US 2016.0000714A1 (19) (12) Patent Application Publication (10) Pub. No.: US 2016/0000714 A1 DiOrio et al. (43) Pub. Date: Jan. 7, 2016

(54) CURCUMIN SOLD LIPID PARTICLES AND Related U.S. Application Data METHODS FOR THEIR PREPARATION AND (60) Provisional application No. 61/773,635, filed on Mar. USE 6, 2013. (71) Applicant: CAPSUGEL BELGIUM NV, Bornem (BE) Publication Classification (72) Inventors: Christopher Diorio, Campbell Hall, NY (51) Int. Cl. (US); John Lokhnauth, Fair Lawn, NJ A619/16 (2006.01) (US) A63L/2 (2006.01) (52) U.S. Cl. (73) Assignee: Capsugel Belgium NV, Bornem (BE) CPC ...... A61K 9/1694 (2013.01); A61K 31/12 (2013.01); A61 K9/1617 (2013.01); A61 K (21) Appl. No.: 14/771,117 9/1623 (2013.01) (22) PCT Fled: Mar. 4, 2014 (57) ABSTRACT (86) PCT NO.: PCT/B2O14/OOO463 Solid lipid particles comprising a lipid hydrophobic matrix S371 (c)(1), and from about 5 wt.% to about 30 wt.% of curcumin, and (2) Date: Aug. 27, 2015 methods of making and treatment thereof.

s 3. Patent Application Publication US 2016/0000714 A1

Patent Application Publication Jan. 7, 2016 Sheet 2 of 3 US 2016/0000714 A1

FIG. 2

Patent Application Publication Jan. 7, 2016 Sheet 3 of 3 US 2016/0000714 A1

utifu) is Ae euised US 2016/0000714 A1 Jan. 7, 2016

CURCUMIN SOLD LIPID PARTICLES AND vol. 60, pp. 171-77 (2007); US 2009/0324703 A1; US 2009/ METHODS FOR THEIR PREPARATION AND 013 1373 A1: WO 2007/101551 A2; and WO 2012/023142 USE A2. 0001 Curcumin (IUPAC name 1.7-bis(4-hydroxy-3- 0006. The present disclosure generally relates to a solid methoxyphenyl)-1E,6E-heptadiene-3,5-dione) is a polyphe lipid particles comprising curcumin. As used herein, the nolic compound derived from the herbal remedy and dietary terms “gallenic system.” “lipidic particle.” “lipid particle.” spice, . Among the various beneficial pharmacologic “droplet” and “lipidic droplet” should be understood to have properties curcumin has been known to possess are antioxi Substantially the same meaning. In one embodiment, Solid dant, antimicrobial, anticarcinogenic, and anti-inflammatory lipid particles comprising curcumin in accordance with the properties. The compound has been involved in induction of present disclosure enable increased of cur cell arrest and , inhibition of tumor invasion and . Solid lipid particles according to the disclosure also angiogenesis, and Suppression of 2 (COX-2) provide one or more of masking of , masking of odor, expression. Curcumin has also been recognized as a neuro-, stabilization of the active curcumin constituent, modulation cardio-, and hepato-protective agent. Preclinical studies of of the release profile of curcumin, ease of handling, predict curcumin indicate therapeutic potential of the compound in ability of dosing, and minimization of any mucosal irritation, treating a variety of diseases including , stroke, Alzhe toxicity, and/or gastro-toxicity. In some embodiments, Solid imer's disease, irritable bowel syndrome (IBS), atheroscle lipid particles comprising curcumin in accordance with the rosis, arthritis, and aging, among others. present disclosure are capable of delayed release of curcumin, 0002. Despite these beneficial pharmacologic properties, particularly so that curcumin is not released into the stomach curcumin’s low bioavailability has proved an impediment to during ingestion. Thus, in a further preferred embodiment, its use. In particular, as discussed in Anand et al., “Bioavail the Solid lipid particles comprising curcumin are resistant to ability of Curcumin: Problems and Promises.” Molecular acidic pH. Pharmaceutics Vol. 4, no. 6, pp. 807-18 (2007), curcumin 0007. It is to be understood that both the foregoing general suffers from low intrinsic activity and poor absorption. The description and the following detailed description are exem chemical structures of curcumin and its downstream meta plary and explanatory only and are not restrictive of the bolic products are shown in FIG.1. These metabolic products claimed Subject matter. do not display the beneficial pharmacologic properties of curcumin itself. Thus, curcumin’s high rate of metabolism by BRIEF DESCRIPTION OF THE DRAWINGS mammalian organisms results in rapid elimination of the 0008 FIG. 1 illustrates chemical structures of curcumin compound and termination of its desirable pharmacologic and metabolites thereof. effects. 