US0088.35509B2

(12) United States Patent (10) Patent No.: US 8,835,509 B2 Kohli et al. (45) Date of Patent: Sep. 16, 2014

(54) SELF EMULSIFYING DRUG DELIVERY (58) Field of Classification Search SYSTEM FOR A CURCUMINOID BASED USPC ...... 514/679; 424/455 COMPOSITION See application file for complete search history. (75) Inventors: Kanchan Kohli, New Delhi (IN); Sunny (56) References Cited Chopra, Chandigarh (IN); Saurabh |U.S. PATENT DOCUMENTS Arora, New Delhi (IN); Roop K. Khar, New Delhi (IN); Kolappa K. Pillai, New 5,965,160 A 10/1999 Benita et al. Delhi (IN) 5,993,858 A 11/1999 Crison et al. 6,054,136 A 4/2000 Farah et al. - e 6,057,289 A 5/2000 Mulye (73) Assignees: Arbro Pharmaceuticals Ltd., New 6,140,375. A 10/2000 Nagahama et al. Delhi (IN); Jamia Hamdard (Hamdard 2007/0243 132 A1 * 10/2007 Russell-Jones et al...... 424/1.1.1 University), New Delhi (IN) FOREIGN PATENT DOCUMENTS (*) Notice: Subject to any disclaimer, the term of this patent is extended or adjusted under 35 wo wº Å. :}; º U.S.C. 154(b) by 181 days. WO 2010/0.10431 A1 1/2010 OTHER PUBLICATIONS (21) Appl. No.: 13/094,457 CN1895239 (A).Jianmingetal. preparation and its making (22) Filed: Apr. 26, 2011 method (Jan. 17, 2007), English translation.* (65) Prior Publication Data * cited by examiner |US 2011/0294900 A1 Dec. 1, 2011 Primary Examiner – Jennifer M. Kim e - - - * * (74) Attorney, Agent, or Firm – Pergament Gilman & (30) Foreign Application Priority Data Cepeda LLP; Milagros A. Cepeda; Edward D. Pergament May 31, 2010 (IN) ...... 1249/DEL/2010 (57) ABSTRACT (51) Int. Cl The present invention discloses a pharmaceutical composi A oiK ºI/I 2 (2006.01) tion in the form of self nano emulsifying drug delivery for A6 IK 9/66 (200 6 of mulation comprising curcuminoids. The pharmaceutical A6 IK 47/34 (2006 oi) composition of the present invention shows an enhanced drug A6 IK 47/44 (200 6 of loading ability, better stability and an improved bioavailabil (52) U.S. Cl - ity. The composition of the present invention comprises of a opó e A61K31/12 (2013.01); A61K 47/34 pharmaceutically effective amount of a curcuminoid, an (2013.01); A61K 47/44 (2013.01) phase, a and a co surfactant. USPC ...... 514/679; 424/455 5 Claims, 1 Drawing Sheet U.S. Patent Sep. 16, 2014 US 8,835,509 B2

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& Test (average) & Control (average)

10 11

Figure 1

Surfactant Sol (mg/mL )

& Soi (mg/mL)

Figure 2 US 8,835,509 B2 1 2 SELF EMULSIFYING DRUG DELIVERY new drugs. Poor oral bioavailability affects the drugs perfor SYSTEM FOR A CURCUMINOID BASED mance and leads to inter and intra patient variability. A num COMPOSITION ber of chemotherapeutic as well as chemopreventive agents suffer from poor oral bioavailability rendering them unsuit FIELD OF INVENTION able for oral delivery. Oral bioavailability depends primarily on–Drug permeability, Aqueous , Dissolution rate, The present invention relates to a pharmaceutical compo Presystemic metabolism, First-pass metabolism and Suscep sition comprising curcuminoid as a self emulsifying drug tibility to efflux mechanisms. Of these low permeability and delivery formulation and the method of preparation thereof. poor solubility are the most common causes of poor oral The pharmaceutical composition of the present invention 10 bioavailability. shows an enhanced drug loading ability, better stability and The advances in understanding the cause of poor bioavail an improved bioavailability. ability have led to significant improvements in the design of BACKGROUND OF THE INVENTION technologies to combat these deficiencies. The strategies to 15 improve oral bioavailability can be grouped into three main Poor bioavailability of drugs has been a major limitation in groups comprising: Pro-drugs and drug conjugates, Medici the successful utilization of many therapeutic effective mol nal chemistry and Formulation design. The present invention ecules. As it happens, most of these molecules are lipophilic proposes the application offormulation design to enhance the in nature and tend to be poorly absorbed in the aqueous oral bioavailability of selected drug candidate. medium present in the Gastrointestinal (GI) tract. The prob 20 Formulation Design