WO2008116602A1 - Cosmetic preparations designed to reduce unsightly cellulite - Google Patents

Cosmetic preparations designed to reduce unsightly cellulite Download PDF

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Publication number
WO2008116602A1
WO2008116602A1 PCT/EP2008/002261 EP2008002261W WO2008116602A1 WO 2008116602 A1 WO2008116602 A1 WO 2008116602A1 EP 2008002261 W EP2008002261 W EP 2008002261W WO 2008116602 A1 WO2008116602 A1 WO 2008116602A1
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Prior art keywords
compound
composition
formula
cellulite
cosmetic
Prior art date
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PCT/EP2008/002261
Other languages
French (fr)
Inventor
Alberto Aleotti
Original Assignee
A.Menarini Industrie Farmaceutiche Riunite S.R.L.
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.)
Filing date
Publication date
Priority to US12/530,257 priority Critical patent/US7989008B2/en
Priority to EP08716661A priority patent/EP2139862A1/en
Priority to NZ579918A priority patent/NZ579918A/en
Priority to BRPI0809280-0A2A priority patent/BRPI0809280A2/en
Priority to CA002682039A priority patent/CA2682039A1/en
Priority to JP2010500121A priority patent/JP2010522222A/en
Priority to MX2009010330A priority patent/MX2009010330A/en
Priority to CN2008800096882A priority patent/CN101652349B/en
Application filed by A.Menarini Industrie Farmaceutiche Riunite S.R.L. filed Critical A.Menarini Industrie Farmaceutiche Riunite S.R.L.
Priority to AU2008232003A priority patent/AU2008232003B2/en
Publication of WO2008116602A1 publication Critical patent/WO2008116602A1/en
Priority to TNP2009000315A priority patent/TN2009000315A1/en
Priority to EC2009009625A priority patent/ECSP099625A/en
Priority to IL201159A priority patent/IL201159A0/en
Priority to MA32301A priority patent/MA31328B1/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
    • C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
    • C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D231/14—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D231/18—One oxygen or sulfur atom
    • C07D231/20—One oxygen atom attached in position 3 or 5
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • 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

