US20050281895A1 - Slimming cosmetic composition containing a substance inducing the production of IL-6 - Google Patents

Slimming cosmetic composition containing a substance inducing the production of IL-6 Download PDF

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Publication number
US20050281895A1
US20050281895A1 US11/192,845 US19284505A US2005281895A1 US 20050281895 A1 US20050281895 A1 US 20050281895A1 US 19284505 A US19284505 A US 19284505A US 2005281895 A1 US2005281895 A1 US 2005281895A1
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United States
Prior art keywords
antagonist
cosmetic composition
substance
adipocytes
production
Prior art date
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Abandoned
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US11/192,845
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English (en)
Inventor
Pierre Casellas
Jean-Marie Derocq
Joelle Guesnet
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Sanofi Aventis France
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Sanofi Synthelabo SA
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
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Priority to US11/192,845 priority Critical patent/US20050281895A1/en
Publication of US20050281895A1 publication Critical patent/US20050281895A1/en
Priority to US12/259,575 priority patent/US8628770B2/en
Abandoned legal-status Critical Current

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K8/00—Cosmetics or similar toiletry preparations
    • A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
    • A61K8/30—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds
    • A61K8/64—Proteins; Peptides; Derivatives or degradation products thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
    • A61Q19/00—Preparations for care of the skin
    • A61Q19/06—Preparations for care of the skin for countering cellulitis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K8/00—Cosmetics or similar toiletry preparations
    • A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
    • A61K8/96—Cosmetics or similar toiletry preparations characterised by the composition containing materials, or derivatives thereof of undetermined constitution
    • A61K8/97—Cosmetics or similar toiletry preparations characterised by the composition containing materials, or derivatives thereof of undetermined constitution from algae, fungi, lichens or plants; from derivatives thereof
    • A61K8/9728—Fungi, e.g. yeasts
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/04—Anorexiants; Antiobesity agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K2800/00—Properties of cosmetic compositions or active ingredients thereof or formulation aids used therein and process related aspects
    • A61K2800/70—Biological properties of the composition as a whole

