Technical Field of the Invention

The present invention relates to a food supplement composition developed for use in the manufacture of main pharmaceutical products and the food industry, and the production method thereof.

State of the Art

Curcuma longa which belongs to Zingiberaceace family, colloquially known as turmeric, is a yellow-flowered, perennial herbaceous plant that has been consumed for food and treatment for thousands of years. The main roots of this plant under the soil are in the form of egg and pear, and the side roots are in the form of tuber. These tubers contain yellow color pigments and are called turmeric.

Curcuminoids and oleoresins are obtained from the root (rhizome) sections of the turmeric plant by means of extraction methods. Curcuminoids is a mixture of curcumin, demethoxycurcumin and bisdemetoxycurcumin components. Curcumin is the main component of the curcuminoid mixture, but demethoxycurcumin and bisdemetoxicurcumin are the minor components of the mixture. Oleoresins consist of resin and essential oils. Essential oils or turmeric essential oils are obtained as a byproduct during the extraction of curcuminoids. The main component of the essential oil is ar-turmeron, also known as turmeron. Ar-turmeron constitutes approximately 40-50 % of turmeric essential oil.

Turmeric powder has been used for centuries for general health problems in traditional medicine. However, curcumin obtained from turmeric extraction has poor water solubility, limited gastrointestinal absorption and rapid excretion from the body. These factors prevent the development of curcumin as a potential therapeutic agent in the state of the art.

In literature, studies carried out regarding turmeric essential oils called oleoresin obtained from the root of the turmeric plant have been encountered. Among these studies, there are studies aimed at eliminating potential antidepressive effects and studies on Alzheimer's disease. Furthermore, turmeric essential oils have been reported to have antifungal, antibacterial and antioxidant properties. The application numbered TR 2019/00120 titled "Food supplement containing curcumin, trans-resveratrol, sulforaphane and bioperin" has been encountered in literature. Herein, a food supplement containing curcumin, trans-resveratrol, sulforaphane, and bioperin, which strengthens the immune system and increases the body's resistance to diseases, is disclosed. Herein, the use of piperine is disclosed so as to increase the bioavailability of curcumin. However, the production of the preparation called "CURCOIL" with increased bioavailability due to the synergistic effect of the supercritical fluid extract of turmeric with curcuminoid is not stated.

Also in the literature, the application numbered WO2013171697A1 titled “A drug or supplement containing an active ingredient with low oral bioavailability” was encountered. The invention here mainly consists of a chitosan salt salted with active ingredient with a low bioavailability, polysorbate and N-acetylcysteine (NAC). Said active substance with low bioavailability may be curcumin. Hereby, chitosan salt is used in addition to polysorbate so as to increase bioavailability However, here the use of the supercritical fluid extract of turmeric is not stated.

As a result, due to the abovementioned disadvantages and the insufficiency of the current solutions regarding the subject matter, a development is required to be made in the relevant technical field.

Brief Description of the Invention

The present invention is related to a composition of a food supplement and production method thereof which fulfills the abovementioned requirements, eliminates all disadvantages and brings some additional advantages.

The main aim of the invention is to develop a food supplement composition that benefits from the synergistic effect of curcumin and turmeric supercritical fluid extract, with increased bioavailability of curcumin in its content and having therapeutic properties.

A similar aim of the invention is to develop a food supplement composition that improves the water solubility of curcumin, gastrointestinal absorption and excretion time from the body and increases the oral bioavailability of curcumin by means of the polysorbate 80 it contains.

A similar aim of the invention is to develop a food supplement composition that increases the bioavailability of curcumin by means of black pepper extract with piperine it contains. In order to fulfill the aims mentioned above, the inventive food supplement composition contains at least one of the polysorbate 80 or polysorbate 20 as emulsifier the supercritical fluid extract of black pepper and the combination of curcuminoid and turmeric with the synergistic effect of the supercritical fluid extract.

The structural and characteristic features of the present invention will be understood clearly by the following detailed description and therefore the evaluation shall be made by taking the detailed description into consideration.

