JP2013139460A - Method and related composition for reducing fat and tightening skin - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a composition and a method for removing a localized fat accumulation containing a fat precipitant associated with lower eyelid fat hernia, lipodystrophia, and cellulite that require neither surgery nor a prolonged recovery time, and for tightening loose skin.SOLUTION: There are provided a composition and a method using bile acid or its salt as a pharmacologically active surfactant, which are useful for reducing a localized fat precipitant and tightening loose skin in a subject requiring this treatment. The pharmacologically active surfactant can additionally contain an antiinflammatory, analgesic drug, dispersant or anti-dispersant, and pharmaceutically acceptable excipient.

Description

This application is a continuation-in-part of 11 / 054,171 filed on 8 February 2005, claiming priority from US provisional application 60 / 572,879 filed 19 May 2004. No. 11 / 134,727, filed May 19, 2005, which is an application, which is incorporated herein by reference in its entirety.

Incorporation of References All references disclosed herein are incorporated by reference in their entirety for any and all purposes.

BACKGROUND OF THE INVENTION Surgical and non-surgical procedures to improve the appearance are becoming increasingly popular as people age and gain weight. Liposuction is a popular cosmetic surgery procedure that involves the surgical removal of fat deposits using suction and optionally assisted by a solution to aid in fat removal. Liposuction is a surgical procedure that removes fat through an incision in the skin into which the cannula is inserted. The cannula is connected to a suction source, and unwanted fat is aspirated through the cannula and discarded. Liposuction is performed under general or local anesthesia depending on the amount and location of the fat removed. However, liposuction and other defatting surgical methods can cause temporary bruises, swelling, paralysis, pain and burning sensations, risk of infection, altered pigmentation, migration to the lungs and death. Formation of fat masses or blood clots obtained, shock, loss of excessive fluids that can lead to the accumulation of fluids that must be excreted, burns or other damage due to friction on the skin or nerves, or perforation to life-supporting organs Associated with serious adverse events, including wounds. In addition, liposuction requires a 1-2 week recovery time during which the patient cannot work or perform certain daily activities. Furthermore, because surgical procedures such as liposuction require local and sometimes general anesthesia, significant anesthetic-related risks are associated with surgical fat removal. Moreover, liposuction and other intense weight loss methods can result in flaccid skin.

  Therefore, it would be desirable to have a composition and method for removing localized fat accumulation and tightening loose skin that does not require surgery or prolonged recovery time.

  The present invention provides compositions, methods, and kits for reducing subcutaneous fat deposits and tightening loose skin.

  In one aspect, the compositions herein are in solution. Preferably the solution is aqueous.

  In one embodiment, the invention relates to a solution for subcutaneous injection comprising: (i) a therapeutically effective amount of one or more pharmacologically active surfactants, or bile acids And / or bile salts, or deoxycholic acid or salts thereof, or sodium deoxycholate; (ii) pharmaceutical, veterinary or cosmetic excipients; and (iii) optionally lipids, wherein The ratio of lipid to bile acid or bile salt is less than 1% w / w and the solution does not contain lipase or co-lipase.

  In some embodiments, the solution may further comprise a second therapeutic agent selected from the group consisting of: an antimicrobial agent, a vasoconstrictor, an antithrombotic agent, an anticoagulant, a foam inhibitor, an anti-antibody Inflammatory agents, analgesics, dispersing agents, antidispersing agents, penetration enhancers, steroids, tranquilizers, muscle relaxants, and antidiarrheal agents.

  In some embodiments, the solution is in a container that contains up to 500 mL of solution. Such a container can be a syringe or a container in which a syringe can be mounted.

  In some embodiments, the solution comprises a bile acid selected from the group consisting of: deoxycholic acid, cholic acid, chenodeoxycholic acid, 7-α-dehydroxylate chenodeoxycholic acid, lithocholic acid, ursodeoxycholic acid, Dihydroxy tauric acid, trihydroxy tauric acid, and any of the above glycine conjugates.

In some embodiments, the solution is sodium (Na ⁺ ), potassium (K ⁺ ), lithium (Li ⁺ ), magnesium (Mg ²⁺ ), calcium (Ca ²⁺ ), barium (Ba ²⁺ ), strontium ( Sr ²⁺ ), and bile salts containing cations selected from the group consisting of ammonium (NH ⁴⁺ ). Preferably, when the solution contains a bile salt, the bile salt is sodium deoxycholate.

In some embodiments, the solution comprises a bile salt comprising an alkali metal or an alkaline earth metal. Preferably, the alkali metal is selected from the group consisting of alkali metals that are sodium (Na ⁺ ), potassium (K ⁺ ), and lithium (Li ⁺ ). Preferably, the alkaline earth metal is selected from the group consisting of magnesium (Mg ²⁺ ), calcium (Ca ²⁺ ), barium (Ba ²⁺ ), and strontium (Sr ²⁺ ).

  The composition (eg, solution) includes a therapeutically effective amount of a pharmacological surfactant (eg, bile acid and / or bile salt). Such a therapeutically effective amount is effective to reduce subcutaneous fat deposits or tighten areas of flaccid skin.

  The bile acid or bile salt in the solution of the present invention may be at a concentration of about 0.001-10, 0.01-5, or 0.1-2% w / w, w / v, or v / v. Preferably, the bile acid or bile salt in the above solution may be at a concentration of about 0.1-5% w / w, or more preferably about 1% w / w.

  In some embodiments, the solutions herein do not contain lipids, phospholipids, or phosphatidylcholines. In some embodiments, the solution herein comprises up to 5% w / w, w / v, or v / v lipid, phospholipid, or phosphatidylcholine.

  In one aspect, the present invention relates to a method for reducing the appearance of skin conditions in a subject's skin area. Such a method comprises the steps of: topically administering to the skin region a composition comprising: (i) an amount of one or more pharmacological agents effective to tighten the skin. A surfactant having activity in, or bile acids and / or bile salts, or deoxycholic acid or salts thereof, or sodium deoxycholate, (ii) pharmaceutical, veterinary, or cosmetic excipients, and (Iii) Optionally lipid.

  In some embodiments, the administering step includes delivering the composition herein via subcutaneous or transdermal injection.

  In some embodiments, the administering step comprises delivering the composition herein via a skin patch, pump, or subcutaneous depot.

  In some embodiments, administering comprises delivering the composition herein, topically or subcutaneously.

  In some embodiments, the skin condition to be treated or ameliorated is selected from the group consisting of: flaccid skin, skin aging, skin irregularities, and wrinkles.

  In some embodiments, the area of skin to be treated is under the eyes, under the chin, under the arms, buttocks, cheeks, forehead, calves, back, thighs, ankles, or abdomen.

  In some embodiments, the composition used to reduce the appearance of skin conditions in the skin area is a formulation in a skin tightening solution.

  Such a skin tightening solution may further comprise a second therapeutic agent selected from the group consisting of: an antimicrobial agent, a vasoconstrictor, an antithrombotic agent, an anticoagulant, a foam inhibitor, an anti-inflammatory agent, Analgesics, dispersing agents, antidispersing agents, penetration enhancers, steroids, tranquilizers, muscle relaxants, and antidiarrheal agents.

  In some embodiments, the skin tightening solution is in a container containing up to 500 mL of solution. Such a container can be a syringe or a container in which a syringe can be mounted.

  In some embodiments, the skin tightening solution comprises a bile acid selected from the group consisting of: deoxycholic acid, cholic acid, chenodeoxycholic acid, 7-α-dehydroxylate chenodeoxycholic acid, lithocholic acid, ursodeoxycholic Acids, dihydroxytauric acid, trihydroxytauric acid, and any of the above glycine conjugates.

In some embodiments, the solution is sodium (Na ⁺ ), potassium (K ⁺ ), lithium (Li ⁺ ), magnesium (Mg ²⁺ ), calcium (Ca ²⁺ ), barium (Ba ²⁺ ), strontium ( Sr ²⁺ ), and bile salts containing cations selected from the group consisting of ammonium (NH ⁴⁺ ). Preferably, when the solution contains a bile salt, the bile salt is sodium deoxycholate.

In some embodiments, the skin tightening solution comprises a bile salt comprising an alkali metal or an alkaline earth metal. Preferably, the alkali metal is selected from the group consisting of alkali metals that are sodium (Na ⁺ ), potassium (K ⁺ ), and lithium (Li ⁺ ). Preferably, the alkaline earth metal is selected from the group consisting of magnesium (Mg ²⁺ ), calcium (Ca ²⁺ ), barium (Ba ²⁺ ), and strontium (Sr ²⁺ ).

  In some embodiments, the skin tightening solution comprises a therapeutically effective amount of a pharmacological surfactant (eg, bile acids and / or bile salts). Such a therapeutically effective amount is effective to tighten the loose skin area.

  In some embodiments, the skin tightening solution contains about 0.001 of one or more pharmacologically active surfactants (eg, bile acids and / or bile salts such as sodium deoxycholate). Contains at a concentration of ˜10, 0.01-5, or 0.1-2% w / w, w / v, or v / v. Preferably, the one or more pharmacologically active surfactants in the skin tightening solution are at a concentration of about 0.1-5% w / w, or more preferably about 1% w / w.

  In some embodiments, the skin tightening solution comprises 100, 50, 20, 10, 5, 2, 1, 0.5, 0.2, 0.05, 0.02, or 0.01 grams of one or more surfactants, bile acids And / or bile salts, deoxycholic acid or salts thereof, or sodium deoxycholate.

  In some embodiments, the skin tightening solution does not include lipids, phospholipids, or phosphatidylcholines. In some embodiments, the solution herein comprises up to 5% w / w, w / v, or v / v lipid, phospholipid, or phosphatidylcholine.

  In one aspect, the invention relates to a method for reducing subcutaneous fat deposits in a subject. Such a method comprises the step of topically administering to a subcutaneous fat deposit in a subject a composition comprising: (i) an amount of one or more pharmacologically effective in dissolving fat. (Ii) pharmaceutical, veterinary, or cosmetic excipients; and (ii) active surfactants, or bile acids and / or bile salts, or deoxycholic acid or salts thereof, or sodium deoxycholate; iii) Optionally, a lipid, wherein the ratio of lipid to bile acid or bile salt is up to 1% w / w and the composition does not contain lipase or co-lipase.

  In some embodiments, the fat deposit is obesity, fat redistribution syndrome, eyelid fat hernia, lipoma, Durham's disease, lipodystrophy, buffalo aneurysm, dorsocervical fat Associated with a condition selected from the group consisting of visceral obesity, breast augmentation, adiposity, diffuse body fat around the trunk and arms, and fat deposits associated with cellulite.

  In some embodiments, the surfactant is deoxycholic acid, cholic acid, chenodeoxycholic acid, 7-α-dehydroxylate chenodeoxycholic acid, lithocholic acid, ursodeoxycholic acid, dihydroxytauric acid, trihydroxytauric acid, and A bile acid selected from the group consisting of any of the above glycine conjugates.

In some embodiments, the surfactant is sodium (Na ⁺ ), potassium (K ⁺ ), lithium (Li ⁺ ), magnesium (Mg ²⁺ ), calcium (Ca ²⁺ ), barium (Ba ²⁺ ), Bile salts comprising a cation selected from the group consisting of strontium (Sr ²⁺ ) and ammonium (NH ⁴⁺ ).

In some embodiments, the surfactant comprises a bile salt having a cation that is an alkali metal or an alkaline earth metal. Preferably, the alkali metal is sodium (Na ⁺ ), potassium (K ⁺ ), or lithium (Li ⁺ ), and the alkaline earth metal is magnesium (Mg ²⁺ ), calcium (Ca ²⁺ ), Barium (Ba ²⁺ ) or strontium (Sr ²⁺ ). More preferably, the bile salt is sodium deoxycholate.

  In some embodiments, the above method does not include performing a procedure on the subject.

  In some embodiments, the administering step is administered topically (eg, subcutaneously or subdermally) to the subject's eye, chin, arm, hip, calf, back, thigh, or abdominal area. Including stages. Administration can be by subcutaneous or transdermal injection.

  The subject to be treated by the compositions herein can be a human or a domesticated animal such as a cat, dog, or horse. In some embodiments, the subject to be treated is a human HIV patient. Such patients may suffer from HIV protease treatment or may experience or be susceptible to lipodystrophy.

  In some embodiments, the administered composition (eg, solution or aqueous solution) comprises up to 5% w / w, w / v, or v / v lipid, phospholipid, or phosphatidylcholine. Preferably, the composition administered (eg, solution or aqueous solution) comprises up to 5% w / w phosphatidylcholine.

  In some embodiments, the administered composition (eg, solution or aqueous solution) is 0.001-10, 0.01-5, or 0.1-2% w / w, w / v, or v / v surfactant. Or bile acids and / or bile salts. More preferably, the composition (eg, a solution herein) comprises about 0.1-5% w / w, or more preferably about 1% w / w, bile salt such as sodium deoxycholate. .

  Preferably, once administered, the composition is not removed from the subject. Furthermore, the compositions herein are preferably administered without surgical procedures (eg, liposuction).

  In some embodiments, the lipolytic solution is 100, 50, 20, 10, 5, 2, 1, 0.5, 0.2, 0.05, 0.02, or 0.01 grams of one or more surfactants, bile acids And / or bile salts, deoxycholic acid or salts thereof, or sodium deoxycholate.

  In one aspect, the present invention relates to a container capable of being loaded with a syringe comprising: (i) one or more pharmacologically actives in an amount effective to dissolve fat or tighten skin. Surfactants having, or bile acids and / or bile salts, or deoxycholic acid or salts thereof, or sodium deoxycholate; (ii) pharmaceutical, veterinary, or cosmetic excipients; and (iii) Optionally, a lipid, wherein the ratio of the bile acid or bile salt to the lipid is greater than 1% w / w and the solution does not contain lipase or co-lipase.

  Preferably, the one or more surfactants herein comprise sodium deoxycholate.

  Preferably, the container contains up to 500, 200, 100, 50, 20, 10, 5, 2, or 1 mL of a sterile solution.

  In some embodiments, the solution comprises an organic solvent, or more preferably benzyl alcohol.

  In some embodiments, the solution comprises 0.001-10, 0.01-5, or 0.1-2% w / w, w / v, or v / v surfactant, or bile acids and / or bile salts. . More preferably, the solution comprises about 0.1-5% w / w, or more preferably about 1% w / w of a bile salt such as sodium deoxycholate.

  In some embodiments, the solution comprises up to 100, 50, 20, 10, 5, 2, 1, 0.5, 0.2, 0.05, 0.02, or 0.01 grams of one or more surfactants, bile acids and / or Or bile salt, deoxycholic acid or its salt, or sodium deoxycholate.

INCORPORATION BY REFERENCE All publications and patent applications mentioned in this specification are to the same extent as each individual publication or patent application was specifically and individually indicated to be incorporated by reference. Which is incorporated herein by reference.

The molecular structures of (a) phosphatidylcholine, (b) sodium deoxycholate, and (c) benzyl alcohol are shown. Phosphatidylcholine bile salt formulation (PBF) (5.0% highly purified soy-derived PC, 4.75% sodium deoxycholate, and 0.9% benzyl alcohol) in sterile water, and deoxy according to the present disclosure Shows the effect of sodium cholate alone on cell viability: (a) MTS assay measuring viability of keratinocytes exposed to PBF and sodium deoxycholate alone; (b) PBF and sodium deoxycholate alone LDH assay measuring the release of lactate dehydrogenase (LDH) by cells exposed to. Indicate the effect of PBF and sodium deoxycholate alone on primary porcine adipose tissue according to the present disclosure: (a) PBS buffer as negative control (-control), sodium deoxycholate alone (DC), MTS assay showing purple cells producing live pigment in fat specimens treated with PBF and Triton surfactant (+ control) as a positive control; (b) Adipocyte survival between different treatments Rate comparison. Fat specimens treated with sodium deoxycholate alone (DC), PBF, Triton detergent as positive control (+ control), and PBS buffer as negative control (−control) in accordance with the present disclosure. Shows calcein fluorescence. Shown are light microscopic observations of pig skin biopsies after treatment showing: (a) control adipocytes, and (b) adipocytes after PBF injection (H & E, original magnification, x20); (c) control Adipocytes and (d) Adipocytes after injection of sodium deoxycholate alone (H & E, original magnification, x10); (e) Control muscle, and (f) Muscle after injection of phosphatidylcholine alone (H & E, original magnification) X10); (g) Fat after injection with Empigen surfactant (H & E, original magnification, x20). FIG. 4 shows lipomas removed from a patient 2 days after injection with deoxycholate according to the present disclosure: (a) gross pathology, and (b) histology (H & E, original magnification, x20). The effects of sodium deoxycholate alone and sodium deoxycholate-1% phosphatidylcholine solution on melanocytes are shown. The effects of sodium deoxycholate alone and sodium deoxycholate-1% phosphatidylcholine solution on adipocytes are shown. The effect of adding phosphatidylcholine to 4.75% sodium deoxycholate solution on viable adipocytes is shown. Figure 5 shows inhibition of lipolysis by preincubation with human lipoma fat. 1 shows a kit for reducing subcutaneous fat accumulation.

