CH622703A5 - Therapeutic compositions for treating deposits of excess fat and infiltrates causing cellulite - Google Patents

Description

The present invention relates to new preparations for treating orally or by local application fatty deposits and cellulite infiltrates.

Fat cells are invaded by triglycerides which are hydrolyzed to fatty acid and glycerol by lipases which only act after their activation by phosphokinases dependent on c3 ', 5'-AMP. This is formed from cytoplasmic ATP thanks to adenylate cyclase, an enzyme located in the plasma membrane. Several hormones including catecholamines stimulate this membrane enzyme, while c3 ', 5'-AMP is hydrolyzed to 5'-AMP inactive by phosphodiesterases. The main known inhibitors of phosphodiesterases are methylxanthines, in particular theophylline (1,3-dimethylxanthine).

Research has unexpectedly found that, on the one hand, 3,5,3'-triiodothyroacetic acid and structurally related iodophenolic products behave as phosphodiesterase inhibitors, and on the other hand that various phenolic amines different from those known so far could replace catecholamines in the activation processes of adenylate cyclase.

From these results, it was possible to develop a new preparation for treating fatty overloads and cellulite infiltrates, which is characterized by the fact that it comprises, mixed with other ingredients, at least one compound activating adenylate. cyclase and at least one phosphodiesterase inhibitor compound.

As activating compound for adenylatecyclase, one or more of the following compounds can be used: adrenaline, noradrenaline, etc., or those carrying a single phenol function in position 4 such as bamethan, neosynephrine (or phenylephrine), salbutamol (or (tert.-butylamino) -2 (4-hydroxy-3-hydroxymethylphenyl) -l ethanol), etc.

As phosphodiesterase inhibitor compound, one or more compounds chosen from the group comprising 1,3-dimethylxanthine, isobutylmethylxanthine, 3,5,3'-triiodothyroacetic acids, 3,5,3'-triiodothyro-propionic acid can be used. , 3,5,3 ', 5'-tetra-iodothyroacetic and 3,5,3', 5'-tétra-iodothyropropionique, 3,5,3'-triiodothyronine, and 3,5,3 ', 5' -tetra-iodothyronine, etc.

The combination of these two types of compounds has the effect of promoting the biosynthesis of intracellular c3 ', 5'-AMP.

Such an association can be completed by adding a compound which acts as an activator of protein kinases. in order to improve the lipolytic properties of the preparation according to the invention. As activator of protein kinases, c3 ', 5'-AMP or one of its derivatives, for example dibutyrylcyclo-3', 5'-AMP, can be used.

When they are intended for local applications, the new preparations of the invention advantageously contain, in addition to suitable excipients such as ketomacrogol, agents facilitating the penetration and the diffusion of the above active components. Non-limiting examples that may be mentioned include paracymene, lauric acid hexylester, Hyaluronidase and mucopolysaccharidases.

The pharmacological activity of the new preparations according to the invention was studied in the following tests.

Example 1:

Noradrenaline and 3,5,3'-triiodothyroacetic acid

Adipocytes isolated from the rat epididymis are incubated in Krebs-albumin medium at pH 7.4 at 35 ° C for 15 min in the presence of 13.2 nmol of adenine labeled with 200 μl of 3H. After incubation, the cells are isolated by centrifugation, washed 3 times and resuspended in Krebs-albumin-glucose medium. The adipocyte suspension is then incubated for 5 min at 37 ° C., then the radioactive c3 ′, 5′-AMP is assayed after separation on a column.

In the presence of 10 "5M norepinephrine, the amount of c3 ', 5'-AMP formed is 27 pmol, and the addition of 3,5,3'-triiodothyroacetic acid 10 ~ 4M causes an increase in the amount of c3 ', 5'-AMP of about 50%.

The following tests were carried out under experimental conditions similar to those described in Example 1.

Example 2:

Adrenaline and 3,5,3'-triiodothyronine

The combination of 10 "5M adrenaline and 3,5,3'-triiodo-thyronine 10_4M increases by 35% the biosynthesis of c3 ', 5'-AMP of adipocytes formed from 3H adenine.