Detailed Description of the Invention

In this detailed description, the inventive pharmaceutical composition and the production method thereof is described only for clarifying the subject matter in a manner such that no limiting effect is created.

The inventive food supplement composition is mainly obtained by supercritical fluid extract of turmeric and the synergistic effect of the curcuminoids. The inventive food supplement composition contains at least one of the polysorbate 80 or polysorbate 20 as emulsifier and supercritical fluid extract of black pepper as oleoresin. The percentages of the components forming the inventive food supplement composition by weight and their preferred amounts are presented in Table 1 in percent.

Table 1. The percentages of the components forming the inventive food supplement composition by weight

In a preferred embodiment of the inventive food supplement composition, polysorbate 80 is used. Polysorbate 80 is a solvent, dispersing agent and emulsifier widely used in pharmaceutical, food and cosmetic industries. Polysorbate 80 facilitates drug absorption when formulated with active substance and provides active substance stabilization for a long time. Curcumin obtained from turmeric extraction has poor water solubility, low gastrointestinal absorption and rapid excretion from the body. Accordingly, its oral bioavailability is low. In a preferred embodiment of the inventive food supplement composition, usage of polysorbate 80 improves the absorption of curcumin. Herein, polysorbate 80 forms micelles with curcumin and ensures to increase the bioavailability of curcumin.

Black pepper which is known as a tangy aromatic flavor is the whole or powdered dried fruit of Piper nigrum (black pepper), a vine specific to India and Asia. Black pepper extract consists of oleoresin between 10-15 %, piperine between 40-50 % and other components. The main volatile components in this 10-15 % oleoresin in the black pepper extract obtained by the supercritical fluid extraction method are as follows; 31 -34 % caryophllene, 7-8 % sabinene, 6-7 % beta pinene, 11-13 % limonene, 8-10 % beta bisabolene. In vitro and in vivo studies on piperine, which is the main component of black pepper, have shown that piperine has anti-carcinogenic, immunomodulatory, anti-asthma, liver protective, anti inflammatory properties. In addition to this, it was shown that piperine increases the absorption of the active substances such as curcumin, rifampicin, sulfadiazine, tetracillin, etc. with anti-oxidant and biotransformative effects. For these reasons, black pepper extract containing 40-50 % piperine is used in the inventive food supplement composition. Therefore, the bioavailability of curcumin is increased.

Studies on turmeric essential oils have shown that aromatic-turmerone has various medical and pharmacological properties such as powerful anti-inflammatory, anti-oxidative, anti fungal etc. In addition to these, there are many studies on turmeric essential oils aimed at eliminating potential antidepressive effects and studies on Alzheimer's disease. In the inventive food supplement composition, it is benefited from the synergistic effect of the supercritical fluid extract of curcumin and turmeric. A new product has been developed with the effect of turmeric essential oils that increase the bioavailability of curcumin.

First of all the emulsifier, preferably polysorbate 80, is heated to a temperature between about 50-60 Ό so as to obtain the inventive food s upplement composition. Then, the curcumin powder is slowly added into the emulsifier under stirring. First of all, this mixture is heated to a temperature range between 90-95 °C and kept for 10 minutes between these temperature values. Therefore, the emulsifier forms micelles with curcumin. In this process step, it is important to increase the temperature above 90Ό by adding curcuminoid powder. Subsequently, the mixture is cooled to below 50TT Supercritical fluid extract of turmeric and black pepper extract are added slowly into the cooled mixture under stirring. Herein, it shall be considered that turmeric and black pepper extracts shall be added after the mixture has cooled down to 5013. The obtained mixture with the addition of turmeric and black pepper extracts is slowly heated up to 70TT This h eated mixture is stirred at a temperature range of 65-75 Ό for 15 minutes. Thus, the preparation called “curcoil" with increased bioavailability are produced with the synergistic effect of the oleoresins and curcuminoids Temperature and time are the points that must be considered for this process. Finally, the mixture is cooled to below 50 TT Thus, the final p roduct obtained is ready for filling. Herein, the filling process shall be carried out below 50 °C. It is possible to produce the obtained final product in various edible or drinkable forms such as tablets, lozenges, pills, hard or soft capsules, throat or nasal spray, drops.

