DE10107575A1 - Non-invasive reduction of adipose tissue, useful for therapeutic or cosmetic application, uses the photodynamic effect to kill fat cells - Google Patents
Non-invasive reduction of adipose tissue, useful for therapeutic or cosmetic application, uses the photodynamic effect to kill fat cellsInfo
- Publication number
- DE10107575A1 DE10107575A1 DE2001107575 DE10107575A DE10107575A1 DE 10107575 A1 DE10107575 A1 DE 10107575A1 DE 2001107575 DE2001107575 DE 2001107575 DE 10107575 A DE10107575 A DE 10107575A DE 10107575 A1 DE10107575 A1 DE 10107575A1
- Authority
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- Germany
- Prior art keywords
- tetrapyrrole
- adipose tissue
- cells
- multiplier
- tissue
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
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Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
- A61Q19/00—Preparations for care of the skin
- A61Q19/06—Preparations for care of the skin for countering cellulitis
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K41/00—Medicinal preparations obtained by treating materials with wave energy or particle radiation ; Therapies using these preparations
- A61K41/0057—Photodynamic therapy with a photosensitizer, i.e. agent able to produce reactive oxygen species upon exposure to light or radiation, e.g. UV or visible light; photocleavage of nucleic acids with an agent
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K41/00—Medicinal preparations obtained by treating materials with wave energy or particle radiation ; Therapies using these preparations
- A61K41/0057—Photodynamic therapy with a photosensitizer, i.e. agent able to produce reactive oxygen species upon exposure to light or radiation, e.g. UV or visible light; photocleavage of nucleic acids with an agent
- A61K41/0071—PDT with porphyrins having exactly 20 ring atoms, i.e. based on the non-expanded tetrapyrrolic ring system, e.g. bacteriochlorin, chlorin-e6, or phthalocyanines
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K8/00—Cosmetics or similar toiletry preparations
- A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
- A61K8/30—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds
- A61K8/49—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing heterocyclic compounds
- A61K8/4906—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing heterocyclic compounds with one nitrogen as the only hetero atom
- A61K8/4913—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing heterocyclic compounds with one nitrogen as the only hetero atom having five membered rings, e.g. pyrrolidone carboxylic acid
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K2800/00—Properties of cosmetic compositions or active ingredients thereof or formulation aids used therein and process related aspects
- A61K2800/80—Process related aspects concerning the preparation of the cosmetic composition or the storage or application thereof
- A61K2800/81—Preparation or application process involves irradiation
Landscapes
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Veterinary Medicine (AREA)
- Chemical & Material Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Epidemiology (AREA)
- Biochemistry (AREA)
- Molecular Biology (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Birds (AREA)
- Dermatology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
Description
Fettzellen werden im menschlichen Organismus bereits im Embryonalstadium angelegt und sind nur sehr schwer abzubauen. Jede Diät sorgt nur für eine Entleerung der Speichervakuolen der vorhandenen Zellen, nicht aber für das Absterben der Zellen. Wird dem Organismus später wieder eine größere Nährstoffmenge zugeführt, so wachsen die Zellen schnell auf ihre ursprüngliche Größe (Jo-Jo-Effekt).Fat cells are created in the human organism at the embryonic stage and are very difficult to dismantle. Each diet only empties the Storage vacuoles of the existing cells, but not for the cell death. If a larger amount of nutrients is added to the organism later, then the cells quickly grow to their original size (yo-yo effect).
Eine dauerhafte Verringerung der Zahl der Fettzellen war bisher ausschließlich durch einen chirurgischen Eingriff möglich. Dieser ist allerdings mit erheblichen Risiken behaftet. Der starke und sehr schnelle Substanzverlust stellt eine Belastung für den Gesamtorganismus dar.A permanent reduction in the number of fat cells was previously only possible surgical intervention possible. However, this is associated with considerable risks afflicted. The strong and very fast loss of substance puts a strain on the Whole organism.
