HU221141B1 - Composition for cellulite treatments and process for its preparation - Google Patents

Abstract

Field of the Invention The present invention relates to a daily topical application to cellulite therapy in areas affected by acellulitis, comprising at least 100% increase in transepidermal water loss (hereinafter: TEWL) after at least 8 weeks of topical application, and comprising the following participants in the composition weight: a) To increase the TEWL level, a cosmetically compatible pH-lowering hydroxycarboxylic acid in an amount of 1-15%; b) a retinoid cell regeneration / cell differentiation modulator excipient in an amount of 0.005 to 6.0%; and c) a cerebrozide barrier inhibitor in the amount of 0.01 to 5% to prevent the restoration of the water barrier of the skin. ŕ

Description

EXTRACT

FIELD OF THE INVENTION The present invention relates to a composition for use in cellulite therapy for daily topical application to areas affected by cellulitis, which comprises at least a 100% increase in transepidermal water loss (hereinafter referred to as TEWL) after 8 weeks of topical application. :

a) a cosmetically compatible, pH-lowering hydroxycarboxylic acid for increasing TEWL levels in an amount of 1-15%;

b) a retinoid cell regeneration / cell differentiation modulator stimulator in an amount of 0.005-6.0%; and

c) a cerebroside barrier repair inhibitor in an amount of 0.01% to 5% to prevent skin water barrier repair.

The scope of the description is 18 pages

HU 221 141 B1

HU 221 141 Β1

FIELD OF THE INVENTION The present invention relates to topical cellulite treatment methods, and to compositions and methods for providing structural improvement in cellulite when applied over a long period of time, e.g.

By "cellulitis" is meant an abnormal mass accumulation of fat cells in the skin, which results in aesthetically unfavorable, localized visible patches on the skin surface.

The term "cellulitis" was coined by Nicole Ronsard in the 1970s (see Webster's New Universal Unabridged Dictionary, 2nd edition, Dorset & Barber, 1983), denoting a widespread condition in which abnormal deposition of irregular fat masses is aesthetically unfavorable. causes lesions on the normally smooth surface of the skin.

From a physiological point of view, cellulitis is caused by the degeneration of the microcirculation on the areas of the body that tend to be fat-deposited. Severe cellulitis is characterized by degeneration of blood vessels under the skin, decreased blood flow, thinning of the epidermal and dermal layers of skin, the presence of hard fat masses surrounded by protein in the subcutaneous areas, and the accumulation and storage of tissue fluids. This results in the appearance of "orange skin" on the skin.

Cellulitis is most common in the thigh, buttock, and upper arm, is less common in the distal limb, upper body, and abdomen, and is generally not significant in the face, neck, hands, and feet. Although often associated with obesity, cellulitis can occur on its own in individuals with normal or near normal weight. It is more common in women than men and more common in Caucasians than individuals with darker skin.

Cellulitis, by adversely affecting a person's appearance, can have profound psychological effects, diminishes the self-esteem of individuals suffering from it, and can seriously undermine the healthy psychological development of some young women and men. Accordingly, there is a great need for effective medical treatment of cellulitis.

Known methods of treating cellulite include local mechanical effects, topical application of chemicals, gymnastics, dietary counseling, and combinations of these therapies. An effective treatment regimen is a combination of diet and exercise, followed for a long time and strictly. Many people are looking for lighter therapy. As I have demonstrated in the clinical studies presented herein, known, easy-to-apply topical treatments provide only superficial improvement and do not significantly improve structural defects.

In the treatment of cellulite according to Stewart's U.S. Patent No. 4,829,987, a compress impregnated with a mineral saline solution is applied to the corresponding body part, followed by passive movement of this body part. This treatment is too uncomfortable or too burdensome for many.

Massage improves microcirculation and stimulates exfoliation, thereby improving the smoothness of the skin surface and increasing blood flow, but only temporarily. Henderson

U.S. Patent No. 086,922 discloses a massager and a method for treating cellulite. The device contains a plurality of pressure-resilient balls that are applied to the body areas to be massaged.

Heat treatment also stimulates microcirculation and can produce temporary improvement, but not long-term structural improvement.

Body lotions, tonics and creams that are presumed to contain active biological material such as witch hazel, goiter (horse chestnut), horse chestnut, algae, sea water or escin may cause temporary and poor microcirculation improvement, but are at best moderately effective.

The aforementioned massages, heat treatments and biological preparations are not aimed at the problem of skin regeneration, liposuction, retention of tissue fluid or regeneration of blood vessels.

Diuretics (herbal supplements that are generally more popular) promote lymphatic circulation, which provides good short-term symptomatic effects, but does not target the problem of skin lesions, fat loss or blood vessel regeneration in the long term.

High concentrations of caffeine, theophylline and other xanthines appear to be effective as diuretics and as lipid enhancers. Aminophylline, a popular active ingredient in thigh creams and thigh smoothing creams today, appears to be potent diuretic in enhancing lymphatic flow but has been reported to have significant toxic side effects (see The Merck Index, 11th edition, Merck Co., Inc. 1989, 477) ). These agents do not affect the basic structural changes of the skin and blood vessels.

Certain cosmetic formulations contain modified caffeine derivatives as the active ingredient disclosed in Trebosc et al., U.S. Patent No. 5,030,451. According to Trebosc et al. (Column 9, lines 15-20), the formulations developed "have excellent and long-lasting lipolytic effects and have thus been shown to be very effective in consumer programs and in the treatment of cellulite".

However, no efficacy data were reported. In column 1, pages 61-65. In turn, Trebosc et al., argue that the faster penetration through the skin provides these agents with priority in the treatment of cellulitis.

Mausner, U.S. Patent No. 5,215,759, refers to the use of methylsilanol theophylline acetate alginate and methylsilanol mannuronate as anti-cellulite agents. In the absence of explanation of the invention, the effect of these substances is presumably the same as that of diuretics.

The disadvantage of stimulant formulations available on the consumer market for treating cellulite (containing caffeine, aminophylline or related compounds as an active ingredient) is that the drug may be marketed as a medicine,

EN 221 141 Β1 to become cosmetic products sold under the counter. Repeated long-term use can cause adverse side effects and may be restricted by state regulations. A further disadvantage is that these agents do not affect the structural problems underlying the skin and blood vessel lesions.

Exfoliating granules act mechanically, rubbing the surface layers of the skin, smoothing the surface of the skin and promoting skin regeneration, but do not assist in lymphatic circulation, long-term microcirculation regeneration or fat loss. Exfoliating granules are hard particles suspended in creams or gels that are used to rub or massage the skin to achieve mechanical exfoliation. Granules are usually polyethylene beads, but natural particles such as peach seeds or apricot kernels are also used. A further disadvantage of these products is that irritation is difficult to control.

Topically applied retinoids, such as those described by Klingman in U.S. Patent 5,051,449, may have a limited effect on cellulitis. Klingman reports qualitative results from comparative efficacy studies with topical application of a retinoic acid formulation and an unspecified non-drug "target" cream for more than six months. The described beneficial effects include thickening of the skin, increase in the number of new blood vessels, and detection of moderately significant improvement (in cellulitis) using a pinch test (column 6, lines 50-61). Quantitative data are not provided, so the value of Klingman's claim in the treatment of cellulitis cannot be evaluated by a person skilled in the art.

Many require and expect greater effectiveness from a cellulite treatment than the modest improvement after six months of treatment. The concentrations of retinoic acid used should be limited to avoid causing irritation (see Klingman Column 2, lines 59-60) so proper efficacy cannot be achieved by increasing the dose. Thus, retinoic acid treatment does not provide sufficiently long-lasting cellulite treatment, so more effective topical treatments are needed. In contrast to Klingman's unsupported generalizations, in quantitative clinical studies, I found that retinoic acid did not provide significant thickening of the skin after three months of daily treatment. Accordingly, there is a need for an easy-to-use cellulite treatment that provides structural improvement within a reasonable period of time.

The present invention relates to a marketable formulation which is easy to apply for topical treatment of cellulite and more effective than hitherto available and which results in significant structural improvement within a reasonable period of time. The present invention provides a topical agent for treating cellulitis which, when applied continuously over a long period of time, results in progressive structural improvement. Preferred embodiments promote significant thickening of the skin in areas affected by cellulitis of the body, thereby improving tissue hardness, reducing thigh diameter, and increasing blood flow through improved microcirculation.

