WO2006007675A1

WO2006007675A1 - Cholic acid and/or its derivatives for the reduction of localized fat in the human body

Info

Publication number: WO2006007675A1
Application number: PCT/BR2004/000123
Authority: WO
Inventors: Marina Emiko Yagima Odo; Luiz Carlos CUCÉ
Original assignee: Libbs Farmacêutica Ltda.
Priority date: 2004-07-20
Filing date: 2004-07-20
Publication date: 2006-01-26
Also published as: AR049210A1; BRPI0418963A

Abstract

The present invention refers to the use of cholic acid and/or its derivatives for the reduction of localized fat in the human body, wherein the active agent is preferably used subcutanously.

Description

CHOLIC ACID AND/OR ITS DERIVATIVES FOR THE REDUCTION OF LOCALIZED FAT IN THE HUMAN BODY.

The present invention concerns pharmaceutically acceptable tensoactive compounds, as well as compositions that comprise them, their use for the reduction of localized fat in the human body, and a method to reduce localized fat through the contact of said tensoactives-with subcutaneous cellular tissue. The invention particularly concerns composition, use and method related to tensoactives found in animal bile, for instance acids and salts, derivatives and isomers thereof. BACKGROUND OF THE INVENTION

The accumulation of fat, or adipose tissue, in specific regions of the human body, associated or not to excess weight, constitutes a physical, aesthetic and even psychological problem, with effects on the physical and mental health of a person. Common body regions where adiposity accumulation happens are: hips, outer and inner thighs, lower and upper abdomen, waist, buttocks, flank, submental region (neck, jowl, chin), inferior eyelid (bag under the eyes), and arms. Depending on specific biotypes, the accumulation of fat may occur in different regions of the body, such as the face, back, breasts, etc. The accumulation of adipose tissue, or localized fat, or still paniculus adiposus, tends to increase with age.

To eliminate accumulation or excess adipose tissue several alternatives have been tested. Weight loss methods, restrictive diets, exercising, topic use of cosmetics, among others, have not demonstrated highly satisfactory results. Many studies and research have been undertaken seeking for results in that sense. Patent documents can be mentioned, for instance US5,507,790, BR9602919, BR9908223, BR9405478 that present topic formulations to that end. Among others, mechanical alternatives are disclosed in Brazilian patent documents such as BR9706529 (vacuum ultrasound equipment), MU8100875 (a roll for aesthetic massage), BR9906194 (bermuda shorts that liberate long infrared rays), with no proof of effective results. Electrolipophoresis and lymph drainage massage, manual or by suction, are other methods employed by aesthetic clinics, with little or- no proof of therapeutic results.

More aggressive alternatives have been employed, such as lipo suction and plastic surgery, in view of more guaranteed results. Lipo suction is one of the most frequent procedures used to eliminate localized fat, with fast results, although very invasive, not applicable to all parts of the body, presenting surgical risks and possibility of adverse effects.

Plastic surgery requires that the patient stays away from everyday activities for a longer period, is an expensive procedure and also the most invasive one, therefore with the highest risk.

During the seventies, an alternative appeared, called mesotherapy or intradermotherapy. It concerns a technique that had as initial objective the treatment of pathologies in the fields of rheumatology, orthopedics and traumatology. It comprises the administration of intradermic micro doses of a medicament, with the aid of low caliber needles, to depths variable between 2 and 6 mm, in regions that are as close as possible to the pathology to be treated. With that same principle the mesotherapy began to be tested, and it is indeed very much used for the treatment of localized fat, as a revitalization and tissue stimulation therapy. It shows advantages with relation to lipo suction and plastic surgery, becoming a choice alternative for not being invasive, presenting fast results, long lasting effects, very low dosage of chemicals, absence of pain and low risk.

Therefore, in association with lipolytic substances, mesotherapy has been used to eliminate localized fat, lipolytic substances being understood as the ones that brake the integrity of fat, enhancing its solubility in aqueous means.

