DESC:FILED OF INVENTION:
The present invention relates to improve Solubility and in vivo Bioavailability of Curcumin by Synergy Phytoconstituents Based Saponin and a method for preparing the same. In particular the present disclosure relates to the Curcumin complex with Phytoconstituents blend of saponin by unique granulation technology. Further invention said invitro Dissolution of Pure 95 % Curcumin and optimized Curcumin Complex shows better enhancement in optimized curcumin complex. Another invention relates to improve solubility curcumin by synergy phytoconstituents based saponin comprises of; Solvents such as isopropanol, ethanol, acetone, and ethylene dichloride and others are typically used to prepare oleoresins of turmeric, which may typically contain about 30% curcumin, 30% volatile oils, 30% fixed oils, and 10% polysaccharides

BACKGROUND OF INVENTION:
Curcumin (1, 7 bis (4-hydroxy-3-methoxy phenyl)-l, 6 heptadiene-3, 5- dione), is a principal curcuminoid of the popular Indian spice Curcuma longa commonly known as turmeric, a perennial herb of Zingiberaceae (ginger) family, which is a 3-5 ft tall bearing oblong, pointed, short-stemmed leaves and funnel- shaped yellow flowers. Turmeric is widely cultivated in India, China and other tropical countries. Curcuminoids are natural phenols that are responsible for the yellow colour of turmeric. Curcumin exists in several tautomeric forms.

The dried turmeric rhizomes generally contain about 5% curcumin. Ground turmeric may be extracted with organic solvents to remove the curcumin and the fixed and volatile oils from the cellulose plant material of the rhizomes, its form oleoresins. Solvents such as isopropanol, ethanol, acetone, and ethylene dichloride and others are typically used to prepare oleoresins of turmeric, which may typically contain about 30% curcumin, 30% volatile oils, 30% fixed oils, and 10% polysaccharides. Oleoresins are used by the food industry to colour pickles, baked goods, poultry products, and in seasoning mixtures for various other food products. The fixed and volatile oil portions of the ground spice or the oleoresin are responsible for the characteristic flavor and bitterness of turmeric. This flavour and bitterness are sometimes undesirable in the finished food product.

It can be difficult to mask taste but with unique granulate palatability also going to improve. Saponin isolated from medicinal plants is a naturally occurring bioorganic molecule with high molecular weight and its aglycone (water non-soluble part) nucleus having 27 to 30 carbon atoms besides one or two sugar moieties (water soluble part) containing at least 6 or 12 carbon atoms respectively. Curcumin is substantially insoluble in water, High concentration of curcumin, lower the solubility. 95% of Curcumin is practically insoluble in aqueous medium hence it has been designed with natural phytoconstituents blend of Saponin as a granulating agent to improve poor characteristic solubility and bioavailability.

US10512616B2 discloses a composition for enhanced bioavailability of curcumin including purified curcuminoid and purified essential oil of turmeric. A method to prepare a composition for enhanced bioavailability of curcumin having purified curcuminoid and purified essential oil of turmeric.

US20220202713A1 discloses a solubilize composed of curcumin in a quantity of less than or equal to 10% by weight, preferable less than or equal to 7.5% by weight, particularly preferable 6% by weight, and at least one emulsifier having an HLB value in the range between 13 and 18, in particular polysorbate 80 or polysorbate 20 or a mixture of polysorbate 20 and polysorbate 80, wherein the average diameter of the micelles loaded with curcumin in between 5 nm and 40 nm, preferable between 6 nm and 20 nm, particularly preferable between 7 nm and 10 nm.

