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 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

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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 for several com medicaments. plexes. 0017 Consequently, the combination which is the subject 0004 Lipoic acid is also a powerful . 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 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 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 ) or alkaline glycogen is then Stored in the muscles so as to be available in earth metal (in particular calcium or ) 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). these two active ingredients are combined with at least one US 2011/023650.6 A1 Sep. 29, 2011 additional active ingredient chosen from the group consisting 0046 By way of example, in the pharmaceutical combi of cisplatin, capsaicin, , miltefosine and B12. nation according to the invention, the lipoic acid or one of the 0029 Multiple pharmaceutical combinations which are pharmaceutically acceptable salts thereof can be present in an preferred in this context are, in particular: amount of between 20 and 800 mg, preferably between 50 0030 triple combinations consisting of the two active and 700 mg, while the hydroxycitric acid can be present in an ingredients identified above and an additional active amount of between 200 and 2000 mg, preferably between 600 ingredient chosen from cisplatin, capsaicin and methotr and 1600 mg, with a view to an administration at a rate of two eXate; or three times a day (NB: the amounts indicated are calculated 0031 multiple combinations consisting: to be administered 3 times a day). An illustrative combination 0032 either of the two active ingredients identified of the invention can thus comprise 600 mg of lipoic acid and above, capsaicin and cisplatin: 1200 mg of hydroxycitric acid in a pharmaceutically accept 0033 or of the two active ingredients identified able excipient for a composition to be taken three times a day. above, capsaicin, miltefosine, choline and vitamin 0047. The pharmaceutical combinations of the invention B12. can be prepared in the usual manner. This preparation com 0034. According to a first embodiment of the invention, prises: which is currently preferred, the above-mentioned pharma 0.048 either the formulation of the active ingredients ceutical combination consists of single dosage units incorpo together in a pharmaceutically acceptable excipient; rating the active ingredients usually in a pharmaceutically 0049 or the separate formulation of each of the active acceptable excipient. ingredients in pharmaceutically acceptable excipients 0035. According to a second embodiment, this pharma which may be identical or different. ceutical combination is in the form of a kit containing: 0050. The formulating techniques which can be used for 0036 firstly, lipoic acid or one of the pharmaceutically this purpose are well known to those skilled in the art and acceptable salts thereof, usually in a pharmaceutically comprise essentially physical mixing of the active ingredient acceptable excipient; and (s) with the pharmaceutically acceptable excipient(s). 0051 Given the high antitumor activity of the combina 0037 secondly, hydroxycitric acid or one of the phar tion which has just been described, the invention is particu maceutically acceptable salts thereof, usually in a phar larly useful for the production of medicaments intended for maceutically acceptable excipient. the treatment of a cell proliferation disease, chosen from the 0038 Regardless of the embodiment envisioned, the group comprising breast cancer, ovarian cancer, cervical can nature and the respective amounts of the various excipients cer, prostate cancer, testicular cancer, esophageal cancer, may be readily determined by those skilled in the art accord stomach cancer, skin cancer, lung cancer, bone cancer, colon ing to the final dosage form desired. cancer, pancreatic cancer, thyroid cancer, bile duct cancer, 0039 Preferably, in the case of single dosage units, the cancer of the buccal cavity and of the pharynx (oral region), active ingredients will be conditioned in a dosage form Suit cancer of the lips, of the tongue, of the mouth, of the pharynx able for oral administration. However, other routes of admin or of the Small intestine, colorectal cancer, cancer of the large istration, for instance intramuscular, intravenous, topical or intestine, rectal cancer, cancer of the brain and of the central cutaneous routes, can be envisioned. nervous system, a glioblastoma, a neuroblastoma, a keratoa 0040 Likewise, preferably, in the case where the active canthoma, an epidermoid carcinoma, a large cell carcinoma, ingredients are provided separately, they will be conditioned an adenocarcinoma, an adenoma, a follicular carcinoma, an independently of one another, each in a dosage form Suitable undifferentiated carcinoma, a papillary carcinoma, a semi for oral administration. However, other routes of administra noma, a melanoma, a sarcoma, a bladder carcinoma, a liver tion can be envisioned for each of the two dosage forms, carcinoma, a kidney carcinoma, myeloid disorders, lymphoid independently. disorders, Hodgkin's disease, a carcinoma with hairy cells, 0041 According to one particular characteristic, a dosage and leukemia. form suitable for the oral route can be chosen from tablets, 0.052 The pharmaceutical combinations of the invention gelatin capsules, powders, granules, lyophilisates, oral Sol can of course be used in a therapeutic treatment as a Supple utes and syrups. ment to other anticancer treatments. 0042. However, tablets constitute the currently preferred 0053. The pharmaceutical combination of the invention dosage form suitable for the oral route. These tablets may be may thus be used with one or more other active agents, in of varied nature, immediate-release, controlled-release or which case the combination of the invention and the other delayed-release, and optionally in effervescent or orodispers agent(s) may be administered as part of the same or separate ible form. dosage forms, via the same or different routes of administra 0043. In general, the dosage will be adjusted according to tion, and on the same or different administration schedules the route of administration and the patient to be treated. according to standard pharmaceutical practice. 0044 Lipoic acid or one of the pharmaceutically accept 0054 The combination of the present disclosure intended able salts thereof can thus be administered, in one, two or for pharmaceutical use may be administered alone or in com three intakes, in an amount of from 0.1 to 100 mg/kg/d, bination with one or more other drugs (or as any combination preferably from 1 to 60 mg/kg/d and more preferably from 5 thereof), in particular with one or more other anti-cancer to 40 mg/kg/d. agents. The combination of the present invention may also be 0045 Hydroxycitric acid or one of the pharmaceutically administered alone or in combination with an another active acceptable salts thereof can be administered, for its part, in agent as a formulation in association with one or more phar one, two or three intakes, in an amount of from 0.1 to 160 maceutically acceptable excipients. mg/kg/d, preferably from 1 to 100 mg/kg/d and more prefer 0055 Preferably, the anti-cancer agent is a chemical or ably from 15 to 70 mg/kg/d. biological Substance which is clinically shown to treat cancer.

