Search Images Maps Play YouTube News Gmail Drive More »
Sign in
Screen reader users: click this link for accessible mode. Accessible mode has the same essential features but works better with your reader.

Patents

  1. Advanced Patent Search
Publication numberUS3764692 A
Publication typeGrant
Publication dateOct 9, 1973
Filing dateSep 30, 1970
Priority dateSep 30, 1970
Publication numberUS 3764692 A, US 3764692A, US-A-3764692, US3764692 A, US3764692A
InventorsJ Lowenstein
Original AssigneeHoffmann La Roche
Export CitationBiBTeX, EndNote, RefMan
External Links: USPTO, USPTO Assignment, Espacenet
Method of treating obesity
US 3764692 A
Abstract
The inhibition of fatty acid synthesis is obtained in biological systems by utilizing a specific stereoisomer of hydroxycitric acid and derivatives thereof such as esters or lactones and the non-toxic salts of these compounds. It is believed that the present method involves the inhibition of citrate cleavage enzyme. Inhibition of fatty acid synthesis by the present method is useful in the treatment of obesity.
Images(5)
Previous page
Next page
Claims  available in
Description  (OCR text may contain errors)

U 4 Unite States Patent [1 1 [111 3,764,692 Lowenstein Oct. 9, 1973 METHOD OF TREATING OBESITY Chemical Abstracts 65: 9373 a [75] Inventor: John M. Lowenstein, Wellesley Chemical Abstracts 67: 69394 G Hills, Mass. Chemical Abstracts 70: 105772 b [73] Assignee: Hoffmann-La Roche Inc., Nutley, Merck Manual 11th Edmon 1966 307-311 NJ. Primary Examiner-Albert T. Meyers Filed? p 1970 Assistant Examiner-Norman A. Drezin App]. No.: 77,042

Related (1.8. Application Data Continuation-impart of Ser. No. 872413, Oct. 29, 1969, abandoned.

US. Cl .i 424/279, 424/313, 424/317 Int. Cl A61k 27/00 Field of Search 424/317, 279, 313

References Cited OTHER PUBLICATIONS Chemical Abstracts 60: 13800 b Chemical Abstracts 63: 16775 g Att0rneySamuel L. Welt, Jon S. Saxe, Bernard S. Leon, William H. Epstein and George M. Gould [57] ABSTRACT 12 Claims, N0 Drawings METHOD OF TREATING OBESITY RELATED APPLICATIONS This application is a continuation-in-part of applicant's copending US. Pat. application Ser. No. 872,4- 13 filed Oct. 29, 1969, now abandoned.

BRIEF DESCRIPTION OF THE INVENTION This invention relates to a method of inhibiting fatty acid synthesis in biological systems by introducing into such systems a specific stereoisomer of hydroxycitric acid or derivatives thereof. The biological systems in which the method of the present invention may be practiced include cell free enzyme preparations containing citrate cleavage enzyme (also identified as ATPzcitrate oxaloacetate lyase), citrate, coenzyme A, ATP (or systems generating ATP), TPNI-I (or systems generating TPNH), and tissue homogenates, tissue slices, perfused organs, and intact mammals, particularly non-ruminating mammals.

The stereoisomers of hydroxycitric acid and its derivatives are related structurally to citric acid wherein a hydroxy group is substituted for one of the four methylene hydrogens of citric acid. Thus, there are four possible stereoisomers of hydroxycitric acid. Of these four stereoisomers one has been found to inhibit substantially fatty acid synthesis in biological systems. This particular isomer is (-)hydroxycitric acid hereinafter called garcinia acid. It is obtainable by isolation from the fruit of Garcinia cambogia using known procedures. For example, this isolation may be accomplished following the procedure described by Lewis in Methods in Enzymology (J. M. Lowenstein, ed.), Vol. 13, page 613 (Academic Press, New York, 1969).

Garcinia acid is usually isolated in the form of its lactone. The free acid may be conveniently obtained from the lactone by base hydrolysis, e.g., sodium hydroxide or potassium hydroxide preferably with heating followed by acidification in a manner known per se.

The term derivatives" as used herein in conjunction with garcinia acid is meant to include garcinia acid lactone, derivatives of one or more carboxyl groups of garcinia acid, e.g., mono, di or tri esters of garcinia acid or mono or di esters of its lactone and non-toxic pharmaceutically acceptable basic salts of garcinia acid or the lactone or esters thereof.