JP6080923B2 discloses water-soluble compositions having enhanced bioavailability and processes for their preparation. More particularly, the present invention relates to a novel water soluble composition containing curcumin with at least one antioxidant, a hydrophilic carrier, and fat and having enhanced bioavailability. Curcumin [1,7-bis (4-hydroxy-3-methoxyphenyl) -1,6-heptadiene-3,5-dione] is a hydrophobic antioxidant that is a powerful antioxidant derived from the spice turmeric. Polyphenol derivatives. Commercially available curcumin contains approximately 77% diferroylmethane, 17% demethoxycurcumin, and 6% bisdemethoxycurcumin. Curcumin is the main active ingredient of turmeric (Curcuma Longa), which has been used since ancient times. Turmeric (turmeric) is a well-known and unique herbal medicine. Turmeric is known for a variety of biological and pharmacological activities, including anti-inflammatory properties, antioxidant properties, anti-proliferative properties, antibacterial properties, anti-carcinogenic properties, and anti-angiogenic properties.

Phytomedicine (Volume 90, September 2021, 153651) Improving oral bioavailability of medicinal herbal compounds through lipid-based formulations – A Scoping Review (Tan, Oi Jin, et al.) discloses although numerous medicinal herbal compounds demonstrate promising therapeutic potential, their clinical application is often limited by their poor oral bioavailability. To circumvent this barrier, various lipid-based herbal formulations have been developed and trialled with promising experimental results.

Journal of Molecular Liquids (Volume 318, 15 November 2020, 113997) Solubility improvement of phytochemicals using (natural) deep eutectic solvents and their bioactivity evaluation (Cao, Jun, et al.) discloses plants serve as major sources of bioactive phytochemicals and provide an enormous space for drug discovery. Most of phytochemicals' utilizations are limited by the low water-solubility and thereby low bioavailability. The development of biocompatible solvents with high solvation is a simple and efficient method to improve the solubilities of phytochemicals. In this work, four water-insoluble phytochemicals were chosen as the models to systematically investigate the potential of (natural) deep eutectic solvents ((NA)DESs) as delivery vehicles. After preliminary screening, ten (NA)DESs from sixty prepared (NA)DESs were found to be low viscous and applied to safety evaluation. The cytotoxicity studies revealed that the ten (NA)DESs were safe enough to be used in pharmaceutical and food industry. The solubilities of four model phytochemicals in (NA)DESs were 252–4453 folds higher than those in water. Several solvatochromic parameters were correlated with the solubilities of phytochemicals to tentatively study the solvation between phytochemicals and (NA)DESs. The high solubility could be interpreted by the solute-solvent interactions between phytochemicals and (NA)DESs, such as dipole-dipole interactions and hydrogen bond interactions. The stabilities and bioactivities of phytochemicals dissolved in (NA)DESs were also investigated. It was indicated that not only the stabilities but also the bioactivities were improved by (NA)DESs. The findings of this study show bright application prospect of (NA)DESs as delivery vehicles, which will be of significance for improving the utilization of plant resources.

OBJECTIVE OF INVENTION
Curcumin has a wide spectrum of biological and pharmacological activities, but it is now approved as a therapeutic agent in Nutraceutical and Phytopharmaceutical industry but drawback is low solubility, bioavailability and photo stability in aqueous solution. To overcome solubility, and Bioavailability as a limitation, curcumin is design to Curcumin complex with Phytoconstituents blend of saponin by unique granulation technology.

Some study suggested SLS improve aqueous solubility of Curcumin but there is no evidence that it improves bioavailability. To overcome these limitations of curcumin, synergy form with Natural saponin blend is developed by unique technology and it is confirmed tremendous improvement in solubility without interaction is confirm by Physical characterization. Invitro Dissolution of Pure 95 % Curcumin and optimized Curcumin Complex shows better enhancement in optimized curcumin complex. After solubility and dissolution confirmation, in vivo oral bioavailability is performed as per CPCSEA guideline. It is found improvement in oral bioavailability. Heavy metals and microbiological testing from NABL lab indicate product are safe as per USP, WHO limits. Stability study also proven stable as per ICH guidelines.

SUMMERY OF THE INVENTION
The present invention relates to improve Solubility and In vivo Bioavailability of Curcumin by Synergy Phytoconstituents Based Saponin and a method for preparing the same.