0009 FIG. 2 is a micrograph of a solid lipid particle having 0003 Various attempts have been made to improve the a size (average particle diameter) of approximately 250 um in bioavailability of curcumin. Anand et al. discloses that con accordance with the present disclosure. current administration of curcumin with , a glucu 0010 FIG. 3 is a micrograph of solid lipid particles com ronidation inhibitor, to rats and humans have shown to prising curcumin, in accordance with the present disclosure. increase in vivo curcumin bioavailability. Other studies have The mean particle size of the Solid lipid particles is approxi used pretreatment with or terpeneol to improve skin mately 400 um. absorption of curcumin. Anand et al. also discloses that com plexes of curcumin with , in particular, phos 0011 FIG. 4 is a graph of curcumin plasma concentration phatidylcholine, has shown a five-fold increase in peak in dogs as a function of time following administration of plasma levels of curcumin in rats. Complexes of curcumin Examples 1 to 5, described below. with phosphatidylcholine are available as a commercial prod DETAILED DESCRIPTION uct trademarked as MERIVAR). Anand et al., further disclose that liposomes, micelles, and solid lipid nanoparticles (SLNs) 0012. As used herein, reference to an element by the have been investigated as drug delivery platforms for cur indefinite article “a” or “an does not exclude the possibility cumin. that more than one of the element is present, unless the con 0004 Kakkaret al., “Exploring solid lipid nanoparticles to text clearly requires that there is one and only one of the enhance the oral bioavailability of curcumin.” Mol. Nutr. elements. The indefinite article “a” or “an' thus usually Food Res. Vol. 55, pp. 495-503 (2011) discloses in vivo stud means “at least one.” The disclosure of numerical ranges ies using oral administration of curcumin-loaded SLNS to should be understood as referring to each discrete point rats. At dosages of 50, 25, 12.5 and 1 mg/kg, Kakkar et al. within the range, inclusive of endpoints, unless otherwise reports increased bioavailability at factors of 39, 32, 59, and noted. The term “about as used in the disclosure of numerical 155, relative to a control of solubilized curcumin at the same ranges indicates that deviation from the stated value is accept dose. able to the extent that the deviation is the result of measure 0005. Other documents addressing curcumin bioavailabil ment variability and/or yields a product of the same or similar ity include: Pawar et al., “Novel lipid based oral formulation properties. of curcumin: Development and optimization by design of 0013 Curcumin may be found in several tautomeric experiments approach. International Journal of Pharmaceu forms, e.g. a 1,3-diketo and forms. Commercial forms of tics Vol. 436, pp. 617-23 (2012); Cuomo et al., “Comparative curcumin may often comprise one or more com Absorption of a Standardized Curcuminoid Mixture and Its pounds, such as (besides curcumin itself), desmethoxycur Lecithin Formulation.” Journal of Natural Products Vol. 74, cumin and bisdesmethoxycurcumin and cumerone oils. An pp. 664-69 (2011); Marcyzlo et al., “Comparison of systemic exemplary embodiment of a commercial form of curcumin availability of curcumin with that of curcumin formulated comprises from about 75% by weight to about 80% by weight with phosphatidylcholine.” Cancer Chemother: Pharmacol. of curcumin, from about 15% by weight to 20% by weight of US 2016/0000714 A1 Jan. 7, 2016 , and from about 1% by weight to about The lipid hydrophobic matrix may also have an end melting 15% by weight of bisdesmethoxycurcumin. A commercial point ranging from about 15° C. to about 85°C., e.g. from form of curcumin may comprise, for example, about 77% by about 15° C. to about 75°C., or from about 30°C. to about 45° weight of curcumin, about 17% by weight of demesthoxycur C., or about 37.5°C. In certain embodiments, the lipid hydro cumin, and about 6% by weight of bisdesmethoxycurcumin. phobic matrix optionally include Surfactant, Surfactant com The chemical structures of several forms of curcumin