WO2012071480A2 - Lipophilic glucocorticosteroid monotherapeutic formulations and methods for the cosmetic treatment of adiposity and contour bulging - Google Patents

Abstract

sProvided herein are pharmaceutical and cosmetic formulations and methods for regional adiposity reduction, and aesthetic treatment of contour defects such as abdominal bulging; comprising an injectable formulation comprising: (a) active ingredient that consists essentially of an adipose tissue-reducing amount of one or more lipophilic glucocorticosteroids, or salts, solvates, or polymorphs thereof; and (b) one or more subcutaneously acceptable inactive ingredients.

Description

LIPOPHILIC GLUCOCORTICOSTEROID MONOTHERAPEUTIC FORMULATIONS AND METHODS FOR THE COSMETIC TREATMENT OF ADIPOSITY AND

CONTOUR BULGING

CROSS-REFERENCE

[0001] This patent application claims the benefit of U.S. Provisional Application Ser. No. 61/417,092 filed November 24, 2010, which is incorporated by reference herein in its entirety.

BACKGROUND OF THE INVENTION

[0002] Cosmetics are substances used to enhance the appearance of the human body.

Traditionally, cosmetics have included skin-care creams, lotions, powders, perfumes, lipsticks, nail polish, eye and facial makeup, and so forth. The United States Food and Drug

Administration (the FDA), which regulates cosmetics in the United States, broadly views a cosmetic as a substance that is intended to be applied to the human body for cleansing, beautifying, promoting attractiveness, or altering the appearance without significantly affecting the body's structure or functions.

[0003] Accumulation of fat stores in humans can occur unevenly in the body, which to certain individuals is considered to be a cosmetic blemish. For example, some persons may accumulate fat predominantly in visceral areas while others predominately in the subcutaneous tissue.

Gender differences may also be apparent with women accumulating fat in the thighs and lateral buttocks and males in the waist. Women may accumulate fatty deposits of the thighs, which have a rumpled or "peau d'orange" appearance, resulting in a condition referred to as cellulite. Cellulite may be related to skin architecture which allows subdermal fat herniation, sometimes referred to as adipose papillae.

SUMMARY OF THE INVENTION

[0004] The present subject matter was conceived, at least in part, upon the discovery that lipophilic glucocorticosteroids when subcutaneously injected as a monotherapy provide a reduction in subcutaneous adiposity in humans. Accordingly, the subject matter described herein provides cosmetic and pharmaceutical monotherapy formulations for the reduction of adiposity. Specifically, described herein are subcutaneous and transcutaneous pharmaceutical and cosmetic monotherapy formulations and methods of treatment for regional adiposity. Also provided herein are pharmaceutical and/or cosmetic formulations for, in certain situations, reducing regional fat deposits in a subject, as well as other cosmetic and pharmaceutical indications.

[0005] In one aspect, provided herein are injectable formulations for regional adiposity reduction comprising: (a) active ingredient that consists essentially of an adipose tissue-reducing amount of one or more lipophilic glucocorticosteroids, or salts, solvates, or polymorphs thereof; and (b) one or more subcutaneously acceptable inactive ingredients. In another aspect, provided herein are cosmetic methods for reducing adiposity in a human patient comprising

subcutaneously administering a pharmaceutical formulation suitable for subcutaneous injection comprising: (a) active ingredient that consists essentially of an adipose tissue-reducing amount of one or more lipophilic glucocorticosteroids, or salts, solvates, or polymorphs thereof; and (b) one or more subcutaneously acceptable inactive ingredients. In another aspect, provided herein are cosmetic methods for inducing lipo lysis in a human patient comprising subcutaneously administering a pharmaceutical formulation suitable for subcutaneous injection comprising: (a) active ingredient that consists essentially of an adipose tissue-reducing amount of one or more lipophilic glucocorticosteroids, or salts, solvates, or polymorphs thereof; and (b) one or more subcutaneously acceptable inactive ingredients. In a further aspect, provided herein is a method for the aesthetic treatment of body contour defects such as abdominal bulging in a human patient comprising subcutaneously administering a formulation suitable for subcutaneous injection comprising: (a) active ingredient that consists essentially of an adipose tissue-reducing amount of one or more lipophilic glucocorticosteroids, or salts, solvates, or polymorphs thereof; and (b) one or more subcutaneously acceptable inactive ingredients. In an aspect provided is a method for aesthetic treatment of cheek contour defect in a human patient by contacting a targeted fat deposit in the cheek with a composition comprising: (a) active ingredient that consists essentially of an adipose tissue-reducing amount of one or more lipophilic glucocorticosteroids, or salts, solvates, or polymorphs thereof; and (b) one or more subcutaneously acceptable inactive ingredients. In another aspect, provided herein are compositions, formulations, methods, and systems for treating thyroid eye disease by contacting a targeted fat deposit in the eye with a composition comprising: (a) active ingredient that consists essentially of an adipose tissue- reducing amount of one or more lipophilic glucocorticosteroids, or salts, solvates, or polymorphs thereof; and (b) one or more subcutaneously acceptable inactive ingredients. BRIEF DESCRIPTION OF THE FIGURES

[0006] Figure 1 illustrates effects of fluticasone propionate on change in inguinal fat pad weight (AIFP) (% reduction; mean ± SEM) following SC injection into the fat pad.

DETAILED DESCRIPTION OF THE INVENTION

[0007] Adipose tissue is the primary energy storage tissue of the body. Fat cells, or adipocytes, store this energy in the form of triglycerides. Triglycerides are mobilized from fat stores to provide caloric energy to the body through hormonal induction of triglyceride hydrolysis. This process releases free or non-esterified fatty acids and glycerol into the blood for use by other body tissues. The breakdown of triglycerides from fat store is referred to as lipo lysis. Growth of new adipocytes also occurs, which is referred to as adipogenesis.

[0008] Lipophilic glucocorticosteroids, such as budesonide, fluticasone, and others, when administered subcutaneously as a monotherapy, reduce regional fat deposits or adipose tissue by binding to the glucocorticosteroid receptors in the adipose tissue. Without being limited by theory, it is believed that the binding of the lipophilic glucocorticosteroids to the

glucocorticosteroid receptors in adipose tissue inhibits glucose uptake, resulting in lipo lysis of the adipose tissue and in turn a reduction in regional adiposity. Administration of

glucocorticosteroids, however, can cause serious adverse side-effects when systemically contacted with glucocorticosteroid receptors which are located ubiquitously throughout human cells. These serious side-effects include, for example, immunosuppression, hyperglycemia, skin fragility and proneness to bruising, negative calcium imbalance, steroid-induced osteoporosis (and subsequent reduced bone density), weight gain, adrenal insufficiency, muscle breakdown, expansion of malar fat pads, irregularity of menstrual cycles of women, growth failure, increased plasma amino acid count, increased urea formation, negative nitrogen balance, central nervous system effects, glaucoma, and cataracts. The subcutaneous administration and the lipophilicity of the glucocorticosteroids described herein reduce the patient's exposure to systemic side- effects. One possible reason for this result is that the lipophilic nature of glucocorticosteroids allows selective partitioning into the adipose tissue relative to blood plasma. Thus, the lipophilicity of the glucocorticosteroid contributes, at least in part, to providing relatively low levels of the active ingredient systemically. Indeed, the formulations described herein are prepared to be administered subcutaneously or transcutaneously, and not systemically.

Accordingly, the formulations and methods of treatment described herein are designed to reduce subcutaneous adipose tissue which is distinct from visceral (systemic) fat. Glossary of Certain Terminology

[0009] A "therapeutically effective amount," as used herein, refers to a sufficient amount of an agent (e.g., a glucocorticosteroid) which will relieve to some extent one or more of the symptoms of the disease or condition being treated. The result can be reduction and/or alleviation of the signs, symptoms, or causes of a disease, or any other desired alteration of a biological system.

[0010] "Cosmetically effective" as used herein, refers to a sufficient amount of an agent (e.g., a lipophilic glucocorticosteroid) which will improve the cosmetic appearance at the localized site of treatment. It is to be understood that a "cosmetically effective" amount can vary from subject to subject, due to numerous factors including for example age, weight, general condition of the subject, the condition being treated, the severity of the condition being treated, and the judgment of the prescribing physician.