In particular the present disclosure relates to the Curcumin complex with Phytoconstituents blend of saponin by unique granulation technology.

Further invention said Invitro Dissolution of Pure 95 % Curcumin and optimized Curcumin Complex shows better enhancement in optimized curcumin complex.

Another invention relates to improve solubility curcumin by synergy phytoconstituents based saponin comprises of; Solvents such as isopropanol, ethanol, acetone, and ethylene dichloride and others are typically used to prepare oleoresins of turmeric, which may typically contain about 30% curcumin, 30% volatile oils, 30% fixed oils, and 10% polysaccharides.

A method of preparation of curcumin neutraceuticals composition comprises of;
Curcumin neutraceuticals are prepared using a pH-driven method. An acidic aqueous surfactant solution is prepared by dissolving saponin in 20 mM phosphoric acid at concentrations of 2, 4, 8, 12 and 16 mg/mL (pH 3). A basic aqueous curcumin solution (2.0 mg/mL) is prepared by dissolving curcumin in 30 mM sodium hydroxide solution (pH 12). Curcumin solutions are then added to saponin solutions (1:1 v/v) while being continuously stirred at 500 rpm on a magnetic stir plate. The resulting solution is incubated for 0.5 h at room temperature and then centrifuged at 10,000 g for 10 min to remove any free curcumin and larger particulate matter. Basic curcumin is added into the acid saponin solutions, the pH rapidly increased to around pH 6.5 within 10 second.

DETAILED DESCRIPTION OF INVENTION:
Detailed Description of the Invention While this specification concludes with claims particularly pointing out and distinctly claiming that, which is regarded as the invention, it is anticipated that the invention can be more readily understood through reading the following detailed description of the invention and study of the included examples.
The following is a detailed description of embodiments of the present disclosure. The embodiments are in such detail as to clearly communicate the disclosure. However, the amount of detail offered is not intended to limit the anticipated variations of embodiments; on the contrary, the intention is to cover all modifications, equivalents, and alternatives falling within the spirit and scope of the present disclosure as defined by the appended claims.

Unless the context requires otherwise, throughout the specification which follow, the word “comprise” and variations thereof, such as, “comprises” and “comprising” are to be construed in an open, inclusive sense that is as “including, but not limited to.”

Reference throughout this specification to “one embodiment” or “an embodiment” means that a particular feature, structure or characteristic described in connection with the embodiment is included in at least one embodiment. Thus, the appearances of the phrases “in one embodiment” or “in an embodiment” in various places throughout this specification are not necessarily all referring to the same embodiment. Furthermore, the particular features, structures, or characteristics may be combined in any suitable manner in one or more embodiments.

The headings and abstract of the invention provided herein are for convenience only and do not interpret the scope or meaning of the embodiments.
Various terms are used herein. To the extent a term used in a claim is not defined below, it should be given the broadest definition persons in the pertinent art have given that term as reflected in printed publications and issued patents at the time of.
Curcumin is a poorly water-soluble drug and its oral bioavailability is very low. Novel granulation technology has been successfully developed to improve the solubility and oral absorption of curcumin. It improves solubility, Photo stability and Micromeritics property also.

SMEDDS and Curcumin Piperine complex method are reported and various research are going on. Both the technology is expensive, also some limitation to improve its oral bioavailability, and without excipients SMEDDS is not possible. Some reported research of curcumin also suggested that in colon PH, solubility and absorption is good as compare to Acidic PH and by addition of surfactant like SLS solubility is going to increased. SLS is not safe for long consumption by oral use, though it’s in law concentration and salt form is not solution for curcumin solubility and bioavailability. After compare and contrast, our developed synergy saponin blend gives good solubility improvement than salt form, Piperine and SLS. The effect also checks by alter PH, it indicated there is no abnormality found in Solubility after changing PH. Various phytoconstituents based saponin stock solution is prepared and compared with SLS, SLES, and alter pH solution to check its aqueous solubility in orbital shaker for 1 hr., 4 hr., 12 hr., 24 hr. and 48 hr. aliquots sample from each stock solution to check absorbance after each time of interval. This invention is directed to overcoming one or more of the problems described above. According to the present invention, a method of preparing a water-soluble curcumin product which gives a crystal-clear yellow solution in water without the aid of an artificial chemical or excipients, and sedimentation rate in Curcumin complex is less than pure form of Curcumin.