Curcumin which is the yellow pigment of turmeric is produced by using oleoresin of turmeric as an industrial raw material. Main components contain approximately 70-80 % essential and fixed oils, resin and insoluble curcumin compounds after isolation of curcumin from oleoresin.

Many biological target and cellular effects exhibiting anti-inflammatory, antioxidant and immunomodulatory activities have been found in the preclinical studies on turmeric carried out in recent years. In addition to these effects, curcumin has been extensively studied as an anticancer agent, by means of its proven antioxidant and anti-inflammatory activities. Turmeric has been suggested to have numerous health benefits in clinical studies, inflammatory conditions such as rheumatoid arthritis (RA), inflammatory bowel disease, psoriasis. However, it has been determined that curcuminoids are not easily absorbed by the human intestine. Therefore, various methods are developed so as to improve the bioavailability of curcumin. The supercritical fluid extract of turmeric is used so as to increase the bioavailability of curcuminoids in the inventive food supplement composition. Here, the curcuminoids are isolated from turmeric whose oil is extracted with supercritical fluid by way of solvent extraction. Extraction is performed at temperatures between 55-75 ° C. The solvent is partially removed so as to obtain a concentrated solution. This solution is cooled so as to crystallize the curcuminoids that are isolated by an appropriate method such as filtration and/or centrifugation. Analysis results of this product consisting of curcuminoid crystals isolated from turmeric shows that it consists of 75-95 % of the curcumin, the remaining part consists of demethoxycurcumin and bisdemetoksicurcumin.

Essential oils are naturally found in turmeric roots (rhizomes) and are usually used for flavoring and coloring. Essential oils contain molecules with high effects on health such as ar-tumerone, a-tumerone, b-tumerone, b-atlantone etc. Studies that have been carried out have shown that aromatic-turmerone has powerful anti-inflammatory and anti-oxidative properties. Today, these therapeutic components been used in traditional Chinese medicinal healing systems for a long time, have been confirmed to have positive effects on health, number of times by scientific data. The turmeric extract is obtained with a supercritical fluid extraction system in a manner such that the extractor pressure is between 150-300 bar and the temperature is between 50-90 ° C. As a result of obtained volatile component analysis of turmeric extract, it contains 40-50 % ar-turmerone, 15-20 % curlone, 5-10 % b-atlantone as the main components, it also contains a-tumerone, b-tumerone, zingiberene, a-caryophyllene.

Pharmacokinetic properties of curcumin, following oral administration, most of the same is excreted without being absorbed by the body, it has been observed that it is poorly absorbed with traces only visible in the blood. For this reason, it is necessary to use different auxiliary substances that can block the metabolic pathways of curcumin so as increase the bioavailability of curcumin. It was reported that piperine which is an alkaloid extracted from black pepper inhibits glucuronidation activity in rats and guinea pigs. It was shown that co administration of piperine and curcumin to humans and rats increases the bioavailability of curcumin. The black pepper extract is obtained with a supercritical fluid extraction system in a manner such that the extractor pressure is between 150-300 bar and the temperature is between 50-90 °C. The main component of piperin e is obtained in a ratio between 40- 50 % as a result of the analysis of the obtained black pepper oleoresin. Furthermore, the essential oils obtained contain turmeric volatile components as the main component and also contains caryophyllene in a ratio between 27-35 %, l-Limonene in a ratio between IQ- 15 %, b-bisabolene in a ratio between 5-10 % as well as b -pinene, a-pinene and other terpenes.

