Technical field of the invention:
The present invention relates to Phytosome based transdermal drug delivery system comprising Curcumin and a process for preparation thereof.
Background of the invention:
Curcumin (bis-a,(3-unsaturated (3-diketone) is a natural polyphenols compound isolated from the rhizomes of the plant Curcuma longa Linn. (Family - Zingiberaceae). It is yellow coloured low-molecular-weight tautomeric diferuloyl methane with hydrophobic properties that is soluble in organic solvents such as dimethyl sulfoxide, ethanol, methanol, chloroform or acetone. Curcumin is primarily used as a food colouring agent because of its strong yellowish colour. Commercially available curcumin is a mixture of approximately 77 % curcumin, 17 % DMC (demethoxycurcumin) and 3 % BDMC (bisdemethoxycurcumin). Curcumin suppress multiple signaling pathways and inhibit cell proliferation, invasion, metastatis and angiogenesis. It inhibits arachidonic acid metabolism, cyclooxygenase, lipoxygenase and pro-inflammatory cytokines. Its medical use includes anti-septic, analgesic, anti-inflammatory, anti-oxidant, anti-malarial, wound healing, liver disorders, diabetic wounds, cough and certain tumors. In addition to its antioxidative and anti-inflammatory activities, curcumin is proposed to possess pleiotropic pharmacological effects on neurodegenerative, cardiovascular, pulmonary, metabolic, autoimmune, and neoplastic diseases. Phase I clinical trials demonstrated that curcumin is safe even at high doses (12 g/day) in humans but exhibit poor bioavailability. However, the applications of curcumin in pharmacological utilization have been impeded due to its extremely low water solubility, degradation in stomach and poor oral bioavailability.
Some of the possible approaches to overcome these problems includes avoidance of hepatic first pass metabolism by Co-administration with another drug or development of prodrugs to reduce presystemic metabolism or use of Novel Drug Delivery Systems; avoidance of degradation in gastrointestinal tract by enhancement of residence time in stomach or by use of floating drug delivery system or bioadhesive system or development of colon targeted drug delivery system. Adjuvants, which can block metabolic

pathways of curcumin, are one of the major means that can be used to improve its bioavailability. Nanoparticles, liposomes, micelles, and phospholipid complexes are other promising novel formulations, which appear to provide longer circulation, better permeability, and resistance to metabolic processes. Curcumin solid lipid particle yielded a high bioavailability and clinically effective curcumin.
Therefore, several approaches have been investigated to increase curcumin biological efficacy, including chemical derivatization, complex formation or interaction with macromolecules and using nanoscale drug delivery system. Chemical modification and nanoemulsion are most promising approaches for solubility enhancement and dissolution of poorly water soluble drugs and hence, its bioavailability.
In spite of its efficacy and safety, curcumin has not yet been approved as a therapeutic agent. Structural modifications of curcumin have been explored to improve the bioavailability. However, the limited evidences showed the improvements in curcumin bioavailability and strategies, including those of nanoparticles, liposomes, and defined phospholipid complexes may offer significant promise and are worthy of further exploration in attempts to enhance the bioavailability, medicinal value, and application of this interesting molecule. Therefore, the present inventors prepared and evaluated the transdermal application of chemically complexed curcumin with phospholipids.
Summary of the invention:
The present invention relates to Phytosome based transdermal drug delivery system comprising Curcumin and a process for preparation thereof.
In an aspect of the invention, the curcumin is complexed with phospholipid, In one aspect, the phospholipid is soya lecithin. In another aspect, the phospholipid is commercially available phospholipid like phospholipon 9QG.

In yet another aspect, the ratio of curcumin to phospholipid is from 1:0.5 to 1:10. In a specific aspect, the ratio is 1:2, 1:5 or 1:10.
In one of the aspect, the drug delivery system is in the form of transdermal patch. In a other aspect, the transdermal patch comprises HPMC E-5, dibutyl phthalate and dimethyl sulphoxide.
In one of the aspects of the invention, the curcumin drug delivery system is used for the treatment of Psoriasis.
Detailed description of the invention:
The present invention relates to Phytosome based transdermal drug delivery system comprising Cucrumin and a process for preparation thereof.
The terms used in the specification are defined as follows.
A "subject," "individual," or "patient," is used interchangeably herein, which refers to a vertebrate, preferably a mammal, more preferably a human. Tissues, cells and their progeny of a biological entity obtained in vitro or cultured in vitro are also encompassed.
Phytosome are advanced form of herbal extract that are absorbed better than conventional herbal extract. These complexes shows much better absorption profile following oral administration owing to improved lipid solubility which enable them to cross the biological membrane, resulting in enhanced bioavailability. Moreover, phytosomes are superior to liposomes due to much better absorption and stability profile.
In an aspect of the invention, the curcumin is complexed with phospholipid. In one aspect, the phospholipid is soya lecithin. In another aspect, the phospholipid is commercially available phospholipid like phospholipon 90G.

