CN1200671A - Topically applied structural cellulite treatment - Google Patents

Abstract

New topically applied treatments for cellulite are shown by comparative data to effect structural improvements in cellulite-afflicted thigh area tissues including skin-thickening, thigh-firming and thigh-reduction. The disclosed treatments disrupt the skin's water barrier and elevate trans-epidermal waterloss (TEWL) for extended periods of weeks or months and includes methods of mechanical or solvent action, for example, tape stripping, or acetone washes. Preferred treatments use creams with active ingredients such as lactic acid to elevate TEWL< a retinoid, preferably vitamin A palmitate to disrupt barrier rebuilding and prolong elevation of TEWL levels, and a cerebroside to inhibit lipid synthesis and intensify the TEWL elevation. Diuretics, for immediate esthetic improvements, anti-irritatts and anti-oxidants for irritation control are optional ingredients.

Description

The structural phlegmonous therapeutic scheme of topical application

The present invention relates to cellulitis (cellulite) therapeutic scheme, compositions and the method for topical application, (when using some months as applying every day) makes the cellulitis disease produce structural improvement when life-time service.Term " cellulitis " refers to subcutaneous a large amount of abnormal accumulation adipose cell, and it produces ugly partial and visible discontinuous skin surface.

Cellulitis is that the term created in 1970 by Nicole Ronsard is (referring to Webster ' s New Universal Unabridged Dictionary, 2nd ed.Dorset﹠amp; Baber 1983), it has described a kind of general disease, and this disease produces ugly disease at the erratic fat lump of subcutaneous abnormal accumulation in the normal slick curvature of skin.

Tend to lipidosis and cause the physiological cellulitis by the degeneration of body surface microcirculation.The fat material that some phlegmonous characteristics are that veins beneath the skin degenerates, blood flow slows down, protein surrounds in the epidermis of skin and skin corium attenuation, the subcutaneous area exists hard lump and accumulation and assembles body fluid.Make skin appearance resemble " Pericarpium Citri tangerinae ".

Cellulitis is most commonly in thigh, buttocks and upper arm, rarely in the limbs outside, the back of the body, trunk and diaphragm and normally unconspicuous on face, neck, hands and foot.Although often with fat relevant, cellulitis also can normally or on the skin near the individuality of normal type occur.The women is more popular and white people are more obvious than the individuality of dark skin than the male.

Because greatly damage individual appearance, cellulitis can have deep psychological application, damages the sense of personal worth of many diseased individuals, perhaps some youth of both sexes healthy psychology of grievous injury is grown.Therefore greatly need to treat effectively cellulitis.

Treat phlegmonous known method and comprise being used in combination of partial mechanism, local use chemical reagent, exercise, dietary adjustments and these treatments.A kind of effective Therapeutic Method is in conjunction with diet and exercise, carries out strict keeping for a long time.Many people seek easier Therapeutic Method.The inventor proves that by clinical trial method described herein the known local therapeutic approaches that is easy to use only produces shallow effect and can not significantly improve structural damaged.

The phlegmonous treatment of United States Patent (USP) 4829987 instruction of Stewart need be used for the lapping of mineral solution soaking suitable body part, then this part of movable health by force.The too inconvenient or many personnel of needs of this treatment.

Massage microcirculation improvement and stimulation are peeled off, and make the smooth and blood flow increasing of skin surface, but only are temporary transient.The United States Patent (USP) 4086922 of Henderson discloses massage machine and the phlegmonous method of treatment.This device comprises the ball that is used to massage impaired body region that a plurality of elasticity are loaded.

Thermal therapeutical also stimulates microcirculation and can produce temporary transient effect, but does not have secular structural improvement.

That body lotions, antasthenic and the cream that contains agent of predictive active bio such as witch hazel, Flos Caraganae Sinicae, Aesculus hippocastanum (horsechestnut), algae, sea water or escine can produce is temporary transient, gentle microcirculation stimulation but be limited activity at the most.

Above-mentioned massage, thermal therapeutical and biological preparation do not relate to the problem of skin recovery, catabolism of fat, body fluid accumulation or revascularization.

Diuretic (vegetable matter is preferred) promotes the lymph discharging, produces the good symptomatic effect of short-term but unresolved secular skin defect, catabolism of fat or role of Vasculogenesis.

Caffeine, theophylline and other xanthine seemingly effectively also can promote catabolism of fat as diuretic when high concentration.As if aminophylline is known common common active component as lower limb frost or the smooth frost of lower limb, and it promotes that as strong diuretic the lymph discharging is effectively but report has significant toxic and side effects (to see The Merck Index the 11 edition, Merck﹠amp; Co.Inc.1989 takes passages numbers 477).The potential structural weak point of unresolved skin of this reagent and blood vessel.

Described some in the United States Patent (USP) 5030451 of Trebosc etc. and be mixed with the cosmetic composition of the caffeine derivant of modification as activating agent.Trebosc etc. have at the 9th hurdle disclosed preparation of 15-20 line description: " good and long-term lipolytic effect and therefore and proof is being very effective aspect fat-reducing and the treatment cellulitis.”

Yet, do not report effect data.Capable at the 1st hurdle 61-65, the transdermal speed faster of instructing such as Trebosc proves the superiority of these reagent aspect the treatment cellulitis.

The United States Patent (USP) 5215759 of Mausner relates to the cellulitis activity of methyl-monosilane alcohol theophylline acetic acid alginate esters and Algisium C..For want of explanatory description, the effect of these materials may be equivalent to diuretic.

A defective that is used for the treatment of phlegmonous stimulating composition (containing caffeine, aminophylline or related reagent as active component) of listing is can occur stoping the cosmetic composition that comprises them to be sold on the sales counter in pharmacy.Life-time service repeatedly can be induced deleterious side effect, and the rules of government can limit market.Another shortcoming is the potential structural issue of unresolved skin of these reagent and vascular defects.

Peel off granule and play mechanism, thereby wipe skin outer layer, glabrous skin surface and promote skin to recover, but fail to promote that lymph is discharged, long-term microcirculation is regenerated or catabolism of fat.Peeling off granule is grit, is generally the cream or the gel of suspension, and friction or massage reach mechanical sapling on skin.Granule is generally the polyethylene ball, yet has used natural granule such as ground Semen Persicae or almond.Another shortcoming of these products is to be difficult to control zest.

The local biostearin (retinoids) (for example, the United States Patent (USP) 5051449 of Kligman is disclosed) that uses can limit phlegmonous degree.Kligman provides the local qualitative report of using the comparative advantage that is obtained behind cream 6 wheat harvesting periods of tretinoin preparation and a kind of definite non-treatment " purpose ".These advantages comprise the skin thickening, increase the quantity of new blood vessel and can be observed cellulitis with shrinkage test and moderate is arranged to tangible the improvement (the 6th hurdle, 50-61 is capable).But do not provide quantitative data, so those skilled in the art can not determine the phlegmonous numerical value of treatment that Kligman instructs.

Many people's requirements and the treatment of the hope ratio more effective phlegmonous therapeutic effect of gentle improvement after 6 months.The working concentration that must limit tretinoin so just can not reach enough effects by increasing dosage to avoid inductive stimulation (see Kligman the 2nd hurdle, 59-60 is capable).Therefore, the treatment of tretinoin can not produce satisfied long-term treatment effect and need more effective local therapeutic approaches cellulitis.Opposite with the unspecific general introduction of Kligman, the inventor finds after tretinoin is treated 3 months every day skin obviously to be thickened in quantitative clinical research.Therefore, need wieldy cellulitis therapeutic agent, it makes structure improve in proper treatment in the phase.

Bao Hu content the invention provides a kind of Therapeutic Method on request.It has solved and has made that consumer is commercially available, the phlegmonous problem of wieldy topical therapeutic, has than the better effect of method mentioned above and in proper treatment to produce the effect that tangible structure is improved in the phase.The present invention makes its phlegmonous method of step by step, structurally improving of topical therapeutic when also having solved continuous life-time service.The skin that embodiment preferred promotes health to suffer from phlegmonous zone obviously thickens the robustness of improving tissue simultaneously and reduces the diameter of lower limb and increase microcirculatory blood flow.

The present invention treats phlegmonous method and has solved problem mentioned above by providing a kind of, and it is that skin recovers basically and makes revascularization that this method obtains by the water barrier characteristics of destroying the skin of suffering from the cellulitis tissue regions for a long time that enhanced effect is enough to.

It is difficult destroying skin barrier with continuous fashion.Clearly, destructive process necessarily can not be too the serious so that skin corium of the sensitivity of injured skin or cause pain or tangible stimulation.The present invention has still obtained useful effect, and this Therapeutic Method not only produces of short duration effect and also continues to destroy barrier function.Because the suitable function of barrier is important, thereby thereby the destruction of barrier carry out repairing fast barrier with natural process.More specifically, barrier function should continue destroyed in the lasting treatment phase (8 week or longer time) in several weeks.