Ester derivatives of garcinia acid which are useful in the practice of the present invention include the lower alkyl, aryl and aryl-lower alkyl esters. Included within the lower alkyl esters of the present invention are branched or straight chain lower alkyl radicals having from one to seven carbon atoms. Preferred lower alkyl esters of garcinia acid include the methyl, ethyl, isopropyl and butyl esters. Examples of aryl esters include the phenyl and substituted phenyl esters, e.g., phenyl substituted with halogen, lower alkyl, lower alkoxy or nitro. Benzyl represents a preferred aryl alkyl ester. The aforesaid esters may be prepared by esterification of garcinia acid with a desired alcohol in the presence of excess mineral acid such as sulfuric acid, hydrobromic acid, or the like. Suitable alcohols include lower alkanols, phenol and benzyl alcohol, for example. Conventional esterification conditions may be employed. Additionally, alkyl or aralkyl esters may be prepared by reaction with diazoalkylenes or diazoarylalkylenes, e.g., diazomethane, diazoethane or phenyldiazomethane in a manner known per se.

The garcinia acid may also be utilized in the form of its pharmaceutically acceptable non-toxic basic salt. Preferred salts for this purpose include the alkali metals, e.g., sodium or potassium; the alkaline earth metals, e.g., calcium; or complex salts such as ammonium or substituted ammonium salts such as a mono-, dior tri-alkylammonium salt or a mono-, dior tri-hydroxyalkylammonium salt.

The inhibition of fatty acid synthesis in biological systems by the use of garcinia acid or its derivatives is believed to arise from the inhibition by such compounds of citrate cleavage enzyme contained in such systems. The cleavage of citrate is catalyzed by citrate cleavage enzyme according to the stoichiometry: citrate CoA ATP acetyl-CoA oxaloacetate ADP P,

In the conversion of carbohydrate and various amino acids to fat by non-ruminant mammals, citrate is the major source of the acetyl group of acetyl coenzyme A which is utilized for the synthesis of fatty acid. Citrate is formed in the mitochondria by the citrate synthase reaction. It is then metabolized via the citric acid cycle. Under conditions when energy intake exceeds energy demand, some citrate is diverted to the extramitochondrial space of the cell where it is used for fatty acid synthesis, that is to say for energy storage.

Garcinia acid and its derivatives are useful in the treatment of obesity. These compounds can be made up in the form of conventional pharmaceutical preparations; for example, the aforesaid compounds can be mixed with conventional organic or inorganic inert pharmaceutical carriers suitable for parenteral or enteral administration such as, for example, water, gelatin, lactose, starch, magnesium stearate, talc, vegetable oil, gums or the like. They can be administered in conventional pharmaceutical forms, e.g., solid forms, for example, tablets, dragees, capsules, suppositories or the like; or in liquid forms, for example, suspensions or emulsions. Moreover, the pharmaceutical composi-' tions containing compounds of this invention can be subjected to conventional pharmaceutical expedients such as sterilization, and can contain conventional pharmaceutical excipients such as preservatives, stabilizing agents, emulsifying agents, salts for the adjustment of osmotic pressure or buffers. The compositioncan also contain other therapeutically active materials.

A suitable pharmaceutical dosage unit can contain from about 15 to 600 mg. of garcinia acid or its derivatives. Suitable parenteral dosage regimens in mammals comprise from 1 mg/kg to about 25 mg/kg per day. However, for any particular subject, the specific dosage regimen should be adjusted according to individual need and the professional judgment of the person administering or supervising the administration of the aforesaid compounds. It is to be understood that the dosages set forth herein are exemplary only and that they do not, to any extent, limit the scope or practice of this invention.

The present invention may be more clearly illustrated by the following examples. All temperatures are in degrees centrigrade.

EXAMPLE 1 Citrate cleavage enzyme was isolated from the liver of rats which had been starved for two days and which were then fed a diet high in glucose for three days. The purification was carried out using the procedure of Inoue et al., J. Biochem. (Japan) 60, 543 (1966).

These steps involved ammonium sulfate precipitation between -30 percent saturation and DEAIE-column chromatography.

The enzyme activity was measured as follows. The reaction mixture contained 20 mM citrate, 20 mM magnesium chloride, 70 mM Tris-HCl buffer (pH 8.0), 200 mM hydroxylamine, mM dithiothreitol, 10 mM ATP, 0.6 mM CoA and citrate cleavage enzyme. The final volume was 1.0 ml. and the temperature was 37 C. The reaction was started by adding the ATP. It was stopped after 20 minutes and the hydroxamate color was developed as described by Inoue et al. cited above. Hydroxamate formation was linear with time for at least 30 minutes.

