FIELD OF THE INVENTION

The invention relates to a stable complex of a cyclic, carbocyclic, or heterocyclic compound containing metals of the periodic system. The invention also relates to medicinal preparations containing organic active ingredients such as diarylheptanoids. The invention also relates to medicinal preparations of undetermined constituents containing material from plants, or derivatives thereof. Plants include Zingiberaceae, Withania, Boswellia, Saptrees and Punica.

BACKGROUND OF THE INVENTION

Turmeric is a rhizomatous herbaceous perennial plant (Curcuma longa) of the ginger family. The medicinal properties of turmeric, the source of curcumin, have been known for thousands of years. Curcuma longa has been traditionally used in Asian countries as a medical herb due to its antioxidant, anti-inflammatory, anti-mutagenic, antimicrobial, and anticancer properties.

Diarylheptanoids and sesquiterpenoids present in Curcuma longa rhizome are believed to be responsible for producing many of the important biological and medicinal activities of turmeric. As the name suggests, diarylheptanoids (diphenylheptanoids) contain the 1, 7-diphenylheptane skeleton. The major diarylheptanoids are the curcuminoids which primarily includes curcumin, demethoxycurcumin and bisdemethoxycurcumin. Curcumin has limited bioavailability because of its low-intestinal absorption, and rapid metabolism. Therefore, there is a need for enhancing the bioavailability in order to increase the pharmacological effects of this bioactive compound.

One way to enhance the bioavailability of curcuminoid is by forming complexes with metals or forming derivatives of curcuminoids. The a,P-unsaturated 0-diketo moiety of curcuminoids is an excellent chelating agent. Curcuminoid-metal complex not only change the physico-chemical property of the curcuminoids but also affect the biological reactivity of metals. Hieu et al synthesized curcumin-metal complexes and investigated its solubility in water using ultrasonic waves. Metal ions used for complex formation are Fe (III), Ca (II), Zn (II). These complexes also showed better antioxidant activity and antimicrobial activity than the free form of curcumin. Curcumin-metal complexes are already known to be useful for the treatment ofAlzheimer’s disease, Cancer, and arthritic/rheumatic activity. Curcumin-metal complexes are known to show Anti-microbial/anti-fungal activity and anti-viral/anti-HIV activity. Ostrowski et al compared the stability of curcumin-metal complexes and demethoxycurcumin-metal complexes. For some metals, curcumin-metal complexes are more stable than demethoxycurcumin-metal complexes and for some metals vice versa. The absorption spectrum of curcumin is altered on complexing with metals, now Curcumin metal complexes are used as radio diagnosis agent (Kunwar. A et al., Transport of liposomal and albumin loaded curcumin to living cells: An absorption and fluorescence spectroscopic study).

US patent 4263333 claiming a water-soluble curcumin-metal complex capable of producing varying hues of the same colours for use in foodstuffs. The metal ions used are stannous ion and Zinc ions and sources of curcumin are spray dried turmeric, single and multiple extract of turmeric, turmeric oleoresin and synthesized curcumin.

US patent 4368208 claiming method of preparing water soluble curcumin-gelatine colouring agent for food.

US patent 8759562 discloses Zn (Il)-curcumin complex, its structure and method of preparation.US patent publication 2009/0098226 is primarily directed towards Zn-curcumin complex but also discloses a cosmetic formulation comprisingderivative, or an association with curcumin to enhance the activity of curcumin. Metals used are calcium, magnesium, copper, bismuth, zinc, aluminium, manganese, antimony, tin, gold, silver, chromium, cobalt, vanadium, boron and titanium. Composition is used for skin disease, cosmetic use etc. The formulation is directed towards cosmetic use and not for medicinal use.

WO2012/136574 discloses an oral care composition comprising a coordination complex in which a metal cation is complexed to one or more ligands which are derived from one or more curcumin compounds. OBJECTS OF THE INVENTION

The principal object of the invention is a composition of diary lheptanoid metal complex compounds.

Another object is to develop said diary lheptanoid metal complex compounds from natural sources such as plant extracts (e.g., turmeric oleoresin or extract).

Another object of the invention is the use of diarylheptanoid metal complex compounds in the field of medicine, nutrition and animal health.

SUMMARY OF THE INVENTION

The disclosure pertains to a composition of Diarylheptanoid compounds of the formula-I:

The Diarylheptanoid compounds are making a complex with a metal ion. Wherein, R R ₂ , R3, and R4 are chosen from a group of hydrogen, -OH, -OCH3, ” OCOCH3, -OCO-CHR-NH2, O- Piperoyl, -O-galloyl and -O- terpenoid. Li and L ₂ are chosen from a group of -OH, -OH ₂ , CT, amine, Diarylheptanoids, flavonoids, phenolic acids, stilbenes, and tannins. DI and D2 are chosen from a group of single and double bond. M is chosen from a group of alkali metals, alkaline earth metal, transition metals, lanthanides, and actinides. Preferably Diarylheptanoid is Diphenylheptanoid with two Phenols groups and complexed with Calcium ion.