Definitions

  • This invention relates to a derivative of aryldimethylpyrazolone useful for the treatment of cellulite, and compositions containing it.
  • Cellulite or "oedematous-fibrosclerotic panniculopathy" is a disorder that affects the hypodermis, a tissue situated below the dermis, which has a mainly adipose nature.
  • Cellulite almost exclusively affects women, and is suffered by approximately 80-85% of the post-adolescent female population, mostly Caucasian, especially those with the "Mediterranean” skin type. Even slim women tend to present more marked adipose accumulations on the thighs.
  • Cellulite is caused by slowing of the venous and lymphatic microcirculation in the adipose tissue, leading to impairment of its most important metabolic functions and an increase in tissue toxins.
  • the visible consequence of this degeneration of the subcutaneous adipose tissue is fluid retention, due to fluid stagnation in the intercellular spaces, and an increase in the volume of the adipose cells.
  • Cellulite has a number of genetic (familial predisposition), constitutional, hormonal and vascular causes, often aggravated by a sedentary lifestyle, stress, smoking, liver disease, hormonal imbalances, incorrect diet, intestinal disorders or disorders characterised by marked fluid retention.
  • Cellulite is mainly a cosmetic problem, and must be considered in that light. At present, cellulite is commonly treated with: 1. physical remedies (laser treatment, iontophoresis, ultrasound treatment and ozone treatment);
  • diet supplements mineral salts (especially potassium), vitamins, plant extracts (which are believed to increase lipid metabolism), diuretics, bowel regulators and bioflavonoids (active on the microcirculation);
  • pharmacologically active products such as caffeine, aminophylline, levothyroxine and escin.
  • cosmetic compositions for the treatment of cellulite mainly contain plant extracts such as extracts of Centella asiatica, Ginkgo biloba, birch and escin, which is extracted from the horse chestnut tree.
  • EP692250 describes the use of flavones to improve the microcirculation.
  • GB1588501 , FR2797765, EP1261310 and EP1259221 describe the cosmetic use of xanthine to activate lipolysis.
  • WO2006063714 describes the use of some aryldimethylpyrazolones to prepare formulations suitable for the treatment of cellulite.
  • Aryldimethylpyrazolones had been previously described by Edmondson et al. in Bioorganic & Medicinal Chemistry Letters (2003), 13, 3983-3987, as potent, selective PDE3B inhibitors. Description of the invention
  • a new aryldimethylpyrazolone derivative has now been found which is surprisingly effective in reducing unsightly cellulite.
  • a first aspect of the invention consequently relates to the compound 5- ⁇ 4-[2-(4-fluoro-benzyl)-3- oxo-cyclohex-i-enylamine ⁇ .S-difluoro-phenylJ ⁇ -dimethyl ⁇ -dihydro- pyrazol-3-one of formula (I):
  • the compound of formula (I) can be salified with cosmetically acceptable acids chosen from among inorganic acids such as hydrochloric, sulphuric or phosphoric acid, or organic acids chosen from among acetic, propionic, succinic, fumaric, lactic, glycolic, citric and tartaric acid.
  • cosmetically acceptable acids chosen from among inorganic acids such as hydrochloric, sulphuric or phosphoric acid, or organic acids chosen from among acetic, propionic, succinic, fumaric, lactic, glycolic, citric and tartaric acid.
  • compositions according to the invention relates to a cosmetic composition containing the compound of formula (I) as active ingredient, preferably at the concentration of 0.1 to 2% by weight, more preferably 0.1 to 1% by weight, and even more preferably 0.2 to 0.5% by weight.
  • the compositions according to the invention improve the compactness of the skin and the body tone, minimising the orange-peel appearance and simultaneously moisturising and smoothing the skin, thus visibly improving its elasticity.
  • Formulations according to the invention can also contain a compound, a mixture of compounds or an extract which are active on the microcirculation, preferably a saponin or flavone, possibly of extractive origin. Extracts of Ginkgo biloba, arnica, pineapple, dong quai (Angelica siniensis), Centella asiatica and the saponin escin are particularly preferred.
  • the compound, extract or mixture of substances active on the microcirculation can be present in the composition at concentrations ranging between 0.1 and 4%.
  • the formulations according to the invention can also contain cosmetically acceptable excipients such as adjuvants, in particular water or alcohols (ethanol), vitamins, in particular tocopherol, dexpanthenol or retinol palmitate, thickeners, preservatives, protective colloids, humidifiers, fragrances, electrolytes, moisturisers, gelling agents, agents that increase permeability through the skin, polymers or copolymers, emulsifiers, emulsion stabilisers and other cosmetically acceptable excipients.
  • the topical formulations can contain polyunsaturated fatty acids known as omega 3, including 10-trans-12-cis linoleic acid and docosahexenoic acid.
  • hypoallergenic substances such as ethyl alcohol or benzyl alcohol as preservatives.
  • Particularly suitable gelling agents include carbomer, especially carbomer 940, polyacrylamide isoparaffin-laureth-7, xanthan gum, carrageenan, gum acacia, guar gum, agar gel, alginates and methylhydroxycellulose, carboxymethylcellulose, hydroxypropylcellulose, hydroxypropyl methylcellulose, hydroxyethylcellulose, ethylcellulose, polyacrylates, polyvinyl alcohol, polyvinylpyrrolidone and colloidal silicon dioxide.
  • Urea and panthenol are examples of moisturisers according to the invention.
  • compositions according to the invention may take the form of a gel, spray-gel, cream, non-oily cream, non-oil formulations, ointments or hydroalcoholic lotions.
  • the techniques for the preparation of the pharmaceutical compositions according to the invention would be known to one skilled in the art, and are described, for example, in Remington's Pharmaceutical Sciences, 18th ed.,
  • composition according to the invention in the form of a non-oily cream could contain:
  • Example 1 Non-oily cream (% composition)
  • Example 6 non-oily cream (% composition)
  • Liquid-crystal thermography was used to conduct an indirect instrumental assessment of the efficacy of the treatment. On the basis of the surface temperature, this technique distinguishes between normal adipose tissue and tissue affected by cellulite, in which the reduced blood flow causes progressive cooling of the skin, proportional to the severity of the cosmetic problem.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Public Health (AREA)
  • General Health & Medical Sciences (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Engineering & Computer Science (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Animal Behavior & Ethology (AREA)
  • Diabetes (AREA)
  • Obesity (AREA)
  • Hematology (AREA)
  • Child & Adolescent Psychology (AREA)
  • Dermatology (AREA)
  • Cosmetics (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Medicines Containing Plant Substances (AREA)
  • Medicinal Preparation (AREA)

