FIELD OF INVENTION
The present invention pertains to pharmaceutical formulations. More specifically, it pertains to a novel formulation of Curcumin which is freely soluble in water and is proposed to have an enhanced bioavailability.
BACKGROUND OF INVENTION
Curcumin is the main phytochemical compound of Turmeric, the latter being widely used as a spice. Use of Curcumin for therapeutic purposes is well-documented in Ayurvedic medicine. Turmeric is a member of the Curcuma Botanical Group, which is a part of the Ginger family of herbs, the Zingiberaceae. The root and rhizome (underground stem) of Curcuma longa L. plant is crushed and powdered into ground Turmeric. Ground Turmeric is used worldwide as seasonings and as the main ingredient in curry. In the United States, Curcumin is used as a coloring agent in cheese, spice, mustard, cereals, pickles, ice creams, soups, potato flakes and yogurts.
Curcumin is the principal Curcuminoid of Turmeric. The other two Curcuminoid being Demethoxycurcumin and Bis-Demethoxycurcumin. Curcumin comprises of total 5% of Turmeric. Curcumin can exist in at least two tautomeric forms, Keto and enol. The enol form is more energetically stable in the solid phase and in solution. The Curcuminoids are polyphenols and are responsible for the yellow color of Turmeric. The phytochemical is pharmacologically safe'.
Curcumin is truly an incredible molecule with multiple bioactivities- It is capable of modulating the activities of a whole range of signaling pathways important in health and diseases2"8. Curcumin has been shown to have a wide variety of clinical effects in a number of research studies. Though shown to have immense potential, one of the major factors limiting widespread use of curcumin, is the poor bioavailability of the molecule. Poor bioavailability may be attributed to the hydrophobic nature of the molecule which leads to a very poor water solubility. Till date, a number of formulations are available only in solid form e.g. capsules. The inherent limitation of poor bioavailability in such formulations due to poor water solubility, naturally results in excess use of the active ingredient 'curcumin', enhancing the cost of the formulation and posing an unnecessary financial burden on the patient. Also, availability of the existing oral formulations,

only in solid form e.g. capsules prevents their use in the pediatric and geriatric segments. The present formulation of curcumin offers the following advantages, not offered by any formulation in the prior art viz.
a. Water solubility: The formulation is freely water soluble
b. Liquid form: enables use in pediatric and geriatric segments
c. Enhanced bioavailability: The formulation is proposed to have a considerably enhanced
bioavailability due to its solubility in water.
d. Cost-effectiveness: Owing to considerable increased bioavailability, the dose requirement may
be reduced.
One of the best-known therapeutic effects of curcumin is its potential in chemoprevention of cancer. It is capable of blocking the undesirable activities of a number of cytokines such as tumor necrosis factor-a (TNF-a) and interleukins which are pivotal molecules in inflammation1. It has been used in various combinations with other substances. A number of studies are present in the literature where curcumin has been used in combination with other additives.
One such example is disclosed in U.S Patent, Pub No 0093457 Al which describes a combination of curcumin and at least one NSAID. The formulation is indicated for the treatment of cancer and inflammatory disorder. The concentration of active curcumin indicated in the formulation is in an amount sufficient to reduce the amount of the NSAID needed while maintaining the same therapeutic effect as compared to administrating the NSAID alone. Unlike the present formulation the patent does not disclose a liquid formulation of curcumin alone.
Patent WO 2006/087759 A2 comprises a pharmaceutical combination of Curcumin and resveratrol. The combination has been indicated for preventing ageing and vascular disease, for the treatment and prophylaxis of cancer, such as prostate carcinoma and even skin diseases e.g. psoriasis. Here, the major emphasis is on the therapeutic properties of the combination as a whole. In contrast, the present invention is in liquid form and comprises of curcumin only.
Patent application number WO02/074319 AI describes a pharmaceutical formulation comprising of red pepper, Vanillin, Gentian root and turmeric. It further relates to the use of formulation for the treatment of cardiovascular diseases. The concentration of turmeric in a single suggested dose