FIELD OF THE INVENTION The present invention relates to a composition for use in cellulite therapy for daily topical application to areas affected by cellulitis, which increases the transepidermal water loss level (hereinafter referred to as TEWL) by at least 100% after 8 weeks of topical application.

a) a cosmetically compatible, pH-lowering hydroxycarboxylic acid for increasing TEWL levels in an amount of 1-15%;

b) a retinoid cell regeneration / cell differentiation modulator stimulator in an amount of 0.005-6.0%; and

c) a cerebroside barrier repair inhibitor in an amount of 0.01% to 5% to prevent skin water barrier repair.

SUMMARY OF THE INVENTION The present invention solves the above problem by providing a highly effective composition for treating cellulite which suspends the water barrier properties of the skin in the areas covered by the cellulite tissue for a long period of time sufficient to provoke significant skin regeneration and blood vessel regeneration.

Permanent suspension of the skin barrier causes problems. Obviously, the suspension process should not be so severe as to damage sensitive skin layers or cause pain or significant irritation. A further advantage of the composition according to the invention is that, when applied, it provides more than a temporary effect by permanently suspending the barrier function. As the dam's proper functioning is a vital condition, its suspension triggers natural processes that quickly restore the dam. More specifically, the operation of the barrier should be suspended for continuous treatment for weeks, for example eight or more weeks.

Transepidermal water loss (TEWL) can be used to monitor barrier function. If TEWL levels were measured after 12 weeks of treatment, with measurements taken at least eight hours after the last treatment, known cellulite treatments other than retinoids had little or no lasting effect on barrier function, and some people seem to lower TEWL levels. The combined use of retinic acid, an exfoliating agent and at least another exfoliating agent, increased TEWL only to a small extent within twelve weeks.

Despite these difficulties, I have found a different treatment regimen that effectively halts the barrier and significantly increases TEWL levels after eight weeks or twelve weeks when used continuously for prolonged periods, such as once or twice daily.

Barrier-suspending treatments useful in the practice of the composition of the present invention include direct physicochemical damage to the lipid structure of the stratum comeum by dermatological application.

It can be treated with organic solvents of low molecular weight non-polar lipids, such as acetone, or with a dermatologically active surfactant such as sodium lauryl sulfate. During these treatments, the barrier component lipids are released and removed. However, it is preferable to use a topical cosmetic composition as a cream to be absorbed into the skin. Such a cream contains chemically active barrier suspension components in an aesthetically beneficial odorless formulation. Other suitable barrier suspension treatments are known or obvious to those skilled in the art.

I have also found that inhibition of skin lipid synthesis can prevent or control water barrier repair and significantly increase long-term 8 or 12-week increases in TEWL levels. As stated by Proksch et al., "Barrier Function Regulates Epidermal Lipid and DNA Synthesis" (British Journal of Dermatology (1993) 128, 473-482), studies in rats have shown that the inhibition of barrier function by free fatty acids, sphingolipids and cholesterol causes in the living layers of the epidermis and leads to the repair of the barrier.

The compositions of the present invention inhibit this synthesis to reduce the amount of free fatty acids, sphingolipids and cholesterol available to restore the water barrier, for example by topical application of absorbable cerebroside. Other suitable inhibitors are known or obvious to those skilled in the art. Where cellulite treatment removes or rinses skin lipids, the lipid synthesis inhibitor should be administered in a separate step from the barrier suspension. Where barrier suspension is achieved by topical absorption, a lipid synthesis inhibitor may also be present in the formulation.

Such use of a lipid synthesis inhibitor can prevent rapid restoration of the water barrier and result in enhanced structural improvement in cellulitis.

I have also found that transepidermal water loss (i.e., a TEWL that is capable of direct measurement) when taken over the entire duration of long-term cellulite treatment for eight weeks or more is a valuable parameter for monitoring the effectiveness of cellulite treatment. The extent of TEWL elevation, if sustained, is also a useful indicator of the efficacy of cellulite treatments, the benefits of which become apparent only after prolonged use, for weeks, or more likely after two to six months. As a result of performing TEWL measurements on different cellulite treatment modalities, which to my knowledge have not been used to evaluate the merits of cellulite therapies, I have found that known therapies cause only a temporary, short-term increase in TEWL and none create TEWL. weeks to months. I have found that by provoking a substantial and sustained rise in TEWL, a valuable structural level improvement in cellulitis can be achieved.

In the course of monitoring TEWL levels induced by various treatments, I have developed novel formulations for the treatment of cellulitis that are effective in maintaining chronic or continuous elevation of TEWL levels over a generally treatment period of usually eight to twelve weeks. Preferably, my new formulations increase the TEWL level by at least one hundred percent over an extended period of time, eight weeks or more. Two to three percent or more, significantly greater growth during the treatment period is desirable.

In one aspect of the invention, there is provided a composition for treating cellulite which is suitable for continuous treatment of a localized water barrier in the affected skin areas, resulting in sustained elevated transepidermal water loss from eight weeks to achieving the desired improvement in cellulitis. The treatment may be administered once or twice daily in the usual manner.

The new formulations can be used in combination with a variety of topical mechanical skin treatments, such as rubbing, stripping epidermis, and solvent extraction. Both treatments must be performed with sufficient strength or aggression to raise the TEWL levels by one hundred percent or more, as noted above, and for a longer period of time. The preferred mode of treatment utilizes a chemical composition that is topically applied, preferably in an emollient (emollient) or cream formulation, and maintains elevated TEWL levels when used several times daily or once daily.

It will be appreciated that the aggressiveness of the compositions of the present invention should be controlled so that it can be tolerated for weeks or months without causing severe or painful irritation, redness, peeling or severe discomfort. However, the mild onset of these symptoms is tolerable for many people for a short time.

In another aspect, the invention provides a cellulitis treatment composition comprising a TEWL-leveling agent that causes immediate or short-term elevation of TEWL levels in association with a barrier suspending agent that maintains elevated TEWL levels. Preferably, the composition comprises a cell regenerating or differentiation promoting agent for maintaining skin regeneration processes. It is further preferred that the composition also comprises a skin lipid synthesis inhibitor to prevent premature restoration of the water barrier and to enhance the cellulite therapeutic effect of the composition.

In a preferred embodiment of the present invention, the TEWL level-increasing agent is a cosmetically compatible, pH-lowering hydroxycarboxylic acid, which preferably has an exfoliating effect and is at least moderately soluble in water or in a hydroalcoholic vehicle to form a cosmetic composition. Such acids include alpha-hydroxycarboxylic acids, in particular lactic acid and glycolic acid, as well as other hydroxycarboxylic acids such as 2-hydroxybenzoic acids, in particular salicylic acid. The efficacy of these acids appears to be related to their ability to lower the pH in the intercellular fluid of the skin. The acid to be used and its concentration4

The B1 is selected by eating the desired increase in TEWL without excessive irritation.

A preferred barrier repair inhibitor is retinoic acid or a derivative thereof, and a particularly preferred retinoic acid derivative is vitamin A palmitate. The clinical trials I conducted, including in vivo studies of the human response to various cellulites, which are detailed below, show an unexpected beneficial interaction between lactic acid and vitamin A palmitate, which is valuable in the long-term treatment of cellulitis. .

A preferred lipid synthesis inhibitor is cerebroside or cerebroside-rich material. Some optional components may be diuretics to stimulate blood flow and excess fluid, and anti-irritants to reduce the irritant side effects of TEWL-raising or cell-regenerating stimulants.

The proportions of the ingredients of the compositions of the present invention which are commercially available as topical cosmetic or therapeutic emollients, lotions or tonics and the amounts to be used are described below. A preferred cosmetic composition is a cream suitable for daily massaging or simply for application or rubbing by the consumer. Other such quantitative parameters that may be used to achieve the advantages of the invention will be apparent to those skilled in the art.

As shown in the experimental data described below, the compositions of the present invention achieve a new quality in the efficacy of cellulite treatment and are able to significantly increase skin thickness, improve blood flow and promote vascularization. As mentioned, these and other product performance characteristics are carefully defined.