Weiterhin muß das umliegende Gewebe sehr große Formänderungen in kurzer Zeit kompensieren, was zu erheblichen Nebenwirkungen führen kann (Löcher etc.). Nicht zuletzt wird dabei dem Organismus eine großflächige Wunde zugefügt, die einen langwierigen Heilungsprozeß nach sich zieht.Furthermore, the surrounding tissue must undergo very large changes in shape in a short time compensate for what can lead to significant side effects (holes, etc.). Not finally, a large wound is inflicted on the organism, the one drawn-out healing process.
Überdies sind chirurgische Verfahren nur lokal anwendbar und ermöglichen keine generelle Reduktion des körpereigenen Fettgewebes oder des Fettanteils in sonstigem Gewebe.In addition, surgical procedures can only be used locally and do not allow any general reduction of the body's own fat tissue or the percentage of fat in other Tissue.
Die photodynamische Therapie (PDT) ist eine nichtinvasive Methode der Photomedizin, die bisher zur Behandlung von Tumoren, Hauterkrankungen und viralen oder bakteriellen Infekten eingesetzt wird.Photodynamic therapy (PDT) is a non-invasive method of Photomedicine, previously used to treat tumors, skin diseases and viral or bacterial infections.
Zahlreiche Photosensibilisatoren wurden in der Vergangenheit auf ihre Phototoxizität untersucht und einzelne auch bereits erfolgreich eingesetzt. Dabei treten hauptsächlich zwei Wirkmechanismen auf: 1) Zerstörung der Zellmembran mit Absterben der Zelle und daraus resultierender Immunantwort des Organismus. 2) Freisetzung von Cytochrom C aus verschiedenen Zellorganellen (je nach Akkumulationsort des Farbstoffes) und daraus resultierende Apoptose ohne Immunantwort des Organismus. Das Hauptinteresse der bisherigen PDT bestand im ersten Mechanismus, um die Immunabwehr des Körpers in die Vernichtung und Beseitigung der Krebszellen mit einzubeziehen.Numerous photosensitizers have been tested for their phototoxicity in the past examined and some have already been used successfully. This mainly occurs two mechanisms of action on: 1) destruction of the cell membrane with cell death and the resulting immune response of the organism. 2) release of Cytochrome C from different cell organelles (depending on the accumulation site of the Dye) and the resulting apoptosis without an immune response from the organism. The main interest of the previous PDT was the first mechanism to get the Immune defense of the body with the destruction and elimination of cancer cells included.
Zur Reduktion der Nebenwirkungen ist eine hohe Selektivität des Wirkstoffes anzustreben. Um diese zu erreichen, wurden in der Vergangenheit verschiedene Möglichkeiten für die Tumortherapie vorgeschlagen: 1. Substitution der Randgruppen, um eine höhere Affinität zum Zielgewebe zu erhalten, 2. Einbettung in/Ankopplung an molekulare Transportsysteme (z. B. Mizellen, Liposomen, LDL, MAK etc.). A high selectivity of the active ingredient is to reduce the side effects desirable. To achieve this, various have been used in the past Opportunities for tumor therapy suggested: 1. substitution of marginalized groups, in order to obtain a higher affinity for the target tissue, 2. embedding in / coupling on molecular transport systems (e.g. micelles, liposomes, LDL, MAK etc.).
Aufgabe der Erfindung ist es, eine verträgliche, nichtinvasive Reduktion der Fettzellen zu bewirken, die auf natürliche Prozesse im Körper zurückgreift und daher den Organismus weniger belastet. Die langsame, kontinuierliche und vor allem homogene Wirkung der Photosensibilisierung bei der Zerstörung von Fettzellen ermöglicht es dem umliegenden Gewebe, sich perfekt anzupassen und ein optimales Behandlungsergebnis zu erzielen.The object of the invention is a tolerable, non-invasive reduction in fat cells effect that uses natural processes in the body and therefore the Organism less stressed. The slow, continuous and above all homogeneous The effect of photosensitization in the destruction of fat cells makes it possible surrounding tissue to adapt perfectly and an optimal treatment result to achieve.
