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(12) Patent Application Publication (10) Pub. No.: US 2011/0236506 A1 SCHWARTZ Et Al

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(12) Patent Application Publication (10) Pub. No.: US 2011/0236506 A1 SCHWARTZ Et Al US 2011 0236506A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2011/0236506 A1 SCHWARTZ et al. (43) Pub. Date: Sep. 29, 2011 (54) PHARMACEUTICAL ASSOCIATION Publication Classification CONTAINING LIPOCACID AND (51) Int. Cl. HYDROXYCTRIC ACIDAS ACTIVE A633/24 (2006.01) INGREDIENTS A63L/385 (2006.01) A63/685 (2006.01) (75) Inventors: Laurent SCHWARTZ, Paris (FR): A63/4985 (2006.01) Adeline GUAIS-VERGNE, A63L/7056 (2006.01) Draveil (FR) A6IP35/00 (2006.01) (73) Assignees: Laurent SCHWARTZ, Paris (FR): (52) U.S. Cl. ........... 424/649; 514/440; 514/77: 514/249; BIOREBUS, Paris (FR) 514/52 (21) Appl. No.: 13/099,897 (57) ABSTRACT Pharmaceutical combination containing lipoic acid and (22) Filed: May 3, 2011 hydroxycitric acid as active ingredients. The present inven tion relates to a novel pharmaceutical combination and to the Related U.S. Application Data use thereof for producing a medicament having an antitumor (63) Continuation of application No. PCT/FR2009/ activity. According to the invention, this combination com 052110, filed on Nov. 2, 2009. prises, as active ingredients: lipoic acid or one of the pharma ceutically acceptable salts thereof, and hydroxycitric acid or (30) Foreign Application Priority Data one of the pharmaceutically acceptable salts thereof. Said active ingredients being formulated together or separately for Nov. 3, 2008 (FR) ....................................... O8574.48 a conjugated, simultaneous or separate use. Patent Application Publication Sep. 29, 2011 Sheet 1 of 9 US 2011/023650.6 A1 lipoic acid alone -29 f2 f Niger of ces i{t} v s 6 g i w 4. 6 8 i 2 Concentrations tumoi.i. (Ca hydroxycitrate alone -29 2 Nitinger of teiis 100- Yaaaaa-Ya-Yaa-va-va-va-va-va-va-Ya-Ya-YYXXuan 8 Š 60 g as it t 6 Concentrations mol.i. FIG.1B Patent Application Publication Sep. 29, 2011 Sheet 2 of 9 US 2011/0236506 A1 lipoic acid alone it. 8. s s { 2 | ---- Concentrations (amoi. (Ca hydroxycitrate alone 24 f 2i Nittler of ces v - — 8. xxaaaaaaaaa. - S as s 6. saaaaaaaaaaaaaaaaaaaaaaaad g i 28 --~~ 8 3 -i-...--Mg-Mm 2. 8t Concentrations timeli) FIG.2B Patent Application Publication Sep. 29, 2011 Sheet 3 of 9 US 2011/023650.6 A1 i.ipoic acid + (Ca hydroxycitrate -2S 2 i Ner of tes t 5 lipoic acid concentration unofi FG.3A tipoic acid + (Ca hydroxycitrate - ig cic acid + ydroxycitrate it A tigia - Bydoxycitrate 280 ( .ipoic acids + hydroxycitate 380 w -- s s 2 lipoic acid concentration tumoi-i} FIG.3B Patent Application Publication Sep. 29, 2011 Sheet 4 of 9 US 2011/023650.6 A1 Lipoic acid (Ca) hydroxycitrate 24 f. Niner of ces 60 tipoic acid hydroxycitrate 8 lipoic acid hydroxycitrate 308 4 tipoic acid + iydroxycitrate 380 s 40- a- m m cxxxx s - 20 0 2 4 6 8 8 lipoic acid concentration inci, tipoic acid + (Ca hydroxycitrate 24; 21 4. st T tipoic acidt hysic-Xylitiate 8B A tipoic scid f hydroxystrate 200 4 Lipoic acid + hydroxycitrate 300 e 2 4 6 8 2 4 6 8 lipoic acid concentration raci. FIG.3D Patent Application Publication Sep. 29, 2011 Sheet 5 of 9 US 2011/023650.6 A1 —·---- ~~~~#~~~~+);sting, actish effekere 3, 8te 8ats: go 8qua Patent Application Publication US 2011/023650.6 A1 N s: : 8s six solar aftary Patent Application Publication Sep. 29, 2011 Sheet 7 of 9 US 2011/023650.6 A1 s s ?638 s s 388 FA 3.5FE 3.8 is 3i. 33 3828A Patent Application Publication Sep. 29, 2011 Sheet 8 of 9 US 2011/023650.6 A1 §§§§ §§§§§)----- {y} atto, KEEF: 383 atti esota sy Patent Application Publication Sep. 29, 2011 Sheet 9 of 9 US 2011/023650.6 A1 {:} axis goaloar afies KY isgart: 3sna 3Ayy US 2011/023650.6 A1 Sep. 29, 2011 PHARMACEUTICAL ASSOCATION 0015. In this context, it has been discovered, and this con CONTAINING LIPOIC ACID AND stitutes the basis of the present invention, that the combina HYDROXYCTRIC ACIDAS ACTIVE tion of lipoic acid or one of the pharmaceutically acceptable INGREDIENTS salts thereof and of hydroxycitric acid or one of the pharma ceutically acceptable salts thereof has a particularly high antitumor activity resulting from a synergistic effect of the 0001. The subject of the present invention is a novel phar constituent active ingredients thereof. maceutical combination comprising, as active ingredients, 0016. It has in particular been demonstrated that this novel lipoic acid or one of the pharmaceutically acceptable salts combination makes it possible to limit tumor growth in an thereof, and hydroxycitric acidor one of the pharmaceutically entirely unexpected manner, the Volume of said tumors sta acceptable salts thereof. bilizing over a period of at least 100 days at values substan 0002 This pharmaceutical combination, which can be in tially equal to the Volume of the tumors at the beginning of the form of single dosage units or in kit form, has a particu treatment. This tumor stabilization effect is, Surprisingly, larly high antitumor activity. greater than that obtained by means of known anticancer 0003 Lipoic acid is a cofactor for several enzyme com medicaments. plexes. 