Definitions

  • the present invention relates to cosmetic compositions containing slimming active substances.
  • the active substances present in the cosmetic composition are chosen from an antagonist of the receptors for neuropeptide Y called hereinafter NPY, an antagonist of the ⁇ 2 receptors and an inducer of the production of interleukin-6 called hereinafter IL-6.
  • the NPY antagonist, the ⁇ 2 antagonist or the inducer of the production of IL-6 may be a nonpeptide compound, a peptide, a cell or tissue extract of animal or plant origin or a product obtained by fermentation by a microorganism, for example a bacterium or a fungus.
  • Patent application EP 838217 describes a slimming cosmetic composition which contains an NPY antagonist and an ⁇ 2 antagonist.
  • the active substances in this composition are obtained by fermentation by two microorganisms deposited at the C.N.C.M. of Institut Pasteur where they were registered under the references I 1332 and I 1778, respectively. In the present description, these active substances will be called substance A and substance B, respectively.
  • the slimming cosmetic composition containing them will be called composition Am1.
  • This slimming composition Am1 acts on the subcutaneous adipose tissue and controls the release of the fat stored in the adipocytes.
  • composition Am1 makes it possible to clear the hypertrophied adipocytes and to avoid any new excessive adipocyte storage by allowing the expression of the ⁇ receptors whose prolipolytic activity is normally masked by the antilipolytic ⁇ 2 and NPY receptors which are largely in excess in the subcutaneous adipose tissues. Composition Am1 thus makes it possible to act effectively on the outflow of the fatty acids stored in the adipocytes.
  • compositions according to the present invention maintain this activity but supplement it, on the one hand, by a retarding action on the entry of fatty acids which exerts itself by a reducing effect on the production of LPL, the enzyme responsible for the entry of fatty acids into the cell and, on the other hand, on the hyperplasia of the adipocytes.
  • This unexpected supplementary effect is obtained by a substance capable of inducing the production of IL-6 by the adipocytes.
  • This substance is produced by a microorganism deposited at the C.N.C.M. of Institut Pasteur registered under the reference I 1844. This active substance will be called hereinafter substance C.
  • the adipocytes have demonstrated during the past few years endocrine and secretory cell functions (Ailhaud G. et al. Médecine/Science 1998, 14, 858-864). Leptin perfectly illustrates this new secretory function of the adipocyte. This protein is specifically produced by the mature adipocyte. It is involved in controlling satiety; it is also thought to be involved in the regulation of fatty deposits. The adipocyte is thus responsible for the production of factors with autocrine and paracrine activity which will modulate the physiology of the adipose tissue.
  • LPA lisophosphatidic acid
  • IL-6 which is a multifunctional cytokine.
  • Substance C is known as an inducer of the production of IL-6 by the keratinocytes. Its method of production is described in international patent application WO 99/40896. It exerts an effect on skin ageing.
  • adipose cells could produce IL-6 whose function at the adipocyte level consists in repressing the synthesis of LPL, the enzyme responsible for the entry of fatty acids into the adipose cell (Greenberg A. S. et al. Cancer Research 1992, 52, 4113-4116).
  • IL-6 The production of IL-6 by the cells of the subcutaneous adipose tissue is positively correlated with an increase in the body mass index (Mohamed Ali V. et al. J. Clin. Endocrinol. Metab. 1997, 82, 4196-4200) but also differs according to the origin of the adipose tissue.
  • the basal adipocytes collected from the omental region releases 2 to 3 times more IL-6 than the subcutaneous adipocytes (Fried S. K. et al. J. Clin. Endocrinol. Metab. 1998, 83, 847-860).
  • IL-6 could also act, through inhibition, on the differentiation of the adipocyte-precursor cells (Hauner H. et al. 8th International Congress on obesity 1999, 47-53).
  • IL-6 therefore appears as a cytokine which has an autocrine action (on LPL) and a paracrine action (on the preadipocytes) for slowing down the development of the subcutaneous adipose tissue.
  • IL-6 is a pleiotropic glycoprotein, that is to say that it exhibits different effects depending on the cell producing it.
  • IL-6 will have effects of a completely different type to those already known with the keratinocyte.
  • the IL-6 synthesized by the cell down-regulates the content and therefore the activity of the enzyme which is responsible for the entry of fats.
  • compositions according to the invention make it possible to control the phenomena of entry and outflow of fatty acids including storage and hypertrophy of the adipocytes. It also makes it possible to act on adipocyte hyperplasia.
  • adipose tissue results from an increase in the size of the adipocytes following the excessive accumulation of fatty acids, as well as from the recruitment of new fatty cells obtained from the multiplication and differentiation of adipocyte-precursor cells, the preadipocytes (Valet P. et al. J. Clin. Invest. 1998, 101(7), 1431-1438).
  • This recruitment of new adipocytes is mediated by soluble factors produced by the hypertrophied adipocytes: in particular by LPA via the stimulation of the ⁇ 2 receptor, and by IL-6 via its controlling power on preadipocyte differentiation.
  • the blocking of the ⁇ 2 receptor is therefore such as to allow, in parallel with its beneficial effect on lipolysis, repression of the release of LPA, with, as advantage, an inhibition of the recruitment of new adipocytes.
  • IL-6 limits the maturation of the preadipocytes into differentiated adipocytes.
  • the adipocyte stimulation of the production of this cytokine by the inducer of IL-6 reinforces this property.
  • the combination of substance B, inhibitor of the receptor, and of substance C, inducer of IL-6, is therefore such as to allow an increased and innovative efficacy on the hyperplasia of the fatty cells.
  • the addition of substance A to this combination makes it possible to obtain a slimming composition which acts on several mechanisms of action, namely hypertrophy and hyperplasia.
  • a slimming cosmetic composition has now been prepared, according to the invention, which contains substances A, B and C and which will be called hereinafter Am2.
  • 3T3-L1 The biological effects of substance C in vitro has been studied on the murine line 3T3-L1.
  • This preadipocyte line routinely cultured in DMEM medium (Dubelco's Minimum Essential Medium) enriched with 10% foetal calf serum has the property of differentiating into mature adipocytes in the presence of inducers such as insulin and indomethacin (Slieker L. J. Biochem. Biophys. Res. Com. 1998, 251, 225-229).
  • inducers such as insulin and indomethacin
  • This passage from the stage of immature cell to the stage of functional adipocyte can be morphologically assessed by the appearance of intracytoplasmic lipid storage vesicles which are visible under the microscope or which can be biochemically detected by measuring the production of leptin, the hormone for satiety produced solely by mature adipocytes.
  • the influence of substance C on the adipocyte activity was evaluated at two levels. On the one hand, by measuring the capacity of this active agent to modulate the production of adipocyte IL-6 and, on the other hand, by evaluating its effect on differentiation into mature adipocytes.
  • Mature adipocytes 3T3-L1 (harvested after 10 days of differentiation induced by the insulin (5 ⁇ g/ml) and indomethacin (125 ⁇ m) combination) are stimulated with substance C at 1% (v/v) for 24 hours. The culture supernatant is then removed and its IL-6 content measured by ELISA (Enzyme Linked Immunosorbent Assay) according to the supplier's instructions (R&D Systems, Abingdon, GB).
