 g corresponds to roughly 1-14 charges/nm ² of surface area. Eudragit ^® RL, an exemplary cationic surface-active material has a charge density of 0.058 mol/100 g and a T _g of 63 °C.

Embodiments of the submicron particle formulations further comprise a matrix material in which the submicron particles are dispersed. In some embodiments, the submicron particles are dispersed within the matrix material such that the submicron particles are partially or fully embedded within or encapsulated by the matrix material. In certain embodiments, the submicron particles are dispersed throughout or substantially throughout the matrix material. FIG. 1 schematically shows a composition 10 comprising submicron particles 12 embedded within or encapsulated by the matrix material 16. Submicron particles 12' not fully encapsulated by the matrix material 16 have at least a portion of their surfaces directly in contact with the matrix material 16. The matrix material provides spacing between the submicron particles.

Advantageously, the matrix material is a polymer that dissolves quickly in a use environment or analogous media, thereby releasing submicron particles into the media. In some embodiments, the matrix material is soluble in the stomach or a simulated gastric media. The matrix material may aid in preventing aggregation of the submicron particles and/or facilitate dispersion and dissolution of the submicron particles in a use environment such as the stomach.

In any or all of the above embodiments, the matrix material may comprise a reverse enteric polymer or a pharmaceutically acceptable salt thereof. In some embodiments, the matrix material has a different composition than the cationic-surface-active material that is present in the submicron particles. In certain embodiments, the matrix material does not consist of the cationic surface-active material that is present in the submicron particles. In any or all of the foregoing embodiments, the matrix material may have a weight average molecular weight within a range of from 5-250 kDa, such as a weight average molecular weight within a range of from 5-200 kDa, 5-100 kDa, 5-50 kDa, 5-25 kDa, or 5-20 kDa. In any or all of the above embodiments, the matrix material may have a solubility of at least 10 mg/mL at pH < 4. In some embodiments, the matrix material has a solubility of at least 20 mg/mL, at least 30 mg/mL, at least 40 mg/mL, at least 50 mg/mL, at least 75 mg/mL, or at least 100 mg/mL at pH < 4. In certain embodiments, the matrix material has a solubility of from 10-1000 mg/mL, 10- 500 mg/mL, 50-500 mg/mL, 100-500 mg/mL, or 100-400 mg/mL at pH < 4.

Suitable matrix materials include, but are not limited to, a reverse enteric amine- functionalized methacrylate or acrylate polymer or copolymer, chitosan, pharmaceutically acceptable salts thereof, or any combination thereof. It is understood that a pharmaceutically acceptable salt of a polymer may refer to a full salt in which all reactive groups on the polymer have been neutralized or a partial salt in which only some reactive groups on the polymer have been neutralized. In some embodiments, the matrix material comprises a full or partial chloride or acetate salt of a reverse enteric polymer. Exemplary matrix materials include Kollicoat ^® Smartseal (a copolymer of methyl methacrylate (MMA) and diethylaminoethyl methacrylate (DEAEMA), BASF Corporation, Florham Park, NJ), Eudragit ^® E (poly(butylmethacrylate-co-(2- dimethylaminoethyl)methacrylate-co-methyl methacrylate, Evonik Industries AG, Essen, Germany), and chitosan. Kollicoat ^® Smartseal polymer has a charge density of 0.24 mol/100 g and a T _g of 84 °C. Eudragit ^® E polymer has a T _g of 48 °C. Chitosan has a charge density of 0.62 mol/100 g; the T _g of chitosan is difficult to determine and reports range from 1 18-203 °C (see, e.g., Dong et ai, Applied Polymer Science 2004; Sakurai et ai, Polymer 2000,

41 (19)7051-7056; Dhawade et ai, Adv. in Appl. Sci. Res. 2012, 3(3):1372-1382). Thus, in some embodiments, the matrix material has a T _g of at least 45 °C or at least 75 °C, such as from 45-210 °C. In one embodiment, the matrix material comprises a copolymer of methyl methacrylate and diethylaminoethyl methacrylate having a weight average molecular weight within a range of 175-225 kDa and a monomer ratio within a range of from 6:4 to 7:3, such 6:4, 2: 1 , or 7:3. In an independent embodiment, the matrix material comprises a full or partial chloride salt and/or a full or partial acetate salt of a copolymer of methyl methacrylate and diethylaminoethyl methacrylate having a weight average molecular weight within a range of 175-225 kDa and a monomer ratio within a range of from 6:4 to 7:3.

In some embodiments, the matrix material further comprises a neutral polymer.

Exemplary neutral polymers include, but are not limited to, polyvinylpyrrolidone (PVP), poly(vinylpyrrolidone-co-vinyl acetate) (PVPVA), hydroxypropyl methylcellulose (HPMC), and the like. Thus, the matrix material may comprise a combination of a reverse enteric polymer and a neutral polymer. In some examples, the matrix material includes up to 75 wt% of a neutral polymer based on a total mass of polymers in the matrix mateiral, such as from 5- 75 wt%, 5-50 wt%, or 5-25 wt% of a neutral polymer.