Detailed Description of the Invention The present invention addresses the problem of localized fat accumulation and flaccid skin in animals such as humans. In one aspect, the present invention provides a composition for reducing fat deposits and tightening the skin. Such compositions comprise one or more pharmacologically active surfactants, more preferably bile acids or bile salts, more preferably deoxycholic acid or salts thereof, or more preferably deoxychol. Contains, consists essentially of or consists of sodium acid. The amount of such surfactant in the composition is an effective amount for dissolving or reducing subcutaneous fat deposits or tightening loose skin. Such an effective amount will depend, in part, on the location of the target site, the size of the target site, the length of treatment, and the like. In some embodiments, the composition comprises at least 2, 3, 4, 5, 6, 7, 8, 9, or 10 pharmacologically active surfactants.

  Pharmacologically active and biologically compatible surfactants include lipophilic surfactants (either ionic or nonionic), hydrophilic surfactants (ionic or nonionic) Ionic surfactants), ionic surfactants, nonionic surfactants, zwitterionic surfactants, glycerides, bile acids, and bile salts, but are not limited thereto.

  Non-limiting examples of lipophilic surfactants include alcohol, polyoxyethylene alkyl ether, fatty acid, bile acid, glycerin fatty acid ester, acetylated glycerin fatty acid ester, lower alcohol fatty acid ester, polyethylene glycol fatty acid ester, polyethylene, among others Glycol glycerin fatty acid ester, polypropylene glycol fatty acid ester, polyoxyethylene glyceride, lactic acid derivative of mono / diglyceride, propylene glycol diglyceride, sorbitan fatty acid ester, polyoxyethylene sorbitan fatty acid ester, polyoxyethylene-polyoxypropylene block copolymer, transesterification Vegetable oils, sterols, sterol derivatives, sugar esters, sugar ethers, sucroglyceri de), a reaction mixture of polyoxyethylene vegetable oil, polyoxyethylene hydrogenated vegetable oil, polyhydric alcohol and at least one member of the group consisting of fatty acids, glycerides, vegetable oils, hydrogenated vegetable oils, and sterols, and mixtures thereof .

  Non-limiting examples of nonionic lipophilic surfactants include, among others, alkyl glucosides, alkyl maltosides, alkyl thioglucosides, lauryl macrogol glycerides, polyoxyethylene alkyl ethers, polyoxyethylene alkyl phenols, polyethylene glycol fatty acid esters, Polyethylene glycol glycerin fatty acid ester, polyoxyethylene sorbitan fatty acid ester, polyoxyethylene-polyoxypropylene block copolymer, polyglycerin fatty acid ester, polyoxyethylene glyceride, polyoxyethylene sterol, derivatives and analogs thereof, polyoxyethylene vegetable oil, Polyoxyethylene hydrogenated vegetable oil, polyhydric alcohol and fatty acid, glyceride, vegetable oil, hydrogenated vegetable oil, and sterol A reaction mixture with at least one member of the group consisting of: tocopherol polyethylene glycol succinate, sugar ester, sugar ether, scroglyceride, and mixtures thereof.

  Non-limiting examples of ionic hydrophilic surfactants include, among others, alkylammonium salts, bile acids and bile salts, analogs and derivatives thereof, amino acids, carnitine, oligopeptides, and fatty acid derivatives of polypeptides, amino acids Oligopeptide and polypeptide glyceride derivatives, acyl lactylates, mono-, diglyceride mono-, diacetylated tartrate, succinoylated monoglyceride, mono-, diglyceride citrate, alginate, propylene glycol alginate Nart, lecithin and hardened lecithin, lysolecithin and hardened lysolecithin, lysophospholipids and their derivatives, phospholipids and their derivatives, alkyl sulfates, fatty acid salts, docusate sodium, and mixtures thereof Including.

  Non-limiting examples of ionic surfactants include but are not limited to cholate, sodium deoxycholate, sodium dodecyl sulfate, and C-16 TAB. In a preferred embodiment, a non-limiting example of an ionic surfactant useful in embodiments of the present invention is sodium deoxycholate.

  Non-limiting examples of nonionic surfactants include Brij35, n-alkyl PEO monoethers such as polyoxyethylene (20) cetyl ether, Lubrol PX, Lubrol WX, nonidet P-40, octylphenol poly (ethylene glycol) N-alkylphenyl PEO, tetramethylbutylphenyl PEO, n-octylglucoside, octyl-thioglucopyranoside, tween-80 and tween-20, and alkylaryl polyethers such as ether) n10 and octylphenol poly (ethylene glycol ether) n7 Including but not limited to alcohol (TritonX-100).

  Non-limiting examples of zwitterionic surfactants include 3-[(3-cholamidopropyl) dimethylammonio] propane-sulfonate (CHAPS), N-tetradecyl-N, N-dimethyl-3-ammonium- Including, but not limited to, 1-propanesulfonate, cholate sulfobetaine, lauryldimethylbetaine (Empigen BB) and zwittergent3-14.

  Non-limiting examples of glycerides include, inter alia, mono-, di-, or tri-glycerides. Such triglycerides include, among others, vegetable oils, fish oils, animal fats, hydrogenated vegetable oils, partially hydrogenated vegetable oils, synthetic triglycerides, modified triglycerides, fractionated triglycerides, and mixtures thereof.

  Non-limiting examples of bile acids include ursodeoxycholic acid, cholic acid, glycolic acid, alcoholic acid, taurocholic acid, deoxycholic acid, glycodeoxycholic acid, taurodeoxycholic acid, chenodeoxycholic acid, glycochenodeoxycholic acid, and tauro Includes chenodeoxycholic acid, ursocholic acid, 7-oxolithocholic acid, lithocholic acid 3-sulfate, norcholic acid, bisnorcholic acid, hyocholic acid, and hyodeoxycholic acid.

  In preferred embodiments, the compositions herein comprise, consist essentially of, or consist of pharmaceutically acceptable surfactant salts and esters. Such salts and esters are within sound medical judgment, are free of inappropriate toxicity, irritation, allergic response, etc., are suitable for use in contact with human and animal tissues, and have a reasonable benefit / risk ratio. And salts and esters that are effective for the intended use. Preferably, the compositions herein comprise, consist essentially of, or consist of bile salts, or more preferably deoxycholate, or more preferably sodium deoxycholate.

  Among the surfactants, bile salts are preferred because they are particularly strong solubilizers for lipid bilayers. All biological cell membranes are composed of the same double lipid structure and are therefore subject to solubilization with surfactants. Solubilization of cell membranes by surfactants distributes the surfactant between lipid bilayers, destabilizes the bilayer, collapses, and then mixed micelles (composed of surfactant and cell membrane lipids) Including the formation of Bile salts, and other surfactants, reduce surface tension at the boundaries of immiscible materials and allow large aggregates to break down into smaller and smaller particles. In tissues, these drugs degrade cell membranes and cause cell lysis. An inflammatory response occurs, causing the body to remove material solubilized by the surfactant.

  Bile salts have been used to improve the water solubility of drugs such as phosphatidylcholine (PC), and more recently, amphotericin B, Taxol, and diazepam. Highly purified phosphatidylcholine is mixed with supplemental sodium bile salt deoxycholate, antimicrobial agent, benzyl alcohol, and water, sterilized rapidly, and stable mixed micelle preparation that can be used for intravenous administration Can form things. Pharmaceutical preparations of this mixture known as Essentiale and Lipostabil are commercially available in other countries for the treatment of liver disease and hyperlipidemia, respectively.

Bile salts may be formed from bile acids in combination with cations such as inorganic bases, ammonia, organic bases, basic amino acids and the like. Examples of inorganic bases include alkali metals (eg, Li ⁺ , Na ⁺ , and K ⁺ ) and alkaline earth metals (eg, Mg ²⁺ , Ca ²⁺ , Sr ²⁺ , Ba ²⁺ ). Examples of organic bases include procaine, 2-phenylethylbenzylamine, dibenzylethylenediamine, ethanolamine, diethanolamine, tris (hydroxymethyl) aminomethane, polyhydroxyalkylamine, and N-methylglucosamine. Examples of basic amino acids include lysine, arginine, ornithine, and histidine. Examples of other salts include halogen ions. Non-limiting examples of salts that can combine with bile acids to form bile salts include ammonium chloride, ammonium sulfate, sodium chloride, sodium bromide, sodium iodide, sodium fluoride, sodium citrate, sodium sulfate, carbonate Sodium, sodium bicarbonate, sodium acetate, sodium nitrate, sodium nitrite, potassium acetate, potassium carbonate, potassium dichromate, potassium chloride, potassium bromide, magnesium bromide, magnesium chloride, potassium iodide, sodium fluoride, hydrochloric acid Hydroxylamine, sodium fluoride, sodium silicate, diammonium phosphate, sodium thiocyanate, potassium thiocyanate, lithium thiocyanate, sodium borohydride, calcium carbonate, barium carbonate, sodium dihydrogen phosphate, lithium lithium chloride , Lithium bromide, and including lithium iodide, but are not limited to. In some embodiments, the salt ion that combines with bile acid to form a bile salt is a cation. Non-limiting examples of cations are sodium (Na ⁺ ), potassium (K ⁺ ), lithium (Li ⁺ ), magnesium (Mg ²⁺ ), calcium (Ca ²⁺ ), barium (Ba ²⁺ ), strontium (Sr ²⁺ ), and ammonium (NH ⁴⁺ ).

  Examples of bile salts that can be formed by the combination of bile acids and cations are sodium cholate, sodium deoxycholate, sodium cholate, sodium chenodeoxycholate, sodium 7-α-dehydroxylate chenodeoxycholate, sodium lithocholic acid, Sodium ursodeoxycholate, potassium deoxycholate, potassium cholate, potassium chenodeoxycholate, 7-α-dehydroxylate potassium potassium deoxycholate, potassium lithocholic acid, potassium ursodeoxycholic acid, lithium deoxycholate, lithium cholate, chenodeoxychol Lithium acid, 7-α-dehydroxylate lithium chenodeoxycholate, lithium lithocholic acid, lithium ursodeoxycholate, magnesium deoxycholate, coal Magnesium, magnesium chenodeoxycholate, 7-α-dehydroxylate magnesium chenodeoxycholate, magnesium lithocholic acid, magnesium ursodeoxycholate, ammonium cholate, ammonium deoxycholate, ammonium cholate, ammonium chenodeoxycholate, 7-α-dehydroxy Including but not limited to ammonium rate chenodeoxycholate, ammonium lithocholic acid, ammonium ursodeoxycholate, any of the above, dihydroxy-, and trihydroxy-, and taurine or glycine conjugates. Preferably, the bile salt of the present invention is sodium deoxycholate. Any of the above bile salts can be used in the compositions herein.

  Other examples of bile salts include steroids having 1 to 3 hydroxyl groups and a side chain of 5 carbon atoms ending with a carboxyl group that can be conjugated to glycine or taurine.

In some embodiments, the compositions herein comprise, consist essentially of, or consist of one or more esters of bile acids. Such esters are optionally substituted C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₃ -C ₁₀ cycloalkyl, C ₃ -C ₁₀ cycloalkyl (C ₁ -C ₆ ) alkyl, substituted which may be C ₆ -C ₁₀ aryl, optionally substituted C ₇ -C ₁₂ aralkyl, di (C ₆ -C ₁₀₎ aryl-methyl, tri (C ₆ -C ₁₀₎ aryl-methyl, or substituted Including, but not limited to, the ester formed by the combination of silyl and a bile acid having a hydrogen of the COOH group.

Examples of _optionally substituted C _1-6 alkyl include, for example, methyl, ethyl, n-propyl, n-butyl, t-butyl, n-pentyl, and n-hexyl, each of which is benzyloxy, C _1-4 alkylsulfonyl (eg, methanesulfonyl), trimethylsilyl, halogen (eg, F, Cl, and Br), acetyl, nitrobenzoyl, mesylbenzoyl, phthalimide, succinoylimide, benzenesulfonyl, phenylthio, di-C _It may be substituted with _1-4 alkylamino (eg dimethylamino), pyridyl, C _1-4 alkylsulfinyl (eg methanesulfinyl), cyano and the like. Such substituted C _1-6 alkyl is, for example, benzyloxymethyl, 2-methanesulfonylethyl, 2-trimethylsilylethyl, 2,2,2-trichloroethyl, 2-iodoethyl, acetylmethyl, p-nitrobenzoyl Including methyl, p-mesylbenzoylmethyl, phthalimidomethyl, succinylimidomethyl, benzenesulfonylmethyl, phenylthiomethyl, and 1-dimethylaminoethyl. The above C _2-6 alkenyl includes, for example, vinyl, aryl, 1-propenyl, isopropenyl, 1-butenyl, 2-butenyl, 1,1-dimethylaryl, 3-methyl, and 3-butenyl. The above C _3-10 cycloalkyl includes, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, norbornyl, and adamantyl. The above C _3-10 cycloalkyl (C _1-6 ) alkyl includes, for example, cyclopropylmethyl, cyclopentylmethyl, and cyclohexylmethyl. The above C _6-10 aryl includes, for example, phenyl, naphthyl, 8-naphthyl, and biphenyl, each of which may be substituted with nitro, halogen (eg, F, Cl, and Br), and the like, and Such substituted aryls include, for example, p-nitrophenyl, and p-chlorophenyl. The optionally substituted C _7-12 aralkyl includes, for example, benzyl, 1-phenylethyl, 2-phenylethyl, phenylpropyl, and naphthylmethyl, each of which is nitro, C _1-4 alkoxy ( For example, it may be substituted with methoxy), C _1-4 alkyl (eg, methyl, ethyl), hydroxy, and the like. Such substituents are exemplified by p-nitrobenzyl, p-methoxybenzyl (PMB), or 3,5-di-t-butyl-4-hydroxybenzyl. The above di (C _6-10 aryl) methyl includes benzhydryl and C _6-10 arylmethyl includes trityl and substituted silyl includes trimethylcytyl and tert-butyldimethylsilyl . Examples of active esters include organophosphates (eg, diethoxyphosphate and diphenoxyphosphate), cyanomethyl esters, and active thioesters are formed with aromatic heterocyclic thio compounds. Including esters (eg, 2-pyridylthioesters).

  Derivatives of bile acids can also be used as surfactants. Such derivatives include bile acid halides, bile acid azides, bile acid anhydrides, mixed bile acid anhydrides, bile acid amides, and bile acid thioesters. Bile acid halides include bile acid chlorides such as deoxycholic acid chloride and bile acid bromides such as deoxycholic acid bromide; mixed bile acid anhydrides include mixed monoalkyl carboxylic acid anhydrides, mixed The active amide includes an aliphatic carboxylic acid anhydride, an aromatic carboxylic acid anhydride, an organic sulfonic acid anhydride, and includes an amide formed from a heterocyclic compound containing an N atom.

  Pharmacologically active surfactants (including bile acids and bile salts) are preferably micelle forming compounds. Micelles can significantly increase the solubility of hydrophobic molecules that are not normally soluble in water (eg, lipids containing cell membranes) by obscuring the hydrophobic portion from an aqueous solvent (eg, water). In some embodiments, the compositions herein comprise homogeneous micelles (micelles produced by a single surfactant). In some embodiments, the compositions herein include mixed micelle forms (micelles produced by two or more compounds, one of which is a surfactant).