It is known that the blood supply to cellulite areas is inadequate. Clinical trials of the compositions of the invention, described below, have shown that blood circulation is immediately improved by 4-8 hours and, in chronic use, by 8-16 weeks. The long-term increase in blood flow is due to angiogenic effects, thus reducing damage to cellulite-affected tissues. Skin thickness also increased in the epidermal-dermal areas of the skin and increased in the subcutaneous region after 8 to 16 weeks of treatment. More importantly, the improvement in tissue density indicates a positive effect, and the dermis and epidermis have become stronger and more elastic, and excess fat and fluid have been reduced in the subcutaneous areas. These structural improvements are due to the use of the compositions of the invention.

Description of cellulitis

The pathogenesis of cellulitis is generally described as a process of three or four stages. Herein, for purposes of presenting a model explaining the pathogenesis of cellulitis, it is described as a three-step process, without limiting the scope of the invention, with the following features:

Stage 1

The blood vessels expand and become permeable in the affected areas. At this stage, surface effects are minimal and treatments to improve vessel integrity and remove excess fluid can be very effective. Laser Doppler examinations may also show abnormal blood flow and biopsy examinations may also show underground defects.

Stage 2

The metabolism of fat cells is greatly disturbed, and the amount of fat and cell size are dramatically increasing. Fat lumps are formed by the adherence of compacted fat cells. Vascular integrity is further reduced and dermal and epidermal lesions are observed. Examples of such lesions are thinning of the epidermis, reduction in the number of blood vessels in the dermis (vascularization), unevenness and grayness of the skin surface due to insufficient microcirculation, and increased surface heterogeneity, ie the onset of the initial symptoms of "orange boron".

Stage 3

In stage three, persistent microvascular insufficiency can be observed with continued fluid accumulation, increased fat formation and reduced fat metabolism rates. Fat cells are compacted, adhered to and surrounded by a collagen envelope made up of abnormal collagen. These detached knots can be a few centimeters in diameter, feel quite well on the surface, and can be quite painful. The fat nodules with collagen repress the capillary network and represent areas where blood flow is reduced. Subcutaneous adipose tissue is severely damaged by fluid retention, the presence of fat lumps, and gravity. The cellulite appeared, the unevenness of the surface was striking. The epidermis and dermis are thinner, less firm and organized. The lesions are easily discernible on the skin surface and are aesthetically unfavorable and confusing to most people with advanced cellulitis.

Definition of cellulitis

A number of biophysical techniques can be used to measure and document cellulitis, such as directly measuring strength and elasticity, such as laser doppler blood flow measurement, thermography, and of course, medical history. Various of these techniques may be useful in determining the effectiveness of a particular cellulite treatment, depending on the symptoms targeted by the treatment. Some additional methods have been developed to evaluate the clinical improvement achieved by the cellulite treatment modalities and compositions described herein. Here is a brief, non-exhaustive list of these methods:

Thigh Measurement: monitors the effectiveness of products that work to thin out cellulite areas. It works best with a diet that includes diet and exercise. Cheap, non-sensitive and non-discriminatory investigation.

Laser Doppler tests: they are capable of detecting a reduction in vascular supply and the effect of a product on the vascular system. A short-term vasodilation caused by a product is easily visible. The angiogenic (vascular) effect produced by products that are more effective in treating the disorder and iron5

Longer-term monitoring of circular integrity can be monitored but more complex and requires good technical expertise.

Ultrasound scans: very effective techniques for detecting changes in subcutaneous adipose tissue, blood vessel distribution, and epidermal and dermal integrity. Skin thickness can be measured by computerized ultrasound scan of the skin. Ultrasound scanning provides a non-invasive way to determine the thickness of the epidermis and dermis objectively and accurately.

Thermography: The laser doppler is more advantageous in that insufficient blood supply can be easily graphically represented.

Cellulitis classification: Cellulitis severity grades, presented below, are aggregated assessments that result from visual examination of skin flaccidity and surface lesions, and perception of the lumps.

Histology: Histology (examination of skin biopsies) can detect changes in collagen and elastin synthesis, the formation of new blood vessels, and describe structural changes. Histology is usually the most accurate way of describing the size of a cellulite lesion and determining the true effects of a product, but it has invasive and other drawbacks.

Photography and Copies: These are of limited value. Consumer impressions are often more reliable. Cellulitis is a "macro" surface lesion and copies often show too much detail. Photos are difficult to evaluate.

Preferred embodiments of the present invention pertain to compositions that induce a diminution of the water barrier function of the skin, thereby inducing the release of factors in the skin that initiate a skin regeneration process. By suspending the barrier function, the skin reacts as if it had been damaged and initiates a general restorative process that increases dermal and epidermal metabolism and angiogenesis (i.e., vascularization) by regulating as yet undefined skin-signaling substances.

Observations made during the recording process of the data disclosed herein indicate that massages, such as the use of abrasive sponges [BUFF-PUFF (trademark)] and exfoliating granules, even if they temporarily increase TEWL levels for a few minutes or hours after application, are not maintained. maintain this effect. Based on these observations, I concluded that sustained elevation of TEWL is required to achieve the desired structural improvements.

Similarly, exfoliating treatments such as facial scrubs ("peeling") with 20-30% lactic or glycolic acid or equivalent acid once or at intervals, such as weekly, increase TEWL levels for a few days after treatment but do not. achieve the desired skin regenerating and cellulite enhancing effects. Again, according to the concept of the present invention, these failures are due to a lack of treatment that does not provide a sustained rise in TEWL for a sufficient period of time, e.g., at least eight weeks.

The experimental data presented below show that there was no known prior art cellulite treatment that resulted in a permanent suspension of barrier function and one that would produce a sufficiently significant effect and that promised cellulite areas would be promising. it can be easily applied in the form of local topical treatment to restore it to normal or near-normal condition.

Determine the TEWL level

TEWL measurements were performed on subjects undergoing various cellulite treatments, including those treated with both conventional and inventive formulations. Baseline blood flow determination, thigh diameter measurement, and comparative clinical classification of cellulitis and induced irritation were also performed.

A SERVO-MED evaporator (evaporimeter) was used for TEWL level determinations. This device has a moisture trap portion that seals a skin surface area. The device measures the moisture-dependent conductivity and reads the TEWL levels when the equilibrium state is reached. The test skin surface was pre-conditioned with air at 68-71 ° C and 30-40% relative humidity. The sensitivity of the device used in the assays described below is approximately 10%.

In the clinical studies described below, the protocol included the determination of TEWL levels in these areas of skin, which received topical cellulite treatment with one cellulite or other comparative topical treatment twice daily and shortly before morning treatment. In many cases, for example, treatment was performed at about 10 am and about 6-8 pm, while TEWL levels were determined at about 9 am, about one hour before morning treatment, and at least eight or more likely twelve hours after evening treatment.

Numerous prior cellulite treatments have been evaluated for their TEWL-leveling ability using the procedure described in the preceding paragraph. Basal blood flow was assessed by laser doppler determination and compared to a comparative scale. The thigh hardness and diameter were determined in a manner known to those skilled in the art, and the skin thickness was determined by ultrasound as described above. Skin thickness was determined for the epidermal-dermal layers (value 1) and for the subcutaneous region (value 2). As the skin structure improves during treatment, the epidermal-dermal layer thickens (increase in value 1) and the soft, fluid-rich subcutaneous layer decreases (negative value in parentheses) as the microcirculation removes excess fluid. The severity of cellulitis was clinically evaluated on a comparative scale as well as on irritation.

In the following clinical trials, cellulitis was graded according to the following scale.

HU 221 141 Β1

0 No surface irregularities or defects 1 Visible discrete depressions on the surface or pits 2 More linear furrow visible (indentations on the surface) 3 Multiple visible and tactile furrows and indentations, uneven skin tone, discoloration 4 Like grade 3, but with tactile underground knots.

The degree of irritation was measured by comparative chromatographic determination of skin color using industry standard procedures (Minolta Chroma Metei, Minolta Camera 15 Co. Ltd.). The subjective sensation of stings, burns, and redness was further recorded after application, and the data was combined with a clinical irritation index ranging from 0 to 5, 0 for no visible or perceptible irritation, and 5 for severe irritation. 20

Clinical trials with previous cellulite treatments

The results of clinical trials with prior conventional therapies are shown in Table 1 below. Each of the previous agents in Table 1 was administered twice daily during the study period. Other embodiments of the present invention are described in Table 2 below.