In an embodiment some Diarylheptanoid compounds make a mixed ligand or a binary ligand compound. When a complex is formed between a metal ion and two Diarylheptanoid compound a formula-II is formed as showed in Fig 6. Diarylheptanoid compounds attached to a single metal ion could be identical or different. The preferred metal is alkaline earth metal and more preferably calcium and the calcium is derived from CaCl ₂ or lime. Another aspect disclosed is the method of preparation of composition of Diarylheptanoid compounds, the source of the Diarylheptanoids is from oleoresin of turmeric, purified curcuminoid, spent turmeric or a combination thereof; and the calcium is derived from CaCI ₂ or lime. A method of producing consist of the step of dissolving spent turmeric and calcium source in organic solvent, ammonia can be added for protonation. Cool the mixture to room temperature to precipitate out composition of Diarylheptanoid compounds.

Another aspect is the usage and the dosage form for such use, the composition is administrable in oral, parenteral, topical or transdermal form to human and animals; and dosage form further includes pharmaceutically acceptable carrier, diluent or selected from a group of powders, sprays, ointments, pastes, creams, lotions, gels, solutions, patches and inhalants.

The dosage form can be used for preventing coccidia infection in birds, improving meat quality of birds, increases in the shell thickness of poultry eggs, improved weight gain in poultry birds, increased milk yield, preventing hypocalcaemia in humans and animals, increased feed conversion ratio in animals, improves bone density and strength, lowering blood glucose in humans and animals, immunomodulatory activity, hepatoprotective activity, anti-inflammatory activity, analgesic activity, treating hyperlipidemia, preventing the drug induced dyslipidemia, treating stress, preventing and treating Alzheimer’s disease, antioxidant activity, antimicrobial activity, preventing metal toxicity in humans and animals, capable of absorption of essential metals, and Formula-I has higher efficacy than Diarylheptanoid.

BRIEF DESCRIPTION OF DRAWINGS

The above and other aspects, features, and advantages of certain exemplary embodiments of the present disclosure will be more apparent from the following description taken in conjunction with the accompanying drawings in which:

FIG.l illustrates a schematic view on preparation of DPH-lime complex.

FIG 2 illustrates a schematic view on preparation of DPH-calcium complex.

FIG 3 illustrates FTIR spectrum of DPH- calcium complex. FIG 4 illustrates UV-visible spectrum of DPH- calcium complex.

FIG 5 Schematic representation of DPH- metal complex of formula I.

FIG 6 Schematic representation of DPH- metal complex of formula II.

DETAILED DESCRIPTION

The disclosure pertains to a stable complex, and a process for preparing said complex. Complex is formed by the reaction of diarylheptanoids (diphenylheptanoids) (turmeric diarylheptanoids) or diarylheptanoid derivatives of turmeric with certain metal ions. Invention also relates to the different uses of the metal-turmeric diarylheptanoid complex.

As used herein, the term “diphenylheptanoids” is an “diarylheptanoid” but both the compounds are referred to as DPH throughout the specification if not specified otherwise.

The disclosure further relates to a stable complex formed by the reaction of individual purified diarylheptanoids with metal ion, as shown in Formula-I:

The disclosure further relates to a stable complex formed by combination of individual purified DPH metal complexes in different ratios. A composition of Formula-I compounds shall be referred to as DPH-metal or DPH-(name of the metal ion).

An aspect of the disclosure is a composition of Diarylheptanoid compounds forming a metal complex of Formula-I, where Ri, R2, R3, and R4 are chosen from a group of hydrogen, -OH, - OCH ₃ , " OCOCH3, -OCO-CHR-NH2, -O-Piperoyl, -O-galloyl, and -O- terpenoid. Li and L ₂ are chosen from a group of -OH, -OH2, CT, amine, Diarylheptanoids, flavonoids, phenolic acids, stilbenes, and tannins. M is selected from a group of alkali metals, alkaline earth metal, transition metals, lanthanides, and actinides.

In an embodiment, Li and L2 from Formula-I together with the M to which they are bounded form a ring with a compound selected from the group consisting of Diarylheptanoids, flavonoids, phenolic acids, stilbenes, tannins. More preferably Li and L2 together with the M to which they are attached form a complex with a Diarylheptanoids of the formula II as shown Fig 6.

In yet another embodiment, the source of the Diarylheptanoids of Formula-I is from oleoresin of turmeric, purified curcuminoid, spent turmeric or a combination thereof; and the M is calcium, it is derived from CaCI ₂ or lime.

Suitable DPH sources include oleoresin of turmeric, debittered or defatted oleoresin of turmeric, or purified curcuminoid, spent turmeric and turmeric powder. Debittered or defatted oleoresins of turmeric or purified curcuminoids are obtained by separating curcuminoids from oleoresin of turmeric by crystallisation.

