CN101076323A - Medicine composition for treating fatmass - Google Patents
Medicine composition for treating fatmass Download PDFInfo
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- CN101076323A CN101076323A CNA2005800427364A CN200580042736A CN101076323A CN 101076323 A CN101076323 A CN 101076323A CN A2005800427364 A CNA2005800427364 A CN A2005800427364A CN 200580042736 A CN200580042736 A CN 200580042736A CN 101076323 A CN101076323 A CN 101076323A
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Abstract
There are disclosed pharmaceutical compositions for topical administration or for use in mesotherapy, containing a PDE3 inhibitor as active ingredient, and their use in the treatment of cellulite.
Description
The present invention relates to be used for the topical therapeutic of liparitosis (cellulite) or the pharmaceutical preparation of mesoderm treatment (mesotherapeutic treatment), it contains the PDE3 inhibitor as active component, alternatively and other have the active material of anti-liparitosis.
Background of invention
The disease that liparitosis or " edema-fibrosclerosis adipose membrane disease " are a kind of subcutaneous tissue that influences (oedematous-fibroscleroticpanniculopathy)---being positioned at the tissue that corium is following, be mainly fatty character---.Liparitosis almost only influences the women, and approximately the adult female crowd of 80-85% suffers from this disease.Subcutaneus adipose tissue accounts for 25% of women's body weight, and exercises 3 basic functions: a) it provides physics and mechanical protection; B) its release is involved in the lipid and the protein of lipid metabolism; And c) it exercises endocrine and paracrine action.
With regard to statistics, this defective effect is to most of pink toes.This problem is much then rare in the women of other ethnic groups.The easiest this disease of trouble be " Mediterranean " women, generally be since its estrogen supply the more cause of horn of plenty.
Even slender women also often presents more obvious thigh athero.
Some factors have adverse effect, cause to have influence on the microcirculatory localized variation of fatty material.Finally, anatomy and function assessment obstacle that this causes the tissue blood vessel system, the subcutaneous tissue that exerts an influence is the problem of corium with the layer that is close on it.
Liparitosis is caused by microcirculatory degeneration of fatty tissue and the change of its most important metabolic function subsequently.
The visible consequence of this tissue deterioration is that the volume of adipose cell increases, the fluid retention and the fluid stagnation of intercellular substance.
Liparitosis may have the reason of heredity (the easy ill tendentiousness of familial), body constitution, hormone and blood vessel aspect, is often increased the weight of by following: sitting life style, pressure, hepatopathy, bad diet, enteric disorders or be the disease of feature with remarkable fluid retention.
Hormone imbalances (influencing ovary, hypophysis and thyroxin) is the reason that liparitosis takes place; Because estrogenic effect and to microcirculatory influence, the women easily suffers from this disease, especially is in the women in adolescence, trimester of pregnancy and stage premenopause, and this moment, the activity of ovarian hormone was positioned at peak value.
Therefore susceptibility to liparitosis mainly is based on hormone but not the factor of heredity.
The architectural feature of subcutaneous connective tissue has tangible sexual dimorphism, and it is irregular outstanding that this makes women Yi Shengcheng dermal fat roll into a ball distinctive fatty tissue.Propose: the women compares subcutaneus adipose tissue lipotropism fat degrading activity (α 2-adrenergic dependency receptor) and preponderates with the male, can promote the thigh lipidosis to increase, therefore liparitosis (Rosenbaum etc. appear, Plastic and ReconstructiveSurgery, 101 (7): 1934-1939,1998).
In addition, the adipose cell that comes from buttocks, hip or thigh position is lower than the adipose cell that comes from visceral adipose tissue response (Lafontan and the Berlan to catecholamine to the steatolysis response of catecholamine, TIPS, 24:276-283,2003), this makes fatty tissue tend to assemble at these positions.
At present, the common following treatment of liparitosis:
-physiotherapy
Except massage technique, be extensive use of at present as electronics steatolysis and more recent technology such as laser therapy, ionophoresis, ultrasound therapy and ozone therapy; But, these technology all can not tackle the problem at its root.
-meals additive
Numerous meals additives (inorganic salt, especially potassium, vitamin, " agent of combustion fat " or diuresis plant extract, intestinal regulator and bioflavonoids) are arranged on the market, and claiming can increase metabolism, improves circulation, protects cell to avoid damage and reduce fat absorption; But there is not the known effect of supporting these meals additive treatment liparitosiss of effective clinical trial.