Recent efforts have also been reported concerning the efficacy and safe use of phospholipid substances, such as phosphatidylcholine, in the dissolution and elimination of localized fat.- Some examples are: "The use of phosphatidylcholines for correction of lower lid building due to prominent fat pads" (Dermatol Surgery 2001 ;27:391 -392) and "The use of phosphatidylcholine for correction of localized fat deposits" (Aesth Plast Surg 2003; 27:315-318). Patent document EP132,9219 cites the phosphatidylcholine as an apoptosis inductor but the studies aim at its use as an anti-cancer agent. Other disclosures of such use are in the article "Phosphatidylcholine in the treatment of localized fat" (Journal of Drugs in Dermatology, Oct 2003). Some clinical tests are mentioned in the article "Treatment of eyelid fat pads using phosphatidylcholine: Clinical trial and review" (Dermatol Surgery 2004; 30: 422- 428) .

One can still mention, as representative of the prior art, the following patent documents: WO02055094, having as an object an injectable hypo-osmolar composition of electrolytes, for the treatment of cellulite and fatty deposits; US6,302,863 and WO0041671, about a method for removal of lipids via a perfluorocarbon tumescent solution, including subcutaneous removal of fat cells in a Iipo suction procedure; EP857.480, concerning a cosmetic treatment by gas injections containing 90 % carbon dioxide applied to lipodystrophic regions of the body; US4,588,724, disclosing the elimination of localized fat in the body by contact, for instance via injections, with alfa-2 adrenergic inhibitors. There exists, as seen, an effort towards finding means to reduce localized fat in the human body, as well as for substances that exert a lipolytic function with efficacy and safety in compositions aimed at the reduction of localized fat, for instance with the help of mesotherapy.

DETAILED DESCRIPTION OF THE INVENTION

The present invention concerns, in one aspect, a composition that comprises one or more pharmaceutically acceptable

5 tensoactive compounds, useful in the reduction or elimination of localized

^■ -— fat in the human body. Such a composition is applied-by injection to the region of localized fat, particularly subcutaneously, acting in the reduction or elimination of the fat contained therein. After the application, the tensoactive substance act upon the fat, reducing or substantially

10 eliminating the flaccidity of the skin existing over the region previously occupied by a fatty deposit. Without being bound by theory, it is believed that tensoactive compounds cause, in a beneficial way, the apoptosis of the fat cells, followed by inflammation and subsequent fibrosis, which then contracts the tissues in the vicinity of the region where the

15 tensoactive had been injected, providing sustainment of the skin, that is, reducing its flaccidity over the region that contained localized fat prior to the treatment.

The composition of the invention is particularly used for the reduction of localized fat in any part of the human body, particularly hips,

20 outer and inner thighs, lower and upper abdomen, waist, buttocks, flank, submental region (neck, jowl, chin), inferior eyelid (bag under the eyes), and arms.

Tensoactive compounds used in the composition of the invention are those pharmaceutically acceptable, particularly the ones found in animal 25 bile, including human bile, without excluding any other alternative.

In a particular embodiment of the invention one uses bile acids and salts that comprise a chemical fragment (I) within the chemical structure, as shown below: Fragment (I)

wherein R is the remaining of the chemical structure, variable with each specific acid or salt. For instance, in the case of bile acids, the following R structures can be found: - OH - NH - CH2 - CH2 - SO3H - O - NH - CH2 - COOH - NH - CH2 - COOH

The bile salts, also useful for this invention, are the salts of the pharmaceutically acceptable tensoactive bile acids, particularly sodium, potassium, magnesium, calcium and ammonia salts. In a very particular embodiment the sodium and potassium salts of bile acids are used. Derivatives of bile acids are also useful, such as C₁-C₅ alkyl esters, as well as isomers of the acids, salts and derivatives.