[0011] As used herein, an "aesthetic treatment" or "cosmetic treatment" refers to any treatment carried out for the purposes of improving the visual appearance. A method for aesthetic treatment refers to a method of improving the visual appearance at the localized site of treatment by providing an effective amount of an agent (e.g., a lipophilic glucocorticosteroid) which will improve the cosmetic appearance at the localized site of treatment. As used herein, the aesthetic treatment of a body contour defect refers to any treatment carried out to achieve a more natural or cosmetically desirable body shape.

[0012] As used herein an "adipose tissue-reducing" amount refers to a sufficient amount of the lipophilic glucocorticosteroid needed to reduce adipose tissue. It is to be understood that the amount sufficient to decrease the adipose tissue will vary from subject to subject due to variation in metabolism of the lipophilic glucocorticosteroid, with age, weight, general condition of the subject, the severity of the condition being treated, and the judgment of the prescribing physician.

[0013] As used herein, "Thyroid Eye Disease" or "Graves' Opthamolopathy" or "Thyroid- associated orbitopathy" or "Grave's orbitopathy" refers to an eye condition that is characterized by one or more of: swelling in the orbital tissues; protrusion of one or both eyeballs-also known as exophthalmos; proptosis, in which the eyes appear to bulge outward. Without being limited by theory, it is believed the clinical symptoms and signs of Thyroid Eye Disease can be explained mechanically by the increase in tissue volume evident within the bony orbit. The expanded orbital tissues cause forward displacement of the globe and impairment of venous and lymphatic outflow from the orbit. These changes, combined with the local production of cytokines and other mediators of inflammation, result in proptosis, periorbital edema, conjunctival erythema and/or chemosis.

[0014] A formulation that is "substantially free" of a specific compound or substance contains an amount that is equal to or less than a trace or therapeutically or cosmetically insignificant amount of the specific compound or substance. For example, a formulation that is "substantially free" of a lipophilic long-acting selective beta-2 adrenergic receptor agonist contains an amount that is equal to or less than a trace of therapeutically or cosmetically insignificant amount of lipophilic long-acting selective beta-2 adrenergic receptor agonists.

[0015] "Plasma concentration" refers to the concentration of a substance such as a therapeutic agent, in blood plasma of a subject. It is understood that the plasma concentration of a therapeutic agent may vary many-fold between subjects, due to variability with respect to metabolism of therapeutic agents. In accordance with one aspect, the plasma concentration of a lipophilic glucocorticosteroid varies from subject to subject. Likewise, in some embodiments, values such as maximum plasma concentration (C_max) or time to reach maximum plasma concentration (T_max), or total area under the plasma concentration time curve (AUC) varies from subject to subject. Due to this variability, the amount necessary to constitute "a therapeutically effective amount" of a glucocorticosteroid varies from subject to subject. It is understood that in some embodiments, when mean plasma concentrations are disclosed for a population of subjects, these mean values include substantial variation.

[0016] "Pharmacodynamics" refers to the factors that determine the biologic response observed relative to the concentration of drug at a site of action.

[0017] "Pharmacokinetics" refers to the factors that determine the attainment and maintenance of the appropriate concentration of drug at a site of action.

[0018] A "measurable plasma concentration" or "measurable plasma concentration" describes the blood plasma or blood plasma concentration, typically measured in mg, μg, or ng of therapeutic agent per mL, dL, or L of blood plasma, of a therapeutic agent that is absorbed into the bloodstream after administration. One in the field is familiar with measuring the plasma concentration or plasma concentration of a glucocorticosteroid.

[0019] A "treatment period" is defined as the period of time the patient is under a physician's care or direction, which may vary from patient to patient, and may be dependent on metabolism of the glucocorticosteroid administered to the patient, age, weight, general condition of the subject, the severity of the condition being treated, and the judgment of the prescribing physician. In some embodiments, the treatment period comprises between 1 week and 52 weeks, longer than 52 weeks, or any amounts of weeks between 1 and 52.

[0020] A "weekly dose" is the total amount of active ingredient administered to a patient during a single week. For example, in situations with more than a single administration occurs during a week, the weekly dose is the total amount of active ingredient provided to the patient in each administration that occurs during the week.

[0021] A "periodic dose" is the frequency at which a dose is administered to a patient during a period.

[0022] A "single session dose" is the total amount of active ingredient administered to a patient during a single visit for treatment by a healthcare professional or, in situations of self- administration, a single session dose is the total amount of active ingredient administered to the patient by self-administration in a single session.

[0023] In some embodiments, a single session dose is divided into smaller amounts and administered to a patient in one or more "sub-doses." In some embodiments, each "sub-dose" is subcutaneously delivered to a patient by injection, e.g., using a syringe or is administered to the patient transcutaneously.

[0024] The phrases "patient" and "subject" are used interchangeably herein. In some embodiments, the patient or subject is a human. In further or additional embodiments, the patient or subject is an animal. In some embodiments, the animal is a human, a common household pet, including for example a cat or a dog, or a species of the animal kingdom. In some embodiments, the patient is a non-murine animal.

Lipophilic Glucocorticosteroids

[0025] In one aspect, provided herein are pharmaceutical and/or cosmetic formulations suitable for subcutaneous or transcutaneous administration and methods of treatment comprising subcutaneously or transcutaneously administering to a patient a pharmaceutical and/or cosmetic formulation (including all of the methods of treatment described herein). In some embodiments, the pharmaceutical and/or cosmetic formulation comprises an injectable formulation for regional adiposity reduction consisting essentially of: (a) active ingredient that consists essentially of an adipose tissue-reducing amount of one or more lipophilic glucocorticosteroids, or salts, solvates, or polymorphs thereof; and (b) one or more subcutaneously acceptable inactive ingredients. In additional embodiments, provided herein is an injectable formulation for regional adiposity reduction consisting of: (a) active ingredient that consists essentially of an adipose tissue- reducing amount of one or more lipophilic glucocorticosteroids, or salts, solvates, or polymorphs thereof; and (b) one or more subcutaneously acceptable inactive ingredients. In further or additional embodiments, provided herein is an injectable formulation for regional adiposity reduction comprising: (a) active ingredient that consists essentially of an adipose tissue-reducing amount of one or more lipophilic glucocorticosteroids, or salts, solvates, or polymorphs thereof; and (b) one or more subcutaneously acceptable inactive ingredients.

[0026] Glucocorticosteroids are also referred herein as "anti-inflammatory steroids,"

"glucocorticosteroids," and/or "corticosteroids." It is believed that glucocorticosteroids increase lipolysis, adipogenesis inhibition, and/or regional fat reduction. Without being limited by theory, it is believed that the binding of the lipophilic glucocorticosteroids to the

glucocorticosteroid receptors in adipose tissue inhibits glucose uptake, resulting in lipolysis of the adipose tissue and in turn a reduction in regional adiposity. Moreover, the lipophilicity and subcutaneous mode of administration of the glucocorticosteroids described herein reduces the systemic side-effects incumbent with non-subcutaneous injection and non- lipophilic

glucocorticosteroids. In some embodiments, the lipophilic glucocorticosteroid is formulated to be suitable for subcutaneous administration. In further or additional embodiments, the lipophilic glucocorticosteroid is formulated suitable for transcutaneous administration.

[0027] In some embodiments, the cosmetic and/or pharmaceutical formulation comprises a lipophilic glucocorticosteroid, or a salt, optical isomer, racemate, solvate, or polymorph thereof. In certain embodiments, the glucorticosteroid is selected from fluticasone, mometasone, beclomethasone, triamcinolone, fluniolide, dexamethasone, ciclesonide, or budesonide, or a salt, optical isomer, racemate, solvate, or polymorph thereof.

[0028] In other embodiments, the glucocorticosteroid is fluticasone or a salt, optical isomer, racemate, solvate, or polymorph thereof. In specific embodiments, the lipophilic

glucocorticosteroid is fluticasone propionate. In yet another embodiment, the

glucocorticosteroid is fluticasone, or a salt, optical isomer, racemate, solvate, or polymorph thereof. In some embodiments, the glucocorticosteroid is fluticasone (shown below as compound 1), or its analogs, prodrugs, metabolites, and isomers thereof. In some embodiments, the lipophilic glucocorticosteroid is fluticasone propionate, fluticasone furoate, or any other salt form of fluticasone.