-pharmacological activity product
(at 32 kinds of analyzed products that are used for liparitosis, modal active component is a caffeine for 10 (8) 596-603,2000 a research, and it comes across in 14 kinds of medical products according to being published in European J.of Dermatology.
Other widely used chemical compounds are:
A) aminophylline is because it increases the ability of cAMP and lipolysis; Active favourable and unfavorable discovery is all delivered about its anti-liparitosis.
B) levothyroxine, it utilizes thyroxin to increase metabolic ability.In view of the high dose of levothyroxine, general may take place to be absorbed, produce the cardiac stimulation effect subsequently and disturb thyroid, this is especially harmful to the hyperthyroid.
C) aescine is because its vascular protection heparinoid ability.
-mesoderm therapy (mesotherapy)
This technology relates to the local intradermal injection of using with the whole body approach usually of medicine.This method allows a spot of product to be injected directly into the liparitosis position; This technology therefore be non-general and do not have very much an infringement.Use the mesoderm therapy can obtain the long-term treatment effect, because medicine is slower in the absorption of skin level.Being used for the chemical compound that the mesoderm therapy of liparitosis treatment uses at present is coenzyme A, phosphatidylcholine, aminophylline, aescine and homeopathic therapeutic method (homeopathic) product.
Adipose cell is the cell that a kind of size changes easily: lipogenesis then volume increases, and steatolysis then volume reduces.
Lipogenesis is caused by LPL (lipoprotein lipase): close on the synthetic and release LPL of adipose cell capillaceous, its hydrolysis is present in the triglyceride (TG) among very low density lipoprotein (VLDL) (VLDL) and the kilomicron.Glycerol and fatty acid are released, caught by adipose cell, and esterified one-tenth triglyceride.
Steatolysis is caused by hormone-sensitive lipase (HSL): the TG in this enzyme hydrolysis adipose cell is free fatty and glycerol.Organized enzyme is by cAMP deopendent protein kinase A phosphorylation.
CAMP is synthetic to depend on two kinds of opposite enzyme systems:
D) adenyl cyclase, it is converted into cAMP with ATP.It is regulated by α 2-adrenoreceptor negativity, is regulated by the Beta-3 adrenergic receptor positivity.
E) phosphodiesterase, it is decomposed into cAMP to HSL is inert AMP.This activity is subjected to the inhibition of caffeine, theophylline and aminophylline.
In addition, adipose cell is secreted the multiple factor, as leptin (leptin) (satiety factors (satietyfactor)), angiogenesis factor (proangiotensin), Prostaglandin PGE
2(lipotropism fat decomposing property) and PGI
2(cell differentiation), lysophosphatidic acid (cell proliferation) and steroid.
Therapeutic strategy
A series of stages have been experienced in the development of the pharmacological basis of liparitosis treatment.In the eighties, use xanthine (caffeine) to suppress phosphodiesterase (PDE).In the nineties, seek to have the active plant extract of draining and edema (flavonoid and saponins (saponosides)) and solve this problem to improve vein lymphatic function deficiency (venolymphatic insufficiency).More recent, attempted rebuilding connective tissue with extracellular matrix and digestive enzyme component.
But it seems that most promising Therapeutic Method be to be designed for to increase adipose cell metabolism and fat-splitting a kind of method.
Steatolysis is by following initiation: a) B-adrenergic receptor stimulates; B) adenosine or α
2-adrenoreceptor suppresses; C) phosphodiesterase suppresses.
Topical application beta-adrenergic stimulant (isoproterenol (isoprenalin)), α have been estimated in existing a series of clinical experiments
2The effect of-1 adrenergic antagonists (Yohimbine) and phosphodiesterase inhibitor (aminophylline).The result shows: need not go on a diet or take exercise by pharmacological method, can obtain local fat and reduce (Greenway etc., Obes res, 3:561S-568S, 1995).
The stimulation B-adrenergic receptor can increase the cAMP concentration in the adipose cell, therefore stimulates steatolysis.The method of the another kind of cAMP of increasing is to prevent its degraded by suppressing phosphodiesterase.