The increase that water is lost (TEWL) by epidermis can be used for detecting the function of barrier.As if TEWL levels (treat for the last time at least and measured in back 8 hours) are measured in treatment 12 week backs, and the inventor finds seldom (if any) lasting impact barrier action and reduce the TEWL level sometimes of known cellulitis therapeutic agent (except the tretinoin).Tretinoin (a kind of exfoliant) and at least a other exfoliant only are on the edge line rising of TEWL when 12 weeks.

Although these difficulties are arranged, the inventor finds a kind of different therapeutic agent, it destroy effectively barrier function and continuously lasting the use (as once a day or twice) time, in 8 weeks or 12 weeks TEWL was significantly increased.

Some barriers that can be used for the inventive method destroy Therapeutic Method and comprise that the organic solvent of the nonpolar lipoid of low-molecular-weight by the corium tolerance such as acetone or surfactant such as the direct physics and chemistry of sodium lauryl sulphate by the corium tolerance destroy cuticular lipoid structure.This Therapeutic Method separation is also removed lipoid composition in the barrier.Yet, preferably use the local cosmetic composition that uses, it contains in the tasteless preparation (as cream) that the comfortable impression is arranged can absorb the chemically active barrier destruction component that enters skin.It is known or conspicuous to those skilled in the art that other suitable barrier destroys Therapeutic Method.

The inventor further finds can suppress or control the reparation of barrier and can substantially aggravate the rising of long-term 8 or 12 all TEWL levels by suppressing the synthetic of skin lipoid.Press people such as Proksch at " barrier function regulates epidermal lipid and DNAsynthesis " British Journal of Dermatology (1993) 128,473-482, instruction, free fatty acid, sphingolipid and the synthetic increase of cholesterol in the active layer of the corium that the destruction that studies show that barrier function of Mus causes making barrier to be repaired.

In one embodiment of the invention, for example, use the cerebroside that absorbs to suppress this synthetic to reduce free fatty, sphingolipid and cholesterol to repairing the availability of water barrier by the part.Other suitable inhibitor is known or conspicuous for this area professional.When cellulitis treatment is removed or during flush away skin lipoid, the lipoid synthetic inhibitor is used for destroying barrier step by step.Barrier destroys the influence that is subjected to the local absorption activating agent, and the lipoid synthetic inhibitor can be included in the preparation.

Use lipoid synthetic inhibitor can be prevented the fast rapid regeneration of sealing barrier and strengthen the structure improvement of cellulitis disease.

The inventor also find when considering omnidistance 8 weeks or longer lasting secular cellulitis treatment water by epidermis lose (TEWL (and to direct measure responsive)) be to detect the valuable parameter of cellulitis therapeutic effect.The degree that TEWL raises on persistent baseline also is the useful index of cellulitis therapeutic effect, and its beneficial effect is only at life-time service, several weeks or more may become obviously after 2 to 6 months or longer use.The TEWL (inventor believes the former advantage of estimating the cellulitis treatment that is not used in of this measurement) of experimenter by measuring the treatment of various cellulitis, the inventor find that TEWL that known Therapeutic Method only produces temporary transient short-term raises and do not make TEWL continue to raise in several weeks and some months.The inventor finds can make the cellulitis disease obtain valuable structural improvement by making the substantial and lasting rising of TEWL.

And by detecting by the inductive TEWL level of various treatments, the inventor can invent new cellulitis Therapeutic Method, and it makes the TEWL level slowly or continuously raise constantly in the whole treatment phase (lasting usually 8 weeks, 12 weeks or longer) effectively.Preferably, the inventor's new Therapeutic Method makes TEWL raise at least 100% in 8 weeks or longer duration.In fact, whole treatment interim 200 300% or higher higher rising be ideal.

On the one hand, the invention provides a kind of method of improving the cellulitis disease, it comprises that partial water barrier destruction Therapeutic Method is imposed on skin region continuously slowly to raise to finishing the water of losing from epidermis in the required improvement of the cellulitis phase to induce for 8 weeks.Common described Therapeutic Method carries out once or twice every day.

The inventor's new cellulitis Therapeutic Method comprises the various local mechanical treatments of skin, for example wipe, make coarse or strip off and solvent extraction treatment, two kinds of treatments are all fully carried out consumingly or on one's own initiative so that the TEWL level raises 100% or the higher and lasting whole treatment phase as mentioned above.Yet preferred treatment comprises the form of emollient or cream dosage form (preferably with) Chemical composition that can locally use and to be less than once a day or twice frequency makes the TEWL level continue to raise when using.

Initiative of the present invention treatment obviously must be controlled in a few weeks or months be can tolerate and do not cause stimulation serious or pain, redden, decortication or undue uncomfortable.Yet the not serious performance of these symptoms can tolerate for many people in a short time.

On the other hand, the invention provides a kind of cellulitis therapeutic combination, it contains the lasting barrier disrupting agent of TEWL level that makes the effective TEWL elevating agents of TEWL level rising with short-term immediately and make rising.Preferably, compositions comprises that cellular-restoring/division regulator is to keep the repair process of skin.Comprise in the preferred composition that also skin lipoid inhibitor prevents the too early reconstruction of sealing barrier and the cellulitis therapeutic effect of enhancing composition.

In the preferred embodiment of this respect of the present invention, the TEWL elevating agents is the hydroxy carboxylic acid that a kind of cosmetics are compatible, reduce pH, preferably have peeling property and medium at least water solublity or a kind of hydration alcohol (hydroalcoholic) carrier that is blended in the cosmetic composition.This acid comprises alpha-hydroxy carboxylic acid compounds, particularly for example lactic acid and glycolic (glycollicacid), and other hydroxy carboxylic acid, 2 hydroxybenzoic acid for example, particularly salicylic acid for example.This sour effectiveness is obviously relevant with the ability of pH of iuntercellular liquid in its reduction skin.Select to use specific acid and concentration thereof to obtain required TEWL rising and not have undue stimulation.

Preferred barrier repair inhibitors is the tretinoin or derivatives thereof, and particularly preferred a kind of tretinoin is a vitamin A palmitate.The clinical trial that the inventor carries out (comprises that the research people is to the reaction of varied cellulitis treatment in the body, hereinafter do play-by-play) show interactional beneficial effect between a kind of very beyond thought lactic acid and the vitamin A palmitate, this is valuable for phlegmonous long-term treatment.

Preferred lipoid synthetic inhibitor is cerebroside or the material that is rich in cerebroside.Some optionally component be the counter-stimulus that stimulates blood flow and remove the diuretic of excess liq and relax the stimulation side effect of TEWL elevating agents or cellular-restoring stimulant.

Suitable relative scale and the applying frequency thereof of preparation with the present composition component of the topical application of cosmetics or medicine emollient, lotion or the sale of nourishing preparation hereinafter described.Preferred cosmetic formulations is the cream that is suitable for consumer's massage every day or simply applies and rub.Other quantitative parameter that can be used to obtain beneficial effect of the present invention will be conspicuous to those skilled in the art.

Shown in the experimental data as mentioned below, compositions of the present invention produces the effect of new height and can obviously increase skin thickness, improves blood flow and promote angiogenesis in the treatment cellulitis.As report, the careful quantitative characteristics of these and other product effect.

The cellulitis zone lacks blood flow.Hereinafter the clinical trial of carrying out with embodiment of the present invention of report shows to use and directly improved blood flow in 4-8 hour and slowly used 8-16 hour, improves blood flow for a long time by the angiogenic growth effect, therefore reduces the damaged of cellulitis influence tissue.And after week, the skin density in increase of the skin thickness of epidermis-corium skin area and the subcutaneous area increases at treatment 8-16.The particularly important is, tissue density improves and to show that this is that positive effect and corium and epidermis are more solid and full of elasticity, and the fat that subcutaneous area has still less also can reduce outside liquid.These structural improvement help treatment of the present invention.Cellulitis is described

Phlegmonous pathogeny is described as 3 or 4 phase process usually.In this article, for the purpose (not limiting the present invention) of interpretation model, the cellulitis pathogeny is counted as 3 phase process with following characteristics:

In the stage 1, the blood vessel of involved area expands and seepage.In this stage, the influence on surface is minimum and treatment is highly effective to repairing vascular integrity and removing excessive liquid.The laser-Doppler inspection can be checked also damaged under the display surface of unusual blood flow and biopsy.

In the stage 2, the adipose cell metabolism is subjected to fat mass and the dramatic remarkable interference that increases of cell size.Congested adipose cell adheres to each other with the fat corpuscles form.Vascular integrity further suffers damage, and notices that corium and epidermis are disturbed.This interferential example be in epidermis attenuation, the corium vascular system tail off, visible skin surface roughening and Lycoperdon polymorphum Vitt, this is because the weak microcirculation and the development of surface heterogeneous medium, the i.e. beginning on " Pericarpium Citri tangerinae " surface.