  • ELISA Enzyme Linked Immunosorbent Assay
  • the quantity of IL-6 secreted is compared with that of a control culture treated only with the solvent for substance C (ethanol/water (50/50) mixture, diluted 1/100 in the culture medium) and of a culture stimulated with a reference IL-6 inducer, TNF- ⁇ at 50 ng/ml (Fried S. K. J. Clin. Endocrinol. Metab. 1998, 83, 847-860).
  • FIG. 1 shows that substance C stimulates the production of IL-6 from the adipocytes 3T3-L1 by a factor of about 5 compared with the solvent control culture (43 pg/ml against 9 pg/ml respectively), that is 83% of the effect obtained with the reference inducer (52 pg/ml).
  • the objective of this second study was to identify the effects of substance C on the formation of new adipocytes.
  • substance C The influence of substance C on the differentiation of the preadipocytes 3T3-L1 into mature adipocytes is studied, on the one hand, by evaluating the synthesis of the hormone leptin, a marker of adipocyte differentiation, and, on the other hand, by observing under the microscope the formation of intracytoplasmic lipid vesicles, other indicators of the functional transformation into mature adipocytes.
  • substance C is introduced into the culture at 1% (v/v) at the beginning of the differentiation process (induced as above) and maintained up to its end.
  • the synthesis of leptin is evaluated every two days by ELISA assay (R&D Systems, Abingdon, GB).
  • FIG. 2 shows that in the presence of substance C, the production of leptin remains at an extremely low level thoughout the 10 days of the experiment and is markedly lower ( ⁇ 200 pg/ml) than that observed in the control culture which, as expected, sees its leptin level increase from the 2nd day following the induction of differentiation, and increases up to a maximum plateau of 1200-1400 pg/ml from the 6th day.
  • the inhibition of the synthesis of leptin by substance C constitutes the first parameter for the blocking of the adipocyte differentiation process.
  • the second is provided by the experiment shown in FIG. 3 which indicates that after 10 days of differentiation, the control cells develop a morphology of mature adipocytes containing large lipid vesicles which occupy practically the entire cytoplasmic space (A), whereas the same cells treated with substance C remain at a very immature stage with a few rare vesicles which are much smaller in size (B).
  • substance C has the dual property of stimulating, in mature adipocytes, the production of IL-6 and of inhibiting, in precursor cells, the transformation into mature adipocytes.
  • Substance C therefore acts upstream by preventing adipocyte maturation and downstream by stimulating, at the level of the mature adipocytes, the production of a cytokine which is involved in limiting the storage of fatty acids.
  • composition Am2 contains the 3 active substances (hereinafter called composition Am2).
  • the first relates to the measurement of the thickness of the subcutaneous adipose tissue, and the second uses the centimetric measurement.
  • the objective of this study is to evaluate the clinical efficacy of the novel composition Am2 containing the 3 active substances.
  • the products are applied twice per day over the whole of the thighs by a circular massage which is stopped after complete penetration of the product.
  • the evaluation of the efficacy was determined over a period of 2 months by measuring the thickness of the subcutaneous adipose tissue at T 0 , T 28 days , T 56 days .
  • the method used is that of echography.
  • the site for the measurement is identified by a skin marking and by the height at which the probe is positioned.
  • the echographic probe is placed on a stable device, which can be adjusted in height and independently of the operator.
  • the average weight remained stable during the entire duration of the study and is not therefore likely to be responsible for the variation in the measurement of the thickness of the subcutaneous adipose tissue of the thighs.
  • composition Am1 after 1 month of application, a reduction of 0.8% of the subcutaneous adipose tissue is observed and at 2 months a reduction of 2.6% is observed.
  • composition Am2 makes it possible to obtain a very significant slimming effect from the 28th day of application (p ⁇ 10 ⁇ 5 ): the reduction in the subcutaneous adipose tissue observed with composition Am2 is ⁇ 2.2% at 1 month and ⁇ 4.3% at 2 months of application.
  • the products are applied twice per day for 2 months.
  • the evaluation of the slimming efficacy was evaluated by centimetry at T 0 , T 28 days and T 56 days at the level of the thighs (at 3 cm below the buttock fold), on the right and on the left.
  • the average weight is substantially constant during the entire duration of the study and is not therefore likely to be responsible for the variations in the measurement of the thickness of the subcutaneous adipose tissue of the various regions studied.
  • Table 1 presents the significant results obtained by centimetry. TABLE 1 Results obtained by centimetry % of subjects Reduction range COMPOSITION 1 month 2 months 1 month 2 months Composition Am1 30 45 1-2.0 cm 1-2.0 cm Composition Am2 72 73 1-3.5 cm 1-2.5 cm
  • composition Am2 has a better slimming activity versus T 0 than composition Am1, from one month of application.
  • the extracts thus constituted are mixed with aqueous or nonaqueous solvents and with conventional diluents which are compatible with a topical use as well as with the active components of the same composition.
  • aqueous or nonaqueous solvents and with conventional diluents which are compatible with a topical use as well as with the active components of the same composition.
  • Appropriate solvents and/or diluents will be chosen according to their capacity to transport the active component of the extract of the invention into the subcutaneous adipose layer.
  • compositions generally contain excipients or additives chosen from the ingredients usually used in compositions intended for local application depending on the requirement of the particular formulations envisaged.
  • They may contain, for example, thickening agents, demulcents, emollients, stabilizers, preservatives, antifoaming agents, surfactants, antioxidants, colorants and/or pigments, and perfumes.
  • They may also contain other active components which have either an effect of the same type, for example products which contribute to the regulation of lipolysis/lipogenesis or products useful in this type of topical composition such as stimulators of the synthesis of collagen, inhibitors of collagenase or of elastase, and vasoprotective agents.
  • the cosmetic compositions of the present invention contain substances A, B or C in proportions of between 0.00001% and 5% relative to the total weight of the composition, in the form of a mixture with the excipients commonly used for the preparation of cosmetic formulations to be applied to the skin.
  • components A, B and C are present in proportions of 0.0001% to 2%.
  • compositions according the invention is a fluid which is topically applied by means of an adhesive support, designated hereinafter “patch”, this patch allowing controlled diffusion of the active components.
  • compositions of the present invention have good stability and can be preserved for the period necessary for use at temperatures between 0° C. and 60° C. without there being sedimentation of the constituents or separation of the phases, or a reduction in activity which can compromise their use.
  • compositions are very well tolerated; they exhibit no phototoxicity and their application to the skin, for prolonged periods, involves no side effect.
  • the skin relief is smooth, the skin becomes more tonic and firm. After applying for one month, the slimming effect appears, the “orange skin” appearance visibly diminishes and the figure becomes slimmer.