Lecithin is a generic term to designate any group of yellow-brownish fatty substances occurring in animal and plant tissues, which are amphiphilic they attract both water (and so are hydrophilic) and fatty substances (lipophilic) and are used for smoothing food textures, dissolving powders (emulsifiers), homogenizing liquid mixtures and repelling sticking materials.
Lecithins are usually phospholipids, composed of phosphoric acid with choline, glycerol or other fatty acids usually glycolipids or triglyceride, acids. Glycerophospholipids in lecithin include phosphatidylcholine, phosphatidylethanolamine, phosphatidylinositol, phosphatidylserine, and phosphatidic acid. Lecithin, as a food additive, is also a dietary source of several active compounds. While lecithin is also a rich source of a variety of types of dietary fats, the small amounts of lecithin typically used for food additive purposes mean it is not a significant source of fats. Lecithin is a source for methyl groups via its metabolite, trimethylglycine (betaine) although this is mostly consumed from plants.
Lecithin has emulsification and lubricant properties, and is a surfactant. It can be totally metabolized by humans, so is well tolerated by humans and nontoxic when ingested; some other emulsifiers can only be excreted via the kidneys. The major components of commercial soybean-derived lecithin are,
33-35%- soybean oil
• 20-21%- inositol phosphatides
• 19-21%-phosphatidylcholine
• 8-20%- phosphatidylethanolamine
• 5-11 %- other phosphatides
• 5%- free carbohydrates 2-5%- sterols
• 1%-moisture
Commercially available lecithin like Phospholipon 90G can be used for the complexation.
Complexation of the curcumin with Soya lecithin/phospholipon 90G at gravimetric ratios of 1:0.5, 1:1, 1:2, 1:5 and 1:10 demonstrated increased

curcumin content (curcumin undergoing complexation) with an increase in soya lecithin till the curcumin-soya lecithin ratio is 1:2.
A phytosome can be prepared by the reaction of a stoichiometric amount of the phospholipid with the standardized extract or polyphenol^ constituents in a non-polar solvent. Phosphatidylcholine is a bi-functional compound composed of lipophilic phosphatidyl moiety and the hydrophilic choline moiety. The choline head of phosphatidylcholine molecule binds to phytocomponent while the lipid soluble phosphatidyl portion comprises the body and tail which then envelops the choline bound material. Hence, the phytoconstituents build up a lipid compatible molecular complex with phospholipid also called as phyto-phospholipid complex.
In yet another aspect, the ratio of curcumin to phospholipid is from 1:0.5 to 1:10. In a specific aspect, the ratio is 1:2, 1:5 or 1:10.
In one of the aspect, the drug delivery system is in the form of transdermal patch. In a other aspect, the transdermal patch comprises HPMC E-5, dibutyl phthalate and dimethyl sulphoxide.
A transdermal patch is a medicated adhesive patch that is placed on the skin to deliver a specific dose of medication through the skin and into the bloodstream.
The main components to a transdermal patch are:
• Liner - Protects the patch during storage. The liner is removed prior to use.
• Drug - Drug solution in direct contact with release liner
• Adhesive - Serves to adhere the components of the patch together along with adhering the patch to the skin
• Membrane - Controls the release of the drug from the reservoir and multi-layer patches
• Backing - Protects the patch from the outer environment
• Permeation Enhancer - These are permeation promoters for drugs, which increases delivery of drug.

• Matrix Filler - It provides bulk to matrix as well as some of fillers acts as
matrix stiffening agent.
Other components includes: Stabilizer (anti oxidants), Preservatives etc.
In one of the aspects of the invention, the curcumin drug delivery system is used for the treatment of Psoriasis.
The curcumin-phospholipid complexes were planned to be prepared and evaluated for anti-psoriatic activity after formulating the complexes into the transdermal patches.
The foregoing examples are illustrative embodiments and are merely exemplary. A person skilled in the art may make variations and modifications without deviating from the spirit and scope of the invention. All such modifications and variations are intended to be included within the scope of the claims.
Example 1: Phytosome based transdermal drug delivery system comprising Curcumin according to the invention.
Preparation of curcumin-Soya lecithin/phospholipon 90G complexes
Curcumin-Soya lecithin/ phospholipon 90G complexes were prepared as per the earlier reported method with some modifications (Maiti et al., 2007).
Complex recovered by cooling
The complexes were prepared by refluxing curcumin(5g) with varrying ratio of soya lecithin (1:0.5), (1:1) and (1:2) in a 200 ml of the mixture of methanol and chloroform (1:1) in 50.0ml round bottom flask attached to a condensor. Following the 24 h reflux, the mixture was set aside for 6 h at room temperature. Crystals formed at the bottom were then then filtered out, dried and stored at room temperature in desiccator.