Stage 3 in the 3rd stage, can be observed microvasculature and constantly damages, and liquid constantly accumulates, and lipogenesis increases and lipid metabolism speed reduces.Adipose cell hyperemia, be bonded together and surround, form unusual collagen protein by the collagen protein shell.The diameter of the brief summary that these are unique can have several centimetres, the surface is very easy feels and may be special pain.The fatty brief summary that forms the collagen protein shell makes capillary network change direction and represents that this zone blood flow is reduced.The structure in subcutaneous fat zone because of liquid holdup, exist fatty brief summary and action of gravity to be subjected to very havoc.Pericarpium Citri tangerinae skin is easy to show that surface heterogeneous medium is obvious.Thinner and the more not solid and inorganization more of epidermis and corium.The unusual naked eyes of skin surface are visible and great majority are suffered from late period phlegmonous people is inaesthetic and embarrassed.Cellulitis is measured

Many biophysics technology are used for measuring and the proof cellulitis, for example can be by the laser-Doppler blood flow, can directly measure solidity and elasticity by thermography and the medical history evaluation that needs certainly.Various such technology can be suitable for measuring the effect that cellular-specific is knitted scorching Therapeutic Method according to the symptom that treatment is produced.Some other technology are developed to improve the clinical evaluation of cellulitis Treatment and composition for as herein described.Hereinafter be the non-exhaustive Therapeutic Method of listing of minority:

Lower limb diameter measurement method: the effect of following the trail of the product in the cellulitis zone that acts on attenuation.Preferably carry out with the scheme that comprises diet and exercise.This is the method for difference, insensitive and non-selectivity.

Laser Doppler measuring: can detect the influence of the infringement of vascular system and product to the vascular system integrity.Observe easily by the inductive short-term vasodilative effect of product.Can detect the angiogenesis function of the long-term observation that produces by better product and vascular integrity but very difficult and need good technical expertise.

Ultrasonic scanning: be unusual otherwise effective technique, detect the change of subcutaneous fat, vascularity and epidermis and corium integrity.Skin thickness can be measured by the computer analysis of skin ultrasonic scanning.Ultrasonic scanning is a kind of real undamaged method of measuring epidermis and dermis thickness fast.

Thermography: be a kind of insufficient method more lively of blood vessel that show than laser-Doppler.

Solid and the elasticity of skin: total health status and the integrity of measuring whole corium, epidermis and subcutaneous area.

The cellulitis classification: hereinafter Bao Gao cellulitis ranked data is comprehensive number, represents that perusal skin is uneven, skin sink and blemish and extruding skin are estimated the result of brief summary.

Medical history: medical history (Skin biopsy) can show the change that also can show structure as the change that collagen protein is measured and elastin laminin is synthetic, neovascularity produces.Medical history is normally described the method the most fast of the real effect of the degree of cellulitis problem and definite product, but produces infringement and have other shortcoming.

Photo and copy: this is the value that limitation is arranged.Consumer's impression often is better instrument.Cellulitis is that " greatly " surface action and copy usually show too many details.Photograph is difficult to estimate.

The preferred embodiment of the invention adopts and makes the forfeiture of skin water barrier function to induce the release that starts the factor of skin repair process in the skin in fact.By destroying barrier function, dermoreaction seems injured but begins generalized repair process, increases epidermis and corium metabolism and angiogenesis (or vascularization), but still the uncertain skin signal controlling that discharges when destroyed by barrier.

The observation of carrying out in the process of the data that obtain hereinafter to report shows such information: although can increase TEWL after a few minutes after the use or several hours, use damage binder (BUFF-PUFF, trade mark) and peel off granule not continue this effect.Observe from these, it is essential that the inventor supposes that slow rising TEWL finishes the desired structure improvement.

Similarly, once use or interval (as a week) are used and are peeled off therapeutic agent such as facial decorticating agent (for example, 20-30% lactic acid or hydroxyacetic acid or equivalent), increase TEWL although treat after several days, do not finish required skin treating and cellulitis and improve effect.And, according to the present invention, believe that these deficiencies are owing to can not (for example continuing at least 8 weeks) produce the speed that TEWL continues rising in the treatment time-continuing process.

Experimental data described below shows previously knownly treats phlegmonous method by easy-to-use Local treatment mode and does not produce function that continue to destroy barrier and also do not produce to make and suffer from the late period phlegmonous zone that is hopeful to recover and reach normal or near normal positive effect fully.TEWL measures

Measure the experimenter's who treats with various cellulitis Therapeutic Method TEWL according to the present invention, comprise conventional Therapeutic Method and new Therapeutic Method more of the present invention.The mensuration of basic blood flow, measurement and the more phlegmonous clinical rank and the inductive stimulation of lower limb diameter have also been carried out.

Use trade mark to measure TEWL as the evaporation measuring instrument of SERVO-MED.This device comprises the moisture collecting chamber that is engaged in skin surface area.This instrument detects and reads the TEWL level when reaching steady-state condition by moisture electric conductive.In advance experimental condition is adjusted to temperature and is about 30-40% for about 68-71 ℃ and relative humidity.The sensitivity of the instrument that test is hereinafter described used is about ± and 10%.

Hereinafter in Bao Gao the clinical trial, the experimental program of measuring the TEWL level of accepting local coating treatment cellulitis skin be use for twice every day cellulitis therapeutic agent or other relatively usefulness the topical therapeutic agent and use in the morning and not long ago measured TEWL.For example, as a rule, in about 10 of mornings with afternoon, 6-8 point was implemented treatment approximately, and implemented the treatment precontract in the morning 1 hour, i.e. 9 of about mornings and after enforcement is treated at night at least 8 or more may in the time of 12 hours, measure TEWL.

The method of using the preceding paragraph to describe is estimated the effect of various existing cellulitis Therapeutic Method rising TEWL levels.Use the basic blood flow of laser-Doppler algoscopy evaluation, compare on by size then.In addition, also measure skin thickness by the solidity and the diameter of method known to those skilled in the art mensuration lower limb by above-described ultrasonic method.The mensuration of skin thickness is divided into epidermis-skin corium (the 1st number in the chart) and subcutaneous area (the 2nd number in the chart bracket).Treatment is when improving skin texture, epidermis-skin corium thickening (the 1st number in the chart increases) and remove excess liq and make the soft subcutaneous area of carrying liquid reduce (negative value in the chart bracket) because of microcirculation improves.Relatively come clinical more phlegmonous seriousness, equally also comparison stimulus effect according to size.

In following clinical experiment, the cellulitis classification is determined by following yardstick:

0 surface does not have inhomogeneous or damaged.

1 visible surface or sparse recess or scrobicula.

2 visible bigger linear stripeds (surperficial recess).

Individual visible and palpable striped and recess, uneven skin health status, change color more than 3.

4 have with 3 grades of identical symptoms and have brief summary under the palpable epidermis.

Adopt industrial standard method, use Minolta Chroma Meter (MinoltaCamera Co.Ltd.) to estimate stimulation by the degree of staining of relatively determining skin color.Record implement other subjective perception of treatment back twinge, burn and red swelling of the skin, the yardstick of these data by 0-5 merged in the clinical stimulation index, wherein 0 expression does not have visible or report stimulation and the serious stimulation of 5 expressions.Carry out clinical trial with known cellulitis Therapeutic Method

Following table 1 has been reported the result of the clinical trial of carrying out with known cellulitis Therapeutic Method.During studying all by the known active substance in twice use every day table 1.

Treatment 1.1 is the simple cream use Vitamin-A Acid (trade name) with 0.5% concentration.

The massage of treatment 1.2 is to use olive oil to carry out by hands with machine tool as massage oil.

Treatment 1.3 is to use caffeine and theophylline with the simple gel of 2% and 0.2% concentration respectively.

Heating and xanthine are adopted in treatment 1.4, and it uses trade name " the Cellular Body Contouring Gel " product from La Prairie, and this product increases skin temperature by chemical reaction.

Peeling off of treatment 1.5 is to use the pinch spalling that is suspended in 5% polyethylene particle in the carbopol gel, applies strongly every day and washes twice.

Treatment 1.6 vasoactive medical herbs is from the brand name of the Orlane commodity for " Rhythme Du Corps ".