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US11/192,845 1999-11-05 2005-07-28 Slimming cosmetic composition containing a substance inducing the production of IL-6 Abandoned US20050281895A1 (en)

Priority Applications (2)

Application Number Priority Date Filing Date Title
US11/192,845 US20050281895A1 (en) 1999-11-05 2005-07-28 Slimming cosmetic composition containing a substance inducing the production of IL-6
US12/259,575 US8628770B2 (en) 1999-11-05 2008-10-28 Slimming cosmetic composition containing a substance inducing the production of IL-6

Applications Claiming Priority (5)

Application Number Priority Date Filing Date Title
FR9913917 1999-11-05
FR9913917A FR2800610B1 (fr) 1999-11-05 1999-11-05 Composition cosmetique amincissante contenant une substance inducteur de la production d'il-6
PCT/FR2000/003048 WO2001032137A1 (fr) 1999-11-05 2000-11-02 Composition amincissante contentant une substance inducteur de la production d'il-6
US12930902A 2002-08-05 2002-08-05
US11/192,845 US20050281895A1 (en) 1999-11-05 2005-07-28 Slimming cosmetic composition containing a substance inducing the production of IL-6

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PCT/FR2000/003048 Continuation WO2001032137A1 (fr) 1999-11-05 2000-11-02 Composition amincissante contentant une substance inducteur de la production d'il-6
US10129309 Continuation 2000-11-02
US12930902A Continuation 1999-11-05 2002-08-05

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US12/259,575 Continuation US8628770B2 (en) 1999-11-05 2008-10-28 Slimming cosmetic composition containing a substance inducing the production of IL-6

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US12/259,575 Expired - Fee Related US8628770B2 (en) 1999-11-05 2008-10-28 Slimming cosmetic composition containing a substance inducing the production of IL-6

