CROSS-REFERENCE TO RELATED APPLICATION

The present application claims the benefit of U.S. Provisional Application Serial No. 61/157,724 filed on March 5, 2009 (Attorney Docket No. 274.00490160), the entirety of which is incorporated herein by reference.

BACKGROUND OF THE INVENTION

Resveratrol (3,4',5-trihydroxystilbene or 3,4',5-stilbenetriol) is a component of red wine and used as a dietary supplement. The crystalline form of resveratrol is stable (see, e.g., Jensen, J.S.; Wertz, C.F.; O'Neill, V.A. "Preformulation Stability of trans- Resveratrol and trans-Resveratrol Glucoside (Piceid)." J. Agric. Food Chem. 2010, 58, 1685-169) but has poor aqueous solubility. Thus, crystalline resveratrol is dissolved slowly in the gastrointestinal tract making its bioavailability less than desirable. Thus, to obtain the positive health effects of resveratrol, typically long-term and/or high levels of consumption are necessary. A need exists for new techniques and products for providing resveratrol in a form having a higher kinetic solubility and bioavailability.

SUMMARY OF THE INVENTION

The present invention provides solid dispersions, formulations thereof, and methods for producing. Such solid dispersions include high amounts of amorphous or molecularly dispersed resveratrol, a stilbene analog thereof, or combinations thereof. Such solid dispersions of the present invention demonstrate higher kinetic solubilities (e.g., higher than crystalline resveratrol), which is believed to contribute to better bioavailability. In one embodiment, the present invention provides a solid dispersion comprising: resveratrol; and a polymer selected from the group consisting of a homopolymer of N-vinyl pyrrolidone, a copolymer of N- vinyl pyrrolidone, and a combination thereof; wherein the resveratrol is substantially non-crystalline upon initial formation of the dispersion; and wherein the resveratrol remains substantially non- crystalline for at least four weeks at 4O ⁰ C and 75% relative humidity. In one embodiment, the present invention provides a solid dispersion comprising: resveratrol; and a polymer selected from the group consisting of a homopolymer of N- vinyl pyrrolidone, a copolymer of N- vinyl pyrrolidone, and a combination thereof; wherein the resveratrol is substantially non-crystalline upon initial formation of the dispersion; and wherein the resveratrol remains substantially noncrystalline for at least one year under controlled room temperature conditions.

In one embodiment, the present invention provides a solid dispersion comprising: resveratrol, a stilbene analog thereof (such as those selected from pterostilbene, pterostilbene glucoside, resveratrol glucoside, pinostilbene, desoxyrhapontigenin, and piceatannol), or a combination thereof; and a polymer selected from the group consisting of a homopolymer of N- vinyl pyrrolidone, a copolymer of N- vinyl pyrrolidone, and a combination thereof; wherein the resveratrol, stilbene analog thereof, or a combination thereof is substantially amorphous upon initial formation of the dispersion. In another embodiment, the present invention provides a spray-dried solid dispersion comprising: resveratrol; and polyvinyl pyrrolidone; wherein the resveratrol is substantially non-crystalline upon initial formation of the dispersion; wherein the resveratrol remains substantially non-crystalline for at least four weeks at 40°C and 75% relative humidity; and wherein the initial kinetic solubility of the initially formed dispersion is at least 100% greater than crystalline resveratrol.

In another embodiment, the present invention provides a spray-dried solid dispersion comprising: resveratrol; and a 60:40 copolymer of N-vinyl pyrrolidone and vinyl acetate; wherein the resveratrol is substantially non-crystalline upon initial formation of the dispersion; wherein the resveratrol remains substantially non- crystalline for at least four weeks at 40°C and 75% relative humidity; and wherein the initial kinetic solubility of the initially formed dispersion is at least 50% (for some embodiments at least 60%, for some embodiments at least 70%, for some embodiments at least 80%) greater than crystalline resveratrol.

The present invention also provides oral dosage forms that include a solid dispersion of the present invention. Oral dosage forms can be capsules, tablets, sachets, syrups, solutions, or suspensions. Preferably the oral dosage form is a capsule or a tablet.

In one embodiment, the present invention provides an oral dosage form comprising a solid dispersion, wherein the solid dispersion comprises: resveratrol; and a polymer selected from the group consisting of a homopolymer of N- vinyl pyrrolidone, a copolymer of N- vinyl pyrrolidone, and a combination thereof; wherein the resveratrol is substantially non-crystalline.

In another embodiment, the present invention provides an oral dosage form comprising a solid dispersion, wherein the solid dispersion comprises: resveratrol; and a polymer selected from the group consisting of a homopolymer of N- vinyl pyrrolidone, a copolymer of N- vinyl pyrrolidone, and a combination thereof; wherein the extent of release of the oral dosage form is at least 50% greater than crystalline resveratrol according to the Kinetic Solubility Test. hi another embodiment, the present invention provides an oral dosage form comprising a solid dispersion, wherein the solid dispersion comprises: resveratrol; and a polymer selected from the group consisting of a homopolymer of N-vinyl pyrrolidone, a copolymer of N-vinyl pyrrolidone, and a combination thereof; wherein the initial kinetic solubility of the oral dosage form is at least 50% greater than crystalline resveratrol according to the Kinetic Solubility Test.

The present invention also provides methods of making a solid dispersion of the present invention.

In one embodiment, the method involves: preparing a feedstock solution under ambient conditions, wherein the feedstock solution comprises: resveratrol, a stilbene analog thereof, or a combination thereof; a polymer selected from the group consisting of a homopolymer of N-vinyl pyrrolidone, a copolymer of N-vinyl pyrrolidone, and a combination thereof; and a solvent; transferring the feedstock solution to a spray dryer; and spray drying the feedstock solution under conditions effective to produce a solid dispersion. hi another embodiment, the method involves: providing a feedstock solution comprising: resveratrol, a stilbene analog thereof, or a combination thereof; a polymer selected from the group consisting of a homopolymer of N-vinyl pyrrolidone, a copolymer of N-vinyl pyrrolidone, and a combination thereof; and a solvent mixture comprising at least two solvents (preferably, a mixture of acetone and methanol); and spray drying the feedstock solution under conditions effective to produce a solid dispersion.

In another embodiment, the method involves: providing a feedstock solution comprising: resveratrol, a stilbene analog thereof, or a combination thereof; a polymer selected from the group consisting of a homopolymer of N-vinyl pyrrolidone, a copolymer of N- vinyl pyrrolidone, and a combination thereof; and a solvent; and spray drying the feedstock solution under conditions effective to produce a solid dispersion; wherein the feedstock solution is free from a nonsolvent.