In any or all of the above embodiments, the matrix material may further comprise a surfactant. The surfactant may be a cationic surfactant, an anionic surfactant, or a non-ionic surfactant. Exemplary surfactants include, but are not limited to, sodium lauryl sulfate, Kolliphor ^® CS 20 (ethoxylated cetyl and stearyl alcohols; BASF Industries), TPGS (tocopheryl polyethylene glycol succinate), polysorbates, sorbitan esters, pegylated oils, poloxamers, and the like. In certain embodiments, the matrix material may include from 0.1 to 10 wt% surfactant.

In any or all of the foregoing embodiments, the matrix material may consist essentially of, or consist of, the reverse enteric polymer or pharmaceutically acceptable salt thereof.

"Consist essentially of means that the matrix material does not include other components in amounts that may materially affect the matrix material properties, such as enteric polymers, active agents, cationic surface-active materials, and the like. However, the matrix material may include trace amounts (e.g., < 1 wt%) of components that do not materially affect the matrix material properties. For example, Kollicoat ^® Smartseal may include trace amounts of macrogol cetostearylether and/or sodium lauryl sulfate as stabilizers.

Some embodiments of the disclosed submicron particle formulations comprise at least

30 wt%, at least 40 wt%, at least 50 wt%, or at least 60 wt% of the plurality of submicron particles, such as 30-80 wt%, 35-75 wt%, 40-70 wt%, 45-60 wt%, or 50-55 wt% submicron particles. Correspondingly, the formulations comprise 20-70 wt%, 25-70 wt%, 30-70 wt%, 30- 65 wt%, 30-60 wt%, 40-60 wt%, 40-55 wt%, or 45-50 wt% of the matrix material. Certain embodiments of the disclosed submicron particle formulations comprise from 20-80 wt%, 25- 75 wt%, 30-70 wt%, 30-60 wt%, or 30-50 wt% of the amorphous active agent, based on a total mass of the submicron particles and the matrix material.

In any or all of the above embodiments, the submicron particle formulation may consist essentially of, or consist of, the plurality of submicron particles and the matrix material. "Consist essentially of" means that the formulation does not include additional components that materially affect the formulation properties. However, the formulation may include trace amounts of components as set forth above that do not materially affect the formulation properties.

In some embodiments, the submicron particle formulation comprises, consists essentially of, or consists of (a) a plurality of submicron particles comprising (i) 60-99.5 wt% of an amorphous active agent and (ii) a quaternary amine-functionalized methacrylate copolymer, and (b) a matrix material comprising a reverse enteric amine-functionalized methacrylate or acrylate polymer or copolymer, chitosan, a pharmaceutically acceptable salt of any of the foregoing polymers, or any combination thereof. The formulation may comprise 30-80 wt% of the plurality of submicron particles and 20-70 wt% of the matrix material. In certain

embodiments, (a) the submicron particles comprise (i) an active agent having a molecular weight > 500 daltons, and (ii) a 1 :2:0.2 copolymer of ethyl acrylate, methyl methacrylate, and trimethylaminoethyl-methacrylate chloride, the copolymer having a weight average molecular weight within a range of 125-175 kDa; and (b) the matrix material comprises a copolymer of methyl methacrylate and diethylaminoethyl methacrylate, or a pharmaceutically acceptable salt thereof, having a weight average molecular weight within a range of 175-225 kDa and a monomer ratio within a range of from 6:4 to 7:3. In any or all of the foregoing embodiments, the amorphous active agent, at pH 5-7, may have (i) a logD > 3, (ii) an aqueous solubility of less than 10 μg/mL, (iii) a T _g > 50 °C, or (iv) any combination of (i), (ii), and (iii).

In any or all of the above embodiments, the submicron particle formulation may have a filter potency of at least 50% in an aqueous medium having a pH of 2 as determined with a 1- μιη filter. In some embodiments, the filter potency in the pH 2 aqueous medium is at least 55%, at least 60%, at least 65%, at least 70%, or at least 75% as determined with a 1-μιη filter. Filter potency determines the concentration of active agent after passing a suspension of submicron particles through a filter. A solid composition comprising the submicron particles is added to an aqueous solution, such as water, phosphate-buffered saline, or a model gastric buffer to form a suspension. The concentration of drug in the so-formed suspension is determined using standard techniques, such as by high-performance liquid chromatography (HPLC). The suspension is stirred for a period of time, e.g., 5 minutes - 120 minutes. The suspension is then filtered through a filter, and the concentration of drug in the filtered sample is determined via standard techniques. A loss in potency after filtering a sample through a filter is an indication that the submicron particles in the sample are larger than the filter pore size.