The above assay procedure was used for a series of tricarboxylic acids which were added to the reaction mixture in the amounts indicated in Table I which follows. The reaction mixture also contained 65 micrograms of protein. A millimolar extinction coefficient of 0.8 at 520 millimicrons was used to calculate the amounts of hydroxamate formed.

TABLE I Citrate concentration (rnM) Substance added 10 Hydroxamate formed (mumoles/mg/rnin.) None 210 405 Homocitrate, 25 mM 6 52 310 Homoisocitrate, 25 mM 12 190 40l Homoaconirate, 25 mM I2 198 385 Garcinia acid, 1 mM 0 2 101 Table I indicates that garcinia acid is a strong inhibitor of citrate cleavage enzyme as evidenced by a lower rate of hydroxamate formation in the presence of this compound. The other analogs of citric acid which were tested produced much less inhibition even though they were used at twenty-five times the level of garcinia acid.

EXAMPLE 2 This example demonstrates the stereo-specific nature of the citrate cleavage enzyme inhibition exhibited by garcinia acid. In this experiment the assay method described in Example 1 was utilized with the exception that garcinia acid and its stereoisomer (+)-allohydroxycitric acid were added in the amounts indicated below in Table 2.

TABLE 2 Citrate concentration (mM) Substance added 0.5 l0

Citrate cleaved (mumoleslmim) None 69 I65 Garcinia acid [0 ,uM 25 I44 I00 M 6 96 (+)-Allohydroxy citric acid 0 prM 68 I62 I000 M 33 140 As seen from the results summarized in Table 2, garcinia acid is a more potent inhibitor of citrate cleavage enzyme than its structurally related stereoisomer (+)-allohydroxy citric acid.

EXAMPLE 3 This example demonstrates the inhibition of lipogenesis effected by treatment with garcinia acid in isolated rat liver slices. In these experiments Charles River female rats l50l75 gm. were fasted for two days and refed ad libitum for three days on a diet containing percent dextrose, 25 percent casein and 5 Phillips and Hart salt mixture.

The rats were killed by decapitation. Their livers were excised quickly, placed directly on ice for 30 seconds and 100-500 mg. slices were cut using a modified Staty Riggs tissue slicer on ice. The serosal slices were discarded. Slices were transferred to 50 ml. beakers in ice containing 10 times the tissue-volume of Hanks solutes dissolved in 5 mM Tris. buffer pH 7.4-7.6. Fatty acid precursor in the form of alanine was included along withthe transaminase acceptor a-keto glutaric acid in molar ratio 2:3 at pH 7.4-7.6. Synthetic garcinia acid was added either in the lactone or free acid form in the final concentration indicated below. Incubations were carried out at 37 C. under an atmosphere of 100 percent oxygen in an Eberbach water bath shaker, usually for 60 minutes unless otherwise indicated. The incubation period began with the addition of *C-alanine (specific activity= 107.2 mc/mM) to a final concentration of 10 ic/gm tissue. Two milliliters of 5N NaOI-I were added to 0" time control samples before C- alanine and appropriate corrections made with the experimental samples.

Slices were removed with forceps, chilled directly on ice, added to 10 ml. glass homogenizing tubes with 2 ml. of water and homogenized with 5 strokes of a teflon pestle. Homogenates were transferred to tubes containing 2 ml. 5N NaOH, and saponification was carried out for 3 hours at 90 C. Samples were acidified with 2.5 ml. 5N H and extracted twice with 5 ml. petroleum ether (boiling point 4060 C.). Supernatants were added directly to glass counting vials, evaporated to dryness and 10 ml. of toluene-PPO-POPOP scintillation fluid was added. Samples were analyzed for radioactivity in a Packard Tri-Carb scintillation counter. Data was expressed as rnpM of C-alanine incorporated/gram of tissue/60minutes.

In the first group of experiments liver slices were incubated for 60 minutes with 10 mM *C-alanine and 15 mM a-ketoglutarate. Table 3 illustrates the inhibition of lipogenesis by garcinia acid under these conditions.

TABLE 3 Sample Additions mnmoleslgmlfifl" Inhibition 1 Control 167.5 2 5 11M Garcinia Acid 159.2 5.0 3 50 p.M Garc'mia Acid 118.9 29.0 4 500 nM Garcinia Acid 80.9 51.7

neutralized to pH 7.4

Table 4 demonstrates the inhibition by both garcinia acid and garcinia acid lactone in liver slices incubated for 60 minutes with 5 mM *C-alanine and 7.5 mM a-ketoglutaric acid. From these data the physiological, apparent inhibition constant (K of garcinia acid was 350 M and the K of garcinia acid lactone was 30 pLM.

neutralized to pH 7.4

Table 5 demonstrates the time kinetics of inhibition by garcinia acid under the same experimental conditions observed in Table 4.