As used herein, the phrase "solid dispersion" refers to at least a two-component solid-state system, wherein solid active (e.g., resveratrol, analog thereof, or combination thereof) is embedded or dispersed in a solid matrix. In certain embodiments, a solid dispersion can include the active dispersed within polymeric particles. Preferably, this does not include the active being coated on polymeric particles. The matrix may consist of one or more components, such as polymers, in crystalline or amorphous form. In the present invention, the active can be present as crystalline particles, amorphous particles or dispersed molecularly, but is preferably substantially non-crystalline.

The phrase "substantially amorphous" refers to resveratrol, a stilbene analog thereof, or a combination thereof being at least 60% by weight (wt-%) amorphous or molecularly dispersed. Preferably, "substantially amorphous" resveratrol (analog or combination thereof) is at least 70 wt-%, more preferably at least 75 wt-%, even more preferably at least 80 wt-%, even more preferably at least 85 wt-%, even more preferably at least 90 wt-%, and most preferably at least 95 wt-%, amorphous or molecularly dispersed. The phrase "substantially non-crystalline" refers to resveratrol including no greater than 40% by weight (wt-%) of crystalline resveratrol (as represented by the PXRD spectrum shown in Figure 23). Preferably, the non-crystalline material is amorphous or molecularly dispersed. The determination can be made based on powder X-ray diffraction or other suitable quantitative technique. Preferably, "substantially non-crystalline" resveratrol is no greater than 30 wt-%, even more preferably no greater than 25 wt-%, even more preferably no greater than 20 wt-%, even more preferably no greater than 15 wt-%, even more preferably no greater than 10 wt-%, and most preferably no greater than 5 wt-% crystalline resveratrol, based on powder X-ray diffraction (the PXRD spectrum of Figure 23). The phrase "chemically degrade" refers to structural and/or electronic changes of a molecule that, for example, adversely impact the effectiveness of the molecule (e.g., an active). Examples of chemical degradation include oxidation, elimination, isomerization, reduction, and the like. The phrase "ambient conditions" refers to the temperature and pressure typically prevalent in a room setting, about 20°C to about 25 ⁰ C and about 1 atm.

"Bioavailability" refers to the degree to which the active becomes systemically available in the body after administration. Typically in determining bioavailability, plasma samples are taken and analyzed for the plasma concentration of the active.

Bioavailability parameters may be expressed as Cmax, the maximum amount of active ingredient found in the plasma, or as AUC, the area under the plasma concentration- time curve. Enhanced bioavailability may be evidenced by an increase in Cmax and/or AUC for the active, metabolites of the active, or both. Compositions in accordance with certain aspects of the invention exhibit enhanced bioavailability compared to a control composition.

"Crystalline resveratrol" refers to the material represented by the PXRD spectrum shown in Figure 23.

All percentages, ratios, and proportions used herein are by weight unless otherwise specified.

The terms "comprises" and variations thereof do not have a limiting meaning where these terms appear in the description and claims.

The words "preferred" and "preferably" refer to embodiments of the invention that may afford certain benefits, under certain circumstances. However, other embodiments may also be preferred, under the same or other circumstances.

Furthermore, the recitation of one or more preferred embodiments does not imply that other embodiments are not useful, and is not intended to exclude other embodiments from the scope of the invention.

As used herein, "a," "an," "the," "at least one," and "one or more" are used interchangeably. Thus, for example, a composition comprising "a" polymer can be interpreted to mean that the composition includes "one or more" polymers.

As used herein, the term "or" is generally employed in its sense including "and/or" unless the content clearly dictates otherwise. The term "and/or" means one or all of the listed elements or a combination of any two or more of the listed elements. Also herein, all numbers are assumed to be modified by the term "about" and preferably by the term "exactly." 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. All numerical values, however, inherently contain certain errors necessarily resulting from the standard deviation found in their respective testing measurements.

Also herein, the recitations of numerical ranges by endpoints include all numbers subsumed within that range (e.g., 1 to 5 includes 1, 1.5, 2, 2.75, 3, 3.80, 4, 5, etc.). Where a range of values is "up to" a particular value, that value is included within the range.

The above summary of the present invention is not intended to describe each disclosed embodiment or every implementation of the present invention. The description that follows more particularly exemplifies illustrative embodiments. In several places throughout the application, guidance is provided through lists of examples, which examples can be used in various combinations. In each instance, the recited list serves only as a representative group and should not be interpreted as an exclusive list.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is an illustration of a spray-drying system used in a method of the present invention.

FIG. 2 is a series of PXRD spectra taken of a resveratrol-PVP solid-dispersion at various time points for material stored at 40°C and 75% RH conditions. FIG. 3 is a series of PXRD spectra taken of a resveratrol-PVP solid-dispersion at various time points for material stored at 40 ⁰ C and Dry conditions.

FIG. 4 is a series of PXRD spectra taken of a resveratrol-PVP solid-dispersion at various time points for material stored at 5°C and Dry conditions.

FIG. 5 is a series of graphs showing the Kinetic Solubility (in micrograms per milliliter (ug/ml or μg/ml)) of a resveratrol-PVP solid-dispersion evaluated at various time points for material stored at 40 ⁰ C and 75% RH conditions.

FIG. 6 is a series of graphs showing the Kinetic Solubility of a resveratrol-PVP solid-dispersion evaluated at various time points for material stored at 40 ⁰ C and Dry conditions. FIG. 7 is a series of graphs showing the Kinetic Solubility of a resveratrol-PVP solid-dispersion evaluated at various time points for material stored at 5°C and Dry conditions.

FIG. 8 is a series of PXRD spectra taken of a resveratrol-PLASDONE solid- dispersion at various time points for material stored at 40 ⁰ C and 75% RH conditions. FIG. 9 is a series of PXRD spectra taken of a resveratrol-PL ASDONE solid- dispersion at various time points for material stored at 40°C and Dry conditions.

FIG. 10 is a series of PXRD spectra taken of a resveratrol-PLASDONE solid- dispersion at various time points for material stored at 5 ⁰ C and Dry conditions. FIG. 11 is a series of graphs showing the Kinetic Solubility of a resveratrol-

PLASDONE solid-dispersion evaluated at various time points for material stored at 40 ⁰ C and 75% RH conditions.

FIG. 12 is a series of graphs showing the Kinetic Solubility of a resveratrol- PLASDONE solid-dispersion evaluated at various time points for material stored at 40°C and Dry conditions.

