WO2000041671A2

WO2000041671A2 - Composition, device, and method for subcutaneous fat removal

Info

Publication number: WO2000041671A2
Application number: PCT/US1999/029374
Authority: WO
Inventors: Nikolai Tankovich
Original assignee: T & T Pharmaceuticals, Ltd.
Priority date: 1999-01-12
Filing date: 1999-12-09
Publication date: 2000-07-20
Also published as: WO2000041671A9; WO2000041671A3

Abstract

A composition of matter, device and method for dissolving fat associated, with or near the skin. The composition is directed to perfluorocarbon compositions, the devices incorporate perfluorocarbons for topical application to the skin, and methods involve either subdermal injection or topical application of perfluorocarbon compositions.

Description

COMPOSITION, DEVICE, AND METHOD FOR SUBCUTANEOUS FAT REMOVAL

FIELD OF THE INVENTION This invention relates to a composition of matter, device, and method for dissolving fat associated with or near the skin. The composition is directed to perfluorocarbon compositions, the devices incorporate perfluorocarbons for topical application to the skin, and methods involve either subdermal injection or topical application of perfluorocarbon compositions.

DESCRIPTION OF RELATED ART The publications and other reference materials referred to herein to describe the background of the invention and to provide additional detail regarding its practice are hereby incorporated by reference.

A major concern relating to human skin is the accumulation of excess layers of fat cells, especially in middle age and elderly people, which causes them to appear fatty and older.

Recent attempts have been made to remove subcutaneous fat as well as treat cellulite utilizing different techniques. Cellulite is a lay term describing the uneven, bumpy texture of skin in specific areas of the female body (primarily hips, thighs, and buttocks) caused by the abnormal accumulation of fatty cells in masses beneath the skin. The main method today for subcutaneous fat removal is liposuction, a method which presents potential risk to the patient.

One of the first comprehensive reports on liposuction appeared in 1983 (Y.G.

Illouz, Body Contouring by Lipolysis: A 5-Year Experience with over 300 cases; Plast.

Reconst. Surg. 72:591 (1983)). A breakthrough occurred with the development of the tumescent technique of Jeffrey Klein (Plast. Reconstr. Surg., 92: 1085 ((93)).

Tumescent anesthesia allows liposuction to be performed over larger areas using local anesthesthetic and a vasoconstrictor in a solution injected in the desired location. U.S.

Patent No. 5,472,416 by Blugerman et al. describes the tumescent lipoplastic method and apparatus. Ultrasonic tumescent liposuction was developed by Dr. Michele Zocchi in 1992 (Clin. Plast. Surg (1996) pp. 575-598). Ultrasound at lMhz with power of

2 W/cm² is applied to the skin for ten minutes before suction, which is described by Parisi et al. in U.S. Patent No. 4,886,491. Ultrasound from 16 to 20,000 Hz alters adipose tissue through mechanical disruption and cavitation with minimal thermal effect. Another method for removal of subcutaneous fat involves vaporization of adipose tissue using a laser. Complications and trauma are major problems with the above methods for removal of subcutaneous fat and treatment of cellulite by liposuction. Excessive bleeding is associated with the procedure because the tools which are inserted into the subcutaneous fat are either shaφ knives or blunt cannulas that are scraped through the site of interest, damaging blood vessels. Complications arise mostly due to damaged blood vessels, causing blood clots that express as irregularities in the overlying skin.

Nerves are also affected by the traumatic aspects of the procedure, causing loss of feeling in the treated area for some months afterwards.

DISCLOSURE OF THE INVENTION The present invention, which overcomes these problems and inefficiencies of subcutaneous fat removal, is directed to compositions of perfluorocarbons and methods of using these compositions for subcutaneous fat removal. The advantage provided by the compositions and method of the invention is based on the ability of perfluorocarbons to rapidly emulsify the fat in the adipose cells without the necessity of a cannula or other blunt or shaφ instrument to mechanically break, tear, or otherwise disconnect the adipose cells from site of interest. E ulsification of the fat in the adipose tissue obviates the use of a cannula or other blunt or shaφ instrument to mechanically break, tear or otherwise disconnect the adipose cells from the site of interest. In the present invention, emulsified fat is easily drawn out of the body by suction without the trauma caused by the presently available techniques of liposuction.

In one aspect, the invention is directed to a composition comprising perfluorocarbon and one or more agents selected from the group consisting of anesthetics and vasoconstrictors. The composition is in association with a pharmaceutical carrier. It is an object of the invention to provide a composition for use in techniques, in particular liposuction techniques, for removal of tissue and fat from a patient.

Another aspect of the invention is a method for subcutaneous removal of lipid or fat cells from a patient. The method comprises the steps of contacting subcutaneous lipid or fat cells in an area of the patient with an effective or sufficient amount of the composition of the invention for a sufficient period of time to emulgate the lipid or fat cells into an emulsion. The emulsion is removed in a subsequent step. A version of the method involves oscillating the lipid or fat cells which were contacted with the composition with a sufficient amount of oscillation energy to enhance emulgation of the fat compared to emulgation without oscillation. It is an object of the invention to provide a tumescent solution which emulsifies skin fat, forming it into a suspension, emulsion or liposomes in the presence of high frequency oscillations suitable for removal by suction without damage to blood vessels. Another object of the invention is to provide a method of removal of fat from a patient with no damage or minimal damage to blood vessels. These and many other features and attendant advantages of the present invention will become better understood by reference to the following detailed description of the invention when taken in conjunction with the accompanying drawings.