F

1

[0029] Without wishing to be bound by theory, it is believed that the subcutaneous

administration of these glucocorticosteroids have an efficacious and enhanced cosmetic effect in patients, by way of a non-limiting example, in improving the appearance of regional fat accumulations and cellulite.

[0030] In some embodiments, a particular dose is administered, for example by subcutaneous or transcutaneous injection, to areas of non- visceral fat deposits on a subject, including for example subcutaneous fat. In some embodiments for which the formulations described herein are useful include, but are not limited to, the inside region of the knees, the middle to upper area of the upper arm, including the tricep area, the submental area, including the area under the chin, for example the wattle (which is understood to refer to the fleshy fold of skin in the submental area of a patient), the abdomen, the hips, the inner thigh, the outer thigh, the buttocks, the lower back, an upper arm region of the patient, the upper back or the chest of the patient.

Dosing of Active Ingredients

[0031] Provided herein are pharmaceutical and/or cosmetic formulations that are suitable for subcutaneous or transcutaneous administration. In some embodiments, the pharmaceutical and/or cosmetic formulations provided herein are suitable for subcutaneous injection, and provide for a volume of up to about 20 mL (including, e.g., about 0.1 mL, about 0.3 mL, about 0.5 mL, about 0.7 mL, about 1.0 mL, about 1.1 mL, about 1.5 mL, about 2 mL, about 2.5 mL, about 3 mL, about 3.5 mL, about 4 mL, about 5 mL, about 6 mL, about 7 mL, about 8 mL, about 9 mL, or any other volume from about 0.1 mL to about 20 mL) of an excipient compatible with subcutaneous administration. In some embodiments, the volume for injection is provided in a range that is between about 0.1 mL to about 20 mL, about 0.2 mL to about 15 mL, about 0.3 mL to about 10 mL, about 0.4 mL to about 7 mL, about 0.5 mL to about 5 mL, about 0.6 mL to about 4 mL, about 0.7 mL to about 3 mL, about 0.8 mL to about 2 mL, or about 1 mL. In some embodiments, the excipient concentration is kept below 1% (e.g., about 0.05%, about 0.2%>, about 0.3%), about 0.4%>, about 0.5%>, about 0.6%>, about 0.8%>, or any other concentration from about 0.05% to less than about 1%. In specific embodiments, the excipient concentration is between about 0.01% to about 1%, about 0.05% to about 0.9%, about 0.2% to about 0.8%, about 0.3% to about 0.7%, about 0.4% to about 0.6%, or about 0.5%.

Periodic Dosing Schedule

[0032] Another aspect of the formulations and methods of treatment provided herein is a periodic dosing schedule. A periodic dose is the frequency at which a single session dose is administered to a patient during a period. For example, in some embodiments, the periodic dose is once per week, and hence in these situations a patient will receive a single session dose once per week. In further or additional embodiments, the periodic dose is 2-7 times per week

(including any interval between 2 and 7), 3-6 times per week (including any interval between 3 and 6), or 4-5 days per week. In some embodiments, the periodic dose is 1-4 times per month (including any interval between 1 and 4), 2-3 times per month, or once or twice per month. In some embodiments, the periodic dose is 1-52 times per year (including any interval between 1 and 52).

[0033] Because the single session doses provided herein are based on once per week dosing, in situations where the periodic dose is different than once per week, in certain situations the single session dose amount administered to the patient is normalized to account for this difference. For example, in some situations where the periodic dose is twice per week, the patient will receive the single session doses in two separate halves (that are about equal or unequal) during the week compared to what is provided herein. Similarly, in some situations where the periodic dose is seven times per week, the amount of active ingredient administered to the patient for each single session dose compared to what is provided herein is divided by seven. As another example, in certain situations where the periodic dose is once per month, the patient will receive a single session dose per month at four times the amount that is provided herein.

Session Dosing

[0034] An additional aspect of the formulations and methods of treatment provided herein is a single session dose. A single session dose is the total amount of active ingredient administered to a patient during a single visit for treatment by a healthcare professional or, in situations of self-administration, it is the amount of active ingredient administered to the patient by self- administration in a single session. The single session doses provided herein are based on a once per week periodic dose, and can be adjusted for a different periodic dose than once per week as provided herein.

[0035] Also provided herein, in further or additional embodiments, including certain methods of treatment comprising administration of the pharmaceutical and/or cosmetic formulations described herein, are pharmaceutical and/or cosmetic formulations wherein a lipophilic glucocorticosteroid is provided for in a single session dose that is less than about 250 μg of the glucocorticosteroid, or a salt, optical isomer, racemate, solvate, or polymorph thereof. In some embodiments, the glucocorticosteroid is fluticasone, or a salt, optical isomer, racemate, solvate, or polymorph thereof. In further embodiments, the glucocorticosteroid is fluticasone propionate or fluticasone furoate. In some embodiments, provided herein are pharmaceutical and/or cosmetic formulations comprising a weekly dose of fluticasone propionate that is between about 5 ng to about 250 μg. In a particular embodiment, provided herein are pharmaceutical and/or cosmetic formulations comprising a weekly dose of fluticasone propionate that is less than about 25 μg.

[0036] In certain embodiments, provided are pharmaceutical and/or cosmetic formulations that are formulated to provide a single session dose of fluticasone propionate between about 25 μg and about 5 ng. In some embodiments, the pharmaceutical and/or cosmetic formulations provided herein comprise a single session dose that is an amount of fluticasone that is equal to or less than about 25 μg (including, e.g., about 5 ng, about 50 ng, about 500 ng, about 1 μg, about 10 μg, about 25 μg, or any other amount between about 25 μg and about 5 ng).

[0037] In still further embodiments, provided are pharmaceutical and/or cosmetic formulations that are formulated to provide a daily dose of a lipophilic glucocorticosteroid. In some embodiments, a glucocorticosteroid to be administered is fluticasone and an adipose tissue- reducing amount of fluticasone to be administered is about 0.001 μg/day to about 1000 μg/day, e.g., about 0.1 μg/day to about 100 μg/day, about 1 μg/day to about 100 μg/day, about 10 μg/day to about 100 μg/day, about 50 μg/day to about 100 μg/day, or any other dose of fluticasone from about 0.001 μg/day to about 1000 μg/day.

[0038] In some embodiments, the lipophilic glucocorticosteroid to be subcutaneously or transcutaneously administered is fluticasone propionate and the therapeutically effective amount of fluticasone propionate is from about 0.05 μg/day to about 500 μg/day, e.g., about 0.05 μg/day to about 400 μg/day, about 0.1 μg/day to about 300 μg/day, about 0.05 μg/day to about 200 μg/day, about 1 μg/day to about 100 μg/day, about 2 μg/day to about 50 μg/day, about 3 μg/day to about 20 μg/day, about 4 μg/day to about 10 μg/day, about 5 μg/day to about 7 μg/day, about 1 μ /day to about 10 μ§^^ or about 2 μg/day to about 5 μ /day of fluticasone propionate, or any other dose of fluticasone propionate from about 0.05 μ /day to about 500 μ§^^ Other embodiments comprise the use of fluticasone or a salt, optical isomer, racemate, solvate or polymorph thereof, such as, by way of example only, the furoate salt of fluticasone. Still other embodiments comprise the fluticasone furoate subcutaneously or transcutaneously administered from about 0.05 μ /day to about 500 μg/day, e.g., about 0.05 μ /day to about 400 μg/day, about 0.1 μ /day to about 300 μ§^^ about 0.05 μ /day to about 200 μg/day, about 1 μg/day to about 100 μg/day, about 2 μg/day to about 50 μg/day, about 3 μ /day to about 20 μg/day, about 4 μ /day to about 10 μ§^^ about 5 μg/day to about 7 μg/day, about 1 μg/day to about 10 μ§^^ or about 2 μg/day to about 5 μ /day of fluticasone furoate, or any other dose of fluticasone furoate from about 0.05 μ /day to about 500 μ§^^ In some embodiments, the lipophilic glucocorticosteroid to be administered is fluticasone propionate and an adipose tissue- reducing amount of fluticasone propionate to be administered is a daily dose that provides less than about 250 μg per week. In some embodiments, the lipophilic glucocorticosteroid to be administered is fluticasone propionate and an adipose tissue-reducing amount of fluticasone propionate to be administered is a daily dose that provides less than about 25 μg per week.