Exemplary filters that can be used include a 1 -μιη glass fiber filter, a 0.45-μιη syringe filter, and a 0.2-μιη syringe filter. One skilled in the art will understand that the pore size of the filter should be selected to ensure the submicron particles are not retained on the filter. For example, a 1 -μιη filter is suitable for submicron particles with a diameter > 250 nm, a 0.45-μιη filter is suitable for 150-300 nm submicron particles, and a 0.2-μιη filter is suitable for submicron particles having a diameter < 200 nm.

There are several potentially useful methods for determining that the active-containing submicron particles and the matrix are present as discrete phases. Often the mobility as a function of temperature of the submicron particles and the matrix will be different. This difference can be determined by measuring the-glass transition temperature(s) of the composite material, e.g., via differential scanning calorimetry (DSC). If there are two separate glass transitions, this indicates the existence of two different phases. The existence of glass transition is noted by a step change in the heat capacity of the material. Another method for determining the existence of two phases is with the use of solid state NMR. The T1 relaxation time of peaks associated with the active agent can be compared to the T1 relaxation time of peaks associated with the matrix polymer. If these relaxation times are different, that is an indication that the two compounds are present in different phases at a length scale of at least tens of nanometers.

In certain embodiments, the presence of submicron particles in the solid composition also may be determined or confirmed using one or more the following alternative procedures. A sample of the solid composition is embedded in a suitable material, such as an epoxy or polyacrylic acid (e.g., LR White from London Resin Co., London, England). The sample is then microtomed to obtain a cross-section of the solid composition that is about 100 to 200 nm thick. This sample is then analyzed using transmission electron microscopy (TEM) with electron energy loss spectroscopy (EELS) analysis. TEM-EELS analysis is sensitive to organic molecule functional groups. In some instances where the active agent includes heavy atoms, the sample may be analyzed using transmission electron microscopy (TEM) with energy dispersive X-ray (EDX) analysis. TEM-EDX analysis quantitatively measures the concentration and types of atoms larger than boron over the surface of the sample. From the TEM-EELS and/or TEM-EDX analysis, regions that are rich in active agent can be distinguished from regions that are rich in the matrix material. Another suitable method for embodiments where the drug is fluorescent is fluorescence microscopy, which can be used to visualize the drug-rich regions. The size of the regions that are rich in active agent typically will have an average diameter of < 400 nm in these analyses, demonstrating that the solid composition comprises submicron particles comprising the active agent in the matrix material. See, for example, Transmission Electron Microscopy and Diffractometry of Materials (2001 ) for further details of the TEM-EDX method.

Embodiments of the disclosed submicron particle formulations may be formulated into monolithic dosage forms. In some embodiments, the submicron particle formulation is compressed to form a monolithic dosage form such as a tablet. In some embodiments, the monolithic dosage form consists essentially of, or consists of, the submicron particle formulation. "Consists essentially of means that the monolithic dosage form may include trace amounts (e.g., less than 1 wt%) of other materials that do not materially affect the properties of the monolithic dosage form, such as trace amounts of a lubricant or glidant. In other embodiments, the tablet may further comprise a binder, a coating (e.g., a coating that is soluble in gastric fluid at acidic pH), a glidant, a colorant, a flavoring agent, or any combination thereof.

The inclusion of submicron particles in the matrix material, and monolithic dosage forms comprising the submicron particle formulations, provides advantages over comparable formulations that do not include submicron particles. A conventional monolithic dosage form 100 including an active agent, a soluble neutral polymer and surfactant is shown in FIG. 2. The active agent is dispersed substantially throughout the dosage form 100. The monolithic dosage form 100 begins to erode in the stomach and the active agent, polymer, and surfactant separate, forming submicron particles 1 10 comprising the active agent and the surfactant as the soluble polymer 120 dissolves. Low loading of the active agent is required for the dosage form to dissolve. At high loadings, the active agent creates a network rather than submicron particles and fails to dissolve. This tendency is exacerbated with high molecular weight, lipophilic, and/or charged active agents, as well as active agents with a low tendency toward crystallization, including many antiviral agents.

In contrast, a monolithic dosage form 200 as disclosed herein comprises a plurality of submicron particles 210 dispersed within a matrix material 220 (i.e., a matrix material comprising a reverse enteric polymer or pharmaceutically acceptable salt thereof) as shown in FIG. 3. The submicron particles 210 comprise an amorphous active agent and a cationic surface-active material. The monolithic dosage form 210 erodes in the stomach, releasing submicron particles 210 as the matrix material 220 dissolves. The dissolution rate may be tuned, in part, by selecting a matrix material having a desirable dissolution profile. The released submicron particles dissolve rapidly in the upper duodenum. Compared to conventional monolithic dosage forms, a higher loading of the active agent is possible because the submicron particles are preformed under controlled processing conditions as stable particles, thereby increasing the dissolution rate of the active agent and avoiding the problems of active agent network formation. In some embodiments, a positively-charged matrix material facilitates dispersion of the submicron particles in a use environment, such as the stomach.