Curcumin has been shown to exhibit potent anti-inflammatory, immunomodulatory, antiproliferative and anticarcinogenic activities and protect cells and tissues against various injury mechanisms. A number of preclinical studies have indicated that curcumin is a promising therapeutic agent for several diseases and clinical conditions, including, for example, the treatment of cancer and leukemia, stroke, myocardial infarction, rheumatoid arthritis, inflammatory bowel disease, pancreatitis, sepsis, hemorrhagic shock, organ transplantations, and radiation injury. Despite the various therapeutic actions displayed by curcumin, its poor aqueous solubility and bioavailability restricts its biological applications. The main reasons contributing to the low bioavailability of curcumin are its very low aqueous solubility and rapid intestinal metabolism, particularly in human subjects. Many formulations of curcumin have been developed and are available in the state of the art. Most of the formulations relied on the use of piperine, a component responsible for the pungency of black pepper and long pepper as an adjuvant due to its ability to inhibit the hepatic and intestinal metabolism of curcumin. However, the use of piperine to increase the absorption rate of curcumin is not successful. Preventing the metabolism alone without enhancing the solubility does not contribute much to the improved bioavailability. The use of other adjutants such as green tea or soya bean extracts is also not found to be good enough in increasing the bioavailability of curcumin. In NDDS also various methods have been tried to enhance curcumin delivery, including its incorporation into liposomes and nanoparticles. So far, these formulations have not been shown to deliver effective concentrations of curcumin into tissues or to enable the treatment of diseases and injuries affecting organs like the brain, lungs, kidney, liver or bladder.
The present invention discloses a curcumin composition to enhance the bioavailability of curcumin in the blood stream. The curcumin composition mainly consists of curcumin and mixture of Saponin blend derived from Phytoconstituents and water. The composition also consists of a natural saponin isolated from Satavari, Aloevera, Liquorice and guar gum and does not contain any synthetic polymers and Curcumin also derived from the natural components of turmeric rhizome. This composition results in increased rate of bioavailability of curcumin in the body fluids as the dietary fibres holds the curcumin for long time, which plays a vital role in prohibiting easy degradation of curcumin inside the tissues. The soluble proteins increase the solubility of curcumin in water thus supporting the increased absorption of curcumin in blood and the essential oil derived from turmeric offers much more dispersibility to the composition.
As there is no validated dissolution method available in the literature. Curcumin complex the composition of the dissolution medium is selected on the basis of solubility data at 37°. Solubility data revealed that addition of prepared solution may be suitable as a dissolution medium. The suitability of dissolution medium (0.5-2.5% Phytoconstituents based Saponin blend in water) relative to the other dissolution medium is evaluated. The selected dissolution media is used for the evaluation of curcumin release.
The results indicated that solubility of curcumin increased with increase in saponin blend concentration and maximum solubility is found in water containing 2% w/v of solution. There is no significant change found after 2% w/v of Solution.
Table 1. Solubility analysis of Curcumin in Various Solution
Medium Concentration µg/ml (n=3)
Water 152±5.1
0.1 N HCl 132±3.4
0.5% w/v Phosphate Buffer (pH 6.8) 192±3.6
0.75% w/v SLS 304±4.3
0.75% w/v SLES 365±2.2
1% w/v Phosphate buffer (pH 7.4) 695±6.7
1.5% w/v Saponin blend 782±5.8
2% w/v Saponin blend 982±4.8

Table 2. In vivo Bioavailability Study
Curcumin content
in blood (ng/g)
Time (h) Curcumin Enhanced Curcumin Complex
0 0 0
1 3.11 9.85
2 7.32 7.29
3 5.42 6.24
4 11.41 93.19
5 9.31 21.22
6 7.67 17.95
7 8.2 24.33
8 1.32 9.63
9 2.19 8.59

The peak absorption of curcumin from curcumin complex occurred at 4hr i.e., 93.19 furthermore, curcumin persisted in small amounts in the blood till 9hr beyond which measurements are not made due to low absorption.