Dabei sollen zell- oder gewebespezifische Erkennungsstellen oder spezielle Moleküle in der Gewebematrix (z. B. Leptin im Falle des weißen Fettgewebes) bzw. eine vom restlichen Gewebe abweichende Pharmakokinetik zur Akkumulation von Photosensibilisatoren mit oder ohne Carrier-System im Fettgewebe genutzt werden. Ein Vorteil bei der Behandlung von Fettgewebe besteht darin, daß der größte Teil des für den Organismus verzichtbaren Fettgewebes direkt unter der Haut liegt und somit eine Belichtung relativ einfach möglich ist (z. B. mit Laserlicht). Gebiete, in denen keine Wirkung eintreten soll, können beklebt oder mit Schutzemulsionen beschichtet werden. Da die Belichtung im allgemeinen von der Hautoberfläche aus erfolgt, wird hauptsächlich Fettgewebe nahe der Oberfläche zerstört und daraufhin vom Organismus selbst entsorgt. Bei dem vorgeschlagenen Verfahren wird hauptsächlich Apoptose favorisiert (ein Absterben der Zelle aus anderen Gründen aber nicht ausgeschlossen), da außer dem naturidentischen Absterben der Zelle keine weitere wesentliche indirekte Reaktion auf die Behandlung zu erwarten ist.Cell- or tissue-specific recognition sites or special molecules in the tissue matrix (e.g. leptin in the case of white adipose tissue) or one of the remaining tissue deviating pharmacokinetics for the accumulation of Photosensitizers with or without a carrier system can be used in adipose tissue. On Advantage in treating adipose tissue is that most of the for the organism dispensable fatty tissue lies directly under the skin and is therefore a Exposure is relatively easy (e.g. with laser light). Areas where no Should take effect, can be glued or coated with protective emulsions. Since the exposure is generally made from the surface of the skin mainly fat tissue near the surface destroyed and then by the organism self-disposed. The proposed method mainly involves apoptosis favored (but the cell cannot die off for other reasons), because apart from the nature-identical death of the cell, no other essential indirect Response to treatment is expected.
Die tatsächliche physische Zerstörung der Fettzellen sollte (ähnlich wie bei einer Fettabsaugung) zu einer nachhaltigen Fettreduktion führen ohne die Risiken eines chirurgischen Eingriffs. Da der Wirkstoff durch das Gewebe diffundieren kann, wird immer ein fließender räumlicher Ansatz der Behandlung sichergestellt.The actual physical destruction of the fat cells should be (similar to that of a Liposuction) lead to sustainable fat reduction without the risks of one surgical intervention. Because the active ingredient can diffuse through the tissue, a fluid spatial approach to treatment is always ensured.
Außerdem kann mit einer geringeren Dosierung über längere Zeiträume der Selbstheilung des Organismus mehr Zeit eingeräumt werden.In addition, with a lower dosage over a longer period of time Self-healing of the organism can be given more time.
Natürlich ist diese Behandlung auch als begleitende Maßnahme zu chirurgischen Eingriffen oder Diäten sinnvoll.Of course, this treatment is also an accompanying measure to surgical Interventions or diets make sense.
Ein weiteres Anwendungsgebiet liegt in der Reduktion von Schädigungen, die durch übermäßiges Einwachsen von Fettgewebe in andere Gewebearten entstehen (z. B. Zellulitis). Dies ist nach unserem Kenntnisstand bisher nicht möglich.Another area of application is the reduction of damage caused by excessive ingrowth of adipose tissue in other types of tissue occurs (e.g. Cellulitis). To our knowledge, this has not been possible to date.