FIG. 13 is a series of graphs showing the Kinetic Solubility of a resveratrol- PLASDONE solid-dispersion evaluated at various time points for material stored at 5°C and Dry conditions.

FIG. 14 is a series of PXRD spectra taken of a resveratrol-PLASDONE solid- dispersion (50:50) after one month for material stored under the following conditions: CRT (controlled room temperature, 25°C/60%RH), sealed (bottom); 40°C/75%RH, open (top).

FIG. 15 is a series of PXRD spectra taken of a resveratrol-PLASDONE solid- dispersion (50:50) initially (bottom) and after three months storage under 4O ⁰ C (dry) conditions (top).

FIG. 16 is a series of graphs showing the Kinetic Solubility of a resveratrol- PLASDONE solid-dispersion (50:50) evaluated at various time points for material stored under various conditions.

FIG. 17 is a series of PXRD spectra taken of a resveratrol-PLASDONE solid- dispersion (30:70) after one month for material stored under the following conditions: CRT (25°C/60%RH), sealed (bottom); 40°C/75%RH, open (top).

FIG. 18 is a PXRD spectrum taken of a resveratrol-PLASDONE solid- dispersion (30:70) after three months storage under 40°C/75%RH conditions (open).

FIG. 19 is a series of graphs showing the Kinetic Solubility of a resveratrol- PLASDONE solid-dispersion (30:70) evaluated at various time points for material stored under various conditions.

FIG. 20 is a series of PXRD spectra taken of a resveratrol-PVP solid-dispersion (70:30) after one month for material stored under the following conditions: CRT (25°C/60%RH), sealed (bottom); 40°C/75%RH, open (top). FIG. 21 is a series of PXRD spectra taken of a resveratrol-PVP solid-dispersion (70:30) initially (bottom) and after three months storage under the following conditions: CRT (25°C/60%RH), sealed, showing a low level of crystallinity with mainly amorphous content (second from bottom); 4O ⁰ C (dry), showing a higher level of crystallite formation with some remaining amorphous content (third from bottom); and 40°C/75%RH, open, showing evidence of crystallite formation with some remaining amorphous content (top).

FIG. 22 is a series of graphs showing the Kinetic Solubility of a resveratrol-PVP solid-dispersion (70:30) evaluated at various time points for material stored under various conditions.

FIG. 23 is a PXRD spectrum of crystalline resveratrol (control) for comparison.

FIG. 24 is a graph of the average plasma concentration of resveratrol versus time following oral administration to rats of a resveratrol solid dispersion and a control.

DESCRIPTION OF THE ILLUSTRATIVE EMBODIMENTS OF THE INVENTION

The present invention provides a solid dispersion comprising: resveratrol, a stilbene analog thereof, or a combination thereof; and a polymer selected from the group consisting of a homopolymer of N- vinyl pyrrolidone, a copolymer of N- vinyl pyrrolidone, and a combination thereof; wherein the resveratrol, stilbene analog thereof, or a combination thereof is substantially amorphous upon initial formation of the dispersion.

Solid dispersions of the present invention exhibit enhanced physical and chemical properties that improve product performance, including, for example, improved solubility and/or improved stability. These improvements, for example, are relative to solid dispersions that include the crystalline form of the active, particularly resveratrol (typically, having more than 40% crystalline resveratrol). Such solubility and stability improvements contribute to bioavailability of formulations comprising amorphous solid dispersions of the active, particularly resveratrol.

Significantly, solid dispersions of the present invention stabilize the amorphous form of the resveratrol, stilbene analog thereof, or combinations thereof. For example, the resveratrol, stilbene analog thereof, or a combination thereof remains substantially amorphous (and preferably, for resveratrol, substantially non-crystalline) for at least two weeks (preferably, for at least four weeks, more preferably, for at least two months, and even more preferably, for at least three months) at 40 ⁰ C and 75% relative humidity. Alternatively or additionally, the resveratrol, stilbene analog thereof, or a combination thereof remains substantially amorphous (and preferably, for resveratrol, substantially non-crystalline) for at least two weeks (preferably, for at least four weeks, more preferably, for at least two months, and even more preferably, for at least three months) at 40°C under dry conditions. Alternatively or additionally, the resveratrol, stilbene analog thereof, or a combination thereof remains substantially amorphous (and preferably, for resveratrol, substantially non-crystalline) for at least two weeks (preferably, for at least four weeks, more preferably, for at least two months, and even more preferably, for at least three months) at 5°C under dry conditions. In certain embodiments, the resveratrol, stilbene analog thereof, or a combination thereof remains substantially amorphous (and preferably, for resveratrol, substantially non-crystalline) for at least two weeks (preferably, for at least four weeks, more preferably, for at least two months, and even more preferably, for at least three months) under controlled room temperature conditions (25 ⁰ C and 60% relative humidity). In certain embodiments, the resveratrol, stilbene analog thereof, or a combination thereof remains substantially amorphous (and preferably, for resveratrol, substantially non-crystalline) for at least one year under controlled room temperature conditions (25 ⁰ C and 60% relative humidity).

Significantly, solid dispersions of the present invention chemically stabilize the resveratrol, stilbene analog thereof, or combinations thereof. For example, in certain preferred embodiments, the resveratrol, stilbene analog thereof, or a combination thereof does not chemically degrade by more than 1% (preferably, by more than 0.5%) after four weeks at 40°C under dry conditions. In certain embodiments, the resveratrol, stilbene analog thereof, or a combination thereof does not chemically degrade by more than 1% (preferably, by more than 0.5%) after four weeks at 5 ⁰ C under dry conditions. In certain embodiments, the resveratrol, stilbene analog thereof, or a combination thereof does not chemically degrade by more than 1% (preferably, by more than 0.5%) after four weeks at 40°C and 75% relative humidity. Preferred embodiments of the present invention include resveratrol, the structure of which is as follows:

Resveratrol

Other embodiments include stilbene analogs of resveratrol, including glucosides, the structures of which are as follows:

Pterostilbene glucoside Resveratrol glucoside

Other stilbene analogs of resveratrol suitable for use in the present invention include the following (with resveratrol shown as well):

Resveratrol Pinostilbene Desoxy rhapontigeni n

Pterostilbene Piceatannol

The amount of the active (i.e., resveratrol, stilbene analog thereof, or combination thereof) present in the solid dispersion is preferably at least 5 wt-%, at least 10 wt-%, at least 15 wt-%, at least 20 wt-%, at least 25 wt-%, at least 30 wt-%, at least 35 wt-%, at least 40 wt-%, or at least 45 wt-%, based on the weight of the active and polymer. The amount of the active (i.e., resveratrol, stilbene analog thereof, or combination thereof) present in the solid dispersion is preferably no greater than 80 wt- %, no greater than 75 wt-%, no greater than 70 wt-%, no greater than 65 wt-%, no greater than 60 wt-%, or no greater than 55 wt-%, based on the total weight of the active and polymer. A suitable solid dispersion includes a weight ratio of active to polymer within a range of 30:70 to 70:30. A preferred solid dispersion includes a weight ratio of active to polymer within a range of 40:60 to 60:40. A more preferred solid dispersion includes a 50:50 weight ratio of active to polymer.