Example 3:

Adrenaline and thyroxine

A trial was carried out by replacing 3,5,3'-triiodothyronine by 3,5,3 ', 5'-tetra-iodothyronine or thyroxine. This association gave results similar to those of Example 2.

Example 4:

Bamethan and 3,5,3'-triiodothyroacetic acid

The combination of 10 "5M bamethan and 10" 4M 3,5,3'-tri-iodothyroacetic acid causes a 37% increase in the amount of adipocyte c3 ', 5'-AMP.

Example 5:

Bamethan and acid 3,5,3 ', 5'-tetra-iodothyroacetic

A test was carried out by replacing 3,5,3'-triiodothyroacetic acid with 3,5,3'-tetra-iodothyroacetic acid. The combination gave results similar to those of Example 3.

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Example 6:

Neosynephrine and 3,5,3'-triiodothyroacetic acid

In the presence of 10 "5M neosynephrine and 3,5,3'-triiodothyroacetic acid, the amount of c3 ', 5'-AMP formed is increased by 28%.

Example 7:

Salbutamol and 3,5,3'-triiodothyropropionic acid In combination, 10 "5M salbutamol and 3,5,3'-triiodothyropropionic acid 10 ~ 4M cause stimulation of adenylate cyclase which results in an increase of 32 % of the quantity c3 ', 5'-AMP.

Example 8:

Salbutamol and 3,5,3 ', 5'-tetra-iodothyropropionic acid

A test was carried out by replacing the triiodic acid by its tetra-iodinated counterpart. This association gave results similar to those of Example 7.

Example 9:

Noradrenaline and isobutylmethylxanthine

In the presence of 10 "5M noradrenaline and 10" 4M isobutylmethyl-xantine, the activation of the adipocyte c3 ', 5'-AMP biosynthesis is increased by 275%.

Example 10:

Adrenaline and isobutylmethylxanthine

The replacement of noradrenaline in example 9 by adrenaline leads to an association which has effects similar to those of example 9.

Example 11:

Bamethan and isobutylmethylxanthine

The 10 "5M bamethan alone causes an increase in the amount of c3 ', 5'-AMP formed by less than 5%; the 10" 4M isobutylmethylxanthine alone has practically no effect on the quantity of the adipocyte cyclonucleotide, while the association of the two compounds leads to an activation of 270% of the c3 ', 5'-AMP formed from adenine 3H.

Example 12:

Bamethan and theophylline

The replacement of isobutylmethylxanthine in example 11 by theophylline 10 "3M leads to an association which presents effects analogous to those of example 11.

Example 13:

Neosynephrine and theophylline

The two products at concentrations of 10 ~ 5M for neosynephrine and 10 "3 for theophylline have a synergistic effect which results in a 145% increase in the adipocyte c3 ', 5'-AMP formed.

Example 14:

Salbutamol and theophylline

The combination of salbutamol 10 "5 and theophylline 10" 3 increases the amount of c3 ', 5'-AMP in adipocytes by 154%.

Example 15:

Adrenaline or noradrenaline and c3 ', 5'-AMP, or dibutyryl c3', 5'-AMP

The aim of this test was to show that the cyclic adenylic nucleotides penetrated through the skin of the rat.

A first series of experiments consisted in applying to a surface of 4 cm 2, the skin of which is shaved beforehand, 50 (11 of an aqueous solution containing 2 (ig of c3 ', 5'-AMP marked by 0.5 nCi The radioactivity found after 3 h at the dern is on average 0.05 nCi and 0.007 fJ.Ci in the underlying muscle. The c3 ', 5'-AMP therefore crosses the skin layer. a penetration agent such as para-cymene, lauric acid hexylester, Hyaluronidase or mucopolysaccharidases, penetration is increased by approximately 50%.

Qualitatively similar results, but quantitatively superior, are obtained with dibutyryl-c3 ', 5'-AMP.

