SYNTHETICALLY PREPARED COMPOSITION FOR TREATMENT AND/OR PROPHYLAXIS OF OVERWEIGHT, AND USE THEREOF

Abstract: The claimed invention relates to a pharmaceutical synthetically prepared hydroxy citric acid composition for the treatment and/or prophylaxis of overweight and use thereof.

Description: Synthetically prepared compoition for treatment and/or prophylaxis of overweight, and use thereof The present invention is related to a pharmaceutical composition containing levorotatory hydroxycitrate; (-)HCA, prepared synthetically by a new synthesis method based on citric acid as a starting compound. The composition is to be used as an appetite reducer, a lipid-reducing agent and in other physiological processes wherein the substance has effect. More particularly, the inventive subject matter may also be used as a flavour additive and a preservative. Problems relating to overweight, enhanced blood fat (lipids) , enhanced blood sugar and high blood pressure are often referred to as the metabolic syndrome. (-)HCA has properties that directly affect the appetite by increasing the liver glycogen stores . This entails a feedback mechanism to the hypothalamus and the hunger centre that is downregulated. A Norwegian study has been performed that shows that the Ca-salt of HCA has this effect (Thorn E., Andrews B; short-term and long-term efficacy of HCA in the treatment of overweight; Abstract presented at the 7 and 8 European Congress on Obesity; Barcelona 1996 and Dublin 1997) . (-)HCA is naturally found as fruit acid in a number of fruits. The fruit that normally is used for the preparation of (-)HCA is Garccinia Cambogia. However, this product contains a number of other substances, and the proportion of (-)HCA constitutes less than 50 % of the total content. To obtain a better product with a more well-defined dose-response profile, a synthetic (-)HCA product is developed that is 100 % pure. The synthesis is based on citric acid as starting point. Citric acid is structurally close related to (-)HCA, and differs only by containing two hydrogen atoms (H) in the molecule instead of two hydroxyl groups. By such a substitution the HCA molecule obtains optical isomerism. The structure of the two molecules is shown in Figure 1. From animal studies it appears that the levorotatory isomer is slightly more effective than the dextrorotatory. Citric acid (-)HCA In the 1960ies and -70ies scientists with the pharmaceutical company Hoffman La Roche performed animal experiments with (-)HCA which showed that this substance clearly influenced the appetite in test animals and entailed that the energy input decreased and the body weight was reduced. In addition, Hoffman La Roche prepared synthetically smaller amounts of (-)HCA for the use in experiments related to a different synthesis pathway than what is used today. This synthesis was protected by patent for more than 25 years ago. Thus, this patent is not valid today. Of reasons that we do not know Hoffman La Roche cancelled the project in the end of the 1970ies before the substance was incorporated in their human research. No data have been published from Hoffman La Roche concerning humans. Thus, an object of the present invention is to provide an effective, non-toxic substance having clearly documented appetite-reducing properties to be used in human nutrition. Regarding toxicity, the toxicity of (-)HCA is at the same level as citric acid. Based on our present knowlegde, (-)HCA should be administered in a dosis from 1-3 g per day. Whether it should be administered before or after a meal to obtain the best possible effect is still not elucidated. The possibility that the timed administration, as compared with the energy intake, does not have any decisive importance for the effect is also present. Only future clinical applications may provide an answer to this question. The present invention is directed to a synthetic ( - ) HCA to be used for medical/pharmaceutical/nutritional purposes . The synthesis of HCA has significant points of difference from the previously described Hoffman La Roche synthesis. The HCA of the present invention is physical-chemical characterised by the following parameters : Molecular formula: C 6 H 8 0 8 , molecular weight: 208,1 Chemical name: 1(S), 2 (S) -1, 2-dihydroxy-l, 2 , 3- propanetricarboxylic acid. Syn. (-) hydroxycitric acid. Chemical form: Crystalline powder. Colour: colourless (white) Melting point: 156,5-158,0 °C [α] D = -8,62 °C in H 2 0 at 25 °C Solubility in water: about lOOg/100 ml at 25 °C In solution the compound will transfer to a lactone (about 10 % in 7 days at 20 °C) . The synthesis pathway is as follows: A solution of citric acid (10 g) and tungstic acid (2,0 g) in 1 N NaOH (143 ml) containing H 2 0 2 (30 %; 6 ml) was stirred for 2 hours at 85 °C. Then the solution was cooled, ION HCl was added and subsequently the solution was completely extracted with ether. Evaporation of the ether layer provided