Solid dispersions include a polymer selected from the group consisting of a homopolymer of N- vinyl pyrrolidone, a copolymer of N- vinyl pyrrolidone, and a combination thereof. For certain embodiments, the polymer is polyvinyl pyrrolidone (PVP). For certain embodiments, the polymer is a copolymer of N- vinyl pyrrolidone. For certain embodiments, the copolymer is a copolymer of N- vinyl pyrrolidone and vinyl acetate. For certain embodiments, the copolymer is a 60:40 copolymer of N-vinyl pyrrolidone and vinyl acetate (such as those available under the trade designation PLASDONE, such as PLASDONE S-630 (VP/VA Copolymer), ISP Technologies, Inc., Wayne, NJ). Combinations (e.g., blends or mixtures) of polymers may also be used.

The amount of the polymer present in the solid dispersion is preferably at least 20 wt-%, at least 25 wt-%, at least 30 wt-%, at least 35 wt-%, at least 40 wt-%, at least 45 wt-%, or at least 50 wt-%, based on the weight of the active and polymer. The amount of the polymer present in the solid dispersion is preferably no greater than 95 wt-%, no greater than 90 wt-%, no greater than 85 wt-%, no greater than 80 wt-%, no greater than 75 wt-%, no greater than 70 wt-%, no greater than 65 wt-%, no greater than 60 wt-%, or no greater than 55 wt-%, based on the weight of the active and polymer.

In addition to the polymer and active, the solid dispersions may also include other ingredients to improve performance, handling, and/or processing. Typical ingredients include, but are not limited to, surfactants, pH modifiers, complexϊng agents, solubilizers, antioxidants, disintegrants, etc. Various combinations of such additives can be used if desired. In certain embodiments, solid dispersions of the present invention can include a surfactant, particularly an anionic or a nonionic surfactant. Exemplary suitable anionic surfactants include, but are not limited to, sodium lauryl sulfate (SLS) and docusate sodium (i.e., the sodium salt of dioctyl sodium sulfosuccinate (DSS)). Exemplary suitable nonionic surfactants include, but are not limited to, polyoxyethylene sorbitan fatty acid esters (e.g., Tween 80 (also available as Polysorbate 80, which is a polyoxyethylene (20) sorbitan monooleate)), sorbitan fatty acid esters (e.g., sorbitan monostearate), and lecithin. A preferred surfactant is SLS. Combinations of various surfactants can be used if desired. If used, a surfactant is preferably present in an amount of less than 10 wt-%, less than 5 wt-%, less than 1 wt-%, less than 0.5 wt-%, or less than 0.1 wt-%, based on the total amount of solids in the feedstock.

In certain embodiments, solid dispersions of the present invention can include one or more antioxidants. Exemplary suitable antioxidants include, but are not limited to, ascorbic acid, sodium bisulfite, a hindered phenol (e.g., 3,5-di-t-butyl-4- hydroxybiphenyl), a hindered amine, a diallyl diamine, a diallyl amine, a hydroquinone, a thioether, a phosphorous ester, fumaric acid, and malic acid. If used, an antioxidant is preferably present in an amount of less than 10 wt-%, less than 5 wt-%, less than 1 wt- %, less than 0.5 wt-%, or less than 0.1 wt-%, based on the total amount of solids in the feedstock. Preparation of solid dispersions of the present invention can be accomplished using a variety of methods, including fusion methods, hot melt extrusion methods, solvent methods (including vacuum drying, spray drying, freeze drying, and spray freeze drying), supercritical fluid methods, and other well-known methods.

In a typical fusion method, a physical mixture of active and polymer is melted at a eutectic composition followed by cooling of the melt. This method is also called a melt method, only when the starting materials are crystalline. A typical hot melt extrusion method is the same as a fusion method except that intense mixing of all components is induced by an extruder.

Typical solvent methods involve the preparation of a feedstock solution containing both a polymer and active, followed by removal of the solvent(s) resulting in formation of a solid dispersion. Such methods can be further divided into subtypes based on the different approaches employed to remove solvent(s): (1) vacuum drying, in which a solution is dried by application of vacuum and different heating rates; (2) spray drying, in which a solution is dispersed as fine particles in hot air and the solvent rapidly evaporates from the large surface area droplets forming and the solid dispersion; (3) freeze drying, in which a solution is frozen below the freezing temperature of the solvent(s) followed by sublimation of the solvent; and (4) spray freeze drying, which involves spraying a solution into liquid nitrogen and the resultant frozen droplets are subsequently freeze dried.

LQ a typical supercritical fluid method, active and polymer are dissolved in supercritical carbon dioxide and sprayed through a nozzle, into an expansion vessel with lower pressure, where particles are immediately formed. Other methods involve the solution of active in organic solvent is sprayed in an aqueous solution containing polymeric surfactants as stabilizers. The obtained colloidal suspension is spray dried, freeze dried or spray freeze dried resulting in solid dispersion. In another method, an anti-solvent is added to a solution of active and polymer and the solid dispersion precipitates out.

Solid dispersions of the present invention can be prepared by spray drying. Spray drying is a well-known process wherein a liquid feedstock is dispersed into droplets by spraying the feedstock through a spray nozzle or atomizer into a drying chamber along with a heated process gas stream, leading to evaporation of solvent and resulting in a powder product, hi preferred methods of the present invention, a feedstock is prepared and/or maintained at ambient conditions of temperature (i.e., at about 20°C to 25 ⁰ C) and pressure (i.e., at about 1 atm).

Spray-dryer operation influences particle characteristics. Solvent evaporation from an atomized sphere is understood to progress through three stages. Initially, when the droplet surface is saturated with solvent, evaporation proceeds at a constant rate and is called the first stage of drying. A change in the drying rate is noted with additional drying, due to the formation of dry solids on the surface. At this point the surface is no longer considered to be freely saturated with solvent. Further solvent evaporation from the droplet proceeds at a slower rate, requiring diffusion or capillary action through the solid surface layer. At this stage of drying, careful operation of the spray dryer is desirable to remove as much solvent as possible and to avoid expanding the droplet and producing a low density powder. Inlet and outlet temperatures are typically controlled, as well as the flow configuration of the drying gas.

