WO2008086400A2 - Sirtuin-activating compounds of enhanced bioavailability - Google Patents

Sirtuin-activating compounds of enhanced bioavailability Download PDF

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Publication number
WO2008086400A2
WO2008086400A2 PCT/US2008/050588 US2008050588W WO2008086400A2 WO 2008086400 A2 WO2008086400 A2 WO 2008086400A2 US 2008050588 W US2008050588 W US 2008050588W WO 2008086400 A2 WO2008086400 A2 WO 2008086400A2
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solvent
sac
polymer
composition
solubility
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PCT/US2008/050588
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French (fr)
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WO2008086400A3 (en
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John Alfred Doney
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Isp Investments Inc.
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Publication of WO2008086400A2 publication Critical patent/WO2008086400A2/en
Publication of WO2008086400A3 publication Critical patent/WO2008086400A3/en

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    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00Medicinal preparations characterised by special physical form
    • A61K9/14Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/141Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers
    • A61K9/146Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers with organic macromolecular compounds
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/045Hydroxy compounds, e.g. alcohols; Salts thereof, e.g. alcoholates
    • A61K31/05Phenols
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00Medicinal preparations characterised by special physical form
    • A61K9/14Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1605Excipients; Inactive ingredients
    • A61K9/1629Organic macromolecular compounds
    • A61K9/1635Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00Medicinal preparations characterised by special physical form
    • A61K9/14Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1605Excipients; Inactive ingredients
    • A61K9/1629Organic macromolecular compounds
    • A61K9/1652Polysaccharides, e.g. alginate, cellulose derivatives; Cyclodextrin

Definitions

  • Stilbenoid, flavonoids, and chalconoids are classes of organic compounds that appear to stimulate sirtuin enzymes, proteins that regulate cellular activity in plants and animals. Increased sirtuin activity may be beneficial in the treatment of insulin-resistant disorders (e.g., diabetes) and preventing obesity. Sirtuin enzymes are also believed to increase cellular lifespan, genomic stability, and silencing transcription. Many of these sirtuin-activating compounds (SACs) occur naturally and are widely marketed as dietary supplements. However, many exhibit water insolubility, making it a challenge to deliver these compounds and achieve therapeutic blood concentrations. There exists the need to improve the bioavailability of stilbenoids, flavonoids, and chalconoids when supplemented to a diet of an animal, especially man.
  • SACs sirtuin-activating compounds
  • the stilbenoid family exhibits a chemical structure based on that of stilbene:
  • stilbenoids that serve as SACs include resveratrol:
  • Flavonoids are compounds based on the chemistry of flavone which has a three- ring structure as indicated below:
  • Flavonoids are also produced by plants and generally exhibit low toxicity to animals and man. SACs that have been identified based on the flavonoid structure include daidzein, fisetin, genistein, kaempferol, pentahydroxyflavone, and quercetin. These compounds are available as dietary supplements, and are believed to promote anti-carcinogenic, antiatherogenic, and anti-osteoporotic activity.
  • Chalconoids are aromatic ketones with a chemistry based on chalcone:
  • Chalconoids that activate a sirtuin response include, but are not limited to, butein and pentahydroxychalcone.
  • U.S. Patent Application Publication Nos. 2005/0171027, 2005/0136537, and 2006/0111435 disclose some of the stilbenoid, flavonoid, and chalconoid chemistries, along with resveratrol analogues, that enhance the activity of sirtuin enzymes as a method for treating obesity or insulin-resistant disorders. These publications are hereby incorporated by reference.
  • a bioenhanced form of SACs that does not require the use of oils, lipids, or gelatins; emulsification technology; liquid formulations based on organic solvents or particle size reduction;
  • compositions of bioenhanced SACs and methods for producing them relate to compositions of bioenhanced SACs and methods for producing them. More particularly, certain aspects of the present invention relate to compositions and methods for preparing bioenhanced SACs utilizing at least one solubility-enhancing polymer.
  • the mixture is prepared by dry blending SACs with a solubility-enhancing polymer.
  • one or more SACs are dissolved in a solvent containing the polymer.
  • a blend of solvent/non-solvent for the polymer is employed.
  • the bioenhanced SAC product is produced by any method suitable to the composition. In one embodiment, direct compression of physically blended SAC-polymer(s) is used.
  • SAC-polymer-solvent or a solvent/non-solvent blend
  • SAC-polymer-solvent is spray dried to produce the SAC in a form that exhibits improved solubility and/or bioavailability.
  • the bioenhanced SAC composition can be prepared by methods other than spray drying as recognized by those skilled in the art. Those methods include, without limitation: melt extrusion, spray congealing, and freeze drying.
  • a significant portion of the SAC is provided in the amorphous state.
  • the SAC is converted almost entirely to the amorphous state.
  • the SAC is converted to the completely amorphous state.
  • compositions containing SACs and methods for producing SAC compositions of enhanced solubility and bioavailability are described . It has been discovered that mixtures of SACs and solubility- enhancing polymers show enhanced aqueous solubility compared to the crystalline form. Examples of compositions that create this enhancement include, without restriction: solid dispersions and physical blends of the components. Surprisingly, simple dry mixtures of a SAC and polymer attain dissolution release characteristics equal to many commercial softgel SAC products, which employ lipids, oils and/or triglycerides. Even faster release with greater extent is produced with amorphous SAC-polymer dispersions, as shown in several embodiments of the invention.
  • the amorphous conversion of the SAC is not a requirement for the enhanced properties.
  • a composition comprising a solid dispersion of a SAC and at least one solubility-enhancing polymer wherein the SAC in the dispersion is substantially amorphous is also provided.
  • the disclosed invention describes the conversion of crystalline SAC to the amorphous state.
  • One method for producing this conversion is through solvent spray drying.
  • Other techniques within the scope of this invention that accomplish this conversion include, without limitation: flash solvent evaporation, melt-congeal spraying, freeze drying, and melt-extrusion. These methods can use a single solubility-enhancing polymer or blends of polymers.
  • products can be developed that serve the vegan/all natural market (e.g., using naturally-occurring ingredients/adjuvants) and a broader market (e.g., using synthetic ingredients/adjuvants).
  • the degree of SAC amorphous conversion depends on both polymer type and amount and processing conditions.
  • a single organic solvent, blends of solvents, or solvent/non-solvent blends can be used.
  • a solution is prepared comprising a solvent, one or more SACs, and one or more solubility-enhancing organic material.
  • solvent is only limited inasmuch as to produce a SAC solution, and examples of suitable solvents include dichloromethane/methanol blends, and chloroform.
  • the solvent may dissolve both the SAC and solubility-enhancing organic material, or a non-solvent for the organic material optionally may be added.
  • the solubility-enhancing organic material comprises a polymer.
  • the solubility-enhancing organic material comprises a carbohydrate.
  • the organic material may be of any type approved for use in pharmaceutical and/or dietary supplement products.
  • the invention relates to spray-dried powders or granulated products comprising amorphous SACs.
  • the resulting powders produced in accordance with certain embodiments typically possess lower residual solvent content and higher tap density than their counterparts produced by conventional methods, due to a change in the particle morphology and size.
  • One aspect of the invention involves amorphous SACs prepared from compositions containing SACs and a solubility-enhancing polymer in a solvent or a solvent blend.
  • This solvent or solvent blend includes a solvent in which the polymer is soluble.
  • soluble means that the attractive force between polymer and solvent molecules is greater than the competing inter- and intramolecular attractive forces between polymer molecules.
  • solvent is simply called “solvent.”
  • Compositions also are described in which the solvent blend contains a solvent for which the opposite is true: The force between polymer and solvent molecules is less than the inter- and intramolecular attractive force between polymer molecules. This second solvent is termed the "non- solvent.” The polymer may swell but does not dissolve in the non-solvent.
  • a solubility-enhancing polymer and a suitable solvent/non-solvent blend are provided.
  • the solvent possesses a lower boiling point than the non-solvent.
  • the solvent and non-solvent are miscible. The ratio of solvent to non-solvent is such that the polymer can be considered "dissolved" in the solvent system.
  • Unique particle properties can be created by evaporating the solvent/non-solvent blend. For example, this evaporation can occur during the spray drying of the feed solution or granulation processes.
  • Atomized droplets containing a blend of solvents will experience a change in the total solvent composition due to evaporation. The method appears to be independent of how the droplets are generated or atomized.
  • the polymer exists in a dissolved state, due to a sufficient amount of the solvent. As it evaporates (the solvent boils at a lower temperature than the non-solvent), the concentration of non-solvent in the droplet increases.
  • the solvent composition is insufficient to maintain the polymer in solution. In doing so, the polymer collapses from solution. This change in polymer conformation can alter the evaporation dynamics of the droplet to create particle morphologies that influence final powder properties.
  • SACs of enhanced solubility and bioavailability can be formed by spray drying from a solution containing solvent alone, there are additional benefits associated with the use of a solvent/non-solvent blend system.
  • This solvent/non-solvent approach can produce a spray dried powder of lower residual solvent content and smaller particle size.
  • a further consequence of this engineered particle morphology is the increase in bulk powder density. Increased powder density is an important attribute for many applications. The extent of polymer collapse — and therefore the net effect on the spray dried powder properties — depends on the polymer solvation factors, such as the initial ratio of solvent to non-solvent, the polymer chemical structure and the polymer molecular weight.
  • the primary polymer may be paired with the solvent/non-solvent system in order to affect not only the morphology of the particle, but also that of the SAC, and thereby affect active loading, crystallinity, solubility, stability and release.
  • additional polymers may contribute to the final particle morphology by their interaction with the first polymer and the solvent system. These additional polymers may also be advantageous to create special release properties of the active.
  • the primary polymer may be paired with the solvent/non-solvent system in order to affect particle morphology, and thereby residual solvent content and bulk powder density.
  • Additional polymeric adjuvants may be added to serve additional purposes: further inhibit active recrystallization, further maximize active concentration, and further enhance/delay/retard dissolution rate. To accomplish these functionalities, it is necessary to suitably match the adjuvant solubilities with the solvent blend selected for the primary polymer.
  • FIGS. 1 - 4 are graphs of melting enthalpy as a function of temperature for compositions produced in accordance with Example 2;
  • FIG. 5 is a graph of resveratrol release as a function of time for compositions produced in accordance with Example 3.
  • FIG 6 is a graph of resveratrol release as a function of time for compositions produced in accordance with Example 5.
  • SAC sirtuin-activating compound
  • SACs include, but are not limited to: ambroxol, apigenin, butein, caffeic acid phenyl ester, (-)-catechin, daidzein, dihydroxyflavone, (-)-epicatechin, fisetin, flavanone, flavone, (-)-gallocatechin, genistein, 6-hydroxyapigenin, 5-hydroxyflavone, isoliquiritigenin, kaempferol, morin, naringenin, pelargonidin chloride, 3,5,6,3 ',4'- pentahydroxyflavanone, piceatannol, quercetin, resveratrol, resveratrol analogues, rhapontin, c ⁇ -stilbene, fr ⁇ ws-stilbene,
  • analogue refers to chemical compounds that share a commonality in structure to a parent compound, but differ with respect to elemental composition, stereochemistry, and/or the addition of moiety group(s).