Preparation of curcumin neutraceuticals
Curcumin neutraceuticals are prepared using a pH-driven method. Briefly, an acidic aqueous surfactant solution is prepared by dissolving saponin in 20 mM phosphoric acid at concentrations of 2, 4, 8, 12 and 16 mg/mL (pH 3). A basic aqueous curcumin solution (2.0 mg/mL) is prepared by dissolving curcumin in 30 mM sodium hydroxide solution (pH 12). Curcumin solutions are then added to saponin solutions (1:1 v/v) while being continuously stirred at 500 rpm on a magnetic stir plate. The resulting solution is incubated for 0.5 h at room temperature and then centrifuged at 10,000 g for 10 min to remove any free curcumin and larger particulate matter. It is proposed that this process leads to the formation of saponin-coated curcumin neutraceuticals due to movement of curcumin molecules into the hydrophobic cores of saponin micelles. After the basic curcumin is added into the acid saponin solutions, the pH rapidly increased to around pH 6.5 within 10 second. Thus, the whole process is very fast and the system reached equilibrium in a short time
,CLAIMS:1. An herbal composition comprising relates to curcumin by synergy phytoconstituents based saponin, solvents such as isopropanol, ethanol, acetone, and ethylene dichloride and others are typically used to prepare oleoresins of turmeric, which may typically contain about 30% curcumin, 30% volatile oils, 30% fixed oils, and 10% polysaccharides.
2. The herbal composition as claimed in claim 1, wherein the herbal composition used to improve in vivo bioavailability of curcumin.
3. The herbal composition as claimed in claim 1, wherein the the dried turmeric rhizomes generally contain about 5% curcumin.
4. The herbal composition as claimed in claim 1, wherein Saponin isolated from medicinal plants is a naturally occurring bioorganic molecule with high molecular weight and its aglycone nucleus having 27 to 30 carbon atoms besides one or two sugar moieties containing at least 6 or 12 carbon atoms respectively.
5. The herbal composition as claimed in claim 1, wherein Curcumin is practically insoluble in aqueous medium hence it has been designed with natural phytoconstituents blend of Saponin as a granulating agent to improve poor characteristic solubility and bioavailability.
6. The herbal composition as claimed in claim 1, wherein composition also consists of a natural saponin isolated from Satavari, Aloevera, Liquorice and guar gum and does not contain any synthetic polymers and Curcumin also derived from the natural components of turmeric rhizome.
7. The herbal composition as claimed in claim 1, wherein composition also consists of a Curcumin which derived from the natural components of turmeric rhizome.
8. A method of preparation of curcumin nutraceuticals composition comprises of;
a. Curcumin neutraceuticals are prepared using a pH-driven method.
b. An acidic aqueous surfactant solution is prepared by dissolving saponin in 20 mM phosphoric acid at concentrations of 2, 4, 8, 12 and 16 mg/mL (pH 3).
c. A basic aqueous curcumin solution (2.0 mg/mL) is prepared by dissolving curcumin in 30 mM sodium hydroxide solution (pH 12).
d. Curcumin solutions are then added to saponin solutions (1:1 v/v) while being continuously stirred at 500 rpm on a magnetic stir plate.
e. The resulting solution is incubated for 0.5 h at room temperature and then centrifuged at 10,000 g for 10 min to remove any free curcumin and larger particulate matter.
f. Basic curcumin is added into the acid saponin solutions, the pH rapidly increased to around pH 6.5 within 10 second