SYNERGISTIC COMBINATION OF PHYTOACTIVES

Abstract

The present invention relates to a combination of phytoactives comprising plant extracts that deliver curcumin, chlorogenic acid and/or catechin. The invention also relates to a process for preparing such combination with enhanced therapeutic and pharmacological effect. The phytoactives combination is used for enhancing endurance and stamina, for significantly reducing cortisol levels thus reducing stress, for elevating hydrolysis of adenosine triphosphate (ATP), for improving blood flow, for quick recovery from sports injury, for better weight and fat loss compared to individual actives, for increasing and strengthening muscles and for increasing maximum oxygen uptake during incremental exercise.

Claims

1. A phytoactive combination comprising: plant extracts that deliver curcumin, chlorogenic acid, and/or catechin.

2. The phytoactive combination of claim 1, wherein the phytoactive combination increases bioavailability of the curcumin.

3. The phytoactive combination of claim 1, wherein the chlorogenic acid and/or the catechin combines with the curcumin synergistically, thereby improving therapeutic and pharmacological effects of the phytoactive combination.

4. The phytoactive combination of claim 1, wherein the phytoactive combination is delivered to a subject such that the subject receives a range of 10 milligrams to 500 milligrams per day of the curcumin, a range of 10 milligrams to 800 milligrams per day of the chlorogenic acid, and a range of 5 milligrams to 1,000 milligrams per day of the catechin.

5. The phytoactive combination of claim 1, wherein the phytoactive combination is dispensed in a dosage form suitable for oral delivery.

6. The phytoactive combination of claim 5, wherein the dosage form is selected from the group consisting of: powder, pellets, beadlets, granules, tablet, capsules, buccal films, and combinations thereof.

7. The phytoactive combination of claim 1, wherein the phytoactive combination is prepared by encapsulating the curcumin, the chlorogenic acid, and/or the catechin.

8. The phytoactive combination of claim 1, wherein the phytoactive combination is prepared by a process comprising combining the plant extracts with one or more encapsulating agents and one or more solvents.

9. The phytoactive combination of claim 8, wherein the phytoactive combination comprises active ingredients having a range of between 1% to 95% w/w and wherein the encapsulating agent has a range from between 5% and 90%.

10. The phytoactive combination of claim 1, wherein the phytoactive combination is used for a purpose selected from the group consisting of: enhancing endurance and stamina, significantly reducing cortisol levels, thereby reducing stress, elevating hydrolysis of adenosine triphosphate (ATP), improving blood flow, quick recovery from sports injury, better weight and fat loss compared to administration of individual ingredients of the phytoactive combination alone, increasing and strengthening muscles, increasing maximum oxygen uptake during incremental exercise, and combinations thereof.

11. The phytoactive combination of claim 9, wherein the active ingredients have a range of between 20% and 50% w/w and wherein the encapsulating agent has a range of between 30% and 70%.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0031] Although prior art applications disclose compositions comprising curcumin or combination with green tea or coffee, none of these applications disclose synergism between the components which is achieved by the present formulation.

[0032] It should be appreciated that the compositions containing one or more items selected from the group consisting of chlorogenic acid and/or catechin combined with curcumin worked synergistically by improving the therapeutic and pharmacological effect of the active ingredients.

[0033] The term “synergy” or “synergistic” as used herein, unless otherwise specified, refers to the interaction of two or more compounds so that their combined effect is greater than the additive sum of their individual effects.

[0034] Synergistic effect of the composition is shown by enhancement in solubility and stability of the active ingredients. Through the present composition the stability and water solubility of curcumin is increased, antioxidant potential of catechin is enhanced and metabolism of chlorogenic acid is reduced.

[0035] Lipophilic nutrients like curcumin has reduced bioavailability within the body due to low intrinsic activity, poor absorption, higher rate of metabolism, inactivity of metabolic products and/or rapid elimination from the body. Thus, there is a need to develop alternate formulation approaches for lipophilic nutrients so as to design dosage forms with enhanced stability and solubility thereby providing enhanced bioavailability.

[0036] In the food-processing field, encapsulation techniques have been widely used to protect food extracts against deterioration or volatile losses. The protective mechanism is to form a membrane, the wall system, around droplets or particles of the encapsulated material, the core. Encapsulation not only protects against losses and chemical changes, but also enables production in the form of powdered products with new properties.

[0037] In an embodiment, the combination of the present invention comprises encapsulating the plant extracts that deliver curcumin, chlorogenic acid and/or catechin.

[0038] In yet another embodiment, the encapsulation process of the present invention enhances the stability and solubility of curcumin which further leads to enhanced bioavailability.

