DESC:FORM 2
THE PATENTS ACT 1970
39 of 1970
&
The Patent Rules 2003
COMPLETE SPECIFICATION
(See sections 10 & rule 13)

WATER MISCIBLE LIQUID CURCUMIN FORMULATION AND PREPARATION THEREOF
1. APPLICANTS (S)
(a) NAME (b) NATIONALITY (c) ADDRESS

SRI KRISHNA PHARMACEUTICALS LIMITED

INDIAN
C-4, INDUSTRIAL AREA, UPPAL, HYDERABAD – 500 039, TELANGANA, INDIA.
2. PREAMBLE TO THE DESCRIPTION

COMPLETE SPECIFICATION

The following specification particularly describes this invention and the manner in
which it is to be performed

WATER MISCIBLE LIQUID CURCUMIN FORMULATION AND PROCESS FOR ITS PREPARATION LIQUID

FIELD OF INVENTION:
[0001] The present invention relates to a process for preparation of water miscible liquid curcumin with complete miscibility in water.

BACKGROUND OF THE INVENTION
[0002] Turmeric is the dried rhizome of the plant Curcuma Longa L, which is used in food industry as colouring and flavouring agent. The dried turmeric rhizomes generally contain about 5-6% curcuminoids, which is principally responsible for its colouring ability.
[0003] Curcumin has also shown therapeutic potential against many diseases. Even today, Indians readily apply it on fresh wounds, chicken-pox scabs, and insect bites. Medical professionals prescribe it for urological diseases, worm infections, and even cancer. Such has been the type that the yellow-golden spice is widely touted as a validation of traditional medicine. But though there have been thousands of research papers and clinical trials disclosing that curcumin has not yet resulted in the effective alternative to medicine.
[0004] Curcumin is a crystalline compound and practically insoluble in water at pH less than 7. It is a well known fact that curcumin has low stability and bioavailability in human body as it undergoes metabolism very rapidly and results in excretion of 98% of the curcumin. The chemical properties of curcumin such as poor absorption, high first pass metabolism are few reasons that results in low bioavailability of curcumin. Enhanced stability and bioavailability of curcumin would take this promising natural product to the vanguard of therapeutic agents.
[0005] To improve the stability and bioavailability of curcumin, numerous approaches have been undertaken. In a study, curcumin has been blended with the piperine to improve stability and bioavailability of curcumin; however it causes ulceration in stomach. Another study has shown that bioavailability of curcumin can be achieved when administered in conjunction with the black pepper extract piperine in both rats and humans, although the efficacy remains controversial. In another study, curcumin has been blended with various oils to improve the bioavailability of Curcumin; however such approach would result in curcumin not being able to be used in tableting and beverage application.
[0006] Curcuminoids can be used in food / pharmaceutical and dietary supplement industry. Also Curcumin is rich in its antioxidant property and can be used as an ice tea or hot tea alone or with green tea. However due to its insoluble nature its use is limited. Water miscible curcumin can be used in the water base foods such as beverages, milk, bread, cake, etc.
[0007] WO2007103435 discloses the compositions comprising curcuminoids, antioxidant, water-soluble pharmaceutically acceptable carrier and optionally an inhibitor. The said formulation with 35% w/w curcumin resulted in improved bioavailability.
[0008] CN100352430C discloses self-micro-emulsified curcumin preparation comprising curcumin, surfactant, co-surfactant, oil phase and solid adsorbent providing self-micro-emulsified system having liquid drops with size below 100 nm. Such compositions show increase in curcumin solubility and absorption in gastrointestinal tract with higher bioavailability.
[0009] WO2010010431 discloses self nano-emulsion compositions comprising curcumin, a lipidic carrier system with a hydrophilic-lipophilic balance (HLB) between 3 to 14 and a pH buffer. The composition further comprises molecular aggregation inhibitor(s), a surface active agent and a co-solvent. The higher concentration of surfactants in the formulation is undesirable as they are likely to cause gastric irritation and gastric mucosal damage.
[00010] PCT/US2007/005829 describes Curcuminoids formulations having enhanced bioavailability are provided and comprise a curcuminoids, antioxidant, glucuronidation inhibitor, and water-soluble, pharmaceutically acceptable inhibitor.
[00011] PCT/KR2004/000529 describes a method for solubilization of curcumin and dispersion into water. The method prepares a water-soluble curcumin by covalent-bonding of sugar with the curcumin, thereby making the curcumin, which was insoluble in water, into a water-soluble curcumin.
[00012] Biji T Kurien et al have described yet another process to solubilize curcumin through the use of heat energy. (Improving the Solubility and Pharmacological Efficacy of Curcumin by Heat Treatment—ASSAY and Drug Development Technologies, Aug. 1, 2007, 5(4): 567-576. doi:10.1089/adt.2007.064)
[00013] Ce Cheng et al. have described a pH-driven, organic solvent-free process to improve the bioavailability of curcumin in liposomes.
[00014] The existing methods to increase the stability and bioavailability and solubility of curcumin, such as the thin film method and the ethanol injection methods are complex and require the use of organic solvents. Since poor stability and bioavailability of curcumin and the relatively high concentrations required for efficacy have limited its use, there is a desirability to improve the bioavailability.