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US (2) US20050281895A1 (ru)
EP (1) EP1229895B1 (ru)
JP (1) JP2003513029A (ru)
KR (1) KR20020063887A (ru)
CN (1) CN1236757C (ru)
AR (1) AR026349A1 (ru)
AT (1) ATE537810T1 (ru)
AU (1) AU782931B2 (ru)
BR (1) BR0015323A (ru)
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CO (1) CO5271719A1 (ru)
ES (1) ES2379768T3 (ru)
FR (1) FR2800610B1 (ru)
HK (1) HK1046855A1 (ru)
HR (1) HRP20020390A2 (ru)
HU (1) HU229027B1 (ru)
IL (2) IL149338A0 (ru)
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NO (1) NO330136B1 (ru)
PL (1) PL201755B1 (ru)
RU (1) RU2258500C2 (ru)
TR (1) TR200201214T2 (ru)
TW (1) TWI253938B (ru)
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US7323162B2 (en) * 2002-12-27 2008-01-29 Avon Products, Inc. Aqueous cosmetic coloring and gloss compositions having film formers

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3793153A (en) * 1970-06-06 1974-02-19 Y Miura Method for propagating yeasts and molds by mixed culturing and method of fermentation thereof
US5194259A (en) * 1990-11-28 1993-03-16 L'oreal Slimming composition based on ginkgo biloba as an alpha-2-blocker
US5637316A (en) * 1993-12-30 1997-06-10 L'oreal Slimming composition for topical treatment, containing two types of liposomes, and use thereof
US5827853A (en) * 1996-10-23 1998-10-27 Sanofi Cosmetic composition containing a neuropeptide Y receptor antagonist

Family Cites Families (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
FR2758724B1 (fr) * 1997-01-24 1999-04-23 Javenech Composition topique a base de protamine pour le traitement de la cellulite et des surcharges ponderales
FR2774695B1 (fr) 1998-02-11 2002-06-14 Sanofi Sa Composition cosmetique contenant un compose a activite stimulatrice de la production d'interleukine-6

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3793153A (en) * 1970-06-06 1974-02-19 Y Miura Method for propagating yeasts and molds by mixed culturing and method of fermentation thereof
US5194259A (en) * 1990-11-28 1993-03-16 L'oreal Slimming composition based on ginkgo biloba as an alpha-2-blocker
US5637316A (en) * 1993-12-30 1997-06-10 L'oreal Slimming composition for topical treatment, containing two types of liposomes, and use thereof
US5843476A (en) * 1993-12-30 1998-12-01 L'oreal Slimming composition for topical treatment, containing two types of liposomes, and use thereof
US5827853A (en) * 1996-10-23 1998-10-27 Sanofi Cosmetic composition containing a neuropeptide Y receptor antagonist
US6114336A (en) * 1996-10-23 2000-09-05 Sanofi Cosmetic composition containing a neuropeptide Y receptor antagonist

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JP2003513029A (ja) 2003-04-08
CA2390129A1 (fr) 2001-05-10
WO2001032137A1 (fr) 2001-05-10
IL149338A0 (en) 2002-11-10
AU1285901A (en) 2001-05-14
RU2258500C2 (ru) 2005-08-20
ES2379768T3 (es) 2012-05-03
HUP0203910A2 (hu) 2003-04-28
EP1229895A1 (fr) 2002-08-14
ATE537810T1 (de) 2012-01-15
KR20020063887A (ko) 2002-08-05
US20090123455A1 (en) 2009-05-14
HRP20020390A2 (en) 2003-10-31
CN1420759A (zh) 2003-05-28
AU782931B2 (en) 2005-09-08
IL149338A (en) 2006-10-31
PL201755B1 (pl) 2009-05-29
CA2390129C (fr) 2012-08-21
NO330136B1 (no) 2011-02-21
CN1236757C (zh) 2006-01-18
EP1229895B1 (fr) 2011-12-21
PL355259A1 (en) 2004-04-05
AR026349A1 (es) 2003-02-05
FR2800610A1 (fr) 2001-05-11
HUP0203910A3 (en) 2005-11-28
UY26428A1 (es) 2001-05-31
US8628770B2 (en) 2014-01-14
FR2800610B1 (fr) 2001-12-28
RU2002112243A (ru) 2004-01-27
NO20022144D0 (no) 2002-05-03
BR0015323A (pt) 2002-07-09
TR200201214T2 (tr) 2002-08-21
TWI253938B (en) 2006-05-01
CO5271719A1 (es) 2003-04-30
HU229027B1 (en) 2013-07-29
MXPA02004518A (es) 2002-10-23
NO20022144L (no) 2002-06-20
HK1046855A1 (zh) 2003-01-30

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