Table 1

The evaluation of conventional cellulitis Therapeutic Method

Therapeutic Method	Blood flow	??TEWL ?g/m2/hr	Solidity	The lower limb diameter	Skin thickness	The cellulitis rank	The zest rank
								????1.1)RETIN?A *8 all 12 weeks of 0.5% baseline	????1 ????X ????1.27	????2.17 ????X ????2.37	????X ????X ????32％	????X ????X ????-8％	????X ????X ??4％(ns)	????4 ????4 ????3	????1 ????2 ????2.5
1.2) massage 8 all 12 weeks of baseline	????1 ????X ????0.97	????2.41 ????X ????1.97	????X ????X ????6％	????X ????X ????-2％	????X ????X ??ns(ns)	????4 ????4 ????4	????1 ????1 ????1.25
								1.3) caffeine/8 all 12 weeks of theophylline baseline	????1 ????X ????1.08	????2.33 ????X ????2.47	????X ????X ????-3％	????X ????X ????-3％	????X ????X ??2％(ns)	????4 ????4 ????3.75	????1 ????1 ????1.25
1.4) heating/xanthinyl opened for 8 all 12 weeks	????1 ????X ????1.03	????2.61 ????X ????2.23	????X ????X ????4％	????X ????X ????-5％	????X ????X ??ns(-2％)	????4.25 ????4.25 ????4	????1 ????1.25 ????2
								1.5) peel off 8 all 12 weeks of baseline	????1 ????X ????1.07	????2.41 ????X ????2.17	????X ????X ????13％	????X ????X ????-3％	????X ????X ??ns(-3％)	????4.25 ????4 ????4	????1 ????1.5 ????2.25
1.6) vasoactive 8 all 12 weeks of medical herbs baseline	????1 ????X ????1.01	????2.23 ????X ????2.41	????X ????X ????7％	????X ????X ????1％	????X ????X ??ns(-3％)	????4.25 ????3.75 ????3.75	????1 ????1.25 ????1.5

^*Johnson﹠amp; The trade mark of the tretinoin of Johnson Co., ns=are not significant to be changed

Analyze preceding 5 hurdle results' significance,statistical, have only after relatively 12 weekly datas of blood flow, solidity and the lower limb diameter of treatment 1.1 to have significance to change.(the cellulitis seriousness on 6 and 7 hurdles and irritating clinical scale are subjective and do not carry out statistical analysis.)

In the data, have only some significances of the treatment 1.1 display base blood flows that use tretinoin to improve, and use the treatment 1.3 of caffeine and peel off that treatment 1.5 shows that blood flows slightly raise but not obvious.

Improve by TEWL level in the table 1 with significance that the visible any known phlegmonous Therapeutic Method of baseline values 12 all levels relatively produces very little (if any), in addition when 12 weeks also like this.The treatment 1.1 of use tretinoin raises at most in known method but only is 10%.As mentioned below, Therapeutic Method of the present invention can make the rising of blood flow surpass 40%.

Treatment 1.5 is peeled off and lower limb solidity and diameter is slightly improved and to treat the improvement that 1.1 tretinoins produce more remarkable.Obtain more significant improvement with the present invention in fact.

Only make skin thickness show very small amount of or unconspicuous improvement by the known cellulitis Therapeutic Method of table 1.

Treat 1.1 tretinoins and make cellulitis seriousness have some general reduce (by clinical scale) but be cost, as described in last 2 hurdles of table 1 with substance increase zest.

The known cellulitis Therapeutic Method of these data show only provides a small amount of beneficial effect, and best result is obtained by tretinoin, is the method for peeling off then.Some improvement that obtain basic blood flow, solidity, lower limb diameter and total cellulitis disease will be cost with significant zest.Can not make the obvious rising of TEWL can not improve skin thickness (the basic structure index of tissue health) with known Therapeutic Method, clearly illustrate that the shortcoming of prior art.Although the present invention is not bound by any particular theory, seem known Therapeutic Method not produce enough the destruction of the skin water barrier function that continues to stimulate significant skin repair.New cellulitis Therapeutic Method

As indicated above, the invention provides the phlegmonous method of a kind of topical therapeutic, it reduces skin water barrier function at least in the time in 8 weeks, preferably make TEWL increase 200-300% or bigger continuously and lentamente, and preferably be extended to for 26 weeks or make cellulitis obtain satisfied 10-20 week for example At All Other Times of improving.

Required TEWL increases and can obtain by carrying out continued treatment with suitable Chemical composition that or mechanical damage or solvent extraction, and condition is the water barrier that this treatment destroys skin fully initiatively.Importance of the present invention is to increase TEWL and keeps the low irritation level that tolerates simultaneously, although the corrosive chemical that destroys barrier of being useful on, the solvent and the surfactant that are used to extract lipoid may stimulate very much.

In the operation of the specific preferred embodiment of the present invention, the inventor finds the not buffered lactic acid (example of alpha-hydroxy acid) and vitamin A palmitate or the collaborative TEWL of increasing of alcoholic acid compositions that uses with higher concentration.Alpha-hydroxy acid destroys skin water barrier and plays the TEWL elevating agents.As if vitamin A palmitate (tretinoin) suppresses the recovery of barrier function and the answer of the TEWL level that delay is raise by the alpha-hydroxy acid treatment.These TEWL stimulus qualities can help the effect of tretinoin to skin cell differentiation.This interaction of vitamin A palmitate and lactic acid is very beyond thought.

Believe and when the preferred embodiments of the invention part is used for skin skin slowly and is seriously peeled off so that induce widely cell loss and the more important thing is and destroy normal barrier function so that make TEWL preferably increase 200-300%.Although physical method can be used for finishing these effects, the present invention finds that the vitamin A palmitate of not buffered lactic acid of 5-10% and 0.1%-3.0% produces reproducible result and has a spot of zest.The compositions of finding 6% lactic acid and 0.5% vitamin A palmitate is effective especially.Believe TEWL slowly two-forty induce the crucial skin growth factor to discharge as produce the interleukin and the transforming growth factor of corium-epidermal growth and angiogenesis function.This treatment is used for skin of face may be too serious, but tend to treat the cellulitis of lower limb, arm and chest, and this class skin has stronger resistance.Thicken and improve the effect of suffering from phlegmonous corium and epidermis and angiogenesis and improve blood flow for a long time with above-mentioned combination treatment.

In order to obtain the TEWL that raises further and more constantly, the inventor finds to add specific cerebroside (I type or II type) and plays synergism with above-mentioned composition." I " of indication and " II " can be understood as and relate to and the corresponding relevant specific molecular structure of ceramide, as referring to Rieger, and Figure2, the 88th page.In the skin lipid metabolism, ceramide be produce by the sphingosine acidylate and cerebroside be the glycation product of ceramide.Ceramide and cerebroside produce a spot of skin lipoid and operate in the skin of skin, therefore mainly find sphingosine and precursor thereof in basal layer.

In the corneocyte of decortication, also find the sphingosine of significant quantity, because ceramide is by enzymolysis in the process of peeling off.

The destructive treatment of barrier of the present invention is sent and is reduced the signal that skin increases the gentle reparation barrier of lipoid (as ceramide) synthetic water.The hypothesis of a kind of indefiniteness of the present invention is that the application of cerebroside I or II can be disturbed this self the repairing of barrier of synthesizing, prevent.The general inhibitor of synthetic or synthetic other end product of skin lipoid of lipoid rather than cerebroside I or II also may be to mentioned above at the long interim lasting rising TEWL of treatment and promote that therefore the treatment of skin repair is effectively to replenish.

Cosmetic﹠amp in Dr.Sergio Cirri proposition recently; Toiletry Conventionin barcelona, Spain, in March 1994 Curri ' the s report, he proposes Profilin matter kinase c (for example passing through sphingosine) is useful for phlegmonous treatment.The hint cerebroside should be not have help in phlegmonous treatment.In the test that this paper does not report, the inventor finds that phospholipid, ceramide and sphingosine have very little effect as the barrier repair inhibitors of the object of the invention and the inventor finds that also it is useless using cerebroside separately in control TEWL or treatment cellulitis.

Treating phlegmonous that further need and important function is the abnormal accumulation that reduces or eliminates the subcutaneous fat piece, and this accumulation is irritating phlegmonous characteristics.According to purpose of the present invention, the slow natural decomposition of the fat that accumulates in the skin can be finished by stimulating lipid metabolism, for example by increasing skin ATP enzyme and Protein kinase C.

The inventor is surprised to find by mix cerebroside in the cosmetic composition of topical application, can suppress lipid metabolism.As if only be subjected to the hereinafter restriction of claim although my invention is not bound by any particular theory, cerebroside has very special effect in stratum corneum barrier regeneration.When barrier is impaired, discharge specific signals, epidermis and corium metabolism trigger the activation.The epidermis lipoid that wherein some signal activation is new synthesizes to be repaired barrier and makes TEWL recover normal.This reparation is closed activating replying of epidermis and corium metabolism (with activating subcutaneous synthetic neovascularity) signal.The cerebroside that brings Selection In (rather than ceramide neither sphingosine) disturbs the barrier reparation, makes the metabolic activation of long term maintenance epidermis and corium to cause improving phlegmonous situation.Disturb the side effect that does not cause the surface by the barrier reparation that the cerebroside of selecting produces.Really, as if the interference of epidermis lipoid generation can make activated epidermis and corium metabolism long term maintenance a few weeks or months.Clinical experiment result by hereinafter report has confirmed these notions.

These conclusions and result that cerebroside has the effect of barrier repair inhibitors are very beyond thought, because common instruction hint cerebroside should be repaired impaired barrier.

The inventor concludes that the effect of cerebroside is very special and acts on horny layer, but this is the theory that proposes by the mode of explaining, is used for illustrating mechanism of the present invention by my best appreciated.I or the exploration in the future of other researcher can propose different mechanism.Cerebroside also may directly influence the metabolism of fatty lipoid in subcutaneous area by the effect of Protein kinase C.