  • Bioavailability refers to the degree to which a compound becomes available in the body after administration. Typically, plasma samples are taken and analyzed for the plasma concentration of the parent compound and/or its active metabolite. These data may be expressed as C max , the maximum amount of the compound found in the plasma, or as AUC, the area under the plasma concentration time curve. Enhanced bioavailability may be evidenced by an increase in C max and/or AUC for the parent compound and/or its active metabolite. Compositions in accordance with certain aspects of the invention exhibit enhanced bioavailability compared to a control composition.
  • solid dispersion refers to a system in a solid state comprising at least two components, wherein one component is dispersed evenly throughout the other component or components.
  • solid dispersion includes systems having small particles either completely crystalline, completely amorphous or any state in between, typically less than about 1 ⁇ m in diameter, of one phase dispersed in another phase.
  • solid solution refers to a type of solid dispersion wherein one component is molecularly dispersed throughout another component such that the system is chemically and physically uniform and homogeneous throughout. These systems do not contain any significant amounts of active ingredients in their crystalline or microcrystalline state as evidenced by thermal analysis (e.g., differential scanning calorimetry), or diffractive (e.g., X-ray diffraction) techniques.
  • solubility-enhancing polymer refers to a polymer that provides at least one of the following properties as a result of its presence in the composition compared to a control composition without the solubility-enhancing polymer:
  • compositions other than SACs are combined with one or more solubility-enhancing polymer(s).
  • solubility-enhancing polymer(s) includes, but is not limited to: blended, co-mingled, dissolved, extruded, granulated, melted, milled, mixed, sieved, slurried, sprayed, stirred, and the combination of these and other methods. Other techniques may be identified by those skilled in the art.
  • compositions of the current invention may include additional active ingredients to the SAC.
  • Active pharmaceutical ingredients include, but are not limited to: analgesics, anti-arrhythmics, anti-bacterials, anti-convulsants, anti-Alzheimer's agents, anti-diabetics, anti-emetics, anti-fungals, anti-histiminics, anti-hyperlipidemics, anti- hyperlipoproteinemics, anti-hypertensives, anti-inflamatory agents, anti-Parkinsonian agents, anti-pulmonary hypertensives, anti-rheumatics, anti-ulceratives, anti-virals, cardiovascular agents, chemotherapy agents, central nervous system sedatives and stimulants, diuretics, gastrointestinal agents, hormones, respiratory agents, skin agents, as well as actives for the treatment of acne, benign prostatic hypertrophy, irritable bowel syndrome.
  • Nutraceutical ingredients include, but are not limited to: herbs, isoflavones, moisturizers, mood regulators, minerals, oils, benzoquinones, carotenoids, protein supplements, skin agents
  • the present invention is not limited to resveratrol spray-dried compositions.
  • the methods described herein are also useful in converting other SACs to the amorphous state of enhanced solubility and bioavailability.
  • Physical mixtures of SACs and a solubility-enhancing polymer that increase the solubility and bioavailability of SACs are also within the scope of the present invention. Physical mixtures can be prepared in accordance with conventional techniques such as a tumble blending, high-shear granulation, fluid bed granulation, film coating, or any of their related technologies.
  • the present invention is related to a method for preparing a spray-dried composition by providing a mixture containing SACs and a polymer in a single solvent, a solvent blend or a blend of a solvent and a non-solvent for the polymer and spray drying the mixture to form the amorphous SAC composition.
  • One aspect of the invention involves the pairing of the polymer with a carefully selected solvent or solvent blend. This approach comprises a solvent in which the polymer is soluble. Guidance in defining polymer solubility is provided by the expansion coefficient ( ⁇ ):
  • Equation ⁇ 1 can be written for branched polymers in an analogous manner, 2 using square-average radius of gyration about the center of gravity, s , and the 2 corresponding unperturbed dimension, s o .
  • Polymer solubility is provided when ⁇ is unity or greater, and solvents that satisfy this condition are called "good solvents,” or simply “solvents.” Solvents uncoil (or expand) the polymer molecule, since the polymer- solvent attractive force is greater than that of polymer-polymer.
  • Light scattering methods such as Viscotek's Triple Detector Array, can be used to determine the variables expressed in equation ⁇ 1.
  • solvents are considered “good solvents" when ⁇ is about equal to 1 or more. It is appreciated that temperature influences ⁇ , such that a good solvent may be transformed into a non-solvent merely by changing the temperature.
  • the solvent blend also contains a solvent for which the opposite is true: Polymer-polymer forces dominate polymer-solvent forces. In this case, ⁇ is less than one and the solvent is termed a "non-solvent," because the polymer exists in a collapsed state.
  • the polymer is provided in a suitable solvent/non-solvent blend.
  • the blend of solvent/non-solvent maintains a ⁇ or solvated state of the polymer, such that the polymer can be considered "dissolved" in the solvent system.
  • the solvent possesses a lower boiling point than the non-solvent. (Solvent/non-solvent pairs that form an azeotrope do not satisfy this criterion.)
  • a polymer system comprising a solubility-enhancing polymer and a suitable solvent/non-solvent blend.
  • suitable polymer/solvent/non-solvent combinations include, without limitation, polyvinylpyrrolidone/dichloromethane/acetone, polyvinylpyrrolidone-co-vinyl acetate/acetone/hexane, and ethylcellulose/acetone/water.
  • Unique particle architectures are created by precipitation of the primary polymer when the non-solvent concentration exceeds a critical value. This critical ratio R 0 can be defined:
  • the ratio R c for a given system can be determined experimentally by identifying the mass fractions of each component that produce a significant increase in solution turbidity. If an R e value can be identified for a polymer system, then the system comprises a solvent/non- solvent blend.
  • a solvent/non- solvent blend is a solution containing about 10% (w/w) polyvinylpyrrolidone, 18% (w/w) dichloromethane, and 72% (w/w) acetone, for which R 0 equals 0.80.
  • Polymer systems typically will be used at solvent/non-solvent blends that are at or below the R 0 value for the system. It may be advantageous to formulate more complex polymer/solvent systems in order to control particle morphology/size as well as the crystallinity, solubility, bioavailability and release characteristics of SACs.
  • the present invention in accordance with other embodiments provides a method to increase the density of spray-dried powders.
  • spray drying produces sphere- like particles with some degree of interior void. This void increases particle bulk without mass and creates low-density material.
  • Adding a non-solvent to the working solution/dispersion changes the particle size and morphology, leading to an increase in density. Particles may be smaller, wrinkled, dimpled, and/or collapsed compared to those prepared using only solvent.
  • the solvent/non-solvent approach also reduces the mean particle size, allowing the powder to pack better.
  • powder flow and powder- powder mixing properties are enhanced.
  • the present invention in accordance with certain aspects provides a method to reduce or eliminate the need for secondary drying of spray-dried powders and granulated materials. These products often contain residual solvent, and it is desirable or necessary to produce a drier product.
  • a high residual solvent content can result from formulation or processing limitations.
  • the general practice has been to use a solvent that dissolves the solids being spray dried. In doing so, solvent can be trapped inside the spray dried powder or granulated bead due to case hardening.
  • the intentional pairing of a lower-boiling solvent with a higher-boiling non-solvent for the materials being processed can yield products of lower residual solvent due to the effect(s) of the non-solvent on the process polymers.
  • the present invention may further provide a method to enhance the aqueous solubility and modify the release of active ingredients through selection of a polymer system with the solvent or solvent/non-solvent blend.
  • the polymer system is chosen so that one (or more) polymer(s) work with the solvent/non-solvents to create novel particle morphologies. Additional polymer(s) may be added as needed to affect the solubility and release properties of the active, as well as particle morphology.
  • Enhanced solubility can be achieved by a number of factors, including (but not limited to): improved wettability, creation of amorphous SACs forms, stabilization against recrystallization, and/or co- solvation effects.
  • Modified release refers to changing the time frame in which the active is released, i.e., immediate, delay, extended. These modified releases are created by matching functional polymer(s) with the appropriate solvent/non-solvent blend.
  • Solvents and non-solvents suitable for use in the process of the present invention can be any organic compound (including water) in which the primary polymer is soluble in the case of solvents, or insoluble, in the case of non-solvents.
  • the choice and ratio of solvent/non-solvent depends on the choice of the primary polymer. Accordingly, the identification of an organic compound as a solvent or non-solvent depends on the primary polymer. Therefore, a solvent in one system may be a non-solvent in another.
  • solvents and non-solvents include, but are not limited to: acetic acid, acetone, acetonitrile, anisole, 1-butanol, 2-butanol, butyl acetate, tert-butylmethyl ether, chlorobenzene, chloroform, cumene, cyclohexane, 1-2-dichloroethane, dichloromethane, 1- 2-dimethoxyethane, N-N-dimethylacetamide, N-N-dimethylformamide, 1-4-dioxane, ethanol, 2-ethoxyethanol, ethyl acetate, ethylene glycol, ethyl ether, ethyl formate, formamide, formic acid, heptane, hexane, isobutyl acetate, isopropyl acetate, methanol, methyl acetate, 2-methoxy ethanol, 3 -methyl- 1-butanol, methyl
  • solvent blends at the azeotropic composition can comprise either the solvent or non-solvent, but not the solvent/non-solvent blend.
  • Solubility-enhancing polymers that are suitable for use in the mixtures of the present invention enhance the solubility of SACs.
  • the solubility-enhancing polymer also inhibits crystallization of SACs and, therefore, the presence of the polymer results in conversion of at least some of the crystalline SAC to the amorphous state.
  • at least one polymer should be soluble in the solvent and not soluble in the non-solvent.
  • useful polymers include, but are not limited to: aliphatic polyesters (e.g., poly D-lactide), carbohydrates (e.g., sucrose), carboxyalkylcelluloses (e.g., carboxymethylcellulose), alkylcelluloses (e.g., ethylcellulose), gelatins, hydroxyalkylcelluloses (e.g., hydroxypropyl cellulose (HPC)), hydroxyalkylalkyl celluloses (e.g., hydroxypropylmethyl cellulose (HPMC)), hydroxyalkylalkylcellulose derivatives, polyamines (e.g., chitosan), polyethylene glycols (e.g., PEG 8000, PEG 20000), methacrylic acid polymers and copolymers (e.g., Eudragit ® series of polymers of Rohm Pharma, GmbH), homo- and copolymers of N-vinyl pyrrolidone (e.g., polyvinylpyrrolidone,
  • hydroxyalkylalkylcellulose derivatives is meant to include, without limitation, hydroxypropylmethyl cellulose phthalate, and hydroxypropylmethyl cellulose acetate succinate.
  • the amount of the polymer present in the mixture may range from about 1% to about 95%, more particularly from about 5% to 90%, by weight of the mixture, and in accordance with certain embodiments from about 25% to 75% by weight. Blends of polymers may also be used.
  • the solubility-enhancing organic material comprises a carbohydrate.
  • the carbohydrate can be a reducing carbohydrate, which is metabolized by the body, or a non-reducing carbohydrate, which is not metabolized by the body.
  • reducing carbohydrates include, without limitation, dextrose, fructose, maltose, starch, and sucrose.
  • non-reducing carbohydrates include, without limitation, aspartame, mannitol, and sucralose.
  • the bioenhanced composition which may comprise a spray-dried mixture, includes SACs as an active ingredient.
  • the mixture may contain from about 1% to about 95% active, more particularly from about 20% to about 80% active, depending on the desired dose of the active.