is often the route of choice for modi lem of poor bioavailability is at times further compounded by fying the oral bioavailability of drugs as it offers a low cost a faster elimination rate which further reduces the efficiency and rapid to these problems particularly for drug of such molecules being used as a drug target of choice. already in the market. As opposed to pro-drug and medicinal Curcuminoids, which are naturally occurring component chemistry approaches, Formulation Design does not require in the common food spice (Curcuma longa), have 25 chemical modification of the drug or creation of New Chemi been known to demonstrate wide range of therapeutic effects cal Entities. This provides considerable advantage in terms of such as anti-inflammatory, anti-oxidant, anti-proliferative reduced cost and development timeline. Poor aqueous solu and anti-angiogenic. Curcumin is the principal curcuminoid bility and dissolution rate frequently affect the oral perfor present in turmeric. Chemically, curcumin is bis-O,5-unsat mance of drugs. This issue has been successfully addressed in urated f diketone (commonly called diferuloylmethane, For 30 the art by using techniques such as, Co , Microniza mula 1). The other curcuminoids present in turmeric are, tion, Solid dispersions, , Nano-Suspensions, mainly, Bisdemethoxy curcumin and Demethoxy curcumin. Micro and Self Emulsifying Drug Delivery Sys In many cases, curcuminoid can be present solely or in com tems (SEDDS). bination with other active ingredients. Pre-formed Emulsions/Phospholipid complexes contain 35 ing the lipophilic entity have been a tried and tested method to achieve a better solubility and absorption. This generally Formula 1 involves forming “ ’ of the lipophilic entity H with the help of suitable surfactant(s). Such micelles are then O So delivered as such at the absorption site. US Patent Publication 40 US 20090324703 discloses one such curcuminoid- OCH, micelles, wherein and the compositionis provided as a micro or solid lipid nanoparticles (SLN). Such micro emulsion or SLN, no doubt, improved the absorption rate of ºc--->HO OH the lipophilic moieties at the absorption site but nevertheless 45 were only marginally better. A study by Suresh et al., (Studies In addition to its application in a wide spectrum of thera on the in vitro absorption of spice principles-curcumin, cap peutic areas, curcuminoids are also found to be safe even in saicin and piperin in rat intestine. Food Chem. Toxicol. 2007, high doses. These features make curcuminoids a potential 45 (8), 1437-42) showed that the absorption of curcumin target for developing therapies across multiple disease seg when present as micelles increased was 56% as compared to ments. Curcuminoids, however, suffer from a major disad 50 47% when present in a free form. vantage which acts as a blockade in its wider acceptance as a The advent of the Self Emulsifying Drug Delivery Systems drug moiety of choice. It is found that curcuminoids has a (SEDDS) technique witnesses a marked improvement in the reduced bioavailability within the body. This has been attrib bioavailability of the lipophilic moieties. SEDDS comprise of uted to the lipophilic nature of curcuminoids and hence its an isotropic mixture of drug, oil, surfactant and/or co-solvents poor absorption in the GI tract, rapid metabolism and quick 55 which upon oral administration gets emulsified in the aque elimination from the body. It was found, for example, by ous media in the GI tract. The distinguishing feature of Rabindranath et al., (Absorption and tissue distribution of SEDDS is its ability to emulsify spontaneously to produce in rat. Toxicology, 1980 16(3), 259-265) that after fine oil-in- emulsions when introduced into an aqueous oral administration of 400 mg of curcumins to rats, no cur phase under gentle agitation. The resulting oil-in-water emul cumin was found in heart blood whereas a trace amount was 60 sion is thermodynamically stable due to the relatively small found in the portal blood from 15 minute to 24 hour after the volume of the dispersed oil phase, the narrow range of droplet administration of curcumin. size distribution and the polarity of the oil droplets (Groves M Oral