As used herein, spent obtained either by removal of curcuminoids alone from oleoresin of turmeric or by removing both curcuminoids and oil from oleoresin of turmeric shall be referred to as “spent turmeric”. Spent turmeric further includes some curcuminoids which did not crystallise out when a solvent extract of turmeric rhizome is cooled and other diarylheptanoids like but not limited to dihydrocurcumin, dihydrobisdemethoxycurcumin, dihydrodemethoxycurcumin, resins, carbohydrates, proteins, fat, and fibres. Curcuminoids that did not crystallise in the crystallisation step is isolated from spent turmeric and the resulting compound without any curcuminoid can also be isolated by forming complexes with metal ions. Resulting compound without any curcuminoid contains DPH like but not limited to dihydrocurcumin, dihydrobisdemethoxycurcumin, dihydrodemethoxycurcumin.

Each DPH present in turmeric can be isolated by forming complexes with metal ions. An aspect of the DPH-metal complex has enhanced bioavailability and bioactivity compared to standard DPH. Derivatives of DPH of turmeric can form complexes with metals. Some DPH derivatives metal complex has enhanced bioavailability and bioactivity. Individual purified diarylheptanoid metal complexes can be combined with other purified diarylheptanoid metal complexes in different ratios. Combination composition has enhanced bioavailability and bioactivity. Diarylheptanoids or its derivative- metal complex can be combining with essential oils in 1:99 to 99:1 w/w ratio.

Curcuminoids include curcumin, demethoxycurcumin, bisdemethoxycurcumin. Other DPH includes but not limited to dihydrocurcumin, dihydrodemethoxycurcumin, dihydrobisdemethoxycurcumin, l-(3, 4-dihydroxyphenyl)-7-(4-hydroxyphenyl)-l, 6-heptadien- 3, 5-dione or 4’-hydroxybisdemethoxycurcumin, letestulanin B, 5-hydroxy-l, 7-bis (4- hydroxyphenyl)-3-heptanone, 1 ,7-bis(4-hydroxyphenyl)-3,5-heptanediol, 1 ,7-bis(4-hydroxy-3- methoxyphenyl)-l,4,6-heptatrien-3-one, 1, 7-Bis (3, 4, 5-trimethoxyphenyl)-l, 6-heptadiene-3,

5-dione, 1, 7-Bis (4-hydroxyphenyl)-l, 6-heptadiene-3, 5-dione, 1, 7-Bis (2-hydroxyphenyl)-l,

6-heptadiene-3, 5-dione, 1, 7-Bis (2, 4, 5 -trimethoxyphenyl)- 1, 6-heptadiene-3, 5-dione, l-(4- hy dr oxyphenyl)-7-(4-hydroxy-3 -methoxyphenyl)- 1, 4, 6-heptatrien-3-one, l-(4-hydroxyphenyl)-

7-(4-hydroxy-3-methoxyphenyl)-4, 6- heptadi en-3 -one, 1, 7-bis (4-hy dr oxy-3 -methoxyphenyl)-4,

6-heptadien-3-one, 1, 7-Bis (3, 4-dihydroxyphenyl)-l, 6-heptadiene-3, 5-dione, 1, 7-Bis (4- hydroxy-3, 5-dimethoxyphenyl)-l, 6-heptadiene-3, 5-dione, 1, 7-Bis (3, 4-dihydroxy-5- methoxyphenyl)-l, 6-heptadiene-3, 5-dione, 1, 7-Bis (4-hy droxy- 3 -methoxyphenyl) heptan-3, 5- dione, 1, 7-Bis (4-hydroxyphenyl) heptan-3, 5-dione, 1, 7-Bis (4-methoxyphenyl)-l, 6- heptadiene-3, 5-dione, 1, 7-Bis (2-hydroxy-5-methoxyphenyl)-l, 6-heptadiene-3, 5-dione, 1, 7- Bis (3, 4-dimethoxyphenyl)-l, 6-heptadiene-3, 5-dione, l-(4-hydroxy-3-methoxyphenyl)-7-(4- hydroxy-3,5-dimethoxyphenyl)-4, 6-heptadien-3-one, 1 -hydroxy- l-(4-hydroxyphenyl)-7-(4- hydroxy-3-methoxyphenyl)-6-hepten-3, 5-dione, l-(3,4-dihydroxyphenyl)-7-(4-hydroxy-3- methoxyphenyl)-6-hepten-3, 5-dione, 5-hydroxy-l, 7-bis(3,4-dihydroxyphenyl)-l-hepten-3-one, l-(4-hydroxy-3-methoxyphenyl)-7-(3, 4-dihydroxyphenyl)-l, 6-heptadiene-3, 5-dione, l-(4- hydroxyphenyl)-7-(3, 4-dihydroxyphenyl)- 1 , 6-heptadiene-3, 5-dione, l-(3,4-Dihydroxyphenyl)-

7-(3-methoxy-4-hydroxyphenyl)-l,6-heptadiene-3, 5-dione, l-(4-Hydroxyphenyl)-7-(4-hydroxy-