Sub-dosing

[0039] In certain situations, the single session dose is administered to the patient in sub-doses (e.g., by subcutaneous injection, transcutaneous application, or otherwise). Accordingly, in another aspect, including certain methods of treatment comprising administration of the pharmaceutical and/or cosmetic formulations described herein, provided are pharmaceutical and/or cosmetic formulations wherein a lipophilic glucocorticosteroid is provided in at least two sub-doses. In some embodiments, all of the sub-doses are provided to a patient in a single session during a single week. In further or additional embodiments, including certain methods of treatment comprising administration of the pharmaceutical and/or cosmetic formulations described herein, provided are pharmaceutical and/or cosmetic formulations wherein a lipophilic glucocorticosteroid is provided in at least two sub-doses whereby all of the sub-doses are provided to a patient in a single session during a single week. In still further embodiments, at least at least two sub-doses are provided to a patient.

[0040] In some embodiments, one or more sub-dose is provided to a patient wherein each sub- dose is a single injection of a fluid comprising a lipophilic glucocorticosteroid. For example, in some embodiments, provided herein are pharmaceutical and/or cosmetic formulations and methods of treatment comprising administration of a pharmaceutical and/or cosmetic formulation wherein a lipophilic glucocorticosteroid is provided to a patient in about a single sub-dose, at least about two sub-doses, at least about three sub-doses, at least about four sub- doses, at least about five sub-doses, at least about six sub-doses, at least about seven sub-doses, at least about eight sub-doses, at least about nine sub-doses, at least about 10 sub-doses, at least about 11 sub-doses, at least about 12 sub-doses, at least about 13 sub-doses, at least about 14 sub-doses, at least about 15 sub-doses, at least about 16 sub-doses, at least about 17 sub-doses, at least about 18 sub-doses, at least about 19 sub-doses, at least about 20 sub-doses, at least about 21 sub-doses, at least about 22 sub-doses, at least about 23 sub-doses, at least about 24 sub-doses, at least about 25 sub-doses, at least about 26 sub-doses, at least about 27 sub-doses, at least about 28 sub-doses, at least about 29 sub-doses, at least about 30 sub-doses, at least about 31 sub-doses, at least about 32 sub-doses, at least about 33 sub-doses, at least about 34 sub-doses, at least about 35 sub-doses, or more than about 35 sub-doses. In further or additional embodiments, a lipophilic glucocorticosteroid is provided to a patient in about a 1 to about 35 sub-doses, about 2 to about 32 sub-doses, in about 3 to about 30 sub-doses, in about 5 to about 28 sub-doses, in about 7 to about 27 sub-doses, in about 9 to about 26 sub-doses, in about 11 to about 25 sub-doses, in about 12 to about 24 sub-doses, in about 14 to about 23 sub-doses, in about 16 to about 22 sub-doses, in about 17 to about 21 sub-doses, or in about 18 to about 20 sub-doses.

[0041] Also provided herein, in further or additional embodiments, including certain methods of treatment comprising administration of the pharmaceutical and/or cosmetic formulations described herein, are pharmaceutical and/or cosmetic formulations wherein a glucocorticosteroid is formulated to be administered to a patient in a sub-dose that is between about 25 μg and about 5 ng. In some embodiments, the glucocorticosteroid is fluticasone, or a salt, optical isomer, racemate, solvate, or polymorph thereof. In further embodiments, the glucocorticosteroid is fluticasone propionate or fluticasone furoate.

[0042] In certain embodiments, provided are pharmaceutical and/or cosmetic formulations that are formulated to provide a sub-dose of fluticasone propionate that is equal to or less than about 25 μg (including, e.g., about 5 ng, about 50 ng, about 500 ng, about 1 μg, about 10 μg, about 25 μg, or any other amount between about 25 μg and about 5 ng).

[0043] Appropriate tissue concentrations of glucocorticosteroids used for the therapeutic methods described herein range from about 0.001 μΜ to about 5 μΜ, e.g., from about 1.0 μΜ to about 5 μΜ, from about 0.1 μΜ to about 2 μΜ, from about 0.1 μΜ to about 1 mM, from about 0.01 μΜ to about 0.1 μΜ or any other tissue concentration of the glucocorticosteroid from about 0.001 μΜ ίο about 5 μΜ.

Pharmacokinetic Parameters

[0044] In one embodiment, the pharmaceutical and/or cosmetic formulation further comprises a glucocorticosteroid or a salt, optical isomer, racemate, solvate, or polymorph thereof. In another embodiment, the glucocorticosteroid is fluticasone or a pharmaceutically acceptable salt, optical isomer, racemate, solvate, or polymorph thereof. In a further embodiment, the

glucocorticosteroid is fluticasone propionate. In yet another embodiment, the

glucocorticosteroid is fluticasone furoate. In one embodiment, the formulation provides a mean plasma fluticasone C_max of about 1 to about 200 pg/mL. In a further embodiment, the formulation provides a mean plasma fluticasone propionate C_max of about 1 to about 200 pg/mL. In yet a further embodiment, the mean plasma fluticasone propionate C_max is about 175, about 150, about 125, about 100 about 90, about 80, about 70, about 60, about 50, about 40, about 30, about 20, about 10, about 3 pg/mL, about 1 pg/mL, or is undetectable using conventional methodology. For purposes of this application, "undetectable using conventional methodology" or "undetectable using current methodology," means that the concentration is lower than the low limit of quantitation (LLOQ) using the Liquid Chromatography/Mass Spectrometry/Mass Spectrometry (LC/MS/MS) method, which is understood in the art to be a type of tandem mass spectrometry for determining C_max levels. In further or additional embodiments, the mean plasma fluticasone propionate C_max is between undetectable levels and about 200 pg/mL, about 1 pg/mL to about 180 pg/mL, about 5 pg/mL to about 170 pg/mL, about 10 pg/mL to about 150 pg/mL, about 15 pg/mL to about 130 pg/mL, about 25 pg/mL to about 110 pg/mL, about 50 pg/mL to about 100 pg/mL, or about 75 pg/mL to about 80 pg/mL.

Partitioning Into Adipose Tissue

[0045] It is believed that the lipophilicity of certain glucocorticosteroids, including but not limited to fluticasone and budesonide, enables the efficacious administration of these compounds without the substantial side-effects associated with systemic exposure to

glucocorticosteroids. Accordingly, in a further aspect, provided is a pharmaceutical and/or cosmetic formulation comprising an adipose tissue -reducing amount a fluticasone or budesonide (i.e., specific lipophilic glucocorticosteroids), or optical isomers, racemates, solvates, or polymorphs thereof and at least one subcutaneously acceptable inactive ingredient, wherein the formulation provides a fluticasone plasma C_max ratio of subcutaneous to intravenous

administration of between about 0.01 to about 0.4 when administered subcutaneously (also known as the "fluticasone partition" ratio). For purposes of this application, the ratio of plasma Cmax of a glucocorticosteroid administered subcutaneously to the plasma C_max of the same glucocorticosteroid administered intravenously is known as the "partition" ratio. In certain embodiments, the formulations described herein provide a partition ratio of the

glucocorticosteroid that is at least about four times lower than the partition ratio for budesonide. In further or additional embodiments, the formulations described herein provide a partition ratio for the glucocorticosteroid that is at least about two times lower than the partition ratio for budesonide. In still further embodiments, the formulations described herein provide a partition ratio for the glucocorticosteroid that is at least about 1.5 times lower than the partition ratio for budesonide.