  • the weight ratio of SACs to polymer typically will be from about 95% SACs : 5% total polymer to about 5% SACs : 95% total polymer, more particularly from about 70% SACs : 30% total polymer to about 30% SACs : 70% total polymer and in accordance with certain aspects from about 60% SACs : 40% total polymer to about 40% SACs : 60% total polymer.
  • the spray dried composition of the present invention when combined with a solubility-enhancing polymer produces a portion of SACs in the amorphous state.
  • amorphous refers to a compound in a non-crystalline state. In other words, an amorphous compound lacks long-ranged, defined crystalline structure.
  • at least some, more particularly at least about 10%, at least about 25%, or at least about 40% of the SACs in the composition is in an amorphous form. In other embodiments, at least a major portion of the compound in the composition is amorphous.
  • the term "a major portion" of the compound means that at least about 50% of the compound in the composition is in the amorphous form, rather than the crystalline form. More particularly, the compound in the composition may be substantially amorphous. As used herein, “substantially amorphous” means that the amount of the compound in the crystalline form does not exceed about 25% (i.e., more than about 75% of the compound is in the amorphous form). In accordance with particular embodiments of the invention, the compound in the composition is "almost completely amorphous" meaning that the amount of drug in the crystalline form does not exceed about 10% (i.e., more than about 90% of the compound is in the amorphous form).
  • compositions are also provided wherein the compound in the composition is considered to be "completely amorphous" meaning that the crystalline form of the drug is not detectable using conventional techniques, such as X-ray diffraction or thermal analysis.
  • Reference to a composition as completely amorphous does not exclude compositions containing trace amounts (less than about 1%) of the crystalline form of the active.
  • Amorphous materials lack some measurable properties, such as melting endotherms as measured by differential scanning calorimetry that characterize crystalline forms.
  • Amounts of crystalline SACs may be measured by powder X-ray diffraction (PXRD), differential scanning calorimetry (DSC), or any other standard quantitative analysis.
  • the amounts of crystalline SACs present in the composition may be detected by any other standard measurement known to those of ordinary skill in the art. It is appreciated that the measurement of such properties is dependent on instrument type, sensitivity, operation, and analysis.
  • the spray dried powder produced in accordance with certain aspects of the present invention provides enhanced solubility and/or bioavailability of SACs compared to products containing the principle crystalline form.
  • the increased bioavailability of the active can also lead to reduced dosage sizes and dose amounts for the active. It has been determined that the rate of SACs release can be controlled through proper selection of the polymers added into the solvent solution for the spray dried process.
  • the spray dried mixture or bioenhanced composition may also contain additional polymeric materials that can modify properties of the composition. For example, certain polymers can be included to control particle morphology/size as well as the solubility and bioavailability and release characteristics of the active ingredient. Additional polymers may also be included in the mixture to further inhibit active recrystallization, further maximize active concentration and further enhance/delay/retard dissolution rate. Additional polymers that can be incorporated into this system are not particularly limited.
  • the mixture to be spray dried typically contains from about 40% to 99.9% by weight total solvent or solvent/non-solvent, more particularly from about 80% to 95% by weight total solvent or solvent/non-solvent based on the total weight of the mixture.
  • the critical ratio R c can vary from about 0.01-0.99, more particularly from about 0.1-0.9, still more particularly from about 0.3-0.8.
  • the mixture to be spray dried may also include other ingredients to improve performance, handling or processing of the mixture.
  • these ingredients also may be admixed into the already-prepared SAC-polymer by methods including, but not limited to tumble blending and granulation technologies.
  • Typical ingredients include, but are not limited to, anti-oxidants, surfactants, pH modifiers, fillers, complexing agents, solubilizer, pigments, lubricants, glidants, flavor agents, plasticizers, taste masking agents, disintegrants, disintegrant aids (e.g., calcium silicates), etc., which may be used for customary purposes and in typical amounts.
  • useful surfactants include, but are not limited to, sodium lauryl sulfate, docusate sodium, sorbitan monooleate, and sorbitan trioleate.
  • useful fillers include, but are not limited to, lactoses, dextrin, sugars, sugar alcohols, and silica.
  • the spray drying apparatus used in accordance with certain aspects of the present invention can be any of the various commercially available apparatus or other devices capable of producing similar particles from liquid mixtures.
  • specific spray drying devices include spray dryers manufactured by Niro Inc. (e.g., SD-Micro ® , PSD- 1 ® , PSD-2 ® , etc.), the Mini Spray Dryer ® by Buchi 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.
  • the term "spray drying” is used conventionally and, in general, refers to processes involving breaking up liquid mixtures into small droplets and rapidly removing solvent from the mixture in a container (spray drying apparatus) where there is a strong driving force for evaporation of solvent from the droplets.
  • Atomization techniques include two- fluid and pressure nozzles, and rotary atomizers.
  • the strong driving force for solvent evaporation is generally provided by maintaining the partial pressure of solvent in the spray drying apparatus well below the vapor pressure of the solvent at the temperatures of the drying droplets. This may be accomplished by either (1) maintaining the pressure in the spray drying apparatus at a partial vacuum; (2) mixing the liquid droplets with a warm drying gas; or (3) both.
  • the temperature and flow rate of the drying gas and the design of the spray dryer are chosen so that the polymer/active solution 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. It is also possible to operate a spray dryer so that product collects on the apparatus wall, and then is collected by removing the material manually, pneumatically, mechanically or other means. The actual length of time to achieve the preferred 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 solid dispersion as it exits the dryer should be low, since this improves the stability of the product.
  • the residual solvent content of the spray-dried composition should be less than about 10% by weight and preferably less than about 2% by weight.
  • the residual solvent content is within the limits set forth in the International Conference on Harmonization (ICH) Guidelines.
  • ICH International Conference on Harmonization
  • Methods to further lower solvent levels include, but are not limited to fluid bed drying, infra-red drying, tumble drying, vacuum drying, and combinations of these and other processes. 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 describe results obtained with a laboratory-scale spray dryer. One of ordinary skill in the art would readily appreciate variables that must be modified to obtain similar results with a production-scale unit.
  • the present invention is not limited to amorphous SACs produced by spray drying.
  • Physical mixtures of SACs with a solubility-enhancing polymer can also enhance the solubility and bioavailability of SACs.
  • Methods for preparing physical mixtures of the polymer and SACs are not particularly limited.
  • physical mixtures of solubility-enhancing polymer and SACs may be formed by tumble blending, co-milling, stirring, granulating, or other methods known to those skilled in the art.
  • compositions of the present invention may be prepared by other processes including, but not limited to, extrusion, spheronization and spray congealing.
  • Extrusion is a well-known method of applying pressure to a damp or melted composition until it flows through an orifice or a defined opening.
  • the extrudable length varies with the physical characteristics of the material to be extruded, the method of extrusion, and the process of manipulation of the particles after extrusion.
  • Various types of extrusion devices can be employed, such as screw, sieve and basket, roll, and ram extruders.
  • Spray congealing is a method that is generally used in changing the structure of the materials, to obtain free flowing powders from liquids and to provide pellets ranging in size from about 0.25 mm to 2.0 mm.
  • Spray congealing involves allowing a substance of interest to melt, disperse, or dissolve in a hot melt of other additives. The molten mixture is then sprayed into an air chamber wherein the temperature is below the melting point of the formulation components, to provide spherical congealed pellets. The temperature of the cooled air used depends on the freezing point of the product. The particles are held together by solid bonds formed from the congealed melts.
  • the particles Due to the absence of solvent evaporation in most spray congealing processes, the particles are generally non porous and strong, and remain intact upon agitation.
  • the characteristics of the final congealed product depend in part on the properties of the additives used.
  • the feed rate and inlet/outlet temperatures are adjusted to ensure congealing of the atomized liquid droplet.
  • the feed should have adequate viscosity to ensure homogeneity.
  • the conversion of molten feed into powder is a single, continuous step. Proper atomization and a controlled cooling rate are critical to obtain high surface area, uniform and homogeneous congealed pellets. Adjustment of these parameters is readily achieved by one skilled in the art.
  • the spray congealing method is similar to spray drying, except that solvent is not used. Instead, the active ingredient(s) is dispersed and/or melted into a matrix comprising melt-processable polymer(s). Spray congealing is a uniform and rapid process, and is completed before the product comes in contact with any equipment surface. Most actives and additives that melt without decomposition are suitable for this method.
  • spray dryers operating with cool inlet air have been used for spray congealing.
  • atomization of molten mass can be employed, such as pressure, or pneumatic or centrifugal atomization.
  • pressure or pneumatic or centrifugal atomization.
  • formulation aspects such as matrix materials, viscosity, and processing factors, such as temperature, atomization and cooling rate affect the quality (morphology, particle size distribution, polymorphism and dissolution characteristics) of spray congealed pellets.
  • the spray congealed particles may be used in tablet granulation form, encapsulation form, or can be incorporated into a liquid suspension form.
  • compositions prepared in accordance with certain aspects of the present invention provide amorphous SACs that exhibits enhanced solubility and bioavailability without requiring the use of significant amounts of lipids or oils.
  • certain aspects of the invention relate to compositions containing amorphous SACs that are substantially free of lipids, triglycerides, or oils.
  • SACs produced in accordance with some embodiments of the invention exhibit enhanced solubility and bioavailability even when present in solid state forms such as solid solutions or solid dispersions.
  • SACs may be present in such compositions at levels exceeding about 5% by weight, more particularly exceeding about 10%, and in some cases exceeding about 25%, 40% or even 50% by weight of the composition and still exhibit enhanced solubility and bioavailability compared to crystalline forms of the compound.
  • Certain polymers function as solubility-enhancing polymers in that the presence of the polymer in the composition improves solubility of the SAC under various conditions.
  • the solubility-enhancing polymer provides at least one of the following properties as a result of its presence in the composition compared to a control composition without the solubility-enhancing polymer or to a composition containing the crystalline form of the SAC:
  • Initial release refers to the percent of SAC released after 15 minutes in accordance with a standard dissolution test method.
  • Extent of release refers to the percent of SAC released after 240 minutes in accordance with the same standard dissolution test method.
  • a composition prepared from a system comprising a polymer and a SAC spray dried from a solvent/non-solvent system as described herein exhibits a dissolution profile wherein the percent SAC released at some point in time is at least about 25%, more particularly at least about 50% and in certain cases at least about 100% greater than a control composition prepared from a system comprising the same polymer and SAC spray dried from the same solvent without the non-solvent.
  • these limits are obtained within about 120 minutes, more particularly within about 60 minutes and still more particularly within about 30 minutes.
  • Dissolution profiles can be determined using USP apparatus II (paddles) (VK 7010 ® , Varian Inc.), with a bath temperature of 37°C and a paddle speed of 50 rpm.
  • a composition prepared from a system comprising a polymer and SAC spray dried from a solvent/non-solvent system as described herein is expected to exhibit an increase in bulk density or tap density wherein the density is at least about 25%, more particularly at least about 50% and in certain cases at least about 100% greater than a control composition prepared from a system comprising the same polymer and SAC spray dried from the same solvent without the non-solvent.
  • SAC compositions prepared from a solvent/non-solvent system typically result in reduced particle size.
  • a composition prepared from a system comprising a polymer and SAC spray dried from a solvent/non-solvent system as described herein results in a reduction of particle size on the order of at least about 50%, more particularly at least about 100% and in certain cases at least about 300% compared to a control composition prepared from a system comprising the same polymer and SAC spray dried under similar conditions from the same solvent without the non-solvent.