1.1. Rethin A (trade mark) treatment was performed at a concentration of 0.5% in a simple cream base.

1.2. During the treatment the massage was done by hand and using a mechanical device, using olive oil as the massage oil.

1.3. caffeine was 2% by weight and theophylline 0.2% by weight in a simple gel.

1.4. During the treatment, we applied heat and xanthines using a product called "Cellular Body Controuring Gel" from La Prairie, which increased the temperature of the skin surface by a chemical reaction.

1.5. peeling treatment was mechanical peeling in a carbopolgel with 5% by weight polyethylene beads. Twice vigorously rubbed and washed.

1.6. vasoactive herbs for treatment are from the commercial product Orlane, "Rhythme Du Corps".

Table 1

Evaluation of conventional cellulite treatments

Treatment blood Flow TEWL, g / m ² / hour Hardness thigh Diameter Skin thickness, s Ccllulitis- classification Irritation- classification 1.1. Retin A * 0.5% starting point 1 2.17 X X X 4 1 8 weeks X X X X X 4 2 12 weeks 1.27 2.37 32% -8% 4% (ns) 3 2.5 1.2. Massage initially 1 2.41 X X X 4 1 8 weeks X X X X X 4 1 12 weeks 0.97 1.97 6% -2% ns (ns) 4 1.25 1.3. Caffeine / theophylline initially 1 2.33 X X X 4 1 8 weeks X X X X X 4 1 12 weeks 1.08 2.47 -3% -3% 2% (ns) 3.75 1.25 1.4. Heat and xanthines are the starting point 1 2.61 X X X 4.25 1 8 weeks X X X X X 4.25 1.25 12 weeks 1.03 2.23 4% -5% ns (-2%) 4 2 1.5. peel initially 1 2.41 X X X 4.25 1 8 weeks X X X X X 4 1.5 12 weeks 1.07 2.17 13% -3% ns (-3%) 4 2.25 1.6. Vasoactive herbs start 1 2.23 X X X 4.25 1 8 weeks X X X X X 3.75 1.25 12 weeks 1.01 2.41 7% 1% ns (-3%) 3.75 1.5

'Johnson & Johnson Co. trademark for retinoic acid formulation ns = not significant)

HU 221 141 Β1

The first five result columns were analyzed for statistical significance, with the result that only the 1.1. 12 week blood flow hardness and thigh diameter data were significant (Clinical classification of cellulitis severity in columns 6 and 7 is subjective and not subject to statistical analysis.)

According to the data only 1.1. retinoic acid treatment showed a significant improvement in baseline blood flow, whereas in the 1.3. caffeine and 1.5. peeling treatments showed a small but not significant increase in blood flow.

Based on the TEWL levels in Table 5 and comparing baseline levels to twelve weekly levels, it can be seen that only a small significant increase (if any) can be achieved with any of the prior cellulite treatments, even with twelve weeks of treatment. 1.1. treatment with retinoic acid shows the highest increase of previous agents, but it is barely 10%. As will be described, the treatments of the present invention achieve a 40% increase in blood flow.

The thigh hardness and diameter slightly improved in 1.5. peeling treatment, and even more significantly in the treatment of 1.1. retinoic acid treatment. Significantly more significant improvement has been achieved with the present invention.

Only a very modest or non-significant improvement in skin thickness was seen with previous cellulite treatments in Table 1.

1.1. Retinoic acid treatment caused a slight overall decrease in the severity of cellulitis according to the clinical classification, but at a significant increase in irritation, as shown in the last two columns of Table 1.

These data indicate that known cellulite treatments have only modest beneficial effects, with best results achieved with retinoic acid followed by exfoliation. There was some improvement in basal blood flow, hardness of the thigh, and general cellulite condition at significant irritation. Neither the significant increase in TEWL nor the improvement in skin thickness, which is a basic structural indicator of tissue health, were achieved with previous treatments, clearly demonstrating the inadequacy of previous treatments. While the present invention is not limited to any particular theory, it appears that no prior art treatment provides for a sufficient period of time to suspend the skin's water barrier function to stimulate significant skin regeneration.

The composition of the present invention

The new formulation developed reduces the water barrier function of the skin, preferably by raising the TEWL level by 200-300% or more, continuously and chronically for at least 8 weeks, preferably for more than 26 weeks, or such other period as is appropriate. improvement in cellulitis, for example, for 10 to 20 weeks.

The desired increase in TEWL levels can be achieved by appropriate chemical formulations or sustained treatment with mechanical barrier suspension or solvent extraction to ensure that the treatment is aggressive enough to suspend the water barrier of the skin. It is essential to the invention that, while increasing TEWL levels, the level of irritation remains low, tolerable, since corrosive chemicals used to break the barrier, solvents and surfactants used to extract lipids can all have a very irritating effect.

In the practice of a particularly preferred embodiment of the present invention, it has been found that non-buffered lactic acid, exemplified by alpha-hydroxy acid and used in relatively high concentrations, and the combination of vitamin A palmitate or alcohol synergistically increases TEWL levels. Alpha hydroxy acid breaks down the skin's water barrier and raises TEWL levels. Vitamin A palmitate, a retinoid, appears to interfere with the restoration of barrier function and delay the decline in TEWL levels, which are elevated by alpha-hydroxy acid treatment. These TEWL-stimulating properties are attributable to the effects of retinoids on skin cell differentiation. The interaction between vitamin A palmitate and lactic acid is completely unexpected.

It is believed that the preferred embodiments of the present invention, when applied topically to the skin, chronologically and greatly exfoliate the skin, causing extensive cell loss, and more importantly disrupting normal barrier function, with an advantageous increase in TEWL levels of 200-300%. Although these effects are physically achievable, an important result of the present invention is that 5-10% by weight of non-buffered lactic acid and 0.1-3.0% by weight of vitamin A palmitate provide this result reproducibly with moderate irritation. The combination of 6 wt% lactic acid and 0.5 wt% vitamin A palmitate was found to be particularly effective. Chronic high levels of TEWL are believed to promote the release of critical skin growth factors, such as interleukins and transforming growth factors, resulting in stimulation of dermis-epidermis growth and angiogenic effects. These treatments would be too vigorous to apply to the face, but the skin is more resistant to cellulite-prone thighs, arms and chest areas. Treatment with the above composition thickens and improves the dermal and epidermal areas of the cellulite area and long-term angiogenic effects improve blood flow.

Working to achieve further and more sustained elevations in TEWL, I have found that specific cerebrosides, type I or II. types, synergists with the above formulation. Types "I" and "II" (available from Sigma, St. Louis, USA) have a specific molecular structure according to the structure of the corresponding ceramides, see, for example, Skin Constituents as Cosmetic Ingredients, Cosmetics and Tioletries. Volume 107, November 1992 (Figure 2 on page 88).

In the lipid metabolism of the skin, ceramides are formed by acylation of sphingosine and cerabrozides are formed by glycosylation of ceramides. Ceramides and cerebrosides a

They make up a small percentage of the skin lipids and are present in the outer layers of the skin, while sphingosine, the precursors of the above, are found primarily in the basal layers. Sphingosine is also found in significant amounts in the peeled stratum comeum cells, while ceramides are enzymatically degraded during the peeling process.

The barrier-suspending compositions of the present invention release signals in the deeper layers of the skin that increase the synthesis of lipids, such as ceramides, and restore the barrier. A non-restrictive hypothesis I or II. The use of type cerebrosides may affect this synthesis, thus preventing the barrier from reestablishing itself. It is possible that lipid synthesis may be associated with I and II. other than general cerebrosides or other end products of skin lipid synthesis are also effective supplements to the above-described treatments for maintaining elevated TEWL levels and thus promoting skin regeneration over a longer period.