[0046] In one embodiment, the partition ratio of fluticasone is about 0.01 to about 0.4. In another embodiment, the fluticasone partition ratio is about 0.05 to about 0.3. In another embodiment, the fluticasone partition ratio is from about 0.1 to about 0.35. In a further embodiment, the fluticasone partition ratio is about 0.1. In another embodiment, the fluticasone partition ratio is between 0.05 to about 0.2. In a further embodiment, the fluticasone partition ratio is between about 0.1 to about 0.2. In yet another embodiment, the fluticasone partition ratio is about 0.01, about 0.02, about 0.03, about 0.04, about 0.05, about 0.06, about 0.07, about 0.08, about 0.09, about 0.1, about 0.11, about 0.12, about 0.13, about 0.14, about 0.015, about 0.16, about 0.17, about 0.18, about 0.19, about 0.2, about 0.21, about 0.22, about 0.23, about 0.24, about 0.25, about 0.26, about 0.27, about 0.28, about 0.29, about 0.30, about 0.31, about 0.32, about 0.33, about 0.34, about 0.35, about 0.36, about 0.37, about 0.38, about 0.39, about 0.40. Additionally, fluticasone- like compounds also selectively partition into the adipose tissue due to their lipophilic nature.

Methods of Reducing Adipose Tissue

[0047] Provided herein is a cosmetic method for reducing adiposity in a human patient comprising subcutaneously administering a pharmaceutical formulation suitable for

subcutaneous injection consisting essentially of: (a) active ingredient that consists essentially of an adipose tissue-reducing amount of one or more glucocorticosteroids, or salts, solvates, or polymorphs thereof; and (b) one or more subcutaneously acceptable inactive ingredients. In some embodiments, the glucocorticosteroid is a lipophilic glucocorticosteroid, or a salt, optical isomer, racemate, solvate, or polymorph thereof. In certain embodiments, the glucorticosteroid is selected from fluticasone, mometasone, beclomethasone, triamcinolone, fluniolide, dexamethasone, ciclesonide, or budesonide, or a salt, optical isomer, racemate, solvate, or polymorph thereof. In select embodiments, the glucocorticosteroid is fluticasone or a salt, optical isomer, racemate, solvate, or polymorph thereof. In yet another embodiment, the salt of the fluticasone is a propionate salt. In a further embodiment, the salt of fluticasone is a furoate salt.

[0048] In a further embodiment, provided is a method for reducing adipose tissue in a subject wherein the pharmaceutical and/or cosmetic formulation further comprises a glucocorticosteroid or a salt or solvate thereof and the formulations provides a reduction in adipose tissue. In certain embodiments, the reduction in adipose tissue is realized after administration to the inside region of the knees, the middle to upper area of the upper arm, including the tricep area, the submental area, including the area under the chin, for example the wattle (which is understood to refer to the fleshy fold of skin in the submental area of a patient), the abdomen, the hips, the inner thigh, the outer thigh, the buttocks, the lower back, an upper arm region of the patient, the upper back or the chest of the patient. In further or additional embodiments, the subcutaneous and transcutaneous methods described herein provide a reduction in adipose tissue without a significant report of a side-effect, or report of relatively minor side-effects. By way of non- limiting, these side-effects include: immunosuppression, hyperglycemia, skin fragility and proneness to bruising, negative calcium imbalance, steroid-induced osteoporosis (and subsequent reduced bone density), weight gain, adrenal insufficiency, muscle breakdown, expansion of malar fat pads, irregularity of menstrual cycles of women, growth failure, increased plasma amino acid count, increased urea formation, negative nitrogen balance, central nervous system effects, glaucoma, and/or cataracts.

Methods of Aesthetic Treatment of Contour Defects such as Abdominal Bulging

[0049] In an aspect, provided herein is a method for the aesthetic treatment of body contour defects or deformities such as abdominal bulging in a human patient comprising subcutaneous or transcutaneous administration of a formulation comprising an adipose tissue-reducing amount of one or more glucocorticosteroids or salts, solvates, or polymorphs thereof. In certain

embodiments, the body contour defect treated is abdominal bulging. In some embodiments, the body contour defect treated is a gluteal contour defect. In an embodiment, the body contour defect treated is in an area which is one or more of the neck, upper arms, female and male breasts, abdomen, flanks, back, hips, buttocks, thighs, knees and ankles. In certain embodiments, the individual being treated has a history of prior treatment of contour defects (e.g.,

abdominoplasty, liposuction, or exposure to ablative or body contouring devices, mesotherapy or lipolytic agents).

[0050] In some embodiments, the glucocorticosteroid is a lipophilic glucocorticosteroid, or a salt, optical isomer, racemate, solvate, or polymorph thereof. In certain embodiments, the glucorticosteroid is selected from fluticasone, mometasone, beclomethasone, triamcinolone, flunio lide, dexamethasone, ciclesonide, or budesonide, or a salt, optical isomer, racemate, solvate, or polymorph thereof.

[0051] In select embodiments, the glucocorticosteroid is fluticasone or a salt, optical isomer, racemate, solvate, or polymorph thereof. In yet another embodiment, the salt of the fluticasone is a propionate salt. In a further embodiment, the salt of fluticasone is a furoate salt.

[0052] In a further aspect, provided herein is a method for the aesthetic treatment of body contour defects in a human patient, said method comprising subcutaneously administering a formulation suitable for subcutaneous injection comprising: (a) active ingredient that consists essentially of a cosmetically effective adipose tissue-reducing amount of one or more lipophilic glucocorticosteroids, or salts, solvates, or polymorphs thereof; and (b) one or more

subcutaneously acceptable inactive ingredients. In certain embodiments, the body contour defect treated comprises abdominal bulging. In some embodiments, the body contour defect treated is a gluteal contour defect. In one embodiment, the lipophilic glucocorticosteroid is fluticasone. In yet another embodiment, the salt of the fluticasone is a propionate salt. In a further embodiment, the salt of fluticasone is a furoate salt. In a further embodiment, the subcutaneous administration reduces or minimizes the risk of producing cardiovascular side effects (by minimizing systemic exposure). In an embodiment, the , formulation provides a mean plasma fluticasone C_max equal that is in the range of about 200 pg/mL to levels that are undetectable using conventional methodology, wherein the body contour defect in the subject is treated.

[0053] In an aspect provided, is a method for aesthetic treatment of cheek contour defects in a human patient by contacting a targeted fat deposit in the cheek with a composition, said composition comprising one or more glucocorticosteroids, or salts, solvates, or polymorphs thereof. In certain embodiments, the fat deposit targeted is buccal fat. In some embodiments, the fat deposit is subcutaneous cheek fat. In certain embodiments, the patient suffers from chipmunk cheeks. In some embodiments, the glucocorticosteroid is a lipophilic glucocorticosteroid, or a salt, optical isomer, racemate, solvate, or polymorph thereof. In certain embodiments, the glucorticosteroid is selected from fluticasone, mometasone, beclomethasone, triamcinolone, flunio lide, dexamethasone, ciclesonide, or budesonide, or a salt, optical isomer, racemate, solvate, or polymorph thereof.

[0054] In select embodiments, the glucocorticosteroid is fluticasone or a salt, optical isomer, racemate, solvate, or polymorph thereof. In yet another embodiment, the salt of the fluticasone is a propionate salt. In a further embodiment, the salt of fluticasone is a furoate salt.

[0055] In a further aspect provided is a method for aesthetic treatment of cheek contour defect in a human patient by contacting a targeted fat deposit in the cheek with a composition comprising: (a) active ingredient that consists essentially of a cosmetically effective adipose tissue-reducing amount of one or more lipophilic glucocorticosteroids, or salts, solvates, or polymorphs thereof; and (b) one or more subcutaneously acceptable inactive ingredients. In an aspect provided is a method for aesthetic treatment of cheek contour defect in a human patient by contacting a targeted fat deposit in the cheek with a composition comprising essentially of: (a) active ingredient that consists essentially of a cosmetically effective adipose tissue-reducing amount of one or more lipophilic glucocorticosteroids, or salts, solvates, or polymorphs thereof; and (b) one or more subcutaneously acceptable inactive ingredients. In another aspect provided is a method for aesthetic treatment of cheek contour defect in a human patient by contacting a targeted fat deposit in the cheek with a composition consisting of: (a) active ingredient that consists essentially of a cosmetically effective adipose tissue-reducing amount of one or more lipophilic glucocorticosteroids, or salts, solvates, or polymorphs thereof; and (b) one or more subcutaneously acceptable inactive ingredients. In certain embodiments, the fat deposit targeted is buccal fat. In some embodiments, the fat deposit is subcutaneous cheek fat. In one

embodiment, the lipophilic glucocorticosteroid is fluticasone. In yet another embodiment, the salt of the fluticasone is a propionate salt. In a further embodiment, the salt of fluticasone is a furoate salt. In a further embodiment, the subcutaneous administration reduces or minimizes the risk of producing cardiovascular side effects (by minimizing systemic exposure). In an embodiment, the , formulation provides a mean plasma fluticasone C_max equal that is in the range of about 200 pg/mL to levels that are undetectable using conventional methodology, wherein the body contour defect in the subject is treated.