Abstract

The invention relates to a new derivative of aryldimethylpyrazolone of formula (I) which is effective in reducing unsightly cellulite, and compositions containing it.

Description

COSMETIC PREPARATIONS DESIGNED TO REDUCE UNSIGHTLY CELLULITE
Field of invention
This invention relates to a derivative of aryldimethylpyrazolone useful for the treatment of cellulite, and compositions containing it.
Background to the invention Cellulite, or "oedematous-fibrosclerotic panniculopathy", is a disorder that affects the hypodermis, a tissue situated below the dermis, which has a mainly adipose nature. Cellulite almost exclusively affects women, and is suffered by approximately 80-85% of the post-adolescent female population, mostly Caucasian, especially those with the "Mediterranean" skin type. Even slim women tend to present more marked adipose accumulations on the thighs.
Cellulite is caused by slowing of the venous and lymphatic microcirculation in the adipose tissue, leading to impairment of its most important metabolic functions and an increase in tissue toxins. The visible consequence of this degeneration of the subcutaneous adipose tissue is fluid retention, due to fluid stagnation in the intercellular spaces, and an increase in the volume of the adipose cells.
Cellulite has a number of genetic (familial predisposition), constitutional, hormonal and vascular causes, often aggravated by a sedentary lifestyle, stress, smoking, liver disease, hormonal imbalances, incorrect diet, intestinal disorders or disorders characterised by marked fluid retention.
Cellulite is mainly a cosmetic problem, and must be considered in that light. At present, cellulite is commonly treated with: 1. physical remedies (laser treatment, iontophoresis, ultrasound treatment and ozone treatment);
2. diet supplements: mineral salts (especially potassium), vitamins, plant extracts (which are believed to increase lipid metabolism), diuretics, bowel regulators and bioflavonoids (active on the microcirculation);
3. mesotherapy using the following active constituents: coenzyme A, phosphatidylcholine, aminophylline, escin or homeopathic products;
4. pharmacologically active products such as caffeine, aminophylline, levothyroxine and escin. There are numerous cosmetic compositions for the treatment of cellulite on the market. They mainly contain plant extracts such as extracts of Centella asiatica, Ginkgo biloba, birch and escin, which is extracted from the horse chestnut tree.
Others contain compounds such as caffeine, β-adrenergic stimulants and methylxanthine. Their cosmetic efficacy is dubious, and the observable improvements are often due to the diet and massage associated with the application of those compositions.
EP692250 describes the use of flavones to improve the microcirculation. GB1588501 , FR2797765, EP1261310 and EP1259221 describe the cosmetic use of xanthine to activate lipolysis.
WO2006063714 describes the use of some aryldimethylpyrazolones to prepare formulations suitable for the treatment of cellulite. Aryldimethylpyrazolones had been previously described by Edmondson et al. in Bioorganic & Medicinal Chemistry Letters (2003), 13, 3983-3987, as potent, selective PDE3B inhibitors. Description of the invention
A new aryldimethylpyrazolone derivative has now been found which is surprisingly effective in reducing unsightly cellulite. A first aspect of the invention consequently relates to the compound 5-{4-[2-(4-fluoro-benzyl)-3- oxo-cyclohex-i-enylamine^.S-difluoro-phenylJ^^-dimethyl^^-dihydro- pyrazol-3-one of formula (I):
Figure imgf000004_0001
(I) The compound of formula (I) can be salified with cosmetically acceptable acids chosen from among inorganic acids such as hydrochloric, sulphuric or phosphoric acid, or organic acids chosen from among acetic, propionic, succinic, fumaric, lactic, glycolic, citric and tartaric acid.
Another aspect of the invention relates to a cosmetic composition containing the compound of formula (I) as active ingredient, preferably at the concentration of 0.1 to 2% by weight, more preferably 0.1 to 1% by weight, and even more preferably 0.2 to 0.5% by weight. The compositions according to the invention improve the compactness of the skin and the body tone, minimising the orange-peel appearance and simultaneously moisturising and smoothing the skin, thus visibly improving its elasticity.