In some embodiments, the composition has an average size of 10 ⁻⁹ m to 10 ⁻⁵ m, 10 ⁻⁶ , 5 × 10 ⁻⁹ m to 10 ⁻⁶ m, 10 × 10 ⁻⁹ m to 10 ⁻⁷ , Or contains micelles in the range of 50 x 10 ^-9 to 10 x 10 ^-8 m. In some embodiments, the average micelle size in the compositions of the invention may be up to 10 ⁻⁵ , 10 ⁻⁶ , 10 ⁻⁷ , 10 ⁻⁸ , 10 ⁻⁹ m. In some embodiments, the average micelle size in the composition of the present invention may be greater than 10 ⁻⁵ , 10 ⁻⁶ , 10 ⁻⁷ , 10 ⁻⁸ , 10 ⁻⁹ m. Furthermore, the micelle shape can vary and can be, for example, prolate, oblate, or spherical; spherical micelles are most typical.

  Table 1 below lists some surfactants contemplated by the present invention, the monomer molecular weight as monomers of these surfactants, and the minimum concentration at which the surfactant is mostly in the form of micelles. Indicates the critical micelle concentration (CMC).

  In some embodiments, the concentration of one or more pharmacologically active surfactant (eg, bile acid or bile salt) in the composition is about the CMC concentration (ie, +/− 5 mM). , Or above the CMC level (eg above the CMC concentration level 1, 5, 10, 15, 20, 25, 30, 35, 40, 50, 55, 60, 65, 70, 75, 80, 85, 90, 99 150, 200, 400, 800, 1600, 3200, 6800, 13,600, 27,200, or 54,400% higher).

  In some embodiments, at least 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, surfactants (eg, bile acids and bile salts) in the composition, 75, 80, 85, 90, 95, or 99% are in micellar form. In other embodiments, up to 90, 80, 70, 60, 50, 40, 30, 20, 10, or 5% of the surfactant (eg, bile acids and / or bile salts) in the composition is in micellar form It is in. In other embodiments, about 10-90, 20-80, 30-70, 40-60, or about 50% of the surfactant (eg, bile acids and bile salts) of the composition is in micellar form.

  In some embodiments, the average molecular weight of micelles in the composition of the present invention is 100,000, 50,000, 40,000, 30,000, 20,000, 10,000, 9,000, 8,000, 7,000, 6,000, 5,000, 4,000, 3,000, 2,000, 1,000, or 500. It may be up to Dalton (D). In some embodiments, the average molecular weight of micelles in the compositions of the present invention is 500, 1,000, 1,500, 2,000, 2,500, 3,000, 3,500, 4,000, 4,500, 5,000, 5,500, 6,000, 6,500, 7,000, 7,500, 8,000, It may be greater than 8,500, 9,000, 9,500, 10,000, or 15,000 D. In some embodiments, the average molecular weight of micelles in the compositions of the present invention may range from 100 to 20,000, 1,000 to 10,000, 2,000 to 1,000, or 3,000 to 5,000 D.

  In any embodiment herein, the concentration of one or more pharmacologically active surfactants (eg, bile acids and / or bile salts, or more preferably sodium deoxycholate) is 20 , 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, 2, 1, 0.5, 0.4, 0.3, 0.2, 0.1, 0.09 , 0.08, 0.07, 0.06, 0.05, 0.04, 0.03, 0.02, 0.01, 0.009, 0.008, 0.007, 0.006, 0.005, 0.004, 0.003, 0.002, 0.001, 0.0009, 0.0008, 0.0007, 0.0006, 0.0005, 0.0004, 0.0003, 0.0002 Or up to 0.0001% w / w, w / v, or v / v. Preferably, the compositions herein comprise a bile salt such as sodium deoxycholate, wherein the bile salt concentration is up to 5, 4, 3, 2, or 1% w / w.

  In any embodiment herein, the concentration of one or more pharmacologically active surfactants (eg, bile acids and / or bile salts, or more preferably sodium deoxycholate) is 0.0001 , 0.0002, 0.0003, 0.0004, 0.0005, 0.0006, 0.0007, 0.0008, 0.0009, 0.001, 0.002, 0.003, 0.004, 0.005, 0.006, 0.007, 0.008, 0.009, 0.01, 0.02, 0.03, 0.04, 0.05, 0.06, 0.07, 0.08 , 0.09, 0.10, 0.20, 0.30, 0.40, 0.50, 0.60, 0.70, 0.80, 0.90, 1.00, 1.25, 1.50, 1.75, 2.00, 2.25, 2.50, 2.75, 3.00, 3.25, 3.50, 3.75, 4.00, 4.25, 4.50 , 4.75, 5.00, 5.25, 5.50, 5.75, 6.00, 6.25, 6.50, 6.75, 7.00, 7.25, 7.50, 7.75, 8.00, 8.25, 8.50, 8.75, 9.00, 9.25, 9.50, 9.75, or 10.00% w / w, w / v or higher than v / v. Preferably, the compositions herein comprise one or more bile salts such as sodium deoxycholate at a concentration greater than 0.0001, 0.001, 0.01, or 0.1% w / w.

  In any embodiment herein, the concentration of the pharmacologically active surfactant (eg, bile acid and / or bile salt) is about 0.0001-50, 0.001-40, 0.01-30, 0.02- 29, 0.03-28, 0.04-27, 0.05-26, 0.06-25, 0.07-24, 0.08-23, 0.09-22, 0.1-21, 0.2-20, 0.3-19, 0.4-18, 0.5-17, It is in the range of 0.6-16, 0.7-15, 0.8-14, 0.9-12, or approximately 1-10% w / w, w / v, or v / v. Preferably, the concentration of one or more pharmacologically active surfactants (eg, bile acids or bile salts) in the compositions of the present invention is about 0.005-15%, 0.01-10%, 0.05 -15%, 0.10-1%, 0.1-10%, or 0.5-1%, 0.5-5% in the range of w / w, w / v, or v / v. It will be appreciated that the final concentration will depend on a number of factors known to those skilled in the art, including but not limited to the location and size of the target site.

  In some embodiments, the composition comprises 10, 9.5, 9.0, 8.5, 8.0, 7.5, 7.0, 6.5, 6.0, 5.5, 5.0, 4.5, 4.0, 3.5, 3.0, 2.5, 2.0, 1.5, 1.0, 0.95, 0.9, 0.85, 0.8, 0.75, 0.7, 0.65, 0.6, 0.55, 0.5, 0.45, 0.4, 0.35, 0.3, 0.25, 0.2, 0.15, 0.1, 0.09, 0.08, 0.07, 0.06, 0.05, 0.04, 0.03, 0.02, One or more pharmacological agents up to 0.01, 0.009, 0.008, 0.007, 0.006, 0.005, 0.004, 0.003, 0.002, 0.001, 0.0009, 0.0008, 0.0007, 0.0006, 0.0005, 0.0004, 0.0003, 0.0002, or 0.0001 grams Active surfactants (eg, bile acids and / or bile salts), or more preferably up to 5, 4, 3, 2, 1, 0.5, 0.4, 0.3, 0.2, or 0.1 grams of deoxy Contains bile salts such as sodium cholate.

  In some embodiments, the composition has 0.0001, 0.0002, 0.0003, 0.0004, 0.0005, 0.0006, 0.0007, 0.0008, 0.0009, 0.001, 0.0015, 0.002, 0.0025, 0.003, 0.0035, 0.004, 0.0045, 0.005, 0.0055, 0.006, 0.0065, 0.007, 0.0075, 0.008, 0.0085, 0.009, 0.0095, 0.01, 0.015, 0.02, 0.025, 0.03, 0.035, 0.04, 0.045, 0.05, 0.055, 0.06, 0.065, 0.07, 0.075, 0.08, 0.085, 0.09, 0.095, 0.10, 0.15, 0.20, 0.25, 0.30, 0.35, 0.40, 0.45, 0.50, 0.55, 0.60, 0.65, 0.70, 0.75, 0.80, 0.85, 0.90, 0.95, 1.0, 1.5, 2.0, 2.5, 3.0, 3.5, 4.0, More than 4.5, 5.0, 5.5, 6.0, 6.5, 7.0, 7.5, 8.0, 8.5, 9.0, 9.5, or 10.0 grams of one or more pharmacologically active surfactants (eg, bile acids or bile Acid salt), or more preferably more than 0.01, 0.02, 0.03, 0.04, 0.05, 0.06, 0.07, 0.08, or 0.09 grams.

  In some embodiments, the compositions herein have 0.0001-10, 0.0005-5, 0.001-8, 0.005-7, 0.01-6, 0.05-5, 0.1-4, 0.5-4, or 1-3. One or more pharmacologically active surfactants (eg bile acids and / or bile salts), or more preferably 0.001 to 10, 0.002 to 9, 0.003 to 8, 0.004-7, 0.005-6, 0.006-5, 0.007-4, 0.008-3, 0.009-2, 0.01-1, 0.02-0.5, 0.03-0.4, 0.04-0.3, 0.05-0.2, or 0.06-0.1 grams In between, include one or more surfactants (eg, sodium deoxycholate).

  In some embodiments herein, the composition comprises one or more lipids, phospholipids, or phosphatidylcholines. Preferably, the amount of lipid, phospholipid or phosphatidylcholine in the composition is 50, 40, 30, 20, 15, 10, 9, 8, 7, 6, 5, 4, 3, 2, 1, 0.95, 0.9. 0.85, 0.8, 0.75, 0.7, 0.65, 0.6, 0.55, 0.5, 0.45, 0.4, 0.35, 0.3, 0.25, 0.2, 0.15, 0.1, 0.09, 0.08, 0.07, 0.06, 0.05, 0.04, 0.03, 0.02, 0.01 , 0.009, 0.008, 0.007, 0.006, 0.005, 0.004, 0.003, 0.002, 0.001, 0.0009, 0.0008, 0.0007, 0.0006, 0.0005, 0.0004, 0.0003, 0.0002, or 0.0001% (w / w, w / v, or v / Concentration up to v). In preferred embodiments, the amount of lipid, phospholipid, or phosphatidylcholine in the composition is up to 5% (w / w, w / v, or v / v). For example, the present invention is a composition comprising one or more surfactants, preferably bile salts, or more preferably sodium deoxycholate, which is 5, 4.9, 4.8, 4.7, 4.6, 4.5, 4.4 , 4.3, 4.2, 4.1, 4.0, 3.0, 2.0, or 1.0% of a composition comprising lipid or phospholipid or phosphatidylcholine is contemplated.

  In some embodiments, the ratio between the surfactant and the lipid, phospholipid, or phosphatidylcholine is such that there is more surfactant by mass than the lipid, phospholipid, or phosphatidylcholine, respectively. For example, in some embodiments, the mass ratio (% w / w) of surfactant to lipid, phospholipid, or phosphatidylcholine is 1.0, 1.2, 1.4, 1.6, 1.8, 2.0, 2.2, 2.4, 2.6, Greater than 2.8 or 3.0% w / w. For example, in some embodiments, the compositions herein can comprise 5% w / w sodium deoxycholate and 4% w / w phosphatidylcholine. In some embodiments, the% w / v ratio of surfactant to lipid, phospholipid, or phosphatidylcholine is 1.0, 1.2, 1.4, 1.6, 1.8, 2.0, 2.2, 2.4, 2.6, 2.8, or 3.0. Greater than% w / v. Further, in some embodiments, the% v / v ratio of surfactant to lipid, phospholipid, or phosphatidylcholine is 1.0, 1.2, 1.4, 1.6, 1.8, 2.0, 2.2, 2.4, 2.6, 2.8, Or greater than 3.0% v / v.

  In some embodiments, the compositions herein do not include phosphatidylcholine, phospholipids, or lipids. In some embodiments, the compositions herein do not include lipase or co-lipase, lipase and co-lipase, platelet activator inhibitor, or all enzymes. In some embodiments, the compositions herein do not include testosterone, prostaglandins, progesterone, estrogens, or steroids. In some embodiments, the compositions herein do not include tyloxapol, or another alkylaryl polyether alcohol. In some embodiments, the compositions herein do not include carprofen, non-steroidal anti-inflammatory compounds, or any anti-inflammatory compound. In some embodiments, the compositions herein do not include lipids, oils, fatty acids, triglycerides, or polyacrylamides, or combinations thereof. Any or all of the above may be excluded from the compositions herein.

  The compositions herein can be formulated for various types of delivery, such as topical, subcutaneous, subdermal, intraadipocyte, intramuscular, etc., by any means known in the art. . Such formulations can be in the form of tablets, powders, gels, solutions, creams, inhalants, ointments and the like. Preferably a pharmacologically active surfactant, more preferably bile acids and / or bile salts, more preferably deoxycholic acid or salts thereof, or more preferably sodium deoxycholate is formulated in solution. Is done. Preferably such a solution is aqueous. As used herein, the term “aqueous” is prepared by dissolving a solid or liquid in water such that dissolved or dissolved molecules of the substance are dispersed among the water molecules. Refers to a solution that is a homogeneous mixture. The pharmacologically acceptable aqueous medium for the composition of the present invention may include, for example, any liquid solution that can dissolve the surfactant and is not toxic to the particular individual receiving the formulation. Examples of pharmaceutically acceptable aqueous media include, but are not limited to, saline, water, benzyl alcohol, and acetic acid. Typically, a pharmaceutically acceptable aqueous medium is sterile.

  In some embodiments, the compositions herein are formulated for veterinary application with one or more veterinary excipients. In some embodiments, the compositions herein are formulated for cosmetic application with one or more cosmetic excipients. For delivery to humans (eg, transdermally or subcutaneously), the compositions herein are formulated with one or more pharmaceutical excipients.

  Examples of pharmaceutical excipients include: buffers, diluents, lubricants, solubilizers, solvents; surfactants, penetration enhancers, polymers, dispersants, wetting agents, emulsifying and suspending agents, As well as preservatives. Examples of dispersants include but are not limited to hyaluronidase and collagenase. Hyaluronidase functions to increase tissue permeability and the diffusion or dispersion of other drugs. Collagenase is used to isolate fat cells from subcutaneous fat and has no lytic effect on the fat cells themselves. Additionally, hyaluronidase and collagenase may facilitate recovery by accelerating the reduction of necrotic tissue after treatment with the surfactant formulation of the present invention. In some embodiments, a dispersing agent such as collagenase is administered prior to administration of the surfactant herein. This may help release adipocytes from the extracellular matrix and enhance exposure to surfactants.

  Examples of wetting agents include, but are not limited to, acetylene glycol, acetylene alcohol, glycol ether, alkylene glycol, lower alcohol, and nonionic surfactant. In addition, other alcohols, water-soluble organic solvents, anionic surfactants, cationic surfactants, zwitterionic surfactants, and sugars can be used alone or in combinations of two or more thereof. May be used. Some examples of lower alcohols are methanol, ethanol, 1-propanol, 2-propanol, 1-butanol, 2-butanol, isobutyl alcohol, tert-butyl alcohol, 1-pentanol, 2-pentanol, 3-pen Tanol, 2-methyl-1-butanol, isopentyl alcohol, tert-pentyl alcohol, 3-methyl-2-butanol, neopentyl alcohol, and ethylene glycol, diethylene glycol, triethylene glycol, propylene glycol, tetraethylene glycol, polyethylene Including, but not limited to, water soluble organic solvents such as glycol, dipropylene glycol, polypropylene glycol, hexylene glycol, thiodiglycol, glycerin, and 1,2,6-hexanetriol. In a preferred embodiment, the excipient is an organic solvent, more preferably an organic alcohol, or more preferably benzyl alcohol.

  Examples of lubricants include, but are not limited to, talc, magnesium stearate, stearic acid, and silica gel.