Modal PDE inhibitor (caffeine, theophylline and aminophylline) is also unsatisfactory, because their specificity is low and the local absorption ability.PDE3, especially PDE3B are present in people's adipose cell; Therefore as if be necessary optionally to suppress the hypotype of these enzymes to obtain to be defined in the effect in the fatty tissue.
Patent about this theme submission:
EP692250 is the purposes about the flavone microcirculation improvement, and GB1588501, FR2797765, EP1261310 and EP1259221 relate to the cosmetic use of xanthine activation lipase.
By the above information that provides as seen, lipolysis activity is necessary but not enough for the treatment of liparitosis.Already used so far Therapeutic Method usually uses phosphodiesterase inhibitor such as xanthine, also is not proved to be to be entirely satisfactory, therefore need especially new, effectively be used for this multifactor, Therapeutic Method that the subcutaneous fat form changes.
At Bioorganic ﹠amp; Medicinal Chemistry Letters, (2003), 13, described one group among the 3983-3987 as selectivity PDE3B inhibitor, potential aryl dihydrogen dazin ketone and the aryl dimethyl pyrazole quinoline ketone compounds that can be used for treating obesity.
Summary of the invention
The inhibitor of the PDE3B isotype of have now found that PDE3 (phosphodiesterase-3) inhibitor, particularly mainly expressing in human fat tissue effectively resists liparitosis surprisingly.
Correspondingly, the invention provides PDE3, preferred PDE3B inhibitor are used for the pharmaceutical composition of the part of liparitosis or mesoderm therapy in preparation purposes.
In the PDE3 inhibitor, preferred compound anagrelide (anagrelide), cilostazol (cilostazoI), pimobendan (pimobendan), milrinone (milrinone), amrinone (amrinone), olprinone, enoximone (enoximone), Cilostamide (cilostamide), vesnarinone (vesnarinone), bent quinolizine (trequinsin) and its pharmaceutically acceptable salt.Preferred especially milrinone, bent quinolizine and Cilostamide.
According to the present invention another to organize preferred PDE3 inhibitor be Bioorganic ﹠amp; MedicinalChemistry Letters, (2003), 13, the chemical compound of describing among the 3983-3987, particularly following chemical compound:
1) 6-[4-(2-benzyl-3-oxo-hexamethylene-1-alkenyl amino)-phenyl]-5-methyl-4,5-dihydro-2-H-pyridazin-3-one (chemical compound 8a)
2) 3-{2-[4-(4,4-dimethyl-5-oxo-4,5-dihydro-1-H-pyrazole-3-yl)-2,3-two fluoro-phenyl aminos]-6-oxo-hexamethylene-1-thiazolinyl methyl }-benzonitrile (chemical compound 18n)
3) 5-{4-[2-(2,6-two chloro-benzyls)-3-oxo-hexamethylene-1-alkenyl amino]-2-fluoro-phenyl }-4,4-dimethyl-2,4-dihydro-pyrazoles-3-ketone (chemical compound 18h)
4) 5-[4-(2-benzyl-3-oxo-hexamethylene-1-alkenyl amino)-phenyl]-4,4-dimethyl-2,4-dihydro-pyrazoles-3-ketone (chemical compound 18a)
5) 5-{4-[2-(3-nitro-benzyl)-3-oxo-hexamethylene-1-alkenyl amino]-2-fluoro-phenyl }-4,4-dimethyl-2,4-dihydro-pyrazoles-3-ketone (chemical compound 18f)
6) 6-[4-(2-benzyl-3-oxo-hexamethylene-1-alkenyl amino)-2-fluoro-phenyl]-5-methyl-4,5-dihydro-2-H-pyridazin-3-one (chemical compound 14)
Term used herein " part " means and is designed for or relates to topical application and effect.Topical compositions is preferably the form of emulsifiable paste, non-oily cream, ointment, oiliness-non-Oily preparation (oil-non oilformulation), gel, spraying-gel and patch.When being used for the mesoderm therapy, compositions should adopt the form that is suitable for local intradermal injection, the form of preferred injection solution.
For the part form, the concentration of active component is 0.1-3%, preferred 1-2% based on composition total weight, and for the injection form that is used for the mesoderm therapy, the concentration of active component is 0.1-1% based on composition total weight.Except the PDE3 inhibitor, can contain mixture or extract according to compositions of the present invention, preferred saponin or flavone or contain their extract to the activated chemical compound of microcirculation, chemical compound.Most preferably extract and the aescine of Semen Ginkgo (Ginkgo biloba), Arnica (arnica), Fructus Ananadis comosi (ananas), Radix Angelicae Sinensis (Angelica siniensis), Herba Centellae (Centella asiatica).