The bile acids most particularly used, without excluding any other, are one or more of the following: cholic, deoxycholic, taurocholic, taurodeoxycholic, tauroursodeoxycholic, taurochenodeoxycholic, taurolithocholic, glycocholic, glycodeoxycholic, glycolithocholic, glycochenodeoxycholic, chenic, chenodeoxycholic, ursocholic, ursodeoxycholic, isoursodeoxycholic, lagodeoxycholic, dehydrocholic, hyocholic, hyodeoxycholic, muricholic, lithocholic or sulpholithocholic acid, and also their salts, isomers and derivatives. In a particular embodiment one or more of the following are used: cholic, deoxycholic, taurocholic, taurodeoxycholic, glycocholic or glycodeoxycholic acid, their salts, isomers and derivatives.

In a very particular embodiment of the invention one uses sodium or potassium deoxycholate.

The tensoactives of the invention, for instance acids or salts found in the bile, as well as their isomers or derivatives, may be natural or synthetic.

In a particular embodiment of the invention, the composition containing the pharmaceutically acceptable tensoactive compound is injectable, preferably subcutaneously, comprising adequate adjuvants and excipients known to one skilled in the art, as needed. The mechanism of action in the subcutaneous tissue of the tensoactives useful to the invention, particularly the ones found in the bile, has not been explained. It is believed, and that does not limit the scope of the invention, that the molecules of those compounds integrate themselves to the adipocyte membranes (fat cells), when applied subcutaneously, leading to the lysis of the membrane.

Rosen (JAOCS, 2:293 (1972), defines tensoactive as a substance that, even when present in small quantities, is adsorbed to the surfaces and interfaces, significantly modifying the superficial and interfacial free energies. It is believed that it is through that tensoactive action that the tensoactive substances employed in the invention cause the lysis of the cell membrane in its lipidic portion, promoting the apoptosis of the fat cells.

In a surprising aspect of the invention, the contact of the tensoactive substance with the localized fat causes the lysis of the membrane cell, promoting the apoptosis of the fat cells and emulsification of the liberated triglycerides. The body reacts with an acute inflammatory process, promoted by neutrophiles and macrophages, with the fagocytosis of the liberated and emulsified fat. In the sequence, there is an inflammatory process by the lymphocytes, and a substantially homogenous tissue reparation process, promoting reduction in the measures of the patient and/or sustainment of the skin with little or no flaccidity, as a function of the replacement of the adipose tissue by fibrosis.

It is believed that there happens a stimulation in the production of elastin and of collagen fibers normally existing in the subcutaneous tissue, enhancing the texture of that tissue, decreasing the flaccidity. Each application of the tensoactive compound of the invention seem to stimulate the fibroblast (cell that produces collagen and elastin), also working as an physical- mechanical incentive for the fibroblast to respond, increasing the production of those fibers.

Another aspect of the invention is the use of pharmaceutically acceptable tensoactive compounds in the manufacture of compositions used for the remotion or elimination of localized fat in the human body. Such use is particularly in the manufacture of an injectable solution. Particularly adequate to said use are the tensoactive compounds previously mentioned.

A further aspect of the invention is a method to reduce localized fat, comprising the contact of one or more pharmaceutically acceptable tensoactive compounds with the localized fat. Preferably, the method of the invention is characterized in that it comprises said contact by means of a subcutaneous injection.

Particularly adequate to said method are the tensoactive compounds previously mentioned.

A typical injectable solution, according to the invention, comprises: 0,5 % to 10%, particularly about 2% to 6%, in weight, of one or more pharmaceutically acceptable tensoactive compounds, which is a lipolytic agent;

0,3 % to 1 ,0 % in weight of an anesthetic and/or preservative agent, for instance benzyl alcohol;

5 % to 10% in weight of a co-solvent, for instance one or more glycols or sorbitol; the remaining quantity of an adequate vehicle, as water.

The composition of the invention may optionally comprise additional lipolytic agents, such as lipase, papain, etc, and any other adequate excipients and adjuvants.