In a recent lecture given by Dr. Sergio Curri at the Cosmetic & Toiletry Congress in Barcelona (Spain, March 1994), he argues that inhibition of protein kinase C by, for example, sphingosine may be useful in the treatment of cellulitis. This suggestion implies that cerebrosides are not useful enough in cellulite treatment. In studies not described herein, I have found that phospholipids, ceramides, and sphingosine exhibit minimal activity as barrier repair inhibitors for the purposes of the present invention, and furthermore, cerebrosides, alone, are not effective in controlling TEWL levels or in treating cellulitis.

A further desirable and essential function of cellulite treatment is the reduction or elimination of abnormal subcutaneous fat deposits, which is an unpleasant characteristic of cellulitis. The invention relates to the slow, natural reduction of fat accumulated in the skin by stimulating lipid metabolism, for example, by increasing the enzymes ATPase and protein kinase C in the skin.

Unexpectedly, I have found that when cerebrosides contain a topical cosmetic formulation, lipid metabolism may be inhibited. Although my invention is not limited by any specific theory, cerebrosides appear to play a very specific role in the barrier regeneration of the stratum comeum. When the barrier function is impaired, special signals are released, triggering activation in the epidermal and dermal metabolism. Some of these signals activate the production of new epidermal lipids to repair the barrier and restore TEWL levels to normal levels. This restorative process reduces the signals responsible for activating the epidermal and dermal metabolism (and activating the formation of new subcutaneous blood vessels). The use of selected cerebrosides (but not ceramides and not sphingosine) prevents barrier regeneration to such an extent that the activation of epidermal and dermal metabolism is sustained over time, resulting in changes that result in improvement in cellulitis. The inhibition of barrier regeneration by selected cerebrosides is not such as to cause a negative effect on the skin surface. Rather, it appears to have an inhibitory effect on epidermal lipid formation, which allows extended maintenance of activated epidermal and dermal metabolism for weeks or months. These assumptions have been confirmed by the results of the clinical trials reported here.

The conclusions and results that cerebrosides play a barrier-regenerating inhibitory role are completely unexpected, since conventional teachings suggest that cerebrosides should repair the damaged barrier.

I concluded that the effects of cerebrosides are completely specific and apply to the stratum comeum; but this theory is only an explanation of the effect of the composition of the invention to the best of my knowledge. Future research done by myself or by others may suggest other mechanism or mechanisms. It is possible that cerebrosides, through the action of protein kinase C, may also directly influence lipid metabolism in the subcutaneous areas.

As part of the topical formulations and treatments described herein, the aforementioned ingredients of cerebroside act for a prolonged period of time, e.g., 10-20 weeks, to improve skin quality and cellulite.

In the experiments described and interpreted below, I have found that a combination of a TEWL-leveler, more particularly lactic acid and a retinoid, particularly vitamin A palmitate, and a skin barrier regenerating inhibitor, particularly a cerebroside, preferably an I or II . type cerebroside, results in sustained and chronic TEWL elevation and reduced barrier function, leading to the desirable skin regenerating and cellulite enhancing effects described above.

Hydroxycarboxylic acids that can be used as TEWL level enhancers are described below.

Preferably, the TEWL leveling agent is soluble in water or in a slightly polar aqueous alcoholic vehicle to form an effective solution of the active ingredient in cosmetic ingredients. Many other alpha-hydroxy acids can be used as an alternative to lactic acid. Lactic acid is a particularly preferred TEWL-leveling agent in the composition of the present invention which is highly effective and naturally occurring in the skin, intracellular fluid and bloodstream.

Some preferred alternatives to lactic acid include glycolic acid, salicylic acid, and mixtures of these acids.

Preferred hydroxybenzoic acids have a molecular weight below about 250, and preferably below 175, for the desired pH-lowering and TEWL-leveling properties, cosmetic compatibility and moderate water or hydroalcohol solubility.

Many useful hydroxycarboxylic acids are disclosed in my International Patent Application WO 94/06640. Some additional alpha-hydroxycarboxylic acids are disclosed in Yu and Van Scott, U.S. Patent Nos. 4,363,815 and 5,091,171.

The acids and acid equivalents disclosed in these publications, which are incorporated herein by reference, are applicable to the present invention.

EN 221 141 Β1 use of the preparation in practice, if the criteria described above are met. Preferably, the alpha-hydroxy acid used in the composition I invented is a linear or branched aliphatic acid having up to three substituents on the aliphatic moiety where the substituents are non-basic and selected from the group consisting of hydroxy, formyl, oxo, carboxylic acid, , and nitro and chlorine.

While acidity and solubility in water or solubility in aqueous alcoholic solution are desirable properties of the alpha-hydroxy acids of the present invention, an exaggeration of these characteristics, such as that shown by a mineral acid, is undesirable since it would tend not only to irritation but to severe clinical symptoms such as , to induce injury to the back and subcutaneous penetration. Such undesirable properties are sometimes encountered in low molecular weight materials, which are not general and unpredictable and often exhibit harmful individual behavior.

Such other hydroxyaliphatic acids useful in the composition of the present invention are preferably monocarboxylic acids selected from the group consisting of 2-hydroxy-n-butanoic acid, 2-hydroxyisobutanoic acid, 2-hydroxy-n-pentanoic acid, 2-hydroxyisopentanoic acid, -hydroxyhexanoic acid, 2-hydroxyisohexanoic acid. Their di- or polyhydroxy analogs can also be used, for example, their 2, X-dihydroxy analogs, wherein "X" is an integer from 3 to 6, which corresponds to the corresponding hydroxy substituent at the carbon atom other than the first and second carbon atoms. Preferably, these dihydroxy acids balance the additional electronegativity attributable to the second hydroxyl group with an additional hydrophobic group as described above. Some examples of suitable dihydroxy acids are maleic (CH-COOH) ₂ and azelaic acid HOOC- (CH ₂ ) ₇ -COOH.

Inhibitors of barrier function restoration are described below.

Preferred inhibitors of the restoration of barrier function according to the invention are retinoids such as tretinine and retinoic acid. However, many retinides or retinoic acid derivatives are unstable and unsuitable for commercial marketing of topical cosmetics. Vitamin A palmitate is a particularly stable retinoid and is therefore preferred for use in this invention. Other suitable stable retinoids for use in the compositions of the present invention include retinyl acetate and retinyl alcohol.

Other retinoids in which a stable retinyl group binds to a fatty acid chain and are thus oil stable and exhibit good solubility in the topical carriers described herein can also be used in the compositions of the present invention. In the practical implementation of the methods of the invention, shelf life should not play a significant role. Accordingly, the stability of the retinoid selected may be negligible if, for example, topical formulations are prepared as required (at the time of application) and not stored for prolonged periods, which allows the use of less stable retinoids.

Many active retinoids are known and useful in the practice of the present invention, such as those listed by Klingman in U.S. Patent 5,051,449 (incorporated herein by reference). Some of these additional retinoids are Avitamin aldehyde, Vitamin A, Vitamin A esters, Isotretinoin, Ethretinate, Acitretine retinoid esters, 13cis and 13-trans-retinoic acid esters and amides and retinyl glycosides.

Barrier repair inhibitors are described below.

As noted above, cerebrosides have been found to play a valuable functional role as a barrier repair inhibitor in the composition of the present invention and are believed to accomplish this role by inhibiting the formation of lipids that are incorporated into the stratum corneum by normal waterfowl. In line with this assumption, other materials are also thought to play the desired inhibitory role in dam restoration.

Cerebrosides for use in the practice of the present invention are commercially available in various forms. Occasionally, they are marketed as glycosphingolipids (GSL), a name used to refer to a sugar-bound lipid with a sphingosine moiety. Cerebrosides are the basic components of GSL, which are crude biological isolates from plants or animals. I and II. a relatively pure (99%) mixture of bovine cerebrosides of type B is available from Sigma Chemical Co.; Catalog number: C 4905.

The composition of the compositions is described below.

The strength of the cellulite compositions of the present invention is limited by the degree of irritation they cause. Areas prone to cellulitis are generally less sensitive than the face on which the skin therapeutic properties of some of the possible ingredients of the compositions of the present invention have been demonstrated or studied in the form of "wrinkle creams" or anti-aging creams that not only superficially promote skin regeneration. Accordingly, due to the lower tissue sensitivity of the areas prone to cellulitis, preferred compositions for treating new cellulite contain higher concentrations or allow greater proportions of active agents than creams for face treatment.