US 2011/023650.6 A1 Sep. 29, 2011

tis), CYC-202 (Cyclacel), AVE-8062 (Aventis), DMXAA 007.9 Thus, according to a second aspect, the present (Rochef Antisoma), Thymitaq (Eximias), Temodar (temoZo application aims to cover the use of a pharmaceutical combi lomide, Schering Plough) and Revilimd (Celegene) and com nation as described above, for producing a medicament hav binations thereof. ing an antitumor activity, intended in particular for the treat 0072. In another embodiment, the anti-cancer agent is ment of the above-mentioned diseases. selected from CyPat (). Histerelin (histre 0080 Finally, the present application aims to cover a lin acetate), Plenaixis (abarelix depot), Atrasentan (ABT method for treating the above-mentioned diseases, compris 627), Satraplatin (JM-216), thalomid (Thalidomide), Ther ing the administration ofatherapeutically effective amount of atope, Temilifene (DPPE), ABI-007 (), Evista a combination as described above, to a patient needing same. (raloxifene), Atamestane (Biomed-777), Xyotax (poly glutamate paclitaxel), Targetin (bexarotine) and combina Definitions: tions thereof. I0081. As used herein, the phrase “pharmaceutically 0073. In another embodiment, the anti-cancer agent is acceptable' indicates that the designated carrier, vehicle, selected from Trizaone (tirapazamine), Aposyn (exisulind), diluent, excipient, salt or prodrug is generally chemically Nevastat (AE-941), Ceplene (histamine dihydrochloride), and/or physically compatible with the other ingredients com Orathecin (rubitecan), Virulizin, Gastrimmune (G17DT), prising a formulation, and is physiologically compatible with DX-8951f (exatecan mesylate). Onconase (ranpirinase), the recipient thereof. BEC2 (mitumoab), Xcytrin (motexafin gadolinium) and I0082. The phrases “therapeutic' and “therapeutically combinations thereof. effective amount as used herein denote an amount of a com 0074. In another embodiment, the anti-cancer agent is pound, composition, medicament or pharmaceutical combi selected from CeaVac (CEA), NeuTrexin (trimetresate glu nation that (a) treats or prevents aparticular disease, condition curonate) and combinations thereof. Additional anti-tumor or disorder; (b) attenuates, ameliorates or eliminates one or agents may be selected from the following agents, OvaRex more symptoms of a particular disease, condition or disorder; (oregovomab), Osidem (IDM-1), and combinations thereof. (c) prevents or delays the onset of one or more symptoms of Additional anti-tumor agents may be selected from the fol a particular disease, condition or disorder described herein. It lowing agents, Advexin (ING 201), TiraZone (tirapazamine), should be understood that the terms “therapeutic' and “thera and combinations thereof. Additional anti-tumor agents may peutically effective' encompass any one of the aforemen be selected from the following agents, RSR13 (efaproxiral), tioned effects (a)-(c), either alone or in combination with any Cotara (131I chTNT 1/b), NBI-3001 (IL-4) and combinations of the others (a)-(c). thereof. Additional anti-tumor agents may be selected from I0083 Representative pharmaceutically acceptable salts the following agents, Canvaxin, GMK vaccine, PEG Interon include, but are not limited to, acetate, aspartate, benzoate, A, Taxoprexin (DHA/pacilitaxel), and combinations thereof. besylate, bicarbonate/carbonate, bisulphate/sulphate, borate, carnsylate, citrate, edisylate, esylate, formate, fumarate, glu 0075. In another embodiment, the anti-cancer agent is ceptate, gluconate, glucuronate, hexafluorophosphate, hiben selected from drugs targeting (directly or not)pyruvate kinase Zate, hydrochloride/chloride, hydrobromide/bromide, (notably M2 isoform) activation, PFKFB3, IDH, Nampt hydroiodide/iodide, isethionate, lactate, malate, maleate, inhibitor, SIRT-1, heat shock protein inhibitor (HSP90 malonate, meSylate, methylsulphate, naphthylate, 2-napsy Ganetespib, Synta Pharmaceuticals), Transketolase like-1 late, nicotinate, nitrate, orotate, oxalate, palmitate, pamoate, (TKTL-1), drugs allowing carbonic anhydrase inhibition, phosphate/hydrogen phosphate/dihydrogen phosphate, sac Phosphoenol pyruvate carboxykinase (PEPCK) inhibition, charate, Stearate. Succinate, tartrate, tosylate, trifluoroacetate NADH dehydrogenase inhibition, lipotropic factors, phos and the like. Other examples of representative salts include pholipase D inhibition, lactacte dehydrogenase inhibition, alkali or alkaline earth metal cations such as sodium, lithium, phosphoenolpyruvate carboxykinase inhibition, cytochrome , calcium, magnesium, and the like, as well as non P450 isoenzymes inhibition, hexokinase inhibition, AMP toxic ammonium, quaternary ammonium and amine cations activated protein kinase (AMPK) activation, choline kinase including, but not limited to, ammonium, tetramethylammo inhibition, phospholipase A2 inhibition, Insulin Growth Fac nium, tetraethylammonium, , arginine, benzathine, tor Binding Protein (IGFBP) activation, Citrate synthase inhi choline, tromethamine, diolamine, , meglumine, ola bition, ATP sensitive potassium channel blocker, Protein mine and the like. The invention further includes mixtures of Phosphatase 2A (PP2A) activation. salt forms. 0076 Preferably, the combination of the invention is used I0084 Compounds of the combination of the present with one or more of an active agent selected from the group invention may be administered as prodrugs. The term “pro consisting of gemcitabine, leucovorin, 5-fluorouracil, oxali drug” refers to a compound that is transformed in vivo to yield platin, , capecitabin, epirubicin, thalidomide and a compound of Formula I or a pharmaceutically acceptable vinorelbin. salt or Solvate of the compound. The transformation may 0077. The term “excipient” is used herein to describe any occur by various mechanisms, such as via hydrolysis in ingredient other than the compound(s) of the invention and blood. includes ingredients such as vehicles, carriers, diluents, pre I0085. A prodrug of a compound of the combination of the servatives and the like. The choice of excipient(s) will largely invention may be formed in a conventional manner with one depend on factors such as the particular mode of administra or more functional groups in the compound, such as anamino, tion, the effect of the excipient(s) on and stability, hydroxyl or carboxyl group. For example, if a compound of and the nature of the dosage form. the present invention contains a carboxylic acid functional 0078 Preferably, the pharmaceutical combinations of the group, a prodrug can comprise: (1) an ester formed by the invention