OBJECTS OF THE INVENTION
[00015] An object of the invention is to provide a process for preparation of water miscible liquid curcumin.
[00016] Another object of present invention is to provide a formulation comprising water miscible liquid curcumin, wherein the concentration of curcumin is 1-20 % w/w.
[00017] Another objective of present invention is to provide an oil free process for preparation of water miscible liquid curcumin.
[00018] Another object of the present invention is to provide therapeutic agent comprising water miscible liquid curcumin.
[00019] Another object of the present invention is to provide a dietary supplement in water based food products comprising water miscible liquid curcumin.

SUMMARY OF THE INVENTION
[00020] In an aspect, the present invention provides a solvent-free and oil free process for the preparation of the water miscible liquid curcumin and improves the stability. The first step in the process for preparation of water miscible liquid curcumin is contacting a curcumin solution with at least one polymer solution. The polymer solution is preferably hydrophilic and performs the function as solubilizer. The second step in the process is the addition of at least one wetting agent and maintaining the solution at a predetermined pH to obtain the liquid curcumin of the present invention.
[00021] In an aspect of the present invention, sweeteners, flavours and antifoaming agents are added. The water miscible liquid curcumin thus obtained is further used in therapeutic agents.
[00022] In yet another aspect, the present invention provides a water miscible liquid curcumin formulation having high miscibility and stability. The formulation according to the present invention comprises curcumin, at least one polymer selected from group consisting of maltodextrin, cellulosic polymer, polyvinylpyrrolidone, guar gum, gum acacia, starch, hypromellose, sodium carboxymethyl cellulose, chitosan, pullulan or mixtures thereof. The formulation also comprises at least one wetting agent selected from a group consisting of sodium lauryl sulphate, polysorbate-20/60/80, docusate sodium, lecithin, sucrose laurate, sodium dihydrogen citrate, glyceryl monostearate, span 80, polyglycerol polyricinoleate or mixtures thereof. The formulation also comprises of at least one organic acid or salt thereof selected from a group consisting of citric acid, ascorbic acid, acetic acid, malic acid, hydrochoric acid, trisodium citrate and sulfuric acid. The formulation comprises at least one anti-foaming agent, preferably simeticone. The formulation comprises at least one preservative selected from group consisting of potassium sorbate, methyl, ethyl, propyl and butyl parabens, sorbic acid, sodium benzoate or mixtures thereof. The formulation also comprises at least one solubilizer selected form group consisting of polyethylene glycol 400, propylene glycol, glycerine or mixtures thereof. The formulation also optionally comprises of flavouring agents.
[00023] Further scope and applicability of the present invention will become apparent from the detailed description given hereinafter. However, it should be understood that the detailed description and specific examples, while indicating embodiments of the invention, are given by way of illustration only, because various changes and modifications within the spirit and scope of the invention will become apparent to those skilled in the art from this detailed description. It is to be understood that both the foregoing general description and the following detailed description are exemplary and explanatory only and are not restrictive of the invention.