  Examples of preservatives include, but are not limited to, benzalkonium chloride, benzethonium chloride, chlorobutanol, phenylethyl alcohol, paraoxybenzoate, and the like. Only a few examples of penetration enhancers are, but are not limited to, dimethyl sulfoxide, n-decylmethyl sulfoxide, N, N-dimethylacetamide, N, N-methyl-2-pyrrolidone, and octylphenyl polyethylene glycol.

  Examples of suitable emulsifiers include, but are not limited to, sodium lauryl sulfate, sodium cetyl stearyl sulfate, sucrose stearate, polysorbate 80.

  Examples of anionic surfactants include fatty acid soaps, N-acyl amino acids, alkyl ether carboxylates, acylated peptides, alkylbenzene sulfonates, alkyl naphthalene sulfonates, naphthalene sulfonate-formalin polymerization condensates, melamine sulfonate-formalin polymerization condensates, Dialkyl sulfosuccinic ester salt, alkyl sulfoacetate, α-olefin sulfonate, N-acyl methyl taurine, sulfated oil, higher alcohol sulfate ester, secondary higher alcohol sulfate ester, alkyl ether sulfate, secondary higher alcohol Ethoxysulfate, polyoxyethylene alkylphenyl ether sulfate, monoglycolate, fatty acid alkylolamide sulfate, alkyl ether phosphate Le salts, and including alkyl phosphate salts, but are not limited to.

  Examples of nonionic surfactants are polyoxyethylene alkyl ether, single chain length polyoxyethylene alkyl ether, polyoxyethylene secondary alcohol ether, polyoxyethylene alkylphenyl ether, polyoxyethylene sterol ether, polyoxyethylene Lanolin derivative, ethylene oxide derivative of alkylphenol-formalin condensate, polyoxyethylene polyoxypropylene block polymer, polyoxyethylene polyoxypropylene alkyl ether, polyoxyethylene glycerin fatty acid ester, polyoxyethylene sorbitan fatty acid ester, polyoxyethylene sorbitol fatty acid ester , Polyethylene glycol fatty acid ester, fatty acid monoglyceride, polyglycerin fatty acid ester, sol Vitan fatty acid ester, propylene glycol fatty acid ester, sucrose fatty acid ester, fatty acid alkanolamide, polyoxyethylene fatty acid amide, polyoxyethylene alkylamine, alkylamine oxide, polyoxyethylene castor oil derivative, polyvinylpyrrolidone, polyvinyl alcohol, carboxymethylcellulose, lecithin , Gelatin, and hyaluronic acid. Any and all of the above may be used in combination with each other as appropriate.

  Other examples of suitable excipients are lactose, dextrose, sucrose, sorbitol, mannitol, starch, gum acacia, calcium phosphate, alginate, tragacanth, gelatin, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, phosphatidylcholine, cellulose, Contains sterile water, syrup, and methylcellulose.

In some embodiments, the compositions herein include: (i) a therapeutically effective amount of one or more pharmacologically active surfactants (eg, bile acids and / or Bile salts); (ii) one or more pharmaceutical, veterinary, or cosmetic excipients; and optionally, one or more lipids, wherein the pharmacologically active with the lipid The ratio of surfactant to having is up to 1% w / w, w / v, or v / v (but not optionally) and the solution does not contain lipase or co-lipase. When the pharmacologically active surfactant is bile acid, in some embodiments, the bile acid is selected from the group consisting of: deoxycholic acid, cholic acid, chenodeoxycholic acid, 7-α- Dehydroxylate chenodeoxycholic acid, lithocholic acid, ursodeoxycholic acid, dihydroxytauric acid, trihydroxytauric acid, and any of the glycine conjugates described above. When the pharmacologically active surfactant is a bile salt, the salt preferably comprises a cation selected from the group consisting of the following in combination with the bile acids listed above: sodium (Na ⁺ ), potassium (K ⁺ ), lithium (Li ⁺ ), magnesium (Mg ²⁺ ), calcium (Ca ²⁺ ), barium (Ba ²⁺ ), strontium (Sr ²⁺ ), and ammonium (NH ^{4 +} ). In some embodiments, the cation is an alkali metal, such as selected from the group consisting of an alkali metal that is sodium (Na ⁺ ), potassium (K ⁺ ), and lithium (Li ⁺ ). In some embodiments, the cation is an alkaline earth metal, as selected from the group consisting of: magnesium (Mg ²⁺ ), calcium (Ca ²⁺ ), barium (Ba ²⁺ ), and Strontium (Sr ²⁺ ). Preferably, the solution comprises a bile salt, wherein the bile salt is sodium deoxycholate.

  A pharmacologically active surfactant, more preferably a bile acid and / or bile salt, more preferably deoxycholic acid or a salt thereof, or more preferably sodium deoxycholate is used in a therapeutically effective amount. It is administered at various concentrations as delivered. A therapeutically effective amount is the amount of surfactant effective to reduce the size of the subcutaneous fat deposits or to reduce the amount or appearance of flaccid skin. In some embodiments, a composition having a therapeutically effective amount of a surfactant has an interface between about 0.001-10, 0.01-5, or 0.01 and 2% w / w, w / v, or v / v. Contains an active agent. In some embodiments, the therapeutically effective amount of surfactant is less than 5, 2, 1, 0.5, 0.2, 0.1, 0.05, 0.02, or 0.01 grams of surfactant. When one or more lipids are also included in the composition, the surfactant to lipid mass ratio is preferably greater than 1% w / w, w / v, or v / v. For example, the solution of the present invention comprises about 5% bile salts (eg, sodium deoxycholate) and lipids, phosphorus up to 5% w / w, w / v, or v / v but not Lipid, phosphatidylcholine may be included.

  When the composition is formulated as a solution (preferably an aqueous solution), the composition may be in a container, such as a syringe or a container in which a syringe can be mounted. The unit dose of solution or solution in a container herein is preferably up to 500, 250, 100, 25, 10, or 2.5 mL.

  In addition to the surfactant, the compositions / solutions herein can also include an additional active ingredient, or a second therapeutic agent. In some embodiments, such second therapeutic agent is selected from the group consisting of: an antimicrobial agent, a vasoconstrictor, an antithrombotic agent, an anticoagulant, a foam inhibitor, an anti-inflammatory agent, an analgesic. Drugs, dispersants, antidispersants, penetration enhancers, steroids, tranquilizers, muscle relaxants, and antidiarrheal agents.

Additional active ingredients In some embodiments of the invention, the composition comprises, for example, an antimicrobial agent, a vasoconstrictor, an antithrombotic agent, an anticoagulant, a foam suppressant, an anti-inflammatory agent, an analgesic, a dispersant, Co-formulation, co-administration, and / or co-marketing with one or more additional active ingredients such as anti-dispersing agents, penetration enhancers, steroids, tranquilizers, muscle relaxants, and antidiarrheal agents Can be done.

  Examples of antimicrobial agents suitable for use in the compositions, methods, and kits herein include, but are not limited to, antibacterial agents, antifungal agents, antiviral agents, and the like, and preferably broad. Effective against spectrum microorganisms.

  Examples of antifungal agents that can be used in the compositions, methods, and kits herein include dithiocarbamate, phthalimide, dicarboximide, organic phosphate, benzimidazole, carboxanilide, phenylamide, phosphite, and the like.

  Examples of antibacterial agents are erythromycin, clarithromycin, penicillin, cephalosporin, aminoglycoside, sulfonamide, macrolide, tetracycline, lincoside, quinolone, chloramphenicol, vancomycin, metronidazole, rifampin, isoniazid, spec Tinomycin, trimethoprim, sulfamethoxazole, penem, carbapenem, monobactam mupirocin, neomycin bacitracin, polymyxin B, l-ofloxacin, tetracycline (chlortetracycline hydrochloride, oxytetracycline hydrochloride, and tetracycline hydrochloride), clinda phosphate Mycin, gentamicin sulfate, benzalkonium chloride, benzethonium chloride, hexyl resorcinol, methyl benzet chloride , Phenol, quaternary ammonium compounds, triclocarbon, triclosan, tea tree oil, and their pharmaceutically acceptable salts, and their pharmaceutically acceptable salts and Including but not limited to esters.

  Other examples of antibacterial agents include acrofloxacin, amoxicillin and clavulonic acid (ie Augmentin), amikacin, ampicillin, aparacillin, apramycin, astromycin, arbekacin, aspoxillin, azidodiline ( Azidozillin), azithromycin, azurocillin, bacitracin, benzathine penicillin, benzylpenicillin, carbencillin, cefaclor, cefadroxyl, cephalexin, cefamandol, cefaparin, cefatirine, cefazoline, cefbepefene, cefbepefene Cefapime, cefatameth, cefixime, cefmetazole, cefminox, cefoperazone, cefolanide, cefotaxime, cefof Tan, Cefotiam, Cefoxitin, Cefpimizole, Cefpyramide, Cefpodoxime, Cefprodil, Cefradine, Cefloxazine, Cefthrozine, Ceftadidim, Ceftriaxone, Cefuroxime, Chloramphenicol, Chlortetracycline, Cyclacillin, Cinoxacin, Ciprofloxacin, Cloflomycin Misolepenicillin, clindamycin, cloxacillin, daptomycin, demeclocycline, desquinolone, dibekacin, dicloxacillin, dirithromycin, doxycycline, enoxacin, epicillin, erythromycin (Erthromycin), ethambutol, fleloxacin, floxaxefl , Flumequine, flurithromycin, fosfomycin, fosmidmai , Fusidic acid, gatifloxacin, gemifloxacin (Gemifloxaxin), gentamicin, imipenem, imipenem, and ciristatin combination, isepamicin, isoniazid, josamycin, kanamycin, kasugamycin, kitasamycin, latamoxefine, levofloxacin, lincolimine, Loracarbaf, limecycline, mesilinum, meropenem, metacycline, methicillin, metronidazole, mezlocillin, midecamycin, minocycline, miokamycin, moxifloxacin, nafcillin, nafcillin, nalidixino, neomycin, neomycin, neomycin, neomycin Ofloxacin (Oflaxacin), oleandomycin, Xacillin, oxolinic acid, oxytetracycline, paromycin, pazufloxacin, pefloxacin, penicillin G, penicillin V, pheneticillin, phenoxymethylpenicillin, pipemidic acid, combination of piperacillin, piperaricin and tazobactam, pyromidic acid, procapropicin penicillin, procain Rifabutin, rifamid (Rifamide), rifampicin, rifamycin SV, rifapentene, roquitamycin, loritetracycline, roxithromycin, rufloxacin, sitafloxacin, sparfloxacin, spectinomycin, spiramycin, sulfadiazine, sulfadoxine, Sulfamethoxazole, sisomycin, streptomycin, sulfamethoxa , Sulfisoxazole, Synercid (Quinupristan-Dalfopristan combination), teicoplanin, telithromycin, temocillin, tetracycline, tetroxoprim, thianphenicol, ticacillin, tigecycline, tobramycin, tosufloxacin , Trimethoprim, trimethrexate, trovafloxacin, vancomycin, and verdamycin, but are not limited thereto.

  Examples of vasoconstrictor agents that can be used in the compositions, methods, and kits of the present invention include dihydroergotamine, ergotamine, and methysergide, and pharmaceutically acceptable salts thereof.

  Examples of antithrombotic agents that can be used in the compositions, methods, and kits of the present invention include argatroban, iloprost, lamifane, taprosten, tirofiban, tissue plasminogen activator (natural or recombinant), tenecteplase (TNK), And inactive lanoteprase (nPA), factor VIIa inhibitors, factor Xa inhibitors, thrombin inhibitors (such as hirudin and argatroban), PAI-1 inhibitors (ie tissue plasminogen activator inhibitor) Agent), α2-antiplasmin inhibitor, streptokinase, urokinase and prourokinase, and anisolated plasminogen streptokinase activator complex, anticoagulant (eg, hirudin, heparin, etc.), plus Minogen activator (eg t-PA, urokinase ), Including fibrinolytic enzymes (e.g., plasmin, etc. subtilisin), anti-platelet aggregation agents (e.g. prostacyclin, such as aspirin) and the like.

  Examples of anticoagulants that can be used in the compositions, methods, and kits of the invention include cilostazol, clopidogrel, ticlopidine, tirofiban, eptifibatide, abciximab, anagrelide, dipyridamole, aspirin, dipyridamole / aspirin, dalteparin, enoxaparin, tinzaparin, heparin (Various), including danaparoid, antithrombin III, lepirudin, argatroban, bivalirudine, warfarin, anisidione, alteplase, reteplase, tenecteplase, drotrecogin, anistreplase, streptokinase, urokinase, and combinations thereof.

Examples of suds suppressors that can be used in the compositions, methods, and kits of the present invention include monocarboxylic fatty acids and soluble salts thereof. Monocarboxylic fatty acids and salts thereof can have a hydrocarbyl chain of about 1 to about 50 carbon atoms, about 10 to about 24 carbon atoms, or about 12 to about 18 carbon atoms. Suitable salts include alkali metal salts such as sodium, potassium, and lithium salts, and ammonium and alkanol ammonium salts. Additional foam inhibitors include, for example, high molecular weight hydrocarbons such as paraffin, fatty acid esters (eg, fatty acid triglycerides), fatty acid esters of monohydric alcohols, aliphatic C ₁₈ -C ₄₀ ketones (eg, stearone), and the like. Including. Other suds suppressors are formed as the product of tri- to hexa-alkyl melamine or cyanuric chloride and 1 to 5 or 2 to 3 moles of primary or secondary amines containing 1 to 24 carbon atoms. N-alkylated aminotriazines such as di- to tetra-alkyldiamine chlorotriazine, propylene oxide, and monostearyl alcohol phosphates, and monostearyl di-alkali metals (eg, K ⁺ , Na ⁺ , and Li ⁺ ) Includes monostearyl phosphate, such as phosphate and phosphate. Hydrocarbons such as paraffin (including mixtures of true paraffin and cyclic hydrocarbons) and haloparaffins can be utilized in liquid form. It is also known to utilize waxy carbohydrates, preferably having a melting point below about 100 ° C. Hydrocarbons constitute a preferred category of suds suppressors for surfactant compositions. Hydrocarbons can include aliphatic, alicyclic, aromatic, and heterocyclic, saturated or unsaturated hydrocarbons having from about 12 to about 70 carbon atoms. Another example of a foam suppressor includes a silicone foam suppressor. This category is a combination of a polyorganosiloxane oil such as polydimethylsiloxane, a dispersion or emulsion of polyorganosiloxane oil or resin, and silica particles of polyorganosiloxane, where the polyorganosiloxane is on silica. Including the use of combinations that are chemisorbed or fused to. Examples also include, but are not limited to, silicones, and silica-silicone mixtures. Silicones can generally be represented by alkylated polysiloxane materials, while silica is commonly used in finely classified forms exemplified by silica aerogels and xerogels, as well as various types of hydrophobic silica. The silicone foam control agent, DC-544, is a siloxane-glycol copolymer and is commercially available from Dow Corning. Other suds suppressors include a mixture of silicone oil and 2-alkyl-alkanol. A suitable 2-alkyl-alkanol is commercially available 2-butyl-octanol.

  Examples of anti-dispersing agents that can be used in the compositions, methods, and kits herein include, but are not limited to, sucrose, glycerol, and glycerin.

  Examples of steroids that can be used in the compositions, methods, and kits herein include betamethasone, chloroprednisone, crocortron, cortisone, desonide, dexamethasone, desoxymethasone, difluprednate, estradiol, fludrocortisone, flumethasone, Flunisolide, fluocortron, fluprednisolone, hydrocortisone, meprednisone, methylprednisolone, parameterzone, prednisolone, prednisone, pregnan-3-α-ol-20-one, testosterone, and triamcinolone, estradiol, estrone, estriol, polyestradiol, Polyestriol, Dienestrol, Diethylstilbestrol, Dihydroergosterone, Cyproterone, Danazol, Tests Teron, progesterone, norethindrone, levonorgestrol, ethinodiol, norgestimate, gestanin, 3-ketone-desogestrel, demegestone, promethoestrol, testosterone, spironolactone and its esters, budesonide, rofleponide, Rofleponide palmitate, ciclesonide, mometasone furoate, fluticasone propionate, tipredane, fluocinolone acetonide, flunisolide, flumethasone, dexamethasone, beclomethasone dipropionate, deflazacote, cortibazole, or cortisol and / or hydrocortisol , Fluorometholone acetate, dexamethasone sodium phosphate, suprofen, fluo Metron, and medrysone, (if there is such a form) its pure isomeric form optionally and including their pharmaceutically acceptable salts, but are not limited to.