is used in combination with at least one other replacement of a hydrogen of the acid group with a group above-mentioned active agents. Such as (C-C)alkyl or (Co-Co) aryl; (2) an activated ester US 2011/023650.6 A1 Sep. 29, 2011 formed by the replacement of the hydrogen of the acid group the invention being used, the type of pharmaceutical compo with groups such as —(CR)COOR', where CR is a spacer sition, the characteristics of the subject in need of treatment and R can be groups such as H or methyl and R' can be groups and the severity of the condition being treated. such as (C-C)alkyl or (C-C)aryl; and/or (3) a carbonate formed by the replacement of the hydrogen of the acid with 0091 Thus, the skilled artisan would appreciate, based groups such as CHROCOOR' where R can be groups such as upon the disclosure provided herein, that the dose and dosing H or methyl and R' can be groups such as (C-C)alkyl or regimen is adjusted in accordance with methods well-known (Co-Co)aryl. in the therapeutic arts. That is, the maximum tolerable dose I0086 Discussions regarding prodrugs and their use can be can be readily established, and the effective amount providing found in, for example, “Prodrugs as Novel Delivery Sys a detectable therapeutic benefit to a patient may also be deter tems.” T. Higuchi and W. Stella, Vol. 14 of the AS Symposium mined, as can the temporal requirements for administering Series, and Bioreversible Carriers in Drug Design, Pergamon each agent to provide a detectable therapeutic benefit to the Press, 1987 (ed. E B Roche, American Pharmaceutical Asso patient. Accordingly, while certain dose and administration ciation). regimens are exemplified herein, these examples in no way 0087. A pharmaceutical combination of the invention, for limit the dose and administration regimen that may be pro example, includes forms suitable for oral administration as a vided to a patient in practicing the present invention. tablet, capsule, pill, powder, Sustained release formulations, 0092. It should be noted that variation in the dosage will Solution, Suspension, or for parenteral injection as a sterile depend on the compound employed, the mode of administra Solution, Suspension or emulsion. Pharmaceutical composi tion, the treatment desired and the disorder (severity and type) tions suitable for the delivery of compounds of the present to be treated or alleviated. The present invention also encom invention and methods for their preparation will be readily passes Sustained release compositions and flash formula apparent to those skilled in the art. Such compositions and tions, i.e. providing a to dissolve in the mouth. methods for their preparation may be found, for example, in 0093. It is to be further understood that for any particular Remington's Pharmaceutical Sciences, 19th Edition (Mack Subject, specific dosage regimens should be adjusted over Publishing Company, 1995). time according to the individual need and the professional 0088. In one preferred embodiment, the combination of judgment of the person administering or Supervising the the invention may be administered orally. Oral administration administration of the compositions, and that dosage ranges may involve Swallowing, so that the compound enters the set forth herein are exemplary only and are not intended to gastrointestinal tract, or buccal or Sublingual administration limit the scope or practice of the claimed composition. For may be employed by which the compound enters the blood example, doses may be adjusted based on pharmacokinetic or stream directly from the mouth. Formulations suitable for pharmacodynamic parameters, which may include clinical oral administration include Solid formulations, such as tab effects such as toxic effects and/or laboratory values. Thus, lets, capsules containing particulates, liquids, or powders; the present invention encompasses intra-patient dose-escala lozenges (including liquid-filled), chews; multi- and nano tion as determined by the skilled artisan. Determining appro particulates; gels, solid solution, liposome, films (including priate dosages and regiments for administration of the che muco-adhesive), ovules, sprays and liquid formulations. Liq motherapeutic agent are well-known in the relevant art and uid formulations include Suspensions, Solutions, syrups and would be understood to be encompassed by the skilled artisan elixirs. Such formulations may be employed as fillers in soft once provided the teachings disclosed herein. or hard capsules and typically comprise a carrier, for (0094. The invention will now be illustrated by the follow example, water, ethanol, polyethylene glycol, propylene gly ing nonlimiting examples and by the appended figures which col, methylcellulose, or a suitable oil, and one or more emul show, respectively: Sifying agents and/or Suspending agents. Liquid formulations (0095 FIGS. 1A and 1B: graphical representation of the may also be prepared by the reconstitution of a solid, for results of the cell viability tests using the HT-29 cell line example, from a Sachet. The compounds of the invention may treated with lipoic acid alone (FIG. 1A) or with calcium also be used in fast-dissolving, fast-disintegrating dosage hydroxycitrate alone (FIG. 1B); forms such as those described in Expert Opinion in Thera 0096 FIGS. 2A and 2B: graphical representation of the peutic Patents, 11 (6), 981-986 by Liang and Chen (2001). results of the cell viability tests using the T-24 cell line treated 0089. In another preferred embodiment, the combination with lipoic acid alone (FIG. 2A) or with calcium hydroxyci of the invention may be administered by parenteral injection. Exemplary parenteral administration forms include sterile trate alone (FIG. 2B); Solutions, Suspensions or emulsions of the compounds of the (0097 FIGS. 3A to 3D: graphical representation of the invention in sterile aqueous media, for example, aqueous results of the cell viability tests using the HT-29 and T-24 cell propylene glycol or dextrose. In another embodiment, the lines treated with a combination of lipoic acid and calcium parenteral administration form is a solution. Such parenteral hydroxycitrate according to the invention, for three increas dosage forms can be suitably buffered, if desired. ing concentrations of calcium hydroxycitrate; 0090 Dosage regimens of the compounds and/or pharma 0.098 FIG. 4A: graphical representation of the results of ceutical composition/combination of the invention may be treatment of mice with the pharmaceutical combination adjusted to provide the optimum desired response. For according to the invention; example, a single bolus may be administered, several divided 0099 FIG. 4B: graphical representation showing the sur doses may be administered over time or the dose may be vival of the mice treated in the study, the results of which are proportionally reduced or increased as indicated by the exi shown in FIG. 4A. gencies of the therapeutic situation. The appropriate dosing 0100 FIG. 5A: graphical representation representing the regimen, the amount of each dose administered and/or the evolution of the average MTB2 tumor volume during a phar intervals between doses will depend upon the compound of maceutical treatment of the invention; US 2011/023650.6 A1 Sep. 29, 2011