BRIEF DESCRIPTION OF THE DRAWINGS

Figure 1 is a diagram of a section of skin. Figure 2 is a block diagram of the tissue layers of skin.

Figure 3 illustrates skin fat liposuction using perfluorocarbons and an oscillator. Figure 4 shows transdermal delivery systems. Figure 5 shows examples of drug release or drug diffusion mechanisms that describe devices and systems used in the present invention to deliver perflurocarbons from polymers to give various release profiles.

MODES OF CARRYING OUT OF THE INVENTION General Description and Definitions

The practice of the present invention will employ, unless otherwise indicated, conventional techniques in cosmetic or aesthetic surgery, including liposuction, and medicinal chemistry and medicinal formulation within the skill of the art. Such techniques are explained fully in the literature. See, e.g. Ronrich, R.J., Beron, S.J., Fodor, P.B., The Role of Subcutaneous Infiltration in Suction-Assisted Lipoplasty: A review. Plast. Reconstr. Surg. (1997) 99:514-519: Hanke, C.W., Bernstein, G., Bullock, S., Safety of Tumescent Liposuction in 15,336 Patients, Dermatol. Surg. (1995) 21 :459-462; Zocchi, M.L. Ultrasonic Assisted Lipoplasty: Technical Refinements and Clinical Evaluations, Clin. Plast. Surg. (1996):pp. 575-598). The following terminology will be used in accordance with the definitions set out below in describing the present invention.

As used herein, the term "perfluorocarbons" (PFCs) means compounds with a highly developed active surface having the capacity to bind lipids in an emulsion, and thereby breakdown skin fat. Topically applied oscillation or vibration enhances the capacity of PFCs to emulsify the fat. The scope of structures included in PFCs used in the present invention are illustrated, but not limited to those in U.S. Patent Nos. 5,455,373; 5,637,318; and 5,679,459 which are incoφorated by reference. As used herein, the term "emulgate" means to form an emulsion. As used herein, the term "tumescent technique" means a technique for liposuction which involves the infiltration of a "tumescent solution." A tumescent solution contains a local anesthetic agent, e.g. lidocaine, and a vasoconstrictor, e.g. epinephrine, in a pharmaceutical carrier which is infiltrated into the subcutaneous fat typically in a liposuction surgical procedure through a cannula or through a needle, in some procedures with the aid of a peristaltic pump. The vasoconstrictor and local anesthetic agent of the tumescent solution, respectively, reduce bleeding and eliminate the need for general anesthetics. The usefulness of prior art tumescent solutions used in prior art liposuction techniques is limited, however, because of excess bleeding from trauma to blood vessels caused by the cannula (blunt or shaφ-edged) as it is scraped through the subcutaneous site of interest and sucks out adipose tissue and fat.

The advantages provided by the present invention will be better understood with reference to Figure 1, which is a cross section of human skin showing the location of fat and blood vessels. Figure 1 illustrates epidermis, dermis and subcutaneous fat with the hair shaft 33 of a hair growing in a hair duct 31 from dermal papilla 32. Also shown is a nerve ending 34, a sweat gland 35, a sebaceous gland 38 , arteries 36, and veins 37. Subcutaneous fat or lipid is predominated with adipocytes, i.e. fat cells which contain cytoplasmic lipids. The subcutaneous fat is both a cushion to prevent mechanical injury as well as a storage depot for high-potency energy sources. Fat is stored in adipocytes, which are enormously distended cells that comprise the majority of cells in adult adipose tissue. The composition and method of the invention provide an effective amount of perfluorocarbon which, in contact with the adipocytes and, in due course, in contact with the fat within the adipocytes at the site of interest, emulgages the fat stored in the adipocytes. Adipocytes are arranged in sheet-like lobules separated by thin, fibrous septa in which blood vessels supply nutrients. These septa anchor the deepest limits of the reticular dermis to underlying fascia, with an intervening cushion of subcutaneous lobules formed by masses of adipocytes. The blood vessel-rich septa are ripped, broken and otherwise traumatized by conventional liposuction techniques using conventional tumescent solutions.

Composition of the Invention

The present invention provides a composition for use in the removal of tissue and fat from a patient. The composition comprises a perfluorocarbon (PFC) and one or more agents selected from the group consisting of anesthetics and vasoconstrictors. The composition can be combined with a pharmaceutical carrier, preferably a pharmaceutical carrier suitable for cosmetic or aesthetic surgical procedures, in particular liposuction, for removal of body fat. Compositions used in the art for such procedures as known as "tumescent solutions."

It is understood that the PFC of the composition is selected from one or more of the group of PFCs consisting of one or more aliphatic straight-chain and branched fluoroalkanes, mono-or bicyclic and optionally fiuoralkly-substituted flurocycloalkanes, perfluorinated aliphatic or bicyclic amines, bis(perfluoroalkl) ethenes; or alternatively from one or more substituted and unsubstituted alkyl, alkenyl, alkynyl, alkoxyl groups which can have straight or branched chains, ring structures including single or fused ring structures, e.g. phenyl, or naphthyl. The unsaturated groups can have a single site of unsaturation or a plurality of sites of unsaturation. Fluorocarbon compositions such as Perftoran and perflubron are included. Medically useful PFCs and syntheses thereof are disclosed in U.S. Patent Nos.