is 450-550 mg along with three other ingredients. In contrast, the present invention consist of only single active ingredient i.e. curcumin.
Patent application number EP1837030A1 describes a phospholipids complex of curcumin claiming to have an improved bioavailability. Further it relates to the use of this complex in chemoprevention. However the preparation of the phospholipids complex includes complex processing and large scale production difficult.
Patent application number US 6492429 Bl describes a composition of curcumin with apocynin for the treatment of osteoarthritis. Other ingredients like bosewellic acid, glucosamine, acetylcysteine and boron enhance the beneficial effects of above combination. The formulation does not claim for its improved bioavailability and claims therapeutics benefits of the combination of apocynin with curcumin.
Patent US 4842589 describes a new composition and process for the treatment of hyperlipidemia and platelet aggregation. The composition has curcumin, aurapten, ferruic acid, Scoparone, fish oil. The formulation does not claim for its improved bioavailability and claims therapeutics affect due to combination of other ingredient with curcumin.
Patent WO2006/129323A1 describes a composition of curcumin with essential oil of turmeric claiming to have an enhanced bioavailability. The formulation disclosed is not water soluble as disclosed in the present invention.
Patent WO2005/020958 A2 describes aerosol delivery of curcumin in which curcumin is dispersed in a lipid vehicle and claimed to be of use in pathological conditions such as hyperproliferative disease, such as cancer. The formulation disclosed is not water soluble.
Patent US 4999205 describes curcumin complex with a water soluble branched chain polysaccharide or water soluble dispersible protein which is water soluble form. The above combination may use gelatin, vegetable gum, cyclodextrine propylene glycol, carboxymethyl cellulose etc in which curcumin is complexed and is in liquid form. The described formulation claims to be use as a coloring agent in food and beverage. The formulation does not claim to have high bioavailability and does not claim to cure or prevent any disease.

Patent US 04368208 describes a water soluble curcumin complex in which curcumin is mixed with gelatin in an aqueous acetic acid solution. The complex is used as a coloring agent in the food and does not claim for the cure or prevention of any disease which limits its utility.
Patent US 2002/0026886 Al describes water dispersible pigment composition of ingredients such as porphyrin pigments, carmine, curcumin and carotenoids which are dispersed in the aqueous phase. The composition is may be used as a coating composition for tablets and dragees.
Patent application numbers US 2003/0153512 Al and WO 2008/051474 describes curcumin derivatives with improved water solubility as compared to curcumin alone and also the process of chemical synthesis of such derivatives. The patents describe the linkage of curcumin with monosaccharide, oligosaccharides or polysaccharides (US 2003/0153512 Al) or linkage with polyethylene glycols (WO 2008/051474) which enhances curcumin solubility. Thus, both the patent applications disclose chemical modification of curcumin structure and claim to be of use in cancer, chronic inflammatory disease and disease associated with retrovirus infection. In contrast, the present invention does not involve modification of the curcumin structure at all. No chemical synthesis or linking of the curcumin molecule to any other soluble group is involved. Rather, enhanced solubility of curcumin in present invention is achieved in a remarkably simplified manner by use of specialized base solution (SBS) and specialized solubilizers (SS), the like of which has not been disclosed in both the applications.
US 2006/0067998 discloses a Curcumin composition in a colloidal drug delivery system,
preferably in liposomal drug delivery system and the method for the treatment of cancer including
breast cancer, pancreatic cancer and melanoma. However, in general liposomal formulations suffer
from the following limitations9 like Non specific release of the drug, pH dependence, Industrial
scale up difficult and mainly intra venous route preferred.
The present formulation is a non-liposomal formulation and hence does not have the above
limitations.
The present invention offers a number of advantages not offered by any of the existing curcumin formulations in the prior art. The advantages are as follows:

1. Enhanced Bioavailability: The single and most significant advantage of the present invention is its proposed enhanced bioavailability as compared solid curcumin or its formulation such as to tablets and capsules.
2. Easy dosage adjustment: Formulation being liquid can easily be divided as per prescription e.g. according to body weight, age etc.
3. Easy patient compliance: Still another advantage is its easy compliance for pediatric and geriatric use owing to presence in liquid form.
4. Cost-effectiveness: The higher bioavailability may result into lower dosage regime, thus contributing to cost-effectiveness.
5. Easier and simpler formulation process: The process of formulation is considerably simpler.
OBJECTS OF THE INVENTION
The main object of the present invention is to disclose an oral formulation of Curcumin which is proposed to have an enhanced bioavailability owing to its high water solubility. Another object of the invention is to disclose a liquid water soluble formulation of Curcumin.
SUMMARY OF THE INVENTION
The present invention discloses a novel water soluble formulation of curcumin which is proposed to have an enhanced bioavailability and is in a liquid form. The same has been achieved by the use of a novel combination of hydrophilic excipients which acts as specific solubilizers (SS) and a specialized base solution (SBS) for solubilizing curcumin. The formulation which is in liquid form is quite stable.
STATEMENT OF INVENTION (NOVELTY OF THE INVENTION)
A formulation of curcumin wherein the same is water soluble and comprises curcumin as the active molecule alongwith specific solubilizers (SS) and a specialized base solution (SBS).
DETAILED DESCRIPTION OF THE INVENTION
The present invention discloses a novel formulation of curcumin, proposed to have an enhanced bioavailability. The same is water soluble and comprises of curcumin as the active molecule alongwith specific solubilizers (SS) and specialized base solution (SBS).