When by described herein when being incorporated in the topical therapeutic, the cerebroside of front long-term (for example 10-20 week) effect can improve skin quality and phlegmonous situation.

As described below with shown in the experiment of reporting, I find TEWL elevating agents (particularly lactic acid) and tretinoin (particularly vitamin A palmitate) and skin barrier repair inhibitors (cerebroside particularly, preferred I type or II type cerebroside) combination cause TEWL continue raise slowly and the destruction of barrier function, produce the effect of above-mentioned ideal skin repair and cellulitis improvement.TEWL elevating agents: hydroxy carboxylic acid

Preferably, sneak into effective solution of the active component in the cosmetic base in TEWL elevating agents water soluble or some the polarity hydration alcohol carriers with generation.Many other 'alpha '-hydroxy acids can be used to replace lactic acid.In practice of the present invention, lactic acid is particularly preferred TEWL elevating agents, has extraordinary effect and is the material of the natural generation found in skin and iuntercellular liquid and blood flow.The preferred substitute of some of lactic acid is glycolic, salicylic acid and these sour mixture.

For the compatible and appropriate water of the characteristic that raises with TEWL that has that ideal pH reduces and cosmetics and the dissolubility of hydration alcohol, preferably the molecular weight of hydroxy benzoic acid is lower than about 250 and preferably be lower than about 175.

Many useful hydroxy carboxylic acid have been described in my International Patent Application WO/94/06640.Some other alpha-hydroxy carboxylic acid compounds has been described in the United States Patent (USP) 4363815 and 5091171 of Yu and Van Scott.Acid of describing in these publications (its disclosed content only is incorporated herein for reference) and acid quite thing can be used in the practice of the present invention, and its condition is that they meet condition mentioned above.Preferably, the 'alpha '-hydroxy acids that is used for the present composition is to have to be no more than 3 substituent straight or branched aliphatic acids on the aliphatic skeleton, described substituent group right and wrong alkalescence and be selected from hydroxyl, aldehyde radical, ketone group, carboxyl, chlorine and nitro.

Although the dissolubility of acid and water or hydration alcohol is the characteristic of the needs of 'alpha '-hydroxy acids of the present invention, but any extreme characteristic (as by as shown in the mineral acid) is unwanted, though because they tend to not induce zest to cause serious clinically just as not burn, damage and subcutaneous infiltration.Low molecular weight material can show these unwanted characteristics sometimes, and described material can be showed unusual and that can not estimate and often be deleterious atopic effect.

Spendable other Alpha-hydroxy aliphatic acid of the present invention is preferably monocarboxylic acid, and it is selected from 2-hydroxyl-n-butyric acie, 2-hydroxyl-isopropylformic acid., 2-hydroxyl-positive valeric acid, 2-hydroxyl-isovaleric acid, 2-hydroxyl-n-caproic acid, 2-hydroxyl-isocaproic acid.Also can use two or polyhydroxy analog of each suitable monohydroxy, for example, 2, X-dihydroxy analog, wherein " X " is the integer of 3-6, specifies second hydroxyl substituent to be arranged on the carbon atom of the carbon atom except that 1 or 2 carbon atoms.Preferably, this dihydroxylated acid balance helps the above-mentioned further other elecrtonegativity of second hydroxyl of hydrophobic part that has.Some examples of suitable dihydroxylated acid are maleic acid (CH.COOH) ₂With Azelaic Acid HOOC. (CH ₂) ₇.COOH.Barrier function recovers inhibitor

According to the present invention, it is biostearin that preferred barrier function recovers inhibitor, for example, and retin-A or tretinoin.Yet many class retin-As or tretinoin are unsettled and are unsuitable for going on the market with cosmetics topical therapeutic composition forms.Vitamin A palmitate is stable especially biostearin, so be preferred for the present invention.Other stable biostearin that is suitable for preparing the present composition comprises retinyl ethyl acetate and retinol.

Thereby other has the stable retinyl group that is connected with fatty acid chain and has oil-proofness and have good deliquescent biostearin in the local carrier that uses as herein described and can be used for the present composition.In the practice of the inventive method, may be unessential storage period.Therefore, for example, if the compositions and the non-long term store of production topical application as required, the stability of the biostearin of selection is accessory, can use more unsettled biostearin.

Many active biostearins are known and regard as in practice of the present invention in the United States Patent (USP) 5051449 as Kligman cited (disclosed content is incorporated herein for reference).The other biostearin be axerophthal, retinoic acid, Davitin A, accutane, etretinate, acitretin biostearin ester, the genial 13-of 13-anti--ester and the amide and the retinyl glucoside of tretinoin.The barrier repair inhibitors

As mentioned above, find that cerebroside has the valuable function as the barrier repair inhibitors of the object of the invention, believe that this effect is to produce finishing synthesizing of lipoid of normal water barrier function in the horny layer by suppressing to be included in.Consistent with this notion, expect that other material has required barrier and repairs inhibitory action.

Cerebroside used in the present invention can some forms be buied.They are sometimes with glycosyl sphingolipid (GSL, it comprises any lipoid with the sphingosine base that is connected with sugar) supply.In the material of being supplied, cerebroside is the main component of GSL, and GSL is the crude product of bio-separation from plant or animal.The mixture of purer (99%) of I type and II type Medulla Bovis seu Bubali cerebroside can be C4905 available from Sigma Chemical Co. catalog number (Cat.No.).The relative proportioning of component

A degree that limiting factor is their inductive stimulations to cellulitis therapeutic combination substrate concentration of the present invention.It is responsive not as facial usually to suffer from phlegmonous zone, when preparation as " crease-resistant " frost or anti-aging cream (it not only plays surface action and promotes that skin rejuvenates), the skin treating characteristic of some possible components in the face proof or the test present composition.Therefore, owing to suffer from the lower structure sensitive properties in cellulitis zone, the new cellulitis therapeutic combination of preferred preparation adopts than active component high mixture ratio or that allow the higher range ratio than the facial skin cream of using of plan.

According to its effectiveness and zest, the useful ratio of blended TEWL elevating agents (being preferably alpha-hydroxy carboxylic acid compounds) is the 1-15 of composition weight in the topical therapeutic compositions, and the ratio of 5-10% intermediate range is preferred, particularly for lactic acid or glycolic.

When using biostearin as the cellular-restoring stimulant, useful ratio is about 0.005-6.0% weight, and about 1.0-4.0% is preferred, although can estimate to work in the ratio of 0.1-1.0 scope, effect is lower.

When using cerebroside or cerebroside mixture as barrier repair inhibitors of the present invention, the useful ratio of barrier repair inhibitors is about 0.01-5%, and the scope that is about 0.05-1% is preferred, and to be about 0.1-0.5% be particularly preferred.

Except as otherwise noted or by in the literary composition obviously as can be known, ratio used herein is for based on the weight ratio of total composition and relate to active component or the ratio of its suitable thing.The PH of therapeutic combination

According to the acidity of TEWL elevating agents, preferred pH is slightly acidic, in fact, believes to continue the destruction that acidity medium but that can tolerate promotes barrier.Therefore, the preferable range of pH is about 3.0-6.2, and 4.5-5.5 is preferred.Component optionally

But the dispensable important optionally feature of the present invention is to comprise the component of improving the direct outward appearance of cellulitis.This can and remove excess liquid by direct increasing blood flow and finish.Known diuresis material (as caffeine, theophylline, methyl salicylate and other materials similar) is highly effective.

In general, respectively or with the useful selectivity annexing ingredient that a kind of and alternative combining form is sneaked into cellulitis therapeutic combination of the present invention is diuretic, counter-stimulus and antioxidant, preferably add with valid density in the known topical cosmetic, for example be about 0.5-7.0% respectively, and 1-3% more preferably from about.

Diuretic promotes lymph discharge and catabolism of fat and causes that the short-term of the user of obviously suffering from the cellulitis disease improves.The example of suitable diuretic is a vasodilation, as caffeine, xanthine etc.

Counter-stimulus and antioxidant can be used for making the TEWL toleration of lasting rising to reach optimum state.The example of suitable antioxidant is kola extract, green tea, Aloe etc., and the example of suitable antioxidant is BHT, NDGA, vitamin E and C and propyl gallate.