3-methoxyphenyl)-l,6-heptadiene-3, 5-dione, l-(4-Hydroxyphenyl)-7-(4-hydroxy-3- methoxyphenyl)-heptan-3, 5-dione, 5-hydroxyl-l-(4-hydroxy-3-methoxyphenyl)-7-(4- hydroxyphenyl)-4,6-heptadiene-3-one, 5-hydroxyl-l,7-bis(4-hydroxy-3-methoxyphenyl)-4,6- heptadiene-3-one, l,7-bis(4-hydroxyphenyl)-l-heptene-3, 5-dione, 5-hydroxyl-7-(4-hydroxy-3- methoxyphenyl)-l-(4-hydroxyphenyl)-4,6-heptadiene-3-one, 3-hydroxy-l,7-bis-(4- hydroxyphenyl)-6-heptene-l, 5-dione, l,5-dihydroxy-l-(4-hydroxy-3-methoxyphenyl)-7-(4- hydroxyphenyl)-4,6-heptadiene-3-one, l,5-dihydroxy-l-(4-hydroxyphenyl)-7-(4-hydroxy-3- methoxyphenyl)-4,6-heptadiene-3-one, l,5-dihydroxy-l,7-bis(4-hydroxy-3-methoxyphenyl)-4,6- heptadiene-3-one, l,5-dihydroxy-l,7-bis(4-hydroxyphenyl)-4,6-heptadiene-3-one, l,5-epoxy-3- carbonyl- 1 ,7-bis(4-hydroxyphenyl)-4,6-heptadiene, and Cyclocurcumin.

Derivatives of DPH are formed by reacting DPH with alkylhalides, acid anhydrides, amino acids, polyethylene glycol, polyphenols, Piperin, gallic acid and carbohydrates.

Metal ions used for forming complexes include alkali metals, alkaline earth metals, transition metals, lanthanides, and actinides. Metals are from a salt or other natural source. Calcium is the preferred one and it may be in salt form or from natural sources. Calcium salt may be calcium chloride, calcium acetate, calcium carbonate, calcium oxide or calcium hydroxide. Natural sources include but not limited to lime, chalk, eggshells, snail shells, sea shells, pearls, Oyster shells.

DPH have been isolated from seeds, fruits, leaves, roots, rhizomes and barks of plants of different families such as Zingiberaceae, Myricaceae, Betulaceae, Aceraceae, Leguminosae, Solanaceae and Burseraceae. Some plants include but not limited to Curcuma, Withania, Boswellia, Saptrees and Punica.

Curcuminoid acts as a ligand and forms stable complexes with almost all the metal ions and nonmetals. In all the complexes, curcuminoid behaved as a monobasic bidentate ligand in which the intramolecularly hydrogen-bonded enolic proton is replaced by the metal ion. Thus far, different methodologies have been used to synthesize metal-curcuminoid complexes. In order to form a curcuminoid-metal complex, it is necessary to obtain the curcuminoid and the metal in a solution format in order for the reaction to occur.

Stable metal complex is formed by combining DPH or its derivatives with certain metals capable of complexing with DPH or its derivatives in the ratio of 2: 1 to 1: 1 mole of DPH or its derivatives to metal. The colour of the complex formed depends upon the ratio of the DPH or its derivatives to the metal and type of metal ion used. Generally, the 1 : 1 complex of divalent metals is synthesized by mixing methanolic solution of curcumin with metal salt at a molar ratio of 1 : 1. In one embodiment of the invention, purified curcuminoid form complex with calcium. The source of calcium may be calcium salt or from natural sources. The ratio of curcuminoid: calcium salt or lime is 5:1 to 1 :1, alternatively 3: 1 to 1:2 on mol bases.

In another embodiment of the invention, Oleoresin of turmeric form complex with calcium. The source of calcium may be calcium salt or from natural sources. The ratio of Oleoresin of turmeric: calcium salt or lime is 99:1 to 1:99 w/w.

In another embodiment, DPH of spent turmeric obtained after removal of curcuminoids from oleoresin form complex with calcium. The source of calcium may be calcium salt or from natural sources. The ratio of spent turmeric: calcium salt or lime is 99:1 to 1:99 w/w. preferred ratio of DPH of spent turmeric and calcium is 10: 1 w/w.

In another embodiment, DPH of spent turmeric obtained after removal of curcuminoids and oil from oleoresin form complex with calcium. The sources of calcium may be calcium salt or from natural sources. Calcium salt may be calcium chloride, calcium acetate, calcium oxide or calcium carbonate or calcium hydroxide. Natural sources include but not limited to lime, chalk, eggshells, snail shells, sea shells, pearls, Oyster shells. The ratio of spent turmeric: calcium salt or lime is 99: 1 to l:99w/w. Preferred ratio of DPH of spent turmeric and calcium is 10:lw/w.

In another embodiment, DPH of spent turmeric after removal of curcuminoids that did not crystallise in the crystallisation step form complex with calcium. Said DPH of spent turmeric after removal of curcuminoids that did not crystallise in the crystallisation step includes but not limited to dihydrocurcumin, dihydrodemethoxycurcumin, dihydrobisdemethoxycurcumin, terpecurcumin and cyclocurcumin. The source of calcium may be calcium salt or from natural sources. The ratio of spent turmeric: calcium salt or lime is 99: 1 to 1 :99.

In another embodiment, each purified DPH form complex with calcium. The source of calcium may be calcium salt or from natural sources. The ratio of purified DPH: calcium salt or lime is 5: 1 to 1 :1.