Table 5 Time (in mmnoles/ Sample Additions minutes) gm/t Inhibition 1 Control 60 1 10.3 2 500 1.1M Garcinia Acid 60 83.7 24.1 3 Control 9 239.6 4 500 pM Garcinia Acid 90 137.4 42.6 5 Control 120 737.4 6 500 11M Garcinia Acid* 120 248.1 66.3 neutralized to pH 7.4

EXAMPLE 4 This example demonstrates the in vivo activity of synthetic garcinia acid and its lactone. Individual groups of Charles River female rats 150-175 gm. were fasted for two days and meal fed from 9-12 a.m. using the diet .containing 70 percent dextrose, 25 percent casein and 5 percent Philipps and Hart salt mixture.

0n the last day of refeeding, approximately 5 hours after feeding, the animals were lightly anesthetized with Penthrane and injected (using a 27 G needle) in the tail vein with the following composition: 12.6 mg. alanine as fatty acid precursor, 30.6 mg. a-ketoglutarate as transaminase acceptor and 5 ac C-alanine (specific activity 156 mc/mM) dissolved in a total volume of 0.25 ml. saline pH 7.4-7.6. Synthetic garcinia acid either in the free acid or lactone form was dissolved in a total volume of 0.25 ml. saline at pH 7.4-7.6.

The rats were killed by decapitation after 30 minutes. Livers were excised rapidly, weighed, placed in 30 ml. beakers with .15 ml. water and crudely minced. They were transferred to glass homogenizing tubes and homogenized with 5 strokes of a teflon pestle. Three milliliter aliquots of liver homogenates in duplicate were added to tubes containing 2.1 ml. 5N NaOH and saponified with 2.6 ml. 5N H 80 and extracted twice with 5 ml. of petroleum ether (boiling point 40-60 C.). Supernatants were added directly, to glass counting vials, evaporated to dryness and 10 ml. of toluene-PPO- POPOP scintillation fluid added. Samples were analyzed for absolute activity in a Packard Tri-Carb scintillation counter. Resulting data was expressed as mumoles of *C-alanine incorporated/gram of tissue/30 minutes.

Fourteen rats were fasted for 2 days and meal fed as above for 3 days. On the last day of refeeding one group received 10 mg. of synthetic garcinia acid in the lactone form dissolved in a total volume of 0.25 ml. saline, pH 7.4-7.6 by tail vein injections 60 minutes prior to C-alanine. An additional 5 mg. of garcinia acid lactone was given with the ,C-alanine. Control animals received only the C-alanine injection. Inhitibion of lipogenesis by garcinia acid lactone is illustrated in Table 6 below. In this table rats numbers 1-7 represent controls while rats numbers 8-14 received garcinia acid lactone.

TABLE 6 (Garcinia Acid 83.5

Lactone) 66.8 S.E.M. 8.5 Inhibition compared with the controls numbers 1-4.

TABLE 7 Rat No. (Controls) mnmoles/gm/30" 1048 S.E.M. 176.3 5 (Garcinia Acid Lactone) 386.1 6 249.1 7 290.9 8 257.8

296 S.E.M. i 31.4 Inhibition 72% EXAMPLE 5 A solution of (+)-garcinia acid lactone (10 g.) in tetrahydrofuran ml.) was treated with a solution of diazomethane in ether until the yellow color persisted. The solution was allowed to stand at room temperature for one hour then the solvent was removed in vacuo and the residue crystallized from ether haxane to give 8.0 g. of (+)-garcinia acid lactone dimethyl ester, m.p. 70-72. A second crop (2.4 g.; m.p. 65-70) was obtained from the mother liquors. Crystallization from ether furnished the analytical sample, m.p. 72-73; [M 25 85.65 (c, 1.0, CHCl ir (CHCl 3550, 1810 and 1755 cm; nmr CDCl;,) 8 4.91 (singlet, 1H, CH), 4.14 (singlet, 1H, OH), 4.91 (singlet, 3H, -OCH;,), 3.78 (singlet, 3H, -OCH;,) and 2.99 (quartet, 2H, jCH

Anal. Calcd for C H O C, 44.04; H, 4.62. Found:

EXAMPLE 6 lowed to evaporate and the residue was dissolved in water (5 ml.) and passed through a column of cation exchange resin (Amberlite IR 10 ml.). The acidic eluent was evaporated to dryness to give a colorless solid. Crystallization from methanol-ethanol afforded 800 mg. of (+)-garcinia acid lactone mono ammonium salt, m.p. 231 (decomposition); [0 +929 (c, 1.0, H 0); 1r (KBr) 3,460-2,500 (broad), 1,800, 1,770 and 1,625 (broad) cm ;nmr(DMSO)8 2.71 (quartet, 2H, CH and 4.60 (singlet, 11-1, CH). Neutralization equivalent: 207 Anal. Calcd for C H NO C, 34.79; H, 4.38; N,

Found: C, 34.65; H, 4.48; N, 6.72.