A spray-drying system used in a method of the present invention is illustrated in Figure 1. The spray-drying system includes a feedstock supply tank (not shown) containing the feedstock. The feedstock in the illustrated embodiment comprises resveratrol, a stilbene analog thereof, or a combination thereof and a polymer in a suitable solvent, preferably a solvent mixture, and optionally a surfactant and/or other additive. In this preferred embodiment, the feedstock solution is maintained in the supply tank at ambient temperature and pressure. Compressed air or inert gas (drying medium) enters at inlet (1), which is heated by electrical heating (2). The feedstock solution is pumped into the spray nozzle (3), where it gets sprayed along with drying medium through the spray nozzle (3) to a spray cylinder (i.e., drying chamber) (4). The spray nozzle (3) distributes the feedstock solution into fine droplets in the drying chamber (4). The fine droplets come in contact with drying medium to facilitate solidification. The solvent(s) evaporates from the droplets within the chamber (4) thereby forming solid dispersion particles having active material and polymer. The solid dispersion particles exit the chamber (4), move to a cyclone (5) where the particles are separated on the basis of their particle size, and are then collected in the product collection vessel (6). The air used in the spray dryer then passes through outlet filter (7) and aspirator (i.e., vacuum pump) (8).

The feedstock includes one or more polymers and one or more solvents in addition to the active (i.e., resveratrol, stilbene analog thereof, or combination thereof). The polymer is selected from the group consisting of a homopolymer of N- vinyl pyrrolidone, a copolymer of N- vinyl pyrrolidone, and a combination thereof as discussed above. One or more optional additives can be included in the feedstock, such as a surfactant.

One aspect of the invention involves the pairing of a polymer and active with a selected solvent or solvent mixture, thereby forming a solution (i.e., in which there are no visible solid particles). The one or more solvents are selected such that both the active and polymer are suffϊcently soluble therein, preferably under ambient conditions.

Solvents suitable for use in the process of the present invention can be any organic compound or water in which the organic material (e.g., active and polymer) is sufficiently soluble under ambient conditions. Examples of suitable solvents include acetone, methanol, or combinations thereof. A particularly suitable solvent includes a combination of acetone and methanol.

In certain embodiments, feedstock solutions are free from a nonsolvent. In this context, "free" means less than 5 wt-%, preferably less than 4 wt-%, less than 3 wt-%, less than 2 wt-%, or less than 1 wt-%, based on the total weight of solids and solvents in the feedstock solution. Most preferably, the feedstock solution is completely free from a nonsolvent (i.e., 0 wt-%). A "nonsolvent" is defined as in U.S. Pat. Pub. No. 2008/0181962.

The amount of solids in the feedstock (i.e., feedstock solution, or simply solution) is preferably at least 1 wt-%, at least 5 wt-%, at least 10 wt-%, or at least 20 wt-%, based on the total weight of solids and solvent in the feedstock solution. The amount of solids in the feedstock is preferably no greater than 40 wt-%, no greater than 35 wt-%, no greater than 30 wt-%, or no greater than 25 wt-%, based on the total weight of solids and solvents in the feedstock solution.

The equipment used in the process of the present invention can take the form of any apparatus that accomplishes the formation of powder and granulated products from a high-energy feedstock. Such equipment includes spray dryers of any commercially viable design. Examples of specific spray-drying devices include spray dryers manufactured by Niro, Inc. (e.g., SD-Micro, PSD-I, PSD-2, etc.), the Mini Spray Dryer connected with inert loop B295 (Bucbi Labortechnik AG), spray dryers manufactured by Spray Drying Systems, Inc. (e.g., models 30, 48, 72), and SSP Pvt. Ltd. Spray- drying processes and spray-drying equipment are described generally in Perry's Chemical Engineers' Handbook, Sixth Edition (R. H. Perry, D. W. Green, J. O. Maloney, eds.) McGraw-Hill Book Co. 1984, pages 20-54 to 20-57. More details on spray-drying processes and equipment are reviewed by Marshall "Atomization and Spray-Drying," 50 Chem. Eng. Prog. Monogr. Series 2 (1954).

Generally, the temperature and flow rate of the drying gas and the design of the spray dryer are chosen so that the atomized droplets are dry enough by the time they reach the wall of the apparatus that they are essentially solid and so that they form a fine powder and do not stick to the apparatus wall. The actual length of time to achieve this level of dryness depends on the size of the droplets, the formulation, and spray dryer operation. Following the solidification, the solid powder may stay in the spray- drying chamber for 5-60 seconds, further evaporating solvent from the solid powder.

The final solvent content of the particle as it exits the dryer should be low, which may improve the handling and stability of the product. Generally, the residual solvent content of the spray-dried composition should be less than 10% by weight and preferably less than 3% by weight. Although not typically required in accordance with the present invention, it may be useful in accordance with certain embodiments of the present invention to subject the spray-dried composition to further drying to lower the residual solvent to even lower levels. Additional detail with respect to a particular spray-drying process is described in more detail in the examples. However, the operating conditions to spray-dry a powder are well known in the art and can be easily adjusted by the skilled artisan. Furthermore, the examples herein describe results obtained with a laboratory scale spray dryer. One of ordinary skill in the art would readily appreciate the variables that are typically modified to obtain similar results with a production scale unit.

Solid dispersions of the present invention improve the kinetic solubility of the active under various conditions. For example, preferred solid dispersions of the present invention containing resveratrol possess at least one of the following properties compared to crystalline resveratrol (represented by the PXRD spectrum shown hi