In Abhänigkeit von der Art des zu behandelnden Fettgewebes kommen verschiedene
Applikationsformen in Frage:
Depending on the type of adipose tissue to be treated, different forms of application are possible:
- - intravenöse Injektion - intravenous injection
- - orale Applikation- oral application
- - subkutane Injektion- subcutaneous injection
- - topische Applikation- topical application
Die beiden ersten Formen kommen für eine globale Wirkung in Frage und erfordern hoch selektive Wirkstoffe (z. B. durch den Einsatz von Antikörpern/Fragmenten) um eine Sensibilisierung anderer Gewebe zu verhindern (nach Ablauf der Clearing-Zeit, d. h. Ausscheidung nicht gekoppelter Wirkstoffe). Eine lokale Wirkung ist hier durch gezielte Belichtung zu erreichen.The first two forms are possible and require a global impact highly selective active ingredients (e.g. through the use of antibodies / fragments) prevent sensitization of other tissues (after the clearing time, d. H. Elimination of non-coupled active substances). A local effect is here to achieve targeted exposure.
Die beiden letzteren Formen kommen für den lokalen Einsatz in sogenannten Problemzonen in Frage. In diesen Fällen sind die Anforderungen an die Selektivität der Sensibilisatoren wesentlich geringer, da die Verteilung des Farbstoffes maßgeblich durch Diffusion erfolgt.The latter two forms come for so-called local use Problem areas in question. In these cases, the requirements for the selectivity of the Sensitizers much lower, since the distribution of the dye is decisive by diffusion.
Die Wirksamkeit der vorgeschlagenen Methode soll mit nachfolgendem Beispiel zur
prinzipiellen Durchführbarkeit belegt werden:
Weißes Fettgewebe von Kaninchen wurde als Zupfpräparat entnommen zum Transport
in PBS gegeben [1], anschließend mit Collagenase Typ II (Sigma) gemäß [2] vereinzelt
und gemäß [3] kultiviert. Als Supplemente wurden 500 µl Penizillin (0.5 M IE/5 ml
PBS) auf 500 ml Medium, 250 µl Streptomycin (1.253 g/5 ml PBS) auf 500 ml
Medium, als Antiobiotika und 125 µl des Antimycotikums Nystatin (0.5 M IE/5 ml
PBS) zugefügt.The effectiveness of the proposed method is to be demonstrated with the following example of the feasibility:
White adipose tissue from rabbits was taken as a plucked preparation for transport in PBS [1], then isolated with collagenase type II (Sigma) according to [2] and cultured according to [3]. 500 µl penicillin (0.5 M IU / 5 ml PBS) on 500 ml medium, 250 µl streptomycin (1,253 g / 5 ml PBS) on 500 ml medium, as antiobiotics and 125 µl of the antimycotic nystatin (0.5 M IU / 5 ml PBS) added.
Die erhaltene Charge wird in vier identische Proben geteilt, wobei Probe 1 als Referenz verbleibt, Probe 2 nur belichtet wird und Probe 3 nur mit Farbstoff inkubiert wird und schließlich Probe 4 inkubiert und belichtet wird.The batch obtained is divided into four identical samples, with sample 1 as a reference remains, sample 2 is only exposed and sample 3 is only incubated with dye and finally sample 4 is incubated and exposed.
Die Belichtung erfolgt, nachdem die Zellen für 24 Stunden mit Phäophorbid a (Pheo)[4] mit einer Konzentration von 5.10-6 im Medium bei 37°C gelagert wurden.The exposure takes place after the cells have been stored for 24 hours with pheophorbide a (Pheo) [4] at a concentration of 5.10 -6 in the medium at 37 ° C.
Anschließend wurde die Probe 2 mal gewaschen und gemäß [1] mit Vitalfärbung Trypanblau gefärbt.The sample was then washed twice and, according to [1], with vital staining Trypan blue colored.
Die Bestrahlungsexperimente erfolgten mit UVA (20 Minuten) in einer 24 Well-Platte. Die Zellen wurden vor und nach der Bestrahlung (A) sowie 24 h später (B) ausgezählt (Fuchs-Rosenthal-Zählkammer).The radiation experiments were carried out with UVA (20 minutes) in a 24-well plate. The cells were counted before and after radiation (A) and 24 hours later (B) (Fuchs-Rosenthal counting chamber).