In one embodiment, dihydrocurcumin form complex with calcium. The source of calcium may be calcium salt or from natural sources. The ratio of purified DPH: calcium salt or lime is 5: 1 to 1: 1. In one embodiment, DPH form complex with calcium salt. The calcium salt may be calcium acetate. The ratio of DPH: calcium salt is 5:1 to 1:1.

In one embodiment, purified curcumin form complex with calcium. The source of calcium may be calcium salt or from natural sources. The ratio of purified curcumin: calcium salt or lime is 5: 1 to 1 :1.

In one embodiment DPH- calcium complex and purified curcumin complex is combined in 5 : 1 to l: lratio. The combination composition has enhanced bioactivity and bioavailability of DPH- calcium complex compared to its natural counterpart, such as DPH.

In one embodiment of the invention, DPH form complex with calcium. The colour of Calcium - DPH complex is brick red. The complex is partially soluble in DMSO, DMF, and ethyl acetate.

In one embodiment, DPH forms complexes with transition metals. In one embodiment, DPH forms complexes with alkali metals. In another embodiment, DPH forms complexes with alkaline earth metals.

In one embodiment, DPH derivatives form complexes with transition metals. In one embodiment, DPH derivatives form complexes with alkali metals. In another embodiment, DPH derivatives form complexes with alkaline earth metals.

In one embodiment diacetylcurcumin forms complexes with calcium. In another embodiment diglutarylcurcumin forms complexes with calcium. In another embodiment dialkylcurcumin forms complexes with calcium. In another embodiment curcumin glycosides form complexes with calcium. In another embodiment amino acid conjugates of curcumin form complexes with calcium.

In addition to DPH, other compounds from turmeric can also form complex with metal ion. Other components include but not limited to resin.

Present invention relates to a composition of DPH and calcium complex, wherein the DPH in the composition ranges from 5% to 80% and Calcium in the composition ranges from 2 to 20%.

In one embodiment, composition of DPH and lime complex, composition comprising Curcuminoids 10-15% and calcium 8-10%. In another embodiment, composition of DPH and calcium complex, composition comprising Curcuminoids 15-20% and calcium 8-10%.

In one preferred embodiment, composition of DPH - calcium complex has at least 10% diarylheptanoid complex compound.

In another preferred embodiment, composition of DPH - calcium complex has not less than 10% curcuminoids and not less than 8% calcium

In one embodiment, composition of DPH- calcium complex has about 12-15% curcuminoids, about 0.5% dihydro curcuminoids, about 31% polyphenols, about 23% triterpenoids, about 0.13% carbohydrates, about 0.5% protein and about 8% calcium.

In another embodiment, composition of DPH-calcium complex has about 15-20% curcuminoids, about 0.5% dihydro curcuminoids, about 30% polyphenols, about 23% triterpenoids, about 0.15% carbohydrates, about 0.8% protein and about 8% calcium.

The formation of DPH- calcium complex is confirmed by FTIR and UV Visible spectra compared to Curcuminoids.

FTIR spectra clearly showed the formation of complexes as the bands assigning to the carbonyl group C=O shifted to the lower wave number when compared with that of the free ligands. As shown in Fig 3, infrared (IR) spectrum of curcuminoids shows a strong band at 1619 cm -1 due to the stretching of the dicarbonyl and the intramolecularly hydrogen-bonded enol functions, respectively. In the IR spectra of the Calcium complex, the band at 1619 cm -1 of the ligand is absent and, instead, a weak band assignable to the stretching of the coordinated carbonyl moiety appeared at -1580 cm-1.

The band in the region 3600 cm-1 for enolic O-H present in curcuminoids disappeared in the spectra of complex indicating the replacement of enolic proton by the metal cation during complexation.

The carbonyl groups involved in bonding with the metal ion is further supported by the appearance of two medium-intensity bands at -420 cm -1 and -470 cm -1 in DPH- metal complex assignable to Ca -O bonding. As shown in Fig 4, UV-visible spectrum of the curcuminoids in DMSO showed absorption maximum at 433 nm assigned to the band it — it* of curcumin. Compared with curcuminoid, the Calcium complex in DMSO shows a maximum absorption shifted to 424 nm with a shoulder at 448 nm, attributed to a curcumin — metal (M2+) charge transfer, specific complex formed.

In one embodiment DPH or its derivative forms complexes with natural lime. Lime in water solution supplies Ca ions and act as an alkali for deprotonation of curcuminoids. DPH-lime complex is a natural product prepared from turmeric and Lime.

As curcuminoid is not water soluble to any great extent, the curcuminoid must be solubilized with various organic solvents. These solvents typically can include methanol, ethanol, and acetone. On the other hand, metals used in the reaction are typically in a salt format that can be solubilized in aqueous solutions.

Present invention also provides a process of preparing DPH- metal complexes. Oleoresin of turmeric or pure curcuminoid or spent turmeric is dissolved in a solvent. Metal ion is also dissolved in a solvent and the two solutions are mixed with stirring. The precipitate formed is filtered, washed with a solvent and dried. Dried precipitate is the DPH- metal complex.