Advantageously, in certain embodiments, the monolithic dosage form remains in the stomach as it erodes, and release of the submicron particles enables rapid absorption of the active agent in the upper intestine. III. Methods of Making Submicron Particle Formulations

Embodiments of a method for making a submicron particle formulation as disclosed herein include (a) preparing submicron particles comprising (i) 60-99.5 wt% of an amorphous active agent and (ii) a cationic surface-active material, wherein the cationic surface-active material is cationic over at least a portion of a pH range < 5; and (b) dispersing the submicron particles in a matrix material comprising a reverse enteric polymer or a pharmaceutically acceptable salt thereof to provide a composition comprising the submicron particles dispersed within the matrix material, such as throughout or substantially throughout the matrix material. In some embodiments, the matrix material has a different composition than the cationic surface- active material present in the submicron particles.

In any or all of the above embodiments, preparing the submicron particles may comprise preparing an emulsion comprising a water-immiscible organic solvent, water or an aqueous solution, the active agent, and the cationic surface-active material, and evaporating the organic solvent to provide the submicron particles. Suitable organic solvents include any solvent or mixture of solvents in which the active agent and the cationic surface-active material are mutually soluble and which immiscible with water or aqueous solutions. As used herein, the term "immiscible" means that the organic solvent has a solubility in the water or aqueous solution of less than about 10 wt%, preferably less than about 5 wt%, and most preferably less than about 3 wt%. In some embodiments, the organic solvent is volatile with a boiling point of 150 °C or less. Exemplary organic solvents include dichloromethane, trichloroethylene, trichloro-trifluoroethylene, tetrachloroethane, trichloroethane, dichloroethane, dibromoethane, ethyl acetate, phenol, chloroform, toluene, xylene, ethyl-benzene, benzyl alcohol, creosol, methyl-ethyl ketone, methyl-isobutyl ketone, hexane, heptane, ether, and mixtures thereof. In certain embodiments, the organic solvents is dichloromethane, ethyl acetate, benzyl alcohol, or a mixture thereof. In any or all of the foregoing embodiments, the emulsion may comprise water. In one embodiment, the active agent and cationic surface-active material are dissolved or suspended in the organic solvent and then mixed with the water or aqueous solution. In an independent embodiment, the active agent is dissolved in the organic solvent, while the cationic surface-active material is dissolved or suspended in the water or aqueous solution, and the two solutions (or solution and suspension) are combined. The mixture of the water-immiscible organic solvent, water or aqueous solution, active agent, and cationic surface-active material is mixed and homogenized to form an emulsion of fine droplets of the water immiscible solvent distributed throughout the aqueous phase. The volume ratio of organic solution to

water/aqueous solution used in the process will generally range from 1 : 100 (organic solution:water/aqueous solution) to 2:3 (organic solution:water/aqueous solution). In some embodiments, the organic solution:water/aqueous solution volume ratio ranges from 1 :9 to 1 :2 (organic solution:water/aqueous solution). The emulsion is generally formed by a two-step homogenization procedure. The organic and water/aqueous solution are first mixed using a rotor/stator or similar mixer to create a "pre-emulsion". This mixture is then further processed with a high-pressure homogenizer that subjects the droplets to very high shear, creating a uniform emulsion of very small droplets. A portion of the organic solvent is then removed forming a suspension of the submicron particles in the water/aqueous solution. Exemplary processes for removing the organic solvent include evaporation, extraction, diafiltration, pervaporation, vapor permeation, distillation, and filtration. In some embodiments, the organic solvent is removed to a level that is acceptable according to The International Committee on Harmonization (ICH) guidelines. Advantageously, the concentration of organic solvent in the submicron particle suspension is less than the solubility of the organic solvent in the water/aqueous solution. In some embodiments the concentration of organic solvent remaining in the aqueous submicron particle suspension is less than about 5 wt %, less than about 3 wt %, less than 1 wt %, or even less than 0.1 wt %. In certain embodiments, at least some of the water also is evaporated.