and/or pounds, and/or Surface-active agents. curcuminoid compounds is shown below: 0018. In one embodiment, the lipid hydrophobic matrix comprises natural and/or synthetic oils and/or waxes includ ing glycerides (e.g. monoglycerides, , triglycer No O 1. ides, etc. with Saturated or unsaturated chains having carbon numbers from C to Cao, e.g. Cls to C2a, Cs to C2, Co to C2a, HO OH Co to C1s, C12 to C1s, etc.), hemisynthetic glycerides or glyceride derivatives with Saturated or unsaturated medium to long chain lengths, palm oil, Carnauba wax, Candellila wax, 21 N C Alfa wax, cocoa , oZokerite, vegetable waxes, rice wax, hydrogenated jojoba wax or florali absolute waxes, bees O O waxes and modified beeswaxes, fatty alcohols, esters of fatty Curcumin acids and of alcohols with high molecular weight, sterols such as cholesterol and its esters, vegetable oils such as , N O groundnut oil, oils of hydrophobic silicones, cyclomethi HO OH cones, petroleum waxes orjellies, paraffin oil, paraffin, linear alkanes, and/or mixtures thereof. 0019. It is also possible to use fatty alcohols with high 21 S c molecular weight (e.g., cetanol, myristoyl alcohol, Stearoyl alcohol), esters of acids and alcohols with high molecular O O weight, for example, esters of linear and Saturated acids with even carbon numbers from C to Co., and linear and Satu DeSmethoxycurcumin rated alcohols with even carbon numbers from C to C. HO OH Esters offatty acids with carbon numbers from C to C with glycols, e.g. ethylene glycol, propylene glycol, may also be used. The lipid hydrophobic matrix may also comprise an oil 21 S. O or a mixture chosen from oils of hydrophobic silicones with a viscosity of from about 5 centistokes to about 9000 centis O O tokes, cyclomethicones, lipophilic organic fluorinated oils, BisdeSmethoxycurcumin and/or perhydrosqualene. Oily compounds may be used, such as oleic alcohol, lanoline, Sunflower oil, palm oil, olive oil, and oils that are immiscible with water and have a melting 0014. As used herein, "curcumin' and/or “curcuminoid point ranging from about 15° C. to about 85°C. The lipid compounds’ is understood to refer to tautomeric, commer hydrophobic matrix may comprise from about 0.5 weight cial, or otherwise chemically equivalent forms of curcumin percent to about 99 weight percent of wax, e.g. from about 1 that Substantially retain the pharmacologic properties of cur weight percent to about 50 weight percent of wax. cumin as discussed (e.g. , antimicrobial, anticar 0020. In preferred embodiments, the lipid hydrophobic cinogenic, anti-inflammatory, etc.), and may include any or matrix comprises waxes which are non-ionizable at physi all of the curcumin and/or curcuminoid compounds sepa ologic pH, approximately. The lipid hydrophobic matrix rately or in a mixture. advantageously may be “strictly hydrophobic' insofar as it 0015. In one embodiment, solid lipid particles in accor does not contain any detectable traces of water. dance with the present disclosure comprise a lipid and/or 0021. In certain embodiments, the lipid hydrophobic hydrophobic matrix (which may be referred to as a “lipid matrix comprises a wax, Such as those mentioned above, and hydrophobic matrix'). In certain embodiments, the lipid and/ a non-neutralized fatty acid. The non-neutralized fatty acid or hydrophobic matrix is non-ionizable such that it is not may be chosen from fatty acids with linear chains with carbon capable of being ionized at physiological pH, where physi numbers ranging from C to Cs, for example such as myristic ological pH is approximately pH 5 to pH 7, more particularly acid, lauric acid, palmitic acid, or oleic acid. about pH 7.4. Thus in one embodiment, the lipid and/or 0022. The lipid hydrophobic matrix may also include, for hydrophobic matrix does not include any acid or basic func the purposes of adjusting consistency, clays or their oily dis tions, such as organic or mineral bases. In another embodi persions, gums of phenylated silicones, starches, and/or fat ment, the Solid lipid particles optionally comprise Surfactant, structuring agents. The lipid hydrophobic matrix may also Surfactant compounds, and/or Surface-active agents. include a certain number of compounds such as mineral fill 