Depending on its efficacy and irritation, the application rate of the TEWL-leveling agent, preferably an alpha-hydroxycarboxylic acid, when present in a topical formulation is from 1 to 15% by weight; a medium ratio of 5 to 10% by weight is preferred, particularly for lactic acid or glycolic acid.

When a retinoid is used to stimulate cell renewal, the appropriate ratio is 0.005-6.0% by weight, preferably 1.0-4.0% by weight, although a ratio of 0.1-1.0% by weight may be considered active but not effective .

When cerebroside or a mixture of cerebrosides is used as the barrier repair inhibitor of the invention, the barrier repair inhibitor is a suitable

It is in the range of 0.01 to 5% by weight, preferably 0.05 to 1% by weight, and most preferably 0.1 to 0.5% by weight.

Unless otherwise indicated or indicated, the ratios herein are by weight relative to the total weight of the formulation and are relative to the active ingredient or equivalent.

The pH of the therapeutic compositions is discussed below.

Depending on the acidity of the TEWL-leveler, the preferred pH is somewhat acidic, and indeed the constant, moderate but tolerable acidity is favored to promote barrier attachment. Accordingly, a preferred pH range is from 3.0 to 6.2, more preferably from 4.5 to 5.5.

Optional components are described below.

It is not necessary, but an essential feature of the composition of the invention, to optionally use a component that immediately improves the appearance of cellulite. This can be achieved by immediately increasing blood flow and removing excess fluid. Known diuretics such as caffeine, theophylline, methyl salicylate and the like are effective. A preferred material is PRONALEN C (trademark Centerchem, Inc.), a natural biological extract that may facilitate initial acceptance of the product.

In general, the optional additives for use in the cellulite therapeutic compositions of the present invention, which may be used alone or in combination, are diuretics, anti-irritants and antioxidants, preferably in effective concentrations known from topical cosmetics, e.g. 3% by weight.

Diuretics promote lymphatic flow and lipid digestion and produce an immediate, short-term improvement in cellulite that is clearly visible to the user. Suitable diuretics include vasodilators such as caffeine, xanthine and the like.

Anti-irritants and antioxidants can be used to optimize the tolerability of persistently elevated TEWL levels. Examples of suitable anti-irritants include cola extract, green tea, aloe and the like, suitable antioxidants BHT, NDGA, vitamins E and C and propyl gallate.

The use of a combination of the appropriate components, if appropriate, provides a broad range of well-balanced cellulite treatments, combining rapid, easy-to-see improvements with long-term structural improvement of the condition while controlling the degree of irritation.

The extent and frequency of application are described below.

Typical applications of the cellulite therapeutic compositions of the present invention described herein may range from 0.01-0.5 mg of active acid per square centimeter of skin, wherein the acid is a low molecular weight hydrophilic acid such as alpha-hydroxycarboxylic acid, preferably in a concentration range of 0.05-0. , 2 mg / cm ² . Cosmetic creams are generally used in concentrations of 2 to 3 mg / cm ² . For an active ingredient content of from 0.15% to 30% by weight, a possible dose of the active ingredient components is 0.003-0.9 mg / cm ² , more preferably 0.05-0.2 mg / cm ² active ingredient per skin area. A preferred amount of the active compounds of about 7% by weight in the composition provides a preferred application dose of 0.15-0.2 mg / cm ² .

This dose is applicable to any skin area in need of treatment, preferably once or twice daily. Three to four times a day, a higher frequency of application seems to mean wasting the product without further positive effects, while less frequent use, namely once a day, results in reduced efficacy. Additional applications may occur occasionally, after washing, bathing, swimming, up to six times a day.

Alternative barrier suspension treatments are described below.

As an alternative to suspending the water barrier in combination with alpha-hydroxy acid and a retinoid, TEWL levels can be increased by solvent extraction of the stratum comeum and the like.

Application of Acetone

Acetone washings, daily or every other day, have also been shown to suspend the water barrier of the skin if the treatment is continuous over a long period, such as two months. Biophysical measurements suggest that such regular acetone washout should also release the long-term skin regeneration effects described above. Acetone removes the formed lipids and prevents barrier repair. However, acetone is a highly irritating, flammable and harmful agent and is not recommended. The data, as shown in Table 2, confirm that the efficacy of the composition of the invention is not solely due to the suspension of dermal water barrier and elevation of TEWL levels, and results of other physical and physicochemical treatments may be utilized to formulate beneficial compositions.

Removal of epithelium with tape

Another effective barrier suspension method is removal of the epidermis 5-10 times with adhesive coated cellophane tape, which increases the TEWL level 2-10 times depending on the individual response of the treated individual. When applied over a period of eight weeks, this treatment can induce positive biological effects that are consistent with an effective cellulite treatment. The positive results obtained with this treatment further strengthen the broad technical scope of the invention. However, tape stripping has many drawbacks when used as a commercial technique, including the fact that the response to stripping varies widely between individuals and requires the use of an expensive laboratory device to monitor barrier function.

Exfoliation with surfactant

In developing the preferred form of the composition of the present invention, it can be used to observe that daily use of a strong surfactant solution can chronically suspend the barrier function.

EN 221 141 Β1 for the first time. It is sufficient to apply a surfactant such as 10% by weight sodium lauryl sulfate (SLS) twice daily. Using SLS alone is irritating when used for periods longer than 8 weeks. The addition of 0.1% by weight sphingosine can effectively suppress or reduce long-term irritation to such an extent that this treatment can be considered mild enough to be used as a practical embodiment of the invention. Because antioxidants and immediate-acting irritants such as colladium extract may also be present, cerebrosides should not be included in formulations containing sphingosine.

If desired, any such or similar non-cream treatment that effectively elevates TEWL levels may be accompanied by topical application of a cream containing a retinoid and, if desired, a cerebroside, to prolong TEWL elevation and skin regeneration.

Suitable carriers are described below.

Any cosmetic carrier that is commercially available and releases skin-regenerating stimulant acids in the skin can be used in the composition of the present invention. Suitable excipients may be aqueous or aqueous alcoholic solutions or may be dispersed in oil or other hydrophobic material for the preparation of general formulations, creams, lotions, tonics and the like. Preferred formulations of the creams are the compositions of the present invention. If desired, the carrier may be simply plain water, although small amounts of alcohol or other organic solvents may be required to dissolve or disperse the hydrophobic retinoid and cerebroside.

If desired, the active compounds may be incorporated into a cosmetic aqueous alcoholic vehicle containing 40-75% water, preferably 55-65 or 60% water, and 25-55%, preferably 25-35 or 30% aliphatic alcohol. Although many lower aliphatic aliphatic alcohols, whether monohydroxy or polyhydroxy, can be used, the most preferred choice is ethanol and propanes. Many additives and auxiliaries are known in the art that are useful constituents of such carriers, e.g. -2% by weight is useful as a moisturizer to counteract the drying effect of alcohol and to provide a better-looking tonic. Other examples of such additives are stabilizers, fragrances and colorants.

Other suitable carriers include dispersions containing from 5% to 60% by weight of a hydrophobic liquid dispersed in water.

If necessary, the pH can be adjusted to a suitable range with an alkaline medium of 0.1 to 10% by weight, for example, with an aqueous solution of sodium hydroxide, arginine or triethanolamine (TEA). Since the pH of the skin regeneration compositions of the present invention plays a significant role in efficacy, the presence of a suitable buffer may also be desirable. Any such buffer or buffer system that works with the alkaline component should naturally have the effect of maintaining the acidic pH within the range described above and preferably maintaining a pH of 4.5 or less. The amount of buffer depends on its strength, but is usually 0.1 to 10% by weight, preferably about 1 or 2% by weight. Suitable buffers include, for example, TRIS (trimethylolaminomethane) buffers and phosphate buffers.

A topical, structural cellulite therapy cream based composition of the invention is described below.

Example

New ternary cellulite therapy composition in a cream carrier

The following participants were mixed according to the instructions below ("C" concentration (wt%) and the number below "Phase" indicates at which stage of the mixing process the participant is added.)