administration is regarded as the preferred route of J, Degalindez D A, The self-emulsifying action of mixed drug intake offering numerous advantages including conve surfactants in oil, Acta Pharm Suec, 13, 1976, 361-372). The nience, ease of compliance, potential for availability to large 65 oil-in-water emulsion shows higher absorption in the GI tract. patent population and cost effectiveness. Thus oral bioavail This approach has found a general acceptance for the lipo ability is a key factor in lead selection and development of philic drugs that suffer from poor absorption rates. The US 8,835,509 B2 3 4 SEDDS approach is being successfully followed in commer It is yet another object of the invention to provide a drug cially available formulations containing cyclosporin A, delivery system for a curcuminoid based pharmaceutical ritonavir and squinavir. composition that has a curcuminoid loading capability more The success of the self emulsifying technique in increasing than 3%. the bioavailability of the drug depends on the oil-surfactant It is an object of the invention to provide a drug delivery pair, surfactant and the temperature at which system for a curcuminoid based pharmaceutical composition self emulsification occurs. It is also widely understood that that does not require the use of a polymeric molecular aggre the droplet size also plays a key role in determining the gation inhibitor to maintain the stability of the composition. absorption rate and hence the overall bioavailability of the It is an object of the invention to provide a drug delivery drug molecule, as a small droplet size provides a large inter 10 system for a curcuminoid based pharmaceutical composition facial area for its absorption. that uses a surfactant which does not cause the curcuminoid to With the recent developments in nanotechnology, oil drop precipitate out of the aqueous medium once the nano emul lets of nano dimensions have been achieved. These nano sized sion is formed. oil droplets are more effective in increasing the bioavailabil 15 ity of the drug molecule, courtesy their size. These drug SUMMARY OF THE INVENTION delivery systems are called Self Nano Emulsifying Drug The present invention discloses a pharmaceutical compo Delivery System (SNEEDS). SEDDS now represent a broad sition in the form of self nano emulsifying drug delivery category typically encompassing emulsions with a droplet formulation comprising curcuminoids. The pharmaceutical size ranging between a few nanometers to several microns, 20 composition of the present invention shows an enhanced drug while SNEDDS is used specifically where oil droplets are loading capability, better stability and an improved bioavail below 150 nm in size. ability. The composition of the present invention comprises of WO2008154705 discloses a curcumin based pre formed a pharmaceutically effective amount of a curcuminoid, an oil nanoemulsion for targeted delivery of a nano-shell containing phase, a surfactant and a co surfactant. the active ingredient. The ’705 published application, how 25 ever, does not contemplate any use of a self emulsifying drug BRIEF DESCRIPTION OF THE FIGURES delivery system. WO2010010431 discloses a self nano emulsifying cur FIG. 1 illustrates the plasma concentration-time profiles cuminoid formulation. The "431 publication discloses use of obtained after oral administration of the self nano emulsify surfactants that invariably cause the active ingredient, cur 30 ing formulation of Example 1 (blue) of the present invention cuminoid, to precipitate out of the aqueous medium even after with the aqueous suspension (Suspension A, Control). Con half an hour of formation of the self emulsifying formulation. centration in ng/mL To combat this, the "431 publication further teaches the use of FIG. 2 illustrates the solubility of Curcumin in surfactants. a polymeric molecular aggregation inhibitor, specifically Hydroxypropyl methyl cellulose (HPMC), in the formula 35 DETAILED DESCRIPTION OF THE INVENTION tion. As is widely known in the art, adding HPMC has its own disadvantages, prominent being the tendency of undissolved The present invention describes a pharmaceutical compo HPMC in an aqueous medium to form lumps. The