|LETTER TO EDITOR
|Year : 2020 | Volume
| Issue : 2 | Page : 177-178
Synthetic curcumin is safe in long-term safety evaluation
Ingredients, Laurus Labs Limited, Hyderabad, Telangana, India
|Date of Submission||28-Aug-2019|
|Date of Acceptance||28-Sep-2019|
|Date of Web Publication||17-Jun-2020|
Dr. Roopesh Jain
Laurus Labs Limited, Serene Chambers, Road #7, Banjara Hills, Hyderabad - 500 034, Telangana
Source of Support: None, Conflict of Interest: None
|How to cite this article:|
Jain R. Synthetic curcumin is safe in long-term safety evaluation. Biomed Biotechnol Res J 2020;4:177-8
Curcumin belongs to the group of curcuminoids and possesses a wide range of health promoting properties., It is traditionally extracted from turmeric along with other curcuminoids, i.e. demethoxycurcumin and bisdemethoxycurcumin having combined purity of total curcuminoids up to 95% only. Curcumin content in natural extracts often varies and co-occurs with other compounds and many of them are unknown with unspecified effects on human health. Curcumin being highly active among other curcuminoids, Laurus Labs has developed a proprietary process for highly pure (up to 99% by high-performance liquid chromatography [HPLC]) and stable synthetic curcumin that can be used in supplements, coloring, and cosmetics. Chemical route of manufacturing provides great control for the production of highly pure curcumin and thereby eliminates potential contaminants. Long-term safety evaluation of nutraceutical ingredients plays an important role in the therapeutic safety system; therefore, Laurus Labs conducted a repeated dose toxicity study of synthetic curcumin (manufactured using proprietary process) at Vimta Labs Limited. Information gained from long-term study is useful to patients, health-care professionals, and regulatory authorities.
The repeated dose toxicity study was designed and conducted to assess safety of test article and to determine the no-observed-adverse-effect level (NOAEL) using Wistar Rats. The test article was highly pure (>99% by HPLC) synthetic curcumin (manufactured by Laurus Labs). The safety profile of synthetic curcumin was established following repeated oral gavage of test article for 90 days in Wistar Rats. Curcumin powder (95%) was used as a reference item for comparison in this study. The study was carried out as per the “Good Laboratory Practices” compliance, and “Organization for Economic Cooperation and Development” and “European Medicines Agency” guidelines. Protocol of the study was approved by the “Institutional Animal Ethics Committee” of Vimta Labs, and the study was performed as per the recommendations of the “Committee for the Purpose of Control and Supervision of Experiments on Animals” guidelines.
The study was conducted in male and female Wistar rats at three dose levels – 250 mg/kg/day (low), 500 mg/kg/day (mid), and 1000 mg/kg/day (high). Based on stability data, 0.5% w/v carboxymethylcellulose sodium salt (CMC, Sigma-Aldrich) solution was used as vehicle to achieve concentrations of 12.5, 25, and 50 mg/mL for respective dose of 250 mg/kg, 500 mg/kg, and 1000 mg/kg. Rats were divided into five groups of twenty rats/sex/group (three test articles, one reference item, and one vehicle control dose groups). Of three test article groups, each group was treated orally with 250 mg/kg/day, 500 mg/kg/day, and 1000 mg/kg/day dose levels, respectively. The reference group was administered with 1000 mg/kg/day, and the vehicle control received an equivalent volume of vehicle formulation (0.5% w/v CMC) to differentiate the effects of vehicle from test and reference items. The test item dose formulations at different concentrations (12.5, 25, and 50 mg/mL) and reference item at 50 mg/mL were administered twice a day (at least 5 h apart) by gavage for 90 consecutive days.
The concentrations of curcumin in the test formulations were determined using a validated HPLC method at each dose level during the 1st week, 7th week, and last week of the treatment period. The concentration of test item in the formulation was within the acceptable limit of 85%–115%. In general, formulation analysis met the acceptance criteria for the study, and animals received the intended dose of test item.
In-life observations included morbidity, mortality, clinical signs of toxicity (daily), detailed clinical examination (at weekly intervals), ophthalmic examination (during acclimatization and near the end of treatment periods), body weight, feed consumption (once in a week), and functional battery observation (during the last week of treatment). Terminal activities included organ weight measurements and detailed gross and histopathological examination. Clinical pathological investigations were carried out at the end of the treatment period. Detailed necropsy of each rat was performed at the end of the treatment period. Specified organs as per the study plan were also collected and weighed. The organ weight ratio was calculated on the basis of body weight.
In summary of the results, no abnormal and treatment-related clinical signs and mortality were observed during the course of the study except the changes in the fur, tail, and fecal color. Change in color was attributed to the yellow color of test item and reference item. No treatment-related ophthalmologic changes were observed. Abnormal behavior was not observed during the conduct of functional battery observation. Treatment-related changes were not observed in body weight and feed consumption in different treatment groups as compared to vehicle control during the study period. Clinical pathology analysis showed no treatment-related changes in test and reference item-treated groups.
No significant changes were observed in terminal fasting body weight, organ weight, and organ weight ratios in treated groups when compared to vehicle control. Terminal fasting body weight, organ weight, and organ weight ratios were comparable between test item and reference item high-dose groups in both the sexes. In gross pathology, yellowish discoloration of lungs was observed microscopically in a few test/reference item-treated group animals. Histopathological changes observed in lungs were attributed to gavage-related reflux due to a higher concentration of test formulation resulting in regurgitation of the test item. The regurgitated test item was seen as yellowish deposits in lungs surrounded by the foreign-body reaction in the form of granuloma and chronic inflammation and fibrosis of interstitium. These lung observations due to gavage-related reflux in rats are common in animal studies and of no toxicologically relevance to humans.
Based on the above findings, it is concluded that NOAEL of synthetic curcumin is 1000 mg/kg b. w. following oral administration for 90 days in Wistar rats, and this ingredient is of no safety concern. In the modern world, health authorities and regulatory bodies are not only concerned about low quality of natural extracts but also presence of fertilizer and pesticide residues, solvents & other co-occurring impurities and uncontrolled exploitation of resources in the extraction of natural products. Well studied nature identical ingredients such as synthetic curcumin sought for a solution. Synthetic curcumin sought for a solution having controlled manufacturing process and no batch-to-batch variation. High purity (>99%) of synthetic curcumin eliminates unspecified impurities and offers a much safer products in comparison of the natural extract. These days most of the lifesaving drugs are manufactured using chemical synthesis and in the same manner synthesis of safe and high-quality nutraceutical ingredients is a welcome trend.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
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