In an alternative embodiment DPH -metal complexes are prepared by a process in which Oleoresin of turmeric or pure curcuminoid or spent turmeric is dissolved in a solvent. Lime is dispersed in a solvent and added slowly to DPH solution. Slurry formed is stirred and complex is precipitated. Wash the precipitate and dried. Dried precipitate is the DPH- metal complex wherein the metal is from a natural source.

Solvents used for complex formation include alcohols, acetone, dimethyl formamide (DMF).

In order to enhance the complex formation various bases like pyridine, Dimethylaminopyridine, NH ₃ , NaHCO ₃ , NaOAc, NaiCCh and NaOH can be used.

In one preferred embodiment method of preparing DPH- lime complexes is provided. Spent turmeric after removal of curcuminoids is dissolved in methanol. Lime dispersed in water is added slowly to the spent turmeric-methanol solution. Slurry obtained is stirred for 2-3 hrs at room temperature. Formed precipitate is filtered and washed with water followed by methanol. Dried at 80°C to form powder of DPH - Calcium complex. In another embodiment of method of preparation of DPH -calcium complex, spent turmeric obtained after removal of curcuminoids is dissolved in methanol. Calcium chloride is dissolved in methanol and added to spent turmeric- methanol solution with stirring for 15 minutes. Ammonia is added slowly to the above solution and stirred for 30 minutes. Excess methanol is added and stirs the mixture for 2 hours at 60°C. Cool the mixture to room temperature and precipitated calcium complex is filtered. Wash the precipitate with methanol and dried at 60°C to form powder of DPH -calcium complex.

Metals can form binary complexes with DPH and other polyphenols like flavonoids, phenolic acids, stilbenes, tannins. Metals can also form binary complexes with DPH and terpecurcumins, curcumin conjugated with amino acids and peptides or piperine.

In one embodiment DPH and other natural bioactive hydroxycinnamic acids can form complex with metal ions. Metal ions used for forming complexes include alkali metals, alkaline earths, transition metals, lanthanides, and actinides. Metals are from a salt or other natural source. Natural sources include but not limited to lime, chalk, eggshells, snail shells, sea shells, pearls, Oyster shells. Bioactive hydroxycinnamic acid include but not limited to Caffeic acid, Cichoric acid, Cinnamic acid, Chlorogenic acid, diferulic acid, Coumaric acid, Ferulic acid, Sinapic acid etc.

Flavonoids found in fruits and vegetables like quercetin, rutin, kaempferol, morin, hesperetin, naringenin, apigenin, luteolin, chrysin and genistein, can also form complex with metal ions along with DPH.

The composition of the present invention can be administered alone, or it can be mixed with a pharmaceutically acceptable carrier or diluent depending on the mode of administration. Oral administration is preferred, but parenteral and topical or transdermal administration can be used. For oral administration, the composition of this invention can be used in the form of tablets, capsules, granules, powders, lozenges, syrups, elixirs, solutions, suspensions and the like, in accordance with the standard pharmaceutical practice. When the dosage unit form is a capsule, it can contain a liquid carrier such as fatty oil. In addition, unit dosage forms can contain various other materials that modify the physical form of the dosage unit, for example, coatings of sugar, shellac, or other enteric agents. The phrase “pharmaceutically acceptable carrier” as used herein means a pharmaceutically acceptable material, composition or vehicle, such as a liquid or solid filler, diluent, excipient, solvent or encapsulating material. Each carrier must be “acceptable” in the sense of being compatible with the other ingredients of the formulation and not injurious to the patient. Some examples of materials which can serve as pharmaceutically acceptable carriers include: (1) sugars, such as lactose, glucose and sucrose: (2) starches, such as corn starch and potato starch; (3) cellulose, and its derivatives, such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; (4) powdered tragacanth; (5) malt; (6) gelatin; (7) talc; (8) excipients, such as cocoa butter and suppository waxes; (9) oils, such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and soybean oil; (10) glycols, such as propylene glycol; (11) polyols, such as glycerin, sorbitol, mannitol and polyethylene glycol; (12) esters, such as ethyl oleate and ethyl laurate; (13) agar; (14) buffering agents, such as magnesium hydroxide and aluminum hydroxide; (15) alginic acid; (16) pyrogen-free water; (17) isotonic saline; (18) Ringer's solution; (19) ethyl alcohol; (20) phosphate buffer solutions; and (21) other non-toxic compatible substances employed in pharmaceutical formulations.

Dosage forms for the topical or transdermal administration include powders, sprays, ointments, pastes, creams, lotions, gels, solutions, patches and inhalants. The composition may be mixed under sterile conditions with a pharmaceutically acceptable carrier, and with any preservatives, buffers, or propellants that may be required.

In an embodiment daily dose to cows is 5 g to 10g of DPH- calcium complex. In an alternative embodiment, the effective dosage ranges from 5mg to 20mg per kg bodyweight per day for cows.

In an embodiment daily dose to birds is 500g in 1000kg feed or 0.5mg/bird daily. In an alternative embodiment, the effective dosage ranges from 0.1 mg to Img per kg bodyweight.