DETAILED DESCRIPTION
[00024] Thus, before describing the present invention in detail, it is to be understood that this invention is not limited to particularly exemplified systems or process parameters that may of course, vary. It is also to be understood that the terminology used herein is for the purpose of describing particular embodiments of the invention only, and is not intended to limit the scope of the invention in any manner.
[00025] The use of examples anywhere in this specification including examples of any terms discussed herein is illustrative only, and in no way limits the scope and meaning of the invention or of any exemplified term. Likewise, the invention is not limited to various embodiments given in this specification.
[00026] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention pertains. In the case of conflict, the present document, including definitions will control.
[00027] It must be noted that, as used in this specification and the appended claims, the singular forms “a,” “an” and “the” include plural referents unless the content clearly dictates otherwise. Thus, for example, reference to a “polymer” may include two or more such polymers.
[00028] The terms “preferred” and “preferably” refer to embodiments of the invention that may afford certain benefits, under certain circumstances. However, other embodiments may also be preferred, under the same or other circumstances. Furthermore, the recitation of one or more preferred embodiments does not imply that other embodiments are not useful, and is not intended to exclude other embodiments from the scope of the invention.
[00029] As used herein, the terms “comprising” “including,” “having,” “containing,” “involving,” and the like are to be understood to be open-ended, i.e., to mean including but not limited to.
[00030] In order to make the matter of the invention clear and concise, the following definitions are provided for specific terms used in the following description.
[00031] In order to make the matter of the invention clear and concise, the following definitions are provided for specific terms used in the following description.
[00032] The term “Miscibility” means is the property of two substances to mix in all proportions (that is, to fully dissolve in each other at any concentration), forming a homogeneous solution.
[00033] As used herein the term ‘wetting agent’ means surface active agent which works by lowering the surface tension of water and enabling solubility of lipophilic compounds.
[00034] In an embodiment the present invention provides a solvent-free and oil free process for the preparation of the water miscible liquid curcumin having high stability. The first step in the process for preparation of water miscible liquid curcumin is contacting a curcumin solution with at least one polymer solution. The polymer solution is preferably hydrophilic. The second step in the process is the addition of at least one wetting agent and maintaining the solution at a predetermined pH to obtain the liquid curcumin of the present invention.
[00035] In an embodiment of the present invention, curcumin solution is prepared by dispersing raw curcumin in at least one polymer solution and a solubilizer. In an embodiment, the curcumin solution and polymer solution is contacted and mixed to form a homogeneous solution.
[00036] In another embodiment the polymer /solubilizer and curcumin solution was homogenized by using rotor-stator mechanism method. The particles size of curcumin is preferably maintained about in the range of 1-50 micron, preferably D-90 should be in the range of 5-15 micron.
[00037] The solubilizer is selected from group of propylene glycol, polyethylene glycol or glycerol or any other food grade solubilizer. Solubilizer can be used alone or in combination or can be used as the combined mixture. The solubilizer synergistically enhances the solubility of the curcumin.
[00038] In an embodiment, the temperature of homogenized solution is increased by passing the homogenized solution through a rotor-stator. The temperature of the homogenized solution is raised, preferably in the range of 80-90°C.
[00039] In yet another embodiment the particle size reduction is a continuous process and during process the process the temperature of mixture is maintained in the range of 80°C to 100°C.
[00040] The polymer solution is selected from a group consisting of ? polyvinylpyrrolidone, vinylpyrrolidone-vinyl acetate, hydroxypropyl methylcellulose, starch, sodium carboxymethyl, methyl cellulose, and other cellulosic derivative, gum acacia, guar gum, etc. Preferably the polymer solution used is a cellulosic polymer alone or combination of polysaccharides, cellulosic polymer along with vinylpyrolidone alone or its derivative. In yet another embodiment polymer solution used in the present invention is vinyl pyrolidone alone or its derivative. In yet another embodiment polymer solution used in the present invention is vinyl pyrolidone alone and its derivative along with addition of polysaccharides or cellulosic polymer.
[00041] The wetting agent is selected from a group consisting of sodium lauryl sulphate, polysorbate-80, polysorbate-60 and docusate sodium.
[00042] In an embodiment, maintaining the pH is facilitated by addition of addition of at least one acid regulator and at least one pH regulator. The pH regulator maintains the pH preferably in the range of about 6 to about 6.5.
[00043] The acid regulator is selected from a group consisting of acetic acid, sorbic acid, citric acid and phosphoric acid, preferably citric acid. The pH regulator is selected from a group consisting of citric acid.
[00044] In an embodiment, anti-foaming agents and flavours are added to the liquid curcumin, preferably below the temperature of 40oC.
[00045] Thus, the process of present invention is simple, economical and less time consuming, which are essential in an industrial setup.
[00046] In an embodiment, the water miscible curcumin formulation of the present invention is in the form of a gel or solution / liquid.
[00047] In an embodiment, water miscible liquid curcumin is in the form of a ready to drink beverage.
[00048] In an embodiment, the water miscible curcumin of the present invention can be used as colorant in food and food products as a natural colorant. In an embodiment, the water miscible curcumin of the present invention can be used in manufacturing of creams, gels, candy, mouthwashes, tea. etc.
[00049] The color of the water miscible curcumin of the present invention is stable for about 30 days.
[00050] The water miscible liquid curcumin thus obtained is further used in a formulation to be used as therapeutic agents.
[00051] In another embodiment, the present invention provides a water miscible liquid curcumin formulation having high miscibility and improves the stability. The formulation according to the present invention comprises curcumin, at least one polymer selected from group consisting of maltodextrin, cellulosic polymer, polyvinylpyrrolidone, guar gum, gum acacia, starch, hypromellose, sodium carboxymethyl cellulose, chitosan, pullulan or mixtures thereof. The formulation also comprises at least one wetting agent selected from a group consisting of sodium lauryl sulphate, polysorbate-20/60/80, docusate sodium, lecithin, sucrose laurate, sodium dihydrogen citrate, glyceryl monostearate, span 80, polyglycerol polyricinoleate or mixtures thereof. The formulation also comprises of at least one organic acid or salt thereof selected from a group consisting of citric acid, ascorbic acid, acetic acid, malic acid, hydrochoric acid, trisodium citrate,sulfuric acid. The formulation comprises at least one anti-foaming agent, preferably simeticone. The formulation comprises at least one preservative selected from group consisting of potassium sorbate, methyl, ethyl, propyl and butyl parabens, sorbic acid, sodium benzoate or mixtures thereof. The formulation also comprises at least one diluent selected form group consisting of polyethylene glycol 400, propylene glycol, glycerine or mixtures thereof. The formulation also optionally comprises of flavouring agents.
[00052] In an embodiment, the water miscible liquid curcumin formulation optionally comprises flavours.
[00053] In an embodiment, the concentration of curcumin in the formulation is preferably 1-20 % w/w.
The compositions of the present invention are water miscible and highly miscible. The compositions prepared by using the water miscible liquid curcumin as per the above process has shown marked increase in the miscibility of Curcumin.
WORKING EXAMPLES
EXEMPLARY FORMULATION: 1
Curcumin 60 g , Polyvinylpyrrolidone 250 g, polyethylene glycol 50 g, propylene glycol 200g , Potassium Sorbate 0.1g, Sodium Lauryl Sulphate 0.1 g, Sucrose 50 g, Simethicone 20 g. Flavor 2 g, Citric Acid 2g, Water 335.9g.
EXEMPLARY FORMULATION: 2
Curcumin 100 g , Polyvinylpyrrolidone 50 g, Polyethylene glycol 100 g, Propylene glycol 200 g , Glycerin 100 g, Potassium Sorbate 0.1g, Sodium Lauryl Sulphate 0.1 g, Sucrose 50 g, Simethicone 10 g. Flavor 2 g, Citric Acid 20 g,Water 367.8 g.
EXEMPLARY FORMULATION: 3
Curcumin 240 g , Polyvinylpyrrolidone 210 g, Polyethylene glycol 250 g, Propylene glycol 20 g , Glycerin 150 g, Potassium Sorbate 0.1g, Polysorbate 20 g, Sucrose 5 g, Simethicone 10 g. Flavor 2 g, Citric Acid 5 g ,Water 88.9 g.
EXEMPLARY FORMULATION: 4
Curcumin 60 g , Polyethylene glycol 350 g, Propylene glycol 320 g , Glycerin 150 g, Potassium Sorbate 0.1g, Polysorbate-80 50 g, Sucrose 5 g, Simethicone 10 g. Flavor 2 g, Citric Acid 10 g ,Water 42.9 g.
EXEMPLARY FORMULATION: 5
Curcumin 60 g , Polyvinylpyrrolidone 100 g, Polyethylene glycol 150 g Propylene glycol 220 g Glycerin 150 g, Potassium Sorbate 0.1g, Polysorbate-80 20 g, Sucrose 5 g, Simethicone 10 g. Flavor 2 g, Sodium Lauryl Sulphate 0.1 Citric Acid 120 , Water 162.8 g.
EXEMPLARY FORMULATION: 6
Curcumin 250 g , Polyvinylpyrrolidone 100 g, Glycerin 250 g, Potassium Sorbate 0.2 g, Sodium Lauryl Sulphate 0.1 g, Sucrose 2 g, Flavor 1.1 g, Citric Acid 100 g , Water 296.6 g.
TEST FOR STABILITY
The stability of the liquid curcumin composition of the present invention was investigated by storing the liquid curcumin (5%) of the invention at a temperature of 40±2oC at a relative humidity 75±5 %. The stability of the curcumin was observed at an interval of one month for a period of six months. From the data it is observed that, no degradation was observed in 6 months for the three batches as shown below.