Formulations according to the invention can also contain a compound, a mixture of compounds or an extract which are active on the microcirculation, preferably a saponin or flavone, possibly of extractive origin. Extracts of Ginkgo biloba, arnica, pineapple, dong quai (Angelica siniensis), Centella asiatica and the saponin escin are particularly preferred.
The compound, extract or mixture of substances active on the microcirculation can be present in the composition at concentrations ranging between 0.1 and 4%.
The formulations according to the invention can also contain cosmetically acceptable excipients such as adjuvants, in particular water or alcohols (ethanol), vitamins, in particular tocopherol, dexpanthenol or retinol palmitate, thickeners, preservatives, protective colloids, humidifiers, fragrances, electrolytes, moisturisers, gelling agents, agents that increase permeability through the skin, polymers or copolymers, emulsifiers, emulsion stabilisers and other cosmetically acceptable excipients. The topical formulations can contain polyunsaturated fatty acids known as omega 3, including 10-trans-12-cis linoleic acid and docosahexenoic acid.
It is preferable to use hypoallergenic substances such as ethyl alcohol or benzyl alcohol as preservatives.
Particularly suitable gelling agents include carbomer, especially carbomer 940, polyacrylamide isoparaffin-laureth-7, xanthan gum, carrageenan, gum acacia, guar gum, agar gel, alginates and methylhydroxycellulose, carboxymethylcellulose, hydroxypropylcellulose, hydroxypropyl methylcellulose, hydroxyethylcellulose, ethylcellulose, polyacrylates, polyvinyl alcohol, polyvinylpyrrolidone and colloidal silicon dioxide. Urea and panthenol are examples of moisturisers according to the invention.
The compositions according to the invention may take the form of a gel, spray-gel, cream, non-oily cream, non-oil formulations, ointments or hydroalcoholic lotions. The techniques for the preparation of the pharmaceutical compositions according to the invention would be known to one skilled in the art, and are described, for example, in Remington's Pharmaceutical Sciences, 18th ed.,
Mack Publishing Co.. For example, a composition according to the invention in the form of a non-oily cream (100 g) could contain:
Active ingredient. % by weight
- Compound of formula (I) 0.2 - 0.5 - escin (optional) 1-3
Excipients:
- (glyceryl monostearate, macrogol cetostearyl ether, liquid paraffin, white vaseline, isopropyl myristate, myristyl alcohol, and p-hydroxybenzoic acid esters) 20-25 - purified water q.s. for 100 g
In view of the structural similarity between the compound of formula (I) and other compounds previously described (WO2006063714 and Bioorganic & Medicinal Chemistry Letters (2003), 13, 3983-3987), some comparative tests have been conducted of formulations containing: A) 3-[2-[4-(4,4-dimethyl-5-oxo-4,5-dihydro-1-H-pyrazol-3-yl)-2)3- difluoro-phenylaminel-θ-oxocyclohex-i-enylmethylj-benzonitrile (hereinafter called "compound A", which corresponds to compound 18n described by Edmondson et al. in Bioorganic & Medicinal Chemistry Letters (2003), 13, 3983-398); B) 5-{4-[2-(4-fluoro-benzyl)-3-oxo-cyclohex-1 -enylamine]-2-fluoro- phenyl}-4,4-dimethyl-2,4-dihydro-pyrazol-3-one (hereinafter called "compound B", which corresponds to compound 18k described by Edmondson et al. in Bioorganic & Medicinal Chemistry Letters (2003), 13, 3983-398); at the concentration of 0.3% by weight. The cosmetic formulations according to the invention containing the compound of formula (I) have proved significantly more effective in reducing unsightly cellulite.
The following examples illustrate the invention without limiting it in any way.
Examples
Example 1 : Non-oily cream (% composition)
Active ingredient
Compound of formula (I) 0.2 escin 2
Excipients: glyceryl monostearate 8 macrogol cetostearyl ether 2.5 liquid paraffin 2 white vaseline 2 isopropyl myristate 4 myristyl alcohol 3 p-hydroxybenzoic acid esters 0.3 purified water q.s. for 100 g
Example 2: Non-oily cream (% composition)
Active ingredient
Compound of formula (I) 0.3