0016. In certain embodiments, the solid lipid particles ers, to modulate its density and plasticity. The mineral fillers according to the disclosure comprise Surfactant, Surfactant may be, for example, talc and/or kaolin. In certain embodi compounds and or Surface active agents. In certain embodi ments, mineral fillers are not used. ments, the solid lipid particles in accordance with the disclo 0023. In one embodiment, the solid lipid particles com Sure do not contain any organic . prise at least one component chosen from lecithin, COMPRI 0017 Certain embodiments of solid lipid particles in TOL(R) E, CAPRYOLR 90, GELUCIRER 43/01, accordance with the disclosure do not contain any fatty acids. LABRAFAC(R) or combinations therefore. For example, in a US 2016/0000714 A1 Jan. 7, 2016

preferred embodiment, a composition of one embodiment the mixture and a second axial blade equipped with a three comprises about 5 wt.% to about 30 wt.% lecithin, preferably Vaned impeller designed to obtain a dispersion having a 10 to 15 wt %, and more preferably about 15%; about 5 wt.% desired droplet size or a dispersion having a discontinuous to about 15 wt.% COMPRITOL(R) E, preferably about 5 wt phase of a desired characteristic size. The temperature of the %; and at least about 40 wt.% GELUCIRE(R) 43/01, prefer gel may be adjusted to be the same as the temperature of the ably about 50 wt.% or about 65 wt %. In another embodi mixture prior to injection. The concentration of the gelifying ment, a composition comprises about 5 wt.% to about 30 wt. agent may range, for example, from about 0.1 g/l to about 30 % CAPRYOLR 90, preferably about 20 wt %; 5 wt.% to g/l, e.g. from about 0.2 g/l to about 20 g/l, or Sufficiently high about 30 wt.% LABRAFACR preferably about 10 wt %; to fix the dispersion. The dispersion may then be cooled about 5 wt.% to about 15 wt.% COMPRITOL(R) E, prefer below the melting point of the mixture. Solid lipid particles ably 5 wt %; and at least about 40 wt.% GELUCIRE(R) 43/01, may then be separated from the gel, after which, the solid lipid preferably about 50 wt.% or about 65 wt %. In a preferred particles may be washed. The particles may be washed with a embodiment, each of these compositions would further com mixture of water and ethanol, e.g. a mixture comprising water prise about 15 wt.% curcumin. and up to 25 weight percent of ethanol. 0024 Processes for preparation of solid lipid particles are 0028. Examples of gelifying agents include carboxyvinyl well known to those skilled in the art, and is described in polymers such as polyacrylic polymers not modified by publications WO 1999/65448, WO 2004/084856, and WO hydrophobic groups or Surfactant groups. Other gelifying 2006/0701417, the disclosures of which are incorporated agents include carrageenans, thickeners and polysaccharidic herein by reference. gels such as Xanthenes, guar and carob gels, alginates, cellu 0025. In one embodiment, the solid lipid particles in lose derivatives, pectins, agar, etc. or mixtures thereof. accordance with the present disclosure are obtained by mix 0029. In certain preferred embodiments, the solid lipid ing a lipid phase under moderate heat. For example, wax and particles in accordance with the present disclosure have par oil may are mixed at a temperature corresponding to the ticle sizes ranging from about 0.5 um to about 1500 um, melting point of the wax, until the mixture obtained has a particularly from about 100 um to about 1500 um, and com melting point lower than the melting point of the wax. The prise curcumin dispersed in a lipid hydrophobic matrix. The initial ratio of the wax to the oil can be modulated so that the Solid lipid particles may further comprise essential oils, fla melting point of the end mixture is lower than the degradation Vorings, pigments, fillers, coloring agents, and temperature of the most heat-sensitive component to be incor coenzymes, preservatives, and other active Substances or porated. In one embodiment, the end mixture is a solid at the active components. In one embodiment, the filling or loading temperature of its utilization. For example, the end mixture ratio of the solid lipid particles ranges from about 0.2 weight may have a melting point of about 