Storage Condition: 40 ± 2°C / 75 ± 5% RH
Time Interval Description Assay (%) pH Remarks
Initial Reddish Orange free flowing liquid 5.37 4.58 PASS
One month Reddish Orange free flowing liquid 5.31 4.66 PASS
Two Months Reddish Orange free flowing liquid 5.64 4.67 PASS
Three Months Reddish Orange free flowing liquid 5.19 4.58 PASS
Six months Reddish Orange free flowing liquid 5.04 4.75 PASS
Storage Condition: 40 ± 2°C / 75 ± 5% RH
Time Interval Description Assay pH Remarks
Initial Reddish Orange free flowing liquid 5.36 4.55 PASS
One month Reddish Orange free flowing liquid 5.35 4.90 PASS
Two months Reddish Orange free flowing liquid 5.57 4.70 PASS
Three months Reddish Orange free flowing liquid 5.23 4.57 PASS
Six months Reddish Orange free flowing liquid 5.03 4.68 PASS
BATCH 1
BATCH 2
Storage Condition: 40 ± 2°C / 75 ± 5% RH
Time Interval Description Assay pH Remarks
Initial Reddish Orange free flowing liquid 5.42 4.46 PASS
One month Reddish Orange free flowing liquid 5.37 4.87 PASS
Two months Reddish Orange free flowing liquid 5.56 4.65 PASS
Three months Reddish Orange free flowing liquid 5.28 4.57 PASS
Six months Reddish Orange free flowing liquid 5.09 4.70 PASS
BATCH 3
,CLAIMS:We Claim:

1) A water miscible liquid curcumin composition, comprising:
curcumin;
at least one polymer;
at least one wetting agent;
at least one organic acid;
at least one anti-foaming agent;
at least one diluents; and optionally, and
at least one flavoring agent.

2) The composition as claimed in claim 1, wherein the amount of curcumin is 1-20 wt %, the amount of polymer is 0.1-90 wt %, amount of wetting agent is0.1-20 wt %, amount of organic acid is1-20 wt %, amount of anti-foaming agent is 0.1-5wt %, amount of diluent is 0.1-5 wt %.

3) The composition as claimed in claim 1, wherein the polymer is selected from group consisting of maltodextrin, cellulosic polymer, polyvinylpyrrolidone, guar gum, gum acacia, starch, hypromellose, sodium carboxymethyl cellulose, chitosan, pullulan or mixtures thereof.

4) The composition as claimed in claim 1, wherein the wetting agent is selected from a group consisting of sodium lauryl sulphate, polysorbate-20/60/80, docusate sodium, lecithin, sucrose laurate, sodium dihydrogen citrate, glyceryl monostearate, span 80, polyglycerol polyricinoleate or mixtures thereof.

5) The composition as claimed in claim 1, wherein the organic acid is selected from a group consisting of citric acid, ascorbic acid, acetic acid, malic acid, hydrochoric acid, trisodium citrate.

6) The composition as claimed in claim 1, wherein the anti-foaming agent, preferably simeticone. The formulation comprises at least one preservative selected from group consisting of potassium sorbate, methyl, ethyl, propyl and butyl parabens, sorbic acid, sodium benzoate or mixtures thereof.

7) The composition as claimed in claim 1, wherein the diluent selected form group consisting of polyethylene glycol 400, propylene glycol, glycerine or mixtures thereof.

8) The composition as claimed in any of preceding claims, wherein the viscosity of the composition is in range of 100 to 2000 Cps.

9) A process for preparation of water miscible liquid curcumin composition comprising the steps of:
(a) contacting powdered curcumin with at least one polymer solution;
(b) homogenizing the mixture of step (a) to obtain a homogenized solution;
(c) adding at least one wetting agent to homogenized solution of step (b);
(d) adding at least one pH regulator to solution of step (c); and
(e) Maintaining the solution of step (d) at a predetermined pH.

10) The process as claimed in 1, wherein the temperature of homogenized solution of step (b) is maintained in the range of 80-90oC.

Nalini Kant Pandey
Bizrights IP Partners LLP
(IN/PA 2187)
Agent for applicant(s)
DATE: 07.06.2019