It was found in a second series of tests that the addition of 10 "5M noradrenaline did not modify the penetration of cyclic adenylic nucleotides.

Similar results are obtained with the combination of c3 ', 5'-AMP or its dibutyric derivative with adrenaline.

Example 16:

3,5,3'-triiodothyroacetic acid and c3 ', 5'-AMP

The plasma membrane of adipocytes is broken by grinding. The homogenate is then centrifuged at 5000 g for 10 min. The upper lipid layer is removed, then the pellet is resuspended in the supernatant. To the homogenate thus reconstituted is added c3 ', 5'-tritiated AMP, in the presence or absence of 3,5,3'-triiodothyroacetic acid. In a medium enriched in triiod derivative at a concentration of 10 "4M, the c3 ', 5'-AMP hydrolyzed into 5'-AMP is only 50% after 30 minutes of incubation at 37 ° C., while in its absence almost 95% are broken down.

This demonstrates that triiodothyroacetic acid decreases the hydrolysis of c3 ', 5'-AMP by phosphodiesterases to inactive 5'-AMP.

Example 17:

Bamethan, isobutylmethylxanthine and dibutyrylcyclo-3 ', 5'-AMP

Tritiated adenine is added to a suspension of adipocytes in a solution containing 10 "4M bamethan, 10 ~ 5M isobutylmethylxanthine and the dibutyl derivative. After incubation for 60 min at 37 ° C., the formation of c3 ', 5'-AMP tritiated. This fact demonstrates on the one hand that adenylate cyclase is stimulated even in the presence of the derivative of c3', 5'-AMP and on the other hand that c3 ', 5'- Tritiated AMP formed is not hydrolyzed by phosphodiesterases, despite the complexity of the incubation medium.

Example 18:

Salbutamol, 3,5,3'-triiodothyroacetic acid and dibutyrylcyclo-

3 ', 5'-AMP

Results similar to those indicated in Example 17 are obtained with this ternary mixture.

Example 19:

Neosynephrine, isobutylmethylxanthine and c3 ', 5'-AMP

The mixture of these three compounds promotes the formation of c3 ′, 5′-AMP labeled from tritiated adenine added to adipocytes.

This demonstrates the phosphodiesterase inhibiting effect of 3,5,3'-triiodothyroacetic acid and its iodo-phenolic analogs.

3,5,3'-triiodothyroacetic acid, as well as similar iodophenolated products, can be prepared, for example, by the following successive reactions:

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a) formation of the compound:

NO.

CHO

by reaction of chlorodinitrobenzaldehyde and p-methoxyphenol in the presence of CH3 - H2 or of a reducing agent such as bisulfite;

b) replacement of the two nitro groups by two —NH2 groups by reduction (Ni Raney) in alcoholic medium;

then diazotization of the non-isolated diamine and Sandmeyer reaction in the presence of an iodo-iodide solution in sulfuric acid medium, in order to replace the two groups - NH2 by two iodo groups;

c) formation of the corresponding acid by treatment by means of PC15 and obtaining the chlorinated derivative, then treatment of the latter with KCN and transformation into nitrile, and hydrolysis by HI in the presence of red phosphorus;

d) iodination controlled by I2 in an ammoniacal medium to provide the desired triiodic derivative.

The new preparations in accordance with the present invention are intended for general administration, such as the oral or injectable route, and for topical administration. Topical administration is preferred, and the preparations then comprise, in addition to the active compounds, suitable excipients which allow their presentation in the form of creams (oil in water or water in oil), ointments, ointments, emulsions, gels (for example based on “Carbopol”), liniments, solutions for ionization, etc. Said preparations also contain penetration and diffusion agents such as those already mentioned and in particular mucopolysaccharidases and hyaluronidases.