0101 FIG. 5B: graphical representation representing the 0118. In phase II of the study (test with the combination of survival rate of the tested mice implanted with MBT2 type the two active ingredients), the same conditions for preparing tumors during a pharmaceutical treatment of the invention. the media and for culturing the cells were adhered to, and the 0102 FIG. 6A: graphical representation representing the active ingredients were combined and added simultaneously evolution of the average LLC tumor Volume during a phar to the culture medium. maceutical treatment of the invention; 0119) The tumor cell lines were incubated with 100 ul 0103 FIG. 6B: graphical representation representing the (96-well plates) or 2 ml (6-well plates) of serum-supple survival rate of the tested mice implanted with LLC type mented culture medium containing the test Substances or the tumors during a pharmaceutical treatment of the invention. reference substance. The culture medium of each culture well 0104 FIG. 7A: graphical representation representing the (supplemented with the test molecule(s)) was renewed every evolution of the average LLC tumor Volume during a phar two days during the treatment. maceutical treatment of the invention; I0120) 1.3- Cell Proliferation and Viability Test 0105 FIG. 7B: graphical representation representing the I0121 Starting from the first day of contact, and every two survival rate of the tested mice implanted with LLC type days after the beginning of the contacting of the culture media tumors during a pharmaceutical treatment of the invention. containing the test Substances and the reference Substances at 0106 FIG. 8A: graphical representation representing the the various concentrations tested, the proliferation and the evolution of the average LLC tumor Volume during a phar cell viability of the cells were evaluated. The cell viability was maceutical treatment of the invention; evaluated in two different ways: 0107 FIG. 8B: graphical representation representing the 0.122 directly, under an optical microscope by statisti survival rate of the tested mice implanted with LLC type cal counting (number of cells), and tumors during a pharmaceutical treatment of the invention. 0123 indirectly, by colorimetric assay based on the degradation of tetrazolium salts by mitochondrial dehy EXPERIMENTS CARRIED OUT drogenases (MIT test). The optical densities (OD) of 0108. The notable antitumor activity of the therapeutic each well were then read with a microplate reader set at combination according to the invention was demonstrated by the appropriate wavelength. means of the experiments described hereinafter. 0.124 1.4—Presentation of the Results 0109 1—Tests on Human Tumor Cell Lines 0.125 For each active ingredient, each concentration 0110 1.1 Cell Lines Used tested and each combination, three cell viability values were 0111. The human tumor cell lines and the culture media measured and corrected, in particular by means of the cali were obtained from the ATCC (American Type Culture Col bration ranges for the optical reading instrument. lection, Manassas, Va., United States). 0.126 The mean of the three cell viability measurement 0112. The HT-29 tumor cell line was isolated in 1964 from values was then divided by the mean of the measurements of a primary colonic adenocarcinoma in a 44-year-old woman viability carried out in parallel in a control culture free of (Fogh J. et al. 1977.J. Nat. Cancer. Inst. 59: 221-6). active ingredients. 0113. The T-24 tumor cell line is a transitional bladder I0127 Table 1 hereinafter recaps the values calculated carcinoma isolated from an 81-year-old woman (O'Toole C from the viability measurements made under an optical M. et al. 1983 Nature 301: 429-30). microscope or by luminescent labeling (number of cells/ 0114 1.2 Culture Conditions MTT) for the HT-29 cell line treated with lipoic acid alone or 0115 The tumor cell lines were cultured in monolayer at with calcium hydroxycitrate alone. 37° C. in a humidified atmosphere (5% CO, 95% air). The I0128. These values have also been reported in graph form culture medium which was used is DMEMGlutamax I (Invit in FIGS. 1A and 1B. rogen) for the two lines, supplemented with 10% of fetal calf serum (Eurobio) and 1/10 000 IU of penicillin and strepto mycin. For carrying out the experiments, the human tumor TABLE 1 cell lines were detached from the culture flask by treatment Ratio of live HT-29 cells after 72 hours for 10 minutes with a solution of trypsin in Hanks medium without calcium or magnesium. The cells were counted in a Molecules Cell line: HT-29 hemocytometer and their viability was determined using the tested alone Counting carried out after 72 hours trypan blue exclusion test. Lipoic acid Concentrations O.1 1 10 0116. The tumor cell lines were amplified and then seeded (FIG. 1A) (Imoll') MTT O.807 0.55 O.452 into 96-well microplates (MTT) or 6-well plates (cell counts) Number of cells O.853 O.S83 0.441 at a concentration which allowed the cells to be in the prolif Calcium Concentrations 10 100 500 eration phase for the 5 days of the culture. They were incu hydroxycitrate (Imoll') bated for 48 hours before the beginning of the treatments in (FIG. 1B) MTT O.743 O.S.19 O.376 the microplates containing culture medium without the test Number of cells 0.777 0.557 O.374 Substances or the reference Substances. 0117. During phase I (test with a single active ingredient), the tumor cell lines were incubated for 5 days at 37°C. under I0129. Table 2 hereinafter recaps the values calculated 5% CO with culture medium containing one of the test sub from the viability measurements made under an optical stances. Each experimental condition was reproduced six microscope or by luminescent labeling (number of cells/ times. Generally, the flasks of culture medium Supplemented MTT) for the T-24 cell line treated with lipoic acid alone or with serum were first of all prepared with the highest concen with calcium hydroxycitrate alone. tration of each test molecule. Each other concentration to be 0.130. These values have been reported in graph form in tested was obtained by Successive dilutions in the serum FIGS. 2A and 2B. Supplemented culture medium. This step was adjusted I0131. In the graphs of FIGS. 1A, 1B, 2A and 2B, the Y-axis according to the particular instability or sensitivity of each indicates the percentage of live cells in each condition relative drug. to a negative control (dilution vehicle) counted with a naked