Mixture to the activated chemical compound of microcirculation, extract or material is contained in the compositions with concentration 0.1-4%.
Can further contain pharmaceutically acceptable excipient according to compositions of the present invention, as adjuvant, particularly water or ethanol (ethanol), vitamin, particularly tocopherol, dexpanthenol or retinyl palmitate, thickening agent, antiseptic, protective colloid, wetting agent, aromatic, electrolyte, wetting agent, gellant, enhancer of cutaneous penetration, polymer or copolymer, emulsifying agent, emulsion stabilizer and other pharmaceutically acceptable excipient.
Preferred antiseptic is the Hypoallergenic material, as ethanol or benzyl alcohol.
Topical formulations can contain oleic unsaturated derivant, as 10-anti--12-is suitable-linoleic acid.
Particularly suitable gellant is a carbomer, more preferably Acritamer 940, polyacrylamide, isoparaffin-laureth 9-7, xanthan gum, carrageenin, Radix Acaciae senegalis, guar gum, agar gel, alginate and methyl hydroxylated cellulose, carboxymethyl cellulose, hydroxypropyl cellulose, hydroxypropyl emthylcellulose, hydroxyethyl-cellulose, ethyl cellulose, polyacrylate, polyvinyl alcohol, polyvinylpyrrolidone, colloidal silica.Urea and pantothenylol are the examples according to wetting agent of the present invention.
The technology of preparation pharmaceutical composition of the present invention is known for those skilled in the art, and it for example is described in Remington ' s Pharmaceutical Sciences, and the XVIII version is among the MackPublishing Co..
The pharmaceutical composition of the above-mentioned PDE3 of containing inhibitor is advantageously used in people, preferred women's the liparitosis topical therapeutic.
Following examples are set forth the present invention in more detail.
Embodiment
Embodiment 1. non-oily creams (% weight)
Active component:
Amrinone 1
Aescine 2
Excipient:
Glyceryl monostearate 8
Polyethylene Glycol 16 octadecane alcohol ethers
(Macrogol cetostearyl ether) 2.5
Liquid paraffin 2
White vaseline 2
Isopropyl myristate 4
Myristyl alcohol 3
Right-hydroxybenzoate 0.3
Purified water is in right amount to 100g
Embodiment 1.2
Active component:
Milrinone 1
Excipient:
Cetostearyl alcohol 4.5
Glyceryl monostearate 8.0
Liquid paraffin 2
White vaseline 2
Simethicone 0.30
Isopropyl myristate 1
Myristyl alcohol 3
Quintessence oil is an amount of
Purified water is in right amount to 100g
Embodiment 1.3
Active component:
Bent quinolizine 2
Excipient:
Oleic acid 5.0
Stearic acid macrogol ester 40
(Macrogol stearate 40) 9.0
Cetostearyl alcohol 6.0
Butylated hydroxyanisole (BHA) 0.02
Trometamol 0.1
Simethicone 0.3
Carbopol (Carbopol) 980 0.3
Propylene glycol 20.0
Sodium sulfite 0.1
Quintessence oil is an amount of
Purified water is in right amount to 100g
Embodiment 2: water alcogel (Hydroalcoholic gel) (% weight)
Active component:
Milrinone 2
Excipient:
Carbomer 1.5
96 ° of EP 40ml of ethanol
Quintessence oil is an amount of
Triethanolamine is in right amount to regulate pH
Purified water is in right amount to 100g
Embodiment 3: lipotropy emulsifiable paste (% weight)
Active component:
Amrinone 1
Excipient:
Two isostearic acid polyglycereol (3) esters 4
Olein 2
Cera Flava 7
Dioctyl ether 10
Hexyldecanol/lauric acid hexyl ester in the last of the ten Heavenly stems 10
85% glycerol 5
Magnesium sulfate heptahydrate 1
Right-hydroxybenzoate 0.1
Quintessence oil is an amount of
Purified water is in right amount to 100g
Embodiment 4: non-oily cream (% weight)
Active component:
3-{2-[4-(4,4-dimethyl-5-oxo-4,5-dihydro-1-H-pyrazole-3-yl)-2,3-two fluoro-phenyl aminos]-6-oxo-hexamethylene-1-thiazolinyl methyl }-benzonitrile: 1
Excipient:
Oleic acid 5.0
Stearic acid macrogol ester 40 9.0
Cetostearyl alcohol 6.0
Butylated hydroxyanisole (BHA) 0.02
Trometamol 0.1
Simethicone 0.3
Carbopol 980 0.3
Propylene glycol 20.0
Sodium sulfite 0.1
Purified water is in right amount to 100g
Following active component can be made non-oily emulsifiable paste according to embodiment 4:
6-[4-(2-benzyl-3-oxo-hexamethylene-1-alkenyl amino)-phenyl]-5-methyl-4,5-dihydro-2-H-pyridazin-3-one;
5-{4-[2-(2,6-two chloro-benzyls)-3-oxo-hexamethylene-1-alkenyl amino]-2-fluoro-phenyl }-4,4-dimethyl-2,4-dihydro-pyrazoles-3-ketone;
5-[4-(2-benzyl-3-oxo-hexamethylene-1-alkenyl amino)-phenyl]-4,4-dimethyl-2,4-dihydro-pyrazoles-3-ketone;
5-{4-[2-(3-nitro-benzyl)-3-oxo-hexamethylene-1-alkenyl amino]-2-fluoro-phenyl }-4,4-dimethyl-2,4-dihydro-pyrazoles-3-ketone;
6-[4-(2-benzyl-3-oxo-hexamethylene-1-alkenyl amino)-2-fluoro-phenyl]-5-methyl-4,5-dihydro-2-H-pyridazin-3-one.
Embodiment 5: the injection solution (5ml/ bottle) (consumption is in mg/ml) that is used for the mesoderm therapy
Active component:
Milrinone 5
Excipient:
Sodium pyrosulfite, lactic acid 0.2-0.5
Add purified water in right amount to 5ml
Embodiment 6: efficacy test
Liparitosis is the difficult problem with multifactorial etiology, wherein lipogenesis performance pivotal role.Therefore, in the starting stage of the potential anti-liparitosis medicine of screening, the external test lipolysis activity is a key element, although it is inadequate for the determining of final drug candidate on the whole.Therefore the in vitro tests of lipolysis activity must combine with the test of effect in the evaluation body.
In vitro tests
● by the mensuration of the extracellular glycerol that steatolysis produced of adipose cell triglyceride
External steatolysis test end user adipose cell carries out, and described adipose cell is by inducing differentiation to derive from the primary culture of adipose cell (Promocell) before its ancester cell.Actual adipose cell differentiation is by measuring glycerol-3-phosphate ester dehydrogenase (enzyme of expressing in a kind of at mature fat cell but not pro-adipose cell) and using oil red O (Sigma) to measure the accumulative lipid of level in the born of the same parents and definite.
With PDE3 inhibitor and adipose cell with variable concentrations preincubate 15 minutes; Add the 10nM isoproterenol (1 μ M isoproterenol can obtain 25% peak response) that can bring out the weak stimulation of steatolysis then.Remove culture medium after 4 hours, with oil red O measure in every hole the amount of accumulative born of the same parents' inner lipid.
Lipolysis activity is estimated by measuring the glycerol that is discharged in the extracellular matrix after the triglyceride hydrolysis.
In this test, have the PDE3 inhibitor, comprise that preparation according to selectivity PDE3 inhibitor of the present invention is proved to compare with the similar formulations that contains non-selective PDE inhibitor (caffeine, theophylline) and has quite or better effect.
Some PDE inhibitor is to being stimulated by the 10nM isoproterenol in people's adipose cell of cultivating
The activity that discharges of glycerol
| Steatolysis increases % 10 μ M | |
| Amrinone anagrelide cilostazol | 20±6 114±11 31±9 |
| The bent quinolizine theophylline of enoximone milrinone pimobendan | 65±4 151±16 159±22 276±59 5±4 |
| Caffeine | 10±5 |
● the mensuration that cAMP generates in the adipose cell
CAMP is courier in the cell, and its level depends on its synthetic (adenylate cyclase activity) and decomposes (phosphodiesterase activity).Adipose cell is transferred in the saline solution, to wherein add steatolysis agent (adenylate cyclase enzyme activator), lipotropism is separated agent (di-phosphate ester enzyme activator) and PDE3 inhibitor.After hatching suitable a period of time, interrupt hatching, extract the cAMP that forms in the cell.With the cell extract lyophilizing, redissolve then and can get colorimetric enzyme immunoassay (EIA) with special commerce (Amersham Cayman) measures.Description according to manufacturer is measured the cAMP level.In this test, the preparation that has according to PDE3 antagonist of the present invention confirms more effective than the preparation that similarly contains non-selective PDE inhibitor (caffeine, theophylline).
