PHARMACEUTICAL COMPOSITION FOR TREATING OBESITY

Abstract: A salt of N,N' sebacoyl bis-sarcosine [S(Sar)>2<] having the formula (CH>2<)>8<-[CO-N(CH>3<)-CH>2<-COOH]>2< (SBS) with L-arginine or L-lysine is used for the treatment of obesity.

Description: PHARMACEUTICAL COMPOSITION FOR TREATING OBESITY FIELD OF THE INVENTION The present invention is in the field of treatment and prevention of obesity and atherosclerosis in human and non-human animals. BACKGROUND OF THE INVENTION Lipids are stored in the body mostly as fat under the skin and consumption of lipids and carbohydrates beyond the metabolic need leads to fattening. The associated medical and aesthetic problem, are a major concern in modern society. Apart from surgery and dietary means, there is a desire for drugs which will reduce fat accumulation by inhibiting lipid and lipoproteins in the liver. The most potent drug, from the group of β,β' tetrametyl substituted α,ω dicarboxylic acids (MEDIC A), was found to be the hexadecane derivative (MEDIC A 16). It was demonstrated that MEDICA, which is a non-naturally occurring fatty acid, could inhibit biosynthetic pathways of triglycerides and cholesterol in the liver. U.S. patent 5,602,104 to Shinitzky et al. discloses a dietary supplement for the treatment of obesity. Among the dietary suplements that is mentioned is the compound N,N' sebacoyl bis-sarcoeine-ethylester [S(Sar) 2 ] having the formula (CH 2 ) 8 -[CO-N(CH 3 )-CH 2 -COOH] 2 . SUMMARY OF THE INVENTION The present invention provides a new SBS formulation wherein the SBS is provided in the form of a salt, with the salt forming anion being L-arginine and or L-lysine. In addition to serving as a source for the nutritionally important amino acid - L-arginine or L-lysine, this salt formulation adds in a synergistic manner a clinically proved absorption of the SBS. By a first of its aspects, the present invention thus provides a method for the treatment of obesity comprising administering to a subject an effective amount of SBS in the form of a salt, with the salt forming anion being L-arginine or L-lysine. The method of the invention is applicable to both human and non-human animals. The SBS can be administered, in accordance with the invention, parenterally, orally, topically, with oral administration being preferred. A suitable oral administration is a capsule or a pill, but other oral administration formulations, such as a drink or a syrup, are not excluded. By another of its aspects the present invention provides a pharmaceutical composition comprising, as its active ingredient, an effective amount of SBS in a salt form, with the salt- forming anion being L-arginine or L-lysine. A particular use of the pharmaceutical composition is in the treatment of obesity. As will be appreciated, the term "pharmaceutical composition" should be understood in the broadest sense and includes, in its scope, a pharmaceutical composition intended as a drug that is indicated for treatment of a certain disease or condition, a cosmetic composition or another composition intended to be used in a non-medicated fashion, e.g. a composition sold over the counter (OTC) without a implied indication, as well as a composition intended for veterinary use. By another of its aspects the present invention provides use of SBS in the form of a salt, with the salt forming anion being L-arginine or L-lysine, for the preparation of a pharmaceutical composition, particularly a pharmaceutical composition for the treatment of obesity. The effective amount is an amount which is effective to cause the treated subject, upon repeated administration, to reduce the amount of the fat in its body and hence its weight. As will be appreciated, the effective amount depends on factors such as the administration regime, for example whether the pharmaceutical composition is administered to the individual several times, e.g. twice daily, once a day, once every two days, once every week, etc. Additionally, the effective amount may also depend on the weight of the treated individual, on its gender, on age or on a number of other physiological parameters. In addition, the effective amount may also depend on other factors such as diseases the individual has, other drug treatments the individual receives, etc. In another aspect, the present invention also provides a use of SBS in combination with L-Arginine or L-lysine, for the preparation of a pharmaceutical composition for the treatment of obesity. The use of SBS can be applied to both human and non-human animals and be administered both topically and orally in a preferably but not limited to capsule form. BRIEF DESCRIPTION OF THE DRAWINGS In order to understand the invention and to see how it may be carried out in practice, one preferred embodiment will now be described, by way of non-limiting example only, with reference to the accompanying drawings, in which: Fig. 1 shows serum SBS level in rabbits after a single oral dose of SBS in the form of SBS-L-arginine immediate release tablets (n = 4 animals in each case); Fig. 2 shows the serum SBS level in rabbits after a single oral dose of SBS in the form of floating tables (n = 4 animals in each case); Fig. 3 shows the serum level in rabbits after a single oral dose of SBS in the form of immediate-release tablets (n = 4 animals in each case); Fig. 4 shows the serum SBS level in rabbits after a single oral dose of SBS in the form of sustained release tablets (n = 4 animals in each case); Fig. 5 shows the serum SBS level in rabbits after a single dose of SBS in the form of enterocoating tablets (n = 4 animals in each case); and Fig. 6 shows the serum SBS level in rabbits after a single dose of SBS in the form of SBS-Na salt solution (n = 4 animals in each case). DETAILED DESCRIPTION OF THE INVENTION In the Example bellow, the invention will be illustrated by a pharmaceutical composition in which L-arginine is used as the salt-forming anion. As L-arginine and L-lysine are chemically similar, the results shown below demonstrate the superiority of the L-arginine-comprising composition of the invention over other compositions of SBS, permits to predict that compositions of the invention with L-lysine the salt-forming anion, will behave in a similar manner. EXAMPLE COMPARATIVE PHARMACOKINETIC EVALUATION OF DIFFERENT SBS FORMULATIONS (ORAL DOSAGE FORMS) IN RABBITS 36 New Zealand male rabbits (4 animals per Formulation's group), 4-6 months old, 2.7-2.9 kg body weight, were given orally the tested tablets, (see Table 1 below) in the morning, after a night of starvation. Blood samples were collected from an ear vein into serum tubes at different time points up ranging from 15 mins. to 7 days after single-dose administration: 15 min, 30 min, 45 min, lh, 1.5 h, 2h, 4h, 6h, 8h, 24h, 48h, 72h, 96h, 120h, 144h, 168h. Serum was separated by centrifugation. SBS concentration in rabbit's serum was tested by analytical HPLC validated method with sensitivity of 0.5 to 1 ug/ml. Pharmacokinatic analysis was calculated using the Extravascular (model 200) noncompartmental analysis (NCA) of Win NoNlin program (WinNonlin® Copyright ©1998-1999, Pharsight Corporation) version 3.1 build 168. The maximum SBS serum concentration was achieved using SBS-L-Arginine tablets (16.8 ug/ml). The figures illustrate the results from Tables 2 A and B. Fig 1. shows serum SBS level in rabbits after a single oral dose of SBS in the form of SBS-L-Arginine immediate release tablets. It can be seen that after a quick increase in the SBS levels, it rapidly and constantly disappears. Fig 2 shows serum SBS level in rabbits after a single oral dose of SBS in the form of floating tablets. It can be seen that it reached maximal levels at a somewhat lower rate than that seen in Fig. 1 and also a lower maximal line. Fig 3 shows serum SBS level in rabbits after a single oral dose of SBS in the form of immediate release tablets. It can be seen that the peak of SBS is reached only after about 5 Oh. Fig 4 shows serum SBS level in rabbits after a single oral dose of SBS in the form of sustained release tablets. It is demonstrated that immediately after the SBS was given, the SBS level reach its peak (lower than demonstrated in Fig 2) and begins its decline immediately after. Figs 5 and 6 show serum SBS level in rabbits after a single oral dose of SBS administered in enterocoated tablets and in the form of sodium salt solution, respectively. It can be seen that the amount of SBS rises very slowly to its highest level (much lower than the rate seen in Fig. 1) and remains in a constant level for a long time. Furthermore, the maximal level is dramatically lower than that seen in Fig. 1. Tables referred to above, are shown below. In these tables the following abbreviations will be used to denote the following pharmacokinetic parameters: Tmax: Time of maximum observed concentration. Cmax: Concentration corresponding to Tmax. T last: Time of last measurable (non-zero) concentration. C last: Concentration corresponding to Tlast. Tι/ 2 : Half-life time. AUC: Area under the curve. Vz, Vz/F: Volume of distribution based on the terminal phase. CL, CL/F: Total body clearance. M T last: Mean residence time from the time of dosing (Dosing_time) to the last measurable concentration, for infusion models. Table 1 - SBS tablet formulations Table 2. A. Model-independent pharmacokinetic parameters for SBS following single oral administration of different tablet forms in NZ Rabbits Table 2. B. Model-independent pharmacokinetic parameters for SBS following single oral administration of different dosage forms in NZ Rabbits