DETAILED DESCRIPTION OF AN EMBODIMENT OF A METHOD TO TREAT

LOCALIZED FAT

In the description that follows the tensoactive substance sodium deoxycholate (DCLNa) is used, simply by ease of explanation, imposing no limitation whatsoever to the scope of the invention beyond the contents of the claims attached hereto.

An injectable solution containing between about 0,5% and about 10% of DCLNa is prepared by conventional pharmacotechnical means, in a sterile way, as required for injectables. The application of the solution to the patient can be performed with the aid of any known devices, appropriate for subcutaneous applications, for instance 15x4.5 or 15x3.0 10 ml syringes

The depth of the application varies, depending on the physical structure of the patients, usually classified as thin, over-weight and obese. Good practice indicates that one must avoid superficial applications, so as not to create skin ulcers, or deep applications that risk to approach the fascia of the muscle.

The contact between the tensoactive compound and the fat is advantageously promoted along more than one application sessions. The total number of sessions varies, depending on the amount of localized fat of each individual patient, typically between 4 and 20 per region to treat.

In each session multiple applications are effected, typically between 2 and 200, particularly between 20 and 50, within a previously determined region of treatment. The interval between sessions is, for instance, between a week and a month, preferably two weeks.

The amount of injectable solution is the adequate one, typically between 50 mg e 125 mg per session, such that the amount of the tensoactive compound varies between for instance 0.5 and 3.5 mg per session, distributed along the several injections.

The results are typically followed by tests and evaluations known to a person skilled in the art, the replacement of fat by fibrosis confirmed for instance by tissue biopsy and/or ultrasonography. The method of the invention may be applied alone or along with other known techniques, such as the invasive ones that are corrective or post¬ surgical, for instance plastic surgery and lipo suction.

A specific embodiment of the invention is now going to be described, imposing no limitation to the scope of the invention other than what is contained in the claims attached hereto.

DESCRIPTION OF THE FIGURES The attached figures are histological tissue cuts.

- FIG. 1 - adipose tissue before the application of the method of the invention;

- FIG. 2 - after two months of follow-up; - Fig. 3 - 4 months after the end of the applications.

EXEMPLE

30 female patients were chosen, ages between 20 e 60, non obese, with localized fat in the inferior abdominal region.

Tests were conducted with random distribution of placebo and an injectable solution with 2.5 % sodium deoxycholate (provided by Sigma Aldrich Chimie), 1 % of benzyl alcohol, 10% propylene glycol and water. The solution was prepared by mixing the ingredients, followed by filtration.

The solution was applied with a 10 ml syringe provided with a 13x3 needle at a depth of 1.3 cm, 125 mg per session, distributed along 100 injections.

The applications were done along 4 sessions, with two-week intervals. Also bi-weekly were the follow-up tests, that were performed up to 6 months after the first application.

The attached figures depict the results obtained with the patients. Figure 1 shows the situation before the treatment. The replacement of fat by fibrosis was confirmed by tissue biopsy (also by ultrasonography, not shown) as shown in figure 2, where one verifies the lysis of the adipocytes, with an acute inflammatory process and fagocytosis of the lipids. Fig 3 shows the aspect of the tissue 4 months after the end of the applications, where one verifies a chronic inflammatory process and fibrosis.

It will be evident to a person skilled in the art, in view of the foregoing, that the invention allows a number of variations and equivalent means, nevertheless without leaving the scope protection provided by the claims attached hereto.

Claims

1. Composition for the reduction of localized fat characterized by the fact that it comprises an effective amount of one or more pharmaceutically acceptable tensoactive compounds, and adequate adjuvants and excipients, as needed.

2. Composition according to claim 1 -characterized by the fact that said tensoactive compound is one or more of the tensoactive compounds of the animal bile.

3. Composition according to claim 1 , characterized by the fact that said tensoactive compound is one or more of the acids comprised in the animal bile, their salts, isomers or derivatives.

4. Composition according to one of the claims 2 or 3 characterized by the fact that said tensoactive compound is a bile acid or salt that contains a structural fragment (I) in its chemical structure

Fragment (I):

wherein R is the remaining of the chemical structure, variable with each specific acid or salt.