37.5°C. The end mixture percent to about 75 weight percent, relative to the total weight is cooled while stirring to a temperature slightly above its of the solid lipid particles. In a preferred embodiment, the melting point, e.g. about 2°C. or about 3°C. above its melting filling or loading ratio of curcumin in the Solid lipid particles point. One or more active pharmaceutical ingredients may ranges from about 0.5 weight percent to about 30 weight then be added. In accordance with the present disclosure, at percent, e.g. from about 5 weight percent to about 30 weight least one of the active pharmaceutical ingredients comprise percent, from about 10 weight percent to about 20 weight curcumin. percent, from about 12 weight percent to about 18 weight 0026. In a preferred embodiment, addition of the active percent, relative to the total weight of the solid lipid particles. pharmaceutical ingredient to the mixture is accomplished In certain embodiments, the Solid lipid particles comprise Such that the ingredient is dispersed throughout—such means about 15 weight percent of curcumin. For oral administration, include the use of a homogenizer, disperser, or the use of the Solid lipid particles may have a size (average particle mechanical agitation or stirring. Sonicators or static mixers diameter) ranging from about 100 um to about 400 um. In a may be also be used. Other ingredients may be similarly preferred embodiment, Solid lipid particles in accordance incorporated at the same or different times. In certain pre with the present disclosure comprise curcumin having an ferred embodiments, the active pharmaceutical ingredient, average particle size diameter ranging from about 100 um to comprising e.g. curcumin and/or other ingredients, may be about 600 um. Subjected to a homogenizing step to form nanoparticles of the 0030 Solid lipid particles in accordance with the present active pharmaceutical ingredient, prior to its addition to the disclosure may comprise at least one additional active com mixture. In some embodiments, the active pharmaceutical ponent, referring to a therapeutic Substance or mixture able to ingredient may be subjected to a homogenizing step to form be advantageously administered to humans or animals to nanoparticles of the pharmaceutical ingredient. The homog diagnose, care for, reduce, treat, or prevent disease—or enizing step may occur before or after addition of the active improve health. As used herein, “active substance.” “active pharmaceutical ingredient to the mixture. The mixture is then component,” “active agent, and “active ingredient have shaped to give solid lipid particles. In certain embodiments, Substantially the same meaning. Non-limiting examples of the Solid lipid particles have Substantially spherical shape as the additional active component include vitamins or provita shown in FIG. 2 and FIG. 3. mins A, B, C, D, E, PP and their esters, , anti 0027. In a preferred embodiment, shaping is carried out radical Substances, hydroxyacids, antiseptics, molecules act using a gel. The gel may be prepared with a gel-forming/ ing on pigmentation or inflammation, biological extracts, gelifying, shear-thinning, non-surface-active agent or Sub , cells and cell organelles, antibiotics, mac stance, with which the mixture is not miscible. The mixture rolides, antifungals, itraconazole, ketoconazole, antiparasit may be injected into the gel, for example, through an orifice ics, antimalarials, adsorbents, hormones and derivatives located at the base of a reaction vesselholding the gel, to form thereof, , antihistamines, steroid and non-steroid a dispersion. Stirring may be continued throughout injection anti-inflammatories, , , cortisone and using a blade equipped with an anchor designed to disperse derivatives thereof, anti- agents, analgesics, local US 2016/0000714 A1 Jan. 7, 2016