  • compositions of the present invention may be delivered by a wide variety of routes, including, but not limited to: buccal, dermal, intravenous, nasal, oral, pulmonary, rectal, subcutaneous, sublingual, and vaginal. Generally, the oral route is preferred.
  • compositions of the invention may be presented in numerous forms. Exemplary presentation forms are powders, granules, and multiparticulates. These forms may be added directly to capsules or may be further compressed to produce tablets, capsules, or pills, or reconstituted by addition of water or other liquids to form a paste, slurry, ointment, suspension or solution. Various additives may be mixed, ground, or granulated with the compositions of this invention to form a material suitable for the above dosage forms.
  • compositions of the invention may be formulated in various forms so that they are delivered as a suspension of particles in a liquid vehicle.
  • Such suspensions may be formulated as a liquid or as a paste at the time of manufacture, or they may be formulated as a dry powder with a liquid, typically water, added at a later time but prior to administration.
  • Such powders that are constituted into a suspension are often referred to as sachets or oral powders for constitution (OPC).
  • Such dosage forms can be formulated and reconstituted via any known procedure.
  • Oral, solid-dose spray dried powders typically have a mean particle size of about 0.5 ⁇ m-500 ⁇ m and are generally prepared from solutions at concentrations of 1% or more total solids, more particularly from about 2%-50%, and still more particularly from about 3%-3O% solids.
  • Oral, solid dose granules typically have a mean particle size of about 50 ⁇ m-5000 ⁇ m. Techniques to produce granules include, but are not limited to, wet granulation and various fluid bed granulating methods.
  • compositions comprising SACs of enhanced solubility and bioavailability described herein may be prepared in accordance with conventional techniques.
  • a dosage form comprising SACs and a disintegrant.
  • the disintegrant used in the composition is preferably of the so-called superdisintegrant type, disintegrants of this type being well-known to the person skilled in the art.
  • these disintegrants the following can be mentioned: cross-linked polyvinylpyrrolidones, particularly crospovidone, modified starches, particularly sodium starch glycolate, modified celluloses, particularly croscarmellose sodium (cross-linked sodium carboxymethylcellulose) and LHPC (low-substituted hydroxypropyl cellulose).
  • the disintegrant or superdisintegrant may be present in an amount of from about 2% to about 90%, preferably from about 3% to 60% of the composition.
  • disintegrants and disintegrant aids examples include alginic acid, calcium alginate, calcium silicates, cellulose, chitosan, colloidal silicon dioxide, docusate sodium, methylcellulose, microcrystalline cellulose, sodium alginate, and sodium starch glycolate.
  • the mass fractions of disintegrants and disintegrant aides may range from about 0.5% to 50% in the compositions.
  • the SAC product produced by these compositions and methods described herein may be administered to man or animal.
  • the compositions described herein may be administered as dietary supplements or as pharmaceutical compositions.
  • the SAC composition may be administered in a therapeutically effective amount to a human or animal in need of such treatment.
  • the term "therapeutically effective amount” as used herein refers to an amount of a pharmaceutical ingredient that is effective to treat, prevent or alleviate the symptoms of a disease.
  • the SAC compositions of the present invention may be used to treat a variety of disease states, including: atherogenesis, cancers, hypercholesterolemia, ischemia and reperfusion, and tumors. These compositions can also be used as a nutrient, a nutritional supplement or a veterinary medicine.
  • the SAC product described herein may be provided in various foods or beverages.
  • suitable foods include baked goods and non-baked goods, such as nutritional bars, cakes, drink mixes and the like.
  • beverages include waters, energy drinks, sport drinks, soft drinks, teas and the like.
  • the SAC product described herein may also be provided in a semi-liquid (or semi-solid) form.
  • examples include, without limitation, ointments, creams, pastes, and salves. These compositions may be administered topically, orally, or sublingually.
  • Example 1 Solvent solutions were prepared containing resveratrol (RES) with 13 pharmaceutically-accepted polymers (Table 1) in which the RES: polymer ratios ranged from 1 :3 to 3: 1.
  • RES crystallinity of the cast films was measured using differential scanning calorimetry (Q1000 ® , TA Instruments) at a scan rate of 10°C/min using crimped aluminum pans.
  • Example 4 [0091] 1. A solvent dispersion was created that contained 45 RES: 45 PVP (Plasdone K- 29/32) : 10 croscarmellose sodium (CCNa) that was added to the working solution prior to spray drying. The solvent blend was dichloromethane and methanol.
  • the powder contained only amorphous RES, as indicated by the lack of a melting endotherm when tested in a crimped aluminium pan at 10°C/min.

Abstract

Sirtuin-activating compounds (SACs) of enhanced solubility and bioavailability are described that contain at least one SAC with at least one solubility-enhancing organic material (solubility-enhancing organic material). Described methods to produce the bioenhanced products include dry blending and solvent spray drying. In one embodiment the solubility-enhancing organic material is polymeric. In accordance with certain embodiments of the invention, the method includes the steps of providing a mixture comprising at least one SAC, a solubility-enhancing polymer and a solvent and removing the solvent to form amorphous SAC. Products made by the invention's compositions and methods include pharmaceuticals, nutraceuticals, cosmetic, and personal care products for man and animal.

Description

SIRTUIN-ACTIVATING COMPOUNDS OF ENHANCED BIOAVAILABILITY
[0001] This application claims the benefit of U.S. Provisional Applications Serial No. 60/879,464, filed January 9, 2007, the contents of which are hereby incorporated by reference.
BACKGROUND OF THE INVENTION
[0002] Stilbenoid, flavonoids, and chalconoids are classes of organic compounds that appear to stimulate sirtuin enzymes, proteins that regulate cellular activity in plants and animals. Increased sirtuin activity may be beneficial in the treatment of insulin-resistant disorders (e.g., diabetes) and preventing obesity. Sirtuin enzymes are also believed to increase cellular lifespan, genomic stability, and silencing transcription. Many of these sirtuin-activating compounds (SACs) occur naturally and are widely marketed as dietary supplements. However, many exhibit water insolubility, making it a challenge to deliver these compounds and achieve therapeutic blood concentrations. There exists the need to improve the bioavailability of stilbenoids, flavonoids, and chalconoids when supplemented to a diet of an animal, especially man.
[0003] The stilbenoid family exhibits a chemical structure based on that of stilbene:
Figure imgf000003_0001
(ϊrαws-stilbene)
Examples of stilbenoids that serve as SACs include resveratrol:
Figure imgf000003_0002
and piceatannol (3,4,3',5'-tetrahydroxy-£rαws-stilbene), which differs from resveratrol only by the presence of a second hydroxyl group on an aromatic ring. Resveratrol, an antioxidant produced by plants in defense from microorganism attack or injury, is found in grapes (where the highest concentration is found in the grape skins), the dried roots and stems of the Japanese knotweed (Polygonium cuspidatum), peanuts, and mulberries. Numerous studies are investigating the phytoalexin properties of SACs in humans, as well as its anti-tumor effects.
[0004] Flavonoids are compounds based on the chemistry of flavone which has a three- ring structure as indicated below:
Figure imgf000004_0001
Flavonoids are also produced by plants and generally exhibit low toxicity to animals and man. SACs that have been identified based on the flavonoid structure include daidzein, fisetin, genistein, kaempferol, pentahydroxyflavone, and quercetin. These compounds are available as dietary supplements, and are believed to promote anti-carcinogenic, antiatherogenic, and anti-osteoporotic activity.
[0005] Chalconoids are aromatic ketones with a chemistry based on chalcone:
Figure imgf000004_0002
Chalconoids that activate a sirtuin response include, but are not limited to, butein and pentahydroxychalcone.
[0006] U.S. Patent Application Publication Nos. 2005/0171027, 2005/0136537, and 2006/0111435 disclose some of the stilbenoid, flavonoid, and chalconoid chemistries, along with resveratrol analogues, that enhance the activity of sirtuin enzymes as a method for treating obesity or insulin-resistant disorders. These publications are hereby incorporated by reference.
[0007] The poor water-solubility of stilbenoids, flavonoids, and chalconoids limits their bioavailability and makes their oral delivery a challenge. Many SACs are only slightly soluble in water (1 part in 100 parts to 1 part in 1,000 parts), some are only very slightly soluble (1 part in 1,000 parts to 1 part in 10,000 parts) and still others are only practically insoluble in water (1 part in more than 10,000 parts). Methods and compositions are needed in order to enhance their aqueous solubility and improve their bioavailabilities.
[0008] Potential technologies for improving the solubility of SACs include the use of oils, lipids and/or surfactants to form self-emulsifying systems; liquid formulations based on organic solvents; complexation with cyclodextrins and/or particle size reduction. However, these technologies are either expensive, limit formulation flexibility for multi- active products, have negative side effects and/or produce suboptimal bioenhancement.
[0009] Accordingly, certain embodiments of the present invention provide one or more of the following benefits:
1. Enhanced aqueous solubility of sirtuin-activating compounds (SACs);
2. Enhanced bioavailability of SACs;
3. A bioenhanced form of SACs that does not require the use of oils, lipids, or gelatins; emulsification technology; liquid formulations based on organic solvents or particle size reduction;
4. Increased flexibility in formulation and final product performance (i.e., release rate, powder compactability, multiple actives);
5. Reduced negative side effects resulting from the bioenhancement technology; and
6. A more cost-effective method for providing enhanced bioavailability than alternative technologies.
[0010] Certain embodiments of the present invention relate to compositions of bioenhanced SACs and methods for producing them. More particularly, certain aspects of the present invention relate to compositions and methods for preparing bioenhanced SACs utilizing at least one solubility-enhancing polymer. In one embodiment, the mixture is prepared by dry blending SACs with a solubility-enhancing polymer. In another embodiment, one or more SACs are dissolved in a solvent containing the polymer. In yet another embodiment, a blend of solvent/non-solvent for the polymer is employed. The bioenhanced SAC product is produced by any method suitable to the composition. In one embodiment, direct compression of physically blended SAC-polymer(s) is used. When necessary, solvent can be removed from compositions to yield the bioenhanced SAC product. In one further development of the invention, SAC-polymer-solvent (or a solvent/non-solvent blend) is spray dried to produce the SAC in a form that exhibits improved solubility and/or bioavailability. The bioenhanced SAC composition can be prepared by methods other than spray drying as recognized by those skilled in the art. Those methods include, without limitation: melt extrusion, spray congealing, and freeze drying. In accordance with particular embodiments of the invention, a significant portion of the SAC is provided in the amorphous state. In accordance with certain embodiments, the SAC is converted almost entirely to the amorphous state. In one embodiment of the invention, the SAC is converted to the completely amorphous state.
SUMMARY OF THE INVENTION
[0011] In accordance with particular embodiments of the present invention, compositions containing SACs and methods for producing SAC compositions of enhanced solubility and bioavailability are described . It has been discovered that mixtures of SACs and solubility- enhancing polymers show enhanced aqueous solubility compared to the crystalline form. Examples of compositions that create this enhancement include, without restriction: solid dispersions and physical blends of the components. Surprisingly, simple dry mixtures of a SAC and polymer attain dissolution release characteristics equal to many commercial softgel SAC products, which employ lipids, oils and/or triglycerides. Even faster release with greater extent is produced with amorphous SAC-polymer dispersions, as shown in several embodiments of the invention.
