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Spray Dried Granulates Of Curcuminoids

Abstract: The present invention relates* to spray dried granulate of curcuminoids and process for preparation thereof. The spray dried granulates have enhanced aqueous solubility and are useful in the preparation of various pharmaceutical and nutraceutical compositions.

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Patent Information

Application #
Filing Date
07 October 2015
Publication Number
17/2017
Publication Type
INA
Invention Field
CHEMICAL
Status
Email
Parent Application

Applicants

AUROBINDO PHARMA LTD
THE WATER MARK BUILDING, PLOT NO. 11, SURVEY NO. 9, KONDAPUR , HITECH CITY, HYDERABAD - 500 084,

Inventors

1. BRAHMESWARA RAO GUDE
AUROBINDO PHARMA LTD, THE WATER MARK BUILDING, PLOT NO. 11, SURVEY NO. 9, KONDAPUR , HITECH CITY, HYDERABAD - 500 084,
2. GIRISH GUPTA
AUROBINDO PHARMA LTD, THE WATER MARK BUILDING, PLOT NO. 11, SURVEY NO. 9, KONDAPUR , HITECH CITY, HYDERABAD - 500 084,
3. MEENAKSHISUNDERAM SIVAKUMARAN
AUROBINDO PHARMA LTD, THE WATER MARK BUILDING, PLOT NO. 11, SURVEY NO. 9, KONDAPUR , HITECH CITY, HYDERABAD - 500 084,