An alternative process to form the submicron particles is a precipitation process. In this process, the active agent and cationic surface-active material are first dissolved in an organic solvent that is miscible with water or an aqueous solution comprising water and any compound or mixture of compounds in which the active agent and cationic surface-active material are poorly soluble, i.e., sufficiently insoluble so as to precipitate to form submicron particles. The resulting organic solution is mixed with the water or aqueous solution causing the submicron particles to precipitate. Solvents suitable for forming the solution of active agent and cationic surface-active material can be any compound or mixture of compounds in which the active agent and cationic surface-active material are mutually soluble and which is miscible in the aqueous solution. Preferably, the organic solvent is also volatile with a boiling point of 150 °C or less. Exemplary solvents include acetone, methanol, ethanol, tetrahydrofuran (THF), and dimethylsulfoxide (DMSO). Mixtures of solvents, such as 50% methanol and 50% acetone, can also be used, so long as the active agent and cationic surface-active material are sufficiently soluble to dissolve. The organic solution and water or aqueous solution are combined under conditions that cause solids to precipitate as submicron particles. The mixing can be by addition of a bolus or stream of organic solution to a stirring container of the water or aqueous solution. Alternately a stream or jet of organic solution can be mixed with a moving stream of water or aqueous solution. In either case, the precipitation results in the formation of a suspension of submicron particles in the water or aqueous solution. Alternatively, the active agent is dissolved in the organic solvent, while the cationic surface-active material is dissolved or suspended in the water or aqueous solution. The submicron particles are then formed using the above precipitation procedure. For the precipitation process, the amount of active agent and cationic surface-active material in the organic solution depends on the solubility of each in the organic solvent and the desired ratios of active agent and cationic surface-active material in the resulting submicron particles. The organic solution may comprise from about 0.1 wt % to about 10 wt % dissolved solids, such as from about 0.1 wt% to about 5 wt% dissolved solids. The organic solution:water/aqueous solution volume ratio should be selected such that there is sufficient water/aqueous solution in the submicron particle suspension that the submicron particles solidify and do not rapidly agglomerate. However, too much water or aqueous solution will result in a very dilute suspension of submicron particles, which may require further processing for ultimate use. Generally, the organic solution:water/aqueous solution volume ratio is within a range of from 1 : 100 to 1 :2 (organic solution:water/aqueous solution) such as from about 1 :20 to about 1 :3. Once the submicron particle suspension is made, a portion of the organic solvent may be removed from the suspension using methods known in the art.

Exemplary processes for removing the organic solvent include evaporation, extraction, diafiltration, pervaporation, vapor permeation, distillation, and filtration. In some embodiments, the solvent is removed to a level that is acceptable according to ICH guidelines. Thus, the concentration of solvent in the submicron particle suspension may be less than about 10 wt %, less than about 5 wt %, less than about 3 wt %, less than 1 wt %, and even less than 0.1 wt %.

In one embodiment, the submicron particles are dispersed in the matrix material without further purification or isolation. In an independent embodiment, the submicron particles are isolated and then dispersed in the matrix material. The submicron particles can be isolated by removing some or all of the liquid from the suspension. Exemplary processes for removing at least a portion of the liquid include spray drying, spray coating, spray layering, lyophilization, evaporation, vacuum evaporation, filtration, ultrafiltration, reverse osmosis, and other processes known in the art.

In any or all of the above embodiments, dispersing the submicron particles in the matrix material may comprise adding the matrix material to an aqueous suspension of the submicron particles. In one embodiment, after mixing thoroughly, the aqueous suspension is spray dried to form the submicron particle formulation. In an independent embodiment, after mixing thoroughly, the aqueous suspension is lyophilized to form the submicron particle formulation.

In any or all of the above embodiments, the composition comprising the preforming submicron particles dispersed within the matrix material is compacted to provide a monolithic dosage form. Compaction can be performed at any pressure effective for forming a stable monolith, i.e., a monolith that can be handled, packaged, etc. without significant friability (e.g., < 1 %). In some embodiments, compaction is performed with a compression force of 150-200 kg and/or a strain of 50-60 MPa. IV. Examples

General Methods

Homogenization and spray-drying: An organic solvent (e.g., dichloromethane, DCM) is combined with the active agent and cationic surface-active material, and mixed (e.g., by vortexing) until all components are dissolved. Water is added to the solution, and the two phases are homogenized with a rotor stator at 10,000 rpm for 1-2 minutes. The emulsion may be further homogenized for 3-5 minutes at a pressure of 15,000 psi (-100 MPa) and a temperature of 15 °C. After homogenization, the organic solvent is removed, e.g., by rotor evaporation, to provide an aqueous suspension of submicron particles. An aqueous solution comprising the matrix material is added to the aqueous suspension of submicron particles and mixed. Unless otherwise specified, the solution comprising the matrix material includes 5 wt% matrix material. The mixed suspension is spray-dried in a conventional manner to provide the submicron particle formulation.

Potency and resuspendability testing: A sample of the, submicron particle formulation is added to a scintillation vial containing a stir bar. Aqueous media at pH 2 (0.01 N HCI) (this is termed "GB media") is added to the vial and stirred for 10 minutes at 37°C. An aliquot of the suspension is removed. Aliquots of the suspension are filtered, e.g., through a 1-μιη filter, a 0.45-μιη filter, or a 0.2-μιη filter. Dynamic light scattering is run on all the unfiltered and filtered aliquots to determine submicron particle size. The aliquots are then diluted with 50-1000 μΙ_ methanol, depending on clarity, and analyzed via HPLC to determine the active agent concentration.