[0012] Although preferable, the amorphous conversion of the SAC is not a requirement for the enhanced properties. A composition comprising a solid dispersion of a SAC and at least one solubility-enhancing polymer wherein the SAC in the dispersion is substantially amorphous is also provided. In one aspect, the disclosed invention describes the conversion of crystalline SAC to the amorphous state. One method for producing this conversion is through solvent spray drying. Other techniques within the scope of this invention that accomplish this conversion include, without limitation: flash solvent evaporation, melt-congeal spraying, freeze drying, and melt-extrusion. These methods can use a single solubility-enhancing polymer or blends of polymers. Accordingly, products can be developed that serve the vegan/all natural market (e.g., using naturally-occurring ingredients/adjuvants) and a broader market (e.g., using synthetic ingredients/adjuvants). The degree of SAC amorphous conversion depends on both polymer type and amount and processing conditions. When required, a single organic solvent, blends of solvents, or solvent/non-solvent blends can be used.
[0013] By converting a substantial portion of crystalline SAC to the amorphous form, its aqueous solubility is increased, which, in turn, improves its bioavailability. In one embodiment, a solution is prepared comprising a solvent, one or more SACs, and one or more solubility-enhancing organic material. The choice of solvent is only limited inasmuch as to produce a SAC solution, and examples of suitable solvents include dichloromethane/methanol blends, and chloroform. The solvent may dissolve both the SAC and solubility-enhancing organic material, or a non-solvent for the organic material optionally may be added. In a preferred embodiment, the solubility-enhancing organic material comprises a polymer. In another preferred embodiment, the solubility-enhancing organic material comprises a carbohydrate. The organic material may be of any type approved for use in pharmaceutical and/or dietary supplement products.
[0014] In one aspect, the invention relates to spray-dried powders or granulated products comprising amorphous SACs. In addition, the resulting powders produced in accordance with certain embodiments typically possess lower residual solvent content and higher tap density than their counterparts produced by conventional methods, due to a change in the particle morphology and size.
[0015] One aspect of the invention involves amorphous SACs prepared from compositions containing SACs and a solubility-enhancing polymer in a solvent or a solvent blend. This solvent or solvent blend includes a solvent in which the polymer is soluble. The term "soluble" means that the attractive force between polymer and solvent molecules is greater than the competing inter- and intramolecular attractive forces between polymer molecules. For simplicity, this solvent is simply called "solvent." Compositions also are described in which the solvent blend contains a solvent for which the opposite is true: The force between polymer and solvent molecules is less than the inter- and intramolecular attractive force between polymer molecules. This second solvent is termed the "non- solvent." The polymer may swell but does not dissolve in the non-solvent. In accordance with one embodiment of the invention, a solubility-enhancing polymer and a suitable solvent/non-solvent blend are provided. Additionally, the solvent possesses a lower boiling point than the non-solvent. Preferably, the solvent and non-solvent are miscible. The ratio of solvent to non-solvent is such that the polymer can be considered "dissolved" in the solvent system.
[0016] Unique particle properties can be created by evaporating the solvent/non-solvent blend. For example, this evaporation can occur during the spray drying of the feed solution or granulation processes. Atomized droplets containing a blend of solvents will experience a change in the total solvent composition due to evaporation. The method appears to be independent of how the droplets are generated or atomized. Initially, the polymer exists in a dissolved state, due to a sufficient amount of the solvent. As it evaporates (the solvent boils at a lower temperature than the non-solvent), the concentration of non-solvent in the droplet increases. Eventually, the solvent composition is insufficient to maintain the polymer in solution. In doing so, the polymer collapses from solution. This change in polymer conformation can alter the evaporation dynamics of the droplet to create particle morphologies that influence final powder properties.
[0017] Although SACs of enhanced solubility and bioavailability can be formed by spray drying from a solution containing solvent alone, there are additional benefits associated with the use of a solvent/non-solvent blend system. This solvent/non-solvent approach can produce a spray dried powder of lower residual solvent content and smaller particle size. A further consequence of this engineered particle morphology is the increase in bulk powder density. Increased powder density is an important attribute for many applications. The extent of polymer collapse — and therefore the net effect on the spray dried powder properties — depends on the polymer solvation factors, such as the initial ratio of solvent to non-solvent, the polymer chemical structure and the polymer molecular weight. In addition to reducing residual solvent content and increasing density, the primary polymer may be paired with the solvent/non-solvent system in order to affect not only the morphology of the particle, but also that of the SAC, and thereby affect active loading, crystallinity, solubility, stability and release.
[0018] The presence of additional polymers may contribute to the final particle morphology by their interaction with the first polymer and the solvent system. These additional polymers may also be advantageous to create special release properties of the active. For example, the primary polymer may be paired with the solvent/non-solvent system in order to affect particle morphology, and thereby residual solvent content and bulk powder density. Additional polymeric adjuvants may be added to serve additional purposes: further inhibit active recrystallization, further maximize active concentration, and further enhance/delay/retard dissolution rate. To accomplish these functionalities, it is necessary to suitably match the adjuvant solubilities with the solvent blend selected for the primary polymer.
BRIEF DESCRIPTION OF THE DRAWINGS
[0019] FIGS. 1 - 4 are graphs of melting enthalpy as a function of temperature for compositions produced in accordance with Example 2;
FIG. 5 is a graph of resveratrol release as a function of time for compositions produced in accordance with Example 3; and
FIG 6 is a graph of resveratrol release as a function of time for compositions produced in accordance with Example 5.
DETAILED DESCRIPTION OF THE INVENTION
[0020] The term "sirtuin-activating compound" (SAC) encompasses organic compounds, naturally occurring and synthetically produced, that increase at least one activity of one sirtuin protein. SACs include, but are not limited to: ambroxol, apigenin, butein, caffeic acid phenyl ester, (-)-catechin, daidzein, dihydroxyflavone, (-)-epicatechin, fisetin, flavanone, flavone, (-)-gallocatechin, genistein, 6-hydroxyapigenin, 5-hydroxyflavone, isoliquiritigenin, kaempferol, morin, naringenin, pelargonidin chloride, 3,5,6,3 ',4'- pentahydroxyflavanone, piceatannol, quercetin, resveratrol, resveratrol analogues, rhapontin, cώ-stilbene, frαws-stilbene, and 3,6,3'6'-tetrahydroxyflavone. Combinations of SACs can also be used.
[0021] The term "analogue" refers to chemical compounds that share a commonality in structure to a parent compound, but differ with respect to elemental composition, stereochemistry, and/or the addition of moiety group(s).
[0022] The term "comprising" encompasses the more restrictive terms "consisting essentially of and "consisting of."
[0023] All percentages, ratios and proportions used herein are by weight unless otherwise specified.
[0024] Bioavailability refers to the degree to which a compound becomes available in the body after administration. Typically, plasma samples are taken and analyzed for the plasma concentration of the parent compound and/or its active metabolite. These data may be expressed as Cmax, the maximum amount of the compound 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 parent compound and/or its active metabolite. Compositions in accordance with certain aspects of the invention exhibit enhanced bioavailability compared to a control composition.
[0025] The term "solid dispersion" as used herein refers to a system in a solid state comprising at least two components, wherein one component is dispersed evenly throughout the other component or components. The term "solid dispersion" includes systems having small particles either completely crystalline, completely amorphous or any state in between, typically less than about 1 μm in diameter, of one phase dispersed in another phase.
[0026] The term "solid solution" as used herein refers to a type of solid dispersion wherein one component is molecularly dispersed throughout another component such that the system is chemically and physically uniform and homogeneous throughout. These systems do not contain any significant amounts of active ingredients in their crystalline or microcrystalline state as evidenced by thermal analysis (e.g., differential scanning calorimetry), or diffractive (e.g., X-ray diffraction) techniques. [0027] The term "solubility-enhancing polymer" refers to a polymer that provides at least one of the following properties as a result of its presence in the composition compared to a control composition without the solubility-enhancing polymer:
a) an increase in initial release of at least about 25%
b) an increase in extent of release of at least about 25%
c) an increase in maximum plasma concentration of at least about 25%
d) an increase in AUCo-24h θf at least about 25%.
[0028] There is no condition placed on the state of the compositions other than SACs are combined with one or more solubility-enhancing polymer(s). The term "combined" includes, but is not limited to: blended, co-mingled, dissolved, extruded, granulated, melted, milled, mixed, sieved, slurried, sprayed, stirred, and the combination of these and other methods. Other techniques may be identified by those skilled in the art. Furthermore, compositions of the current invention may include additional active ingredients to the SAC. Active pharmaceutical ingredients include, but are not limited to: analgesics, anti-arrhythmics, anti-bacterials, anti-convulsants, anti-Alzheimer's agents, anti-diabetics, anti-emetics, anti-fungals, anti-histiminics, anti-hyperlipidemics, anti- hyperlipoproteinemics, anti-hypertensives, anti-inflamatory agents, anti-Parkinsonian agents, anti-pulmonary hypertensives, anti-rheumatics, anti-ulceratives, anti-virals, cardiovascular agents, chemotherapy agents, central nervous system sedatives and stimulants, diuretics, gastrointestinal agents, hormones, respiratory agents, skin agents, as well as actives for the treatment of acne, benign prostatic hypertrophy, irritable bowel syndrome. Nutraceutical ingredients include, but are not limited to: herbs, isoflavones, moisturizers, mood regulators, minerals, oils, benzoquinones, carotenoids, protein supplements, skin agents, ultraviolet blocking agents, and vitamins.
[0029] Although the following description is primarily directed to the preparation of a spray-dried composition containing resveratrol, the present invention is not limited to resveratrol spray-dried compositions. The methods described herein are also useful in converting other SACs to the amorphous state of enhanced solubility and bioavailability. Physical mixtures of SACs and a solubility-enhancing polymer that increase the solubility and bioavailability of SACs are also within the scope of the present invention. Physical mixtures can be prepared in accordance with conventional techniques such as a tumble blending, high-shear granulation, fluid bed granulation, film coating, or any of their related technologies.
[0030] In accordance with one embodiment, the present invention is related to a method for preparing a spray-dried composition by providing a mixture containing SACs and a polymer in a single solvent, a solvent blend or a blend of a solvent and a non-solvent for the polymer and spray drying the mixture to form the amorphous SAC composition.
[0031] One aspect of the invention involves the pairing of the polymer with a carefully selected solvent or solvent blend. This approach comprises a solvent in which the polymer is soluble. Guidance in defining polymer solubility is provided by the expansion coefficient (α):
Figure imgf000012_0001
— 2 2 where r is the mean-square distance between chain ends, and ro is the unperturbed dimension. (Equation § 1 can be written for branched polymers in an analogous manner, 2 using square-average radius of gyration about the center of gravity, s , and the 2 corresponding unperturbed dimension, so .) Polymer solubility is provided when α is unity or greater, and solvents that satisfy this condition are called "good solvents," or simply "solvents." Solvents uncoil (or expand) the polymer molecule, since the polymer- solvent attractive force is greater than that of polymer-polymer. Light scattering methods, such as Viscotek's Triple Detector Array, can be used to determine the variables expressed in equation § 1. These concepts are defined in the text Polymer Chemistry, An Introduction, by Malcolm P. Stevens, which is incorporated by reference.