  Examples of anti-inflammatory agents that can be used in the compositions, methods, and kits herein include both steroidal and non-steroidal anti-inflammatory agents. Suitable steroidal anti-inflammatory agents include corticosteroids such as hydrocortisone, hydroxyltriamcinolone alphamethyldexamethasone, dexamethasone phosphate, beclomethasone dipropionate, clobetasol valerate, desonide, desoxymethasone, deoxycorticostero acetate , Dexamethasone, dichlorizone, diflorazone diacetate, diflucortron valerate, fluadrenolone (fluadrenolone), fluclarolone acetonide (fluclarolone acetonide), fludrocortisone, flumethazone pivalate, fluocinolone acetonide (fluosinolone acetonide) , Fluocinonide, flucortine butylester, fluocortron, fluprednidene acetate (fluprednidene), fluland renolone (flurand renolone), harsinonide, hydrocortisone acetate, hydrocortisone butyrate, methylprednisolone, triamcinolone acetonide, cortisone, cortodoxone, flucetonide, fludrocortisone, difluorosone diacetate, fluradrenalone acetonide (tonal) Medolizone, amciafel, amcinafide, betamethasone and its ester equilibrium, chlorprednisone, chlorprednisone acetate, crocortelone, clescinolone, dichlorpredone, difluprednate, difluprednate, difluprednate flucloronide), flunisolide, fluorometallone, fluperolone, fluprednisolone, hydrocortisone valerate, hydro Le Chizon cyclopentyl proprionate (cyclopentylproprionate), hydro Coulter formate, meprednisone, paramethasone, prednisolone, prednisone, beclomethasone dipropionate, betamethasone dipropionate, triamcinolone, and mixtures thereof, but not limited to.

  Suitable nonsteroidal anti-inflammatory agents include piroxicam, isoxicam, tonexicam, sudoxicam, and oxicams such as CP-14,304; salicylic acid, aspirin, disalcid, benorylate, trilisate, safapryn, solprin , Diflunisal, and fendsal; diclofenac, fenclofenac, indomethacin, sulindac, tolmetine, isoxepac, flofenac, thiopinac, zidometacin, acematacin (acematacin), fenthiazac, zomepilac, zypirac Acetic acid derivatives; fenamates such as mefenamic acid, meclofenamic acid, flufenamic acid, niflumic acid, and tolfenamic acid; ibuprofen , Naproxen, benoxaprofen, flurbiprofen, ketoprofen, fenoprofen, fenbufen, indoprofen, pyrprofen, carprofen, oxaprozin, pranoprofen, miloprofen, thixaprofen, suprofen, aluminoprofen, and thia Propionic acid derivatives such as tiaprofenic; and pyrazoles such as, but not limited to, phenylbutazone, oxyphenbutazone, feprazone, azapropazone, and trimethazone. Mixtures of these non-steroidal anti-inflammatory agents can also be used as well as their pharmaceutically acceptable salts and esters.

  Examples of analgesics that can be used in the compositions, methods, and kits of the present invention to reduce inflammation discomfort are lidocaine, mepivacaine, bupivacaine, procaine, chloroprocaine, etidocaine, prilocaine dichronin, hexyl Caine, procaine, cocaine, ketamine, morphine, pramoxine, propophol, phenol, naloxone, meperidine, butorphanol or pentazocine, or morphine-6-glucuronide, codeine, dihydrocodeine, diamorphine, dextropropoxyphene, pethidine, fentanyl, Alfentanil, alphaprozin, buprenorphine, dextromorphamide, diphenoxylate, dipipanone, heroin (diacetylmorphine), hydrocodone (dihydroco) INON), hydromorphone (dihydromorphinone), levorphanol, meptazinol, methadone, methopone (methyldihydromorphinone), nalbuphine, oxycodone (dihydrohydroxycodeinone), oxymorphone (dihydrohydroxymorphinone), phenadoxone, Including but not limited to phenazosin, remifentanil, tramadol, tetracaine, and mixtures thereof, and pharmaceutically acceptable salts and esters thereof. In a preferred embodiment, the composition comprises an analgesic selected from the group consisting of lidocaine, hydromorphone, oxycodone, morphine, and pharmaceutically acceptable salts thereof.

  Examples of tranquilizers and sedatives that may be included in the compositions, methods, and kits herein are chlordiazepoxide, benactidine, benzquinamide, flurazepam, hydroxyzine, loxapine, promazine, and acceptable salts thereof and Including but not limited to esters.

  Examples of muscle relaxants that may be included in the compositions, methods, and kits herein include cinnamedrine, cyclobenzaprine, flavoxate, orphenadrine, papaverine, mebevelin, idavelin, ritodrine, dephenoxylate, dantrolene , Azumolene, and pharmaceutically acceptable salts thereof.

  Examples of antidiarrheal agents that can be included in the compositions, methods, and kits herein include, but are not limited to, loperamide, and pharmaceutically acceptable salts thereof.

  Examples herein and other active agents can be co-formulated or co-administered with one or more pharmacologically active surfactants (eg, bile acids or bile salts). . When co-formulated with a surfactant (eg, bile salt), the additional agent is 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9 of the composition. , 8, 7, 6, 5, 4, 3, 2, 1, 0.5, 0.4, 0.3, 0.2, 0.1, 0.09, 0.08, 0.07, 0.06, 0.05, 0.04, 0.03, 0.02, 0.01, 0.009, 0.008, 0.007 , 0.006, 0.005, 0.004, 0.003, 0.002, 0.001, 0.0009, 0.0008, 0.0007, 0.0006, 0.0005, 0.0004, 0.0003, 0.0002, or 0.0001% w / w, up to w / v, or v / v, or 0.0001, 0.0002, 0.0003, 0.0004, 0.0005, 0.0006, 0.0007, 0.0008, 0.0009, 0.001, 0.002, 0.003, 0.004, 0.005, 0.006, 0.007, 0.008, 0.009, 0.01, 0.02, 0.03, 0.04, 0.05, 0.06, 0.07, 0.08, 0.09, 0.1, 0.2, 0.3, 0.4, 0.5, 1.0, 1.25, 1.50, 1.75, 2.0, 2.25, 2.50, 2.75, 3.0, 3.25, 3.50, 3.75, 4.0, 4.25, 4.50, 4.75, 5.0, 5.25, 5.50, 5.75, 6.0, 6.25, 6.50, 6.75, 7.0, 7.25, 7.50, 7.75, 8.0, 8.25, 8.50, 8.75, 9.0, 9.25, 9.50 9.75, 10, 10.25, 10.50, 10.75, 11, 11.25, 11.50, 11.75, 12, 12.25, 12.50, 12.75, 13, 13.25, 13.50, 13.75, 14, 14.25, 14.50, 14.75, 15, 15.25, 15.50, 15.75 , 16, 16.25, 16.50, 16.75, 17, 17.25, 17.50, 17.75, 18, 18.25, 18.50, 18.75, 19, 19.25, 19.50, 19.75, or 20% (w / w, w / v, or v / v) It can be larger.

  In some embodiments, the additional active ingredient is approximately 0.001-50, 0.001-40, 0.01-30, 0.02-29, 0.03-28, 0.04-27, 0.05-26, 0.06-25, 0.07 of the composition. -24, 0.08-23, 0.09-22, 0.1-21, 0.2-20, 0.3-19, 0.4-18, 0.5-17, 0.6-16, 0.7-15, 0.8-14, 0.9-12, or 1- With one or more pharmacologically active surfactants (eg bile acids or bile salts) to a concentration in the range of 10% w / w, w / v, or v / v. Formulated.

  In some embodiments, the composition comprises 10, 9.5, 9.0, 8.5, 8.0, 7.5, 7.0, 6.5, 6.0, 5.5, 5.0, 4.5, 4.0, 3.5, 3.0, 2.5, 2.0, 1.5, 1.0, 0.95, 0.9, 0.85, 0.8, 0.75, 0.7, 0.65, 0.6, 0.55, 0.5, 0.45, 0.4, 0.35, 0.3, 0.25, 0.2, 0.15, 0.1, 0.09, 0.08, 0.07, 0.06, 0.05, 0.04, 0.03, 0.02, An active ingredient that is not a surfactant up to 0.01, 0.009, 0.008, 0.007, 0.006, 0.005, 0.004, 0.003, 0.002, 0.001, 0.0009, 0.0008, 0.0007, 0.0006, 0.0005, 0.0004, 0.0003, 0.0002, or 0.0001 grams, or 0.0001, 0.0002, 0.0003, 0.0004, 0.0005, 0.0006, 0.0007, 0.0008, 0.0009, 0.001, 0.0015, 0.002, 0.0025, 0.003, 0.0035, 0.004, 0.0045, 0.005, 0.0055, 0.006, 0.0065, 0.007, 0.0075, 0.008, 0.0085, 0.009, 0.0095, 0.01, 0.015, 0.02, 0.025, 0.03, 0.035, 0.04, 0.045, 0.05, 0.055, 0.06, 0.065, 0.07, 0.075, 0.08, 0.085, 0.09, 0.095, 0.1, 0.15, 0.2, 0.25, 0.3, 0.35, 0.4, 0.45, 0.5 0.55, 0.6, 0.65, 0.7, 0.75, 0.8, 0.85, 0.9, 0.95, 1.0, 1.5, 2.0, 2.5, 3.0, 3.5, 4.0, 4.5, 5.0, 5.5, 6.0, 6.5, 7.0, 7.5, 8.0, 8.5, Additional active ingredient greater than 9.0, 9.5, or 10 grams, or about 0.0001-10, 0.0005-9, 0.001-8, 0.005-7, 0.01-6, 0.05-5, 0.1-4, 0.5-4, Or contain non-surfactant active ingredients in the range of between 1 and 3 grams.

  In some embodiments, the pharmacologically active surfactants herein (e.g., bile acids and bile salts) are administered directly to fat deposits or subcutaneously under loose skin or Formulated for subdermal injection. Formulations for injection may be in unit dosage form, eg, in ampoules, syringeable containers, or multi-dose containers, with added preservatives. Injectable formulations may take such forms as suspensions, solutions, or emulsions in oily or aqueous media, and as suspensions, stabilizers, antidispersants, and / or dispersants. Various drugs. Such a formulation may further comprise an agent having activity, such as a vasoconstrictor, to prevent the compositions herein (eg, deoxycholic acid or salts thereof) from entering the vasculature.

  The compositions of the present invention can be formulated to provide rapid, sustained or delayed release of the active ingredient after administration to a patient by using procedures known in the art. . In some embodiments, the compositions herein are formulated for slow release. Slow release formulations or biodegradable controlled release dosage forms are compositions for extending the effect of an amount of bile acids or bile salts effective to solubilize fat in vivo at the desired site of treatment I will provide a. In some embodiments, a surfactant (eg, bile acid or salt thereof) herein is formulated with a pharmaceutically acceptable enhancer effective to further extend the duration of the effect of the surfactant. It becomes. Controlled release formulations can be formed into slabs, rods, pellets, microparticles (eg, microspheres, microcapsules), spheres, paste solutions, sprays, patches, and the like. Such formulations can be used to form suspensions in isotonic saline, or other physiological buffers, or solutions acceptable to subcutaneous injections, patches, pumps, or depots.

  Slow release formulations are compositions described herein (eg, injectable microspheres filled with bile acids or bile salts in sustained release form) at the target site or adjacent to provide treatment. Administration can be by contacting the site, implanting, inserting, or injecting. In some embodiments, the compositions herein are administered to the target site using in situ gel implantation. In some embodiments, the pharmacologically active composition comprises poly (DL-lactide-co-glycolide); poly (lactide-co-glycolide); poly (DL-lactide); poly (L-lactide) Encapsulated in a polymer carrier such as, but not limited to: poly (glycolide); poly (ε-caprolactone); poly (DL-lactide-co-caprolactone).

Unit doses The present invention also contemplates unit doses of the compositions herein. Such unit dose is preferably in a container, a syringe, or a container in which a syringe can be mounted. Such unit doses are, for example, 500, 400, 300, 200, 100, 90, 80, 70, 60, 50, 40, 30, 20, 10, 9, 8, 7, 6, 5, 4, 3 , 2, 1, 0.9, 0.8, 0.7, 0.6, 0.5, 0.4, 0.3, 0.2, 0.1, 0.09, 0.08, 0.07, 0.06, 0.05, 0.04, 0.03, 0.02, 0.01, 0.009, 0.008, 0.007, 0.006, 0.005 , 0.004, 0.003, 0.002, 0.001, 0.0009, 0.0008, 0.0007, 0.0006, 0.0005, 0.0004, 0.0003, 0.0002, or 0.0001 mL total volume. In some embodiments, the unit dose is 0.0001-500, 0.0005-400, 0.001-300, 0.005-200, 0.01-100, 0.05-90, 0.06-80, 0.07-70, 0.08-60, 0.09 per target site. -50, 0.1-40, 0.2-30, 0.3-29, 0.4-28, 0.5-27, 0.6-26, 0.7-25, 0.8-24, 0.9-23, 10-22, 11-21, 12-20 , 13-19, 14-18, or 15-17 mL in total volume range. Other embodiments contemplate unit doses having a total volume in the range of 0.01-30, 0.02-20, 0.03-10, 0.4-5, or 0.5-1 mL total volume. In some embodiments, the unit dose is greater than 0.0001, 0.0002, 0.0005, 0.001, 0.002, 0.005, 0.01, 0.02, 0.05, 0.1, 0.2, 0.5, 1, 2, 5, 10, 20, 50, 100 mL Having a total volume of Preferably, the unit dose has a total volume of up to 1.0, 0.8, 0.6, 0.4, or 0.2.

  A unit dose comprises an amount of one or more pharmacologically active surfactants (eg, bile acids and bile salts, or more preferably deoxycholic acid or salts thereof) in a therapeutically effective amount. Consist essentially of or consist of. Such amount can be determined by one skilled in the art and depends in part on the location of the fat deposit or flaccid skin, the size of the fat deposit or flaccid skin, and the concentration of the active agent. I will.

  In some embodiments, the unit dose is 10, 9, 8, 7, 6, 5, 4, 3, 2, 1, 0.9, 0.8, 0.7, 0.6, 0.5, 0.4, 0.3, 0.2, 0.1, 0.09, 0.08, 0.07, 0.06, 0.05, 0.04, 0.03, 0.02, 0.01, 0.009, 0.008, 0.007, 0.006, 0.005, 0.004, 0.003, 0.002, 0.001, 0.0009, 0.0008, 0.0007, 0.0006, 0.0005, 0.0004, 0.0003, 0.0002, Or up to 0.0001 grams of pharmacologically active surfactant. In some embodiments, the unit dose comprises a range of approximately 0.00001-10, 0.00005-1.0, 0.0001-0.5, 0.0005-0.1, 0.001-0.05, or 0.005-0.01 grams. Preferably, the unit dose comprises about 0.01 grams of bile acid or bile salt (eg, sodium deoxycholate).

  The unit dose may further comprise a lipid such as a phospholipid, or more preferably phosphatidylcholine. Such lipids can be added in the amounts and concentrations identified herein. However, in preferred embodiments, the unit dose has up to 5% w / w, w / v, or v / v lipid, phospholipid, or phosphatidylcholine. Preferably, the ratio of% w / w of surfactant to% w / w of lipid (eg phosphatidylcholine) at unit dose is greater than 1, 1.2, 1.4, 1.6, 1.8, 2.0, 2.2, 2.4, 2.6 Greater than 2.8, or 3.0.

Uses The compositions herein are for preventing or reducing the appearance of skin conditions, preventing or reducing sleep apnea symptoms, and preventing the appearance or effects of fat conditions in a subject. Or can be used to reduce. Such subjects include animals, more preferably mammals, more preferably primates (eg, monkeys, chimpanzees, etc.), domesticated animals (eg, dogs, cats, horses, etc.), farm animals (eg, Goats, sheep, pigs, cows, etc.), laboratory animals (eg, mice, rats, etc.), or more preferably humans.