5,455,373; 5,637,318; and 5,679,459 which are incorporated by reference. The scope of PFCs that find use in the present invention is illustrated but not limited by the PFCstructures disclosed therein. Guidance for formulating compositions comprising PFCs is also disclosed therein, and further disclosed in Dean, J.A. Lange's Handbook of Chemistry, (1992), Sections 10.12, 10.30-10.33.

Combined with an anesthetic and/or a vasoconstrictor, and a pharmaceutical carrier, the composition of the invention provides a tumescent solution. The amount of PFC in the composition is in the range from about 0.1% to about 100% w/v, preferably in the range from about 10% to about 70%. A particularly preferred range is from about 50% to about 65%. Pharmaceutical carriers, particularly for cosmetic surgical procedures, are well known in the art, and include but are not restricted to solutions, emulsions, transferosomes (Krantz and Carr, Textbook of Pharmacological Principals of Medical Practice, (1964), pp. 26-32; Lippold, B.C. Pharmacy International (1980) 3:1-60; Gregoriadis, G. and Neerunjun, D.E., Liposomes and Their Uses in Biology and Medicine (1977), pp. 14-16.

Methods for making tumescent solutions are well known in the art (Ostad, A., Kageyama, N., Moy, R.L., Tumescent Anesthesia with a Lidocaine Dose of 55 mg/kg Is Safe for Liposuction, Dermatol. Surg. (1996) 22:921-927; Replogle, S.L., Experience With Tumescent Technique in Lipoplasty (1993) 17:205-209. Accordingly, the amount of anesthetic and/or vasoconstrictor for use in the compositions of the invention are readily determined by one of ordinary skill in the art. Furthermore, methods are well known in the art for determining the efficacy of a tumescent solution of the invention (Klein, J.A., The Tumescent Technique for Liposuction Surgery, Am. J. Cosmet. Surg. (1987) 4:263-267. Vasoconstrictors which are useful in the composition of the invention include but are not restricted to epinephrine, levarterenol, phenylephrine, athyladrianol, ephedrine.

Anesthetics which are useful in the composition of the invention include but are not restricted to lidocaine, marcaine, nesacaine, diprivan, novocaine, ketalar, xylocaine.

EXAMPLE 1 - Tumescent Solution A preferred tumescent solution is a composition which comprises the PFC Perftoran¹"¹, a vasoconstrictor, and an anesthetic. Perftoran is obtained from Pharmpreparaty Company, Russia. Perftoran contains 12 mEq of sodium carbonate per liter, 15.2 % perfluorodecalin, 7.6% perfluoromethylcyclohexypiperidin, 4% Proxanol-268, 0.039% potassium chloride, 0.6% sodium chloride, 0.019% magnesium chloride, 0.028 % calcium chloride, 0.13% sodium hydrocarbonate, 0.02% sodium hydrophosphate, 0.2% glucose, the remainder being water. Accordingly, the preferred tumescent solution is a mixture of 5% by volume 2% lidocaine (total 0.1% in solution), 1% epinephrine, and Perfotoran. The tumescent solution is directed into the site of interest where lipids need to be extracted. METHOD OF THE INVENTION In another aspect, the invention is directed to a method for subcutaneous removal of lipid from a patient. The method comprises the step of contacting the subcutaneous lipid with an effective or sufficient amount of a composition comprising PFC for a sufficient period of time to emulgage the lipid into an emulsion. Another step involves removing the emulsion from the patient. A preferred version of the method involves administering oscillation to the lipid after the PFC is in contact with the lipid for a sufficient period of time. A sufficient amount of oscillation is administered to speed up or enhance emulgation so that more emulsion is formed than without oscillation.

In one aspect, the method involves contacting the lipid with a composition of PFC, preferably a composition of PFC in a pharmaceutical carrier. The amount of PFC in the composition is in the range of about 50% to about 80%.

In yet another aspect, the composition of PFC further comprises one or more agents selected from the group consisting of anesthetics and vasoconstrictors, and preferably in association with a pharmaceutical carrier to form a tumescent solution. The amount of PFC in the composition as well as amounts of vasoconstrictor and local anesthetic are as described above for the compositions of the invention.

As described above, methods in the art are well known for making tumescent solutions, determining their efficacy, and determining the optimal periods of time for contact between the compositions and the fat in the site of interest. Furthermore, methods are also well known in the art for applying oscillation to areas of concern, determining a sufficient amount of time to apply oscillation to the area of concern, and for measuring the efficacy of the oscillation energy for enhancing the emulgation. The step of contacting subcutaneous lipid with a sufficient amount of a composition comprising perfluorocarbon can be achieved by administering the composition to the area of concern with a cannula or by injection with a needle (Figure 3). Figure 3 shows a syringe (4) containing the composition of the invention inserted through the epidermis (1), projecting down into the dermis (2) where subcutaneous fat (SCF) (3) is located in order to contact the subcutaneous lipid in the site of interest with a sufficient or effective amount of the composition for a sufficient period of time to emulgate the lipid into an emulsion. An ultrasonic transducer (UST) (6) applies oscillation to the SCF or lipid in the adipocytes. The step of removing the emulsion can be achieved by aspirating with a cannula or needle (8). The steps of contacting and removing comprise the well known surgical procedure of liposuction These techniques are well known in the art, as disclosed in U.S. Patent No. 5,472,416, incorporated by reference, and in Fisher, G., Liposculpture in J. Derm. Surg. (1997) pp. 1183-1187.