Complex recovered by nonsolvent addition
Following 24 h reflux of curcumin alone or with soya lecithin in different ratio (1:2, 1:5, 1:10) or phospholipon 90G (1:2) the reaction mixture was added in 100 ml of either double distilled water or n-hexane with continuous stirring and set aside for 24 h. The recovered complexes were then separated by filtration, dried and stored at room temperature in desiccator.
Curcumin-soya lecithin complexes prepared in varying ratio and recovered by different methods were formulated using HPMC E-5, dibutyl phthalate and dimethyl sulphoxide into transdermal patches and evaluated for thickness, moisture content, moisture uptake and curcumin content.
Complexation of the curcumin with Soya lecithin/phospholipon 90G at gravimetric ratios of 1:0.5, 1:1, 1:2, 1:5 and 1:10 demonstrated increased curcumin content (curcumin undergoing complexation) with an increase in soya lecithin till the curcumin-soya lecithin ratio is 1:2.
The transdermal patches containing curcumin or complex had the thickness ranging from 0.26 - 0.51 mm which indicates that they are uniform in thickness. Determination of moisture content revealed that the complexes recovered by cooling have higher moisture content and lower moisture uptake, whereas the complexes recovered from water and n-hexane have lower moisture content and higher moisture uptake. Moisture uptake of complexes recovered by water was higher as compared to those recovered from n-hexane. It is likely that the complexes recovered by cooling may have water of crystallization which lowers with increasing phospholipid content due to decreased crystallanity. The curcumin content present in patch of 1 cm2 was proportional to its solubility in methanol. Curcumin being soluble in methanol, was contained in higher amount as compared to other patches. Increased lipophilicity of complexes decreased the solubility of complexes in methanol, which is reflected from the lower curcumin content in transdermal patch of similar dimension.

In the present study, the significant difference in pharmacokinetic parameters, mainly bioavailability and half-life, between the free curcumin and the soya lecithin complexed curcumin containing transdermal patch suggested and found to prolong drug release and increase the extent after complexation.
The prepared transdermal patches demonstrating higher curcumin content were evaluated for antipsoriatic activity in imiquimod induced psoriasis in rats. Psoriasis was induced by applying imiquad cream (5%) for six consecutive days. Following induction of psoriasis, animals were treated by applying transdermal patch of 1cm2 on the affected skin. The severity of skin inflammation was scored daily according to structured PASI scale. To demonstrate the effect of complexation in varying curcumin-soya lecithin ratio on the bioavailable fraction of curcumin, plasma obtained from the blood withdrawn after 1, 2, 3, 6, 9, 12, 18 and 24 h of patch application was analyzed for curcumin levels.-
Histological analysis of psoriatic skin was showed increased epidermal ' thickening, hyperproliferation of keratinocytes and altered normal skin architecture which observed repaired in curcumin or curcumin-soya lecithin/phospholipon 90G patch treated rats. The repair or recovery from the psoriatic skin inflammation was more for the rats treated with curcumin-soya lecithin (1:10) complex.
The pharmacokinetic studies showed that transdermal patch prepared using curcumin and its complex with increased Cmax indicates that the soya lecithin complexation effectively increased the drug permeation and the delayed Tmax demonstrates an obvious sustained release of curcumin. The distribution and metabolism of curcumin were found decreased from transdermal patches pf complexed curcumin. Soya lecithin complexation in the ratio 1:5 and 1:1.0 decreased the curcumin volume of distribution by 3 folds compared to free curcumin. Overall the complexation with soya lecithin demonstrated the increased bioavailable fraction of curcumin from transdermal patches.

Bioavailability studies of curcumin reports maximum serum concentration of 1.35±0.23 ug/ml following oral administration of 2 g/kg curcumin to rats at time 0.83 h, whereas in humans, the same dose of curcumin resulted into undetectable or low (0.006±0.005 ug/ml) serum levels. In addition to this, several studies have demonstrated low, random or unpredictable serum levels following oral administration of curcumin. Evidence from numerous literatures revealed that curcumin has poor absorption, biodistribution, metabolism, and bioavailability. In summary, transdermal patches of chemically complexed curcumin with soya lecithin increases the bioavailability and permeability and may be resistance to metabolic processes.

We claim:
1. Phytosome based transdermal drug delivery system comprising Curcumin.
2. The drug delivery system according to claim 1, wherein curcumin is complexed with phsopholipid.
3. The drug delivery system according to claim 1, wherein phospholipid is soya lecithin.
4. The drug delivery system according to claim 2, wherein the ratio of curcumin to phospholipids is from 1:0.5 to 1:10.
5. The drug delivery system according to claim 4, wherein the ratio of curcumin to phospholipids is 1:5 to 1:10.
6. The drug delivery system according to claim 1, wherein the drug delivery system is in the form of transdermal patch.
7. The drug delivery system according to claim 6, wherein the transdermal patch comprises HPMC E-5, dibutyl phthalate and dimethyl sulphoxide.
8. The drug delivery system according to claim 1, wherein the curcumin drug delivery system is used for the treatment of Psoriasis.