DPH-metal complex is hydrolysable in stomach pH to give slow and sustained release of active curcuminoids and calcium ions.

In one embodiment, composition of the invention is used in the field of animal health and nutrition. In one embodiment, composition of DPH-metal or its derivative-calcium complex is found to have anticoccidial effect. Coccidiosis is a protozoan disease of birds caused by virulent and pathogenic Eimeria species and causing considerable economic loss in poultry industry. Chickens fed with DPH-calcium complex showed no bloody diarrhoea after 15 days of treatment. Whereas in groups fed with amprolium and regular turmeric extract, bloody diarrhoea is minimized at the end of the study. Mortalities are reduced to zero in group treated with DPH- calcium complex. The DPH-metal, especially DPH-calcium was also found to have Immunomodulatory activity, improves bone density and strength, increases in the shell thickness of poultry eggs, improved weight gain in poultry birds, increased feed conversion ratio in animals, and increased milk yield.

In another embodiment, composition of the invention is used for preventing hypocalcaemia. Clinical hypocalcemia is the most recognized disease in dairy cattle by dairy farmers, with an incidence rate around 5%. Incidence increases with higher milk production and successive lactation. Animals fed with DPH- calcium complex showed a significant improvement in serum calcium levels compared to animals fed with Agrimin forte.

In another embodiment, composition of the invention is used to improve the meat quality in animals. Birds fed with normal poultry feed along with DPH- calcium complex showed an improvement in meat quality.

In another embodiment, composition of the invention is used to prevent Necrotic enteritis in animals.

DPH or its derivative-metal complex has antioxidant activity, antimicrobial activity. Complexation with DPH or its derivatives reduces the toxicity of the metals. DPH or its derivative-metal complex composition enhances the bioavailability of actives like curcumin, demethoxycurcumin (DMC) bisdemethoxycurcumin (BDMC) and its functional derivatives and other components in blood plasma and tissues. Composition of diarylheptanoids or its derivative- metal complex has anti-inflammatory activity, analgesic activity, for treatment of hyperlipidemia, for preventing the drug induced dyslipidemia, for the management of stress and depression, blood glucose lowering property, antidiabetic effect and hepato protective activity.

The presence of essential metals (sometimes referred to as trace minerals) in sufficient and biologically available forms in the diet is essential for maintaining the health and well-being of livestock and poultry. It has been observed that the absorption of essential metals has significantly improved when they are administered in Diarylheptanoids complex form. The oral calcium administration in the animal studies showed different bioavailability for calcium salt and DPH-complex. It was observed that the bio-absorption capacity of calcium significantly improved when administered in a DPH-complex form as compared to a calcium salt. Complexes of Diarylheptanoids with some metals lead to better antioxidant properties from the complex. This could be useful in the field of cancer treatment. Nano curcumin metal complex has a practical application in the drug delivery system.

Present invention relates a DPH or its derivative-calcium complex, used in animal feed to enhance the availability of calcium and DPH in animals. Present invention relates a DPH or its derivative -Calcium complex, to enhance the bioavailability of calcium and DPH in humans. Amino acid conjugates of DPH -calicum complex is used to enhance the bioavailability of calcium and DPH in animals and humans. Possible amino acids include but not limited to Glycine, Alanine, Valine, Glutamic acid, serine, and cysteine. DPH or its derivative- calcium complex showed enhanced bioavailability of curcumin, demethoxycurcumin (DMC), bisdemethoxycurcumin (BDMC) and its functional derivatives and other DPH in blood plasma as compared to regular turmeric extract. Some embodiment provides a DPH or its derivativecalcium complex to enhance the availability of curcumin, demethoxycurcumin (DMC), bisdemethoxycurcumin (BDMC) and other DPH in major tissues of rats. The major tissues are brain, liver, kidneys, lungs, heart etc.

In another embodiment, composition of DPH or its derivative -calcium complex showed antiinflammatory activity. In an acute model of inflammation in rats, the composition showed significantly better inhibition of inflammation when compared with regular turmeric extract. In chronic anti-inflammatory studies, the composition was significantly better in prevention and treatment of inflammation in rats when compared with regular turmeric extract.

In another embodiment, composition of DPH or its derivative-calcium complex showed analgesic activity. Analgesic activity of the composition was significantly higher than regular turmeric extract in animal models of analgesia.

Composition of the present invention significantly prevented the drug induced dyslipidemia in rats and was also highly effective in the treatment of hyperlipidemia in animals. In another embodiment, composition of DPH or its derivative -calcium complex is found to be significantly better than regular turmeric extract in the management of stress and depression in animals.

The blood glucose lowering property of the composition was significantly better than regular turmeric extract in oral glucose tolerance test (OGTT) in rats. Composition has also shown significant antidiabetic effects in drug induced diabetes in rats. There was significant increase in insulin levels and decrease in glycosylated haemoglobin (HbAlc) levels in rats.

The hepatoprotective activity of the composition was significantly better than regular turmeric extract in both preventive and treatment models of alcohol induced liver injury in rats. There was significant decrease in SGOT, SGPT, alkaline phosphatase and serum bilirubin levels in the group administered with DPH-metal complex (composition with Formula-I cinpounds).