0017 Consequently, the combination which is the subject 0004 Lipoic acid is also a powerful antioxidant. It assists of the present invention is particularly original owing to the in protecting cells against damage by free radicals. potentiating synergy of the actions of each of these active 0005. This product is known as an active ingredient of ingredients. medicaments. It is in particular recommended for the treat 0018 Thus, according to a first aspect, the present appli ment of diabetes-related neuropathies, of mitochondrial myo cation aims to cover a pharmaceutical combination which pathies and of multiple Sclerosis. comprises: 0006. It is perfectly tolerated and its toxicity is very low. 0.019 firstly, lipoic acid or one of the pharmaceutically By way of example, it can be administered in an amount of acceptable salts thereof; and between 600 and 1800 mg/d. 0020 secondly, hydroxycitric acid or one of the phar 0007. The use of lipoic acid or one of the water-soluble maceutically acceptable salts thereof. salts thereof, alone or in combination with ascorbic acid, has 0021. In the context of the present description, the term been recommended in the treatment of cancer, in particular by “lipoic acid' is intended to cover the compound which exists document WO 00/48594 corresponding to U.S. Pat. No. in the acid form and also the compound which exists in the 6,448,287. reduced form, also known as dihydrolipoic acid and its phar 0008 Moreover, the use of lipoic acid derivatives or the maceutical acceptable salts. pharmaceutically acceptable salts thereof has also been rec 0022. Moreover, lipoic acid and hydroxycitric acid have, ommended in the treatment of neoplastic diseases by docu respectively, 1 and 2 asymmetric carbon atoms. They can ment WO 00/24734 corresponding to U.S. Pat. No. 6,951, therefore exist in the form of enantiomers or diastereoiso 887. mers. These enantiomers and diastereoisomers, and also mix 0009. However, no medicament based on lipoic acid or tures thereof, including racemic mixtures, are part of the one of the derivatives thereof or one of the pharmaceutically invention. Preferably, the R form of lipoic acid and the 2S, 3S acceptable salts thereof appears, at this time, to be in the form of hydroxycitric acid will be used. process of development for cancer treatment. 0023. In general, the two active ingredients characterizing 0010 Hydroxycitric acid is a natural product which is the pharmaceutical combination according to the invention found in the natural state in the skins of the fruits of the can beformulated together (single dosage units) or separately Malabar tamarind (Garcinia). The calcium salt thereof (cal cium hydroxycitrate) is known to inhibit fatty acid biosyn (kit). thesis. 0024. Also in general, the two active ingredients, formu 0011. The use of calcium hydroxycitrate has thus been lated together or separately, can be administered simulta recommended for weight loss, in combination with a low-fat neously or separately with a time interval which can be desir diet, the recommended dosage being from 500 mg to 1500 mg able for optimization of their conjugated action in view of the three times a day before meals. nature of their respective formulation. 0012. It is a substance that is perfectly well tolerated in 0025. A pharmaceutically acceptable salt of lipoic acid adults and in children. can be a water-soluble salt as described in U.S. Pat. No. 0013. In parallel, calcium hydroxycitrate is known to 6,448,287. increase the oxidation of fatty acids in hepatic cells, thereby 0026. A pharmaceutically acceptable salt of hydroxycitric allowing the conversion of said fatty acids to glycogen. The acid can be an alkali metal (in particular sodium) or alkaline glycogen is then Stored in the muscles so as to be available in earth metal (in particular calcium or magnesium) salt. the event of physical exercise. Hydroxycitrate is thus used in 0027. The pharmaceutical combinations of the invention many dietetic diets for the treatment of obesity. It in particular comprise the two active ingredients identified above. Accord has the advantage of not modifying the blood glucose level. ing to one particular embodiment, they comprise no other U.S. Pat. No. 6,207,714 emphasizes that hydroxycitrate can active ingredient. Alternatively, the presence of at least one be used as a hypoglycemic agent for treating individuals other active ingredient in these novel combinations can be Suffering from insulin-resistant diabetes. envisioned. 0014 Moreover, hydroxycitrate is mentioned among the 0028. Thus, it has been shown that the efficacy of the very large number of compounds that can be used in the pharmaceutical combinations of the invention comprising the treatment of cancer cells having a high rate of aerobic glyco two active ingredients identified above can be improved when lysis (document WO 2004/100885).
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