undis sition comprising curcuminoids as a self nano emulsifying solved HPMC is present in the medium even after protracted drug delivery formulation with an enhanced drug loading periods of agitation, thus the problem of lump formation 40 capability, better stability and an improved bioavailability. poses a serious risk to the stability of the formulation. The In an embodiment, the pharmaceutical composition of the formulation of '431 publication, thus, suffers from an inher present invention comprises of a pharmaceutically effective ent disadvantage of their choice of surfactant and then adding amount of the curcuminoid, an oil phase, a surfactant and a an extra additive to address that disadvantage. co-surfactant It is, therefore, a need in the art to develop a self emulsify 45 In another embodiment of the present invention, the ing curcuminoid composition which has an enhanced drug amount of curcuminoid is about 1% to 10% (w/w), preferably loading ability as well as an increased bioavailability and between 4% and 8% (w/w), most preferably between 5% to better stability. Further, a self emulsifying curcuminoid com 6% (w/w) of the composition. position of such nature must also be able to address the In an embodiment, the pharmaceutical composition of the lacunas present in the existing art, specifically as elaborated 50 present invention comprises of: in the preceding paragraphs. Further, it would be desirable 5-6% (w/w) of the curcuminoid; that such a composition is based on creating a nano emulsion 25-33% (w/w) of the oil phase; at the absorption site so as to markedly increase the absorp 35-45% (w/w) of the surfactant, and tion efficiency. 8-16% (w/w) of the co surfactant, 55 In a preferred embodiment, the curcuminoid is curcumin. OBJECT OF THE INVENTION In an embodiment, the oil phase of the composition of the present invention can be selected from a group comprising, It is an object of the invention to provide a drug delivery propylene glycol esters, medium chain mono-, di-, or triglyc system for a curcuminoid based pharmaceutical composition. erides, long chain fatty acids, edible , or a mixture thereof. It is an object of the invention to provide a stable drug 60 In a preferred embodiment, the oil phase is selected from delivery system for a curcuminoid based pharmaceutical commercially available oils including, but not limited to, composition which results in an increased bioavailability of CAPTEXR 100 (Propylene Glycol Dicaprate), CAPTEXR curcuminoid. 300 (Glyceryl Tricaprylate/Tricaprate), CAPTEXR 355 It is an object of the invention to provide a drug delivery (Glyceryl Tricaprylate/Tricaprate), MIGLYOLR 810 (Ca system for a curcuminoid based pharmaceutical composition 65 prylic/Capric Triglyceride), MIGLYOLR 812 (Caprylic/Ca that spontaneously forms a nano-emulsion after coming in pric Triglyceride), MIGLYOLR 818 (Caprylic/Capric/Li contact with the gastric fluid. noleic Triglyceride), MIGLYOLR, 829 (Caprylic/Capric/ US 8,835,509 B2 5 6 Succinic Triglyceride), and DYNACERINR 660 (Oley] 600), propylene glycol derivatives, and commercially avail Erucate), CAPRYOLTM 90, CAPTEXR 200 (Propylene Gly able products like TRANSCUTOLR) (diethylene glycol col Dicaprylocaprate) and MIGLYOLR 840 (Propylene Gly monoethyl ether), CAPRYOLTM (Propylene glycol monoca col Dicaprylate/Dicaprate), and the like. In another embodi prylate-Type I), CAPRYOLTM 90 (propylene glycol monoca ment, the oil phase is selected from a group comprising edible prylate-Type II), CAPMULR (glyceryl caprylate), TETRA oils. In a preferred embodiment the edible oil is selected from GLYCOLTM (tetrahydrofurfuryl diethylene glycol ether), a group comprising soyabean oil, castor oil, cottonseed oil, LABRAFILR (Polyglycosyl glycerides), LUTROLR F68 Arachis oil, sesame oil, sweet orange oil, canola oil, sun (polaxomer 188), CARBITOLTM (diethylene glycol monoet flower seed oil, peanut oil, rapeseed oil, and oleic acid. The hyl ether) and the like. In a preferred embodiment, the co active medicament generally has greater solubility in com 10 surfactant is polyethylene glycol (PEG) with molecular mercially available oil phases, and therefore, they are pre weight of 200, commonly known as PEG-200. In