EXAMPLE 7 Acetyl chloride (3.0 ml.) was added to aboslute ethano] (50 ml.), then after several minutes (+)-garcinia acid lactone (5.0 g.) was added and the solution heated under reflux for three hours. Molecular sieve 3A in a Sohxlet apparatus was used as a water scavenger. The solvent was removed in vacuo to give 75 g. of a pale yellow oil which was purified by reduced pressure distillation to give 5.2 g. of a water-white viscous liquid, b.p. 136-1400.1-0.15 mm; ir (CHCl 3,600, 1,810 and 1,745 cm. Nmr analysis indicated that it was a 2:1 mixture of (+)-gar'cinia acid lactone diethyl ester and garcinia acid triethyl ester.

The triester was converted to the diester lactone upon repeated distillation and pure diester lactone can be obtained in this manner.

EXAMPLE 8 Capsule Formulation Per Capsule Garcinia acid lactone 10 mg Lactose, U.S.P. 165 mg Com Starch. U.S.P. 30 mg Talc. U.S.P. 5. mg Total Weight 210 mg Procedure EXAMPLE 9 Capsule Formulation Per Capsule Garcinia acid lactone 50 mg Lactose. U.S.P. 1 25 mg Corn Starch. U.S.P. 30 mg Talc. USP. mg

Total Weight 210 mg Procedure 1. Garcinia acid lactone was mixed with lactose and corn starch in a suitable mixer.

2. The mixture was further blended by passing through a Fitzpatrick Comminuting Machine with a 1A screen with knives forward.

3. The blended powder was returned to the mixer, the talc added and blended thoroughly.

4. The mixture was filled into 4 hard shell gelatin capsules on a Parke Davis capsulating machine.

EXAMPLE 10 Tablet Formulation Per Tablet Garcinia acid lactone 25.00 mg Dicalcium Phosphate Dihydrate, Unmilled 175.00 mg Corn Starch 24.00 mg Magnesium Stearate 1.00 mg Total Weight 225.00 mg Procedure 1. Garcinia acid lactone and corn starch were mixed together and passed through an 00 screen in Model J" Fitzmill with hammers foward.

2. This premix was then mixed with dicalcium phosphate and onehalf of the magnesium stearate, passed through a 1A screen in Model .1 Fitzmill with knives EXAMPLE ll Tablet Formulation Per Tablet Garcinia acid lactone 100 mg Lactose, U.S.P. 202 mg Corn Starch, U.S.P. mg Amijel B011 20 mg Calcium Stearate 8 mg Total Weight 410 mg A prehydrolyzed food grade corn starch. Any similar prehydrolyzed corn starch may be use Procedure 1. Garcinia acid lactone, lactose, corn starch, and Amijel B011 were blended in a suitable mixer.

2. The mixture was granulated to a heavy paste with water and the moist mass was passed through a 12 screen. It was then dried overnight at 1 10 F.

3. The dried granules were passed through a 16 screen and transferred to a suitable mixer. The calcium stearate was added and mixed until uniform.

4. The mixture was compressed at a tablet weight of 410 mg. using tablet punches having a diameter of approximately three-eight inch. (Tablets may be either flat or biconvex and may be scored if desired.)

I claim:

1. A method for treating obesity which comprises administering to a mammal in need of such treatment an effective amount of a compound selected from the group consisting of garcinia acid, garcinia acid lactone, mono-, diand trilower alkyl, phenyl and benzyl esters of garcinia acid, monoand di-lower alkyl, phenyl and benzyl esters of garcinia acid lactone, wherein lower alkyl is from one to seven carbon atoms, and non-toxic pharmaceutically acceptable basic salts thereof.

2. The method of claim 1 wherein garcinia acid is administered.

3. The method of claim 1 wherein garcinia acid lactone is administered.

4. The method of claim I wherein anester of garcinia acid or garcinia lactone is administered.

- 5. The method of claim 4 wherein said ester is a lower alkyl ester.