In a preferred aspect of the method, after the step of contacting the lipid at the site of interest with the composition of the invention, oscillations, i.e. the mechanical vibrations of high frequency are topically applied to promote emulgation, i.e. to enhance the process of the fat molecules binding to the PFC and emulsification, i.e., dissolving of fat molecules. The suspension or emulsion is sucked out without blood vessel damage, a major advantage of the invention. Ultrasonic instruments and methods for applying oscillation to the lipid in a patient in an area of concern are known in the art, as disclosed in U.S. Patent Nos. 5,419,761 and 4,886,491; and in M. Zocchi, Clin. Plast. Surg. (1996) pp. 575-598.

Transferosome Compositions of Perfluorocarbons Another aspect of the invention is directed to a transferosome composition which comprises transferosomes which comprise one or more perfluorocarbons (PFCs). "Transferosomes" are lipid vesicles which have the unique property, unlike conventional lipid suspensions (such as standard liposomes or mixed lipid micelles) of being sufficiently flexible or deformable to pass through pores or other biological apertures which are appreciably smaller than the size of the transferosome (G. Cevc et al., Biochimica et Biophysica Acta 1368:201-215, 1998). Tranferosomes provide the advantage of maximizing, relative to conventional liposomes, the transdermal delivery of a therapeutic agent. Accordingly, an objective of the invention involves providing a composition suitable for topical application to the skin, the composition for transporting therapeutic amounts of perfluorocarbon to the hypodermis to thereby contact and emulgate subcutaneous fat deposits therein.

Methods for preparing transferosomal compositions are cited in G. Cevc et al. (ibid). For example, a soybean phosphatidylcholine (SPC) composition of liposomes is first made by the standard method. In brief, an organic solution of the required lipid mixture is first dried under vacuum overnight. The resulting lipid film is then hydrated with triethanolamine-HCl buffer (pH=6.5) to prepare a 10% lipid suspension. The suspension is sonicated for 60 minutes at 4° until the desired vesicle radius is achieved. The vesicle radius is measured by dynamic light scattering. General methods for making liposomes are found in O. Braun-Falco, H.C. Korting, H.I. Maibach. Liposome Dermatis. Springer- Verlag, 1992. Transferosomes are prepared by mixing an ethanolic SPC solution with the appropriate amount of an edge-active molecule, such as sodium cholate. Other biocompatible surfactants could be used in different suspensions (G. Cevc, 1991, European Patent 91 114 163.8-2114). The suspension is subsequently mixed with triethanolamine-HCL buffer to yield total lipid concentration of 10 wt%. The resulting suspension is sonicated, frozen and thawed (2-3 times) and brought to the desired size (as measured by means of photon correlation spectroscopy) by ultrasonication or intermediate-pressure homogenization. Vesicle suspension is ultimately sterilized by filtration through a 0.2 micron porous filter (Poretics, CA). The final vesicle size is confirmed by dynamic light scattering. Further guidance for preparing transfersomal compositions is provided in G.

Cevc, Lipid properties as a basis for the modeling and design of liposome membranes, in G. Gregoriadis, Ed., Liposome Technology, 2nd ed., CRC -Press, Boca Raton, FL, 1992, pp. 1-36; and in G. Cevc, Material Transport across permeability barriers by means of lipid vesicles in: R. Lipowsky (ed.), Handbook of Physics of Biological Systems, vol. I, Elsevier Science, Chap. 9, 1995, pp. 441-466. A variety of transferosome compositions are described in detail in G. Cevc, 1991, European Patent 91 1 14 163.8-2114). Guidance for preparing conventional liposomal preparations which comprise perfluorocarbons is found in O.Braun-Falco, H.C. Korting, H.I. Maibach. Liposome Dermatis. Springer- Verlag, 1992, Pp. 82 - 172. J.R. Phillipot, F. Schuber. Liposomes as Tools in Research and Industry. CRC Press, 1994, pp. 36 -

201.; and in U.S. Patent No. 5,637,318, which discloses liposomal preparations for dermatological use, as distinguished from the subcutaneous use of the present invention; and U.S. Patent no. 5,679,459 which discloses vesicular or liposomal compositions comprising perfluorocarbons. As above, the scope of chemical structures included in perfluorocarbons

(PFCs) used in the present invention are illustrated, but not limited to those in U.S. Patent Nos. 5,455,373; 5,637,318; and 5,679,459 which are incoφorated by reference. It is understood that the PFC of the composition is selected from one or more of the group of PFCs consisting of one or more aliphatic straight-chain and branched fluoroalkanes, mono-or bicyclic and optionally fiuoralkly-substituted flurocycloalkanes, perfluorinated aliphatic or bicyclic amines, bis(perfluoroalkl) ethenes; or alternatively from one or more substituted and unsubstituted alkyl, alkenyl, alkynyl, alkoxyl groups which can have straight or branched chains, ring structures including single or fused ring structures, e.g. phenyl, or naphthyl. The unsaturated groups can have a single site of unsaturation or a plurality of sites of unsaturation. Fluorocarbon compositions such as Perftoran and perflubron are included.