[0032] When α equals unity, a special condition exists in that polymer-solvent and polymer-polymer forces are balanced. Solvents that enable this condition are called θ solvents. Within the context of this invention, solvents are considered "good solvents" when α is about equal to 1 or more. It is appreciated that temperature influences α, such that a good solvent may be transformed into a non-solvent merely by changing the temperature.
[0033] In yet another embodiment of this invention, the solvent blend also contains a solvent for which the opposite is true: Polymer-polymer forces dominate polymer-solvent forces. In this case, α is less than one and the solvent is termed a "non-solvent," because the polymer exists in a collapsed state. In accordance with one embodiment of the invention, the polymer is provided in a suitable solvent/non-solvent blend. The blend of solvent/non-solvent maintains a θ or solvated state of the polymer, such that the polymer can be considered "dissolved" in the solvent system. Additionally, the solvent possesses a lower boiling point than the non-solvent. (Solvent/non-solvent pairs that form an azeotrope do not satisfy this criterion.)
[0034] In accordance with another aspect of the invention, a polymer system is provided comprising a solubility-enhancing polymer and a suitable solvent/non-solvent blend. Specific examples of suitable polymer/solvent/non-solvent combinations include, without limitation, polyvinylpyrrolidone/dichloromethane/acetone, polyvinylpyrrolidone-co-vinyl acetate/acetone/hexane, and ethylcellulose/acetone/water. Unique particle architectures are created by precipitation of the primary polymer when the non-solvent concentration exceeds a critical value. This critical ratio R0 can be defined:
mass nonsolvent
Rc = , (§2) mass solvent + nonsolvent
which is the maximum fraction of the non-solvent before polymer precipitation occurs. The ratio Rc for a given system can be determined experimentally by identifying the mass fractions of each component that produce a significant increase in solution turbidity. If an Revalue can be identified for a polymer system, then the system comprises a solvent/non- solvent blend. One example is a solution containing about 10% (w/w) polyvinylpyrrolidone, 18% (w/w) dichloromethane, and 72% (w/w) acetone, for which R0 equals 0.80. Polymer systems typically will be used at solvent/non-solvent blends that are at or below the R0 value for the system. It may be advantageous to formulate more complex polymer/solvent systems in order to control particle morphology/size as well as the crystallinity, solubility, bioavailability and release characteristics of SACs.
[0035] The present invention in accordance with other embodiments provides a method to increase the density of spray-dried powders. Typically, spray drying produces sphere- like particles with some degree of interior void. This void increases particle bulk without mass and creates low-density material. Adding a non-solvent to the working solution/dispersion changes the particle size and morphology, leading to an increase in density. Particles may be smaller, wrinkled, dimpled, and/or collapsed compared to those prepared using only solvent. The solvent/non-solvent approach also reduces the mean particle size, allowing the powder to pack better. In addition, powder flow and powder- powder mixing properties are enhanced.
[0036] The present invention in accordance with certain aspects provides a method to reduce or eliminate the need for secondary drying of spray-dried powders and granulated materials. These products often contain residual solvent, and it is desirable or necessary to produce a drier product. A high residual solvent content can result from formulation or processing limitations. The general practice has been to use a solvent that dissolves the solids being spray dried. In doing so, solvent can be trapped inside the spray dried powder or granulated bead due to case hardening. The intentional pairing of a lower-boiling solvent with a higher-boiling non-solvent for the materials being processed can yield products of lower residual solvent due to the effect(s) of the non-solvent on the process polymers.
[0037] The present invention may further provide a method to enhance the aqueous solubility and modify the release of active ingredients through selection of a polymer system with the solvent or solvent/non-solvent blend. The polymer system is chosen so that one (or more) polymer(s) work with the solvent/non-solvents to create novel particle morphologies. Additional polymer(s) may be added as needed to affect the solubility and release properties of the active, as well as particle morphology. Enhanced solubility can be achieved by a number of factors, including (but not limited to): improved wettability, creation of amorphous SACs forms, stabilization against recrystallization, and/or co- solvation effects. In doing so, a supersaturatured solution of the SAC is produced. "Modified release" refers to changing the time frame in which the active is released, i.e., immediate, delay, extended. These modified releases are created by matching functional polymer(s) with the appropriate solvent/non-solvent blend.
[0038] Solvents and non-solvents suitable for use in the process of the present invention can be any organic compound (including water) in which the primary polymer is soluble in the case of solvents, or insoluble, in the case of non-solvents. The choice and ratio of solvent/non-solvent depends on the choice of the primary polymer. Accordingly, the identification of an organic compound as a solvent or non-solvent depends on the primary polymer. Therefore, a solvent in one system may be a non-solvent in another.=Particularly useful solvents and non-solvents include, but are not limited to: acetic acid, acetone, acetonitrile, anisole, 1-butanol, 2-butanol, butyl acetate, tert-butylmethyl ether, chlorobenzene, chloroform, cumene, cyclohexane, 1-2-dichloroethane, dichloromethane, 1- 2-dimethoxyethane, N-N-dimethylacetamide, N-N-dimethylformamide, 1-4-dioxane, ethanol, 2-ethoxyethanol, ethyl acetate, ethylene glycol, ethyl ether, ethyl formate, formamide, formic acid, heptane, hexane, isobutyl acetate, isopropyl acetate, methanol, methyl acetate, 2-methoxy ethanol, 3 -methyl- 1-butanol, methylbutylketone, methylcyclohexane, methylethyl ketone, methylisobutyl ketone, 2-methyl-l-propanol, N- methylpyrollidone, nitromethane, pentane, 1-pentanol, 1-propanol, 2-propanol, propyl acetate, pyridine, sulfolane, tetrahydrofuran, tetralin, 1-2-2-trichloroethene, toluene, water, and xylene. Mixtures of solvents and mixtures of non-solvents can also be used. In accordance with particular embodiments, solvent blends at the azeotropic composition (which boil at one common temperature) can comprise either the solvent or non-solvent, but not the solvent/non-solvent blend.
[0039] Solubility-enhancing polymers that are suitable for use in the mixtures of the present invention enhance the solubility of SACs. In accordance with particular aspects of the present invention, the solubility-enhancing polymer also inhibits crystallization of SACs and, therefore, the presence of the polymer results in conversion of at least some of the crystalline SAC to the amorphous state. In accordance with those embodiments wherein a solvent/non-solvent blend is used, at least one polymer should be soluble in the solvent and not soluble in the non-solvent. Specific examples of useful polymers include, but are not limited to: aliphatic polyesters (e.g., poly D-lactide), carbohydrates (e.g., sucrose), carboxyalkylcelluloses (e.g., carboxymethylcellulose), alkylcelluloses (e.g., ethylcellulose), gelatins, hydroxyalkylcelluloses (e.g., hydroxypropyl cellulose (HPC)), hydroxyalkylalkyl celluloses (e.g., hydroxypropylmethyl cellulose (HPMC)), hydroxyalkylalkylcellulose derivatives, polyamines (e.g., chitosan), polyethylene glycols (e.g., PEG 8000, PEG 20000), methacrylic acid polymers and copolymers (e.g., Eudragit® series of polymers of Rohm Pharma, GmbH), homo- and copolymers of N-vinyl pyrrolidone (e.g., polyvinylpyrrolidone, polyvinylpyrrolidone-co-vinyl acetate), homo- and copolymers of vinyllactam, polysaccharides (e.g., alginic acid), poly glycols (e.g., propylene glycol, polyethylene glycol), polyvinyl esters (e.g., polyvinyl acetate), and refined/modified shellac. The term "hydroxyalkylalkylcellulose derivatives" is meant to include, without limitation, hydroxypropylmethyl cellulose phthalate, and hydroxypropylmethyl cellulose acetate succinate. The amount of the polymer present in the mixture may range from about 1% to about 95%, more particularly from about 5% to 90%, by weight of the mixture, and in accordance with certain embodiments from about 25% to 75% by weight. Blends of polymers may also be used.
[0040] In accordance with one aspect of the invention, the solubility-enhancing organic material comprises a carbohydrate. The carbohydrate can be a reducing carbohydrate, which is metabolized by the body, or a non-reducing carbohydrate, which is not metabolized by the body. Examples of reducing carbohydrates include, without limitation, dextrose, fructose, maltose, starch, and sucrose. Examples of non-reducing carbohydrates include, without limitation, aspartame, mannitol, and sucralose.
[0041] The bioenhanced composition, which may comprise a spray-dried mixture, includes SACs as an active ingredient. The mixture may contain from about 1% to about 95% active, more particularly from about 20% to about 80% active, depending on the desired dose of the active. The weight ratio of SACs to polymer typically will be from about 95% SACs : 5% total polymer to about 5% SACs : 95% total polymer, more particularly from about 70% SACs : 30% total polymer to about 30% SACs : 70% total polymer and in accordance with certain aspects from about 60% SACs : 40% total polymer to about 40% SACs : 60% total polymer.
[0042] The spray dried composition of the present invention when combined with a solubility-enhancing polymer produces a portion of SACs in the amorphous state. The term "amorphous" refers to a compound in a non-crystalline state. In other words, an amorphous compound lacks long-ranged, defined crystalline structure. In accordance with certain embodiments of the present invention, at least some, more particularly at least about 10%, at least about 25%, or at least about 40% of the SACs in the composition is in an amorphous form. In other embodiments, at least a major portion of the compound in the composition is amorphous. As used herein, the term "a major portion" of the compound means that at least about 50% of the compound in the composition is in the amorphous form, rather than the crystalline form. More particularly, the compound in the composition may be substantially amorphous. As used herein, "substantially amorphous" means that the amount of the compound in the crystalline form does not exceed about 25% (i.e., more than about 75% of the compound is in the amorphous form). In accordance with particular embodiments of the invention, the compound in the composition is "almost completely amorphous" meaning that the amount of drug in the crystalline form does not exceed about 10% (i.e., more than about 90% of the compound is in the amorphous form). Compositions are also provided wherein the compound in the composition is considered to be "completely amorphous" meaning that the crystalline form of the drug is not detectable using conventional techniques, such as X-ray diffraction or thermal analysis. Reference to a composition as completely amorphous does not exclude compositions containing trace amounts (less than about 1%) of the crystalline form of the active.
[0043] Amorphous materials lack some measurable properties, such as melting endotherms as measured by differential scanning calorimetry that characterize crystalline forms. Amounts of crystalline SACs may be measured by powder X-ray diffraction (PXRD), differential scanning calorimetry (DSC), or any other standard quantitative analysis. The amounts of crystalline SACs present in the composition may be detected by any other standard measurement known to those of ordinary skill in the art. It is appreciated that the measurement of such properties is dependent on instrument type, sensitivity, operation, and analysis.
[0044] By providing the SACs in the amorphous form, the spray dried powder produced in accordance with certain aspects of the present invention provides enhanced solubility and/or bioavailability of SACs compared to products containing the principle crystalline form. The increased bioavailability of the active can also lead to reduced dosage sizes and dose amounts for the active. It has been determined that the rate of SACs release can be controlled through proper selection of the polymers added into the solvent solution for the spray dried process. [0045] The spray dried mixture or bioenhanced composition may also contain additional polymeric materials that can modify properties of the composition. For example, certain polymers can be included to control particle morphology/size as well as the solubility and bioavailability and release characteristics of the active ingredient. Additional polymers may also be included in the mixture to further inhibit active recrystallization, further maximize active concentration and further enhance/delay/retard dissolution rate. Additional polymers that can be incorporated into this system are not particularly limited.