Specification

FIELD OF THE INVENTION The present invention relates to a spray dried granulate, of curcuminoids and process for preparation thereof. The present invention relates to a spray dried granulate of curcumin and process for preparation thereof. The present invention also relates to process for making a spray dried granulate of curcuminoid. The present invention also relates to compositions comprising a spray dried granulate of >, curcuminoid and process of preparation thereof. The present invention also relates to nutraceutical and pharmaceutical compositions comprising a spray dried granulate of curcuminoid and process of preparation thereof. The present . invention relates to compositions comprising spray dried granulate of curcuminoid which exhibit an enhanced solubility profile. The present invention relates to use of spray dried granulate of curcuminoid and compositions thereof, for making nutraceuticals such as beverages and energy drinks, and pharmaceutical preparations such as colorant for tablet coating, tablets, capsules, liquids, etc. BACKGROUND OF INVENTION The interest in turmeric and its molecular components is rising. Curcumin in particular has become an important focus of pharmaceutical development. A June 2011 report stated that 61 clinical trials registered with the U.S. National Institutes of Health were completed or . underway on the use of dietary curcumin in treating a variety of clinical disorders. Turmeric is a curry spice obtained from the rhizome of Curcuma longa of the ginger family, and has a long history of use in ayurvedic medicine and in traditional Asian diets. The :. N Jrinc^H F Bi6afiiveC Wcfe^lJcMefttl of QtiSineticQv>is2 fp^rcymin ^(l,7--bis[4-hydroxy-3- methoxyphenyl]-l,6-heptadiene-3,5-dione), a yellow pigment first identified in 1910. Curcumin is used widely in the United States for food coloring (e.g, in mustard, cheese, . spices, cereals, potato flakes, soups, pickles, ice cream, and yogurt), but also as a nutraceutical. The rhizomes of Curcuma longa (turmeric) also contain minor amounts of oils and resins such as sesquiterpenes (ketones and' alcohols;- alpha-turmerone, beta-turmerone, curlon, zingiberene, ar-turmerone, turmenorol A and turmenorol B. Curcumin is obtained by extraction with solvent from the rhizome of Curcuma longa dried, and the extract must be separated from the flavourings i.e purification by crystallisation. It is accompanied by small amounts of its demethoxy- and bis-demethoxy-derivatives, i.e. derivatives which lack one or both -OCH3 groups. The product obtained is liposoluble, with a bright greenish-yellow colour. Structurally curcumin exists as a tautomer; the enol form tends to predominate both in solution and in the solid phase. Commercial curcumin contains curcumin itself (77%), desmethoxycurcumin (DMC, 17%) and bisdesmethoxycurcumin (BDMC, 3%); the latter two differ from curcumin only by lacking one or both methoxy groups, respectively. As a group these compounds and their derivatives for pharmaceutical use are referred to as curcuminoids. Among the major cellular metabolites of these three compounds are the tetrahydrocurcuminoids, in which both vinylidene groups are reduced, i.e., THC (i.e., tetrahydrocurcumin), TDMC and TBDMC. The tetrahydrocurcuminoids retain the bioactivity but are colorless and more chemically stable than the curcuminoids; In order to have curcumin be suitable for dietary use, the sum of the curcumin and the demethoxylated derivatives thereof must be not less than 90% of the total weight. Curcumin's medicinal properties include substantial effects that are antioxidative, anti-inflammatory, antiviral, antibacterial and antifungal, and it is safe for human consumption even at the level of 8 g/day ingestion for sustained periods. Studies have shown that to varying degrees curcumin promotes wound healing and has therapeutic and or preventive effects against diabetes, asthma, allergies, cataracts, atherosclerosis, Alzheimer's disease, Parkinson's disease, myelodysplastic syndromes, cystic fibrosis, myocardial infarctions, high cholesterol, stroke, malaria, HIV, HSV-1, psoriasis, and others. Among the diseases for which curcumin has ameliorative effects are autoimmune diseases, including multiple sclerosis, rheumatoid arthritis, psoriasis, inflammatory bowel disease, Sjogren's syndrome, systemic lupus erythematosus, type I diabetes mellitus, neurodegenerative diseases, and several types of cancer. Medicinal use of curcumin has been limited because the compound is virtually insoluble (dissolution of only ca. 600 ng/mL) in water at acidic and physiological pH and hydrolyzes rapidly at alkaline pH. Plasma concentrations from high human oral doses (8-12 g/day) of curcumin are just in the nanomolar range. Most therapeutic in vitro studies on curcumin have solubilized it in organic solvents. Those solvents include dimethylsulfoxide (DMSO), acetone and ethanol but they have limited suitability for in vivo studies themselves. Surfactants or co-. surfactants can be used to improve solubility in water, but are often undesirable for other reasons. The curcuminoids also have poor solubility in lipids. Curcumin has been solubilized by sulfation and glucuronidation; however those derivatives cannot penetrate the blood brain barrier whereas the parent compound can. And other derivatives cause concerns because their effects and side effects are not as well known. Human clinical trials demonstrate that curcumin is a poorly bioavailable molecule when taken orally i Specifically, curcumin is rapidly conjugated at hepatic and intestinal level to curcumin glucuronide and curcumin sulphate, or reduced to hexahydrocurcumin; these metabolites perform a lower biological activity than curcumin. Pharmacokinetics studies have demonstrated that if curcumin is taken at doses lower than 3.6-4 g/day, curcumin and its metabolites may be undetectable in the plasma. Scientific evidence exists that curcumin, when administered orally, tends to accumulate in the tissues of the digestive apparatus, where it performs its most interesting, proven biological and therapeutic activities. Immediate release curcumin formulations are known to be available in the market, but their active ingredient release profile is unsatisfactory because it does not guarantee homogenous release throughout the colonic tract. In view of these properties, a particularly desirable objective is colon-specific release of curcumin starting from the distal ileum with a suitable lag time until the distal part of the small intestine is reached, thus ensuring slow, gradual, constant release of the product throughout the colonic tract. WO 2013/171270 discloses gastroresistant formulations of curcumin combined with absorption promotors (chitosan, black pepper extract, N-acetylcysteine, grapefruit extract). WO 2008/059522 discloses a reservoir system based on pellets with different gastroresistant coatings. Curcumin is exemplified in a multiparticulate reservoir system which can be coated with various gastroresistant polymers, wherein hydroxypropylmethylcellulose is used to promote loading of the curcumin on the pellets, and not to modify its release, which takes place in less than 15 minutes. CN 101791298 discloses curcumin tablets coated with zein, pectin and microcrystalline cellulose for release in the colon. It is a "reservoir" formulation which, depending on the quantity of coating, produces substantially pH-independent controlled releases with the aim of reaching the distal, part of the ileum / initial part of the colon. The release mechanism is therefore regulated only by the coating and can provide controlled or delayed release, depending on the quantities of zein. The release of the active ingredient in the enteric tract, especially the colon, cannot take place gradually and constantly over time. US 5861415 discloses bioprotectant composition, method of use and extraction process of curcuminoids, method for neutralizing free radicals and for preventing the formation of free radicals in a patient, comprising administering to a patient in need of such treatment an effective amount of a composition comprising the following components: curcumin, demethoxy-curcumin, and bis^demethoxy curcumin, wherein said components are purified individually or in combination and adjusted to the following ranges: 75-81% curcumin, 15-19% demethoxy curcumin, and 2.2-6.5% bis demethoxy curcumin. US 2008/0031980 Al discloses a composition comprising 50-80 wt. % of at least one curcumin compound; 10-50 wt. % quercetin; > 3 wt. % papain; and > 3 wt. % bromelain; wBefeifi fihCc^p<£sijtjqii i^ suitable for qr^J administration to a human. US.2014/0161915 discloses a protess for solubilizing and stabilizing curcumin in an aqueous solution, comprising: (a) providing a quantity of water; (b) providing over 0.008 mg curcumin per mL water; (c) optionally providing at least 0.01 mL lower alcohol per mL of water; (d) optionally providing at least 0.01 mL polyalkyleneoxide per mL of water; (e) combining the water, curcumin and optional lower alcohol in any order and optionally with mixing; and (f) heating the combined water, curcumin and optional lower alcohol to a temperature in excess of 100%, optionally at a pressure exceeding 1 atmosphere; wherein steps (a), (b) and (c) may be done in any order, and wherein the process includes at least one of combining the lower alcohol or optional polyalkyleneoxide in step (e) and applying a pressure exceeding 1 atmosphere in step (f). US 2005/084526 Al discloses a process for the preparation of a self-dispersing or self-emulsifying immediate release tablet comprising the steps of mixing a granulation medium containing an active lipophilic substance with one or more non-swellable fillers and optional binders, granulation of said mixture into granules, drying of said granules, sieving the granules into a size below 1 mm, mixing of the granules with tableting aids, and compressing said mixture into tablets, characterized in that the granulation medium comprises an oil, a surfactant selected from the group consisting of fatty acid esters of glycerol, and fatty acid esters of polyethylene glycol, and a polar liquid. US 2011/0274809 discloses a method for masking curcumin flavor which comprises mixing curcumin with a modified starch. WO 2014/111956 discloses a sustained release curcuminoid composition comprising a * bioavailable curcumin composition and a release rate controlling excipient, wherein the bioavailable composition, of curcumin comprises a curcuminoid mixture and an added v essential oil of turmeric, and wherein the curcuminoid mixture comprises curcumin, demethoxycurcumin and bisdemethoxycurcumin, and, the added essential oil of turmeric comprises about 40 % to about 50% of ar-turmerone. US 2005/0084526 provides a process for solubilizing and stabilizing curcumin in an aqueous . solution, comprising: (a) providing a quantity of water; (b) providing over 0.008 mg ■■f 5urc#rftnFpSr fmB watepH &)\|.' ^. * .-. ' ... ,. ■ '. _ • Tapped Density: 0.3-0.6 • • Solubility: Soluble in water (up to 150 mcg/ml) • • Physical Appearance of granulate in purified water: Clear solution • • Particle Size Distribution: Retention on ASTM #60 mesh -> Not more than 5.0 % Manufacturing Process of Film coating solution: 1. Adjust pH of purified water between 3 to 5 with citric acid. 2. Dissolve HPMC E5 under stirring. 3. Dissolve Polyethylene Glycol 6000 under stirring. 4. Dissolve Sodium carboxymethylcellulose under stirring. 5. Disperse Talc under stirring. 6. Add Curcumin Spray Dried Powder under stirring to obtain the film coating solution. We claim: 1. Spray dried granulate of curcuminoid having solubility greater than about 1 mg/ml. 2. Spray dried granulate of curcuminoid having solubility greater than about 10 mg/ml. 3. Spray dried granulate according to claim 1 and 2, wherein the said curcuminoid is curcumin. 4. Spray dried granulate of curcuminoid according to claims 1-3, which is prepared by process comprising the following steps: a) Adding curcuminoid to a solvent or mixture of solvents; b) Heating the material till a clear solution is obtained; c) Adding one or more binders to the solution of step (b); d) Preparing an aqueous solution comprising one or more surfactants; e) Adding material of step (c) to the material of step (d); f) Optionally adding one or more additives to step (e); g) Spray-drying the material of step (f) to obtain the spray dried granulate; and h) Optionally sifting the material of step (g) before filling into suitable pack. 5. The solvent according to claim 4, which is selected from a group comprising ethanol, dichloromethane and mixtures thereof. 6. The surfactant according to claim 4, which is selected from a group comprisin sodium lauryl sulfate, fatty acid esters of glycerol, fatty acid esters of polyethylen glycol and mixtures thereof. 7. The'additive according, to claim 4,. which is selected from a group comprisin diluents, glidants, anti-adherents, lubricants and mixtures thereof. 8. The binder according to claim 4, which is selected from a group comprisin polyvinylpyrrolidone, , cross-linked polyvinylpyrrolidone, cellulose gums pregelatinized starch, acacia, guar gum, alginic acid, carbomer, dextrin, maltodextri 9. The glidant according to claim 6, which is selected from a group1 comprising talc, colloidal silicon dioxide, corn starch, and mixtures thereof. 10. Compositions comprising spray dried granulate of curcuminoid according to any of the preceding claims 1-9.