Medically useful PFCs and syntheses thereof are disclosed in U.S. Patent Nos. 5,455,373; 5,637,318; and 5,679,459 which are incoφorated by reference. The scope of PFCs that find use in the present invention is illustrated but not limited by the PFC structures disclosed therein. Guidance for formulating compositions comprising PFCs is also disclosed therein, and further disclosed in Dean, J.A. Lange's Handbook of Chemistry, (1992), Sections 10.12, 10.30-10.33.

Example

Preparation of Transferosome Composition Comprising Perfluorocarbon

A starting perfluorocarbon solution which is Perftoran contains approximately of 12 mEq of sodium carbonate per liter, 15.2 % perfluorodecalin, 7.6% perfiuoromethylcyclohexypiperidin,4% Proxanol-268, 0.039% potassium chloride, 0.6%) sodium chloride, 0.019% magnesium chloride, 0.028 % calcium chloride, 0.13% sodium hydrocarbonate, 0.02% sodium hydrophosphate, 0.2% glucose, the remainder being water. To prepare 100 ml of a transferosome composition comprising Perftoran, 82 ml of the starting solution is mixed, for example, with 0.9 g of SPC and approx. 0.1 g of sodium cholate or an approximate amount of other detergent in 10 ml of ethanol. The resulting crude suspension is homogenized to yield a mixture of vesicle with a radius of approximately 100 nm. These transferosomes are then sterilized by filtration through a 0.22 micron pore filter (Sartorius, Gottingen, Germany) and used for experiments. The final concentration of Perftoran in the transferosomal preparation is about 82 U/ml

Transfersomes Comprising Perfluorocarbons in Combination With Transdermal Delivery System

As used herein, the term "transdermal delivery system" essentially means any type of a substrate, formulation, or composition that contains a substance that allows a drug or therapeutic agent (e.g. molecular agent or vesicle containing said agent) to transit from the outside of the skin through the various skin layers and into a target subcutaneous area or finally into the circulatory system to exert a pharmacological action . Transdermal Delivery System

Transdermal delivery systems used in the present invention and guidance for combining the transfersome composition comprising PFC of the present invention with transdermal delivery systems are disclosed in detail in generally available references, including Topical Drug Bioaλ'ailab/ity, Bioequivalence, and Penetration (eds Vinod

P Shah and Howard I Maibach, Plenum Press, 1993), and in Skin Barrier, Principles of Percutaneous Absorption (Hans Schaefer and Thomas E. Redelmeier, Karger Publ., 1996) These references provide ample guidance for methods of using the compositions of the invention in the methods of the invention for removing subcutaneously located fat deposits by applying the compositions in an amorphous form or in the form of a patch to an area of skin for a sufficient period of time to deliver a sufficient amount of PFC to the fat deposits beneath the amplication to emulgate the fat deposits

Transdermal delivery systems used in the compositions, methods, and devices of the invention range in design from amoφhous ointments to solid-state laminates or patches Many transdermal products have reached the marketplace in the world to date (Shah et al., ibid, Table III, p. 31) Categories of solid state laminates or patches include "membrane-controlled," "reservoir", "matrix," or "monolithic" types (Shah et al., ibid, pp 32-33; Schaefer et al., ibid, pp. 214-215) A reservoir is considered a storage place for the drug. The reservoir can be in a polymeric "matrix," in a

"monolith," or even in a liquid medium. Layers that are present in these products may serve as a structural support and not as a modulator (e.g., rate-controlling membrane) for the drug There are many different types of transdermal systems under development today. Methods of classifying them are discussed in Shah et.al ( ibid, p 32), along with illustration of four basic designs (Figure 4 from Shah, p. 32, fig 5), which, without limitation, are used in the present invention:

(1) Semisolid amoφhous ointment, cream, lotion, or viscous dispersion applied directly to the skin, e.g Nitro-Bid (Marion Merrel Dow), Progestaqgel and Oestragel (Besins-Icovesco), Nitrol (Adria) Included in this category of transdermal delivery system are emulsions, microemulsions (V Lebedenko and N Tankovich, Technological Process ofDrug Microencapsulation, J. Pharmacia, 1983, 2.17-20, Microemulsations' Formulation Guide, Gattefosse Co., France; , coacervate drops (Kharkevich, D et al., Magnetic Field Application for Curare-like Drug Targeting, J. Pharmacology and Toxicology, 1985, 5:32-35) microspheres (N. Tankovich, Theoretical and Practical Aspects of Magnetosensitive Carrier Development for Transblood- vessels Drug Targeting, J. of Mendeleev chemical Society, 1987, 5:37- 42; Borisova, L., et al., Current State of the Problem of Drug Targeting by Magnetic Microspheres, Prepreint IAE#2184-84, 1987, v. 44) and microseeds.

(2) Liquid form, fill and seal laminate structure, e.g. Transdermal Nitro (Summit) and Estraderm (Ciba); Duragesic (Janssen).

(3) Peripheral adhesive laminate structure, e.g. Nitro TDS (Several companies); Nitrodisc (Searle); Nitro-Dur I (Key); Prostep (Lederle.

(4) Solid-state laminate structure, e.g. Transderm-Scop V (Ciba); Catapres-

TTS (Boehringer-Ingelheim); Nitro-Dur II (Key); Deponit (Schwartz); Minitran (3M), Habitrol (Ciba); Nicotrol (Parke-Davis); Nicoderm (Marion Merrel Dow); Hertzer (Taiho); Millisrol (Nippon Kayaku); and frandol (Yamanouchi).