anesthetics, antivirals, antibodies and molecules acting on the 0036 Curcumin was added at a loading of about 15 weight immune system, cytostatics and anticancer agents, hypolipi percent and mixed into the vessel with an agitator (RPM demics, vasodilators, vasoconstrictors, inhibitors of angio ranging from about 200 RPM to about 600 RPM, e.g. 400 tensin-converting and phosphodiesterase, fenofi RPM). The resulting mixture of curcumin in lipid suspension brate and derivatives thereof, statins, nitrate derivatives and was maintained at a temperature from about 45° C. to about anti-anginals, beta-blockers, inhibitors, anti-diuret 75° C. (e.g. 60° C.). ics and diuretics, bronchodilators, opiates and derivatives thereof, barbiturates, benzodiazepines, molecules acting on Preparation of Gel Phase the central nervous system, nucleic acids, , anthrace nic compounds, paraffin oil, , mineral 0037. An appropriate amount of USP water or deionized salts, antispasmodics, gastric anti-Secretory agents, clay gas water was weighed and transferred to a jacketed reactor tric dressings and polyvinylpyrrolidone, aluminum salts, cal equipped with an agitator. A polyacrylic polymer gelifying cium carbonates, magnesium carbonates, starch, derivatives agent (commercially available under the trademark CAR of benzimidazole, and mixtures of the foregoing. Solid lipid BOPOL(R) was added. The concentration of the gelifying nanoparticles in accordance with the present disclosure may agent was from about 0.1 weight percent to about 0.8 weight also comprise a glucuronidation inhibitor, for example, pip percent (e.g. about 0.2 weight percent). The mixture was erine. stirred at from about 200 RPM to about 800 RPM (e.g. about 0031. In certain embodiments, the solid lipid particles are 400 RPM) until the dissolution of the gelifying agent was devoidofactive ingredient on their surface. Elimination of the achieved. The pH of the gel was adjusted with 1N sodium active ingredient is obtained, for example, by washing the hydroxide to a pH of about 3.5 to about 8.0 (e.g. about 4.5). particles or by a suitable method. Thus, in a preferred embodi The gel was then heated to about 60° C. under stirring/agita ment, Solid lipid particles in accordance with the present tion. disclosure have no curcumin present at their surface. Thus, Solid lipid particles in accordance with the present disclosure Flash Injection may not be coated. 0038. While stirring the gel (RPM ranging from about 200 0032 Solid lipid particles in accordance with the present RPM to about 800 RPM, e.g. 500 RPM), the lipid suspension disclosure may be incorporated into any composition, includ obtained above was transferred via peristaltic pump directly ing any cosmetic, pharmaceutical, veterinary, or food com into the gel held in the jacketed reactor. Agitation was termi position. nated upon complete transfer. A dispersion was thus obtained. 0033. The present disclosure also relates to a composition containing at least one solid lipid particle as herein described. Cooling and Separation The composition may include any additive intended to 0039. The temperature of the jacketed reactor was modify its appearance or rheology. Additives that improve the adjusted to a temperature of about 2°C. to about 10°C. (e.g. fluidity of the solid lipid particles may also be included. For 5° C.). The temperature of the lipid phase of the dispersion example, lubricants may be added, including, e.g., talc, was monitored to ascertain hardening. 1N sodium chloride starches, silica powders, anti-static agents, etc. In certain solution was then added to the hardened lipid particles in the embodiments, the composition may be in the form of an gel to break-up the gel. Agitation at about 100 RPM was used aqueous Suspension, syrup, or Sachet. The composition may to aid gel break-up. be in the form of any appropriate galenic formulation, Such as 0040. The contents of the jacketed reactor were then trans capsules, gelatine capsules or gel capsules, granules, oral ferred to a Buchner funnel equipped with a membrane filter powders, dispersible powders, tablet, hydrodispersible and (50 um to 100 um pore size) and vacuum capability. Vacuum orodispersible tablets, etc. The composition may also be was applied until the Solid lipid particles appeared dry and no injectable. In this case, such compositions may include Solid more liquid was removed. The particles were washed with lipid particles having sizes ranging from about 0.5 um to water and vacuum filtered again. about 5um. Desired particle size distributions of solid lipid 0041. The filtered solid lipid particles were