Methods of Treatment of Thyroid Eve Disease

[0056] In an aspect_provided herein are compositions, formulations, methods, and systems for treating thyroid eye disease by contacting a targeted fat deposit in the eye with a composition, said composition comprising: one or more glucocorticosteroids, or salts, solvates, or polymorphs thereof. In some embodiments is provided a method of treating proptosis by subcutaneous administration of a composition comprising one or more lipophilic glucocorticosteroid, or salts, solvates, or polymorphs thereof.

[0057] In some embodiments, the glucocorticosteroid is a lipophilic glucocorticosteroid, or a salt, optical isomer, racemate, solvate, or polymorph thereof. In certain embodiments, the glucorticosteroid is selected from fluticasone, mometasone, beclomethasone, triamcinolone, flunio lide, dexamethasone, ciclesonide, or budesonide, or a salt, optical isomer, racemate, solvate, or polymorph thereof.

[0058] In select embodiments, the glucocorticosteroid is fluticasone or a salt, optical isomer, racemate, solvate, or polymorph thereof. In yet another embodiment, the salt of the fluticasone is a propionate salt. In a further embodiment, the salt of fluticasone is a furoate salt.

[0059] In a further aspect, provided herein is a method for treating thyroid eye disease by contacting a targeted fat deposit in the eye with a composition comprising: (a) active ingredient that consists essentially of a cosmetically effective adipose tissue-reducing amount of one or more lipophilic glucocorticosteroids, or salts, solvates, or polymorphs thereof; and (b) one or more subcutaneously acceptable inactive ingredients. In some embodiments is provided a method of treating proptosis by subcutaneous administration of a composition comprising: (a) active ingredient that consists essentially of a cosmetically effective adipose tissue-reducing amount of one or more lipophilic glucocorticosteroids, or salts, solvates, or polymorphs thereof; and (b) one or more subcutaneously acceptable inactive ingredients. In some embodiments, the lipophilic glucocorticosteroid is fluticasone propionate or fluticasone furoate.

Pharmaceutically and Cosmetically Acceptable Excipients

[0060] In a further embodiment, the at least one subcutaneously acceptable inactive ingredient is a co-solvent. In further or additional embodiments, the co-solvent is selected from about 0.25 to about 40% polyethylene glycol. In further or additional embodiments, the polyethylene glycol is about 0.8 - about 1%. In a further embodiment, the polyethylene glycol is PEG 400.

[0061] In a further embodiment, the formulations provided herein comprise at least one co- solvent that is selected from about 0.25 to about 40%> polyethylene glycol, or from about 0.5 to about 20%) polyethylene glycol, or from about 0.75 to about 10%> polyethylene glycol, or from about 1 to about 5% polyethylene glycol, or from about 2 to about 4% polyethylene glycol. In further or additional embodiments, the polyethylene glycol is from about 0.8 - about 1%, or is about 0.9% polyethylene glycol. In a further embodiment, the polyethylene glycol is PEG 400.

[0062] In yet a further embodiment, the formulations described herein comprise at least one subcutaneously acceptable excipient that is selected from about 0.01 to about 10% polysorbate, about 0.05 to about 5% polysorbate, about 0.1 to about 2% polysorbate, or about 0.5 to about 1%) polysorbate. In some embodiments, the polysorbate is about 0.01 to about 2% polysorbate. In still further embodiments, the polysorbate is about 0.04%. In one embodiment, the polysorbate is polysorbate 80.

[0063] Excipients used in the formulations described herein include, but are not limited to, suspending agents, surfactants, solubilizers such as, for example, PEG 400, stabilizers, diluents and the like, and should be selected on the basis of compatibility with the glucocorticosteroid. In some embodiments, a polyalkylene glycol or a mixture of different polyalkylene glycols is used as a solubilizer. Polyalkylene glycols from the group of polypropylene glycols or polyethylene glycols are particularly suitable in this connection because of the physiological tolerance. In this connection, the use of polyethylene glycols is utilized in some embodiments presented herein. In some embodiments, polyethylene glycols such as, for example, PEG 400, is contemplated herein.

[0064] Additives increasing the bioavailability of a lipophilic glucocorticosteroids, such as, fluticasone are, in some embodiments, organic compounds, salts thereof, optical isomers or racemates thereof, emulsions or dispersions containing organic compounds or salts thereof, e.g. dispersions of polar lipids, or any combination. Organic compounds useful in the subcutaneous formulation are e.g. amino acids, peptides, proteins, and polysaccharides. Peptides include dipeptides, tripeptides, oligopeptides, such as collagen and gelatin. In some embodiments, the collagen and gelatin is hydrolyzed. Polysaccharides include e.g., chitosans, cyclodextrins, starch, hyaluronic acids, dextrans, cellulose, and any derivatives, combinations. In further embodiments, the starch is hydrolyzed. The emulsions include oil-in-water emulsions with oil as the dispersed phase and water-in-oil dispersions with oil as the continuous phase. In other embodiments, the oil is of vegetable or of animal origin or synthetically produced. In further embodiments, the polar liquids are one or more phospholipids or glyco lipids or any combination thereof.

[0065] In further embodiments, before administration, one or more aqueous solutions or dispersions are added, in any mixture or sequence, to the lipophilic glucocorticosteroid which is a stable aqueous solution. In other embodiments, the formulation is a stable aqueous solution ready for administration. In some embodiments, a dispersion, e.g. a suspension, a liposomal formulation or an emulsion is provided. In yet other embodiments, the formulation also comprises a salt in order to give an isotonic solution, e.g., NaCl, KC1, and/or in further embodiments, it comprises one or more other isotonicity establishing compounds.

[0066] In yet other embodiments, an amino acid is used to buffer the system. In some embodiments, a suitable buffer is glycine, lysine, arginine, histidine or glycylglycine, in other embodiments, the buffer is glycylglycine.

[0067] In some other embodiments, a non-ionic surfactant is also present in the formulation. In some embodiments, the surfactant is chosen from block-copolymers, such as a poloxamer, e.g., poloxamer 188, or a polyoxy ethylene sorbitan fatty acid ester, such as polyoxyethylene-(20)- sorbitan monolaurate or polyoxyethylene-(20)-sorbitan monooleate. Also disclosed herein are formulations using polyoxyethylene-(20)-sorbitan monolaurate (Tween 20). In one

embodiment, the formulation described herein used polyoxyethylene-(20)-sorbitan monooleate (Tween 80). In other embodiments, the non-ionic surfactant, is present in an amount above the critical micelle concentration (CMC).

[0068] Also presented herein are mono- or disaccharides (e.g., sucrose), polysaccharides such as low molecular weight dextrins, or sugar alcohols (e.g., sorbitol, glycerol or mannitol) used in the subcutaneous formulations. In some embodiments, the formulation also comprises antioxidants such as bisulfite, ascorbate glutathione, acetylcystein, tocopherol, methionine, EDTA, citric acid, butyl hydroxy toluene and /or butyl hydroxy anisole. In other embodiments, complexing agents, such as EDTA and citric acid are also present in small concentrations for stabilizing the lipophilic glucocorticosteroid. Furthermore, in other embodiments, preservatives such as benzyl alcohol, phenol, sorbic acid, parabens, and chlorocresol are added. In further or additional embodiments, the lipophilic glucocorticosteroid, such as, fluticasone or budesonide is prepared as a lyophile. In further or additional embodiments, a lyophilized lipophilic long-acting beta-2 adrenergic receptor agonist is prepared such that it can be reconstituted for administration via subcutaneous injection to a patient.