Polysorbate 80 is a substance that is formulated by the reaction of sorbitan fatty acid ester (a nonionic surfactant) with ethylene oxide. It is commonly used in many countries, including the USA and the EU, as an emulsifier, solvent, dispersing agent in food and pharmaceutical products. It is observed in studies that polysorbate 80 substantially increases the bioavailability of curcumin. REFERENCES:

1. Chattopadhyay, , et ah, Turmeric and curcumin: Biological actions and medicinal applications. CURRENT SCIENCE-BANGALORE-, 2004. 87: p. 44-53.

2. Gupta, S.C., G. Kismali, and B.B. Aggarwai, Curcumin, a component of turmeric: from farm to pharmacy. Biofactors, 2013. 39(1): p. 2-13.

3. Lai, J., Turmeric, curcumin and our life: a review. Bull Environ Pharmacol Life Sci, 2012. 1(7): p. 11-17.

4. Mishra, S. and K. Palanivelu, The effect of curcumin (turmeric) on Alzheimer's disease: An overview. Annals of Indian Academy of Neurology, 2008. 11(1):p. 13.

5. Negi, P., et ah, Antibacterial activity of turmeric oil: a byproduct from curcumin manufacture. Journal of agricultural and food chemistry, 1999. 47(10): p. 4297-4300.

6. Tayyem, R.F., et ah, Curcumin content of turmeric and curry powders. Nutrition and cancer, 2006. 55(2): p. 126-131.

7. Imaizumi, A., Highly bioavailable curcumin (Theracurmin): its development and clinical application. PharmaNutrition, 2015. 3(4): p. 123-130.

8. Toden, S. and A. Goel, The holy grail of curcumin and its efficacy in various diseases: is bioavailability truly a big concern ? Journal of restorative medicine, 2017. 6(1): p. 27.

9. Ahmed, T. and A.H. Gilani, Therapeutic potential of turmeric in Alzheimer's disease: curcumin or curcuminoids? Phytotherapy Research, 2014. 28(4): p. 517-525.

10. Antony, B., Treatment of alzheimer's with a curcuminoid mixture and essential oil of turmeric having 45% Ar-turmerone. 2014, Google Patents.

11. Funk, J.L., et ah, Anti-arthritic effects and toxicity of the essential oils of turmeric (Curcuma longa L.). Journal of agricultural and food chemistry, 2010. 58(2): p. 842-849.

12. Hishikawa, N., et ai, Effects of turmeric on Alzheimer's disease with behavioral and psychological symptoms of dementia. Ayu, 2012. 33(4): p. 499.

13. Liju, V.B., K. Jeena, and R. Kuttan, Acute and subchronic toxicity as well as mutagenic evaluation of essential oil from turmeric (Curcuma longa L). Food and Chemical Toxicology, 2013. 53: p. 52-61.

14. Coors, E.A., et ai., Polysorbate 80 in medical products and nonimmunologic anaphylactoid reactions. Annals of Allergy, Asthma & Immunology, 2005. 95(6): p. 593-599.

15. Varma, R., et ai., Polysorbate 80: a pharmacological study. Arzneimittel-Forschung, 1985. 35(5): p. 804-808.

16. Wang, G. and S. Sukumar, Characteristics and antitumor activity of polysorbate 80 curcumin micelles preparation by cloud point cooling. Journal of Drug Delivery Science and Technology, 2020. 59: p. 101871.

17. Aggarwai, B.B., A. Kumar, and A.C. Bharti, Anticancer potential of curcumin: preclinical and clinical studies. Anticancer research, 2003. 23(1 /A): p. 363-398. 18. Ba§pmar, Y., et ah, Response Surface Methodology for Extraction of Curcumin from Turmeric and Piped ne from Black Pepper. Celal Bayar IJniversitesi Fen Bilimleri Dergisi, 2017. 13(3): p. 747-754.

19. Meghwal, M. and T. Goswami, Piper nigrum and piperine: an update. Phytotherapy Research, 2013. 27(8): p. 1121-1130.

20. Perakis, C., V. Louli, and K. Magoulas, Supercritical fluid extraction of black pepper oil. Journal of food engineering, 2005. 71(4): p. 386-393.