The doses of active components which the preparations in accordance with the present invention contain are advantageously the following:

bamethan salbutamol adrenaline noradrenaline isobutylmethylxanthine triiodothyroacetic acid triiodothyronine thyroxine c3 ', 5'-AMP dibutyrylcyclo-AMP hyaluronidase mucopolysaccharidases

1 The therapeutic effect of the preparations in accordance with the present invention has been studied on women with significant cellulite infiltrates, with reduced skin flexibility and the phenomenon known as orange peel. Eight creams were thus tested, the composition of these creams, as well as the results obtained obtained appearing in Examples A to H below.

The excipients of creams are almost always the same and generally have the following composition:

5 to 100 to 100 to 10 to 10 to 5 to 5 to

1,000 to 2,000 IU 10,000 to 15,000 TRU

30 mg 300 mg 200 mg 200 mg 200 mg 15 mg 15 mg self-emulsifying ketomacrogol lauric acid hexylester petrolatum oil water

12 g 50 g 0.5 g qs. 100

100 to 1500 mg 5 to 100 mg 5 to 30 mg

The preservatives are those indicated for each formula and in the absence of indication: methyl parahydroxybenzoate and propyl parahydroxybenzoate for the fatty phase, and the sodium salts of the same for the aqueous phase. The proportion to be introduced into 100 g of cream from the above preservatives is of the order of 0.05 g for each of them.

30 Example A

a) Composition of the cream:

- bamethan 300 mg

- isobutylmethylxanthine 300 mg 35— dibutyrylcyclo-3 ', 5'-AMP 10 mg

- excipient with antioxidant qs 100 g such as tocopherol acetate b) The above cream was applied 1 time per day, without any associated treatment other than dietetic and hygienic rules

40 normal, such as the reduction in consumption of salt and starchy foods to 8 women aged 35 to 48 years, suffering from cellulite.

c) Results:

Duration of treatment (weeks)

Skin flexibility before after

Phenomenon of orange peel skin appearance before after

Decrease in measurements (in cm) waist hips thighs

Good zero tolerance

+ +

amel.

3

2

3

good avg. good

+

normal

6

4

5

good zero amel.

+

normal

2

1

2

good null good

7 5 3

good avg. good

+++ normal amel.

5 5 4

good null good

+ +

amel.

6 5 3

good zero zero good good

+ + + + normal normal

5 2 2

good

7 6 5

good

NB

+: presence of the orange peel phenomenon + +: significant presence of the orange peel phenomenon

+ + +: very significant presence of the orange peel phenomenon

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By good tolerance is meant that women who have undergone the anti-cellulite treatment have not had any detectable side effects.

Example B

a) Composition of the cream:

- bamethan

- isobutylmethylxanthine

300 mg 300 mg

- excipient with antioxidant qs 100 g such as tocopherol acetate (see example A)

b) The above cream was applied twice a day without any associated treatment other than normal dietary and hygienic rules, to 5 women aged 28 to 42 with cellulite.

c) Results:

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3

4

5

Duration of treatment

(weeks) "

6

6

6

6

6

Skin flexibility

before zero zero zero zero average after good good good ace. good perfect

Phenomenon of the

Orange peel

appearance of the skin

before

+ +

+

+ +

+

+ + +

after improved improved normal normal normal

Decrease

measurements

(in cm)

cut

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hips

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4

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thighs

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2

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1

4

Tolerance good good good good good

NB: see table example A.

Example C

a) Composition of the cream:

- 3,5,3'-triiodothyroacetic acid

- noradrenaline

- p-chlorocresol + Na metabisulfite, as preservatives

- excipient qs 100 g

(idem ex. A, with an additional 1.5 g of petroleum jelly)

b) The above cream was applied twice a day without

35 associated treatment other than dietetic and hygienic rules

100 mg normal for 6 women aged 30 to 42 with cellulite. 20 mg c) Results:

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2

3

4

5

6

Duration of treatment

3

4

5

2

4

3

(weeks)

Skin flexibility

before null null null null null null after good improved good good good good

Phenomenon of the

Orange peel

appearance of the skin

before

+

+ +

+ +

+

+ + +

+

after improved normal normal improved normal normal

Decrease

measurements

(in cm)

cut

2

4

3

0

3

3

hips

2

3

2

1

2

4

thighs

2

6

2

1

1

1

Tolerance good good good good good good

NB: see table example A.