US 2011/023650.6 A1 Sep. 29, 2011

0152 2.2 Culture and Inoculation of Tumors (0168 After randomization of the animals in various 0153. The MBT-2 tumor cell line is a transitional bladder groups, the treatments with the various active ingredients carcinoma induced by FANFT (N-4-(5-nitro-2-furyl)-2- were carried out every day intraperitoneally (IP). Since the thiazolyl)formamide) in a mouse of the C3H/HeN line (Solo active ingredients have a short half-life (less than 12 hours), way MS. et al. 1973 Surg. Forum. 24: 542-4). they were adminitered twice a day (morning and evening) (cf. 0154) The MBT-2 line was cultured in monolayer at 37°C. table 5). in a humidified atmosphere (5% CO, 95% air). The culture (0169. The treatment with 5-FU (positive control) was medium which was used is DMEMGlutamax I (Invitrogen) administered intraperitoneally with a dose of 10 mg/kg once supplemented with 10% of fetal calf serum (Eurobio) and 1/10 000 IU of penicillin and streptomycin. a day for 4 days. The mice treated with 5-FU were monitored (O155 The cells were detached from the culture flask by in the same way as the other mice. means of a treatment for 10 minutes with a trypsin/EDTA 0170 2.4 Monitoring and Results Solution and then counted. 0171 Every five days, the evolution of the tumor was 0156 The MBT-2 cell line was placed in culture at a den monitored by various measurements: weight of the animals, sity of 3x10 cells/16mm well of a 24-well plate, and then tumor size (caliper rule), mortality. cultured in monolayer at 37°C. The cells were detached from 0172 A daily monitoring of the animals was carried out the culture flask by means of a treatment for 10 minutes with once a day and made it possible to determine precisely the day a trypsin/EDTA solution and then counted. on which the animals died and to autopsy them rapidly. This 0157. The MBT-2 cells were dissociated in a cell suspen monitoring also made it possible to isolate or euthanize the Sion, and an injection was carried out via a 25-gauge diameter weak or moribund animals according to the recommenda needle in the flankofa 6-week-old male C3Hmouse: 10° cells tions of the EEC, of the ASAB, of the Canadian Council on (120 ul). The treatment began nineteen days after the implan Animal Care and of the UKCCCR. tation. 0173 The results of measurement of the average tumor 0158 2.3 Combinations Tested 0159. The pharmaceutical combination according to the Volume in each of the groups of treated mice, as a function of invention was tested in Vivo: time, are reported in the graph of FIG. 4A. 0160 The following products were used to prepare this 0.174. In this graph, the Y-axis indicates the increase in combination: percentage of average Volume (relative to the Volume mea 0.161 alpha-lipoic acid (T1395 Sigma-Aldrich) sured on the first day of treatment) of the tumors measured in 0162 calcium hydroxycitrate (55128 Sigma-Aldrich) the mice. (0163 Control mouse batches were treated using compo (0175. The X-axis indicates the number of days for which sitions comprising: the mice were monitored. 0.164 a pyridine analog used as a medicament in cancer 0176 The results showing the survival of the mice treated treatment: 5-fluorouracil (5-FU) (Sigma F6627), in this study are reported in the graph of FIG. 4B. 0.165 the isotonic saline solution (9 g/l) used for the 0177. In this graph, the Y-axis indicates the number of intraperitoneal injection without active ingredient, mice alive. 0166 the vehicle for dissolving the active ingredients 0.178 The X-axis indicates the number of days for which (0.05% ethanol) (neutral control). the mice were monitored. 0167. The concentrations tested and the experimental con 0179 Moreover, in FIGS. 4A and 4B: ditions used are recapped in the following tables 5 and 6. 0180 the hatched part between days 19 and 40 repre sents the period during which the treatment was admin istered; TABLE 5 0181 the following symbols were used: Number of intraperitoneal injections per day and amounts 0182 o:lipoic acid--calcium hydroxycitrate; of molecules iniected according to the conditions 0183 () : saline solution control; Number of 0.184 *: 5-FU; injections per Amount per 0185. A: ethanol control. Active ingredients day injection 0186 2.5—Interpretation of the Results Alpha-lipoic acid 2 10 mg/kg 0187. As shown by the graph of FIG. 4A, the pharmaceu Calcium hydroxycitrate 2 250 mg/kg tical combination according to the invention makes it possible to limit the growth of the tumors, the volume of which stabi lizes, over a period of at least 100 days, at values of 100% of TABLE 6 the volume reached by the tumors at the beginning of the treatment. Groups of animals tested and Corresponding experimental conditions 0188 This result should be compared with the volume Duration reached by the tumors in the control mice, the increase of Number of which is of the order of 500%. Group Treatment of animals treatment 0189 It is interesting to note that the treatment according 1 Naive mice 18 to the invention made it possible, entirely surprisingly and 2 Implantation medium alone 18 unexpectedly, to obtain a significantly greater tumor stabili 3 Saline solution 18 21 days zation effect than that obtained using 5-FU, which is an anti 4 Saline solution + 5-FU 18 4 days cancer medicament. 5 Saline solution + 0.05% ethanol 18 21 days 6 Lipoic acid and calcium hydroxycitrate 18 21 days 0190. As shown by the graph of FIG. 4B, the pharmaceu tical combination according to the invention made it possible to significantly increase the Survival time of the treated mice. US 2011/023650.6 A1 Sep. 29, 2011