The present invention is not limited to the above mentioned designs of transdermal systems as new approaches and combinations of each design are possible. In combination with PFCs, all of these systems, however, deliver PFCs to the skin surface so that the PFC migrates through the skin to subcutaneous locations of fat deposits. The basic designs and relative advantages and disadvantages are well known to those skilled in the art to allow a transdermal system designer to incoφorate the most suitable PFC release mechanism for the application required, and to establish efficacy of the transdermal delivery system using methods well known in the art. By using the appropriate plasticizers or vehicles, polymers, films, or membranes to match the diffusivity of PFC through the skin, the desired delivery rate for a desired active delivery area and the optimum PFC drug level in subcutaneous fat deposit locations are effectively achieved. Accordingly, the transdermal products of the present invention achieve the objective of delivering into the subcutaneous area below the application of the transdermal product an effective amount of perfluorocarbon into subcutaneous fat deposit locations to emulgate said fat deposits. It should be understood that in contrast with conventional transdermal products, which are designed for delivery of a drug to the systemic circulation to achieve a system therapeutic effect, the transdermal products of the present invention are functionally designed for regional delivery, which involves the application of perfluorocarbons to the skin for the puφose of contacting subcutaneous fat deposits beneath the application with the perfluorocarbons to emulgate the subcutaneous fat deposits. An objective of the invention is to accentuate the pharmacological action of the perfluorocarbons within the subcutaneous region beneath and around the site of application.

Not only may the design of a transdermal be customized by the physical chemistry of PFCs and other components, but the release mechanism of the PFC from the system can be custom fit into almost any of the system designs. Figure 5 (Shah, p. 33, fig. 6) shows examples of drug release or drug diffusion mechanisms that describe devices and systems used in the present invention to deliver PFC from polymers to give various release profiles. The invention is not limited to these six mechanism shown in Figure 5. These mechanisms serve as a guide for the system designer in formulating transdermal delivery systems of the present invention.

Method for Removing Subcutaneouslv Located Fat Deposits

The invention includes methods for removing subcutaneously located fat deposits. The method involves the step of applying a composition comprising perfluorocarbon to an area of skin for a sufficient period of time to deliver a sufficient amount of said perfluorocarbon to the fat deposits beneath the application in order to emulgate the fat deposits.

These methods for applying compositions of perfluorocarbons to the skin involve use of perfluocarbon compositions as described above, namely, a transferosome composition comprising perfluorocarbon (PFC-Transferosome), or a PFC-Transferosome composition in combination with a transdermal delivery systems described above. Another composition of perfluorocarbon that is useful in the method involves liposomal or other vesicular compositions of PFCs which are well known in the art (M.G. Madzhidov et al., Perfluorocarbon Active Media and Emulsions for

Medical and Biological Applications. Proceeding of PFC Symposium, Puschino, 1993. S.M. Chilaya et al., Journal of Anesthesiology and Resuscitation, 4, 1985, pp.36 - 40). Such liposomal or other vesicular compositions of PFCs are applied to the skin either alone or in combination with any of the transdermal delivery systems described above. Enhancing Skin Permeability

The invention is also directed to variations on the method of applying a composition of perfluorocarbon to an area of the skin The variations are directed to the step of applying In these variations, the step of applying comprises treating an area of the skin, preliminary to applying the composition of perfluorocarbon to that area The preliminary step involves treating the skin with a physical agent to increase the permeability of the skin barrier in that area of skin to perfluorocarbon These physical approaches for skin penetration enhancement include, but are not limited to, exfoliation (i e stripping off exterior layer of the stratum cernuum) and depilation Methods for exfoliation are described in Topical Drug Bioavailablity,

Bioequivalence, and Penetration, Chapter 9, (eds Vinod P Shah and Howard I Maibach, Plenum Press, 1993), and in Skin Barrier, Principles of Percutaneous Absorption, p 146, (Hans Schaefer and Thomas E Redelmeier, Karger Publ , 1996) Exfoliation in the method of the invention is also accomplished by treating the skin with laser (For example, see U.S Patent Nos 5,423,803 - Skin Surface Peeling

Process Using Laser, and 5,713,845 -Laser Assisted Drug Delivery)

Methods of depilation are well known in the art A widely practiced method of depilation involves waxing with subsequent removal of wax (Richards, Robert N., et al Cutis 45 199-202, 1990). Plucking is another widely used method of depilation (Urushibata, O et al., Journal of Dermatology, 22.738-742, 1995) When a hair shaft is removed from its follicle by plucking, depilation or otherwise, it is believed that a follicular penetration pathway opens for topically applied drug (Skin Barrier, Principles of Percutaneous Absorption by Hans Schaefer and Thomas E Redelmeier, Karger Publ , 1996, at p. 198, and in Topical Drug Bioavailablity, Bioequivalence, an Penetration (eds Vinod P Shah and Howard I Maibach, Plenum Press, 1993, pp

136-138, 379-380), the pathway leading down the empty follicular shaftway to the hair matrix at the bottom of the follicle where a membrane a thin connective tissue/cell monolayer membrane is effectively transparent for molecules up to molecular weight of 10,000 to 15,000 The drug, which in the present invention is perfluorocarbon or a composition comprising perfluorocarbon, easily diffuses through the membrane into subcutaneous fat deposits located proximate the hair matrix