Poor aqueous solubility of curcumin results in low bioavailability. This is one of the major challenge for a formulation scientist. A novel approach was adopted for solubility enhancement of curcumin. In this approach curcumin was first added to a specialized base solution (SBS) followed by addition of specific solubilizers (SS). This unique combination of ingredients results in a novel curcumin formulation which is freely water soluble and is proposed to have an enhanced bioavailability.
Various combinations of solubilizers were evaluated and eventually a combination of triricinoleate ester of ethoxylated glycerol, small amount of polyethylene glycol ricinoleate, the corresponding free glycol with fatty acid esters of polyoxyethylene sorbitan derivatives was found to be optimum for formulating a water soluble curcumin formulation. Further, a specialized base solution (SBS) was developed specifically for curcumin and comprised of Sorbitol, Glycerin, Propylene Glycol and Polyethylene glycol (Grades ranging from 200 to 6000) in a particular ratio. Additional stabilizing agent may be added to the formulation which includes Xanthan gum, Carbomer derivatives, sodium Carboxymethyl cellulose derivatives, Silicon dioxide, Tragacanth gum, Polyvinyl pyrrolidone derivatives with or without suitable flavours alone or in combination. An illustrative composition of the formulation is given in Table 1:
Table 1

(Table Removed)

Method of making the formulation and details of the composition of the formulation are illustrated by way of example given below:

Example 1: 2.5% Water soluble curcumin
Step 1: Add curcumin (2.5%) to the specialized base solution (SBS) and stir for 20-30 minutes at
medium speed.
Step 2: Add specific solubilizers (SS) to the composition of step 1 and again stir for 20-30 minutes
at medium speed at room temperature till a distinct viscous solution having reddish orange
appearance is obtained.
Composition of specialized base solution (SBS) for example 1 is given in Table 2
Table 2

(Table Removed)

Composition of specific solubilizers (SS) for example 1 is given in Table 3
Table 3

(Table Removed)

In the preferred embodiment, the concentration of curcumin can be easily increased e.g. upto 7% as
given in table 1. Appropriate variation in concentration of the components of SBS and SS can be
carried out to achieve a soluble curcumin formulation. Embodiments using higher curcumin
concentration, e.g. Curcumin 5% is illustrated in the example given below:
Example 2:
5% Water soluble curcumin formulation
Step 1: Add curcumin (the quantity equivalent to 5% of formulation) into the specialized base
solution (SBS) and stir for 20-30 minutes at medium speed.

Step 2: Add specific solubilizers (SS) to the composition of step 1 and again stir for 20-30 minutes at medium speed at room temperature till a distinct viscous solution having reddish orange appearance is obtained.
Composition of specialized base solution (SBS) for example 2 is given in Table 4 Table 4

(Table Removed)

Composition of specific solubilizers (SS) for example 2 is given in Table 5:
Table 5

(Table Removed)

The above detailed description discloses the method and composition of preparing a water soluble formulation of curcumin. The basic innovation lies in the unique, specialized base solution (SBS) and specific solubilizers (SS) to which curcumin is added. Depending upon the concentration of curcumin which is to be solubilized, appropriate change in the composition of solubilizers can be made as illustrated by way of example 2, in a preferred embodiment using a higher concentration of curcumin.
Once the concept of using a combination of specialized base solution and specific solubilizers as disclosed herein is understood, variations to the same using different concentration of curcumin can easily be carried out by one skilled in the art.

The pharmaceutical composition containing the water soluble curcumin may be administered orally in solid dosage form such as capsules, tablets, and powder, or in liquid dosage from, such as elixirs, syrup and suspension. It can also be administered parenterally (such as by intramuscular or intravenous injection), in sterile liquid dosage form. Furthermore, pharmaceutically composition may be administered by transmucosal delivery via solid, liquid or aerosol forms of transdermally via a patch mechanism or ointment. Various types of transmucosal. administration include respiratory tract mucosal administration, nasal mucosal administration, oral transmucosal (such as sublingual and buccal) administration and rectal transmucosal administration.
Experimental studies were carried out to determine:
a) Antioxidant activity
b) Dissolution profile
c) Stability studies
of the innovative formulation. Data obtained is discussed below.
A.) Antioxidant activity
Methodology: The antioxidant activity of the innovative formulation was determined by the DPPH
assay.
Results: The results obtained are given in Table 6
Table 6

(Table Removed)

Curcumin shows antioxidant activity in DPPH assay. The activity is expressed as EC50 value which means effective concentration is that at which 50% of the free radicals produced are quenched, i.e. lower the value of EC50, higher the antioxidant activity of the compound. The results indicate that the antioxidant activity of the innovative curcumin formulation is double than that of curcumin ordinary formulation.