an embodi ferred over edible oils. In a most preferred embodiment, the ment, the co-surfactants of the present invention also act as oil phase is propylene glycol monocaprylate, commercially solubilizers in the resulting composition. available as CAPRYOLTM 90. In an embodiment, the oil In an embodiment, the composition of the present inven phase also acts as a co surfactant in the composition. The 15 tion can comprise additives conventionally used for preparing Hydrophilic-Lipophilic Balance (HLB) of the oil phase is pharmaceutical formulations. These can include pH buffers, between 2 and 10, more preferably between 4 and 8. The HLB gelling agents, and stabilizing components. In an embodi value provides a means for ranking surfactants based on the ment, the pH buffer is selected from a group comprising balance between the hydrophilic and lipophilic portions of acetic acid, glacial acetic acid, lactic acid, citric acid, phos the surfactant or emulsifying agent. The higher the HLB 20 phoric acid, carbonic acid, histidine, glycine, barbital, number, the more hydrophilic the surfactant or emulsifying phthalic acid, adipic acid, ascorbic acid, maleic acid, succinic agent. acid, tartaric acid, glutamic acid, benzoic acid, aspartic acid, In an embodiment, the surfactants of the composition of the and salts (e.g., potassium, sodium, etc.) or combinations present invention are selected from ionic or non ionic surfac thereof. tants. 25 In an embodiment, the gelling agent is selected from a In a preferred embodiment, the surfactants used in the group comprising of xanthan gum, carrageenan, locust bean present invention comprise non-ionic surfactants. In yet gum, guar gum, modified celluloses, low-esterified pectines, another embodiment, the non-ionic surfactants are selected and colloidal silicon dioxide. In a preferred embodiment, the from a group comprising polyoxyethylene products of hydro gelling agent is colloidal silicon dioxide, commercially avail genated vegetable oils, polyethoxylated castor oils or poly 30 able as Aerosil. ethoxylated hydrogenated castor oil, polyoxyethylene-sorbi In an embodiment, the stabilizing component of the for tan-fatty acid esters, polyoxyethylene castor oil derivatives or mulation is selected from a group comprising of O-toco a combination thereof. These are commercially available as pherol, ascorbyl palmitate, BHT (butyl hydroxytoluene), CREMOPHORR (From BASF) such as CREMOPHORR BHA (butyl hydroxyanisole), propyl gallate or malic acid. EL (PEG-35 castor oil), CREMOPHORR. RH40 (PEG-40 35 The curcuminoid composition of the present invention hydrogenated castor oil), CREMOPHORR. RH60 (PEG-60 forms an oil/water nanoemulsion instantaneously when hydrogenated castor oil), LABRASOLR (PEG-8 Caprylic/ brought into contact with the aqueous medium of the GI tract Capric Glycerides), GELUCIRE(R) (Stearoyl polyoxylglycer with mild agitation provided by gastric mobility in the tract ides), Polysorbates, PLURONICR) L-64 and L-127 (block region. The formation of nanoemulsion leads to a superior copolymers based on ethylene oxide and propylene oxide), 40 absorption and enhanced bioavailability of the curcuminoid TRITONTM X 100 (Polyethylene glycol tert-octylphenyl enabling reduction in dose, more consistent temporal profiles ether), SIMULSOLTM (polyoxyethylated products compris of drug absorption, and protection of drugs from the hostile ing Polyoxyethylated lauric alcohol, Polyoxyethylated ceto environment in gut. stearyl alcohol, Polyoxyethylated stearic acid and the like) In a preferred embodiment, the droplet size of the compo NIKKOLTM HCO-50 (Polyoxyethylene (50) hydrogenated 45 sition of the present invention is 60-150 nm. The composition castor oil), NIKKOLTM HCO-35 (Polyoxyethylene (35) of the present invention, by virtue of its choice of surfactants, hydrogenated castor oil), NIKKOLTM HCO-40 (Polyoxyeth does not lead to any precipitation of the active ingredient, and ylene (40) hydrogenated castor oil), NIKKOLTM HCO-60 subsequently also does away with the use of any polymeric (Polyoxyethylene (60) hydrogenated castor oil) (From Nikko molecular aggression inhibitors, thus providing a composi Chemicals Co. Ltd.), and TWEENSR (Polysorbates) (From 