In vivo test
10 healthy adult women that the outer top of thigh is obvious liparitosis check.
Every patient is as himself contrasting to estimate effectiveness and safety.The emulsifiable paste that will contain active component (1% milrinone) is coated on the outside of a thigh with random fashion, and emulsifiable paste matrix (non-activity composition) is coated on the same zone of another thigh.
Use the emulsifiable paste treatment of about 2-3cm, massage 2-3 minute, repeat twice every day, continue 2 months until being absorbed.
In the process of the test, the patient does not implement exercise plan and is not subjected to any dietary restriction.
The girth at every thigh of periodic measurement 2/3rds places between knee and greater trochanter is when treatment finishes.The thigh of Drug therapy is compared with untreated thigh, and girth has shortened 2.9 ± 0.7cm, and its scope is 1.3-4.7cm.
Observing latter stage in stage, measuring the PDE3 in the blood, do not detecting the existence of chemical compound.
Claims (19)
1. the pharmaceutical composition that is used for local application, it contains the PDE3 inhibitor as active component, is used for the treatment of liparitosis.
2. the desired pharmaceutical composition of claim 1, it contains PDE3B isotype inhibitor as active component.
3. the desired compositions of claim 1-2, wherein said inhibitor is selected from down group: anagrelide, cilostazol, pimobendan, milrinone, amrinone, olprinone, enoximone, Cilostamide, vesnarinone and bent quinolizine.
4. the desired compositions of claim 3, wherein said inhibitor is milrinone, Cilostamide or bent quinolizine.
5. the desired compositions of claim 1-2, wherein said inhibitor is selected from down group:
A) 6-[4-(2-benzyl-3-oxo-hexamethylene-1-alkenyl amino)-phenyl]-5-methyl-4,5-dihydro-2-H-pyridazin-3-one;
B) 3-{2-[4-(4,4-dimethyl-5-oxo-4,5-dihydro-1-H-pyrazole-3-yl)-2,3-two fluoro-phenyl aminos]-6-oxo-hexamethylene-1-thiazolinyl methyl }-benzonitrile;
C) 5-{4-[2-(2,6-two chloro-benzyls)-3-oxo-hexamethylene-1-alkenyl amino]-2-fluoro-phenyl }-4,4-dimethyl-2,4-dihydro-pyrazoles-3-ketone;
D) 5-[4-(2-benzyl-3-oxo-hexamethylene-1-alkenyl amino)-phenyl]-4,4-dimethyl-2,4-dihydro-pyrazoles-3-ketone;
E) 5-{4-[2-(3-nitro-benzyl)-3-oxo-hexamethylene-1-alkenyl amino]-2-fluoro-phenyl }-4,4-dimethyl-2,4-dihydro-pyrazoles-3-ketone;
F) 6-[4-(2-benzyl-3-oxo-hexamethylene-1-alkenyl amino)-2-fluoro-phenyl]-5-methyl-4,5-dihydro-2-H-pyridazin-3-one.
6. the desired compositions of claim 1-5, it is the form of gel, spray gel, emulsifiable paste, non-oily cream, oiliness-non-Oily preparation, ointment or plaster.
7. the desired compositions of claim 1-5, it is the form that is suitable for local intradermal injection or mesoderm therapy.
8. the desired compositions of claim 7, it is the form of injection solution.
9. the desired compositions of claim 1-8, wherein the amount of active component is 0.1-3% by weight.
10. claim 6 and 9 desired compositionss, wherein said amount is 1-2% by weight.
11. the desired compositions of claim 7-9, wherein said amount is 0.1-1% by weight.
12. the desired compositions of claim 1-11 further contains mixture or extract to the activated chemical compound of microcirculation, material.