Examples 1 Application of PFC to an area of skin in the form of an amoφhous ointment or cream or lotion or viscous disperson or emulsion or microemulsion or coacervate drops or microspheres or microseed involves a topical deposition of 2 - 3 ml of the composition per 100 cm² of the skin, massaging and rubbing in during 1 - 2 minutes until the mixture is absorbed by the skin Topical compositions of PFC as disclosed herein are readily absorbed by the skin surface in large quantities by normal skin as described above The step of skin exfoliation or depilation enhances and increasing the quantity of PFC deposited to the subdermal (i e subcutaneous) fat through the skin. The application must be performed once a day as a minimum For better effect, the application could be performed 2- 4 times a day

2 Applying PFC to area skin in the form of a patch As disclosed above, guidance for making patches comprising PFC is available in Topical Drug Bioavailablity, Bioequivalence, and Penetration (eds Vinod P Shah and Howard I Maibach, Plenum Press, 1993), and in Skin Barrier, Principles of Percutaneous Absorptwn (Hans Schaefer and Thomas E Redelmeier, Karger Publ., 1996) Accordingly, without undue experimentation, patches comprising PFC are made in forms suitable for transdermal delivery of PFC for a defined time ranging from about one day to about one month.

3. Application involving exfoliation treatment to an area of skin prior to applying PFC to that area of skin. A version of the claimed method is directed to the step of applying in which applying comprises a step of exfoliating an area of skin pnor to applying PFC to the area of skin A well known method of exfoliation comprises treatment of an area of skin with an Erbium YAG laser, although the method of the invention is not limited to this form of laser treatment An example of Erbium YAG laser treatment, known as Naturalase treatment, is provided by the Advanced

Dermatology Center, Sarasota, Florida (http //hairwrinkleveinaway com/naturala htm)

4 Application involving depilation of an area of skin prior to applying

PFC to that area of skin A version of the claimed method is directed to the step of applying in which applying comprises a step of depilating an area of skin prior to applying PFC to the area of skin

Depilation typically involves skin waxing or hair plucking, although other methods of depilation are available, such as laser depilation The hair waxing process is a preferred embodiment, and involves waxing the area of skin with Azulene Wax consisting of colofodium, parafin, glycerine, parafinum liquidum, BHT, Guai-azulene, CI 75810 and made by "HAJJAAWAY" company. Melted wax is applied to the skin which has been cleaned with 70% isopropyl alcohol. The liquid wax is covered by 4 x 4 cotton gauze. After the wax becomes cold and solid, the gauze is removed against the hair growth. The residue of the wax left on the skin is removed by multiple touch/removed procedure with the same gauze with wax. After that the PFC composition or PFC patch or the mixture is topically applied.

Other Enhancers of skin penetration or permeability

In the compositions, methods, and devices of the invention, chemical and physical approaches in combination with PFCs are used to lower the stratum cernuum barrier properties and enhance transdermal permeation of PFCs. Chemical approaches using molecules such as dimethyl sulfoxide (DMSO), 1 -dodecylazacycloheptan-2-one (azone), surfactants, solvents, and binary polar and apolar systems well known in the art to provide enhancement of skin permeability (see Chapter 14 in Topical Drug Bioavailablity, Bioequivalence, and Penetration (eds. Vinod P. Shah and Howard I.

Maibach, Plenum Press, 1993). Such chemicals are used in the composition or devices of the invention in combination with PFC to increase permeability of the skin to PFC. Alternatively, such chemicals are used to treat an area of skin preliminary to the application of PFC to the area of skin. In the compositions, devices and methods of the inventions, enhancers in the form of various vehicles find use in modifying the penetrability of the stratum cernuum. When a topical formulation or device is applied to skin, it may produce several effects on the stratum cernuum which will modify the permeability characteristics of the stratum cernuum toward any included drug, such as perfluorocarbon. To enhance permeation of the skin, the present invention incorporates any of the following common vehicles in combination with perfluorocarbons: transdermal patch, occlusive dressing, lipophilic substances, absoφtion base, emulsifying base, water-in-oil emulsion, oil-in-water emulsion, humectant, and powder (Ibid, Chapter 14).

In addition to the chemical approach, several physical approaches for skin penetration enhancement are used in the invention. These physical approaches for skin penetration enhancement include, but are not limited to application of thermal energy, iontophoresis, and ultrasound. Phonophoresis, sonophoresis, and ultrasonophoresis are defined as the movement of PFC through living intact skin and into the subcutaneous area containing fat deposits under the influence of an ultrasonic perturbation. It should be understood that the concentration of PFC in the compositions, methods, and devices of the invention depend on the particular PFC agent chosen, on its efficacy, on a comparison of its bioavailability administered in the form of the transdermal delivery systems disclosed herein through various skin regions, and on the desired frequency of administration combined with the desired single or multiple doses of the formulation. Such pharmacological data can routinely be obtained by the skilled artisan from animal and human experiments in protocols and experimental model systems disclosed in Topical Drug Bioavailablity, Bioequivalence, and Penetration (eds. Vinod P. Shah and Howard I. Maibach, Plenum Press, 1993), and in Skin Barrier, Principles of Percutaneous Absorption (Hans Schaefer and Thomas E.

Redelmeier, Karger Publ., 1996), and other widely available literature references.