Excipients: cetostearyl alcohol 4.5 glyceryl monostearate 8.0 liquid paraffin 2 white vaseline 2 dimethicone 0.30 isopropyl myristate 1 myristic alcohol 3 essential oils q.s. purified water q.s. for 100 g Example 3: Non-oily cream (% composition)
Active ingredient
Compound of formula (I) 0.5
Excipients: oleic acid 5.0 macrogol stearate 40 9.0 cetostearyl alcohol 6.0 butyl hydroxyanisole 0.02 trometamol 0.1 dimethicone 0.3
Carbopol 980 0.3 propylene glycol 20.0 sodium sulphite 0.1 essential oils q.s. purified water q.s. for 100 g
Example 4: Hydroalcoholic gel (% composition)
Active ingredient
Compound of formula (I) 0.2
Excipients carbomer 1.5
96° ethyl alcohol EP 40 ml essential oils q.s. triethanolamine q.s. to adjust pH purified water q.s. for 100 g Example 5: Lipophilic cream (% composition)
Active ingredient
Compound of formula (I) 0.3
Excipients polyglyceryl-3 diisostearate 4 glyceryl oleate 2 beeswax 7 dicapryl ether 10 hexyldecanol/hexyldecyl laurate 10
85% glycerin 5 magnesium sulphate 7HbO 1 p-hydroxybenzoic acid esters 0.1 essential oils q.s. purified water q.s. for 100 g
Example 6 (comparative): non-oily cream (% composition)
Active ingredient
Compound A 0.3
Excipients: cetostearyl alcohol 4.5 glyceryl monostearate 8.0 liquid paraffin 2 white vaseline 2 dimethicone 0.30 isopropyl myristate 1 myristic alcohol 3 essential oils q.s. purified water q.s. for 100 g Example 7 (comparative): non-oily cream (% composition)
Active ingredient
Compound B 0.3
Excipients: cetostearyl alcohol 4.5 glyceryl monostearate 8.0 liquid paraffin 2 white vaseline 2 dimethicone 0.30 isopropyl myristate 1 myristic alcohol 3 essential oils q.s. purified water q.s. for 100 g
Efficacy test Cellulite is mainly a cosmetic problem. We therefore examined the cosmetic efficacy of a preparation based on the compound of formula (I) (composition described in example 2) by comparison with a preparation containing product A and product B (compositions described in examples 6 and 7) in reducing unsightly cellulite. Compounds A and B were used as comparators as they are the known compounds most similar to the compound of formula (I).
21 Healthy adult women with evident problems of cellulite in the thigh, hip and buttock areas were divided into three groups. Each group was given a cream chosen from among those described in examples 2, 6 or 7 to be spread on the part of the thigh affected by cellulite and massaged in until absorbed, twice a day every day for two months. The treatment was always to be given on one thigh only so that the other untreated thigh could be used as control. The efficacy of the cosmetic cream was assessed at the end of the period by comparing the treated thigh with the untreated thigh on a 5- point scale. The parameters considered were: reduction of the orange-peel effect, overall appearance of the skin (uniformity and smoothness of the skin, tissue tone and elasticity, moisturisation, considering that of areas distant from those affected by cellulite as ideal), and reduction in thigh circumference. The presence of side effects associated with the treatment, such as redness or itching, was also considered.
The tests clearly demonstrated the satisfaction of the patients treated with the formulation described in example 2, containing the compound of formula (I), which proved much more effective than the formulations described in examples 6 and 7, containing the two comparator compounds.
Figure imgf000011_0001
Liquid-crystal thermography was used to conduct an indirect instrumental assessment of the efficacy of the treatment. On the basis of the surface temperature, this technique distinguishes between normal adipose tissue and tissue affected by cellulite, in which the reduced blood flow causes progressive cooling of the skin, proportional to the severity of the cosmetic problem.
After repeated treatment with compound (I), the difference in temperature between the normal skin area (unaffected by cellulite) and the affected area had reduced considerably, about 70% of the temperature reduction previously observed having been eliminated. The effects of treatment with compounds A and B were evaluated for comparison purposes. Both proved less effective than compound (I), as only some 50% of the temperature difference compared with normal tissue was eliminated.