[0046] The mixture to be spray dried typically contains from about 40% to 99.9% by weight total solvent or solvent/non-solvent, more particularly from about 80% to 95% by weight total solvent or solvent/non-solvent based on the total weight of the mixture. When a solvent/non-solvent blend is used, the critical ratio Rc can vary from about 0.01-0.99, more particularly from about 0.1-0.9, still more particularly from about 0.3-0.8.
[0047] In addition to the solvent, polymer and SACs, the mixture to be spray dried may also include other ingredients to improve performance, handling or processing of the mixture. Alternatively, these ingredients also may be admixed into the already-prepared SAC-polymer by methods including, but not limited to tumble blending and granulation technologies. Typical ingredients include, but are not limited to, anti-oxidants, surfactants, pH modifiers, fillers, complexing agents, solubilizer, pigments, lubricants, glidants, flavor agents, plasticizers, taste masking agents, disintegrants, disintegrant aids (e.g., calcium silicates), etc., which may be used for customary purposes and in typical amounts. Examples of useful surfactants include, but are not limited to, sodium lauryl sulfate, docusate sodium, sorbitan monooleate, and sorbitan trioleate. Examples of useful fillers include, but are not limited to, lactoses, dextrin, sugars, sugar alcohols, and silica.
[0048] The spray drying apparatus used in accordance with certain aspects of the present invention can be any of the various commercially available apparatus or other devices capable of producing similar particles from liquid mixtures. Examples of specific spray drying devices include spray dryers manufactured by Niro Inc. (e.g., SD-Micro®, PSD- 1®, PSD-2®, etc.), the Mini Spray Dryer® by Buchi Labortechnik AG, spray dryers manufactured by Spray Drying Systems, Inc. (e.g., models 30, 48, 72), and SSP Pvt. Ltd. [0049] 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). The relevant contents of these references are hereby incorporated by reference.
[0050] The term "spray drying" is used conventionally and, in general, refers to processes involving breaking up liquid mixtures into small droplets and rapidly removing solvent from the mixture in a container (spray drying apparatus) where there is a strong driving force for evaporation of solvent from the droplets. Atomization techniques include two- fluid and pressure nozzles, and rotary atomizers. The strong driving force for solvent evaporation is generally provided by maintaining the partial pressure of solvent in the spray drying apparatus well below the vapor pressure of the solvent at the temperatures of the drying droplets. This may be accomplished by either (1) maintaining the pressure in the spray drying apparatus at a partial vacuum; (2) mixing the liquid droplets with a warm drying gas; or (3) both.
[0051] Generally, the temperature and flow rate of the drying gas and the design of the spray dryer are chosen so that the polymer/active solution 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. It is also possible to operate a spray dryer so that product collects on the apparatus wall, and then is collected by removing the material manually, pneumatically, mechanically or other means. The actual length of time to achieve the preferred 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 solid dispersion as it exits the dryer should be low, since this improves the stability of the product. Generally, the residual solvent content of the spray-dried composition should be less than about 10% by weight and preferably less than about 2% by weight. In accordance with certain embodiments, the residual solvent content is within the limits set forth in the International Conference on Harmonization (ICH) Guidelines. Although not typically required in accordance with certain aspects of the present invention, because the presence of a non-solvent produces a spray-dried powder of lower residual solvent content, 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. Methods to further lower solvent levels include, but are not limited to fluid bed drying, infra-red drying, tumble drying, vacuum drying, and combinations of these and other processes. 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 describe results obtained with a laboratory-scale spray dryer. One of ordinary skill in the art would readily appreciate variables that must be modified to obtain similar results with a production-scale unit.
[0052] As indicated above, the present invention is not limited to amorphous SACs produced by spray drying. Physical mixtures of SACs with a solubility-enhancing polymer can also enhance the solubility and bioavailability of SACs. Methods for preparing physical mixtures of the polymer and SACs are not particularly limited. In accordance with one aspect of the present invention, physical mixtures of solubility-enhancing polymer and SACs may be formed by tumble blending, co-milling, stirring, granulating, or other methods known to those skilled in the art.
[0053] In addition to spray drying, compositions of the present invention may be prepared by other processes including, but not limited to, extrusion, spheronization and spray congealing.
[0054] Extrusion is a well-known method of applying pressure to a damp or melted composition until it flows through an orifice or a defined opening. The extrudable length varies with the physical characteristics of the material to be extruded, the method of extrusion, and the process of manipulation of the particles after extrusion. Various types of extrusion devices can be employed, such as screw, sieve and basket, roll, and ram extruders.
[0055] In melt extrusion, components can be melted and extruded with a continuous process with or without a solvent and with or without inclusion of other additives. Such a process is well-established and well-known to skilled practitioners in the art. [0056] Spheronization is the process of converting material into spheres, the shape with the lowest surface area to volume ratio. Spheronization typically begins with damp extruded particles. The extruded particles are broken into uniform lengths instantaneously and gradually transformed into spherical shapes. In addition, powdered raw materials, which require addition of either liquid or material from a mixer, can be processed in an air- assisted spheronizer.
[0057] Spray congealing is a method that is generally used in changing the structure of the materials, to obtain free flowing powders from liquids and to provide pellets ranging in size from about 0.25 mm to 2.0 mm. Spray congealing involves allowing a substance of interest to melt, disperse, or dissolve in a hot melt of other additives. The molten mixture is then sprayed into an air chamber wherein the temperature is below the melting point of the formulation components, to provide spherical congealed pellets. The temperature of the cooled air used depends on the freezing point of the product. The particles are held together by solid bonds formed from the congealed melts. Due to the absence of solvent evaporation in most spray congealing processes, the particles are generally non porous and strong, and remain intact upon agitation. The characteristics of the final congealed product depend in part on the properties of the additives used. The feed rate and inlet/outlet temperatures are adjusted to ensure congealing of the atomized liquid droplet. The feed should have adequate viscosity to ensure homogeneity. The conversion of molten feed into powder is a single, continuous step. Proper atomization and a controlled cooling rate are critical to obtain high surface area, uniform and homogeneous congealed pellets. Adjustment of these parameters is readily achieved by one skilled in the art.
[0058] The spray congealing method is similar to spray drying, except that solvent is not used. Instead, the active ingredient(s) is dispersed and/or melted into a matrix comprising melt-processable polymer(s). Spray congealing is a uniform and rapid process, and is completed before the product comes in contact with any equipment surface. Most actives and additives that melt without decomposition are suitable for this method.
[0059] Conventional spray dryers operating with cool inlet air have been used for spray congealing. Several methods of atomization of molten mass can be employed, such as pressure, or pneumatic or centrifugal atomization. For persons skilled in the spray congealing art, it is well known that several formulation aspects, such as matrix materials, viscosity, and processing factors, such as temperature, atomization and cooling rate affect the quality (morphology, particle size distribution, polymorphism and dissolution characteristics) of spray congealed pellets. The spray congealed particles may be used in tablet granulation form, encapsulation form, or can be incorporated into a liquid suspension form.
[0060] Compositions prepared in accordance with certain aspects of the present invention provide amorphous SACs that exhibits enhanced solubility and bioavailability without requiring the use of significant amounts of lipids or oils. In fact, certain aspects of the invention relate to compositions containing amorphous SACs that are substantially free of lipids, triglycerides, or oils.
[0061] SACs produced in accordance with some embodiments of the invention exhibit enhanced solubility and bioavailability even when present in solid state forms such as solid solutions or solid dispersions. SACs may be present in such compositions at levels exceeding about 5% by weight, more particularly exceeding about 10%, and in some cases exceeding about 25%, 40% or even 50% by weight of the composition and still exhibit enhanced solubility and bioavailability compared to crystalline forms of the compound.
[0062] Certain polymers function as solubility-enhancing polymers in that the presence of the polymer in the composition improves solubility of the SAC under various conditions. The solubility-enhancing polymer provides at least one of the following properties as a result of its presence in the composition compared to a control composition without the solubility-enhancing polymer or to a composition containing the crystalline form of the SAC:
a) an increase in initial release of at least about 25%, more particularly at least about 100% and in accordance with certain embodiments at least about 200%
b) an increase in extent of release of at least about 25%, more particularly at least about 100% and in accordance with certain embodiments at least about 200%
c) an increase in maximum plasma concentration of at least about 25%, more particularly at least about 100% and in accordance with certain embodiments at least about 200% d) an increase in AUCo-24hθf at least about 25%, more particularly at least about 100% and in accordance with certain embodiments at least about 200%.
[0063] Initial release refers to the percent of SAC released after 15 minutes in accordance with a standard dissolution test method. Extent of release refers to the percent of SAC released after 240 minutes in accordance with the same standard dissolution test method.
[0064] In accordance with particular embodiments of the present invention, a composition prepared from a system comprising a polymer and a SAC spray dried from a solvent/non-solvent system as described herein exhibits a dissolution profile wherein the percent SAC released at some point in time is at least about 25%, more particularly at least about 50% and in certain cases at least about 100% greater than a control composition prepared from a system comprising the same polymer and SAC spray dried from the same solvent without the non-solvent. Preferably these limits are obtained within about 120 minutes, more particularly within about 60 minutes and still more particularly within about 30 minutes. Dissolution profiles can be determined using USP apparatus II (paddles) (VK 7010®, Varian Inc.), with a bath temperature of 37°C and a paddle speed of 50 rpm.
[0065] In accordance with particular embodiments of the present invention, a composition prepared from a system comprising a polymer and SAC spray dried from a solvent/non-solvent system as described herein is expected to exhibit an increase in bulk density or tap density wherein the density is at least about 25%, more particularly at least about 50% and in certain cases at least about 100% greater than a control composition prepared from a system comprising the same polymer and SAC spray dried from the same solvent without the non-solvent.
[0066] SAC compositions prepared from a solvent/non-solvent system typically result in reduced particle size. In accordance with particular embodiments of the present invention, a composition prepared from a system comprising a polymer and SAC spray dried from a solvent/non-solvent system as described herein results in a reduction of particle size on the order of at least about 50%, more particularly at least about 100% and in certain cases at least about 300% compared to a control composition prepared from a system comprising the same polymer and SAC spray dried under similar conditions from the same solvent without the non-solvent. [0067] Compositions of the present invention may be delivered by a wide variety of routes, including, but not limited to: buccal, dermal, intravenous, nasal, oral, pulmonary, rectal, subcutaneous, sublingual, and vaginal. Generally, the oral route is preferred.
[0068] Compositions of the invention may be presented in numerous forms. Exemplary presentation forms are powders, granules, and multiparticulates. These forms may be added directly to capsules or may be further compressed to produce tablets, capsules, or pills, or reconstituted by addition of water or other liquids to form a paste, slurry, ointment, suspension or solution. Various additives may be mixed, ground, or granulated with the compositions of this invention to form a material suitable for the above dosage forms.
[0069] Compositions of the invention may be formulated in various forms so that they are delivered as a suspension of particles in a liquid vehicle. Such suspensions may be formulated as a liquid or as a paste at the time of manufacture, or they may be formulated as a dry powder with a liquid, typically water, added at a later time but prior to administration. Such powders that are constituted into a suspension are often referred to as sachets or oral powders for constitution (OPC). Such dosage forms can be formulated and reconstituted via any known procedure.