Claims: CLAIMS: 1. A method for the treatment of obesity comprising administrating to a subject N,N' sebacoyl bis-sarcoeine-ethylester [S(Sar)2] having the formula (CH 2 )8-[CO-N(CH 3 )-CH 2 -COOH] 2 (SBS) in the form of a salt with L-Arginine or L-lysine as the salt-forming anion. 2. A method according to Claim 1, wherein the administration is oral. 3. A method according to Claim 2, wherein the SBS is administered in the form of a pill or a capsule. 4. A method according to Claim 1, wherein the SBS is administered to treat obesity. 5. A method according to Claim 1, wherein the subject is a non-human animal. 6. A method according to Claim 1, wherein the subject is a human. 7. A pharmaceutical composition comprising an effective amount of N,N' sebacoyl bis-sarcoeine-ethylester [S(Sar) 2 ] having the formula (CH 2 )8-[CO-N(CH 3 )-CH 2 -COOH]2 (SBS) in the form of a salt with the salt forming anion being L-Arginine or L-lysine. 8. A pharmaceutical composition according to Claim 7, for the treatment of obesity. 9. A pharmaceutical composition according to Claim 8, for oral administration. 10. A pharmaceutical composition according to Claim 9, in the form of a pill or a capsule. 11. A pharmaceutical composition according to Claim 7, for use in the treatment of obesity. 12. A pharmaceutical composition according to Claim 11, for the treatment of a non-human animal. 13. A pharmaceutical composition to Claim 9, for the treatment of a human. 14. Use of N,N' sebacoyl bis-sarcoeine-ethylester [S(Sar) 2 ] having the formula (CH 2 )8-[CO-N(CH 3 )-CH 2 -COOH] 2 (SBS) in a salt form with L-Arginine or L-lysine as the salt-forming anion, for the preparation of a pharmaceutical composition for the treatment of obesity. 5 15. Use according to Claim 14, for the preparation of an oral pharmaceutical composition. 16. Use according to Claim 15, for the preparation of a pharmaceutical composition. 17. Use according to Claim 14, for the preparation of a pharmaceutical l o composition for the treatment of obesity. 18. Use according to Claim 14, for the preparation of a pharmaceutical composition for the treatment of a non-human animal. 19. Use according to Claim 14, for the preparation of a pharmaceutical composition for human use. 15

Inventors: SHENFELD AVNER, SHINITZKY MEIR, SHENFELD, AVNER, SHINITZKY, MEIR
Applicants: LEAN EX LTD, SHENFELD AVNER, SHINITZKY MEIR, LEAN-EX LTD., SHENFELD, AVNER, SHINITZKY, MEIR
Application year: 2001
Main classification: A61K31
IPC codes: A61K9, A61K31, A61P3