Unless expressly stated otherwise, all percentages of components are percent by weight.

Example 1

Itraconazole Submicron Particles

Submicron particles comprising itraconazole (ITZ) were prepared as described in the General Methods. Emulsification was performed by homogenization using a Silverson pressure-driven rotor-stator (ca. 1-cm diameter; Silverson, East Longmeadow, MA) at 10,000 rpm for 1 minute, followed by homogenization in a Microfluidics M-1 10S materials processor for 3 minutes (Microfluidics, Newton, MA). The DCM and some of the water was removed by roto- evaporation. The composition details are provided in Table 2 where DCM is dichloromethane, RL is Eudragit ^® RL 1 :2:0.2 copolymer of ethyl acrylate, methyl methacrylate, and

trimethylaminoethyl-methacrylate chloride with a weight average molecular weight of 150 kDa (Evonik Industries AG, Essen, Germany) and P188 is poloxamer 188. Table 2 - ITZ/RL and ITZ/RL/P188 Particle Formulations

Dynamic light scattering (DLS) showed the average diameter of the submicron particles prior to lyophilization ranged from 200-400 nm (Table 3). Smaller submicron particles appeared to be more stable. Size increased with decreasing Eudragit ^® RL concentration for the ITZ/RL system.

Table 3 - ITZ/RL and ITZ/RL/P188 Particle Sizes

Submicron particles were prepared with a positive charge for dispersion in gastric media using an insoluble amine-functionalized methacrylate copolymer (Eudragit ^® RL). Some examples further included a neutral (ethyl cellulose (Ethocel™ 4 ethylcellulose, The Dow Chemical Company)). The ratio of active agent to Eudragit ^® RL defines the charge density on the submicron particle surface. Preparation of all samples involved dissolving ITZ, Eudragit ^® RL and/or Ethocel™ 4 in DCM (dichloromethane) using a vortex, adding water to the DCM phase, an initial emulsification at 10,000 rpm on the Silverson rotor stator and then homogenizing on the Microfluidics M1 10S with a Y chamber for 3 minutes at about 13,000 PSI. The resulting emulsion was typically 35 - 38 mL due to some additional water in the system to start and used to flush the material from the system. The DCM and some water was removed by rotary evaporation resulting in a final volume typically between 15 and 30 mL. The prepared formulations are shown in Table 4.

Table 4 - ITZ/RL and ITZ/RL/Ethocel™ 4 Formulations

Particle size was analyzed by DLS the following day and filter potency was determined using a 1-micron glass filter or a 0.45-micron PTFE filter as summarized in Table 5.

Table 5 - ITZ/RL and ITZ/RL/Ethocel™ 4 Particle Size and Filter Potency

The effect of adding Eudragit ^® RL to the DCM phase with itraconazole is shown in FIG. 4. The size decreased rapidly between 5 and 10% Eudragit® RL and then stabilized at a size of about 130 nm as Eudragit ^® RL increased further (the size decreased only slightly).

The filter potency (FIG. 5) was consistent with the DLS data. All samples had excellent recovery through a 0.45-μιη PTFE filter. The addition of Ethocel™ 4 polymer to ITZ/Eudragit ^® RL submicron particles at a constant Eudragit ^® RL concentration of 10% (dry basis) did not have a significant impact on the particle size of the submicron particles and negatively impacted the filter potency. The filter potency decreased as Ethocel™ 4 concentration increased, suggesting that the "harder" submicron particles did not pass as easily through the filter (FIG. 7). This observation, however, may have little relevance to reconstitution from a spray dried powder.

The submicron particles were analyzed again after 3 days of storage. The size of the submicron particles increased modestly and the filter potency of some samples decreased. After 3 days' storage, the size of the submicron particles as a function of Eudragit ^® RL loading was a smooth function (Table 6). Additionally, the amount of sample lost through a 0.45-micron filter increased after storage for samples with 5 or 10% Eudragit ^® RL, but not at higher Eudragit ^® RL loading (Table 7). FIG. 8 shows submicron particle size as a function of Eudragit ^® RL polymer content in itraconazole/Eudragit ^® RL polymer submicron particles (formulations 1-5) after 3 days' storage. FIG. 9 shows the filter potency as measured after filtration with a 0.45- micron filter for formulations 1-5 after 3 days' storage. The stability of the submicron particles in aqueous suspension over 3 days was significantly better for submicron particles containing a least 20 wt% Eudragit ^® RL polymer.