6. The method of claim 1 wherein the compound is administered in the range of from about 1 to about 25 mg/kg per day.

7. A pharmaceutical composition for the treatment of obesity comprising a pharmaceutical carrier and an effective amount of a compound selected from the group consisting of garcinia acid, garcinia acid lactone, mono-, diand tri-lower alkyl, phenyl and benzyl esters of garcinia acid, monoand di-lower alkyl, phenyl and benzyl esters of garcinia acid lactone, wherein lower alkyl is from one to seven carbon atoms, and non-toxic pharmaceutically acceptable basic salts thereof.

8. The composition of claim 7 wherein said compound is garcinia acid.

9. The composition of claim 7 wherein said compound is garcinia acid lactone.

10. The composition of claim 8 wherein said compound is an ester of garcinia acid or garcinia acid lactone.

11. The composition of claim 10 wherein said ester is a lower alkyl ester.

12. The composition of claim 7 wherein said compound is present in the range of from about 15 to 600 mg.

Non-Patent Citations
Reference
1 *Chemical Abstracts 60: 13800 b
2 *Chemical Abstracts 63: 16775 g
3 *Chemical Abstracts 65: 9373 a
4 *Chemical Abstracts 67: 69394 G
5 *Chemical Abstracts 70: 105772 b
6 *Merck Manual, 11th Edition, 1966 pp. 307 311
Referenced by
Citing PatentFiling datePublication dateApplicantTitle
US4312885 *Dec 26, 1978Jan 26, 1982Hoffmann-La Roche Inc.Chlorocitric acids
US5536516 *Aug 24, 1994Jul 16, 1996Renaissance Herbs, Inc.Hydroxycitric acid concentrate and food products prepared therefrom
US5656314 *Apr 17, 1996Aug 12, 1997Moffett; Scott AlexanderHydroxycitric acid concentrate and food products prepared therefrom
US5783603 *Mar 31, 1997Jul 21, 1998Sabinsa CorporationPotassium hydroxycitrate for the suppression of appetite and induction of weight loss
US6054128 *Sep 29, 1997Apr 25, 2000Wakat; DianeDietary supplements for the cardiovascular system
US6160172 *Apr 14, 1998Dec 12, 2000Vittal Mallya Scientific Research FoundationSoluble double metal salt of group IA and IIA of (-) hydroxycitric acid, process of preparing the same and its use in beverages and other food products without effecting their flavor and properties
US6207714 *Sep 14, 2000Mar 27, 2001Dallas L. ClouatreMethods and pharmaceutical preparations for improving glucose metabolism with (−)-hydroxycitric acid
US6395296Aug 11, 2000May 28, 2002Karanam BalasubramanyamSoluble double metal salt of group IA and IIA of hydroxycitric acid, process of preparing the same and its use in beverages and other food products without effecting their flavor and properties
US6413545Sep 1, 1999Jul 2, 2002Access Business Group International LlcDiet composition and method of weight management
US6441041Jun 20, 2001Aug 27, 2002Dallas L. Clouatre(-)-hydroxycitric acid for the prevention of osteoporosis
US6447807Sep 14, 2000Sep 10, 2002Dallas L. ClouatrePotassium (-)-hydroxycitric acid methods for pharmaceutical preparations for stable and controlled delivery
US6476071May 7, 2001Nov 5, 2002Dallas L. ClouatreCorrecting polymorphic metabolic dysfunction with (−)-hydroxycitric acid
US6482858Jun 20, 2001Nov 19, 2002Dallas L Clouatre(−)-hydroxycitric acid for wound healing and immunomodulation
US6489492 *Sep 5, 2001Dec 3, 2002Department Of Science And TechnologyChiral derivatives of Garcinia acid bearing lactone ring moiety and process for preparing the same
US6703515Sep 5, 2001Mar 9, 2004Department Of Science And Technology, Technology BhavanChiral derivatives of Hibiscus acid bearing lactone ring moiety, process for preparing the same and a convenient method for the large-scale isolation of Hibiscus acid
US6706899 *Sep 5, 2001Mar 16, 2004Department Of Science And Technology, Technology BhavanAcyclic chiral compound from garcinia acid and process for preparing the same
US6770782 *May 22, 1998Aug 3, 2004Sabinsa CorporationProcess for the production of potassium hydroxy citric acid, and compositions containing the potassium hydroxy citric acid