Figure 23): (a) an increase in initial kinetic solubility of at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, at least 100%, at least 150%, or in accordance with certain embodiments at least 200%; (b) an increase in extent of release (i.e., kinetic solubility at 240 minutes) of at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, at least 100%, at least 150%, or in accordance with certain embodiments at least 250%. Although these values refer herein to solid dispersions containing resveratrol as compared to crystalline resveratrol, it is envisioned that similar improved kinetic solubility results would be obtained for stilbene analogs of resveratrol when compared to appropriate crystalline forms thereof. "Initial kinetic solubility" refers to the percent of active released after 30 minutes in accordance with the dissolution test method (Kinetic Solubility Test) specified hi the Examples Section. "Extent of release" refers to the percent of active released (i.e., dissolved) after 240 minutes in accordance with the dissolution test method (Kinetic Solubility Test) specified in the Examples Section. The unproved kinetic solubility of the active, e.g., of resveratrol, in the solid dispersions of the present invention is believed to contribute to improved bioavailability of the active, e.g., resveratrol, and/or its metabolites. For example, increased plasma concentrations of one or more of such compounds may result. Alternatively, or additionally, an increase in AUC _0-24h may be realized. hi pharmaceutical applications, compositions of the present invention may be delivered by a wide variety of routes, including, but not limited to, oral, nasal, rectal, vaginal, subcutaneous, intravenous, and pulmonary. Generally, the oral route is preferred. Thus, the solid dispersions of the present invention are preferably in an oral dosage form. Exemplary presentation forms are powders, granules, and multiparticulates. These forms may be used directly or further processed to produce tablets, capsules, or sachets, or reconstituted by addition of water or other liquids to form a syrup, a suspension, or a solution. In certain embodiments, the oral dosage form is a capsule, a tablet, or a sachet. In certain embodiments, the oral dosage form is in a syrup, a suspension, or a solution. Such formulations are suitable for human consumption.

Preferred oral dosage forms include capsules (e.g., soft gelatin capsules, hard gelatin capsules, hypromellose capsules, and starch capsules). A composition in the form of a capsule can be prepared using routine encapsulation procedures. For example, the solid dispersion can be prepared using standard carriers and then filled into a hard capsule; alternatively, a dispersion or suspension can be prepared using any suitable pharmaceutical carrier(s), for example aqueous gums, celluloses, silicates or oils and the dispersion or suspension then filled into a soft capsule.

Pharmaceutical compositions of the present invention may be formulated to incorporate one or more physiologically acceptable carriers comprising excipients or additives. Such additives may be mixed, ground, or granulated with the compositions of this invention to form a material suitable for the above product forms. Examples of such additives include, but are not limited to, surfactants, pH modifiers, complexing agents, solubilizers, antioxidants, disintegrants, disintegrant aids, plasticizers, glidants, lubricants, pigments, taste masking agents, flavoring agents, fillers, flow control agents, processing aids, etc. Various combinations of such additives can be used if desired.

Pharmaceutical compositions of the present invention may be manufactured in a manner that is itself known, e.g., by means of conventional mixing, granulating, encapsulating, entrapping, or tabletting processes. Pharmaceutical compositions of the present invention include compositions where the ingredients are contained in an amount effective to achieve its intended purpose. The exact formulation, route of administration, and dosage for the pharmaceutical compositions of the present invention may be chosen, for example, by a physician (if a prescription product) in view of the patient's or subject's condition. The exact dosage may be determined on an active-by-active basis, in most cases.

Dosage amount and interval may be adjusted individually to provide plasma levels of the active ingredients/moieties that are sufficient to maintain the modulating effects, or minimal effective concentration (MEC). The MEC varies for each compound but can be estimated from in vitro data. Dosages necessary to achieve the MEC will depend on individual characteristics and route of administration. However, HPLC assays or bioassays can be used to determine plasma concentrations. The amount of composition administered will, of course, be dependent on the subject being treated, on the subject's weight, the condition to be treated, the manner of administration, and the judgment of the prescribing physician.

The compositions may, if desired, be presented in a pack or dispenser device which may contain one or more unit dosage forms containing the active ingredient. The pack may for example comprise metal or plastic foil, such as a blister pack. The pack or dispenser device may be accompanied by instructions for administration. The pack or dispenser may also be accompanied with a notice associated with the container in form prescribed by a governmental agency regulating the manufacture, use, or sale of pharmaceuticals, which notice is reflective of approval by the agency of the form of the active for human or veterinary administration. Such notice, for example, may include labeling approved or required by the U.S. Food and Drug Administration, or an approved product insert.

It will be understood by those of skill in the art that numerous and various modifications can be made without departing from the spirit of the present invention. Therefore, it should be clearly understood that the forms of the present invention are illustrative only and are not intended to limit the scope of the present invention.

EXAMPLES

Objects and advantages of this invention are further illustrated by the following examples, but the particular materials and amounts thereof recited in these examples, as well as other conditions and details, should not be construed to unduly limit this invention.

Experimental: Preparation of Solid Dispersions Evaluated in Figures 2-13

The correct amount of solvent system was measured into a graduated cylinder and dispensed into a suitably sized mixing vessel. A strong vortex was created by placing an overhead mixer into liquid. Active and polymer (PVP obtained as PLASDONE K-12 (PVP), (l-ethenyl-2-pyrrolidinone homopolymer), from ISP

Technologies, Inc., Wayne, NJ, and PLASDONE S-630 (VP/VA Copolymer) obtained from ISP Technologies, Inc. Wayne, NJ) in the ratio of 1 : 1 (parts by weight) were individually added slowly and directly into the vortex of the solvent. The final concentrations of active and polymer in the solvent system were 5% w/v of each. Spray drying was carried out using laboratory-scale Mini Spray Dryer connected with inert loop B295 (Buchi Labortechnik AG) under the following setting conditions: inlet temperature 65°C (acetonermethanol); outlet temperature 40-45°C, feed rate 20-25%; aspiration 100%. The resulting solid dispersion was collected and stored at -80°C until further analysis or handling.

Additional Resveratrol Amorphous Solid Dispersions Evaluated in Figures 14-22

In order to understand how variations in the amorphous solid composition may relate to stability behavior, several additional amorphous solid dispersions were manufactured and evaluated for stability. For the Resveratrol/PLASDONE system, additional data at longer stability time points was desired to better understand the 50:50 composition. The formulations evaluated were: Resveratrol/PLASDONE S-630, 30:70 (%w/%w) ratio; Resveratrol/PVP, 70:30 (%w/%w) ratio; Resveratrol/PLASDONE S- 630, 50:50 (%w/%w) ratio.

Other compositions that were manufactured include: Resveratrol/PVP K- 12, 80/20 ratio, there was evidence of crystallinity during initial XRD testing; Resveratrol/PVP K- 12, 75/25 ratio, amorphous during initial testing but no stability stability testing done; Resveratrol/PLASDONE S-630, 80/20 ratio, there was evidence of crystallinity during initial XRD testing.

