THE PATENTS ACT, 1970 (39 of 1970)
PROVISIONAL SPECIFICATION (See section 10 and rule 13)
1. TITLE OF THE INVENTION
PHARMACEUTICAL COMPOSITIONS OF CURCUMIN

2. APPLICANT(S)
(a) NAME : CADILA PHARMACEUTICALS LIMITED
(b) NATIONALITY: An INDIAN Company
(c) ADDRESS : "Cadila Corporate Campus", Sarkhej - Dholka Road, Bhat,
Ahmedabad -382210, Gujarat, India

3. PREAMBLE TO THE DESCRIPTION
PROVISIONAL SPECIFICATION
The following specification describes the
invention.

4. DESCRIPTION
(Description starts from next page)

FIELD OF THE INVENTION:
The present invention is in the field of formulation and more particularly the invention deals with a clear stable liquid pharmaceutical composition of curcumin or its pharmaceutically acceptable salts or derivatives devoid of pH buffer and/or molecular aggregator inhibitor (s).
BACKGROUND OF THE INVENTION:
Curcumin is a potent natural antioxidant and anti-inflammatory agent and has shown therapeutic potential in many pre-clinical culture and animal models for diseases. These include cancers (colon, prostate, breast, skin, leukemia, etc.), atherosclerosis, stroke, CNS alcohol toxicity, traumatic brain injury, Huntington's disease, Marie-Charcot Tooth, multiple sclerosis and Alzheimer's disease.
Curcumin is a highly staining polyphenolic compound with antioxidant properties. The molecular weight of the curcumin is 368.37 and molecular formula of curcumin is C21H2006 Curcumin is a crystalline compound and very poorly soluble in water at pH less than 7.
The poor aqueous solubility and bioavailability has been the major limitation of preparing the pharmaceutical!/ acceptable formulation of curcumin, in spite of its efficacy and safety. Major reasons contributing to the lower plasma and tissue levels of curcumin are due to poor absorption; high first pass metabolism and rapid systemic elimination. Most of the curcumin is not absorbed and simply passes through the Gl tract and is excreted. Garcea, G. et al. (2004) report that with patients taking 3.6 gms of curcumin a day (as a standard powder extract capsule supplied by Sabinsa Corporation), blood and liver levels achieved are negligible. Inventor concluded that "doses of curcumin required to furnish hepatic levels sufficient to exert pharmacological activity are probably not feasible in humans."
WO 2006 022012 discloses solid dispersion of curcumin and process for producing the same. The solid dispersion was prepared by dissolving curcumin and polyvinylpyrrolidone in an alcoholic solvent followed by spray-drying to produce spray dried curcumin solid dispersion with improved water solubility. Solid dispersions shows progressive decrease in dissolution of drug substance due to

its conversion from amorphous to crystalline state on prolong storage during self life of product.
CN101147727 discloses oil-in-water submircoremulsion of curcumenol having grain size of below 500 nm and medicine carried quantity is 0.02 mg/ml-30 mg/ml. The said preparation is to provide pre-formed oil-in-water emulsion, having poor drug loading capacity.
US 20030232095 discloses nano sized self assembled structured concentrate comprises of water, co-solvent, surfactant, co-surfactant and oil phase to solubilize the lipophilic compounds. The said process is to provide pre-formed microemulsion and nano sized self assembled concentrate need to dilute with either in water or in oil to maintaining their structure.
CN100352430C discloses the self micro emulsified curcumin preparation consists of Curcumin, surfactant, co-surfactant, oil phase and solid adsorbent providing self micro emulsified system having liquid drops with size of below 100 nm. This composition increases curcumin solubility and absorption in gastrointestinal tract with higher bioavailability. Though inventors are able to increase the solubility and subsequent bioavailability of Curcumin but the concentration of Curcumin in finished product is too low (50 part of Curcumin in 3200 - 15050 part) that require higher volume of formulation for unit dose of Curcumin.
WO 2010010431 discloses a curcuminoid composition comprises Curcumin or curcuminoids, a lipidic carrier system with an HLB value between 3 and 14, molecular aggregation inhibitor(s), and a pH buffer, which forms a self nano-emulsions and process for preparing the same. The said process involves use of pH buffer and/or molecular aggregation inhibitor(s). There is a limitation of use of pH buffer and/or molecular aggregation inhibitor(s) in the prior art formulation. Further, prior art formulation stating the limitation of the excipient(s).
Curcumin is not soluble at acidic pH and breaks down when solubilized and diluted with water at neutral or alkaline pH (e.g., in the Gl tract, after the small intestine), due to keto-enol transformations in the |3-diketone bridge. In addition, curcumin is susceptible to rapid glucuronidation / sulfation.