Component C (t%) Phase Cetearyl alcohol and ceteareth-20 (BASF, Mount Olive, NJ, (USA) 3.5 ¹ GMS-PEG 100 stearate (Uniqeme, Paterson, NJ, USA) 3.5 1 PEG 100 stearate (Uniqema, Peterson, NH, USA) 2.0 1 dimethicone (BASF, Mount Olive, NJ, USA) 5 1 squalene (Sigma, St Louis, MO, USA) 6 1 Capric Acid Triglycerides (Uniqema, Paterson, NJ, USA) 4 1 Propyl Paraben (Sigma, St. Louis, MO, USA) 0.1 1 Vitamin A palmitate (Sigma, St. Louis, MO, USA) 1.5 1 Water 45 2 Glycerol (Sigma, St. Louis, MO, USA) 5 2 butylene (Penreco, The Woodlands, Texas, USA) 6 2 Carbomer 941 (BF Goodrich, Charlotte, NC, USA) 0.2 2 Methyl paraben (Sigma, St. Louis, MO, USA) 0.25 2 Triethanolamine (The Chemistry Store, Pampano Beach, FL, USA) 3.1 3 Milk (Sigma, St. Louis, MO, USA) 8 4 Type I and Type II cerebrosides (Sigma, St. Louis, MO, USA) 0.15 5

HU 221 141 Β1

Table (continued)

Component C (t%) Phase Pronalen AC (Centerchem, Norwalk, CT, USA) 5 6 fragrance QS 7 Water QS to 100% -

One of ordinary skill in the art knows how to make a topical cream consisting of these components for topical application. The oil phase (1) is slowly added to phase (2) at 80 ° C with stirring. After the resulting emulsion begins to congeal, phase (3) is added and the cream thickens. The following phase (4) is added, followed by the components of phase (5-7) when the cream has cooled to 55 ° C. The mixture was then cooled to room temperature with stirring.

From this example, it becomes clear that vitamin A palmitate, lactic acid, and I and II. Type Cerebrosides are the active components of the invention, while the balance of the components is formed by a cream carrier.

Clinical trials of the compositions of the invention are described below.

The results of the clinical trials are presented in Table 2 below. A 2.1-2.4. experiments were performed using the cream vehicle described in the above example with the active ingredients and amounts described in the table. A 2.1-2.3. and 2.5. Formulations used in the treatment of formula (I) contain an ingredient that is included in the composition of the invention, but is essentially for comparative purposes (as in treatments 2.6 and 2.7) and not preferred embodiments of the invention. That is, Table 2.4. The composition corresponds to a preferred embodiment of the present invention.

Table 2

Comparison of cellulite therapies

Treatment blood Flow TEWL g / m ² / h TEWL incr. (%) Hard- ness Thigh- diameter Skin- thickness Cellulitis- classification Irritation- classification 2.1. Lactic acid 0.5% starting 1 2.07 X X X 4.25 1 8 weeks X 2.33 13 X X X 4 1.5 12 weeks 1.11 2.47 19 27% -3% 7% (ns) 3.75 1.5 2.2. Lactic acid 10% starting point 1 2.11 X X X 4.25 1 8 weeks X 2.69 27 X X X 3.5 1.5 12 weeks 1.07 2.83 34 30% -1% 10% (ns) 3 2 2.3. 10% LA / 1% AVP Start 1 2.03 X X X 4.25 1 8 weeks X 3.47 71 X X X 3.5 2 12 weeks 1.12 3.67 81 29% -5% 8% (-4%) 2.75 2.5 10% LA / 1% AVP / 0.5% GSL 2.4. MEMORANDUM 1 1.91 X X X 4.25 1 8 weeks X 3.87 102 X X X 2.75 2 12 weeks 1.43 6.88 260 43% -11% 10% (-8%) 2 2.5 Daily 2xBUFF-PUFF X 2.5. initially 1 2.14 X X X 4.25 1 8 weeks X 2.39 8 X X nanoseconds (ns) 4 1.5 12 weeks 1.07 2.31 8 6% 2% 3.75 2 Daily 5-10 χ tape 2.6. initially 1 2.14 X X X 4.25 1 8 weeks X 5.37 151 11% X 6% (ns) 3.75 2.5 12 weeks 1.17 6.07 184 17% -8% 10% (-5%) 3 3 Acetone wash X (Every 2 days) 6% (3%) 2.7. initially 1 2.17 X X X 4 1 8 weeks 1.12 6.92 219 7% -3% 3 2.75 23 weeks X X X X X X

LA = tcjsav; AVP = vitamin A palmitate; GSL = glycosphingolipid; ns = ncm significant

HU 221 141 Β1

According to Table 2, a slightly larger increase in TEWL was achieved in the lactic acid-containing 2.1. and 2.2. treatments, while using a highly exfoliating 10% lactic acid preparation 2.2. treatment rate is only about 33%. Higher levels are desirable to achieve the beneficial effect of the present invention.

In Figure 2.3. Vitamin A palmitate added to lactic acid showed an increase of about 71% after 8 weeks and about 81% after 12 weeks. Although these increases in TEWL levels are more significant than those achieved with known treatments, the inventive 2.4 and the comparative 2.6. and 2.7. barrier suspension treatments achieve much greater elevations in TEWL levels, ranging from above 100% to 260%. The degree of irritation remained tolerable despite some growth.

Baseline blood flow, which is reported in column 1, showed a modest response to all treatments except those in section 1.1. treatment (Table 1) in which retinoic acid was used; there was an increase of 27% in Week 12, with the exception of Section 2.4. treatment using a preferred topically absorbable formulation of the invention, which resulted in a much greater increase in baseline blood flow at week 12 by about 43%.

For the general cellulite condition, which is evaluated from the next column to the last column, see sections 1.2-1.6. and 2.1. and 2.5. the improvement attributable to treatments is either not significant or very modest. Moderate improvement was achieved in 1.1. retinic acid at week 12, which resulted in a 1 point decrease (see cellulite classification). While 2.2, 2.3, 2.4. and 2.6. each resulted in an improvement of more than 1 point; has achieved an improvement of more than 2 points with the preferred embodiment of the invention. A 2.7. during treatment with acetone, 1 point improvement improved the concept of the invention.

Clinical irritation was evaluated for safe protection. Severe irritating treatments should not be used. If the irritation rating reaches three points, this marks the beginning of an undesirable rating, and it should be noted that Section 2.7. treatment, the acetone wash was expected to show a significant irritation level of 2.75 at week 8, compared with 2.4. A preferred, less irritating embodiment of the treatment showed a 2-value irritation.

The femoral hardness was significantly (almost 30%) improved with lactic acid (treatments 2.1 and 2.2), but no further improvement was observed with the addition of retinoid (AVP) (treatment 2.3). The addition of cerebroside-containing glycosphingolipids according to the invention (treatment 2.4) resulted in a further significant increase of 43%, indicating a marked structural improvement of the tissue condition.

Peel strip removal (treatment 2.6) resulted in a more moderate improvement, while "BUFF-PUFF" and acetone wash (treatments 6.5 and 6.7) caused a slight improvement in hardness.

The thigh diameter was significantly reduced by the advantageous 2.4. during treatment, to a lesser extent with acetone wash (treatment 2.6), and not significantly or only slightly to other treatments.

While 2.1-2.4. and 2.6. each of the treatments showed some improvement in epidermal-dermal skin thickness, only the 2.4. and comparative 2.3. and 2.6. treatment showed a decrease in thickness in the subcutaneous area, see brackets. The preferred embodiment 2.4 according to the invention. treatment showed essentially the best results in both categories.

In summary, according to the data presented in Table 2, Table 2.3., 2.4., 2.6. and 2.7. treatments cause elevations in TEWL compared to the other therapies tested and are associated with improvements in blood flow and skin structure; treatment showed.

To evaluate the improvement of microcirculation, detailed blood flow tests were performed using ultrasound analysis as described above, and the results are shown in sections 3-6 below. Tables show.

Table 3

Laser Doppler examination of microcirculation

The studied Table 2.4. effect of the product on the rate of normal skin blood flow in 5 participants Summarizing the results obtained with 10 measurements on the forearm

test Group Less than 1 1 to -3 3-5 5-7 > 7 beforehand 3 11 22 10 4 After 8 weeks 1 9 20 14 6 After 16 weeks 0 5 21 17 7 Irritant 0 0 0 3 47

Blood flow measurement results shown in Table 3 are plotted as arbitrary ratios. Of the total 50 measurements, as shown in the last row of Table 3, the control irritant stimulated blood flow to a value greater than 7 in almost every measurement, namely 47 out of 50.