  In some embodiments, the compositions herein are used to prevent or reduce the appearance of skin conditions selected from the group consisting of flaccid skin, skin aging, skin irregularities, and wrinkles. The Such a method comprises the step of topically administering to the skin area of interest a composition of the invention comprising: (i) one or more pharmacologically active surfactants; More preferably one or more bile acids or bile salts, more preferably deoxycholic acid or salts thereof, or more preferably sodium deoxycholate; (ii) pharmaceutical, cosmetic or veterinary excipients And (iii) optionally one or more lipids. One or more surfactants are administered in an amount effective to tighten the skin. In some embodiments, up to 5, 4, 3, 2, 1, 0.5, 0.4, 0.3, 0.2, 0.1, 0.05, 0.04, 0.03, 0.02, or 0.01 grams of surfactant is administered. In some embodiments, the composition is 5, 4, 3, 2, 1, 0.5, 0.4, 0.3, 0.2, 0.1, 0.05, 0.04, 0.03, 0.02, or 0.01% w / w, w / v, or Contains up to v / v surfactant. When one or more lipids are optionally included, such lipids can be phospholipids, or more preferably phosphatidylcholines. The mass or volume ratio of surfactant to lipid (eg,% w / w, w / v, or v / v) in the delivered composition is preferably greater than 1. In some embodiments, the composition is 5, 4, 3, 2, 1, 0.5, 0.4, 0.3, 0.2, 0.1, 0.05, 0.04, 0.03, 0.02, or 0.01% w / w, w / v, or Contains up to v / v lipids, phospholipids, or phosphatidylcholines. In any of the above aspects, the composition to be administered is preferably in an aqueous solution. Such a solution preferably has a total volume of up to 500 mL, 100 mL, 50 mL, 10 mL, or 5 mL.

  The above composition is preferably administered locally to the target area in order to generate an inflammatory response that causes scar formation. Scar formation results in tightening of the skin, particularly to the extent that the skin has little or no tension and provides little resistance to scar contraction. Such a procedure may be associated with a number of clinical scenarios, such as, but not limited to, commonly performed liposuction, including but not limited to multivolume liposuction. The latter may be associated with skin relaxation after the treatment (relaxing skin in the area of fat removal) and skin surface irregularities. Thus, in some embodiments, a composition comprising a therapeutically effective amount of a surfactant or bile salt may be administered to a liposuction site after completion of a liposuction procedure.

  In some embodiments, the target area is under the eye, under the chin, under the arm, buttocks, calf, back, thigh, abdomen, cheek, forehead, or aging, wrinkles, flaccid skin, or irregular skin Is any other skin area showing.

  In some embodiments, the compositions herein are delivered to the target area via subcutaneous injection, pumps, patches, or subcutaneous depots. In some embodiments, the compositions herein are administered topically.

  In one aspect, the compositions herein are used to reduce subcutaneous fat deposits in a subject. Subcutaneous fat deposits include, for example, obesity, fat redistribution syndrome, eyelid steatosis, lipoma, lipodystrophy (including buffalo aneurysm), dorsal neck fat, visceral obesity, abundant Such as chest, hyperlipidemia, diffuse body fat around the trunk and arms, fat deposits associated with cellulite, Durham's disease, Madelung's neck, lipoedema, compression nodules, Ronova-Cleret syndrome, and pterythroxanthosis Can be associated with fat conditions. Subcutaneous fat deposits include under the eyes, under the chin, under the arms, buttocks, calves, back, thighs, abdomen, cheeks, forehead, "luxury around the belly", ankles, fingers, lips, trachea, etc. It can be located in a body range that is not limited to.

  Subcutaneous fat deposits can be reduced by locally administering to the fat deposits a composition comprising: (i) one or more pharmacologically active surfactants, more preferably One or more bile acids or salts thereof, more preferably deoxycholic acid or salts thereof, or more preferably sodium deoxycholate; (ii) a pharmaceutical or veterinary excipient; and (iii) optionally, The ratio of lipid, where lipid and bile acid or bile salt is up to 1% w / w. Preferably the composition does not comprise a lipase or a co-lipase. The above method preferably does not include performing surgery (eg, liposuction) on the subject.

  Preferably, the one or more pharmacologically active surfactants are 5, 4, 3, 2, 1, 0.5, 0.4, 0.3, 0.2, 0.1, 0.05, 0.04, 0.03, 0.02, or 0.01. Administered in an amount effective to dissolve fat, such as up to grams of surfactant. In some embodiments, the composition is 5, 4, 3, 2, 1, 0.5, 0.4, 0.3, 0.2, 0.1, 0.05, 0.04, 0.03, 0.02, or 0.01% w / w, w / v, or Contains up to v / v surfactant. Preferably, the composition comprises between about 0.001-10% w / w surfactant or bile salt, or more preferably between about 0.01 and 5% w / w surfactant or bile salt. including.

  When one or more lipids are optionally included, such lipids can be phospholipids, or more preferably phosphatidylcholines. The mass or volume ratio of surfactant to lipid (eg,% w / w, w / v, or v / v) in the delivered composition is preferably greater than 1. In some embodiments, the composition is 5, 4, 3, 2, 1, 0.5, 0.4, 0.3, 0.2, 0.1, 0.05, 0.04, 0.03, 0.02, or 0.01% w / w, w / v, or Contains up to v / v lipids, phospholipids, or phosphatidylcholines. In any of the above aspects, the composition to be administered is preferably in solution, or more preferably in an aqueous solution. Such a solution preferably has a total volume of up to 500 mL, 100 mL, 50 mL, 10 mL, or 5 mL.

  Subcutaneous fat deposits are obesity, fat redistribution syndrome, eyelid fat hernia, lipoma, dercum disease, lipodystrophy, buffalo aneurysm lipodystrophy, dorsal neck fat, visceral obesity, breast augmentation, It can be associated with a fat condition selected from the group consisting of adiposity, diffuse body fat around the trunk and arms, and fat deposits associated with cellulite. Thus, the compositions herein can be used to treat or ameliorate conditions associated with such conditions. In some embodiments, the compositions herein reduce subcutaneous fat deposits at such sites under the subject's eyes, under the chin, under the arm, buttocks, calves, back, thigh, or abdomen. To be administered topically.

  For example, in some embodiments, a composition (eg, a pharmacologically active surfactant, or more preferably a bile salt, or more preferably sodium deoxycholate) is used in a human HIV patient. Used to treat or ameliorate lipodystrophy conditions in subjects such as Literopathy is a condition that is often a side effect from HIV treatment (eg, treatment with protease inhibitors). Lipodystrophy is characterized by local or systemic subcutaneous fat loss, or abnormal fat redistribution and metabolic disorders. Symptoms of lipodystrophy may include an expanded abdomen with loss of tissue from the face, arms and legs, which can result in the appearance of hollow eyes and protruding cheekbones. Other signs of lipodystrophy include fat accumulation behind the neck, sometimes referred to as buffalo aneurysm (diffused fat accumulation). Female HIV patients may also be treated for breast augmentation attributable to lipodystrophic syndrome.

  In some embodiments, the compositions herein are used to treat lipomas. Lipomas localize to fat accumulation, a benign neoplastic growth. Various forms of lipoma exist and in some embodiments; the compositions herein are used to treat multiple familial lipomatosis.

  In some embodiments, the compositions herein are used to prevent, treat, or improve fat in animals such as cats, dogs, or horses.

  In some embodiments, the compositions herein are used to treat obstructive sleep apnea. Obstructive sleep apnea is characterized by repeated pauses in breathing during sleep due to obstruction of the upper airway (throat) and / or collapse, usually with a decrease in blood oxygen saturation and to breathe Awakening continues. It is a dangerous (sometimes life-threatening) condition that often affects obese people. Obese people have a large amount of fat around the trachea, which can cause the airways to collapse when the muscles relax during sleep. In one embodiment, the compositions herein (eg, sodium deoxycholate) are used to treat obstructive sleep apnea by dissolving fat around the trachea. In such embodiments, the compositions of the invention are administered locally (eg, via injection) to a target site of fat around the trachea in a therapeutically effective amount.

  For the treatment of fatty conditions, the compositions herein (eg, pharmacologically active surfactants, bile salts, or sodium deoxycholate) are preferably locally applied to the site of fat accumulation. Be administered. Topical delivery can be made, for example, via subcutaneous or transdermal injection, external or internal pumps, skin patches, subcutaneous depots, or any other means known in the art.

  In some embodiments, the compositions herein are delivered via a skin patch. Skin patches are self-adhesive units and are worn on the patient's body. Skin patches deliver a small volume of drug to the skin where it then diffuses into the skin. The patch incorporates a series of thin, flexible films: support layer, drug reservoir, rate control film and adhesive. To further increase the penetration of the drug through the skin, an enhancer may be added. The patch can be coupled with low level electron energy to actively transport the drug through intact skin.

  In some embodiments, the compositions herein are delivered via external or internal pumps. A pump is a specialized device that delivers drugs into the body via a small catheter. For example, an infusion pump can be programmed to deliver a drug at the correct dosage and delivery rate. These pumps may have feedback devices that control drug delivery according to need. The size of the pump depends on the amount of drug and the length of treatment planned.

  In some embodiments, the compositions herein are delivered via a depot. A depot is a non-biodegradable and osmotically driven implant that is used to allow delivery of a therapeutic drug. The depot is activated by osmosis, incorporates a small metal alloy cylinder, and can provide continuous drug delivery from a few days to a year. In some embodiments, the compositions herein may be administered parenterally. Parenteral routes of administration include injections into various compartments of the body, such as but not limited to intravenous, subcutaneous, intramuscular, intraperitoneal and the like.

  In one example, two injections of up to 1 mL each are administered under the chin, where each injection is between 0.005 and 0.5, or more preferably between 0.002 and 0.08 grams of sodium deoxycholate. including. In another embodiment, three treatments of 2 mL of 1% w / w sodium deoxycholate are administered in the buccal area.

In any of the embodiments herein, therapeutic therapy can include administering one or more unit doses to the target site. The target site can be, for example, from 0.1 cm ² to about 5 cm ² . The compositions herein may be administered to the same, adjacent, or near target sites, as disclosed herein, at various intervals, dosages, and volumes. When delivered, the composition may be administered at various levels below the dermis including, for example, 0.1-4, 0.2-3.5, 0.3-3, 0.4-2.5, or 0.5-2 inches below the dermis.

  For example, in some embodiments, 100, 10, 9, 8, 7, 6, 5, 4, 3, 2, 1, 0.9, 0.8, 0.7, 0.6, 0.5, 0.4, 0.3, 0.2, 0.1, 0.09, Up to 0.08, 0.07, 0.06, 0.05, 0.04, 0.03, 0.02, or 0.01 mL of solution is delivered locally to the target site (eg, site of fat accumulation or loose skin) at a time. The solution may contain one or more pharmacologically active surfactants (eg, bile acids or salts thereof, or more preferably deoxycholic acid or salts thereof, more preferably sodium deoxycholate) It can consist essentially of or consist of them, where the solution comprises up to 5, 4, 3, 2, 1% w / w surfactant. Such a solution may contain up to 5% w / w, w / v, or v / v lipid, or phospholipid, or phosphatidylcholine, or in some embodiments, free of phosphatidylcholine. In some embodiments, the compositions (eg, solutions) herein are free of lipase or complement lipase, or contain no lipase and no lipase. In some embodiments, the compositions (eg, solutions) herein do not include an enzyme. In some embodiments, 10, 9, 8, 7, 6, 5, 4, 3, 2, 1, 0.9, 0.8, 0.7, 0.6, 0.5, 0.4, 0.3, 0.2, 0.1, 0.09, 0.08, 0.07, Up to 0.06, 0.05, 0.04, 0.03, 0.02, or 0.01 grams of a surfactant herein (preferably a bile acid or bile salt) is administered locally at one time to the target site. In other embodiments, more than 0.001, 0.002, 0.003, 0.004, 0.005, 0.006, 0.007, 0.008, 0.009, or 0.01 g is delivered to the target site at one time. In general, the total volume, unit dose, and number of treatments administered will vary depending on the amount of fat at the target site, the location of the target site, the type of fat composition, and the desired result. In general, the greater the amount of fat that is treated, the greater the dose that is administered. Also, the greater the amount of flaccid skin in the target area, the more doses that will be delivered or the greater the number of injections. The compositions and unit doses herein may be administered to an individual as part of a treatment therapy and at the same time are not necessarily actively removed (eg, via aspiration) from the individual as part of the treatment therapy But it should be noted.

  In any embodiment herein, therapeutic therapy can include administration of at least 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 unit doses to the target site. Such unit doses can be delivered simultaneously or over a period of time. For example, administration can occur 1, 2, 3, or 4 times per hour, day, week, month, or year. In some embodiments, multiple administrations are between 1-100, 2-50, 3-30, 4-20, 5-10 times in 1 hour, 1 day, 1 week, 1 month, or 1 year Administration to the target site. In some embodiments, multiple administrations are performed up to 10, 9, 8, 7, 6, 5, 4, 3, or 2 target sites per year, week, day, or hour. Including administration. The total number of doses in therapeutic therapy can be completed over a period of 1 year, 6 months, 5 months, 4 months, 3 months, 2 months, 1 month, 3 weeks, 2 weeks, or 1 week or less.

  In any embodiment herein, the method does not include surgical removal of one or more localized fat deposits in the subject. Non-surgical methods of fat reduction do not include liposuction, lipoplasty, or suction fat removal. For example, in some embodiments, non-surgical methods herein do not include liposuction. In some embodiments, the methods herein also eliminate non-invasive means for reducing fat, such as ultrasonification. In other embodiments, non-invasive means can be used with the compositions herein.

  Any of the disclosed treatments may be supplemented by further administering additional active ingredients to the patient. Such additional agents can be administered separately or in combination with the compositions herein. The second agent can be administered locally or systemically. In some embodiments, the second agent is co-formulated with a surfactant. In other embodiments, the second agent is administered prior to, simultaneously with, or after administration of the surfactant.

Kit FIG. 11 is an illustration of a kit 101 for non-surgical reduction of subcutaneous fat and / or tightening of loose skin. Kit 101 includes one or more containers 102. For example, the first container 102 can contain a therapeutically effective amount of a pharmacologically active surfactant (eg, bile acid and its salts), and up to 5% w / v phosphatidylcholine, and The second container 102 may contain a therapeutically effective amount of a pharmacologically active surfactant and may be free of phosphatidylcholine. The container 102 is preferably mountable with a syringe. Containers 102 may each hold one or more unit doses. For example, the container 102 can hold up to 500, 100, 20, 10, 5, or 1 mL.

  In some embodiments, the container 102 can include one or more additional active ingredients, either independently or in combination with one or more surfactants herein. Examples of additional active ingredients are antimicrobial agents, antithrombotic agents, anticoagulants, foam suppressors, anti-inflammatory agents, analgesics, anesthetics, antidispersants, dispersants, penetration enhancers, steroids, tranquilizers Includes drugs, muscle relaxants, and antidiarrheal agents.

  In one example, the container 102 contains up to 5% w / v phospholipid (eg, phosphatidylcholine) or is free of phospholipid (eg, phosphatidylcholine) and is 10, 5.0, 1.0, or 0.5% w. Contains surfactants up to / w.

  In one example, the container 102 contains 0.01, 0.1, 1.0, 2.0, 3.0, 4.0, or 5.0% w / w, w / v, or more than pharmacologically active surfactant (eg, , Bile acids or bile salts) and up to 5% w / v phospholipids (eg phosphatidylcholine) or phospholipids (eg phosphatidylcholine).