The combined result of suitable optional ingredient is to produce comprehensive, equilibrated cellulitis treatment, significantly improves combining with the long-term structural adjustment of disease wherein fast, easily, and zest also is controlled simultaneously.Usage rate and frequency

The scope of the conventional usage rate of cellulitis therapeutic combination of the present invention as herein described is about the active acid component of every square centimeter skin 0.01-0.5 milligram, and wherein acid is low-molecular-weight hydrophilic acid such as alpha-hydroxy carboxylic acid compounds, the 0.05-0.2 milligram/centimetre ²Be preferred.Cosmetic cream usually with about 2-3 milligram/centimetre ²Ratio use.When having about 0.15-30 weight % active component proportioning, the possible ratio that active component is used is about 0.003 milligram/centimetre ²-0.9 milligram/centimetre ²Preferred range be about the 0.01-0.5 milligram/centimetre ², per unit skin area 0.05-0.2 milligram/centimetre ²Active component be preferred.When using the optimum ratio of active component of about total amount 7%, preferred usage rate be about the 0.15-0.2 milligram/centimetre ²

Whether no matter need the skin area for the treatment of, preferably with once a day or use this dosage twice.Use 3 or 4 wastes of product seemingly more continually every day, do not have to produce more useful effect, and lower frequency of utilization (being less than once a day) causes rendeing a service and reduces.Washing, can use after having a bath or swimming accidentally in addition up to the highest every day about for 6 times.Other barrier destroys to be handled

The compositions of 'alpha '-hydroxy acids and tretinoin constitutes destroys the water barrier in addition, and can peel off by horny layer, solvent extraction etc. increases TEWL.

Acetone: also find with acetone once a day or per two days one-time continuous rinsing a period of times (for example, two months) can destroy skin water barrier.Biophysics is measured this acetone rinsing processing of hint can alleviate above-mentioned long-term skin repair effect.Acetone can be removed the lipoid of formation and disturb the barrier reparation.Yet acetone has strong impulse, inflammable and poisonous, thereby does not recommend to use.As the data of report in the table 2 help to prove the present invention widely notion be not subjected to cosmetic composition to be used to destroy the restriction of skin water barrier and rising TEWL but extend to other physics and physicochemical treatment.

Band shape is peeled off: peeling off skin with the clear tape of sticker parcel is for 5-10 time another kind of effectively barrier destruction methods, and its increases TEWL2-10 doubly, the variation to some extent with the specific reaction of experimenter's individuality.Through the treatment in 8 weeks, can induce and the consistent male biological effect of useful cellulitis treatment.The positive findings of this treatment further proves technical scope widely of the present invention.Yet band shape is peeled off as commercial methods many shortcomings, includes but not limited to that the reaction that different individualities peels off band shape has a great difference and costliness, because must use Laboratory Instruments to detect barrier function.

Surfacial spalling: also find to use every day dense aqueous tenside solution can slowly destroy barrier.Twice use every day surfactant is enough as sodium lauryl sulphate (SLS).Use separately, the treatment in 8 weeks is interim, and SLS produces stimulation.Secular stimulation be controlled or be reduced to the sphingosine of adding 0.1% can effectively, thinks that like this treatment is the gentle embodiment that is enough to be used as reality of the present invention.Although can comprise the counter-stimulus of antioxidant and immediate effect, in containing the compositions of sphingosine, should not mix cerebroside yet.

If desired, use to prolong in the part that TEWL raises and the containing tretinoin and optionally in the cream of cerebroside, can use the non-white therapeutic agent of effective rising TEWL of skin repair process.Suitable carriers

In practical operation of the present invention, can adopt acceptable being generally used for of any cosmetics that the zest acid that skin recovers is discharged into carrier on the skin.Suitable carriers can be aqueous or hydration alcohol, or adopt oil or other lyophobic dust of dispersion form to be mixed with cream, lotion, nourishing agent etc. together.For topical therapeutic of the present invention, cream is preferred.If desired, carrier can be simple light water, although need a spot of alcohol or other organic solvent to dissolve or disperse a spot of hydrophobicity tretinoin used in the present invention and cerebroside.

If desired, can prepare active component in the acceptable hydration alcohol carrier of cosmetics, it contains the 40-75% water of having an appointment, preferred 55-65% or about 60% and about 25-55%, preferably about 25-35 or about 30% aliphatic alcohol.Although many lower aliphatic alcohols, all can the using of monohydroxy with polyhydroxy, ethanol and propanol are most preferred.Useful many additives and the supplementary material that are included in this class carrier are well known in the art, and what for example resist alcoholic acid desiccation up to the glycerol of 5% (being preferably 1 or 2%) as wetting agent and improve nourishing agent feels it is useful.Stabilizing agent, spice and dyestuff are the examples of other additive.

Other suitable carriers comprises the hydrophobic dispersion of about 5-60% (weight ratio) hydrophobic liquid that is dispersed in aqueous medium and the water.

If desired, can use the alkaline medium (for example sodium hydrate aqueous solution, arginine or triethanolamine (TEA)) of 0.1-10% (weight ratio) that pH regulator is arrived acceptable scope.Because skin of the present invention recovers the pH of stimulating composition it is renderd a service the generation material impact, therefore, it also may be ideal using suitable reducing.Any buffer agent that plays relevant effect with alkaline medium or buffer system should play certainly and make the effect of acid pH in above-mentioned, and preferably keep pH 4.5 or lower.The amount of buffer agent depends on its intensity, but is about 0.1-10% (weight ratio) usually, preferred about 1 or 2%.Some suitable reducing are TRIS () Tris buffer agent and phosphate buffer.

The example that part of the present invention is used for the cream preparation of structural cellulitis treatment is now described.

Embodiment

New three component cellulitis therapeutic agents in the cream carrier

Mix following component (" Concn. "=concentration and " Phase " number be the component group of different phase adding in the mixed process) by indication hereinafter:

Component Concn. Phase

Spermol (Cetearyl alcohol) 3.5 1

(with) ceteareth-20

GMS-PEG100 stearate 3.5 1

PEG-100 stearate 2.0 1

Dimethicone 51

Squalene 61

Capric acid triglyceride 41

Propyl parabene 0.1 1

Vitamin A palmitate 1.5 1

Water 45 2

Glycerol 52

Butylene glycol 62

Carbopol 941 0.2 2

Nipagin 0.25 2

Triethanolamine 3.1 3

Lactic acid 84

Cerebroside 1﹠amp; 2 0.15 5

pronalen?AC(Centerchem)????5??????????6

Spice an amount of 7

Water in right amount to 100-

％

To those skilled in the art, can be familiar with these set of dispense are made the method for the slick local cream that uses.80 ℃ of temperature also under agitation, oil phase (1) slowly is added to phase (2).After gained Emulsion begins to form, add phase (3) and make the cream retrogradation.Then add phase (4) and when cream is cooled to 55 ℃, add phase (5-7) component.Mix cool to room temperature.

In this embodiment, obviously vitamin A palmitate, lactic acid and cerebroside I and II are active component of the present invention and remaining component constitutes the cream carrier.The clinical trial of carrying out with new cellulitis therapeutic agent

In table 2, reported the result of the clinical trial of carrying out with new cellulitis therapeutic agent.Active component described in cream carrier described in the embodiment and the table and proportioning were carried out above therapeutic agent 2.1 to 2.4 was to use.Therapeutic agent 2.1-2.3 and 2.5 may be new, but is not the preferred embodiments of the invention for comparison purposes.

Table 2

Cellulitis therapeutic agent of the present invention

Therapeutic scheme	Blood flow	????TEWL ???g/m2/hr	TEWL increases %	Solidity	The lower limb diameter	Skin thickness	Cellulitis	Zest
									2.1) 8 all 12 weeks of 5% lactic acid b1	????1 ????X ????1.11	????2.07 ????2.33 ????2.47	????13 ????19	????X ????X ????27％	????X ????X ????-3％	????X ????X ????7％(ns)	????4.25 ????4 ????3.75	????1 ????1.5 ????1.5
2.2) 8 all 12 weeks of 10% lactic acid b1	????1 ????X ????1.07	????2.11 ????2.69 ????2.83	????27 ????34	????X ????X ????30％	????X ????X ????-1％	????X ????X ????10％(ns)	????4.25 ????3.5 ????3	????1 ????1.5 ????2
									2.3) 8 all 12 weeks of 10%LA/1%VAP b1	????1 ????X ????1.12	????2.03 ????3.47 ????3.67	????71 ????81	????X ????X ????29％	????X ????X ????-5％	????X ????X ????8％(-4％)	????4.25 ????3.5 ????2.75	????1 ????2 ????2.5
2.4) 8 all 12 weeks of 10%LA/1%VAP/0.5 %GSL b1	????1 ????X ????1.43	????1.91 ????3.87 ????6.88	????102 ????260	????X ????X ????43％	????X ????X ????-11％	????X ????X ????10％(-8％)	????4.25 ????2.75 ????2	????1 ????2 ????2.5
									2.5) every day in 8 all 12 weeks of 2X BUFFPUFF b1	????1 ????X ????1.07	????2.14 ????2.39 ????2.31	????8 ????8	????X ????X ????6％	????X ????X ????2％	????X ????X ????ns(ns)	????4.25 ????4 ????3.75	????1 ????1.5 ????2
2.6) every day in 8 all 12 weeks of 5-10X strip b1	????1 ????X ????1.17	????2.14 ????5.37 ????6.07	????151 ????184	????X ????11％ ????17％	????X ????X ????-8％	????X ????6％(ns) ????10％(-5％)	????4.25 ????3.75 ????3	????1 ????2.5 ????3
									2.7) 8 all 12 weeks of b1 washing with acetone the next day	????1 ????1.12 ????X	????2.17 ????6.92 ????X	????219	????X ????7％ ????X	????X ????-3％ ????X	????X ????6％(3％) ????X	????4 ????3 ????X	????1 ????2.75 ????X

The b1=baseline, LA=lactic acid, VAP=vitamin A palmitate, GSL=glycosyl sphingolipid, ns=there was no significant difference

In the table 2, obtain slightly high TEWL level by the treatment 2.1 of using lactic acid and 2.2, but even the level in the treatment 2.3 of 10% lactic acid composition that peels off by force also only be about 33%.Higher level the invention has the beneficial effects as follows desirable for acquisition.The treatment 2.3 that use is added with the vitamin A palmitate of lactic acid shows that TEWL raise about 71% and raise about 81% during in 12 weeks when 8 weeks.Although the such rising of TEWL substantially is higher than and is obtained by known Therapeutic Method, barrier of the present invention destroys treatment 2.4,2.6 and 2.7 and reaches high many TEWL levels and scope from 100% to 260%.Although the zest level slightly raises, but still can tolerate.