0191 Thus, in the groups corresponding to the saline reduce the tumor development by 32% compared with solution and ethanol controls, approximately 50% of the mice the ALA/HCA combination alone (LL/2 model). are still alive after 27 days of implantation. 0210. The use of a combination of ALA, HCA, capsai (0192. In the group treated with 5-FU, 50% of the mice are cin, miltefosine, choline and vitamin B12 makes it pos still alive after 39 days of implantation, which corresponds to sible to reduce the tumor development by 21% com an increase in Survival of 12 days. pared with the ALA/HCA combination alone (LL/2 0193 In the group of mice treated with the pharmaceutical model). combination according to the invention, 50% of the mice are 0211 3- Further Antitumor Activity Tests on C3H and still alive after 74 days, which corresponds to an increase in C57BL/6J Mice (Corresponding to FIG. 5A through to 8B) survival of 35 days compared with 5-FU (survival time mul tiplied by 1.9) and of 47 days compared with the control mice 0212. 3.1 Murine Model (survival time multiplied by 2.7). 0213. The compositions described hereinafter were tested 0194 Thus, it is interesting to note that the treatment against two syngeneic tumor models: according to the invention made it possible, entirely surpris 0214) Abladder carcinoma MBT-2 implanted in synge ingly and unexpectedly, to increase the Survival rate of the neic C3H mice, mice in a significantly large manner compared with the treat 0215. A pulmonary carcinoma LL/2 (or LLC1) called ment using 5-FU. or ). US 2011/023650.6 A1 Sep. 29, 2011 10

0228. 3.3 Tested Combinations 0243 The results showing the survival rate of the traited 0229. The pharmaceutiol combination of the invention mice in the present study are summarised in FIGS. 5B, 6B, 7B was tested in Vivo: and 8B. 0230. The following products were used to prepare this 0244. In these graphs, the Y-axis indicates the number of combination: mice which have survived. The X-axis indicates the number 0231 alpha-lipoic acid (T1395 Sigma-Aldrich) of days during which the mice have managed to Survive from 0232 Calcium/potassium hydroxycitrate (Garcinia the tumor implantation. Further, the greyed area on each Cambodia extract, 60% HCA, Indo World Trade com graph represent the treatment duration i.e. the period of time pany) during which the treatment was administered. 0233 Capsaicine (Sigma-Aldrich 12084) 0245 3.5—Results Discussion 0234. A platinum-containing organometallic complex 3.5.1. Efficiency of the ALA/HCA Treatment when Used used as an active agent in the treatment of cancer: cis with Cisplatine platine (CIS) (Sigma 479306), 0246. In the MBT-2 model (FIG. 5A), the treatment using 0235 Methotrexate (Sigma-Aldrich M9929) the ALA/HCA/CIS combination resulted in a 70% decrease 0236 Groups of control mice were treated using compo of the tumor volume relative to the control ethanol (60 days). sitions comprising: 0247 This tumor growth reduction observed when using 0237. An isotonic salt solution (9 g/L) used for the the ALA/HCA/CIS treatment is associated with a significant intraperitoneal injection without any active agents, increase of the mice life-span (FIG. 5B) i.e. with a survival 0238 A dissolution carrier for the actives agents (etha time increase of up to about 31 days between control animals nol 0.5%) (control). (100% of survival during 55 days) and animals traited with 0239. The tested concentrations and the experimental con the ALA/HCA/CIS treatment (100% of survival during 86 ditions used in the present study are Summarised in the fol days). lowing tables 7 et 8. 0248. In the LLC model (FIG. 6A), the ALA/HCA/CIS treatment enabled the average tumor volume to be decreased TABLE 7 by more than 43% relative to the average tumor volume Number of intraperitoneal injections per day and amounts of measured in mice groups using the control ethanol (55 days). molecules injected according to the conditions. 0249. This tumor growth reduction observed when using Abbre- Amount per Experimental the ALA/HCA/CIS treatment is associated with a significant Active agents viation Injection rate injection model increase of the mice life-span (FIG. 6B) i.e. with a survival, time increase of up to about 10 days between control animals alpha-lipoic ALA Every 12 hours 10 mg/kg MBT-2, acid LLC (100% of survival during 50 days) and animals treated with CaK HCA Every 12 hours 250 mg/kg MBT-2, the ALA/HCA/CIS treatment (100% of survival during 60 Hydroxycitrate LLC days). Cisplatine CIS Every other 1 mg/kg MBT-2, day LLC 3.5.2. Efficiency of the ALA/HCA/CAP Treatment when Methotrexate MTX Every 24 hours 1 mg/kg LLC Used with Cisplatine Capsaicine CAP Every 24 hours 0.75 mg/kg LLC (0250. In the LLC model (FIG. 7A), the ALA/HCA/CIS/ CAP treatment enabled the average tumor volume to be decreased by more than 59% relative to the average tumor Volume measured in mice groups using the control ethanol TABLE 8 (57 days). Groups of animals tested and corresponding experimental conditions 0251. This tumor growth reduction observed when using the ALA/HCA/CIS/CAP treatment is associated with a sig Groups treatment Experimental model nificant increase of the mice life-span (FIG. 7B) i.e. with a 1 Salt solution + ethanol 0.5% MBT-2, LLC survival time increase of up to about 35 days between control 2 CIS MBT-2, LLC animals (89% of survival during 65 days) and animals treated 3 MTX LLC with the ALA/HCA/CAP/CIS treatment (89% of survival 4 ALAx HCA MBT-2, LLC 5 ALAx HCA X MTX LLC during 100 days). 6 ALAx HCAx CIS MBT-2, LLC 3.5.3. Efficiency of the ALA/HCA Treatment when Used 7 ALAx HCAx CIS X CAP LLC with Methotrexate (0252) In the LLC model (FIG. 8A), the ALA/HCA/MTX 0240 3.4 Results treatment enabled the average tumor volume to be decreased 0241. For the four tumor models herein described, the by more than 56% relative to the average tumor volume results corresponding to the measured average tumor Volume measured in mice groups using the control ethanol (35 days). in each of the treated mouse group, plotted against the treat 0253) This tumor growth reduction observed when using ment duration, are shown in FIGS.5A, 6A, 7A et 8A. the ALA/HCA/MTX treatment is associated with a signifi 0242. As shown in the graphs, the Y-axis indicates the cant increase of the mice life-span (FIG. 8B) i.e. with a increase of average tumor Volume in percent (relative to the survival time increase of up to about 10 days between control tumor Volume as measured on the first day of treatment) as animals (100% of survival during 30 days) and animals measured in the tested mice. The X-axis indicates the number treated with the ALA/HCA/MTX treatment (100% of sur of days during which the mice have survived starting from the vival during 52 days). tumor implantation. Further, the greyed area on each graph 0254 4—Antitumor Activity Tests on Human Patients represent the treatment duration i.e. the period of time during 0255. The ALA/HCA combination of the invention was which the treatment was administered. administered to a number of cancer patients alone or with one US 2011/023650.6 A1 Sep. 29, 2011