  The solution in container 102 is administered according to instructions 103 for use. Instructions 103 for use may provide dosing instructions that may depend on, for example, the location of the target site, the animal being treated, the desired result, the size of the target site, the concentration of surfactant in the composition, etc. . Preferably, instructions for use 103 are for treatment of animals such as humans, dogs, cats, or horses. Instructions for use 103 also include information for the treatment of other domestic animals and / or farm animals. Instructions for use 103 may also include, for example, fat deposits that are localized under the eyes, under the chin, under the arms, buttocks, cheeks, forehead, calves, back, thighs, ankles, or abdomen, or relaxed Contains information regarding the use of the compositions herein to treat specific target sites, such as skin areas. In some embodiments, instructions for use 103 include obesity, fat redistribution syndrome, dorsal neck fat, visceral obesity, breast augmentation, hyperlipidemia, eyelid fat hernia, lipoma, steatosis About the use of the compositions herein for treating nutrition, buffalo lipodystrophy, diffuse body fat around the trunk and arms, or fat conditions of fat deposits associated with cellulite The explanation will be described in detail.

  In some embodiments, the instructions for use 103 include a composition herein for treating a skin condition selected from the group consisting of flaccid skin, skin aging, skin irregularities, and wrinkles. The explanation about the use of is described in detail.

  Instructions for use 103, if any, may include information regarding reasonable diluent and dilution volume of container 102, if any. Instructions 103 for use may also provide information regarding the proper administration of the compositions herein, such as frequency of administration and dosage.

  Kit 101 may be used alternatively or in addition to container 102 to deliver the compositions herein (eg, those in container 102) to a target site of fat accumulation or flaccid skin. Multiple syringes 104 or other suitable delivery devices (eg, patches, subcutaneous depots) may be included. In some embodiments, the syringe or other delivery device 104 may be pre-filled with one or more unit doses of the compositions herein.

  Preferably, the kit is a local subcutaneous injection of a solution having a total volume of up to 100 mL comprising between 0.1-10% bile acid or salt, or more preferably deoxycholic acid or salt thereof, or sodium deoxycholate. For one or more syringes. The solution preferably does not contain lipase or complementary lipase, or both. The solution preferably contains or does not contain phosphatidylcholine.

  The present invention relates to a first container comprising a pharmacologically active surfactant and up to 5% w / v phosphatidylcholine and a document for reducing subcutaneous fat deposits in mammals without surgical use A kit having the instructions is contemplated. Preferably, the kits herein may be used to reduce fat deposits in various mammals such as, for example, humans, horses, dogs, or cats. In some embodiments, the mammal is a human.

  In some preferred embodiments, the first container has a total volume of up to 500 mL and / or is provided as an injectable formulation. In other preferred embodiments, the first container may contain greater than% w / v surfactant of phosphatidylcholine or no phosphatidylcholine. In one preferred embodiment, the present invention provides a surfactant at a concentration above the critical micelle concentration (CMC). Kits vary, for example, lipophilic surfactants, hydrophilic surfactants, ionic surfactants, nonionic surfactants, glycerides, bile salts, and zwitterionic surfactants A pharmacologically active surfactant may be included. In a more preferred embodiment, the active surfactant is a bile salt, most preferably sodium deoxycholate. The first container in the kit herein may in some embodiments contain up to 3 g of surfactant. In other embodiments, the first container in the kit herein may contain more than 0.0002 g of surfactant. In any embodiment herein, the first container may further comprise a second surfactant.

  Preferably, the first container is, for example, an antimicrobial agent, a vasoconstrictor, an antithrombotic agent, an anticoagulant, a foam inhibitor, an anti-inflammatory agent, an analgesic, a dispersant, an antidispersant, a penetration enhancer, a steroid Secondary therapeutic agents such as tranquilizers, muscle relaxants, and antidiarrheal agents. In some embodiments, the second therapeutic agent is an analgesic, antimicrobial, or anti-inflammatory agent. More preferably, the second therapeutic agent is an analgesic, or most preferably lidocaine. In another embodiment, the kit provides a second container comprising a second therapeutic agent as described herein.

  One embodiment of the present invention contemplates a kit herein for reducing fat deposits under the eyes, chin, or arm of a mammal, as well as the buttocks, calves, back, thighs, ankles, or abdomen. To do. In another embodiment, the kit comprises, for example, lid fat hernia, lipoma, lipodystrophy, buffalo lipodystrophy, diffuse body fat around the trunk and arms, or fat deposition associated with cellulite Specific types of fat deposits, such as objects, may be reduced.

Business Methods The methods and kits disclosed herein can be used to perform business services and / or sell commercial products.

  In some embodiments, the present invention contemplates business methods for selling the kits herein or providing treatment services. For example, a business may make a formulation based on the compositions described herein. And the business method in this specification can manufacture the kit containing such a formulation, and can sell such a kit in exchange for a charge. In some embodiments, the business method allows a third party to manufacture the kit. In some embodiments, the business contracts with sales support to sell such kits.

  The business may alternatively or additionally provide treatment services in exchange for service fees. Services can be provided directly to the patient and the fee can vary depending on the length of the procedure and / or the amount of surfactant having activity used.

  After reading and understanding the specification and examples, it is understood that there are many other aspects and methods of using the present invention that will be apparent to those skilled in the art. The following examples are meant to illustrate one or more embodiments of the invention and are not meant to limit the invention to what is described below.

Example 1
Sodium deoxycholate and phosphatidylcholine formulation Phosphatidylcholine bile salt formulation (PBF) (5.0% highly purified soy-derived PC, 4.75% sodium deoxycholate, and 0.9% benzyl alcohol in sterile water, Table 2) From Hopewell Pharmacy, Hopewell, NJ. Sodium deoxycholate and Triton X-100 surfactant (Triton, alkylaryl polyether alcohol) were obtained from Sigma-Aldrich Corp. (St. Louis, MO). Empigen BB surfactant (Empigen, lauryl dimethyl betaine) was obtained from Calbiochem, Biosciences, Inc., (La Jolla, CA). An injectable PBF solution was made according to Table 2 below. Stock reagents (5% dilution) were prepared in PBS buffer.

(Table 2) Injectable PBF

  The molecular structures of (a) phosphatidylcholine, (b) sodium deoxycholate, and (c) benzyl alcohol are shown in FIG.

Example 2
Effect of sodium deoxycholate and phosphatidylcholine solution on cultured cells To measure cell viability after detergent treatment, HaCaT human keratinocyte cells were treated with DMEM (Dulbecco modified with 10% fetal bovine serum, penicillin, and streptomycin. Method Eagle medium). HaCaT cells are cultured in 6-well plates and use an MTS assay (a tetrazolium compound that produces a color change when bioproduced by metabolically active cells (CellTiter 96 Aqueous Non-Radioactive Cell Proliferation Assay, Prior to determination of cell viability using Promega, Corp. Madison, Wis.), Incubation with 0, 0.005, 0.050, or 0.500% PBF or sodium deoxycholate for 30 minutes at 37 ° C. Cell viability was determined by absorbance spectrophotometer (at 490 nm) after 4 hours incubation with the assay at 37 ° C. To determine cell viability in fresh tissue, fat specimens were incubated with stock reagents and MTS assay in 4 hour 24 well plates. Tissue specimens were then visualized for color change and the amount of MTS in the supernatant was measured by absorbance (at 490 nm). All research was done in triplicate. Absorbance at 490 nm (OD 490) is proportional to the number of living cells in the culture. There was a comparable OD 490 in both the control and 0.005% diluted compounds (Figure 2a), indicating that at this concentration these substances had little effect on cell viability. Cell viability decreased progressively with both 0.05% and 0.5% strength solutions.

  Cell lysis in response to detergent treatment was determined in HaCaT cells incubated with reagents at 37 ° C. for 30 minutes at the indicated cell dilutions. Lysis in cultured cells was measured using a lactate dehydrogenase (LDH) assay and using calcein, a fluorescent marker retained in cells with intact cell membranes in tissues. The LDH assay measures the activity of LDH, a cytoplasmic enzyme that is released when cells are lysed. The release of lactate dehydrogenase was measured by absorbance (at 490 nm) after 1 hour incubation with the LDH assay as recommended by the manufacturer (CytoTox 96 Non-Radioactive Cytotoxicity Assay, Promega). All research was done in triplicate. LDH release is directly proportional to absorbance at 490 nm (OD 490). Cell culture was used to determine the dilutions of reagents (PBF and deoxycholate) needed to affect the cells, since penetration into intact tissue is likely to be a limiting factor. As shown in FIG. 2a, sodium deoxycholate greatly reduced the viability of cultured cells almost as much as complete PBF. This finding was reproduced in tissues by exposing porcine fat to PBF and deoxycholate (Figure 3). These results support the unexpected finding that sodium deoxycholate plays a major, active role in PBF. There was minimal LDH release from control cells and cells incubated with both compounds at 0.005% dilution (FIG. 2b). Furthermore, cell cultures treated with both PBF and deoxycholate showed a concentration-dependent increase in cell lysis (FIG. 2b). Furthermore, the direct lytic effect observed in cultured cells treated with these agents suggests an activity independent of endogenous lipase. At 0.05% and 0.5% PBF and deoxycholate there was progressively more released LDH. Comparing the effects of PBF in cell culture with deoxycholate led to the surprising result that deoxycholic acid resulted in a similar reduction in cell viability but less cell lysis. These data unexpectedly show that deoxycholate acts as an active element in PBF.

Example 3
Effect on Porcine Tissue of Sodium Deoxycholate and Phosphatidylcholine Solutions Porcine tissue was obtained immediately after sacrifice, shaved, and placed on ice for up to 4 hours before use. Fat specimens were obtained and trimmed by removing punch biopsy epidermis and dermis with a scalpel. Fat specimens were filled with calcein dye by incubation with Calcein-AM (Sigma) for 1 hour at 37 ° C. Stock reagents were added to the fat specimens and incubated for 30 minutes at 37 ° C. with gentle agitation. Calcein retention was determined by tissue fluorescence using a purple (411 nm) light and visually observing the emitted green (500 nm) light using a luminescent filter.

  Histology injected stock reagent solution (0.5 mL) into full thickness porcine skin at various levels (epidermis, dermis, and subcutaneous tissue) using 1.0 mL syringe and 30 gauge, 0.5 inch needle Was done by Needle depth was visualized along the edge of the porcine tissue for the purpose of saturating the target tissue. After 1 hour incubation with PBS at 37 ° C., multiple 5.0 mm biopsy specimens were obtained from the injected site and each condition was performed in triplicate. Tissues were fixed in formaldehyde, embedded in paraffin, and stained with hematoxylin-eosin. The specimens were evaluated by a board-certified dermatopathologist who was not informed of the treatment protocol.

  Fresh porcine skin was used to determine whether the effects of these surfactant substances on cultured cells were similar in tissues. FIG. 3a shows dark purple pigment production (representing live cells) in adipose tissue treated with PBS buffer (negative control) using the MTS assay. A 5% solution of PBF and deoxycholate and Triton surfactant (positive control) showed a comparable decrease in purple pigment (indicating cell death) in the treated fat specimens. The difference in adipocyte viability between solutions was quantified by measuring the absorbance (at 490) of the supernatant collected from the treated fat specimens (Figure 3b). All reagents had a significant effect on fresh tissue adipocyte viability.

  Cell lysis was confirmed using a calcein dye release assay. Calcein becomes fluorescent after hydrolysis and is retained in cells with intact cell membranes. Since dead cells are not labeled and are lost under conditions that cause cell lysis, a decrease in green fluorescence in adipose tissue samples filled with the dye calcein indicates cell lysis (FIG. 4). Samples treated with deoxycholate, PBF, and Triton surfactant (positive control) showed similar fluorescence reduction.

  The histological changes resulting from injection of PBF, deoxycholate, and Empigen are shown in FIG. Phosphatidylcholine bile salt formulations (Figure 5b) and deoxycholate (Figure 5d) are caused by two well-characterized experimental surfactants, Empigen (Figure 5g) and Triton (not shown) Produced similar histological effects. These changes were evident in both fat and muscle. After injection of both PBF (FIG. 5b) and deoxycholate (FIG. 5d), significant blurring and lysis of adipocyte cell membranes with disruption of normal lobule structures was seen. FIG. 5f shows muscle fiber disruption and atrophy after PBF injection. Similar changes in muscle tissue were seen in specimens treated with deoxycholate and Triton and Empigen surfactants. There was no change in the epidermis, dermis, or appendage structure after reagent injection, except for Empigen, which caused a decrease in fibroblast nuclear staining and hyalinization of cutaneous collagen. Furthermore, clinical reports reveal that an active inflammatory response such as erythema or edema occurs after injection with a surfactant. Repeated inflammation can potentially lead to fibrosis, especially after multiple injections. Fibrosis has been reported in several patients who developed tight nodules at the site of injection after administration of PBF, which was eventually divided over several months.

  Histological findings indicate that injectable PBF and deoxycholate alone cause structural destruction in fat and muscle, but have no apparent effect on the epidermis, dermis or appendages (Figure 5) . However, Empigen BB, a powerful experimental surfactant, had a profound histological effect on skin collagen (connective tissue). Alternatively, fat and muscle can be more sensitive to surfactant treatment than these other structures at the concentrations tested (similar to those used in clinical practice).

  Through a series of laboratory experiments utilizing fresh tissue specimens and cell cultures, it has been shown that PBF commonly used in subcutaneous injection for lipolysis works primarily by causing non-specific lysis of cell membranes. Cell membranes are a constituent of all tissue types; in particular, we have shown that these surfactants cause fat, muscle, and connective tissue solubilization. As such, sodium deoxycholate, the bile salt component of the formulations used to dissolve phosphatidylcholine, was the main active ingredient in these prior art formulations. This conclusion is supported by the fact that pharmacologically active surfactants such as bile salts are potent solubilizers of cell membranes.

Example 4
Clinical experience with sodium deoxycholate composition Lipoma, a patient with a collection of benign isolated adipose tissue, was injected directly into the lipoma with a sodium deoxycholate (DC) solution without phosphatidylcholine. The results of this study show that the surfactant effect of deoxycholate seen with fat in animal tissues is clinically reproducible in humans. All injected lipomas decreased in size after at least one treatment with various concentrations of deoxycholate (Table 3). A lipoma from one patient injected with 1% DC was removed after treatment for pathological and histological analysis. Among the excised lipomas, necrosis is with a well-defined range of bleeding and necrosis at the end of the side that extends into the middle of the lipoma fat, which contrasts with the brighter normal lipoma fat in color, Roughly seen (Figure 6a). Histological analysis (Figure 6b) reveals a well-defined bleeding range and a significant inflammatory response in contrast to necrotic fat and adjacent normal circular clear adipocytes.

Table 3. Reduction in lipoma size after DC treatment

Example 5
Treatment of lipodystrophy in HIV patients with sodium deoxycholate composition Having a symmetrical fat deposit on the ventral face of the master muscle (to speak, the mouth of a chipmunk on the cheek) HIV lipodystrophic patients were injected with 1% deoxycholate. At 1 month follow-up, there was a 50% clear decrease in deposit volume on both sides. The results of this study indicate that the effects of deoxycholate seen with fat in animal tissues are clinically reproducible in humans.

Example 6
Effects of sodium deoxycholate and sodium deoxycholate-phosphatidylcholine solution on melanocytes
On 96-well dishes, melanocytes in melanocyte medium differentiated in a week in a humidified 5% CO ₂ incubator at 37 ° C. The medium was aspirated and washed once with 1 × PBS. Cells were treated with different concentrations of DC (0-0.5%) with or without 1% PC in 1 × PBS. Each treatment was done in triplicate (Table 4). Plates were incubated at 37 ° C. for 30 minutes in a humidified 5% CO ₂ incubator. Incubated plates were aspirated and washed with 1 × PBS.

  10 mL of MTS (3- (4,5-dimethyl-2-yl) -5- (3-carboxymethoxyphenyl) -2- (4-sulfophenyl) -2H-tetrazolium, inner salt) assay solution prepared (Mixed with 40 uL of MTS (Promega, Madison WI) per 1 × Mel PBS). 100 ul of MTS solution was added to each well of the plate. The plate was incubated for 120 minutes in a 37 ° C. incubator (unhumidified). The OD value was obtained at 490 nm using a spectrophotometer.