Routes of Administration

[0069] Injectable formulations are administered using any method known in the art, for example, using a single needle, multiple needles, and/or using a needleless injection device. In some embodiments, a tissue loading dose of the active ingredients formulated in a suitable carrier delivered by injection. In some embodiments, delivery comprises single needle injection. In some embodiments, delivery comprises injection using a multi-needle array, which, in some embodiments, provides a wide dispersion of the formulation in the target tissue. In some embodiments, formulations are injected in a manner that allows dispersal into the appropriate layer of subcutaneous fat in or near regional fat areas.

[0070] Transcutaneous formulations, also contemplated as a route of delivery for the pharmaceutical and/or cosmetic formulations and methods of treatment provided herein, are administered using any known method in the art.

[0071] Embodiments of the composition are formulated for administered by any suitable method, for example, as described in Remington: The Science And Practice Of Pharmacy (21st ed., Lippincott Williams & Wilkins). Exemplary routes of administration include, but are not limited to parenteral, subcutaneous, or intramuscular. In some embodiments, the composition is formulated for injection of an area at which treatment is desired, for example, in or near a regional fat deposit.

[0072] Any suitable pharmaceutically acceptable excipient appropriate for a particular route of administration can be used. Examples of pharmaceutically acceptable carriers include, but are not limited to, buffers, saline, or other aqueous media. The compounds described herein are in some embodiments, soluble in the carrier which is employed for their administration (e.g., subcutaneous). Some embodiments comprise any suitable lipophilic carrier, for example, modified oils (e.g., Cremophor^® BASF, Germany), soybean oil, propylene glycol, polyethylene glycol, derivatized polyethers, combinations thereof, and the like. Some embodiments comprise one or more carriers or agents, suitable for subcutaneous administration. Some embodiments comprise excipients suitable for stable suspensions for glucocorticosteroids.

[0073] In some embodiments, the pharmaceutical and/or cosmetic formulations comprise polyethylene glycol in an amount of from about 0.5% to about 40%. In another embodiment, the formulation suitable for subcutaneous administration comprises polyethylene glycol in an amount from about 0.5%> to 40%>, about 1% to about 35%, about 2% to about 30%, about 3% to about 25%o, about 4% to about 20%>„ about 5% to about 15%, about 10% to about 12%, or is about 1%), about 2%, about 3%, about 4%, about 5%, about 10%, about 15%, about 20%, about 25%o, about 30%), about 35%, or about 40%. In a further embodiment, polyethylene glycol is in an amount of about 20%. In yet a further embodiment, polyethylene glycol is PEG 400. In yet another embodiment, the pharmaceutical and/or cosmetic formulations comprise polysorbate in an amount of from 0.01% to about 10%. In another embodiment, the formulation suitable for subcutaneous administration comprises polysorbate in an amount from about 0.01% to about 10%, about 0.02% to about 9%, about 0.03% to about 8%, about 0.04% to about 7%, about 0.05% to about 6%, about 0.06% to about 5%, about 0.07% to about 4%, about 0.08% to about 3%, about 0.09% to about 2%, 0.1% to about 1%, about 0.2% to about 0.5%, or is about 0.01%, about 0.02%, about 0.03%, about 0.04%, about 0.05%, about 0.1%, about 0.2%, about 0.3%, about 0.4%, about 0.5%, about, about 0.6%, about 0.7%, about 0.8%, about 0.9%, about 1%, about 2%>, about 3%, about 4%, about 5%, about 6%, about 7%, about 8%, and about 9%. In a further embodiment, polysorbate is in an amount of about 10%. In yet a further embodiment, the polysorbate is polysorbate 80. In further or additional embodiments, the lipophilic glucocorticosteroid is prepared as a lyophile. In further or additional embodiments, a lyophilized lipophilic long-acting beta-2 adrenergic receptor agonist is reconstituted for administration via subcutaneous injection to a patient.

[0074] In other embodiments, another delivery mode comprises a needless pressurized injection device. In some embodiments, of these devices, the formulation is pressurized mechanically or pneumatically, for example, using a gas such as helium or carbon dioxide, and then forced through a small orifice into the body tissues, thereby delivering the formulation subcutaneously. Suitable formulations for needless injections are known, for example, liquid, solutions, suspensions, gels, colloids, emulsions, and dry powders. An advantage of this system is a wide dispersal area compared with typical needle injection systems. Needless injection under the appropriate pressure forces the formulation into a more planar delivery pattern, with fingers of formulation spreading out radially following paths of least resistance. In contrast, delivery by a typical needle injection results in a globular delivery of the formulation. Needless injection also permits precise control of the depth of penetration by controlling the injection pressure and orifice size. Thus, needless injection is a delivery method for a sub-dermal injection

contemplated herein of a formulation for treating superficial fat accumulations, which is useful, for example, for smoothing skin dimpling caused by fat. In other embodiments, needless injection is also used for deeper fat accumulations. In further embodiments, a needless device also provides easy and convenient multiple injections of the formulation over a defined region with a large lateral spread.

[0075] In some embodiments, the subject to be treated is provided a sustained release or non-sustained release formulation. In some embodiments, the non-sustained release formulation is provided and, after a single dose, provides activity of one or glucocorticosteroids for a duration from about 4 hours to about 24 hours, e.g., about 6 hours, 8 hours, 10 hours, 12 hours, 16 hours, 18 hours, 21 hours, or any other duration of glucocorticosteroid activity from about four hours to about 24 hours.

Treatment of Other Conditions

[0076] In some embodiments, the above-mentioned drugs are used for treating immune and inflammation-related dermal conditions including psoriasis, atopic dermatitis, vitiligo, hypopigmentation, stria, and wrinkles or rhytids. In one embodiment, the formulations described herein are used to treat a cancerous condition. In some embodiments, the lipophilic glucocorticosteroid is administered subcutaneously for the treatment of skin wrinkles and skin stria, or stretch marks. Cutaneous stria are characterized by a thinning of the dermis, with a loss of collagen and hypopigmentation.

[0077] In other embodiments, provided are methods for decreasing cellulite in a subject, also known as adiposis edematosa, dermopanniculosis deformans, status protrusus cutis, and gynoid lipodystrophy, comprising administering via subcutaneous methods, a subcutaneous formulation consisting essentially of a glucocorticosteroid and a subcutaneously acceptable excipient thereof, wherein the formulation decreases cellulite in the subject.

[0078] Areas of fat deposits on a subject, such as for example a human patient, for which the formulations described herein are useful include, but are not limited to, the inside region of the knees, the middle to upper area of the upper arm, including the tricep area, the submental area, including the area under the chin, for example the wattle (which is understood to refer to the fleshy fold of skin in the submental area of a patient), the abdomen, the hips, the inner thigh, the outer thigh, the upper arms, the buttocks, the lower back and the chest.

[0079] In some embodiments, inducing lipo lysis and inhibiting fat cell growth in regional fat accumulations, have additional health benefits through the shrinkage of the average fat cell diameter or volume. Large volume fat cells actively secrete pro -inflammatory and deleterious hormones such as TNF-alpha and interleukins ("adipokines"), which contribute to comorbidities associated with fat, such as diabetes. By reducing the size of these fat cells and therefore the deleterious adipokine secretion, improvements in fat-related comorbidities are realized.

[0080] In some embodiments, the disclosed formulations (e.g., subcutaneous and transcutaneous formulations) are used for treating obstructive sleep apnea. Obstructive sleep apnea occurs when the airway is temporarily blocked during sleep, leading to hypoxia, high blood pressure, cardiac dysrhythmia, and a higher risk of death. Excessive fat in the pharynx and soft palate it believed to contribute to this blockage. Obese people have a higher incidence of sleep disorders and persons with sleep apnea have excessive fat in the palate and pharynx on MRI. Thus, in some embodiments, formulations described are administered to a subject to reduce the symptoms of sleep apnea. In some embodiments, the formulations are administered locally (e.g., by injection) into the palate or pharynx transorally. In some embodiments, the formulations are administered by subcutaneous into the region the neck to reduce the obstructive symptoms.