The details of practicing the invention furnished in the disclosure and examples herein should not be construed so as impose any kind of limitation to the scope of the invention. Applicant considers that the above-described inventions can reasonably be extrapolated to generalize transdermal delivery of perfluorocarbon compositions to the hypodermal region for removal of subcutaneous fat deposits without limiting the validity of the appended claims by any particular theory or mechanism of action. Thus, perfluorocarbon compositions, devices comprising perfluorocarbon for transdermal delivery of perfluorocarbon, and methods of using the compositions and devices have been disclosed herein as effective for removal of subcutaneous fat deposits. And, while specific embodiments have been disclosed herein, the scope of the invention is not to be limited except through interpretation of the appended claims.

Claims

What is claimed is:

1. A composition comprising transfersomes, said tranferosomes comprising perfluorocarbon.

2. The composition of claim 1 in combination with a transdermal delivery system selected from the group of transdermal delivery systems consisting of a semisolid amoφhous ointment, cream, lotion, viscous dispersion, emulsion, microemulsion, coacervate drops, microspheres, and microseeds; liquid form, fill and seal laminate structure; peripheral adhesive laminate structure; and solid state laminate structure.

3. The composition of claim 1 wherein said perfluorocarbon is selected from one or more of the group consisting of aliphatic straight-chain and branched fluoroalkanes, mono-or bicyclic and optionally fluoralkly-substituted flurocycloalkanes, perfluorinated aliphatic or bicyclic amines, bis(perfluoroalkl) ethenes.

4. The composition of claim 1 wherein said perfluorocarbon is selected from one or more of the group consisting of substituted and unsubstituted alkyl, alkenyl, alkynyl, alkoxyl groups which can have straight or branched chains, ring structures including single or fused ring structures, e.g. phenyl, or naphthyl, wherein the unsaturated groups can have a single site of unsaturation or a plurality of sites of unsaturation.

5. A method for removing subcutaneously located fat deposits, said method comprising the step of applying a composition comprising perfluorocarbons to an area of skin for a sufficient period of time to deliver a sufficient amount of said perfluorocarbon to said fat deposits beneath said application to emulgate said fat deposits.

6. The method of claim 5 wherein said composition comprises transferosomes comprising perfluorocarbon.

7. The method of claim 6 in combination with a transdermal delivery system selected from the group of transdermal delivery systems consisting of a semisolid amorphous ointment, cream, lotion, viscous dispersion, emulsion, microemulsion, coacervate drops, microspheres, and microseeds; liquid form, fill and seal laminate structure; peripheral adhesive laminate structure; and solid state laminate structure.

8. The method of claim 5 wherein said perfluorocarbon is selected from one or more of the group consisting of aliphatic straight-chain and branched fluoroalkanes, mono-or bicyclic and optionally fluoralkly-substituted flurocycloalkanes, perfluorinated aliphatic or bicyclic amines, bis(perfluoroalkl) ethenes.

9. The method of claim 5 wherein said perfluorocarbon is selected from one or more of the group consisting of substituted and unsubstituted alkyl, alkenyl, alkynyl, alkoxyl groups which can have straight or branched chains, ring structures including single or fused ring structures, e.g. phenyl, or naphthyl, wherein the unsaturated groups can have a single site of unsaturation or a plurality of sites of unsaturation.

10. The method of claim 5 wherein said perfluorocarbon comprises a liposomal or vesicular composition comprising perfluorocarbon.

11. The method of claim 5 wherein the step of applying comprises the step of exfoliating said area of skin to create an exfoliated area of skin preliminarily to said applying said composition to said area of skin.

12. The method of claim 11 wherein the step of exfoliating comprises treatment of said area of skin with a laser.

13. The method of claim 5 wherein the step of applying comprises the step of depilating said area of skin to create a depilated area preliminarily to said applying said composition to said area of skin.

14. The method of claim 13 wherein said step of depilating comprises the steps of:

(a) waxing said area of skin; and

(b) removing said wax.

15. The method of claim 13 wherein said step of depilating comprises the step of plucking hair from said area of skin.

16. A device for delivering perfluorocarbon to subcutaneously located fat deposits, said device comprising a patch for application to the skin, said patch comprising a sufficient amount of said perfluorocarbon to emulgate said fat deposits beneath said application.

17. The device of claim 16 wherein said perfluorocarbon is selected from one or more of the group consisting of aliphatic straight-chain and branched fluoroalkanes, mono-or bicyclic and optionally fluoralkly-substituted flurocycloalkanes, perfluorinated aliphatic or bicyclic amines, bis(perfluoroalkl) ethenes.

18. The device of claim 16 wherein said perfluorocarbon is selected from one or more of the group consisting of substituted and unsubstituted alkyl, alkenyl, alkynyl, alkoxyl groups which can have straight or branched chains, ring structures including single or fused ring structures, e.g. phenyl, or naphthyl, wherein the unsaturated groups can have a single site of unsaturation or a plurality of sites of unsaturation.

19. The device of claim 16 wherein said patch is selected from the group of devices consisting of membrane-controlled, reservoir, matrix, or monolithic type patches.

20. The device of claim 16 wherein said patch is selected from the group of patches consisting of liquid form, fill and seal laminate structure, peripheral adhesive laminate structure, and solid state laminate structure.

21. The device of claim 16 wherein said perfluorocarbon is in combination with one or more of the group of vesicles consisting of consisting of liposomes, transfersomes, emulsions, microemulsions, coacervate drops, microspheres. and microseeds.