Hence, there is a need to develop a clear stable self-emulsifying liquid pharmaceutical composition of Curcumin or its pharmaceutically acceptable salts or derivatives devoid of pH buffer and/or molecular aggregator inhibitor (s).
OBJECT OF THE INVENTION:
An object of the present invention is to provide a clear stable liquid pharmaceutical composition of Curcumin or its pharmaceutically acceptable salts or derivatives devoid of pH buffer and/or molecular aggregator inhibitor (s) with improved bioavailability and higher drug loading ability, which improve patient compliance.
SUMMARY OF THE INVENTION:
The present invention provides a clear stable liquid pharmaceutical composition of Curcumin or its pharmaceutically acceptable salts or derivatives devoid of pH buffer and/or molecular aggregator inhibitor (s) wherein the Curcumin is solubilized in liquid pharmaceutical composition to make a clear stable liquid pharmaceutical composition.
DETAILED DESCRIPTION OF THE DRAWING:
Figure 1 shows comparative bioavailability study of different pharmaceutical compositions of Curcumin
DETAILED DESCRIPTION OF THE INVENTION:
Accordingly, the present invention is to provide a clear stable liquid pharmaceutical composition of Curcumin or its pharmaceutically acceptable salts or derivatives devoid of pH buffer and/or molecular aggregator inhibitor (s) with improved bioavailability and higher drug loading ability, which improve patient compliance.
The present invention provides a liquid pharmaceutical composition of curcumin or its pharmaceutically acceptable salts or derivatives having improved bioavailability and higher drug loading ability, which improve patient compliance comprises of surfactant, co-surfactant/solvent, oil and optionally anti-oxidant.
The amount of Curcumin in the liquid pharmaceutical composition is about 1 - 400 mg/mL, and preferably about 10 - 240 mg/mL Curcumin salts and derivatives are

includes but not limited to phosphatidylcholine-curcumin complex, Hydrazinocurcumin etc.
Surfactant used in the present invention is selected from the group of polysorbate, polyoxyethylene derivatives, Vitamin E TPGS, polyoxyethylene polyoxypropylene block copolymer, cremophor. The concentration of the surfactant in the composition ranges from 2% - 60% and more preferably 47%.
Co-surfactant used in the present invention is selected from the group of glycofurol, polyethylene glycol, glycerol, polypropylene glycol, propylene glycol, glycerin, benzyl alcohol, N-methyl-2-pyrolidone and alcohol. The concentration of the Co-surfactant in the composition ranges from 0.5% to 90%
For the purpose of present invention oil phase system in the present composition is selected from 1) fatty acid triglycerides, preferably medium chain fatty acid triglycerides, such as fractionated coconut oil (Miglyol®, Huls; and Captex®, Abitec), Caprylic/capric triglyceride (Crodamol GTCC®),(2) mono-, di-or mono/di-glycerides, preferably mono-or di-glycerides of oleic acid, (3) esters of fatty acids and monovalent alkanols, such as isopropyl myristate, isopropyl palmitate, ethyl linoleate and ethyl oleate, (4) propyleneglycol mono-or di-fatty acid esters such as propyleneglycol dicaprylate, propyleneglycol monocaprylate, propyleneglycol dilaurate, propyleneglycol isostearate, propyleneglycol monolaurate and propyleneglycol ricinolate, (5) carbohydrates such as squalene and squalane, The concentration of the oil phase in the composition ranges from 5% to 80%.
Anti-oxidant is selected from tocopheryl derivative such as alpha-tocopherol. The concentration of the antioxidant in the composition ranges from 0% to 5%.
The present invention also provide the process for preparing a clear stable self-emulsifying liquid pharmaceutical composition of Curcumin or its pharmaceutically acceptable salts or derivatives devoid of pH buffer and/or molecular aggregator inhibitor (s) comprising the steps of:
(i), Dissolving curcumin in suitable solvent or in mixture of solvent and
cosolvent; (ii) adding surfactant to the drug solution of step (i) and mix well; and (iii) Blending of oil to the solution of step (i) to prepare suitable pharmaceutical dosage form.