or more other active agents (such as the ones usually used in Surgery and several sessions of radiotherapy and chemo chemotherapy treatments) and we describe here the data that therapy the disease reappeared showing metastases, notably were obtained. in bones and liver. 4.1. Patient 1: Metastatic Pancreatic Cancer 0261 The patient was then administered with a combina 0256 This patient was a 80 year-old female with pancre tion of several drugs, among them docetaxel, capecitabin and atic cancer showing liver metastasis (TNM staging: pt3 pN1 the ALA/HCA combination (see Table 11). After 9 months, (12/28) M1; G3). She was treated with a treatment using, the docetaxel/capecitabin combination was replaced by epi amongst others, the combination of the present invention (see rubicine, the other drugs being maintained. Thirteen months table 9) during 8 months and showed a meaningful improve after the beginning of the ALA/HCA combination, the dis ment of the survival time relative to the estimated survival ease was still stable. time without treatment. 0257 Anamelioration of all parameters was observed dur TABLE 11 ing several months, such as an increase of body weight, a decrease of CA19-9 tumor marker and a regression of liver Drugs and dosage prescribed to patient 2 tumor observed by CT-scan. Drugs Dosageschedule 0258. After 5 months, the patient decided to modify her Docetaxel 75 mg/mg every 28 days treatment regimen by taking herself off the treatment of some Capecitabin 1500 mg per os every day of the administered drugs. Three months later, the tumor Garcinia Cambogia (60% HCA) 1200 mg per os every day reappeared. C. lipoic acid (tiobec (R) 1200 mg per os every day 0259. This to the administration of a new chemo 20 mg per os per day at 9pm therapy regimen, FOLFOX, associated with ALA/HCA and Trans Retinoic acid 50 mg per os every other day others (see table 10). The disease stabilized again during six Wobenzym (R) 2 cps per os per day at morning more months until it progressed again. Overall, the patient of Silibinum 2002 times a day the present study survived 18 months after diagnosis of its pancreas cancer while her estimated Survival was 3-6 months according to diagnosis based on clinical observations and 4.3. Patient 3: Glioblastoma CA19-9 tumor marker values. 0262 This patient was a 39 year-old female with glioblas TABLE 9 toma in the temporal frontal area (TNM staging: pT4NOMO). After Surgery and several sessions of radiotherapy and che Drugs and dosage administered to patient 1 - motherapy the disease was still progressing. The patient was This treatment was administered during an 8-month period. then admininstered with a combination of several drugs, Drugs Dosageschedule among them thalidomide and the ALA/HCA combination Gemcitabine 1200 mg every 28 days (see Table 12). Nine months after the beginning of this Garcinia Cambogia (60% 1200 mg per os every day therapy, the disease was still stable. HCA) C. lipoic acid (tiobec (R) 1200 mg per os every day TABLE 12 Celecoxib (Celebrex (R) 200 mg per os per day Retinoic acid 50 mg per os every other day Drugs and dosage prescribed to patient 3 Melatonin 20 mg per os per day at 9pm Prosure (R) (Abbott) 2 vials per os per day Drugs Dosageschedule Thalidomide 20 mg per os every day Garcinia Cambogia (60% HCA) 1200 mg per os every day TABLE 10 C. lipoic acid (tiobec (R) 1200 mg per os every day Melatonin 20 mg per os per day at 9pm Drugs and dosage administered after tumor reappearance in patient Bosweiia 400 per os every day 1 - This treatment was administered for the last 6 months of treatment. Drugs Dosageschedule 4.4. Patient 4: Metastatic Parotid Gland Cancer FOLFOX (Folinic acid, 5 2-week cycle: day 1, concomitant leucovorin fluorouracil, oxaliplatin) 300 mg/m and oxaliplatin 120 mg/m IV infusions followed-up 0263. This patient is a 55 year-old male with parotid gland by 5-FU 600 mg/mg’: day 2 of leucovorin cancer (TNM staging: pT3b N2). Subtotal excision revealed a followed-up by 5-FU, same doses poorly differentiated (Grade 3) pleomorphic carcinoma of the Garcinia Cambogia (60% 1200 mg per os every day parotid. After Surgery and several sessions of radiotherapy HCA) C. lipoic acid (tiobecTM) 1200 mg per os every day and chemotherapy the disease progressed with signs of Celecoxib (Celebrex TM) 200 mg per os per day metastases, notably in the brain. Retinoic acid 50 mg per os every other day Melatonin 20 mg per os per day at 9pm 0264. The patient was then administered weekly with epi Naltrexone 1 mg per os per day at 9pm rubicine and the ALA/HCA combination (lipoic acid, 600 mg Prosure TM (Abbott) 2 vials per os per day three times a day, and hydroxycitrate from Garcinia Cambod gia, 1 gr three times a day). A partial remission was observed with a decrease at all tumor sites. 4.2. Patient 2: Metastatic Breast Cancer 0265. Three months later, epirubicine was replaced by 0260 This patient was a 53 year-old female with breast vinorelbin and gemcitabine combined with the ALA/HCA cancer with metastases (TNM staging: pT2 N2 M1). After combination with a very good partial remission. US 2011/023650.6 A1 Sep. 29, 2011

0266 Six months after of vinorelbin and gemcitabine 3. The method as claimed in claim 1, wherein said combined with ALA/HCA treatment, it was stopped with an hydroxycitric acid salt is a calcium salt. almost complete disappearance of the tumor (90%). 4. The method as claimed in claim 1, wherein said active 0267. The patient then returned to a normal life and ingredients are provided: regained 10 kilograms. together, in a galenical form suitable for oral administra 0268. Two months after treatment interruption, a local tion; or relapse in the parotid with a brain metastasis was observed. separately, independently of one another, each in a galeni Chemotherapy (vinorelbin and gemcitabine) in combination cal form suitable for oral administration. with the combination of the present invention ALA/HCA was 5. The method as claimed in claim 4, wherein said galenical administered again. form suitable for oral administration is selected from the 0269. A regression of the tumor mass and of the brain group consisting of tablets, gelatin capsules, powders, gran metastasis was observed which was treated by Gamma knife ules, lyophilisates, oral Solutes and syrups. one month after chemotherapy restart. 6. The method as claimed in claim 1, wherein said phar 0270 Four months after the chemotherapy had resumed, maceutical combination is in a unitary form in which the said the tumor was still being treated but was stable. active ingredients, together, are in the form of tablets. 