US7015250Feb 13, 2001Mar 21, 2006Glykon Technologies Group, LlcMethods and pharmaceutical preparations for normalizing blood pressure with (-)-hydroxycitric acid
US7119110Oct 4, 2002Oct 10, 2006Interhealth Nutraceuticals IncorporatedMethod and composition for preventing or reducing the symptoms of insulin resistance syndrome
US7153877Dec 9, 2004Dec 26, 2006Interhealth Nutraceuticals IncorporatedMethod and composition for preventing or reducing the symptoms of insulin resistance syndrome
US7189416Nov 23, 2002Mar 13, 2007Glykon Technologies Group, LlcMethod for stable and controlled delivery of (-)-hydroxycitric acid
US7214823Apr 13, 2004May 8, 2007Indfrag LimitedHydroxycitric acid complex metal salts, composition, and methods
US7335651Aug 3, 2004Feb 26, 2008Interhealth Nutraceuticals IncorporatedCompositions incorporating(-)-hydroxycitric acid and related methods for promoting fat oxidation
US7846970 *Sep 22, 2005Dec 7, 2010Showa Denko K.K.Hydroxycitric acid derivatives and skin external preparations containing the same
US7927636 *Jul 13, 1998Apr 19, 2011Interhealth Nutraceuticals, Inc.Hydroxycitric acid compositions, pharmaceutical and dietary supplements and food products made therefrom, and methods for their use in reducing body weight
US7943186 *Aug 22, 2005May 17, 2011Interhealth Nutraceuticals, Inc.Hydroxycitric acid compositions, pharmaceutical and dietary supplements and food products made therefrom, and methods for their use in reducing body weight
US8097286Nov 3, 2006Jan 17, 2012Inqpharm Sdn BhdHerbal composition weight management
US8394856Jul 2, 2003Mar 12, 2013Glykon Technologies Group, Llc(-)-Hydroxycitric acid for controlling inflammation
US8563051Dec 23, 2011Oct 22, 2013Inqpharm Sdn BhdHerbal composition for weight management
US20010044469 *Feb 13, 2001Nov 22, 2001Clouatre Dallas L.Methods and pharmaceutical preparations for normalizing blood pressure with (-)-hydroxycitric acid
US20030133992 *Oct 4, 2002Jul 17, 2003Debasis BagchiMethod and composition for preventing or reducing the symptoms of insulin resistance syndrome
US20040014692 *Dec 20, 2002Jan 22, 2004Debasis BagchiCompositions incorporating(-)-hydroxycitric acid, chromium, and gymnemic acid, and related methods for promoting healthy body weight and improving related health factors
US20040063940 *Jun 26, 2003Apr 1, 2004Pfizer Inc3,3-Biarylpiperidine and 2,2-biarylmorpholine derivatives
US20040101555 *Nov 23, 2002May 27, 2004Clouatre Dallas L.Method for stable and controlled delivery of (—)-hydroxycitric acid
US20040157929 *Apr 1, 2002Aug 12, 2004Ohia Sunny E.Method for increasing serotonin levels in a person by administration of a composition incorporating(-)hydroxycitric acid, and related compositions thereof
US20040171694 *Jun 14, 2002Sep 2, 2004Van Laere Katrien Maria JozefaDietetic preparation and use of an alpha-hydroxy carboxylic acid(citric acid for the treatment of obesity
US20040200983 *Apr 13, 2004Oct 14, 2004Hisataka FujimakiParticle beam irradiation equipment and particle beam irradiation method
US20050008722 *Aug 3, 2004Jan 13, 2005Interhealth Nutraceuticals IncorporatedCompositions incorporating(-)-hydroxycitric acid, chromium, and gymnemic acid, and related methods for promoting healthy body weight and improving related health factors
US20050009919 *Jul 7, 2003Jan 13, 2005Clouatre Dallas L.Treating cachexia and excessive catabolism with (-)-hydroxycitric acid
US20050013887 *Aug 3, 2004Jan 20, 2005Interhealth Nutraceuticals IncorporatedCompositions incorporating (-)-hydroxycitric acid, chromium, and gymnemic acid, and related methods for promoting healthy body weight and improving related health factors
US20050032901 *Jul 2, 2003Feb 10, 2005Clouatre Dallas L.(-)-Hydroxycitric acid for controlling inflammation
US20050096369 *Nov 4, 2003May 5, 2005Hoang Ba X.Compositions and methods for treating cellular proliferation disorders