[0039] In the present invention, Curcuma longa (commonly known as turmeric) is used as the source for curcumin; Green coffee bean i.e. coffee seeds (beans) of Coffee fruits that have not yet been roasted is used as the source of chlorogenic acid and Green tea (obtained from Camellia sinensis that is not fermented but produced by steaming fresh leaves at high temperature) is used as source for catechin.

[0040] The curcumin, chlorogenic acid and/ or catechin is extracted from the sources mentioned above by using conventional or non-conventional extraction methods that are known to a person skilled in art.

[0041] According to one embodiment, the combination of the present invention is prepared by a process comprising plant extracts that deliver curcumin, chlorogenic acid and/or catechin; encapsulating agent(s) and solvent(s).

[0042] The ratio of components used in the composition of the present invention are as follows: active ingredient ranges from 1%-95% w/w preferably 20%-50% w/w and encapsulating agent ranges from 5%-90% w/w preferably 30%-70% w/w.

[0043] The encapsulating agent(s) used in the composition of the present invention is selected from modified starch, gum acacia, dextrin, dried glucose syrup, starch, maltodextrin or combinations thereof.

[0044] Preferably the encapsulating agent used in the present invention is modified starch and/or maltodextrin.

[0045] The solvent(s) used in the present invention are selected from the group such as, but not limited to, acetone, hexane, ethyl acetate, isopropyl alcohol, ethanol, dichloromethane, methanol, and a mixture thereof.

[0046] Preferably the solvent(s) used in the present invention are acetone, ethanol, dichloromethane, isopropyl alcohol. More preferably dichloromethane, ethanol and isopropyl alcohol.

[0047] In yet another embodiment, the combination of the present invention delivers the active ingredients in the range of—Curcumin: 10 mg to 500 mg/day; Chlorogenic acid: 10 mg to 800 mg/day and Catechin: 5 mg to 1000 mg/day.

[0048] The combination of phytoactives of the present invention is prepared by a process comprising: [0049] (i) dissolving the active ingredients in a solvent or mixture of solvents to form a clear solution; [0050] (ii) dissolving the encapsulating agent in water [0051] (iii) adding step (i) solution in step (ii) under stirring; [0052] (iii) removing the solvent by evaporation; and [0053] (iv) drying the residue to obtain powder or granules.

[0054] In an embodiment the process of the present invention further comprises of suitable pharmaceutical and/or nutraceutical excipient, but not limited to co-solvent, glidant, binder, thickener, surfactant or combination thereof.

[0055] In a preferred embodiment, the drying of residue in the process of present invention is carried out by using bottom spray, top spray fluid bed processor or by tangential spray, top spray Flex Stream process.

[0056] In an embodiment, the combination of the present invention is formulated for delivery by the oral route.

[0057] The combination of the present invention is dispensed in dosage forms selected from powder, pellets, beadlets, granules, tablet, capsules, buccal films and the like.

[0058] In a further embodiment, the combination of phytoactives of the present invention enhances endurance and stamina, significantly reduces cortisol levels thus stress, elevates hydrolysis of adenosine triphosphate (ATP), improves blood flow, helps in quick recovery from sports injury, promotes better weight and fat loss compared to individual actives, increases muscle strength and also increases maximum oxygen uptake during incremental exercise.

[0059] The composition of the present invention which is a combination of curcumin, chlorogenic acid and/or catechin is planned to be tested for efficacy in rats. The details of the study are captured below:

TABLE-US-00001 Object of the study To evaluate the efficacy in Muscle injury model Type of Study Efficacy Animal Strain Male Sprague-Dawley Rats Body weight of animals 200-250 g Study Duration 15 days Acclimatization period 5 days Total duration of the study 22 days Number of animals/Time Point 6 Groups 4 Groups Group 1: Normal Control Group 2: Muscle Injury Control Group 3: Test Item Dose 1 Group 4: Reference Control Total number of animals 24 Route of administration Oral Frequency of Test product Once daily administration

[0060] All the rats will receive their respective treatments from day 1 of the study till 14 days. Control group animals will receive saline. After 7 day of the treatment, Barium Chloride will be injected intramuscularly in the quadriceps of the left extremity in the rats to induce muscle injury, causing total degeneration of the muscle. In the rats of control group (Group 1), 200 μl of saline solution will be injected. At seven days after Barium Chloride injection, rats will be sacrificed and samples will be obtained to determine the effects of Barium Chloride-induced muscle injury.

[0061] Before sacrificing the animals, blood will be collected to estimate TNF-α and IL-1β as an indicator of muscle injury. The muscled from the site of injection will be collected and divided into two portions. One portion will be fixed in 10% neutral buffered formalin for further histopathological evaluation while second portion of muscle will be homogenized in suitable buffer to estimate the oxidative stress.