Documents

Application Documents

# Name Date
1 5359-CHE-2015-Other Patent Document-071015.pdf 2015-10-24
2 5359-CHE-2015-Form 2(Title Page)-071015.pdf 2015-10-24
3 5359-CHE-2015-Form 1-071015.pdf 2015-10-24
4 5359-CHE-2015-OTHERS-191015.pdf 2016-03-22
5 5359-CHE-2015-Form 1-191015.pdf 2016-03-22
6 5359-CHE-2015-Correspondence-191015.pdf 2016-03-22
7 Form5_After PS_07-10-2016.pdf 2016-10-07
8 Form2 Title Page_Complete_07-10-2016.pdf 2016-10-07
9 Description Complete_After PS_07-10-2016.pdf 2016-10-07
10 Correspondence by Applicant_CS After PS_07-10-2016.pdf 2016-10-07
11 Claims_After PS_07-10-2016.pdf 2016-10-07
12 Abstract_After PS_07-10-2016.pdf 2016-10-07
13 Form5_After Filling_17-10-2016.pdf 2016-10-17
14 Correspondence by Applicant_After Filling_17-10-2016.pdf 2016-10-17
15 Claims_Signature Page_17-10-2016.pdf 2016-10-17
16 Form 3_After PS_27-03-2017.pdf 2017-03-27
17 Correspondence by Applicant_Form 3_27-03-2017.pdf 2017-03-27