Es ergab sich eine Überlebensrate der einzelnen Proben gemäß folgender Übersicht
The survival rate of the individual samples was shown in the following overview
Die Standardabweichung liegt bei ca. 12%.The standard deviation is approx. 12%.
Damit kann belegt werden, daß eine toxische Wirkung auf die Zellen durch Anwendung der PDT vorliegt und daß diese Toxizität maßgeblich durch Photosensibilisierung und den damit generierten Singulett-Sauerstoff verursacht wird.It can thus be demonstrated that application has a toxic effect on the cells the PDT is present and that this toxicity is largely due to photosensitization and the singlet oxygen generated with it is caused.
Als Trägersysteme kommen eine nicht-kovalente Einbettung oder eine kovalente Ankopplung in größere Moleküle oder Systeme in Frage.A non-covalent embedding or a covalent one comes as carrier systems Coupling into larger molecules or systems in question.
Geeignete Liposomen können z. B. gemäß [5] beladen werden. Die Verwendung von Liposomen als Carrier für den Farbstoff ergab im Falle der hier untersuchten Fettzellen vergleichbare Ergebnisse wie bei reinem Pheo.Suitable liposomes can e.g. B. loaded according to [5]. The use of Liposomes as carriers for the dye resulted in the fat cells examined here comparable results to pure Pheo.
Eine Kopplung an biologische Trägersubstanzen (z. B. Antikörper, Dendrimere) ist leicht möglich, wenn der Farbstoff über eine Carboxyl-Gruppe verfügt. Diese kann in Dioxan mit N-hydroxy-Succinimid (Succ) in Anwesenheit von Dihexylcarbodiimid (DCC) leicht aktiviert werden. Dazu werden der Farbstoff, Succ und DCC im Molverhältnis 1 : 2 : 3 für einen Tag bei Raumtemperatur gerührt, und anschließend mit Wasser gewaschen. Die Umsetzung erfolgt nahezu quantitativ.Coupling to biological carrier substances (e.g. antibodies, dendrimers) easily possible if the dye has a carboxyl group. This can be in Dioxane with N-hydroxy-succinimide (succ) in the presence of dihexylcarbodiimide (DCC) can be easily activated. The dye, succ and DCC in the Molar ratio 1: 2: 3 stirred for one day at room temperature, and then with Washed water. The implementation is almost quantitative.
Diese aktivierte Carboxyl-Gruppe reagiert in geeigneten Lösemitteln (je nachdem, was beide Reaktionspartner vertragen (Dendrimere z. B. Dichlormethan) innerhalb von 48 h bei Raumtemperatur in Anwesenheit von geringen Mengen Triethylamin als Katalysator mit vorhandenen NH2 oder SH-Gruppen (NH2 im Falle von DAB-Am-Dendrimeren (Aldrich)). Dabei wird der Farbstoff in einem Überschuß von ca. 10% eingesetzt. Die anschließend erforderliche Trennung ist durch die veränderten Löslichkeiten (Im Fall von Pheo und DAM-Am-Dendrimeren z. B. in Methanol. Das gekoppelte Pheo fällt aus.) oder durch die veränderte geometrische Größe mit Hilfe von Dialyse möglich.This activated carboxyl group reacts in suitable solvents (depending on what both reactants can tolerate (dendrimers e.g. dichloromethane) within 48 h at room temperature in the presence of small amounts of triethylamine as a catalyst with NH 2 or SH groups (NH 2 in the case of DAB-Am dendrimers (Aldrich)) The dye is used in an excess of about 10%. The subsequent separation is due to the changed solubilities (in the case of Pheo and DAM-Am dendrimers, for example in methanol. The coupled pheo fails.) or due to the changed geometric size with the help of dialysis.