13. the desired compositions of claim 12 contains the extract of Arnica, Semen Ginkgo, Fructus Ananadis comosi, Radix Angelicae Sinensis (Angelica siniensis) or Herba Centellae.
14. the desired compositions of claim 12, wherein said chemical compound are saponin or flavone.
15. the desired compositions of claim 14, wherein said chemical compound are aescine.
16. the desired compositions of claim 12-15 wherein exists with the concentration of 0.1-4% by weight the mixture of the activated chemical compound of microcirculation, material or extract.
17.PDE3 inhibitor is used for the purposes of the pharmaceutical composition of the part of liparitosis or mesoderm therapy in preparation.
18. the desired purposes of claim 17, wherein the PDE3B inhibitor is selected from down group: anagrelide, cilostazol, pimobendan, milrinone, amrinone, olprinone, enoximone, Cilostamide, vesnarinone, bent quinolizine.
19. the desired purposes of claim 17, wherein the PDE3B inhibitor is selected from down group:
A) 6-[4-(2-benzyl-3-oxo-hexamethylene-1-alkenyl amino)-phenyl]-5-methyl-4,5-dihydro-2-H-pyridazin-3-one;
B) 3-{2-[4-(4,4-dimethyl-5-oxo-4,5-dihydro-1-H-pyrazole-3-yl)-2,3-two fluoro-phenyl aminos]-6-oxo-hexamethylene-1-thiazolinyl methyl }-benzonitrile;
C) 5-{4-[2-(2,6-two chloro-benzyls)-3-oxo-hexamethylene-1-alkenyl amino]-2-fluoro-phenyl }-4,4-dimethyl-2,4-dihydro-pyrazoles-3-ketone;
D) 5-[4-(2-benzyl-3-oxo-hexamethylene-1-alkenyl amino)-phenyl]-4,4-dimethyl-2,4-dihydro-pyrazoles-3-ketone;
E) 5-{4-[2-(3-nitro-benzyl)-3-oxo-hexamethylene-1-alkenyl amino]-2-fluoro-phenyl }-4,4-dimethyl-2,4-dihydro-pyrazoles-3-ketone;
F) 6-[4-(2-benzyl-3-oxo-hexamethylene-1-alkenyl amino)-2-fluoro-phenyl]-5-methyl-4,5-dihydro-2-H-pyridazin-3-one.
Applications Claiming Priority (5)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| ITMI20042371 ITMI20042371A1 (en) | 2004-12-14 | 2004-12-14 | TOPICAL PHARMACEUTICAL COMPOSITIONS FOR CELLULITE TREATMENT |
| ITMI2004A002371 | 2004-12-14 | ||
| ITMI20051739 ITMI20051739A1 (en) | 2005-09-20 | 2005-09-20 | TOPICAL PHARMACEUTICAL COMPOSITIONS FOR CELLULITE TREATMENT |
| ITMI2005A001739 | 2005-09-20 | ||
| PCT/EP2005/013041 WO2006063714A1 (en) | 2004-12-14 | 2005-12-06 | Pharmaceutical compositions for the treatment of cellulite |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN101076323A true CN101076323A (en) | 2007-11-21 |
| CN101076323B CN101076323B (en) | 2010-12-15 |
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN2005800427364A Expired - Fee Related CN101076323B (en) | 2004-12-14 | 2005-12-06 | Medicine composition for treating fatmass |
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|---|---|
| CN (1) | CN101076323B (en) |
| IT (1) | ITMI20042371A1 (en) |
| UA (1) | UA94033C2 (en) |
| ZA (1) | ZA200704859B (en) |
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| FR2802811B1 (en) * | 1999-12-24 | 2002-02-15 | Silab Sa | PROCESS FOR EXTRACTING AN ACTIVE INGREDIENT FROM BIGARADE PETALS, PARTICULARLY FOR THE TREATMENT OF CELLULITE, ACTIVE INGREDIENT OBTAINED, COSMETIC COMPOSITIONS AND SUITABLE TREATMENTS |
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| Publication number | Publication date |
|---|---|
| CN101076323B (en) | 2010-12-15 |
| UA94033C2 (en) | 2011-04-11 |
| ZA200704859B (en) | 2009-05-27 |
| ITMI20042371A1 (en) | 2005-03-14 |
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