The compositions according to the present invention are easily prepared using well known process and techniques with standard equipment. The composition as prepared in the present invention can be administered by oral, topical or parenteral route; preferably the compositions are administered by oral route.
The invention is further illustrated with following non-limiting examples:
Example 1: A pharmaceutical composition of Curcumin was prepared as given table 1:
Table 1: Composition for example 1

s.
No. Ingredients Qty % w/w
1. Curcumin 5.00
2. Cremophor RH40
(Polyoxyl Hydrogenated Castor Oil) 47.00
3. Crodamol GTCC
(Caprylic / Capric Triglycerides) 25.00
4. Ethyl Alcohol 9.2
5. Alpha-Tocopherol 0.47
6. Propylene Glycol q. s. 100
1. Curcumin was dissolved in ethyl alcohol.
2. Cremophore RH 40 was added to Curcumin solution from step-1 with gentle mixing and heating.
3. Crodamol GTCC, Propylene glycol and Alpha-tocopherol was added to the mixture from step-2 and mixed thoroughly.
The product was found to be clear and stable as there was no particle settlement in the formulation after dilution with water (1:1000) and also with 0.1 N HCI (1:1000). After 24 hours the particle size of the formulation was found to be 26 nm.
Example 2: A pharmaceutical composition of Curcumin was prepared as given in table 2:

Table 2: Composition for example 2

s.
No. Ingredients Qty % w/v
1 Curcumin 5gm
2 Glycofurol 20
3 Propylene Glycol 20
4. Polysorbate 80 q. s. 100
1. Curcumin was dissolved in Glycofurol under continuous stirring.
2. Propylene Glycol was added to Curcumin solution from step-1.
3. Polysorbate 80 was added to the mixture from step-2 and mixed thoroughly.
Example 3: A pharmaceutical composition of Curcumin was prepared as table 3
Table 3: Composition for example 3

S. No. Ingredients Qty % w/w
1. Curcumin 21
2. Cremophor RH40
(Polyoxyl hydrogenated castor
oil) 35
3. Crodamol GTCC (Caprylic / Capric Triglycerides) 17.5
4. Ethyl Alcohol 15.5
5. Propylene Glycol q. s. 100
1. Curcumin was dissolved in ethyl alcohol.
2. Cremophore RH 40 was added to Curcumin solution from step-1 with gentle mixing and heating.
3. Crodamol GTCC and Propylene glycol were added to the mixture from step-2 and mixed thoroughly.
Particle settlement was observed in the above formulation. Particle size analysis of the same formulation was 222 nm.

Example 4: A pharmaceutical composition of Curcumin was prepared as table 4
Table 4: Composition for example 4

s.
No. Ingredients Qty % w/w
1. Curcumin 5
2. Curcumin Oil in Soybean Oil (0.5%) 25
3. Cremophor RH40
(Polyoxyl hydrogenated castor
oil) 44
4. Ethyl Alcohol 12
5. Alpha-Tocopherol 0.52
6. Propylene Glycol q. s. 100
1. Curcumin and Curcumin oil were dissolved in ethyl alcohol
2. Cremophor RH 40 was added to Curcumin mixture from step-1 with gentle mixing and heating..
3. Propylene glycol and Alpha-tocopherol were added to the mixture from
step-2 and mixed thoroughly.
Example 5:
Pharmaceutical composition from example 1 to example 4 were further subjected to bioavailability study in rat (n=6) at dose of 150mg/kg body weight as table 5 Table 5: different formulation subjected to animal study:

Groups Pharmaceutical Composition Dosing Method
Control drug dispersed in 2 % sodium CMC As such
Test I Example 1 Undiluted
Test II Example2 Undiluted
Test III Example 3 Undiluted
Test IV Example 1 Diluted up to 3X with purified water
Test V Example 4 Diluted up to 3X with purified water

Test I, Test II and Test V demonstrated enhanced bioavailability as compared to control and Test III (fig. 1).
Example 6:
Pharmaceutical Composition of example 1 was further subjected to accelerated stability study as per ICH guideline and product was found stable for 3 months at 40°C /75%RH (table 6):
Table 6: Stability data at 40°C/75% RH

Parameters Initial 1M 2M 3M
Assay 106.3% 98.2% 98.8% 90.9%
pH (10% aqueous solution) 5.2 5.32 5.34 5.62
Globule size {10% aqueous solution) 49.4 nm 54.5 nm 53.64 39.59 nm