Table 6 - ITZ/RL and ITZ/RL/Ethocel™ 4 Particle Size after Storage

Table 7 - ITZ/RL and ITZ/RL/Ethocel™ 4 Filter Potency after Storage

3 102 1 18

4 1 13 101

5 106 95

6 82 104

7 71 63

8 45 29

Example 2

Lyophilized Itraconazole Submicron particle/Matrix Material Compositions Submicron particles comprising ITZ and Eudragit ^® RL polymer and/or spray-dried Kollicoat ^® Smartseal polymer (a copolymer of methyl methacrylate and diethylaminoethyl methacrylate, BASF Corporation, Florham Park, NJ) were prepared as described in General Methods. The formulations are shown in Table 8 where ITZ is itraconazole, RL is Eudragit ^® RL polymer, SS is spray-dried Kollicoat ^® Smartseal 30D polymer, and DCM is dichloromethane.

Table 8 - ITZ/RL and ITZ/RL/SS Formulations

Submicron particle size and filter potency were determined as described in General Methods. The results are shown in Table 9. Good filter potency and size was obtained for both samples A and B, which contained 20% ionizable polymer in the organic phase. The total charge density of the submicron particles in sample B was about 3 times higher than for sample A, but includes both a ternary and quaternary amine.

Table 9 - ITZ/RL and ITZ/RL/SS Particle Size and Filter Potency

Lyophilized powders were prepared to evaluate the resuspendability of the submicron particles after drying into powders. Lyophiles were prepared by adding an amount of submicron particle suspension equaling 10 mg of ITZ (theoretical), an amount of 1 % aqueous matrix solution equal to 10 mg of polymer, and then diluting to 5 mL total volume with water and lyophilizing for > 40 hr. The formulations are shown in Table 10 where PVP is

polyvinylpyrrolidone (MW = 10 kDa).

Table 10 - ITZ/RL and ITZ/RL/SS Lyophile Formulations

The resulting powders were suspended in 5 mL of GB media (0.01 N HCI, pH 2). Submicron particle size and filter potency were determined. The results are shown in Table 1 1

Table 11 -Particle Size and Filter Potency of Lyophiles

Filter Potency (%),

Ref. Diameter (nm)

0.45 micron

A-1 a 137 70

A-1 b 148 50

A-2 200 27

A-3 204 74

A-4 188 77

A-5a 174 83

A-5b 160 37

B-1 182 31

B-2 212 69

B-3 209 8 The effect of the matrix on suspendability in gastric media is summarized in FIGS. 10- 1 1 (1 : 1 NP/matrix ratio only) where solid circles (A) represent 80 wt% itraconazole/20 wt% Eudragit ^® RL polymer submicron particles and open squares (B) represent 80 wt% itraconazole/ 10 wt% Eudragit ^® RL polymer/10 wt% Kollicoat ^® Smartseal 30D polymer submicron particles dispersed in a matrix material comprising varying amounts of polyvinylpyrrolidone and Kollicoat ^® Smartseal 30D polymer. Acceptable filter potency was obtained across a range of matrix materials at the 1 :1 submicron particle/matrix ratio. At a 2: 1 submicron particle/matrix ratio (A-1 b and A-5b), the filter potency was reduced through a 0.45 micron filter. Filter potency with a 1 micron filter was not tested.

Example 3

Lyophilized Telaprevir Submicron particle/Matrix Material Compositions Submicron particles comprising telaprevir with Eudragit ^® RL polymer were prepared as described in General Methods. The formulations are shown in Table 12 where TLV is telaprevir, and RL is Eudragit ^® RL polymer.

Table 12 - TLV/RL Particle Formulations

Lyophiles were prepared with 10 mg telaprevir in each sample. An amount of submicron particle suspension equivalent to 10 mg telaprevir, 1 -2 mL, was combined with 1 -2 mL of matrix solution and then lyophilized. The formulations are shown in Table 13 where SS spray-dried Kollicoat ^® Smartseal 30D polymer (dissolved in aqueous solution with 1 molar equivalent of acetic acid) and PVP is polyvinylpyrrolidone (MW = 10 kDa).

Table 13 - TLV/RL Lyophile Formulations

D-3 90 10 100 1 : 1

E-1 80 20 100 1 : 1

E-2 80 20 50 50 1 : 1

E-3 80 20 100 1 : 1

The resulting powders were suspended in 5 mL of GB media. Submicron particle filter potency was determined. The results in gastric buffer are shown in Table 14 and FIG. 12.

Table 14 - Filter Potency of Lyophiles

The filter potency data shows that regardless of submicron particle formulation, more PVP in the matrix reduces the filter potency. This data suggests that using Kollicoat ^® Smartseal 30D polymer as a matrix material will provide acceptable GB resuspension.

Example 4

Spray-Dried Itraconazole Submicron particle/Matrix Material Compositions and Compacts Itraconazole/Eudragit ^® RL polymer submicron particles were prepared as follows. ITZ and Eudragit ^® RL polymer were weighed out in the amounts shown in Table 15.