50 tion that is effective and stable over a wide period of time. ICI Chemicals). In a preferred embodiment, the surfactant is Further, a stable self nano emulsifying composition with a CREMOPHORREL. In yet another embodiment, the surfac curcuminoid loading ability of around more than 3%, hitherto tant has a HLB between 9 and 18 and more preferably unachieved, is a marked advancement over the existing art between 11 and 16. and paves way for further research and development on cur The surfactant is capable of forming a stable emulsion, 55 cuminoids as a better, safer and efficient drug of choice. preferably a fine emulsion and more preferably a nanoemul The curcuminoid composition of the present invention is sion, of the present composition when it is brought into con ideal for oral delivery systems, since they are homogeneous, tact with aqueous fluid, such as in the G.I. tract. The surfactant thermodynamically stable, have uniform droplet sizes, and of the present invention does not precipitate out the active are optically clear. The curcuminoid composition of the ingredient curcuminoid from the emulsion, and hence offers 60 present invention can be administered in the form of liquid or better stability of the formulation than the existing art. It also solid dosage form. In an embodiment, when administered as does away with the use of polymeric molecular aggregation a liquid dosage form, the composition is filled in hard or soft inhibitors, as used in the existing art, to avoid the formation of gelatin capsules. curcuminoid precipitation. Oral unit dosage forms in accordance with the present In an embodiment, the co-surfactants of the present inven 65 invention will suitably comprise from 5 to 400 mg and more tion is selected from a group comprising polyethylene glycol preferably from 20 to 200 mg of the curcuminoid. The dosage chain lengths (preferably having a molecular weight of 200 to of the drug and the number of times it is administered to the US 8,835,509 B2 7 8 patient will vary depending on several factors including but be apparent to those skilled in the art. Such changes and not limited to the age of the patient, the severity of the con modifications may be made without departing from the scope dition of the patient, past medical history, among other fac of the invention. tors, and will be determined by the physician in his sound discretion. Example 1 The composition of the present invention are preferably administered to mammals, such as dog, cat, horse, pig, mice, Self Nano Emulsifying Drug Delivery Formulation rat and especially humans. When the composition of the (SNEEDS) present invention is prepared in the form of a soft or hard capsule, the composition may be encapsulated in a gelatin 10 shell which contains any conventional plasticizer. Preferably, Component Composition (in 9% w/w) the plasticizer is selected from a group consisting of glycer CREMOPHOR(R) EL 40.98 ine, sorbitol, hexanetriol propylene carbonate, hexane glycol, CAPRYOLTM 90 28.82 sorbitans, tetrahydrofuryl alcohol ether, diethylene glycol 15 TRANSCUTOL(R) HP 11.03 monoethyl ether, 1,3-trimethyl-2-imidazolidone, and dim PEG 200 13.59 ethylisosorbide Curcuminoid 5.58 The composition of the present invention can be adsorbed on silicates/microcrystalline cellulose and subsequently Procedure of Preparation: 20 a) Curcuminoid was added to CAPRYOLTM 90 to form a compressed into tablets. dispersion; The pharmaceutical compositions of the present invention b) CREMOPHORR EL was added to the dispersion were prepared by the following steps: formed in Step (a): a) Curcuminoid was added to CAPRYOLTM 90 to form a c) TRANSCUTOLR HP was added to the dispersion dispersion; 25 formed in Step (b) d) PEG 200 was added to the dispersion formed in Step (c) b) CREMOPHORR EL was added to the dispersion e) The dispersion obtained from Step (d) was ready for formed in Step (a): encapsulation and was filled in hard gelatin capsules. c) TRANSCUTOLR HP was added to the dispersion formed in Step (b) 30 Example 2 d) PEG 200 was added to the dispersion formed in Step (c) e) The dispersion obtained from Step (d) was ready for Self Nano Emulsifying Drug Delivery Formulation encapsulation and was filled in hard/soft gelatin cap sules. 