B. Dissolution profile
Methodology: Dissolution studies were carried out on the innovative curcumin formulation along
with curcumin ordinary formulation (without SBS &SS) using USP type II dissolution apparatus
with 900 ml Phosphate Buffer pH 6.8 and samples were analyzed by HPLC Method.
Results: The cumulative percentage drug release from innovative formulation was observed to be
50.03% in 30 minutes as against no drug release from conventional formulation.
Table 7

(Table Removed)

C. Stability data:
Methodology: The stability studies were carried out as per ICH guidelines. The samples were
tested for its color change, pH change, assay, dissolution profile etc. The accelerated studies were
carried out at 40°C±2°C/75±5% RH in glass containers.
Results: No degradation was observed with respect to its assay value. In addition there was no
change in color, taste and pH. The mean assay results of 2.5% formulation are given in table:
Table 8

(Table Removed)

References:
1. Kawanishi S, Oikawa S, Murata M,. Evaluation for safety of antioxidant chemopreventive agents. Antioxidants & Redox Signaling 2005,7 (11-12): 1728-39.
2. Maheshwari RK, Sing AK, Gaddipati J, Srimal RC,. Multiple biological effects of curcumin: a short review, Life Sci, 2006, 78:2081-87.
3. Bengmark S,. Curcumin, an atoxic antioxidant and natural NFkappaB, cyclooxygenase-2, lipooxygenase, and inducible nitric oxide synthase inhibitor: a shield against acute and chronic diseases, JPEN J Patenter Enter Nutr, 2006, 30:45-51.
4. Aggarwal BB, Shishodia S,. Molecular targets of dietary agents for prevention and therapy of cancer, Biochem Pharmacol, 2006, 71:1397-1421.
5. Sharma RA, Gescher AJ, Steward WP,. Curcumin: the story so far, Eur J Cancer, 2005, 41:1955-68.
6. Duvoix A, Blasius R, Delhelle S, et al. Chemopreventive and therapeutic effects of curcumin, Cancer Lett, 2005, 223:181-90.
7. Joe B, Vijayakumar M, Lokesh BR,. Biological properties of curcumin-cellular and molecular mechanisms of action, Crit Rev Food Sci Nutr, 2004, 44:97-111.
8. Arajuo CC, Leon LL,. Biological activities of Curcuma longa L, Mem Inst Oswaldo Cruz, 2001, 96:723-28.
9. Fielding RM,. Liposomal drug delivery: Advantages and limitations from a clinical pharmacokinetic and therapeutic perspective, Clin Pharmacokinet. 1991, 21(3): 155-64.

Claims:
1. We claim a formulation of curcumin wherein the formulation is freely soluble in water and
comprises in combination
a. Bioactive curcumin in range of 0.1 -7%
b. specific solubilizers which are hydrophilic excipients
c. specialized base solution
2. The formulation of claim 1 wherein the bioactive curcumin is of 95% purity
3. The formulation of claim 1 wherein the specific solubilizers comprise, triricinoleate ester of ethoxylated glycerol, polyethylene glycol ricinoleate with corresponding free glycol or its derivatives thereof and fatty acid esters of polyoxyethylene sorbitan or its derivatives.
4. The formulation of claim 3 wherein the ratio of triricinoleate ester of ethoxylated glycerol, polyethylene glycol ricinoleate with corresponding free glycol derivatives and fatty acid esters of polyoxyethylene sorbitan derivatives in the formulation ranges from 0.1:99.9 to 99.9:0.1
5. The formulation of claim 3 wherein the concentration triricinoleate ester of ethoxylated glycerol, polyethylene glycol ricinoleate with corresponding free glycol or its derivatives thereof in the formulation ranges from 1-50% depending upon the concentration of curcumin in the formulation.
6. The formulation of claim 3 wherein the concentration of fatty acid esters of polyoxyethylene sorbitan or its derivatives thereof in the formulation ranges from 1-50% depending upon the concentration of curcumin in the formulation.
7. The formulation of claim 1 wherein the specialized base solution comprises Sorbitol, Glycerin, Propylene Glycol and Polyethylene glycol of various grades ranging from 200 to 6000 in particular ratios.
8. The formulation of claim 1 wherein the specialized base solution comprises Sorbitol, Glycerin, Propylene Glycol and Polyethylene glycol of various grades ranging from 200 to 6000 in particular concentrations ranging from 40% to 95%.
9. The formulation of claim 7 wherein the concentration of ingredients in the specialized base solution is as follows:

- Sorbitol: 10-60%
- Glycerine: 1-10%

- Propylene glycol: 1-50%
- Poly ethylene glycol: 1-50%

10. A process for the preparation of formulation of claim 1 comprising the step of adding curcumin to either SBS or SS with stirring for 20 minutes till a distinct viscous solution having reddish orange color is obtained.
11. A water soluble formulation of curcumin as substantially described herein with reference to the detailed description and examples.