Shown in hurdle 1, the basis blood flow all shows gentle reaction to all treatments except that treatment 1.1 (tables 1), treatment 1.1 adopts tretinoin to show during 12 weeks increases by 27%, and surprisingly, adopt the treatment 2.4 of the preferred local adsorbing therapy of the present invention to show higher basic blood flow, increase about 43% during 12 weeks.

About fractionated total cellulitis disease in the right hand the 2nd hurdle, treatment 1.2-1.6, treatment 2.1 and treat the apparent improvement shown in 2.5 or inapparent or as mild as a dove.Treat 1.1 tretinoins and when 12 weeks, obtain gentle improvement, show and reduce by 1 classification point.All show improvement greater than 1 point and treat 2.2,2.3,2.4 and 2.6, wherein preferred embodiment of the present invention 2.4 shows improves the points of the classification above 2.Washing with acetone treatment 2.7 shows the improvement of 1 point, has proved viewpoint of the present invention.

Clinical zest classification display has safety assurance.The treatment of overstimulation is unacceptable.The zest classification reaches 3 beginnings and does not cater to the need and can notice washing with acetone treatment (treatment 2.7 is not beyond thought) to show 2.75 significant stimulation level when 8 weeks only and the embodiment demonstration zest ratio for the treatment of 2.4 preferred low irritants only is 2.

Lactic acid (treatment 2.1 and 2.2) significantly (about 30%) improves the lower limb solidity and does not produce further improvement when comprising biostearin (VAP) (treatment 2.3).Add the glycosyl sphingolipid that contains cerebroside, the present invention's (treatment 2.4) produces and further is increased to 43% significantly, shows the structural improvement of described lower-hierarchy.Peel off (treatment 2.6) and show the improvement of milder and " BUFF-PUFF " and washing with acetone (treatment 6.5 and 6.7) show that the solidity improvement is not obvious.

It is lower and other treatment is unconspicuous or only be to be situated between between the two that preferred treatment 2.4 significantly reduces degree that lower limb diameter, washing with acetone (treatment 2.6) reduce.

Although treatment 2.1-2.4 and 2.6 all show epidermis-corium skin thickness aspect some improve (the 1st number), treatment 2.3,2.4 only of the present invention and 2.6 shows reduce (data in the bracket) of subcutaneous area thickness.In fact, preferred 2.4 the treatment on two projects, all show best result.

In a word, the data show the present invention described in the table 2 treat 2.3,2.4,2.6 and 2.7 when producing strong TEWL rising effect of manying and rising than comparative treatment with the improvement of blood flow and skin texture, this be by comparative treatment can not obtain.The treatment 2.4 of the preferred present composition shows best result undoubtedly, has tangible TEWL rising effect and with bigger improving blood flow and significant macrostructure and the skin of microstructure and the improvement of deep tissues.

In order to estimate microcirculatory improvement, use ultrasonic analysis to carry out studying in great detail of blood flow as stated above, the gained result is presented among the following table 3-6.

Table 3

By laser-Doppler determining displacement microcirculation

Subject composition is to the influence of normal SkBF speed

To 5 experimenters, the result's that every experimenter's preceding arm measure is 10 times general introduction

Blood flow measurement

Test group	????＜1	Between the 1-3	Between the 3-5	Between the 5-7	????＞7
						Before the test	????3	????11	????22	????10	????4
After 8 weeks	????1	????9	????20	????14	????6
						After 16 weeks	????0	????5	????21	????17	????7
Stimulant	????0	????0	????0	????3	????47

Shown measuring of blood flow result is with arbitrary relative report of counting in the table 3.By last column of table 3 as seen, in 50 of all mensuration always counted, the blood flow that the control stimulation agent is stimulated had almost occupied all measure dot number greater than 7 count,, i.e. 47 in 50 points.Also can find out by this table, by the time from the beginning reading to each group after 8 and 16 weeks of cellulitis therapeutic combination treatment of test, counting of reading arranged by left-hand is right.This substance that shows that the use of subject composition causes higher blood flow measurement to be counted increases.

Counting in view of the blood flow of reading in the middle column (its value is between 3 and 5) almost keeps constant, 5 when being lower than 10 and 16 weeks of 3 count (the 1st hurdle and 2 hurdle measure dot number and) when being reduced to for 8 weeks by 14 of beginning.By the measure dot number that surpasses 5 before the visible treatment in the right hand two hurdles only is 14, but rises to 20 and be 24 when 16 weeks when 8 weeks.Generally speaking, blood flow is counted and is from left to right raise in time.Therefore, table 3 show use the cellulitis therapeutic combination when 8 weeks for to produce significant blood flow stimulation be effectively and continue to use therapeutic combination that blood flow is continued to increase, when 16 weeks, show further and improve.

Notice that the mensuration of data is to carry out in the table 3 on the normal no cellulitis skin of experimenter's forearm.These data provide the clearly situation of topical application compositions blood flow stimulus quality, eliminate simultaneously by suffering from the complication that anomalous structure produces in the cellulitis tissue.

Table 4

Microcirculation by the laser-Doppler determining displacement

The leg area circulatory problems

10 experimenter result's general introductions of blood flow rate: all show 2/3 stage cellulitis signal, every experimenter surveys

Measure 30 times

Test group	????＜1	Between the 1-3	Between the 3-5	Between the 5-7	????＞7
						Before the test	????68	????133	????42	????43	????14
After 8 weeks	????45	????123	????67	????52	????13
						After 16 weeks	????17	????67	????128	????71	????17
Do not suffer from phlegmonous matched group	????6	????51	????128	????110	????5

Reference data: 23.6 years old mean age of matched group, in this test method, use known stimulant such as Balsam of Peru makes blood flow rate rising 10-12.

Reported 300 measurement results that leg area is always counted on 10 experimenters in the table 4, the experimenter suffers from the cellulitis in late period, meets phlegmonous standard of 2 or 3 stages mentioned above.The bottom line reading is the control value of measuring on the phlegmonous skin area not suffering from.Table 4 data are read with the method identical with table 3.Pay particular attention to: show big count in measured zone less than 1 very low blood flow rate as suffering from phlegmonous result in the data on the 1st hurdle, the measure dot number less than 1 only is 6 in the cellulitis group and do not suffer from.

Local to use test cellulitis therapeutic combination of the present invention be effectively reducing aspect 1 measure dot number, 68 is reduced to 45 and the treatment of treatment during 8 weeks 17 during 16 weeks before treating.This is counted and is offset to the right and further skew to the right when 16 weeks when showing for 8 weeks, shows the lasting improvement of blood flow, is attributable to test the beneficial effect of cellulitis therapeutic combination.

Table 5

Microcirculation lower limb zone circulatory problems by the laser-Doppler determining displacement

Blood flow rate

2/3 stage of experimenter #1 cellulitis		46 years old, before the treatment
					????1.04	????1.22	????4.67	????4.56	????1.11
????2.45	????0.45	????0.56	????2.67	????0.98
					????2.22	????0.67	????0.67	????3.55	????0.76
????0.67	????2.19	????0.78	????2.78	????3.67
					????0.78	????3.11	????0.88	????2.55	????3.56
????2.67	????3.42	????5.6	????8.89	????5.66
2/3 stage of experimenter #1 cellulitis		46 years old, treated for 16 weeks after
					????1.33	????1.92	????5.11	????5.03	????1.44
????2.55	????1.59	????2.56	????3.03	????1.22
					????2.78	????2.22	????3.12	????4.03	????1.33
????1.87	????2.45	????1.44	????3.11	????3.99
					????1.12	????3.84	????1.09	????2.77	????4.03
????3.04	????4.30	????6.15	????6.89	????5.88

Table 5 has been reported studying in great detail that cellulitis compositions of the present invention acts on an experimenter.Measurement with two groups of significant data report relative blood flows.In 30 comparing property of diverse location measurement of experimenter, the reading before the first half of this table report treatment and reading after the latter half report 16 weeks of treatment of showing.Therefore, the reading of any ad-hoc location of this table the first half can be shown the influence that the reading of opposite position in the latter half compares the confirmed test therapeutic combination with this, i.e. treatment " preceding " and " back " comparison.