5. Composition according to claim 3 characterized by the fact that said bile salts are salts of pharmaceutically acceptable tensoactive bile acids, particularly sodium, potassium, magnesium, calcium or ammonia salts, or by the fact that said derivatives are Ci-C₅alkyl esters.

6. Composition according to claim 5 characterized by the fact that said salts are particularly sodium or potassium salts.

7. Composition according to claim 3 characterized by the fact that such tensoactive compound is one or more of the following: cholic,

"leoxycholic, taurocholic,- taurodeoxycholic, tauroursodeoxycholic, taurochenodeoxycholic, taurolithocholic, glycocholic, glycodeoxycholic, glycolithocholic, glycochenodeoxycholic, chenic, chenodeoxycholic, ursocholic, ursodeoxycholic, isoursodeoxycholic, lagodeoxycholic, dehydrocholic, hyocholic, hyodeoxycholic, muricholic, lithocholic or sulpholithocholic acid, their salts, isomers and derivatives.

8. Composition according to claim 4 characterized by the fact that the tensoactive compound is one or more of the following: cholic, deoxycholic, taurocholic, taurodeoxycholic, glycocholic or glycodeoxycholic acid, their salts, isomers and derivatives.

9. Composition according to claim 3 characterized by the fact that said tensoactive compound is sodium or potassium deoxycholate.

10. Composition according to claim 1 wherein said tensoactive compound is natural or synthetic.

11. Composition according to claim 1 characterized by the fact that it is an injectable solution.

12. Composition according to claim 11 characterized by the fact that it comprises 0.5 % to 10% in weight of one or more pharmaceutically acceptable tensoactive compounds, particularly between about 2% and 6%.

13. Composition according to claim 12 characterized by the fact that it comprises 0.3 % to 1.0 % in weight of an anesthetic and/or preservative agent, particularly benzyl alcohol;

14. Composition according to claim 12 characterized by the fact that it comprises 5 % to 10% in weight of a co-solvent, particularly one or more glycols or sorbitol;

15. Composition according to one of the claims 1 to 14 characterized by the fact it contains additional lipolytic agents, particularly lipase or papain.

-16. Use of pharmaceutically acceptable tensoactive compounds mentioned in one of claims 2 to 10 characterized by the fact that such use is in the manufacture of compositions for the remotion or elimination of localized fat in the human body.

17. Use according to claim 16 characterized by the fact that said tensoactive compound is sodium or potassium deoxycholate.

18. Use according to claims 16 or 17 characterized by the fact tha said composition is an injectable solution.

19. Method to reduce localized fat in the human body characterized by the fact that it comprises the contact of one or more pharmaceutically acceptable tensoactive compounds as mentioned in one of claims 2 to 10 with said localized fat.

20. Method according to claim 19 characterized by the fact that said tensoactive compound is sodium or potassium deoxycholate.

21. Method to reduce localized fat characterized by the fact that it comprises the contact of a composition mentioned in one of claims 1 to 10 with said localized fat.

22. Method according to claim 21 characterized by the fact that said composition comprises sodium or potassium deoxycholate.

23. Method according to one of claims 21 and 22, characterized by the fact that said composition is an injectable solution according to one of claims 11 to 15.

24. Method according to one of claims 21 to 23, characterized by the fact that said injectable solution is applied subcutaneously.

25. Method according to any of claims 19 to 24 characterized by the fact that is promotes the lysis of the fat cell membrane, apoptosis of the fat cell, inflammatory process by neutrophils and macrophages, inflammatory process by lymphocytes, and tissue reparation process by fibrosis.

26. Method according to ^"any of claims 19 to 25 characterized by the fact that said localized fat is in the hips, outer and inner thighs, lower and upper abdomen, waist, buttocks, flank, submental region (neck, jowl, chin), inferior eyelid, arms, face, back, breasts.