It can be seen from the table that as the time scale progresses from the baseline to the 8 and 16 weeks of treatment with the cellulite therapy product under study, the number of leolvaθθ values shifts to the right in each group.

HU 221 141 Β1

This indicates that the application of the test composition resulted in a significant increase in the number of measurements with higher blood flow.

While the blood flow numbers in the middle column (values between 3 and 5) remained approximately constant, those below 3 (sum of the numbers in columns 1 and 2) from the initial 14 to 8 within 10 weeks , Dropped to 5 in 16 weeks. From the columns to the two right hands, it can be seen that the number of measurements above 5 increased to only 14 before treatment, but to 20 after 8 weeks and 24 after 16 weeks. Numbers move everywhere to the right as the blood flow improves. Accordingly, Table 3 shows that the cellulite therapy composition used is effective in achieving a significant blood flow enhancement within 8 weeks, and that the continuous application of the therapeutic composition produces a sustained increase in blood flow, which is further improved. week.

As mentioned, the definitions in Table 3 were performed on the participants' forearms on normal, cellulite-free skin. These data provide a clear picture of the blood flow stimulating properties of topical formulations while eliminating complications due to structural abnormalities in the tissues affected by cellulitis.

Table 4

Laser Doppler examination of microcirculation

Circulatory disorders in the thigh in person as described in Table 2 2.4. a summary of the results of the test for the preparation. All subjects showed symptoms of stage 2/3 of cellulitis. 30 measurements were made on each individual. V vascular flow measurements

test Group Less than 1 1-3 3-5 5-7 > 7 beforehand 68 133 42 43 14 After 8 weeks 45 123 67 52 ¹³ After 16 weeks 17 67 128 71 17 Irritant 6 51 128 110 5

Reference data: mean age of control group 23.6 cv. A known irritant, such as Pcru Balm, increased blood flow by 10-12 in this assay.

Table 4 shows the results of a measurement of a total of 300 thighs obtained from 10 advanced cellulite individuals, where the cellulitis has met the criteria for stage 2 or 3 as described above. The values in the bottom line are control measurements for skin areas free of cellulite. The data in Table 4 can be interpreted in the same way as in Table 3. Particularly noteworthy is the data in the first column, which, from a large number of measured values, indicates very low blood flow below 1, as a result of the cellulite condition, whereas in the non-cellulite group there were only 6 measurements below 1.

Topical application of the test cellulite therapeutic composition of the invention effectively reduced the number of one-to-one measurements from 68 before treatment to 45 during eight weeks and to 17 during 16 weeks treatment. The numbers show a general right shift at 8 weeks and a further right shift at 16 weeks, demonstrating a steady improvement in blood flow, which is attributable to the beneficial effect of the cellulite therapeutic formulation under investigation.

Table 5

Laser Doppler Examination of Microcirculation (Preparation: Preparation 2.4 of Table 2) Circulatory disorders in the thigh area V vascular flow measurements

1 person, stage 2/3 cellulitis Age: 46 years before 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

HU 221 141 Β1

Table 5 (continued)

1 person, stage 2/3 cellulitis Age: 46 years before treatment 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 shows a detailed examination of the efficacy of the cellulite therapy composition of the invention in a single subject. Relative blood flow measurements are presented in two separate tables. Comparative studies were performed on the subject in 20 different locations, with pre-treatment data in the upper half of the table and data obtained after 16 weeks of treatment in the lower half of the table. Thus, any correct data in the upper half of the table can be compared to the same table in the lower half of the table to determine the effect of the therapeutic agent under study as a "before" and "after" comparison.

All but one of the data improved after treatment. The exception is the abnormally high 8.89. This is due to reduced blood flow in the surrounding areas. All values below 1 improved to above 1, some of them rising dramatically. Thus, the third value in column 2 improved from 0.67 before treatment to 2.22 after treatment. Table 5 also shows a very significant overall improvement in the extensive cellulite-affected area of a person's thigh due to the improvements in microcirculation structure caused by the treatments of the present invention.

Table 6

Ultrasonic examination of skin thickness (Preparation: Preparation 2.4 of Table 2) The average of the data of 10 persons was measured on the thigh of each person

test Group Epidermis-dermis thickness Epidermis-dermis density Subeutan fabric thickness Subeutan density beforehand 2.34 68% 4.12 33% In 8 weeks 2.56 74% 3.99 41% In 16 weeks 3.12 82% 3.25 62%

Reference data: mean age of control group 23.6 cv. A known irritant, such as Peru Balm, increased blood flow from 10 to 12 in this test procedure.

Table 6 shows that after 8 weeks of treatment, the thickness of the epidermal-dermal skin layers increased and the size of the sub-cutaneous skin layers decreased. Both showed a significant increase in density. Further significant improvement was achieved after 16 weeks of treatment with the formulation used. These data suggest that the compositions of the present invention result in significant structural improvement of the skin condition, which can lead to long-term improvement of the cellulite condition.

Industrial applicability

The present invention is particularly suitable for use in the cosmetic industry to provide novel formulations and methods in cellulite and skin treatments.

Although an embodiment of the invention has been described above for purposes of illustration, it will be understood that various modifications will be apparent to those skilled in the art. These modifications are within the spirit and scope of the invention, which are limited and defined by the appended claims.

Claims (10)

PATIENT INDIVIDUAL POINTS 1. Cellulite therapy composition for daily topical application in areas affected by cellulitis, wherein the composition increases the transepidermal water loss level (TEWL level) by at least 100% after 8 weeks of topical application, and comprises the following components for the total weight of the composition. date: a) To increase the TEWL level, a cosmetically compatible pH-lowering hydroxycarboxylic acid in an amount of 1-15%; 22 221 141 1 b) a retinoid cell regeneration / cell differentiation modulator stimulant in an amount of 0.005 to 6.0%; and c) a cerebroside barrier inhibitor in the amount of 0.01 to 5% to prevent the restoration of the water barrier of the skin. A composition according to claim 1 comprising 5-10% TEWL-leveling agent selected from lactic acid, salicylic acid and glycolic acid. The composition of claim 1, wherein component a) is 5-10% lactic acid, glycolic acid or salicylic acid, component b) is 0.3-3.0% vitamin A palmitate, and c) 0.1-0% component, Contains 5% cerebroside. 4. A composition according to claim 1 comprising 5-10% lactic acid as component a), 0.5-4.0% vitamin A palmitate as component b) and 0.1-0.5% cerebroside as component c). . 5. A composition according to any one of claims 1 to 4, optionally comprising at least one further component of: - diuretics to stimulate blood flow and - anti-irritants and antioxidants to reduce irritation caused by component a) or b). 6. A method for the preparation of a composition for use in cellulite therapy, which composition may be used for topical application in the areas affected by cellulitis, wherein the composition increases the transepidermal water loss level (TEWL level) by at least 100% after 8 weeks of topical application. mixing the following components with percentages based on the total weight of the preparation: a) To increase the TEWL level, a cosmetically compatible pH-lowering hydroxycarboxylic acid in an amount of 1-15%; b) a retinoid cell regeneration / cell differentiation modulator stimulant in an amount of 0.005 to 6.0%; and c) a cerebroside barrier inhibitor in the amount of 0.01 to 5% to prevent the restoration of the water barrier of the skin. 7. A process according to claim 6, wherein component a) is used in an amount of 5 to 10% and is selected from lactic acid, salicylic acid and glycolic acid. Process according to claim 6, characterized in that a) 5-10% lactic acid, glycolic acid or salicylic acid as component b), 0.3-3.0% vitamin A palmitate as component b) and 0.1- 0.1% as component c). 0.5% cerebroside is used. 9. The method of claim 6, wherein the component a) is 5-10% lactic acid, 0.5-4.0% vitamin b component as component palmitate and 0.1-0.5% as component c). cerebroside is used. 10. From 6-9. A method according to any one of claims 1 to 3, characterized in that at least one additional component is optionally used: - diuretics to stimulate blood flow and - anti-irritants and antioxidants to reduce irritation caused by component a) or b).