7. The method as claimed in claim 1, comprising: 4.5. Patient 5: Metastatic Breast Cancer lipoic acid or one of the pharmaceutically acceptable salts thereof in an amount of between 20 and 800 mg: 0271 This patient was a 50 year-old female with breast hydroxycitric acid or one of the pharmaceutically accept cancer with metastases to bones. After Surgery and several able salts thereof in an amount of between 200 and 2000 sessions of radiotherapy and chemotherapy the disease ng. recurred showing metastases. 8. The method as claimed in claim 1, wherein said phar 0272. After several years of treatment, the patient refused maceutical combination further comprises at least one addi to be treated with any kind of usual chemotherapy treatment. tional active ingredient selected from the group consisting of So she was only administered with a ALA/HCA combination cisplatin, capsaicin, choline, miltefosine, methotrexate and (lipoic acid, 400 mg a day, and hydroxycitrate from Garcinia vitamin B12. Cambodgia, 1.2 graday). Thirteen months after the begin 9. The method as claimed in claim 8, wherein said addi ning of the ALA/HCA combination, the progression of the tional active ingredient is selected from the group consisting disease was observed to be significantly impaired. of cisplatin, capsaicin and methotrexate. 0273. The pharmaceutical combination of the present 10. The method as claimed in claim 8, wherein said phar invention is therefore useful in the treatment of cancer when maceutical combination comprises both cisplatin and capsai used alone or together with another anticancer treatment as C1. exemplified using cancer cell lines, animal studies and human 11. The method as claimed in claim 8, wherein said phar studies. maceutical combination comprises all of capsaicin, Vitamin B12, choline and miltefosine. Example of a Pharmaceutical Composition According to the 12. The method as claimed in claim 2, wherein said Invention hydroxycitric acid salt is a calcium salt. 0274. A pharmaceutical composition according to the 13. The method as claimed in claim 2, wherein said active invention can be, for example, formulated in the form of a ingredients are provided: gelatin capsule containing the following ingredients: together, in a galenical form suitable for oral administra 0275 50 mg of alpha-lipoic acid, tion; or 0276 400 mg of hydroxycitric acid, separately, independently of one another, each in a galeni 0277 109 mg of a shell consisting of hydroxypropylmeth cal form suitable for oral administration. ylcellulose, 14. The method as claimed in claim 2, wherein said phar 0278 20 mg of anti-aggregating agents, combination of maceutical combination is in a unitary form in which the said plant magnesium Stearate and of silicon dioxide, active ingredients, together, are in the form of tablets. 0279 15 mg of binder (hydroxypropylcellulose). 15. The method as claimed in claim 4, wherein said phar 0280 Such a composition can be administered according maceutical combination is in a unitary form in which the said to this dosage at a rate of 2 gelatin capsules, 3 times a day, a active ingredients, together, are in the form of tablets. minimum of one hour before meals. 16. The method as daimed in claim 2, comprising: lipoic acid or one of the pharmaceutically acceptable salts 1. A method for the treatment of tumors comprising a step thereof in an amount of between 20 and 800 mg: of administering to a patient in need thereof a pharmaceutical hydroxycitric acid or one of the pharmaceutically accept combination comprising, as active ingredients: able salts thereof in an amount of between 200 and 2000 lipoic acid or one of the pharmaceutically acceptable salts ng. thereof, and 17. The method as maimed in claim 4, comprising: hydroxycitric add or one of the pharmaceutically accept lipoic acid or one of the pharmaceutically acceptable salts able salts thereof thereof in an amount of between 20 and 800 mg: said active ingredients being formulated together or sepa hydroxycitric acid or one of the pharmaceutically accept rately, for a conjugated, simultaneous or separate administra able salts thereof in an amount of between 200 and 2000 tion. ng. 2. The method as claimed in claim 1, wherein said 18. The method as claimed in claim 6, comprising: hydroxycitric acid salt is an alkali metal or alkaline-earth lipoic acid or one of the pharmaceutically acceptable salts metal salt. thereof in an amount of between 20 and 800 mg: US 2011/023650.6 A1 Sep. 29, 2011

hydroxycitric acid or one of the pharmaceutically accept tional active ingredient selected from the group consisting of able salts thereof in an amount of between 200 and 2000 cisplatin, capsaicin, choline, miltefosine, methotrexate and ng. vitamin B12. 23. The method as claimed in claim 1, wherein the phar 19. The method as claimed in claim 2, wherein said phar maceutical combination is used in a therapeutic treatment as maceutical combination further comprises at least one addi a Supplement to other anticancer treatments. tional active ingredient selected from the group consisting of 24. The method as claimed in claim 1, wherein the phar capsaicin, choline, miltefosine, methotrexate and vitamin maceutical combination is used in a therapeutic treatment as B12. a Supplement to other anticancer treatments. 25. The method as claimed in claim 2, wherein the phar 20. The method as claimed in claim 4, wherein said phar maceutical combination is used in a therapeutic treatment as maceutical combination further comprises at least one addi a Supplement to other anticancer treatments. tional active ingredient selected from the group consisting of 26. The method as claimed in claim 4, wherein the phar cisplatin, capsaicin, choline, miltefosine, methotrexate and maceutical combination is used in a therapeutic treatment as vitamin B12. a Supplement to other anticancer treatments. 21. The method as claimed in claim 6, wherein said phar 27. The method as claimed in claim 6, wherein the phar maceutical combination further comprises at least one addi maceutical combination is used in a therapeutic treatment as tional active ingredient selected from the group consisting of a Supplement to other anticancer treatments. 28. The method as claimed in claim 7, wherein the phar cisplatin, capsaicin, choline, miltefosine, methotrexate and maceutical combination is used in a therapeutic treatment as vitamin B12. a Supplement to other anticancer treatments. 22. The method as claimed in claim 7, wherein said phar maceutical combination further comprises at least one addi c c c c c