[0062] Further, a prospective, double blind, reference controlled randomised interventional study to evaluate the efficacy and safety of the phytoactive combination of the present invention as a supplement in accelerating healing from sports injury is to be soon initiated.

[0063] The details of the Interventional study are as follows:

TABLE-US-00002 Study Title Prospective, double blind, reference controlled randomised interventional study to evaluate the efficacy and safety of phytoactives combination of the present invention as a supplement in accelerating healing from sports injury. Investigational Product Phytoactives combination of the present invention Comparator Physical Mixture of Curcumin Extract and Green Coffee Bean Extract Phase Interventional Study Indication Muscular injury caused due to high endurance sports. Study Design Prospective, double blind, randomised interventional study Study Duration 3 months Treatment Duration 1 week Sample Size Minimum 12(1:1) Dose/Dosage regimen Phytoactives combination of the present invention - 500 mg BID Physical Mixture of Curcumin Extract and Green Coffee Bean Extract- 500 mg BID Objective Primary: To evaluate the efficacy of Investigational Product as a supplement in accelerating healing from injury caused due to high endurance sports. This will be assessed through the following 3 parameters:  1. Recovery from muscle damage due to sports injury  2. Increased Endurance  3. Reduce Inflammation  4. Secondary: To evaluate the safety of Investigational Product during the entire study duration Endpoints Primary (Efficacy): Change in following biomarker test from baseline to end of treatment:  1. Recovery from muscle damage due to sports injury Creatine Kinase Myoglobin Blood Urea Nitrogen Lactate Dehydrogenase  2. Increased Endurance Serum ferratin Total iron concentration Transferrin Sodium Physical tests: squats, pushups, core  3. Reduce Inflammation CBC Secondary (Safety):  1. Occurrence of any AE or SAE during the study.  2. Occurrence of any clinically significant abnormality as per the Principal Investigator in the following safety marker test: Urine-routine Random Blood Sugar Heart Rate POMS questionnaire Respiratory Rate Inclusion Criteria  1. Male or Female aged 18-50 years  2. Subjects willing to comply to study procedure and sign written informed consent  3. Subjects with acute muscular injury like muscle strain (grade 1-3), Cramp, acute compartment syndrome. Exclusion Criteria  1. Subjects requiring surgery for the injury  2. Subjects with open wounds  3. Subjects with injury involving skeletal system or deep soft tissue injury  4. Subjects already on medication for any sports injury  5. Subjects on steroids or ergogenic users  6. Subjects with uncontrolled systemic disease since past 3 months.  7. Subject with neurological disorders  8. Subjects on drug abuse, narcotic abuse, alcoholism or smoking  9. Breast feeding women 10. Pregnant women 11. Subject planning to conceive 12. Subjects participating in another clinical trial or subjects participated in any clinical trial within last 6 months. 13. Any condition that in the opinion of the investigator does not justify the subject's inclusion for the study. Statistical Methodology ANOVA and suitable statistical method will be followed.

[0064] From the details given above it can be observed that the composition of the present invention is not a mere admixture resulting in a composition which having the aggregation of the properties of the components used but a composition formed by the synergistic activities of the components used.

[0065] The nature of the invention, its objects and advantages are explained hereunder in greater detail in relation to non-limiting exemplary embodiments.

[0066] The following examples are for the purpose of illustration of the invention only and are not intended in any way to limit the scope of the present invention.

EXAMPLE 1

[0067]

TABLE-US-00003 Sr. No Name of Ingredient Qty for 100 g 1 Curcumin Extract 12.63 2 Green coffee bean extract 53.33 3 Polyethylene glycol 6000 24.00 4 Maltodextrin 10.04 5 Isopropyl alcohol 25.00

[0068] 24.00 g of Polyethylene glycol 6000 was melted at temperature of 75° C. and 12.63 g of curcumin extract was added to it and dissolved. The mixture was cooled upto 35° C. and 25.00 g isopropyl alcohol was added. To this mixture 53.33 g of Green coffee bean extract and 10.04 g of maltodextrin were added. The temperature was gradually raised and mixing was continued till all solvent had evaporated. After evaporation the solid mass obtained was cooled and milled to obtain uniform granules.

EXAMPLE 2

[0069]

TABLE-US-00004 Sr. No Name of Ingredient Qty for 100 g 1 Curcumin Extract 2.10 2 Green Coffee Bean Extract 17.77 3 Ethanol 50.0 4 Methylene Dichloride 70.0 5 Modified Starch 77.13 6 Tween 80 3.00 7 Purified Water 180.0

[0070] 2.10 g of curcumin extract was dissolved in mixture of 50 g ethanol and 70 g of methylene dichloride. 77.13 g modified starch and 3.00 g of Tween 80 was dissolved in 180 g of hot purified water at 50° C. The solvent phase was added slowly to the aqueous phase using both a high rate of mixing and a high shear force mixer. After the addition, the emulsion temperature was maintained at 50° C. and 17.77 g of green coffee bean extract was added and high speed shear mixing was continued for 15 min. The temperature was gradually raised and mixing was continued until all solvent was evaporated. During the evaporation procedure, distilled water was added to the emulsion to maintain a suitable viscosity. After all the ethanol and methylene dichloride was removed, the distilled water was added and thoroughly admixed with the emulsion to achieve an emulsion. The emulsion was then sprayed using spray dryer to obtain a powder.