US20050100614 *Dec 9, 2004May 12, 2005Interhealth Nutraceuticals IncorporatedMethod and composition for preventing or reducing the symptoms of insulin resistance syndrome
US20050215644 *Mar 16, 2005Sep 29, 2005Interhealth Nutraceuticals, Inc.Methods for increasing neurotransmitter levels using hydroxycitric acid
US20050282894 *Aug 22, 2005Dec 22, 2005Interhealth Nutraceuticals, Inc.Hydroxycitric acid compositions, pharmaceutical and dietary supplements and food products made therefrom, and methods for their use in reducing body weight
US20060025482 *Jun 14, 2005Feb 2, 2006Clouatre Dallas L(-)-Hydroxycitric acid for the modulation of angiotensin-converting enzyme
US20060025483 *Jul 5, 2005Feb 2, 2006Clouatre Dallas L(-)-Hydroxycitric acid for protection against soft tissue and arterial calcification
US20060141030 *Nov 28, 2005Jun 29, 2006Clouatre Dallas LMethod and composition for stable and controlled delivery of (-)-hydroxycitric acid
US20060292216 *Mar 8, 2006Dec 28, 2006Clouatre Dallas LEnteric delivery of (-)-hydroxycitric acid
US20070293577 *Sep 22, 2005Dec 20, 2007Showa Denko K.K.Hydroxycitric Acid Derivatives And Skin External Preparations Using The Same
US20080139657 *Feb 19, 2008Jun 12, 2008Interhealth Nutraceuticals, Inc.Method for increasing serotonin levels in a person by administration of a composition incorporating (-)hydroxycitric acid, and related compositions thereof
US20080268075 *Nov 3, 2006Oct 30, 2008Iovate T. & P. Inc.Herbal Composition Weight Management
US20100273884 *Nov 30, 2009Oct 28, 2010Glykon Technologies Group, LlcMethod for stable and controlled delivery of (-)-hydroxycitric acid
US20100323031 *Jun 22, 2009Dec 23, 2010Glykon Technologies Group, LlcSynergistic combination to enhance blood glucose and insulin metabolism
EP0016867A1 *Dec 21, 1979Oct 15, 1980F. HOFFMANN-LA ROCHE & CO. AktiengesellschaftMonochlorcitric acid derivatives, pharmaceutical compositions containing them and process for the preparation of these derivatives
EP0739629A1 *Apr 24, 1996Oct 30, 1996Ravi ShrivastavaAssociations comprising (-)hydroxycitrate and having new therapeutical activities
EP0803202A2 *Apr 24, 1997Oct 29, 1997SIRC S.p.A. NATURAL & DIETETIC FOODSDietary composition containing chitosan, Garcinia cambogia hydroxycitrate and organic chromium
EP0803202A3 *Apr 24, 1997Apr 29, 1998SIRC S.p.A. NATURAL & DIETETIC FOODSDietary composition containing chitosan, Garcinia cambogia hydroxycitrate and organic chromium
EP0841011A1 *Oct 22, 1997May 13, 1998SIRC S.p.A. NATURAL & DIETETIC FOODSDietary preparation comprising chitosan and other soluble fibres combined with ascorbic acid, organic chromium, vanadium and garcinia hydroxycitrate for lipid absorption lowering and glucide metabolism stabilization
EP0974349A1 *Feb 9, 1998Jan 26, 2000Nippon Shinyaku Co., Ltd.Athletic endurance increasing agent
EP0974349A4 *Feb 9, 1998Mar 14, 2001Nippon Shinyaku Co LtdAthletic endurance increasing agent
EP1396494A1 *Apr 24, 1996Mar 10, 2004Hydroxydase Societe Des Eaux Minerales Naturelles Et Des Laboratoires Du BreuilMagnesium (-)hydroxycitrate and its applications
EP1713454A1 *Sep 10, 2004Oct 25, 2006Glykon Technologies Group LLCEnteric delivery of (-)-hydroxycitric acid
EP1713454A4 *Sep 10, 2004Jul 2, 2008Glykon Technologies Group LlcEnteric delivery of (-)-hydroxycitric acid
EP2484345A1Nov 3, 2006Aug 8, 2012InQpharm Sdn BhdHerbal composition for weight management
WO1996036585A1 *May 15, 1996Nov 21, 1996Sabinsa CorporationA new process for the production of potassium hydroxy citric acid, and compositions containing the potassium hydroxy citric acid
WO2000015051A1 *Sep 14, 1999Mar 23, 2000Interhealth Nutraceuticals, Inc.Hydroxycitric acid compositions
Classifications
U.S. Classification514/449, 514/533, 514/547, 514/909, 514/574
International ClassificationC07C59/245
Cooperative ClassificationY10S514/909, C07C59/245
European ClassificationC07C59/245