35 The present invention provides a drug delivery system for Component Composition (in 9% w/w) a curcuminoid based pharmaceutical composition. CREMOPHOR(R) EL 42.36 The present invention provides a stable drug delivery sys CAPRYOLTM 90 30.35 tem for a curcuminoid based pharmaceutical composition TRANSCUTOL(R) HP 10.46 which results in an increased bioavailability and curcumi 40 PEG 200 13.59 noid. Curcuminoid 3.24 The present invention provides a drug delivery system for a curcuminoid based pharmaceutical composition that spon taneously forms a nano-emulsion after coming in contact Example 3 45 with the gastric fluid. Self Nano Emulsifying Drug Delivery Formulation The present invention provides a drug delivery system for a curcuminoid based pharmaceutical composition that has a curcuminoid loading capability of more than 3%. The present invention provides a drug delivery system for 50 Component Composition (in 9% w/w) a curcuminoid based pharmaceutical composition that does CREMOPHOR(R) EL 46.32 not require the use of a polymeric molecular aggregation CAPRYOLTM 90 25.28 inhibitor to maintain the stability of the composition. TRANSCUTOL(R) HP 11.03 PEG 200 12.25 The present invention provides a drug delivery system for Curcuminoid 5.12 a curcuminoid based pharmaceutical composition that uses a 55 surfactant which does not cause the curcuminoid to precipi tate out of the aqueous medium once the nano emulsion is formed. Example 4

60 Self Nano Emulsifying Drug Delivery Formulation EXAMPLES The present invention is further explained in the form of following examples. However it is to be understood that the Component Composition (in 9% w/w) foregoing examples are merely illustrative and are not to be 65 CREMOPHOR(R) EL 39.73 taken as limitations upon the scope of the invention. Various CAPRYOLTM 90 24.90 changes and modifications to the disclosed embodiments will US 8,835,509 B2 10 -continued TABLE 2 Component Composition (in 9% w/w) Solubility of Curcumin in surfactants TRANSCUTOL(R) HP 14.32 Surfactant (used in PEG 200 14.84 100% conc) Sol (mg/mL) Curcuminoid 6.21 TRANSCUTOL(R) HP 96.400 CREMOPHOR(R) RH 38.710 CREMOPHOR(R) EL 36.621 Example 5 PEG 200 1.045 10 LABRASOL(R) 0.846 PEG 400 0.512 Self Nano Emulsifying Drug Delivery Formulation TWEENR) 80 0.484 PEG 600 0.123 TWEENR) 60 0.034

Component Composition (in 9% w/w) 15 CREMOPHOR(R) EL 38.71 TABLE 3 CAPRYOLTM 90 28.51 TRANSCUTOL(R) HP 11.03 Solubility of Curcumin in milk. BSA and Casein PEG 200 16.32 Curcuminoid 5.43 20 Solubility mg/mL Milk 23.776 BSA 0.024 Procedure of preparation of Examples 2 to 5: Same proce Casein 0.014 dure was followed in Example 2-5 as given for Example 1. Example 6 25 Example 7 Solubility Test In Vivo Activity of Self-Emulsifying Self Nano The solubility of curcumin in a number of oils such as 30 citronella oil, castor oil, ethyl oleate, and palm rose oil, coco Emulsifying Drug Delivery Formulation nut oil, CAPRYOLTM 90 and a number of surfactants such as TWEENR 80, CREMOPHORR) EL, PEG 200 and TRAN Tests were carried out to compare bioavailability of cur SCUTOLR) HP were determined in order to find out the cumin after oral administration of the self nano emulsifying appropriate oils and surfactants as compositions of SNEDDS. 35 formulation of Example 1 of the present invention with the Solubility was also determined in milk, BSA and casein. aqueous suspension (Suspension A). An excess amount of curcumin was added to 5 ml of oil or Twenty animals were fasted overnight. Ten animals (5 surfactant . The resultant mixture was shaken recip Males and 5 Females) were administered orally Y mL For rocally at 37°C. for 72 h, followed by centrifugation at 12000 mulation A using rat feeding tube which was subsequently rpm for 10 min. The supernatant was filtered through a mem 40 followed by feeding them 1 mL of water using rat feeding brane filter (0.45 pum) to remove the remaining insoluble tube and ten animals (5 Males and 5 Females) were adminis curcumin. After the appropriate dilution with methanol, the tered Z mL Suspension A of Curcumin. Dose selected in both drug concentration in the filtrate was quantified by HPLC. test and control rats was 180 mg/kg body weight. Blood The results of the solubility test are provided in Table 1, 2 and samples (0.5 mL) were withdrawn from the retro orbital 3 and FIG. 2. 