Have only an exception, all readings all have raising after treatment.Exception is unusual 8.89 high readings.This may be owing to the low blood flow of adjacent area.All are lower than 1 reading and are elevated to more than 1, and wherein some is very significant.Therefore, 0.67 2.22 after being elevated to treatment before the 3rd reading in the 2nd hurdle is by treatment.And table 5 shows the overall improvement of suffering from the extensive region blood flow highly significant of cellulitis lower limb an experimenter, is attributable to be treated by the present invention the improvement of the structural microcirculatory vascular that causes.

Table 6

The ultrasonic analysis of skin thickness

The meansigma methods of 10 experimenter's shank measurement results

Test group	Epidermis/dermis thickness	Epidermis/dermis density	Subcutaneous thickness	Subcutaneous density
					Before the treatment	??2.34	??68％	????4.12	???33％
After treating for 8 weeks	??2.56	??74％	????3.99	???41％
					After treating for 16 weeks	??3.12	??82％	????3.25	???62％

After table 6 showed 8 weeks of treatment, epidermis-corium skin layer thickness increased and subcutaneous skin area shows and reduces.Two density show that all significance increases.Obtain further to improve significantly with 16 week of the combination treatment back of using.These data suggest compositions of the present invention produces significant structural improvement aspect skin, this can produce secular beneficial effect to the cellulitis disease.

The present invention is specially adapted to provide the new cellulitis and the preparation and the method for skin treating for cosmetics industry.

Although more than described illustrative embodiment of the present invention, certainly can understand that to carry out various modifications be conspicuous for those of ordinary skills.These are modified within the spirit and scope of the present invention, and it only limits and define by additional claim.

Claims (31)

1, a kind of method for the treatment of the cellulitis disease, it is characterized in that being included in 8 weeks to finish the required treatment of cellulitis during, the partial water barrier is destroyed therapeutic agent be used to suffer from the skin area of cellulitis tissue continuously to induce the slow rising that water is lost by epidermis, up to reaching required phlegmonous improvement.

2, the method for claim 1 is characterized in that described TEWL is in described continuous 8 week of treatment back rising at least 100%.

3, the method for claim 1 is characterized in that described continuous treatment continued for 4 weeks at least again.

4, the method for claim 1 is characterized in that described treatment is effective to the described TEWL at least 100% that raises and from 8 to 26 weeks at least described treatment phase.

5, the method for claim 1 is characterized in that described treatment comprises the local cosmetic composition that contains following component that uses, and its proportioning is calculated by the weight of compositions:

A) cosmetics hydroxy carboxylic acid compatible, that reduce pH and rising TEWL, proportion is about 1-15%; With

B) biostearin cellular-restoring/differentiation regulator, proportion is about 0.005-6.0%.

6, the method for claim 1 is characterized in that described cosmetic composition also contains:

C) cerebroside barrier repair inhibitors is to suppress the reparation of skin water barrier, and proportion is about 0.01-5%.

7, the method for claim 6 is characterized in that the local use twice every day of described cosmetic composition, uses for 8 weeks at least.

8, the method for claim 1 is characterized in that described cosmetic composition contains the lactic acid of the 5-10% that has an appointment, hydroxyacetic acid or salicylic acid, the cerebroside material of the vitamin A palmitate of about 0.3-3.0% and about 0.1-0.5%.

9, the method for claim 1 is characterized in that described treatment is selected from the skin water barrier destruction treatment of the exfoliant, mechanical erosion and the solvent extraction hydrophobicity skin barrier composition that use the solution form.

10, a kind of every day, the part was used to suffer from the cellulitis therapeutic combination of cellulitis skin area, and described compositions uses for the part that TEWL is raise at least 100% is effectively, and described therapeutic combination comprises that proportioning is calculated by the weight of compositions:

A) cosmetics hydroxy carboxylic acid compatible, that reduce pH and rising TEWL, proportioning is about 1-15%;

B) biostearin cellular-restoring/differentiation regulator stimulant, proportioning is about 0.005-6.0%; With

C) suppress the cerebroside barrier repair inhibitors that skin water barrier is repaired, proportioning is about 0.01-5%.

11, the cellulitis therapeutic combination of claim 10 contains lactic acid, hydroxyacetic acid or the salicylic acid of the 5-10% that has an appointment, the cerebroside material of the vitamin A palmitate of about 0.3-3.0% and about 0.1-0.5%.

12, the cellulitis therapeutic combination of claim 10, contain at least a optional ingredient that is selected from following material: the diuretic of stimulation blood flow, control are by described TEWL elevating agents or by the inductive irritating counter-stimulus of described cellular-restoring/differentiation regulator and antioxidant and composition thereof.

13, a kind of cellulitis therapeutic combination contains TEWL elevating agents, the skin cell differentiation regulator of effective dose and suppresses the barrier repair inhibitors that skin water barrier is repaired.

14, the cellulitis therapeutic combination of claim 13 is pressed composition weight and is calculated, and contains the TEWL elevating agents of 1-15%.

15, the cellulitis therapeutic combination of claim 14, the proportioning that it is characterized in that described TEWL elevating agents are that about 5-10% and described TEWL elevating agents are lactic acid, salicylic acid or hydroxyacetic acid.

16, the cellulitis therapeutic combination of claim 15 is characterized in that described cellular-restoring/differentiation regulator is the biostearin that proportioning is about 0.005-6.0% weight.

17, the cellulitis therapeutic combination of claim 13 is characterized in that described barrier repair inhibitors is the cerebroside that proportioning is about 0.01-5.0% weight.

18, the cellulitis therapeutic combination of claim 13 is characterized in that containing at least a optional ingredient that is selected from following material: the diuretic of stimulation blood flow, control are by described TEWL elevating agents or by the inductive irritating counter-stimulus of described cellular-restoring/differentiation regulator and antioxidant and composition thereof.

19, the cellulitis therapeutic combination of claim 13 is characterized in that containing lactic acid, the vitamin A palmitate of 0.5-4.0% and the cerebroside of 0.1-0.5% of 5-10%.

20, the cellulitis therapeutic combination of claim 13, it is characterized in that using continuously 8 all backs is effective to TEWL rising at least 100%.

21, a kind of every day part of preparing is used to suffer from the cellulitis therapeutic combination method of cellulitis skin area, described compositions uses for the part that TEWL is raise at least 100% is effective, described method is characterised in that and comprises, mixes following component by the proportioning that composition weight calculates:

A) cosmetics hydroxy carboxylic acid compatible, that reduce pH and rising TEWL, proportioning is about 1-15%;

B) biostearin cellular-restoring/differentiation regulator stimulant, proportioning is about 0.005-6.0%; With

C) suppress the cerebroside barrier repair inhibitors that skin water barrier is repaired, proportioning is about 0.01-5%.

22, the method for claim 21 is characterized in that containing have an appointment lactic acid, hydroxyacetic acid or the salicylic acid of 5-10%, the cerebroside material of the vitamin A palmitate of about 0.3-3.0% and about 0.1-0.5%.

23, the method for claim 21 is characterized in that containing at least a optional ingredient that is selected from following material: the diuretic of stimulation blood flow, control are by described TEWL elevating agents or by the inductive irritating counter-stimulus of described cellular-restoring/differentiation regulator and antioxidant and composition thereof.

24, a kind of method for preparing the cellulitis therapeutic combination is characterized in that comprising TEWL elevating agents, the skin cell differentiation regulator that mixes effective dose and suppresses the barrier repair inhibitors that skin water barrier is repaired.

25, the method for claim 24 is characterized in that calculating by composition weight, contains the TEWL elevating agents of 1-15%.

26, the method for claim 25, the proportioning that it is characterized in that described TEWL elevating agents are that about 5-10% and described TEWL elevating agents are lactic acid, salicylic acid or hydroxyacetic acid.

27, the method for claim 26 is characterized in that described cellular-restoring/differentiation regulator is the biostearin that proportioning is about 0.005-6.0% weight.

28, the method for claim 24 is characterized in that described barrier repair inhibitors is the cerebroside that proportioning is about 0.01-5.0% weight.

29, the method for claim 21 is characterized in that containing at least a optional ingredient that is selected from following material: the diuretic of stimulation blood flow, control are by described TEWL elevating agents or by the inductive irritating counter-stimulus of described cellular-restoring/differentiation regulator and antioxidant and composition thereof.

30, the method for claim 24 is characterized in that containing lactic acid, the vitamin A palmitate of 0.5-4.0% and the cerebroside of 0.1-0.5% of 5-10%.

31, the method for claim 24, it is characterized in that using continuously 8 all backs is effective to TEWL rising at least 100%.