Experimental: Preparation of Solid Dispersions Evaluated in Figures 14-22

A correct amount of solvent system was measured using volumetric glassware and added directly into a suitably sized mixing vessel. The solvent used was a 50:50 (% volume/% volume) mixture of acetone/methanol. A strong vortex was created by placing an overhead mixer into the solvent. Active and suitable polymer (PVP obtained as PLASDONE K- 12 (PVP), (l-ethenyl-2-pyrrolidinone homopolymer), from ISP Technologies, Inc., Wayne, NJ, and PLASDONE S-630 (VP/VA Copolymer) obtained from ISP Technologies, Inc. Wayne, NJ) were individually added slowly and directly into the vortex of the solvent in the following amounts:

Spray drying was carried out as above, under the following setting conditions: inlet temperature 65°C (acetone:methanol); outlet temperature 40-45°C, feed rate 20- 25%; aspiration 100%. The resulting solid dispersion was collected and stored at -80 ⁰ C until further analysis or placing under controlled environmental conditions.

Experimental: Storage of Samples Evaluated in Figures 2-13

The prepared solid dispersions were weighed and transferred to aluminum foil packets and sealed to obtain dry conditions and stored at 5 ⁰ C or 40 ⁰ C (referred to herein as "5 ⁰ C and Dry" and "4O ⁰ C and Dry", respectively).

The prepared solid dispersions were weighed and transferred to open vials and stored at 75% relative humidity and 4O ⁰ C (referred to herein as "4O ⁰ C and 75% RH").

The prepared solid dispersions are weighed and transferred to sealed aluminum foil packets and stored at controlled room temperature conditions (25 ⁰ C and 60% relative humidity).

Experimental: Storage of Samples Evaluated in Figures 14-22

The amorphous state of each freshly made material was confirmed by PXRD in initial testing. The apparent solubility test was also performed as part of initial testing. After initial testing, the solid materials were evaluated for stability under the following conditions: 40°C/75%RH (open), 4O ⁰ C (dry, sealed Al pouch) and CRT (controlled room temperature, 25°C/60%RH, sealed Al pouch). The time points evaluated are summarized below.

The tests at each time point include kinetic solubility and PXRD. Chemical stability by HPLC assay was also performed at the three-month time point. Experimental: Physical Characterization By Powder X-ray Diffractometry (PXRD) of Samples

About 20 mg of sample was filled in a shallow quartz holder and exposed to Cu Ka radiation (45 kV x 40 mA) in a wide-angle X-ray diffractometer (Model D5005, Siemens, Madison, WI). The instrument was operated in the step-scan mode, in increments of 0.05° 2Θ. The angular range was 5 to 45° 2Θ, and counts were accumulated for 1 second (s) at each step. The slit arrangement utilized was lmm (before), 1 mm (after), empty (after), 0.6 mm (after) and 0.6 mm (after). The data collection and analyses were performed with commercially available software (JADE, version 8, Materials Data, Inc., Livermore, CA).

As a reference, Figure 23 shows the PXRD for high purity resveratrol (> 98%) obtained from Interpharma Praha, Modrany, Czech Republic. The resveratrol originated from polygonum cuspidatum (Japanese Knotweed). The material was received as a fine, off-white powder. The PXRD technique for evaluating the pure resveratol was the same as that used for the solid dispersions. An aliquot of resveratrol was packed into the quartz sample holder and analyzed using the D5005 diffractometer. The pure, solid resveratrol was not micronized, ground or modified in any way prior to analysis.

Experimental: Kinetic Solubility Evaluation of Samples

Active dissolution studies were conducted using USP apparatus 2 (paddles) with 900 milliliters (ml) of media per vessel. Dissolution media was 0.01% SLS solution. Paddle speed was held at 100 revolutions per minute (rpm) with the media at 37 ± 0.5°C. Samples were withdrawn at appropriate time points using plastic syringes with stainless steel cannula. The cannula was fitted with a 10 micrometer (μm) porous filter (QLA, porous full flow filter, P/N FILOlO-Ol). Following withdrawal of a sample, the cannula/filter was removed and a Millex-LCR filter (Millipore, hydrophilic PTFE, 0.45 μm, P/N SLCR025NK) was attached to the syringe. The sample was filtered into a scintillation vial. The filtered solution was further diluted 100 times with distilled water prior to measure UV absorbance at 305 nanometers (nm).

Experimental: Chemical Stability of Samples Evaluated in Figures 2-13

Chemical stability of solid-dispersions maintained at four- week stability conditions was tested by HDPLC. A reversed phase FJPLC assay was used to quantify the level of degradation in the solid dispersions at the four- week time point. Solvents used for preparation of mobile phase were HPLC-grade. A Hypersil Gold HPLC column (Thermo Scientific, 250 millimeter (mm) X 4.6 mm ED, 5 μm particle size, part#25005- 254630) was used for separation. An Agilent 1100 series HPLC system was utilized with a diode array detector. The HP ChemStation (Rev A. 10.01) was used for integration and evaluation of the data. The samples for analysis were prepared in 50:50 methanol: water (v/v) at a nominal concentration of active at approximately 0.23 mg/ml. The chromatographic conditions were as follows: injection volume, 10 μl; a linear gradient method starting with 100% water to 100% methanol at 20 minutes (min); flow rate 1.4 ml/min; and detector wavelength 306 nrn.

Experimental: Chemical Stability of Samples Evaluated in Figures 14-22

Chemical stability of solid dispersions maintained at three-month stability conditions was evaluated by reverse-phase HPLC, as described above.

Results: Initial Solid Dispersions of Samples Evaluated in Figures 2-4 and 8-10

PXRD reveals that all solid dispersions (see Figures 2-4 and 8-10) were initially amorphous in nature.

Results: Resveratrol-PVP Solid Dispersion Physical Stability and Kinetic Solubility of Samples Evaluated in Figures 2-7

Results from PXRD (see Figures 2-4) shows that resveratrol-PVP solid dispersion was stable and amorphous even after being held at 40°C/75%RH for 4 weeks. This solid dispersion was also stable up to 4 weeks in the other two conditions (40 ⁰ C and Dry, 5 ⁰ C and Dry). The kinetic solubility results showed the initial solid dispersion had more than three-fold increase in the kinetic solubility compared to crystalline resveratrol. Results also revealed that the accelerated storage conditions of 40°C/75%RH did not appreciably change the solubility of resveratrol-PVP solid dispersion. There was a slight decrease in the kinetic solubility (see Figures 5-7) at the other two stability conditions, but as PXRD revealed these dispersions were still amorphous so the observed changes in kinetic solubility might not be significant. Results: Resveratrol-PLASDONE Solid Dispersion Physical Stability and Kinetic Solubility of Samples Evaluated in Figures 8-13

PXRD results (see Figures 8-10) showed that resveratrol-plasdone solid dispersion was amorphous up to 4 weeks at 40°C/75%RH and 5°C/Dry conditions, whereas resveratrol crystalline peaks started appearing even after 1-week stability at 40°C/Dry condition. The kinetic solubility (see Figures 11-13) of this solid-dispersion was almost double that of the crystalline resveratrol; however, this increased kinetic solubility was maintained only under the 40°C/75%RH stability conditions. At 40°C/Dry and 5°C/Dry conditions, kinetic solubility decreased as the storage time increased.