The composition of the invention is used as anti-tumour agent. The composition has antioxidant activity and antimicrobial activity. Composition of the invention is used for preventing and treating Alzheimer’s disease.

Other modifications and variations to the disclosure are apparent to those skilled in the art from the foregoing disclosure and teachings. The scope of the invention is not limited to the turmeric extract prepared in the above illustrations, and person killed in the art can use extracts prepared from otherknown methods. Thus, while only certain embodiments to showcase the applicability of the invention have been specifically described herein, it will be apparent that numerous alterations are possible without departing from the spirit and scope of the invention.

Examples

Example 1

Method of preparation of DPH- lime complex.

100 Kg of spent turmeric after removal of curcuminoids was dissolved in 200L methanol. lOKg of Lime was dispersed in 200L of water and added slowly to the DPH-methanol solution. Slurry obtained was stirred for 2-3 hrs at room temperature. Precipitate was formed. Filtered and washed the precipitate with 200 L of water followed by 200L of methanol. Precipitate was dried at 80°C to form 80Kg of DPH - Lime complex. Powder of DPH -Lime complex has about 12-15% curcuminoids and about 8% Calcium.

Example 2

Method of preparation of DPH - Calcium complex

100 Kg spent turmeric after removal of curcuminoids was dissolved in 200L methanol. lOKg of CaC12.2 H2O was dissolved in 25L methanol and added to DPH-methanol solution. Solution was stirred for 15 minutes. 30L ammonia was slowly added to DPH- calcium solution and stirred for 30 minutes. Excess methanol was added to DPH- calcium solution and stirred the mixture for 2 hours at 60°C. Cooled at room temperature and precipitate formed was filtered. Washed the precipitate with 500L of methanol and dried at 60°C to form 40Kg powder of DPH -calcium complex.

Powder of DPH-Lime complex has about 15-20% curcuminoids and about 8% Calcium.

Example 3

Anticoccidial effect of DPH- calcium complex

Six hundred, 28-days old poultry birds were allotted into four groups of 150 birds each. Common mortality rate in the farm was 30% and 10% Coccidia was found in samples.

■ Group 1 is untreated control.

■ Group 2 received regular feed but amprolium was added to drinking water.

■ Group 3 received 0.5mg DPH- calcium complex per 100g feed.

■ Group 4 received 0.5mg regular turmeric extract (with 95% curcuminoids) per 100g feed.

Duration of the study was 2 months.

Birds were observed twice daily for clinical signs. Bloody diarrhoea was investigated daily and samples (faecal matter) were collected at 15 days interval. The degree of bloody diarrhoea was recorded as score from 0 - 4 where 0 (-) is normal and 4 (++++) is the maximum degree of bloody diarrhoea. Excreted oocysts were counted. Mortalities were recorded and chicken in each group were weighed at the end of the experiment. Table 1: Score of Bloody diarrhoea in chickens after treatment

Bloody diarrhoea was observed in Group 1 chickens during the study period. In group 3 chickens received feed with DPH- calcium complex showed no bloody diarrhoea after 15 days of treatment. In group 2 and 4 chickens fed with amprolium and regular turmeric extract respectively, bloody diarrhoea was minimized at the end of the study.

Excreted oocysts in the groups treated with DPH- calcium complex was markedly lower than that of the infected control group. In the groups treated with regular turmeric extract and amprolium, the peak excretion of oocysts was delayed 2 days relative to the control infected group.

Table 2: Percentage mortality in chickens after treatment

At the end of the experiment, mortalities were reduced to zero in group treated with DPH-metal complex. In group 2 and 4 animals, mortalities were reduced compared to untreated control group.

Example 4

Effect of DPH-calcium complex for preventing hypocalcaemia in cows.

The study was conducted at a dairy farm with 20 cows which is divided into 4 groups of 5 cows in each group. Average blood calcium levels of 20 cows were 6.2mg/dl. Normal calcium level in cow is 8.05 to 11.48 mg/dl. First group was untreated control and second and third group was fed with 5g and 10g DPH-Calcium complex respectively. Fourth group was fed with 10g Agrimin forte.

After two month of continuous feeding, Serum calcium levels were noted. Animals fed with DPH- calcium complex in two doses showed a significant improvement in serum calcium levels compared to animals fed with Agrimin forte. Average serum calcium level in animals treated with 5g and 10g DPH-Calcium complex was 10.2 and 13.5mg/dl respectively. In untreated control animals of group 1, calcium level was still around 6.2mg/dl.

Table 3: Serum Calcium levels after treatment. From the result it was concluded that DPH-calcium complex is a good source of Calcium supplement which can prevent hypocalcaemia which leads to downer in cows and its antimicrobial character help to prevent mastitis.

I have brought out the novel features of the invention by explaining some of the preferred embodiments of the invention, enabling those skilled in the art to understand and visualize the disclosure. It is also to be understood that the present invention is not limited to the details outlined in the above description or as illustrated in the examples. Although the invention has been described in considerable detail with reference to certain preferred embodiments thereof, various modifications can be made without departing from the spirit and scope of the invention as described herein above.