Dichloromethane (DCM), 20 g (15 mL) was added, and the mixture was shaken until the solids were fully dissolved. The DCM solution was mixed with 70 mL of water and homogenized for 1 minute in the Silverson rotor stator, and then further homogenized using the Microfluids M1 10S for 10 minutes. The DCM was removed under vacuum.

Table 15 - ITZ/RL Particle Formulations

The submicron particles were mixed with a matrix material - a chloride salt of Kollicoat ^® Smartseal 30D polymer or PVP - at a loading of 45 wt% active agent (theoretical basis). The submicron particles were divided as indicated in Table 16. The matrix materials were prepared as follows. The Smartseal chloride was prepared by diluting 10 mL of Smartseal 30D suspension (30 wt% aqueous suspension) with 40 mL of deionized water. The 10-mL aliquot of Smartseal 30D contains 3 g of Smartseal, which corresponds to 7.2 mmol of basic amine groups. Dilute HCI (1 N, 4 mL) was added to the diluted Smartseal, and additional 1 N HCI was added dropwise until the suspension turned transparent. Theoretically, 7.2 mL of 1 N HCI is required to completely titrate all of the basic amine groups, but less may be required to solubilize the polymer. The pH was measured, and the solution was diluted to a final volume of 60 mL (5 wt% polymer). PVP 10 (MW 10,000 Da), 1 g, was added to 20 mL water and stirred to dissolved.

The specified amount of matrix material was added to each portion of the submicron particles, and the suspensions were spray dried using a spray dryer.

Table 16 - Spray-Dried Formulations

The filter potency and submicron particle size of the spray-dried compositions were evaluated. The results are shown in Table 17. The filter potency in gastric buffer (GB) was ve good for samples A-1 (80:20 ITZ/RL in Smartseal) and B2 (70:30 ITZ/RL in PVP) and reasonably good for B1 (70:30 ITZ/RL in Smartseal).

Table 17 - Particle Size and Filter Potency of Spray-Dried Formulations

Compacts were then prepared to evaluate the ability of the compacts to erode in GB. The spray-dried compositions were directly compressed with no fillers or disintegrants

(Table 18).

Table 18 - Compacts made from Spray-Dried Formulations

The filter potency and submicron particle size of the compacts was evaluated after 2 hours dispersion in GB (Table 19). FIGS. 13-15 are photographs showing the dispersion of compacts A1 (FIG. 13), B1 (FIG. 14), and B2 (FIG. 15) over a period of one hour. The dispersion of samples A1 and B1 is promising.

Table 19 - Filter Potency of Compacts

Less than 10% of the active agent passed through the filter for the PVP-based compact (B2). Without wishing to be bound by a particular theory of operation, the results suggest that electrostatic-assisted disintegration may be more robust to compression than steric separation only, as with PVP. In subsequent studies, chitosan was also investigated as a matrix material. The performance of the chitosan-CI samples was comparable to the Smartseal-CI samples (not shown).

Example 5

Effect of Submicron Particle Loading on Gastric Dispersion Submicron particles comprising 80 wt% itraconazole and 20 wt% Eudragit ^® RL polymer were prepared as described in General Methods; 40-mL batches were homogenized separately and then combined after evaporating DCM. The formulation is shown in Table 20. The submicron particle yield and filter potency are shown in Table 21. Table 20 - ITZ/RL Particle Large-Batch Formulation

Table 21 - Filter Potency of Large Batch Formulation

A chloride salt of Kollicoat ^® Smartseal 30D polymer was prepared by diluting 20 mL of the 30% suspension (6 g of Smartseal, which corresponds to 14.4 mmol of basic amine groups) with 80 mL deionized water. Dilute HCI (1 N, 8 mL) was added to the suspension, and additional 1 N HCI was added dropwise until the suspension turned transparent. Theoretically, 14.4 mL of 1 N HCI is required to completely titrate all of the basic amine groups, but less may be required to solubilize the polymer. The resulting pH was measured, and the solution was then diluted to a final volume of 120 mL (5 wt% polymer).

Spray-dried compositions were prepared with the compositions shown in Table 22. The amounts of the components were based upon the following parameters: submicron particle suspension having a submicron particle concentration 1 1.25 mg/mL and a submicron particle active agent concentration 9 mgA/mL, Smartseal chloride salt solution concentration 5 wt%.

Table 22 - Spray-Dried Formulations

Table 23 shows the percent active agent and filter potency of the spray-dried compositions dispersed in GB media for 5 minutes at a concentration of 4 mgA/mL. The filter potency is also shown graphically as a function of percent active in FIG. 16. Table 23 - Active Loading and Filter Potency of Spray-Dried Formulations

In view of the many possible embodiments to which the principles of the disclosed invention may be applied, it should be recognized that the illustrated embodiments are only preferred examples of the invention and should not be taken as limiting the scope of the invention. Rather, the scope of the invention is defined by the following claims. We therefore claim as our invention all that comes within the scope and spirit of these claims.