[1] Fried, S. K.; Moustaid-Moussa, N. In: Adipose Tissue Protocolls-Methodes in
Moleculat Biology. Vol. 155, Chap. 17 Culture of Adipose Tissue and Islated
Adipocytes, pp. 197-212, Humana Press: Totowa, New Jersey, 2001.
[2] Rodbell, M. The methabolism of isolated fat cells. I. Effects of hormones on
glucose metabolism and lipolysis. J. Biol. Chem. 239: 375-380, 1964.
Marshall, S.; Garvey, W. T.; Geiler, M. Primary culture of isolated adipocytes:
a new model of study insulin receptor regulation and insulin action. J Biol. Chem.
259: 6376-6384, 1984.
Birguet-Laugier, V.; Quignard-Boulange, A.; Dugail, I; Argeson, A. C.;
LeLiepvre, X; Lavau, M. White adipocytes from young obese Zucker rates
maintin excessive lipogenic enzyme activity in long term culture, in Obesitv in
Europe 91 (Ailhaud, G.; Gyu-Grand, B.; Lafontan, M. Ricquier, D., eds.)
Libbey, London, pp. 95-99.
[3] Halleux,C. M.; Dervais, I; Reul, B. A.; Detry, R.; Brichard, S. M. Multihormolal
control of ob gene expression and leptin secretion from cultured human viscerval
adipose tissue: increased responsiveness to glucocorticoides in obesity. J. Clin.
Endocrinol. Metab. 83: 902-910, 1998.
[4] Willstätter A., Stoll R.: Untersuchungen über Chlorophyll, Springer, Berlin, 1913
[5] Kremer, M. H.; v. d. Esker, M. W. J.; Pathmamanohrama, C. Wiersema, P. H.
Vesicles of variable diameter prepared by a modified injections method, Biochem.
16: 3932-3935, 1977.[1] Fried, SK; Moustaid-Moussa, N. In: Adipose Tissue Protocols-Methodes in Moleculat Biology. Vol. 155, Chap. 17 Culture of Adipose Tissue and Islated Adipocytes, pp. 197-212, Humana Press: Totowa, New Jersey, 2001.
[2] Rodbell, M. The metabolism of isolated fat cells. I. Effects of hormones on glucose metabolism and lipolysis. J. Biol. Chem. 239: 375-380, 1964. Marshall, S .; Garvey, WT; Geiler, M. Primary culture of isolated adipocytes: a new model of study insulin receptor regulation and insulin action. J Biol. Chem. 259: 6376-6384, 1984. Birguet-Laugier, V .; Quignard-Boulange, A .; Dugail, I; Argeson, AC; LeLiepvre, X; Lavau, M. White adipocytes from young obese Zucker rates maintin excessive lipogenic enzyme activity in long term culture, in Obesitv in Europe 91 (Ailhaud, G .; Gyu-Grand, B .; Lafontan, M. Ricquier, D., eds. ) Libbey, London, pp. 95-99.
[3] Halleux, CM; Dervais, I; Reul, BA; Detry, R .; Brichard, SM Multihormolal control of ob gene expression and leptin secretion from cultured human viscerval adipose tissue: increased responsiveness to glucocorticoides in obesity. J. Clin. Endocrinol. Metab. 83: 902-910, 1998.
[4] Willstätter A., Stoll R .: Studies on chlorophyll, Springer, Berlin, 1913
[5] Kremer, MH; vd Esker, MWJ; Pathmamanohrama, C. Wiersema, PH Vesicles of variable diameter prepared by a modified injections method, Biochem. 16: 3932-3935, 1977.
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| EP1928466A4 (en) * | 2005-08-02 | 2012-12-19 | Ceramoptec Gmbh | METHOD OF TREATING ANTI-CELLULITE THERAPY AND COSMETIC APPLICATIONS |
| KR101330120B1 (en) * | 2005-08-02 | 2013-11-15 | 바이오리텍 파마 마케팅 엘티디. | Pdt treatment method for cellulites and cosmetic use |
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