a white powder which, after crystallisation from ether-methylen- chloride, provided an epoxide with melting point 167-169 °C. Then the epoxide was further treated with chloroform (40 ml) pog-extracted with two parts (35 ml and 15 ml) 1 N NaOH solution. The combined aqueous extracts was washed with chloroform (2 x 10 ml) and subsequently acidified with IN HCl and evaporated to dryness in vacuum. The treatment of the dry material with ethylacetate and evaporation of the mixture resulted in an oily product that by fractional crystallisation from ethylacetate-carbon tetrachloride resulted in a levorotatory epoxide with the above-specified physical-chemical properties . In order to stabilise (-)HCA the Na and K salts that both are water soluble will be prepared. These are less hygroscopic than the acid itself. Analytical methods to identify the products are developed. For the treatment of overweight the product will be prepared in 500 mg soft capsules. The daily dosis is 3-4 capsules per day. Below the present invention is described in closer detail by examples that should not be regarded as limiting for the scope of the invention. Example 1: Hydroxycitrate (HCA) in the treatment of overweight. Erling Thorn. Abstract presented on the 7 th European Overweight Congress in Barcelona, May 1996. Sixty patients, 44 women and 16 men with overweight were included in a randomised placebo controlled double-blind study to investigate the effect and tolerance of hydroxycitrate (-)- HCA by weight reduction. The double-blind study persisted for 8 weeks . HCA, or an identical placebo capsule, was ingested 3 times per day (e.i.d.) , 30 minutes before breakfast, lunch and dinner. In addition, all the patients were given a diet having a low fat content of 1 200 kcal/d. Also, the patients were encouraged to perform physical exercise 3 times/week. The daily dosis of HCA was 1 320 mg/d. The average weight reduction in the HCA group (30 patients) was 6,4 kg, whereas the patients in the placebo group showed an average weight reduction of 3,8 kg. The difference in weight reduction is highly statistical significant p<0,001. The distribution of the weight loss, determined by NIR (near infrared light) , shows that 87 % of the weight loss in the HCA group is due to the loss of fat, whereas corresponding figures in the placebo groups are 80 %. Blood pressure, total cholesterol and hip and waist measures were also significantly reduced in both groups. A statistical significant difference in favour of the HCA group was observed in all these parameters (p<0,001). Appetite score, by using visually analogous scales, showed a significant reduction in the HCA group, but not in the placebo group (p<0,001) . The tolerability of the treatment was excellent. Two patients terminated the treatment due to abdominal pains, one in the HCA group and one in the placebo group. The patients were subsequently observed for 12 months in an open follow-up study (Example 2) wherein all the patients were given HCA. Conclusion: HCA is an effective and tolerable short time treatment of overweight and obesity when it is combined with a sensible low fat diet and exercise. Long term data are necessary to judge effect and tolerability by continuous use over time . Example 2: Long term data regarding effect and tolerability of HCA in the treatment of overweight. 52 of the patients that participated in the above- mentioned short time study were further observed in 12 months where all the patients were given the same dosis of HCA as above (1 320 mg/d) . The previously placebo treated patients now experienced a considerable weight loss, and after 12 months the average weight loss for the whole group was 13,8 kg. This constitutes 15 % of the initial weight. This must be regarded as a very satisfactory weight reduction in 1 year. The tolerability was excellent. Conclusion: HCA has a documented long-term effect as a weight reduction agent, combined with a low fat diet and exercise. There are no signs of development of tolerance, even after long term use (14 months) .

Claims: P a t e n t c l a i m s 1. Pharmaceutical composition in the form of a synthetic crystalline powder, for the treatment of overweight prohlems and other problems associated with the lipid metabolism in humans . 2. Pharmaceutical composition of claim 1, c h a r a c t e r i s e d i n that the ( - ) HCA has been prepared by a novel synthesis pathway. 3. Synthetic (-)HCA (hydroxycitric acid) prepared by a novel method of synthesis and c h a r a c t e r i s e d b y the indicated physical- chemical parameters, followed by the preparation of water soluble alkali salts (sodium/potassium) based on this synthesis for human application.

Inventors: KJELDSTADLI JARL, THOM ERLING, KJELDSTADLI, JARL, THOM, ERLING
Applicants: KJELDSTADLI JARL, PEMBY LTD, THOM ERLING, KJELDSTADLI, JARL, PEMBY LTD., THOM, ERLING
Application year: 1998
Main classification: A61K31
IPC codes: A61K31, C07C59