  FIG. 7 shows melanocyte survival in sodium deoxycholate solution and sodium deoxycholate solution with 1% phosphatidylcholine. A375P is a melanoma cell line (P represents low metastatic potential). On the y-axis, 1 represents 100% survival when no DC is added. All% concentrations are w / v%. The LD50 of sodium deoxycholate solution alone (the concentration at which 50% adipocytes die) for the melanocyte cell line was found to be about 0.04% sodium deoxycholate. Addition of sodium deoxycholate solution with 1% phosphatidylcholine increases LD50 by 5-6 fold.

  The results of this study show that the addition of 1% phosphatidylcholine inhibits apoptosis in vitro, i.e., the presence of PC makes DC 5 times more difficult to kill melanocytes, and PC is a cell of DC Indicates that the killing ability is impaired and, therefore, not enhanced.

Table 4: Melanocytes after treatment with DC only and DC + 1% PC

Example 7
Effects of sodium deoxycholate and sodium deoxycholate-phosphatidylcholine solution on adipocytes
On 96-well dishes, adipocytes in adipocyte medium were differentiated at 37 ° C. in a humidified 5% CO ₂ incubator for 1 week. The medium was aspirated and washed once with 1 × PBS. Cells were treated with different concentrations of DC (0-0.5%) with or without 1% PC in 1 × PBS. Each treatment was done in triplicate (Table 5). Plates were incubated at 37 ° C. for 30 minutes in a humidified 5% CO ₂ incubator. Incubated plates were aspirated and washed with 1 × PBS.

  10 mL of MTS (3- (4,5-dimethyl-2-yl) -5- (3-carboxymethoxyphenyl) -2- (4-sulfophenyl) -2H-tetrazolium, inner salt) assay solution prepared (40 uL of MTS (Promega, Madison WI) was mixed per 1 mL of 1 × PBS). 100 ul of MTS solution was added to each well of the plate. The plate was incubated for 120 minutes in a 37 ° C. incubator (unhumidified). The OD value was obtained at 490 nm using a spectrophotometer.

  FIG. 8 shows adipocyte survival in sodium deoxycholate solution and sodium deoxycholate solution with 1% phosphatidylcholine. Adipocytes are primary (ie, freshly harvested) adipocytes that have been cultured in vitro and matured prior to treatment with DC. On the y-axis, 1 represents 100% survival when no DC is added. All% concentrations are w / v%. The LD50 of sodium deoxycholate solution alone (concentration at which 50% fat cells die) for the adipocyte cell line was found to be about 0.02% sodium deoxycholate. Addition of sodium deoxycholate solution with 1% phosphatidylcholine increases LD50 by 5-6 fold.

  The results of this study show that the addition of 1% phosphatidylcholine inhibits apoptosis in vitro, i.e., the presence of PC makes DC 5 times more difficult to kill adipocytes, and PC has fat in DC Shows that it impairs and therefore does not enhance cell killing ability.

Table 5: Adipocytes after treatment with DC only and DC + 1% PC

Example 8
Effect of Addition of Phosphatidylcholine to 4.75% Sodium Deoxycholate on Viable Adipocytes FIG. 9 shows adipocyte survival when phosphatidylcholine is added to a 4.75% sodium deoxycholate solution. On the y-axis, 1 represents 100% survival. All% concentrations are w / v%. Cell survival in the absence of DC and PC averages 0.113.

  The result of this study is that deoxycholate is both necessary and sufficient to mediate 100% lipolysis of cultured adipocytes, so the addition of phosphatidylcholine to sodium deoxycholate solution does not necessarily reduce lipolysis in vitro. Indicates no contribution. Furthermore, a thorough discussion of these data (Table 6) shows that 5% of phosphatidylcholine actually slightly inhibits lipolysis, which indicates that the 5-50 in LD50 given by the addition of phosphatidylcholine. From the point of view of a 6-fold increase (as shown in Example 7), it is not surprising. These data collectively support the concept that sodium deoxycholate is an active ingredient for lipolysis and phosphatidylcholine is not only unnecessary, but actually inhibits fat removal.

(Table 6) Adipocytes after addition of PC to 4.75% DC

Example 9
Inhibition experiments of lipolysis by preincubation with human lipoma fat were performed on a series of immortalized melanocyte cell lines. The excised human lipoma was ground and the medium containing DC was mixed with human fat and stirred for 24 hours. The material was centrifuged to pellet the insoluble content. The supernatant was then added on top of the cultured melanocytes. The control was medium containing the same DC that was not exposed to the fat mass. Fat alone (no medium) was also added as a control.

  FIG. 10 shows that preincubation with 0.1% DC fat (Table 7) appears to reduce killing. It may be due to releasing some form of inhibitor (eg, Example 7 shows that PC inhibits killing of DC in vitro) or into fat pellets removed in centrifugation This may be due to DC being retained. However, it is clear in this experiment that the presence of fat limits the killing properties of DC, possibly by direct inhibition (like PC) or sequestration (ie into fat pellets). This may further explain the observation that injection of DC into fat leaves the surrounding tissue.

TABLE 7 Inhibition of lipolysis by preincubation with human lipoma fat

Example 10
Human lipoma study using sodium deoxycholate composition
Six patients with 12 lipomas were injected with sodium deoxycholate (DC) solution over a period of 6 months. All injected lipomas decreased in size after at least one treatment (Table 8). Measurements were made by physical measurements and ultrasound imaging. The results of this study show that the deoxycholate surfactant effect seen in fat in animal tissues is clinically reproducible in humans and that there is a significant reduction in the size of lipomas after treatment. Show.

Table 8: Human lipoma study using sodium deoxycholate composition

  Unless otherwise indicated, all numbers used in the specification and claims to indicate the amount of a component, characteristics such as molecular weight, reaction conditions, etc. are referred to in all examples by the term “about”. It should be understood as being modified. Accordingly, unless indicated otherwise, the numerical parameters set forth in the following specification and attached claims are approximate numbers that may vary depending on the desired properties sought to be obtained by the present invention. It is. At least, and not as an attempt to limit the application of equivalent doctrines to claims, each numeric parameter takes into account at least the number of significant digits reported, and Should be interpreted by applying normal error adjustment techniques. Although the numerical ranges and parameters representing the broad range of the present invention are approximate, the absolute size sizes (cm) indicated in the specific examples are reported as accurately as possible. Any absolute value, however, inherently contains certain errors necessarily resulting from the standard deviation found in their respective test measurements.

  The terms “a” and “an” and “the” and like indicators used in the context of describing the present invention (especially in the context of the appended claims) are used herein in other ways. It should be construed to encompass both the singular and plural unless specifically indicated otherwise or by the context. The citation of a range of values herein is merely intended to serve as a shorthand for referring individually to each discrete value contained within the range. Unless otherwise indicated herein, each individual value is incorporated herein as if it were individually recited herein. All methods described herein can be performed in any suitable order unless otherwise indicated herein or otherwise clearly contradicted by context. The use of any and all examples or exemplary language (eg, “like”) provided herein is merely intended to better clarify the invention, No limitation is presented with respect to the scope of the present invention claimed in this manner. No language in the specification should be construed as indicating any non-claimed element essential to the practice of the invention.

  Groupings of alternative elements and embodiments of the invention disclosed herein are not to be construed as limitations. Each group part may be referred to and claimed individually or in any combination with other parts of the group or other elements found herein. One or more parts of the group may be included in the group or deleted from the group for convenience and / or patentability reasons. When any such inclusion or deletion occurs, the specification shall include the modified group and thus meet the description requirements of all Markush groups used in the appended claims. Think in the book.

  Preferred embodiments of this invention are described herein, including the best mode known to the inventors for carrying out the invention. Of course, variations on the preferred embodiments will become apparent to those skilled in the art upon reading the foregoing description. The inventor expects those skilled in the art to properly use such variants, and the inventor believes that the present invention is a different method than that specifically described herein. Is intended to be implemented in Accordingly, this invention includes all modifications and equivalents of the subject matter recited in the claims appended hereto as permitted by applicable law. In addition, any combination of the above-described elements in all possible variations thereof is herein intended unless otherwise indicated herein or otherwise clearly contradicted by context. Is included.

  Furthermore, numerous references have been made to patents and printed publications throughout this specification. Each reference and printed publication cited above is individually incorporated herein by reference in its entirety.

  In conclusion, it is to be understood that the embodiments of the invention disclosed herein are illustrative of the principles of the present invention. Other modifications that may be used are within the scope of the invention. Accordingly, alternative arrangements of the present invention may be utilized in accordance with the disclosure herein by way of example and not limitation. Accordingly, the present invention is not limited to that precisely as shown and described.

Claims (52)

Pharmaceutical solutions for subcutaneous injection, including:
A pharmaceutically effective amount of bile acids or salts thereof;
A pharmaceutical excipient; and
Optionally, lipids,
Here, the ratio of lipid to bile acid or bile salt is less than 1% w / w and the solution does not contain lipase or co-lipase.   2. The solution according to claim 1, wherein the solution further comprises a second therapeutic agent selected from the group consisting of: an antimicrobial agent, a vasoconstrictor, an antithrombotic agent, an anticoagulant, a foam inhibitor, and an antiinflammatory agent. Analgesics, dispersants, antidispersants, penetration enhancers, steroids, tranquilizers, muscle relaxants, and antidiarrheal agents.   2. The solution of claim 1, wherein the solution is in a container containing up to 500 mL of solution.   The solution according to claim 1, wherein the bile acid is selected from the group consisting of: deoxycholic acid, cholic acid, chenodeoxycholic acid, 7-α-dehydroxylate chenodeoxycholic acid, lithocholic acid, ursodeoxycholic acid, dihydroxytaurine Acid, trihydroxytauric acid, and any of the above glycine conjugates. Bile salts are sodium (Na ⁺ ), potassium (K ⁺ ), lithium (Li ⁺ ), magnesium (Mg ²⁺ ), calcium (Ca ²⁺ ), barium (Ba ²⁺ ), strontium (Sr ²⁺ ) And a cation selected from the group consisting of ammonium (NH ⁴⁺ ).   2. The solution according to claim 1, wherein the bile salt contains an alkali metal or an alkaline earth metal. The solution according to claim 6, wherein the alkali metal is selected from the group consisting of alkali metals that are sodium (Na ⁺ ), potassium (K ⁺ ), and lithium (Li ⁺ ). The solution according to claim 6, wherein the alkaline earth metal is selected from the group consisting of magnesium (Mg ²⁺ ), calcium (Ca ²⁺ ), barium (Ba ²⁺ ), and strontium (Sr ²⁺ ).   2. The solution according to claim 1, wherein the bile salt is sodium deoxycholate.   2. The solution of claim 1 comprising up to 5% w / w lipid.   2. The solution according to claim 1, wherein the lipid is phosphatidylcholine.   The solution of claim 1, wherein the bile acid or bile salt is at a concentration of about 0.001% w / w to about 10% w / w.   2. The solution of claim 1, wherein the bile acid or salt thereof is at a concentration of about 0.01% w / w to about 5% w / w.   2. The solution of claim 1, which is aqueous.   2. The solution of claim 1, wherein the pharmaceutically effective amount is effective for fat dissolution and skin tightening. A method for reducing the appearance of skin conditions in a subject's skin area comprising the following steps:
Topically administering to the skin area a composition comprising:
(I) at least one bile acid or bile salt in an amount effective to tighten the skin,
(Ii) a pharmaceutical excipient, and (iii) optionally a lipid.   17. The method of claim 16, wherein the administering comprises delivering the composition via subcutaneous or transdermal injection.   17. The method of claim 16, wherein administering comprises delivering the composition via a skin patch, pump, or subcutaneous depot.   17. The method of claim 16, wherein the administering comprises delivering the composition locally or subcutaneously.   17. The method of claim 16, wherein the skin condition is selected from the group consisting of: flaccid skin, skin aging, skin irregularities, and wrinkles.   17. The method of claim 16, wherein the skin area is under the eyes, under the chin, under the arms, buttocks, cheeks, forehead, calf, back, thighs, ankles, or abdomen.   17. The method of claim 16, wherein the bile acid is deoxycholic acid.   17. The method of claim 16, wherein the bile salt is sodium deoxycholate.   17. The method of claim 16, wherein the bile salt is sodium deoxycholate and up to 5% w / w.   17. The method of claim 16, wherein the ratio of lipid and bile acid or bile salt is up to 1% w / w.   17. The method of claim 16, wherein the lipid is phosphatidylcholine.   17. A method according to claim 16, wherein the lipid is phosphatidylcholine and up to 5% w / w.   17. A method according to claim 16, wherein the composition is an aqueous solution.   19. The method of claim 18, wherein the aqueous solution has a total volume up to 500 mL. A method for reducing subcutaneous fat deposits in a subject comprising the following steps:
Topically administering to the subcutaneous fat deposit a composition comprising:
(I) one or more bile acids or bile salts in an amount effective to dissolve fat;
(Ii) a pharmaceutical or veterinary excipient; and (iii) optionally a lipid,
Here, the ratio of lipid to bile acid or bile salt is up to 1% w / w and the composition does not contain lipase or co-lipase.   The conditions are obesity, fat redistribution syndrome, eyelid fat hernia, lipoma, Durham's disease, lipodystrophy, buffalo aneurysm lipodystrophy, dorsal neck fat, visceral obesity, breast augmentation, adiposity 32. The method of claim 30, wherein the method is selected from the group consisting of: diffused body fat around the trunk and arms, and fat deposits associated with cellulite.   Bile acids are deoxycholic acid, cholic acid, chenodeoxycholic acid, 7-α-dehydroxylate chenodeoxycholic acid, lithocholic acid, ursodeoxycholic acid, dihydroxytauric acid, trihydroxytauric acid, and any of the above glycine conjugates 32. The method of claim 30, wherein the method is selected from the group consisting of: Bile salts are sodium (Na ⁺ ), potassium (K ⁺ ), lithium (Li ⁺ ), magnesium (Mg ²⁺ ), calcium (Ca ²⁺ ), barium (Ba ²⁺ ), strontium (Sr ²⁺ ) ^32. The method of claim 30, comprising a cation selected from the group consisting of: and ammonium (NH ⁴⁺ ).   32. The method of claim 30, wherein the bile salt comprises an alkali metal or an alkaline earth metal. 35. The method of claim 34, wherein the alkali metal is sodium (Na ⁺ ), potassium (K ⁺ ), or lithium (Li ⁺ ). 35. The method of claim 34, wherein the alkaline earth metal is magnesium (Mg ²⁺ ), calcium (Ca ²⁺ ), barium (Ba ²⁺ ), or strontium (Sr ²⁺ ).   32. The method of claim 30, wherein the bile salt is sodium deoxycholate.   32. The method of claim 30, wherein the method does not include performing a procedure on the subject.   31. The method of claim 30, wherein the composition is administered topically under the subject's eyes, under the chin, under the arm, buttocks, calves, back, thigh, or abdomen.   32. The method of claim 30, wherein the step of administering is by subcutaneous or transdermal injection.   32. The method of claim 30, wherein the subject is a human, a cat, a dog, or a horse.   32. The method of claim 30, wherein the subject is a human HIV patient.   32. The method of claim 30, wherein the composition comprises up to 5% w / w lipid.   32. The method of claim 30, wherein the lipid is phosphatidylcholine and the composition comprises up to 5% w / w of the lipid.   32. The method of claim 30, wherein the composition comprises from about 0.001% w / w to about 10% w / w bile acid or bile salt.   32. The method of claim 30, wherein the composition comprises between about 0.01% w / w and about 5% w / w bile acids or bile salts.   32. The method of claim 30, wherein the composition is in solution.   48. The method of claim 47, wherein the solution is aqueous. A container that can be equipped with a syringe, including:
An amount of bile acid or bile salt effective to dissolve fat or tighten skin;
A pharmaceutical or veterinary excipient; and optionally a lipid,
Here, the ratio of the bile acid or bile salt to the lipid is greater than 1% w / w and the solution does not contain lipase or co-lipase.   48. A container in which a syringe can be mounted according to claim 47, wherein the bile salt is sodium deoxycholate.   48. A container in which the syringe of claim 47 further comprising an organic solvent.   48. A container capable of carrying a syringe according to claim 47, comprising up to 10 g of bile acid or bile salt.

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