EXAMPLE 3

[0071]

TABLE-US-00005 Sr. No Name of Ingredient Qty for 100 g 1 Curcumin Extract 11.52 2 Green Coffee Bean Extract 53.32 3 Ethanol 129.0 4 Methylene Dichloride 300.0 5 Modified Starch 31.16 6 Tween 80 4.00 7 Purified Water 100.0

[0072] 11.52 g of curcumin extract was dissolved in a mixture of 129.0 g ethanol and 300.0 g of methylene dichloride. 31.16 g modified starch and 4.00 g Tween 80 was dissolved in 100 g of hot purified water at 50° C. The solvent phase was added slowly to the aqueous phase using both a high rate of mixing and a high shear force mixer. After the addition was completed, the emulsion temperature was maintained at 50° C. and 53.32 g of green coffee bean extract was added. High speed shear mixing was continued for 15 min, temperature was gradually raised and mixing was continued until all solvent got evaporated. To the residue, distilled water was added and thoroughly mixed to achieve an emulsion. The emulsion was sprayed using spray dryer and powder was obtained.

EXAMPLE 4

[0073]

TABLE-US-00006 Sr. No Name of Ingredient Qty for 100 g 1 Curcumin Extract 11.52 2 Green Tea Extract 22.50 3 Green Coffee Bean Extract 22.50 4 Ethanol 129.0 5 Methylene Dichloride 300.0 6 Modified Starch 39.48 7 Tween 80 4.00 8 Purified Water 100.0

[0074] 11.52 g of curcumin extract was dissolved in mixture of 129.0 g ethanol and 300.0 g of methylene dichloride. 39.48 g modified starch and 4.00 g of Tween 80 were dissolved in 100 g of hot purified water at 50° C. The solvent phase was added slowly to the aqueous phase using both a high rate of mixing and a high shear force mixer. After the addition was completed, the emulsion temperature was maintained at 50° C. and 22.50 g of green coffee bean extract and 22.50 g green tea extract were added. High speed shear mixing was continued for 15 min. The temperature was gradually raised and mixing was continued until all solvent had evaporated. During the evaporation procedure, distilled water was added to the mixture to achieve an emulsion. This resulting emulsion was spray dried to get powder.

EXAMPLE 5

[0075]

TABLE-US-00007 Sr. No Name of Ingredient Qty for 100 g 1 Curcumin Dispersible Powder 20% 50.00 2 Green Coffee Bean Extract 50.00 3 Purified Water 400.00

[0076] 50.0 g of curcumin dispersible powder 20% and 50.0 g of Green Coffee Bean Extract were dissolved in 400 ml of purified water under constant stirring for 30 min. The dispersion obtained was dried on a spray dryer to get granules.

EXAMPLE 6

[0077]

TABLE-US-00008 Sr. No Name of Ingredient Qty for 100 g 1 Curcumin Dispersible Powder 40% 25.00 2 Green Tea Extract 25.00 3 Green Coffee Bean Extract 25.00 4 Modified starch 25.00 5 Purified Water 400.00

[0078] 25.0 g of curcumin dispersible powder 40%, 25.0 g of Green Coffee Bean Extract, 25.0 g of Green Tea Extract and 25.0 g of modified starch were dissolved in 400 ml of purified water under constant stirring for 30 min to obtain a dispersion. This dispersion was then sprayed using spray dryer to get final powder.

[0079] It will be readily apparent to one skilled in the art that varying substitutions and modifications may be made to the invention disclosed herein without departing from the spirit of the invention. Thus, it should be understood that although the present invention has been specifically disclosed by the preferred embodiments and optional features, modification and variation of the concepts herein disclosed may be resorted to by those skilled in the art, and such modifications and variations are considered to be falling within the scope of the invention.

[0080] It is to be understood that the phraseology and terminology used herein is for the purpose of description and should not be regarded as limiting. The use of “including,” “comprising,” or “having” and variations thereof herein is meant to encompass the items listed thereafter and equivalents thereof as well as additional items.

[0081] It must be noted that, as used in this specification and the appended claims, the singular forms “a,” “an” and “the” include plural references unless the context clearly dictates otherwise.