[0070] Oral, solid-dose spray dried powders typically have a mean particle size of about 0.5 μm-500 μm and are generally prepared from solutions at concentrations of 1% or more total solids, more particularly from about 2%-50%, and still more particularly from about 3%-3O% solids.
[0071] Oral, solid dose granules typically have a mean particle size of about 50 μm-5000 μm. Techniques to produce granules include, but are not limited to, wet granulation and various fluid bed granulating methods.
[0072] Compositions comprising SACs of enhanced solubility and bioavailability described herein may be prepared in accordance with conventional techniques. In accordance with one aspect of the invention, a dosage form is provided comprising SACs and a disintegrant. The disintegrant used in the composition is preferably of the so-called superdisintegrant type, disintegrants of this type being well-known to the person skilled in the art. As examples of these disintegrants the following can be mentioned: cross-linked polyvinylpyrrolidones, particularly crospovidone, modified starches, particularly sodium starch glycolate, modified celluloses, particularly croscarmellose sodium (cross-linked sodium carboxymethylcellulose) and LHPC (low-substituted hydroxypropyl cellulose). The disintegrant or superdisintegrant may be present in an amount of from about 2% to about 90%, preferably from about 3% to 60% of the composition.
[0073] Examples of other disintegrants and disintegrant aids include alginic acid, calcium alginate, calcium silicates, cellulose, chitosan, colloidal silicon dioxide, docusate sodium, methylcellulose, microcrystalline cellulose, sodium alginate, and sodium starch glycolate. In accordance with certain embodiments, the mass fractions of disintegrants and disintegrant aides may range from about 0.5% to 50% in the compositions.
[0074] The SAC product produced by these compositions and methods described herein may be administered to man or animal. The compositions described herein may be administered as dietary supplements or as pharmaceutical compositions. The SAC composition may be administered in a therapeutically effective amount to a human or animal in need of such treatment. The term "therapeutically effective amount" as used herein refers to an amount of a pharmaceutical ingredient that is effective to treat, prevent or alleviate the symptoms of a disease. The SAC compositions of the present invention may be used to treat a variety of disease states, including: atherogenesis, cancers, hypercholesterolemia, ischemia and reperfusion, and tumors. These compositions can also be used as a nutrient, a nutritional supplement or a veterinary medicine.
[0075] The SAC product described herein may be provided in various foods or beverages. Examples of suitable foods include baked goods and non-baked goods, such as nutritional bars, cakes, drink mixes and the like. Examples of beverages include waters, energy drinks, sport drinks, soft drinks, teas and the like.
[0076] The SAC product described herein may also be provided in a semi-liquid (or semi-solid) form. Examples include, without limitation, ointments, creams, pastes, and salves. These compositions may be administered topically, orally, or sublingually.
[0077] The present invention is described in more detail by the following non-limiting examples.
[0078] Example 1 [0079] Solvent solutions were prepared containing resveratrol (RES) with 13 pharmaceutically-accepted polymers (Table 1) in which the RES: polymer ratios ranged from 1 :3 to 3: 1.
[0080] The solutions were cast to make films and then allowed to dry.
[0081] RES crystallinity of the cast films was measured using differential scanning calorimetry (Q1000®, TA Instruments) at a scan rate of 10°C/min using crimped aluminum pans.
[0082] At the ratio 1 RES: 3 polymer, all polymers produced amorphous RES, as indicated by the lack of a melting endotherm.
Table 1 : Pharmaceutically-accepted polymers used for the RES film study
Figure imgf000026_0001
[0083] Example 2
[0084] 1. RES spray dried dispersions were created using a Mini Spray Dryer (Buchi Labortechnik AG) with the polymers identified in Example 1. The solutions and spray dried compositions are identified in Table 2. Product powders were collected from the spray dryer cyclone and collector.
[0085] 2. All powders contained amorphous RES, as indicated by the lack of a melting endotherm (FIG 1-4).
Table 2: RES-polymer solutions and spray dried compositions described in Example
2.
Figure imgf000027_0001
[0086] Example 3
[0087] 1. The aqueous release was measured for two spray dried dispersions of Example 2 and compared to the crystalline form of RES. USP apparatus II (VK 7000, Varian Inc.) was used with a paddle speed of 50 rpm, and RES release was detected by ultraviolet- visible detection (Cary 50, Varian Inc) at a wavelength of 306 nm. The medium was USP water maintained at 37°C, and the tested dose was standardized to 50 mg RES.
[0088] 2. The spray dried dispersion containing 1 RES : 1 PVP K-29/32 provided a release profile that was essentially identical to crystalline RES (FIG 5).
[0089] 3. An increase in the polymer content to 1 RES : 3 PVP K-29/32 lowered the release profile due to poor dispersibility of the spray dried dispersion (FIG 5).
[0090] Example 4 [0091] 1. A solvent dispersion was created that contained 45 RES: 45 PVP (Plasdone K- 29/32) : 10 croscarmellose sodium (CCNa) that was added to the working solution prior to spray drying. The solvent blend was dichloromethane and methanol.
[0092] 2. The solvent dispersion was spray dried using the Mini Spray Dryer (Buchi Labortechnik AG). A powder collected in the product cyclone jar.
[0093] 3. The powder contained only amorphous RES, as indicated by the lack of a melting endotherm when tested in a crimped aluminium pan at 10°C/min.
[0094] Example 5
[0095] 1. The aqueous release was measured for crystalline RES and two spray dried dispersions of Examples 2 and 4 that contained equal ratios of RES and PVP. The dissolution and detection methods were the same as described in Example 3, except the paddle speed was 100 rpm.
[0096] 2. The spray dried dispersion containing 1 RES : 1 PVP provided about 25% lower release than crystalline RES (FIG. 6).
[0097] 3. The addition of croscarmellose sodium assisted dispersion of the powder and improved the RES release by about 15% in the first 30 minutes of testing.
[0098] Changes may be made by persons skilled in the art in the compositions and/or in the steps or the sequence of steps of the method of manufacture described herein without departing from the spirit and scope of the invention as defined in the following claims.
[0099] WHAT IS CLAIMED IS:

Claims

1. A composition comprising a solid dispersion wherein the solid dispersion comprises one or more sirtuin-activating compounds (SAC) and one or more solubility-enhancing polymer(s) wherein said SAC is substantially amorphous and exhibits enhanced bioavailability compared to a control composition without the solubility-enhancing polymer.
2. The composition of claim 1 wherein said SAC is completely amorphous.
3. The composition of claim 1 wherein the polymer is selected from the group consisting of polyvinylpyrrolidone, hydroxypropylcellulose hydroxypropylmethylcellulose, hydroxypropylmethylcellulose acetate succinate, hydroxypropylmethylcellulose phthalate and mixtures thereof.
4. The composition of claim 1 wherein the ratio of SAC to solubility-enhancing polymer is between about 25% SAC: 75% polymer to about 75% SAC: 25% polymer.
5. The composition of claim 1 wherein the composition comprises spray dried particles of SAC and polymer.
6. The composition of claim 1 wherein the SAC is selected from the group consisting of stilbenoids, flavonoids, chalconoids and mixtures thereof.
7. The composition of claim 6 wherein the SAC comprises a stilbenoid selected from the group consisting of resveratrol, resveratrol analogues, piceatannol, rhapontin, cώ-stilbene, trans-stilbene, 3,6,3'6'-tetrahydroxyflavone and mixtures thereof.
8. The composition of claim 7 wherein the stilbenoid is resveratrol or a resveratrol analogue.
9. The composition of claim 6 wherein the SAC comprises a flavonoid selected from the group consisting of apigenin, (-)-catechin, daidzein, dihydroxyflavone, (-)-epicatechin, fisetin, flavanone, flavone, (-)-gallocatechin, genistein, 6- hydroxyapigenin, 5 -hydroxy flavone, kaempferol, morin, naringenin, pentahydroxyflavone, quercetin and mixtures thereof.
10. The composition of claim 6 wherein the SAC comprises a chalconoid selected from the group consisting of butein, pentahydroxychalone and mixtures thereof.
11. A dosage form comprising the composition of claim 1.
12. The dosage form of claim 11 wherein the dosage form comprises an oral, solid- dosage form.
13. The dosage form of claim 12 wherein the dosage form provides at least one of:
a) a maximum plasma concentration for an active form of SAC that is at least 1.25 times greater than that of a control composition containing crystalline SAC;
b) an increase in the exposure (AUCo-24h) of at least 1.25 times that of a control composition containing crystalline SAC.
14. A method for providing SAC to a subject comprising administering to said subject the oral, solid dosage form of claim 12.
15. The method of claim 14 wherein said dosage form is administered to treat an insulin-resistant disorder.
16. The method of claim 15 wherein the insulin-resistant disorder is diabetes.
17. The method of claim 14 wherein said dosage form is administered to treat obesity.
18. A method of preparing a SAC composition comprising:
contacting a quantity of SAC with a solubility-enhancing polymer in a solvent system comprising a solvent for the polymer, and removing the solvent to form a SAC -polymer composition wherein the SAC exhibits enhanced bioavailability.
19. The method of claim 18 wherein the solvent is removed by spray drying the mixture to form particles comprising SAC.
20. The method of claim 18 wherein the solvent system further comprises a non- solvent for the polymer.
21. The method of claim 20 wherein the solvent and non-solvent are present at a ratio of from about 5% solvent: 95% non-solvent to about 95% solvent : 5% non-solvent.
22. The method of claim 20 wherein the SAC exhibiting enhanced bioavailability exhibits faster dissolution, greater extent of dissolution, or both compared to a SAC composition made without a non-solvent for the polymer.
23. The method of claim 20 wherein the concentration of the polymer in the mixture is from about 1% to about 90%.
24. The method of claim 20 wherein the SAC in said mixture is almost completely amorphous.
25. A method for preparing a composition comprising amorphous SAC comprising:
a. providing a mixture comprising SAC and a solubility-enhancing polymer in a solvent or a blend of a solvent and non-solvent for the solubility- enhancing polymer;
b. distributing the mixture into either droplets or granules, and
c. evaporating the solvent or solvent and non-solvent from the mixture to form a composition comprising particles wherein the particles comprise amorphous SAC.
26. The method of claim 25 wherein the solubility-enhancing polymer is selected from the group consisting of hydroxypropylmethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose acetate succinate, hydroxypropylmethylcellulose phthalate, polyvinylpyrrolidone and mixtures thereof.
27. The method of claim 25 wherein the particles have an average size of from about 0.5 μm to about 5000 μm.
28. The method of claim 25 wherein the mixture comprises a blend of a solvent and non-solvent for the solubility-enhancing polymer.
29. The method of claim 28 wherein said particles possess less crystalline SAC than particles produced from a mixture containing solvent alone.
30. The method of claim 28 wherein the mixture comprises a solubility-enhancing polymer/solvent/non-solvent combination selected from the group consisting of polyvinylpyrrolidone/dichloromethane/acetone, polyvinylpyrrolidone/ethanol/cyclohexane, polyvinylpyrrolidone-co-vinyl acetate /acetone/hexane, and ethylcellulose/acetone/water.
31. The method of claim 25 wherein the composition is substantially free of lipids and oils.
32. The method of claim 25 wherein at least about 20% of the SAC is released in 15 minutes when tested in aqueous media.
PCT/US2008/050588 2007-01-09 2008-01-09 Sirtuin-activating compounds of enhanced bioavailability WO2008086400A2 (en)

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