45 plexus of rats at following time points 0, 0.25, 0.5, 1, 2 h, 3 h, 4 h, 6 h, 8 h and 10 h using heparinised rat bleeding capillary. TABLE 1 Blank samples were taken in the same way in the beginning without administering rat with any drug and was coded BL Solubility of Curcumin in oils Plasma was extracted (by centrifuging blood samples at Oil Sol (mg/mL) 50 3000 rpm for 8 min) from blood Samples and suitably diluted Citronella 13.204 which was subsequently analyzed on LC/MS CAPRYOLTM 90 7.575 Palm Rose 6.033 TABLE 4 Castor 4.420 Labrafilm F2125 3.593 55 Rats administered with Suspension of curcumin (CONTROL Lavender 3.445 Lauroglycol 2.613 S. No Weight of Rats Dose administered (Z mL) Labrafilm F 1944 2.562 Cocconut Oil 1.683 1. 210 2.057 Emu oil 1.585 2. 225 2.205 Almond 1.250 3. 210 2.057 PM 1.128 60 4. 200 1.959 Ethyl Oleate 0.589 5. 190 1.862 Oilve 0.501 6. 225 2.205 Linseed Oil 0.277 7. 220 2.1.56 Arachis Oil 0.160 8. 325 3.185 Glyc Mono ol 0.154 9. 300 2.939 Light Paraffin 0.007 65 10. 300 2.939

US 8,835,509 B2 13 14 tions. SNEDDS containing 60 mg of curcumin was filled in one or more co-surfactant(s) present in a range of 8-16% hard gelatin capsules and introduced into 500 ml of a disso (w/w), wherein said co surfactant(s) is/are different from lution medium and maintained at 37°C. in USPII dissolution said surfactant; apparatus using Japanese sinkers. The revolution speed of the further wherein said composition is substantially free of paddle was kept constant at 100 rpm. The aliquot of 5 ml was polymeric molecular aggregation inhibitor; withdrawn at 0, 10, 20, 30, 50 and 60 min, and filtered through further wherein said pharmaceutical composition sponta 0.45 pum membrane filters. The concentration of curcumin neously forms a nano emulsion when brought in contact was determined spectrophotometrically at 423 mm. The with an aqueous fluid of human gastrointestinal tract; removed volume was replaced each time with 5 ml of fresh further wherein said composition at 40° C./75 relative medium. The dissolution of each capsule is calculated and the 10 humidity is stable for at least 6 months; results are shown in Table 10. further wherein said composition has drug loading capa bility of more than 3%; and TABLE 10 further wherein said composition has at least 8 fold increase in Cmax and at least 4 fold increase in AUC as Results of the Dissolution Study compared to curcuminoid aqueous suspension. 15 2. The system as claimed in claim 1, wherein said curcumi % drug released noid is Curcumin. Time 4.5 Acetate 6.8 Phosphate 3. The system as claimed in claim 1, wherein said surfac (min) 0.1N HCI buffer buffer tant is a non-ionic surfactant and selected from a group con sisting of polyoxyethylene products of hydrogenated veg O O O O 20 10 83.5 83 82 etable oils, polyethoxylated castor oils or polyethoxylated 20 96.8 96.4 95.7 hydrogenated castor oil, polyoxyethylene-Sorbitan-fatty acid 30 99.5 99.2 98.6 esters, polyoxyethylene castor oil derivatives or a combina 45 99.7 99.5 99.3 tion thereof. 60 100 100 100 4. The system as claimed in claim 1, wherein said co 25 surfactant is selected from a group consisting of polyethylene We claim: glycol, diethylene glycol monoethylether, glyceryl caprylate, 1. A self-emulsifying drug delivery system for a pharma tetrahydrofurfuryl diethylene glycol ether, polyglycosyl ceutical composition, said system comprising, glycerides, polaxomer 188 and diethylene glycol monoethyl ether. a pharmaceutically effective amount of curcuminoid 30 present in a range of 1-10% (w/w); 5. The system as claimed in claim 1, wherein said pharma an oil phase wherein said oil phase is propylene glycol ceutical composition is in an oral dosage form and further monocaprylate present in a range of 25-33% (w/w); comprises of pharmaceutically acceptable additives selected a surfactant, wherein said surfactant is a polyoxyethylene from a group comprising of pH buffers, gelling agents, and or polyethoxyl derivative of a vegetable oil present in a 35 stabilizing components and their combinations thereof. range of 35-45% (w/w);