transferred to particles in accordance with the present disclosure may be a drying tray and allowed to air dry. Alternatively, vacuum obtained by sieving or equivalent sizing techniques. drying until the particles are free-flowing with no apparent 0034. Other embodiments of the present disclosure will be apparent to those skilled in the art from consideration of the moisture may be used. The solid lipid particles were then specification and practice of the disclosed embodiments. The sieved to obtain a desired size distribution and collected. following examples should be considered as exemplary only, Example 2 with a true scope and spirit of the present disclosure being indicated by the claims. 0042. The procedure of Example 1 was followed as above with the exception that instead of lecithin, propylene glycol Example 1 caprylate (commercially available as CAPRYOLR 90) and medium-chain length triglycerides (carbon number ranging Preparation of Lipid Phase from C to C, commercially available as LABRAFAC(R) 0035. The following materials were melted in a jacketed were used. vessel held attemperature ranging from about 45° C. to about Example 3 75° C. (e.g. about 60° C.): a mixture of mono-, di-, and triglycerides having carbon number from Co to Cls (com 0043. The procedure of Example 1 above was followed as mercially available as GELUCIRE(R) 43/10); glycerol dibe above with the following exception. Prior to adding curcumin henate (commercially available as COMPRITOL(R) E); and during preparation of the lipid phase, the curcumin was Sub lecithin (soy, Sunflower). jected to particle size reduction using a wet bead milling US 2016/0000714 A1 Jan. 7, 2016

process for 30 minutes using a DYNO(R-MILL to render the TABLE 2 curcumin nanosized. The resulting curcumin particles had a particle size (average particle size diameter) ranging from Example AUC (hing ml) C (ng/ml) T(hr) about 0.1 um to about 10 Lum. Example 6 49.4 14.9 4 Example 7 136 40.7 2.3 0044) The compositions of the Examples are summarized Example 8 131 39.2 2 in Table 1, along with Examples 4 and5, which do not employ solid lipid particles. Examples 1 to 5 were administered to fasted Beagle dogs weighing 10-12 kg. The curcumin equiva 1. Solid lipid particles comprising: a lipid hydrophobic lent dosage was 750 mg. Blood samples were taken at 0.5, 1. matrix; and from about 5 wt.% to about 30 wt.% of curcumin, 2, 4, 6, and 8 hours following oral administration (oral gav wherein said lipid hydrophobic matrix is substantially free of age). Tests were run in triplicate. Curcumin concentration in water and wherein said Solid lipid particles have an average the blood plasma was measured and recorded. A plot of the particle size diameter ranging from 100 um to 1500 um. results (concentration of total over time) is 2. The solid lipid particles according to claim 1, wherein shown in FIG. 4. the lipid hydrophobic matrix has a melting point ranging from about 15° C. to about 85°C. 3. The solid lipid particles according to claim 1, wherein TABLE 1. the lipid hydrophobic matrix has a melting point ranging from Example about 30° C. to about 45° C. No. Description Composition Dosage 4. The Solid lipid particles according to claim 1, wherein the lipid hydrophobic matrix optionally contains at least one 1 SLP wiLecithin 15 wt.% Lecithin 5g Surfactant. 15 wt.% Curcumin 5 wt.% COMPRITOL (RE 5. The solid lipid particles according to claim 1, wherein 65 wt.% GELUCIRE OR 43,01 the curcumin has an average particle size diameter ranging 2 SLP wi 2O wt.% CAPRYOL OR 90 5g from about 0.1 um to about 10 Lum. propylene 10 wt.% LABRAFAC (R) 6. (canceled) glycol caprylate, 15 wt.% Curcumin 7. The solid lipid particles according to claim 1, wherein medium-chain 5 wt.% COMPRITOL (RE the Solid lipid particles have a Substantially spherical shape. triglycerides SO wt.% GELUCIRE OR 43,01 3 SLP winanosized 20 wt.% CAPRYOL (R) 90 5g 8. The solid lipid particles according to claim 1, wherein curcumin, 10 wt.% LABRAFAC (R) the lipid hydrophobic matrix comprises at least one of: propylene 15 wt.% Curcumin (nanosized: a mixture of monoglycerides, diglycerides, and triglycer glycol caprylate, 0.1 m to 10 m) ides having a carbon number ranging from C to Cao, medium chain 5 wt.