Results: Chemical Stability of Samples Evaluated in Figures 2-13

Chemical stability results showed less than 2% degradation in all solid dispersions and in many cases, the degradation was less than 0.5%.

Results: Resveratrol-PLASDONE 50:50 Solid Dispersion Physical Stability, Chemical

Stability, and Kinetic Solubility of Samples Evaluated in Figures 14-16 Analysis by PXRD (shown in Figures 14-15) shows this material (Resveratrol/PLASDONE S-630, 50:50 (%w/%w) Ratio) to be mainly amorphous at all time points, including the 3 -month time point. A small amount of crystallinity is seen forming for the 2-month 40°C/75%RH (open) and 2-month 4O ⁰ C (dry) condition, although the sample is still mainly amorphous. At the 3 -month time point the 40°C/75%RH (open) was amorphous and 4O ⁰ C (dry) condition had a trace of crystallinity. These results are consistent with a level of crystallinity close to the limit- of-detection of the X-ray diffractometer and indicate the samples are mainly amorphous. For the CRT condition the material was amorphous at the 3 -month time point. Review of the apparent solubility data (see Figure 16) for the 240-minute time point reveals a solubility increase ranging from 50% to 200% depending on the packaging configuration and storage condition. FfPLC assay of samples at the 3 -month time point shows degradation of less than 0.5%.

Results: Resveratrol-PLASDONE 30:70 Solid Dispersion Physical Stability, Chemical Stability, and Kinetic Solubility of Samples Evaluated in Figures 17-19

This composition (Resveratrol/PLASDONE S-630, 30:70 (%w/%w) Ratio) was found to remain in an amorphous form by PXRD (see Figures 17 and 18), even for the 3-month samples under all three storage conditions. Due to the high polymer content, dispersability in the dissolution vessels was poor. The apparent solubility test shows no enhancement in kinetic solubility (see Figure 19) at the 30-minute time point and a slight enhancement (for most samples) at the 240-minute time point. It is important to note that the kinetic solubility test performed only evaluated the amorphous solid dispersion as a powder. A typical formulation (capsule or compressed tablet) could contain excipients to enhance performance and improve dispersability. An appropriate formulation (including, e.g., a disintegrant) could be used to overcome the dispersability limitation seen in the analysis of the bulk amorphous solid powder.

Additionally, HPLC assay of samples at the 3 -month time point shows degradation of less than 0.5%.

Results: Resveratrol-PVP 70:30 Solid Dispersion Physical Stability, Chemical Stability, and Kinetic Solubility of Samples Evaluated in Figures 20-22

This material (Resveratrol/PVP, 70:30 (%w/%w) Ratio) recrystallized to some extent on stability, as seen by PXRD studies (Figures 20 and 21). The CRT condition appears to still be mainly amorphous at the 3 -month time point. The 40°C (dry) and 40°C/75%RH open condition have a higher amount of crystallinity; however some remaining amorphous content is still seen in these samples. Solubility (see Figure 22) is variable at the 30-minute time point but the 240-minute time point shows solubility enhancement in the range of 50% - 200% compared to the crystalline control. This is additional evidence that the samples tested retain a level of amorphous content consistent with enhanced apparent solubility relative to the 100% crystalline control. HPLC assay of samples at the 3-month time point shows degradation of less than 0.5%.

Pharmacokinetic Assessment for Resveratrol Amorphous Solid Dispersions in a Rat Model

Selected formulations of solid dispersions comprising resveratrol were dosed orally in male Sprague-Dawley rats, along with a control crystalline formulation. The solid dispersions selected for this study were of 50:50 Resveratrol/PVP. The solid dispersion was prepared in a manner such as that described.

Both the crystalline control and the solid dispersion were dosed as suspensions prepared in a vehicle consisting of 0.1% sodium lauryl sulfate (SLS) and 0.1% sodium carboxymethylcellulose (NaCMC) in water. Each dosing suspension was prepared on the day of dosing to contain 10 mg/mL of resveratrol. Resveratrol was administered to fasted male Sprague-Dawley rats at 50 mg/kg.

Plasma concentrations were determined by LC-MS/MS. Results are summarized in the table below and displayed in Figure 24. In comparison to the control formulation, oral exposure to resveratrol was higher after dosing of the solid dispersion. Average Cmax and AUClast were higher after dosing of the solid dispersion (794 ± 574 ng/mL and 836 ± 113 hr*ng/mL) in comparison to the control formulation (132 ± 17.6 ng/mL and 469 ± 152 hr*ng/mL). Absorption of resveratrol from the solid dispersion was rapid, with maximum plasma concentrations observed at the first plasma sample (15 minutes post-dose), while absorption after the control formulation dose was much slower with tmax reached between 2 and 4 hours post-dose.

Figure 24 shows a comparison of the average plasma concentration profiles of the solid dispersion and control. As can be seen, the solid dispersion exhibits a faster initial rate of resveratrol absorption as well as a higher extent of absorption as demonstrated by the higher AUC values.

Concentrations of resveratrol glucuronide far exceeded those of resveratrol. Average Cmax for resveratrol glucuronide after dosing of the control and solid dispersion formulations was 7310 ± 1487 and 12400 ± 4158, respectively. Systemic exposure to resveratrol glucuronide was similar between the two groups with average AUClast values of 41064 ± 7289 for the control and 43362 ± 5501 for the solid dispersion formulation. The half-life of resveratrol glucuronide was consistent between the two dosing groups with values ranging from 2.03 hours to 2.96 hours.

These results demonstrate that resveratrol amorphous solid dispersions, as described in this invention, offer improved pharmacokinetic advantages over crystalline resveratrol.

Average Pharmacokinetic Parameters (±SD) for Resveratrol and Resveratrol Glucuronide After Oral Administration of a Control or Solid Dispersion Formulation to Rat Model

*n=l

The complete disclosures of the patents, patent documents, and publications cited herein are incorporated by reference in their entirety as if each were individually incorporated. Various modifications and alterations to this invention will become apparent to those skilled in the art without departing from the scope and spirit of this invention. It should be understood that this invention is not intended to be unduly limited by the illustrative embodiments and examples set forth herein and that such examples and embodiments are presented by way of example only with the scope of the invention intended to be limited only by the claims set forth herein.