Claims

1. The compound 5-{4-[2-(4-fluoro-benzyl)-3-oxo-cyclohex-1-enylamine]- 2,3-difluoro-phenyl}-4,4-dimethyl-2,4-dihydro-pyrazol-3-one of formula (I):
Figure imgf000013_0001
(I) and its cosmetically acceptable salts.
2. Cosmetic composition for topical administration containing the compound of formula (I), or a cosmetically acceptable salt thereof, as claimed in claim 1 , for the treatment of cellulite.
3. Composition as claimed in claim 2, containing the compound of formula (I) at the concentration of 0.1 to 2% by weight.
4. Composition as claimed in claim 3, containing the compound of formula (I) at the concentration of 0.1 to 1 % by weight.
5. Composition as claimed in claim 4, containing the compound of formula (I) at the concentration of 0.2 to 0.5% by weight.
6. Composition as claimed in claims 2-5 in the form of gel, spray-gel, cream, non-oily cream, non-oil formulations or ointment.
7. Composition as claimed in claims 1 to 6, also containing a saponin and/or a flavone selected from escin or extracts of Ginkgo biloba, arnica, pineapple, dong quai (Angelica siniensis) and Centella asiatica.
8. Cosmetic composition as claimed in claims 1-7, also containing a polyunsaturated omega-3 fatty acid selected between 10-trans-12-cis linoleic acid and docosahexenoic acid.
9. Use of a compound as claimed in claim 1 for the cosmetic treatment of cellulite.
PCT/EP2008/002261 2007-03-26 2008-03-20 Cosmetic preparations designed to reduce unsightly cellulite WO2008116602A1 (en)

Priority Applications (13)

Application Number Priority Date Filing Date Title
MX2009010330A MX2009010330A (en) 2007-03-26 2008-03-20 Cosmetic preparations designed to reduce unsightly cellulite.
NZ579918A NZ579918A (en) 2007-03-26 2008-03-20 5-{4-[2-(4-fluoro-benzyl)-3-oxo-cyclohex-1-enylamine]-2,3-difluoro-phenyl}-4,4-dimethyl-2,4-dihydro-pyrazol-3-one to reduce unsightly cellulite
BRPI0809280-0A2A BRPI0809280A2 (en) 2007-03-26 2008-03-20 COSMETIC PREPARATIONS DESIGNED TO REDUCE CELLULITE DISORDER
CA002682039A CA2682039A1 (en) 2007-03-26 2008-03-20 Cosmetic preparations designed to reduce unsightly cellulite
JP2010500121A JP2010522222A (en) 2007-03-26 2008-03-20 Cosmetic formulation designed to reduce unsightly cellulite
US12/530,257 US7989008B2 (en) 2007-03-26 2008-03-20 Cosmetic preparations designed to reduce unsightly cellulite
CN2008800096882A CN101652349B (en) 2007-03-26 2008-03-20 Cosmetic preparations designed to reduce unsightly cellulite
EP08716661A EP2139862A1 (en) 2007-03-26 2008-03-20 Cosmetic preparations designed to reduce unsightly cellulite
AU2008232003A AU2008232003B2 (en) 2007-03-26 2008-03-20 Cosmetic preparations designed to reduce unsightly cellulite
TNP2009000315A TN2009000315A1 (en) 2007-03-26 2009-07-30 Cosmetic preparation designed to reduce unsightly cellulite
EC2009009625A ECSP099625A (en) 2007-03-26 2009-09-10 COSMETIC PREPARATIONS DESIGNED TO REDUCE ANTISTETIC CELLULITIS
IL201159A IL201159A0 (en) 2007-03-26 2009-09-24 Cosmetic preparations designed to reduce unsightly cellulite
MA32301A MA31328B1 (en) 2007-03-26 2009-10-22 COSMETIC PREPARATIONS TO REDUCE DISGRACIOUS CELLULITE