21. Pino, J., et al., Chemical and sensory properties of black pepper oil (Piper nigrum L). Food/Nahrung, 1990. 34(6): p. 555-560.

22. Ramprasad, C. and M. Sirsi, Observations on the pharmacology of Curcuma longa. Studies in Indian plants Curcuma longa Linn.-Effects of curcumin and essential oil of C. longaon bile secretion. J. Sci. Res. Inst, 1956. 15: p. 212-216.

23. Sehgal, A., et al., Combined effects of curcumin and piperine in ameliorating benzo (a) pyrene induced DNA damage. Food and chemical toxicology, 2011. 49(11): p. 3002-3006.

24. Soliman, G., Effect of curcumin, mixture of curcumin and piperine and curcum (turmeric) on lipid profile of normal and hyperlipidemic rats. The Egyptian Journal of Hospital Medicine, 2005. 21(1): p. 145-161.

25. Sacchetti, G., et al., Comparative evaluation of 11 essential oils of different origin as functional antioxidants, antiradicals and antimicrobials in foods. Food chemistry, 2005. 91(4): p. 621-632.

26. Amairaj, A., et al., Biological activities of curcuminoids, other biomolecules from turmeric and their derivatives-A review. Journal of traditional and complementary medicine, 2017. 7(2): p. 205-233.

27. Boroumand, N., S. Samarghandian, and S.l. Hashemy, Immunomodulatory, anti-inflammatory, and antioxidant effects of curcumin. Journal of Herbmed Pharmacology, 2018. 7(4): p. 211-219.

28. Hatcher, H., et al., Curcumin: from ancient medicine to current clinical trials. Cellular and molecular life sciences, 2008. 65(11): p. 1631-1652.

29. Aggarwal, B.B. and K.B. Harikumar, Potential therapeutic effects of curcumin, the anti inflammatory agent, against neurodegenerative, cardiovascular, pulmonary, metabolic, autoimmune and neoplastic diseases. The international journal of biochemistry & cell biology, 2009. 41(1): p. 40-59.

30. Collison, S., Curcumin and Inflammatory Diseases: Learn About Its Potential Role in Prevention and Treatment. Today’s Dietitian, 2014. 16(9): p. 56p.

31. Gupta, S.C., S. Patchva, and B.B. Aggarwal, Therapeutic roles of curcumin: lessons learned from clinical trials. The AAPS journal, 2013. 15(1): p. 195-218.

32. He, Y., et al., Curcumin, inflammation, and chronic diseases: how are they linked? Molecules, 2015. 20(5): p. 9183-9213.

33. Antony, B., et al., A pilot cross-over study to evaluate human oral bioavailability of BCM-95® CG (Biocurcumax™), a novel bioenhanced preparation of curcumin. Indian journal of pharmaceutical sciences, 2008. 70(4): p. 445. 34. Dosoky, N.S. and W.N. Setzer, Chemical composition and biological activities of essential oils of Curcuma species. Nutrients, 2018. 10(9): p. 1196.

35. Ibanez, M.D. and M.A. Blazquez, Ginger and turmeric essential oils for weed control and food crop protection. Plants, 2019. 8(3): p. 59. 36. Li, S., et ah, Chemical composition and product quality control of turmeric (Curcuma longa L.).

2011.

37. Reen, R.K., et ah, Impairment of UDP-glucose dehydrogenase and glucuronidation activities in liver and small intestine of rat and guinea pig in vitro by piperine. Biochemical pharmacology, 1993. 46(2): p. 229-238. 38. Shoba, G., Influence of piperine on the pharmacokinetics of curcumin in animals and human volunteers, Planta Medica. 1998.

39. Singh, J., R. Dubey, and C. Atal, Piperine-mediated inhibition of glucuronidation activity in isolated epithelial cells of the guinea-pig small intestine: evidence that piperine lowers the endogeneous UDP-glucuronic acid content. Journal of Pharmacology and Experimental Therapeutics, 1986. 236(2): p. 488-493.