% COMPRITOL (RE esters of fatty acids having a carbon number ranging from triglycerides SO wt.% GELUCIRE OR 43,01 C to C with ethylene glycol or propylene glycol, 4 Neat curcumin NA 750 mg 5 Commerical Curcumin complex with 5.3g a mixture of triglyceridies having medium chain length; or product phosophatidylcholine a mixture of glycerides having a carbon number ranging MERIVA (R) (formulation includes from Cs to C. phosphate, maltodextrin, 9. The solid lipid particles according to claim 1, wherein silica, magnesium stearate) the lipid hydrophobic matrix comprises a mixture of a wax and at least one non-neutralized fatty acid. 10. A process for preparing Solid lipid particles according to claim 1, wherein the process comprises: Examples 6, 7, and 8 dispersing a lipid phase having a melting point ranging from about 15° C. to about 85°C. in a gel phase at a 0045 Solid lipid particles were made according to the temperature above the melting point of the lipid phase to Example 1. Example 6 was solid lipid particles comprising form a dispersion; 80% Suppocire DM, 5% Compitrol E, and 15% curcumin. cooling the dispersion to obtain Solid lipid particles; Example 7 was solid lipid particles comprising 70% Suppo separating the Solid lipid particles; and cire DM, 5% Compitrol E, 10% sunflower liquid lecithin, and 15% curcumin. Example 8 was solid lipid particles compris optionally, washing the solid lipid particles; ing 75% Suppocire DM, 5% Compitrol E, 6% sunflower wherein the solid lipid particles comprise a lipid hydropho bic matrix; and from about 5 wt.% to about 30 wt.% of powdered lecithin, and 15% curcumin. curcumin. 0046. The particles from Examples 6, 7, and 8 were dosed 11. The process according to claim 9, wherein the solid into a fasted animal model (Beagle dogs, 10-12 kg, three dogs lipid particle further comprise Surfactant. per Example). Dogs were administered 750 mg curcumin in 12. A pharmaceutical composition comprising one or more size 11 capsules. Tests were run in triplicate. Blood sampling solid lipid particles according to claim 9. was performed at 0.5. 1, 2, 4, 6, and 8 hours; plasma samples 13. A Solid lipid particle according to claim 1, comprising were treated with glucorodinase and Sulfatase. about 5 wt.% to about 15 wt.% curcumin 0047 Table 2 shows the pharmacokinetic results (average, about 5 wt.% to about 30 wt.% lecithin, preferably 10 to n=3). Examples 6, 7, and 8 gave good blood results with 15 wt %, and more preferably visually appealing, spherical Solid lipid particles free of about 15 wt.%; about 5 wt.% to about 15 wt.% glycerol organic solvents. behenate, preferably about 5 wt %; US 2016/0000714 A1 Jan. 7, 2016

and at least about 40 wt.% mixture of monoglycerides, 17. The solid lipid particle of claim 15 comprising: diglycerides, and triglycerides having a carbon number 15 wt.% curcumin wherein the curcumin has an average ranging from C to Cao, preferably about 50 wt %, or particle size diameter from about 0.1 um to about 10um; about 65 wt %. 20 wt.% propylene glycol caprylate; 14. The solid lipid particle of claim 13 comprising 10 wt.% propylene glycol dicaprylate/dicaprate; about 15 wt.% curcumin 5 wt.% glycerol behenate, and about 15 wt.% lecithin; 50 wt.% a mixture of monoglycerides, diglycerides, and about 5 wt.% glycerol behenate; and triglycerides having a carbon numberranging from C to about 65 wt.% mixture of monoglycerides, diglycerides, C40. and triglycerides having a carbon number ranging from 18. A solid lipid particle according to claim 1, wherein the Cs to Cao. curcuminis comprised in an amount of from 5% wt to 15% wt 15. (canceled) and wherein said solid lipid particle comprises: 16. The solid lipid particle of claim 1 comprising 5% wt to 30% wt propylene glycol monocaprylate, 15 wt.% curcumin 20 wt.% propylene glycol monocaprylate, 5% wt to 30% wt propylene glycol dicaprylate/dicaprate, 10 wt.% propylene glycol dicaprylate/dicaprate, 5% wt to 15% wt glycerol behenate, 5 wt.% glycerol behenate, and and at least 40% wt a mixture of monoglycerides, diglic 50 wt.% a mixture of monoglycerides, diglycerides, and erides, and triglicerides having a carbon number ranging triglycerides having a carbon numberranging from C to from C6 to C40. C40.