Example D

a) Composition of the cream:

- 3,5,3'-triiodothyroacetic acid 100 mg

- bamethan 1000 mg

- mucopolysaccharidases 13500 TRU

- excipient qs 100 g b) The above cream was applied twice a day without any associated treatment other than normal dietary and hygienic rules to 5 patients, women, aged 29 to 45 years, suffering from cellulite.

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c) Results:

6

Duration of treatment (weeks)

Skin flexibility before after

Orange peel before after Measurements D (in cm)

waist hips thighs Tolerance decreased decreased decreased decreased decreased good good good good good good

+ + + + +

improved normal normal improved improved

10 5 B

6 5 2 B

4

5 2 B

4 6 4 B

4 4 2 B

NB: see table example A.

Example E

a) Composition of the cream:

- adrenaline 20 mg

- 3,5,3 ', 5-tetra-iodothyronine or thyroxine 50 mg

- p-chlorocresol + Na metabisulfite as preservatives

- excipient qs 100 gb) The above cream was applied twice a day without any associated treatment other than normal dietary and hygienic rules to 5 patients, women aged 29 to 51, suffering from obesity and cellulite .

c) Results:

1 2 3 4 5

Duration of treatment

3

3

4

3

3

(weeks)

Skin flexibility

before zero zero zero zero zero after improved improved improved improved improved

Skin phenomenon

orange

before

+ +

+ +

+ + +

+ +

+ +

after improved normal improved normal normal

Measurements D

(in cm)

cut

2

2

4

2

2

hips

2

3

3

5

2

thighs

1

2

1

2

1

Tolerance good good good good good

NB: see table example A.

Example F

a) Composition of the cream:

- salbutamol 100 mg

- 3,5,3 ', 5'-tetra-iodothyronine 100 mg

- excipient qs 100 g

65 b) The above cream was applied 2 to 3 times a day without any associated treatment other than normal dietary and hygienic rules to 4 patients, women aged 34 to 37 years, suffering from cellulite.

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c) Results:

12 3 4

Duration of treatment (weeks)

Skin flexibility before after

Phenomenon of orange peel before after

Measurements D (in cm)

waist hips thighs Zero tolerance improved

+++ improved

3 2 1

good zero improved

+

normal

4 3 1

good null good

+

normal

3 1 0

good zero improved

+ +

improved

2 2 Vi good

NB: see table example A. Example G

a) Composition of the cream:

- bamethan

- 3,5,3 ', 5'-tetra-iodothyronine

- excipient b) The above cream was applied twice a day without any associated treatment other than dietary and hygienic rules 2oo mg normal to 4 patients, women aged 34 to 39 years, suffering from 100 mg30 • of cellulite.

qs 100 g c) Results:

Duration of treatment (weeks)

Skin flexibility before after

Orange peel phenomenon before after Measurements decrease expressed (in cm)

waist hips thighs tolerance zero zero zero bad improved normal normal normal

+ + + + normal normal

3 3 1

good

4 3 1

good

+ + + + normal normal

3 2 1

good

3 2 2

good

NB: see table example A.

Example H

a) Composition of the cream:

- bamethan 200 mg

- isobutylmethylxanthine 200 mg

- 3,5,3'-triiodothyroacetic acid 100 mg

- excipient qs 100 g b) The above cream was applied twice a day without massage or associated treatment other than normal dietary and hygienic rules to 6 patients, women, aged 23 to 36, suffering from cellulite.

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c) Results:

Duration of treatment (weeks)

Skin flexibility before after

Phenomenon of orange peel before after

Measurements decrease expressed (in cm)

none zero improved good

2x3 2x3 2x3

null null null null improved good good good

+++ normal

+ +

+ +

improved normal

+ + + + + + + improved improved improved size

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4

4

5

7

6

hips

4

2

3

4

4

5

thighs

1

1

1

2

1

3

Tolerance good good good good good good

NB: see table example A.