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
ITMI2007A604 2007-03-26
IT000604A ITMI20070604A1 (en) 2007-03-26 2007-03-26 COSMETIC PREPARATIONS FOR THE REDUCTION OF CELLULITE IMPRESSIONS

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WO2008116602A1 true WO2008116602A1 (en) 2008-10-02

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EP (1) EP2139862A1 (en)
JP (1) JP2010522222A (en)
CN (1) CN101652349B (en)
AR (1) AR065846A1 (en)
AU (1) AU2008232003B2 (en)
BR (1) BRPI0809280A2 (en)
CA (1) CA2682039A1 (en)
CL (1) CL2008000859A1 (en)
CO (1) CO6231029A2 (en)
EC (1) ECSP099625A (en)
IL (1) IL201159A0 (en)
IT (1) ITMI20070604A1 (en)
MA (1) MA31328B1 (en)
MX (1) MX2009010330A (en)
NZ (1) NZ579918A (en)
PE (1) PE20090065A1 (en)
RU (1) RU2009132190A (en)
TN (1) TN2009000315A1 (en)
TW (1) TW200900089A (en)
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US11523702B1 (en) * 2018-05-10 2022-12-13 Charles F O'Toole, III Infuser implement and method of manufacture

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Publication number Priority date Publication date Assignee Title
WO2006063714A1 (en) * 2004-12-14 2006-06-22 Menarini Ricerche S.P.A. Pharmaceutical compositions for the treatment of cellulite

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2006063714A1 (en) * 2004-12-14 2006-06-22 Menarini Ricerche S.P.A. Pharmaceutical compositions for the treatment of cellulite

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Title
EDMONDSON S D ET AL: "Benzyl vinylogous amide substituted aryldihydropyridazinones and aryldimethylpyrazolones as potent and selective PDE3B inhibitors", BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, OXFORD, GB, vol. 13, no. 22, 17 November 2003 (2003-11-17), pages 3983 - 3987, XP002366774, ISSN: 0960-894X *

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PE20090065A1 (en) 2009-02-13
EP2139862A1 (en) 2010-01-06
RU2009132190A (en) 2011-05-10
AU2008232003B2 (en) 2012-02-02
MA31328B1 (en) 2010-04-01
TN2009000315A1 (en) 2010-12-31
CO6231029A2 (en) 2010-12-20
ITMI20070604A1 (en) 2008-09-27
MX2009010330A (en) 2009-10-16
IL201159A0 (en) 2010-05-17
JP2010522222A (en) 2010-07-01
AU2008232003A1 (en) 2008-10-02
CA2682039A1 (en) 2008-10-02
ECSP099625A (en) 2009-10-30
TW200900089A (en) 2009-01-01
US7989008B2 (en) 2011-08-02
CL2008000859A1 (en) 2008-05-30
BRPI0809280A2 (en) 2014-10-14
AR065846A1 (en) 2009-07-08
CN101652349A (en) 2010-02-17
NZ579918A (en) 2011-05-27
US20100112104A1 (en) 2010-05-06

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