The preparation of the above creams is done according to the following general principle. The self-emulsifying ketomacrogol is melted without overheating. The lauric acid hexylester and the paraffin oil are added when about half the mass is melted. The adequate quantity of water previously brought to the same temperature and in which the intended preservatives have been dissolved is added to the melted mass. Stir and allow to cool with slow stirring.

Preparation A:

The three constituents are suspended in paraffin oil and add this suspension to the excipient when the latter has returned to a temperature of 35 to 40 ° C.

Preparation B:

The two constituents are treated as for preparation A.

Preparation C:

Triiodothyroacetic acid is dissolved hot in fatty substances.

Adrenaline is added cold to the finished mass after the addition of antiseptics and preservatives. Mix long and carefully.

Preparation D: Preparation identical to C Preparation E: Preparation identical to B Preparation F: Preparation identical to B Preparation G: Preparation identical to B Preparation H: Preparation identical to B

Gel:

When you want to make a gel, which is possible with most formulas, you dissolve the active ingredients therein mg mg mg g

The excipient includes:

- carbopol 940 1 to 2% 40 - triethanolamine sufficient quantity

- water

Carbopol is swelled in water overnight. Neutralized with triethanolamine to obtain gelation.

45 Baméthan and isobutylmethylxanthine are dissolved in water. Triiodothyroacetic acid in propylene glycol. These two solutions are incorporated with slow stirring so as not to introduce air.

so Liniment:

Le Uniment is simply prepared by solution in propylene glycol, an oil such as almond oil, Labrafil (M.D. Gattefossé) for example, constituents:

triiodothyroacetic acid, bamethan, and isobutylmethylxanthine 55 which are soluble therein. A penetration factor, p-cymene or Hyaluronidase for example, is added.

Of course various modifications can be made by those skilled in the art to the preparations which have just been described only by way of nonlimiting examples, without departing from the scope 60 of the invention.

soluble in alcohol at 95 ° C and / or propylene glycol and the others in water. Water-soluble preservatives such as sodium sorbate and / or sodium methyl p-hydroxybenzoate are used.

Example:

- bamethan 200

- methylisobutylxanthine 200 35 - triiodothyroacetic acid 100

- excipient qs 100

R

Claims (8)

622,703 CLAIMS 1. Therapeutic composition for treating fatty overloads and cellulite infiltrates, characterized in that it comprises at least one compound activating adenylate cyclase and at least one compound inhibiting phosphodiesterases. 2. Composition according to claim 1, characterized in that the activator compound of adenylate cyclase is chosen from the group comprising adrenaline, noradrenaline, bamethan, phenylephrine and (tert.-butylamino) -2 (hydroxy -4-3-hydroxymethylphenyl) -l ethanol. 3. Composition according to claim 1, characterized in that the phosphodiesterase inhibitor compound is chosen from the group comprising 1,3-dimethylxanthine, isobutylmethylxanthine, 3,5,3'-triiodothyroacetic acids, 3,5,3 '-triiodothyropropionic, 3,5,3', 5'-tetra-iodothyro-acetic and 3,5,3'-tetra-iodothyropropionic, 3,5,3'-tri-iodothyronine and 3,5,3 ' , 5'-tetra-iodothyronine or thyroxine. 4. Composition according to one of claims 1 to 3, characterized in that it also comprises at least one compound activating protein kinases. 5. Composition according to claim 4, characterized in that the activator protein kinase compound is c3 ', 5'-adenosinemonophosphoric acid or one of its derivatives. 6. Composition according to claim 5, characterized in that the derivative of c3 ', 5'-adenosinemonophosphoric acid is dibutyrylcyclo-3', 5'-adenosinemonophosphoric acid. 7. Composition according to one of claims 1 to 6, characterized in that it is in a form applicable topically. 8. Composition according to one of claims 1 to 6, characterized in that it is in a form intended to be administered orally.