[0081] While certain embodiments have been described, these embodiments have been presented by way of example only, and are not intended to limit the scope of the disclosure. The formulations, methods, and systems described herein may be embodied in a variety of other forms. Furthermore, various omissions, substitutions and changes in the form of the

formulations, methods, and systems described herein may be made without departing from the spirit of this disclosure. The accompanying claims and their equivalents are intended to cover such forms or modifications.

EXAMPLES

[0082] The following specific examples are to be construed as merely illustrative, and not limitative of the remainder of the disclosure in any way whatsoever. The examples described herein reference and provide non-limiting support to the various embodiments described in the preceding sections.

Example 1: Human Clinical Trial Comparing Lipophilic Glucocorticosteroids with Beta-2 Adrenergic Receptor Agonists, Their Combination, and Placebo

reduction of abdominal adiposity.

• To evaluate the safety and efficacy of subcutaneous injection of 1.0 μg FP/mL once weekly for 8 weeks for the treatment of abdominal contour defects.

• To evaluate the safety and efficacy of subcutaneous injections of 0.02 μg SX/mL once weekly for 8 weeks for the reduction of abdominal adiposity.

• To evaluate the safety and efficacy of subcutaneous injections of SX + FP combo (1.0 μ§ FP + 0.02 μ SX/mL once weekly for 8 weeks) for the reduction of abdominal adiposity.

Study Design A double-masked, multiple-dose study of the safety and efficacy of 1.0 μg/mL of FP alone compared with 0.02 μg/mL of SX alone, 1.0/0.02 μg/mL (FP/SX) combo, and to placebo. Doses will treat a region of adiposity and/or contour defect and will be administered as nineteen 1 mL subcutaneous injections once a week for 8 weeks in 200 subjects with measurable abdominal subcutaneous adipose tissue.

Study Drug The drug products used in the study will be supplied as fluticasone

propionate for Injection. A lyophile of the FP drug product will be supplied in glass vials to be reconstituted with Sterile Water for Injection.

Immediately prior to administration, the lyophile drug products will be reconstituted and diluted with Sterile Saline Solution USP (0.9% Sodium Chloride). The supplied drug products (fluticasone propionate for Injection and Salmeterol Xinafoate for Injection) should be stored at room temperature (15°C to 25°C). The reconstituted solution of each drug product (the FP, SX, and combo) should be protected from light until administration.

The fluticasone propionate and salmeterol xinafoate for Injection and for Injection drug products will be provided in bulk nested packaging.

Placebo: Sterile Saline, USP (0.9%> Sodium Chloride) will be used as the placebo. Treatment Eligible subjects in this multiple-dose study will be randomized into Groups four groups of 50 to receive twenty 1 mL subcutaneous injections of either a combination of 1.0 μg/mL FP+0.02 μg/mL SX, or 1.0 μg/mL FP alone, or 0.02 μg/mL SX alone, or Placebo.

The 20 subcutaneous injections will be spaced approximately 4 cm apart and will treat a pre-marked abdominal area of adiposity that is approximately 400 cm².

The sequence of once weekly subcutaneous injections will continue for 8 consecutive weeks for a total of 160 injections administered into the marked abdominal area.

Comprehensive safety assessments will be performed at each subject visit through the End of Study Visit on Day 78 ± 2 days.

Duration of Screening period: up to 30 days.

Treatment

The expected study duration is 12 weeks comprised of an 8 week treatment period and 1 and 4 week post-therapy follow-up visits for assessment of safety and efficacy.

Duration Approx. 7 months

Study The study population will consist of qualified male and female

Population subjects, 18 years of age and older, inclusive who have provided

written, informed consent. Qualified subjects, who meet all inclusion and exclusion criteria, will be enrolled into the study.

Total No. of At least 200 subjects will be enrolled. The final subject number will be Subjects determined following an interim analysis to be conducted once 180 subjects have completed treatment or discontinued from the study.

Subjects who give informed consent in writing but who do not receive study drug for any reason will be considered screen failures and will be replaced.

Sites Up to 10 sites Inclusion 1) Healthy male and female patients, 18 years and older, who have Criteria provided written, informed consent prior to any study procedures

(including pre-treatment and screening) being performed

2) Patients who have a localized area of abdominal subcutaneous adiposity, which is Grade 3 or higher on the Patient and Clinician Photonumeric Scales

3) Patients who have satisfactory abdominal skin elasticity as

assessed by the investigator

4) BMI ^25 kg/m2 and stable body weight as shown by a weight variance < 3% between Screening and Day 1

5) History of a stable diet and exercise routine in the 3 months prior to Screening

6) Female subjects who have a negative urine pregnancy test at Screening and Day 1, and who agree to use adequate birth control methods (abstinence, female partner, stabilized on oral contraceptives for at least two months, implant, injection, IUD, patch, NuvaRing®, condom and spermicidal, diaphragm and spermicidal) throughout the entire study until completion of the Week 12 End of Study Visit procedures

Exclusion 1) History of prior treatment of abdominal subcutaneous adipose Criteria tissue (e.g., abdominoplasty, liposuction, or exposure to

ablative or body contouring devices, mesotherapy or lipolytic agents)

2) Female subjects who are within 12 months post-partum, or who are pregnant, lactating, and/or who are of childbearing potential but not using adequate birth control methods

3) Any skin conditions in the treatment area that may affect study procedures or evaluations - including but not limited to skin infections, psoriasis, eczema, tattoos, striae, keloids, or hypertrophic or tethered scars, or excessive skin wrinkles, or a pannus

) Subjects planning to embark on a weight loss or exercise program during study participation

) Subjects who partake of abdominal massaging and who are

unwilling to discontinue this therapy during the study

) Known hypersensitivity to the study drugs and/or any of their components

) Prior or current enrollment in any Lithera study involving FP, SX. or SX + FP.

) Concurrent enrolment in another investigational drug or device study; or use of any experimental or investigational drug or device within 30 days, or for drugs within 6 times the elimination half-life prior to Day 1 if that is longer

) Any medical condition that in the opinion of the investigator might jeopardize the subject's safety or complicate study procedures or assessments, including, but not limited to: (a) any bleeding, or connective tissue disorders; (b) asthma, COPD, diabetes (Type I and II) or cardiovascular disease (subjects with well-controlled hypertension will not be excluded unless they are taking beta- blocker drugs); (c) history of major surgery within 30 days prior to Day 1, or planned surgery during the study period; (d) any lymphatic disease causing lymphedema in the treatment area; (e) abdominal hernias, abdominal recti muscle divarication or diastasis, visible abdominal organomegaly, or abdominal asymmetry due to musculoskeletal abnormalities; (f) a history of any DSM-IV psychiatric disorder; (g) any clinically-significant physical examination findings, as determined by the Investigator, at Screening or Day 1 ; (h) any clinically-significant abnormal laboratory result during Screening and/or Day 1, as determined by the investigator 10) Use of drugs with anticoagulant activity (including aspirin and

NSAIDs), immunomodulators (including steroids), anti-metabolites, β-adrenergic receptor agonists or blockers, strong CYP 3A inhibitors, or nonpotassium -sparing diuretics (e.g., loop or thiazide diuretics) prior to Day 1 during the study

11) Use of tricyclic antidepressants or monoamine oxidase inhibitor medications within 14 days prior to Day 1, or during the study

12) Subjects unlikely or unable to comply with protocol procedures or adhere to the study visit schedule

Procedures All injections will be performed in an outpatient setting. At each visit, subjects will receive a total of 20 subcutaneous injections (1 mL) to infiltrate an area of approximately 400 cm². Subjects will maintain their usual diet and exercise routine during the study: any fat treatment, including but not limited to liposuction, mesotherapy and abdominal massaging will not be allowed.

Screenins Procedures

Subjects will undergo screening procedures at the Screening Visit. This visit must occur within 30 days (Day -30 to Day 0) prior to study randomization at Day 1. Study procedures will be explained to each subject and written, informed consent must be obtained prior to initiating any study-related procedures, including screening procedures.

Qualified subjects, who meet all Inclusion/Exclusion criteria, with baseline screening laboratory tests results within normal limits as defined per protocol, will be scheduled for the Randomization Visit on Day 1.

It is required that all Randomization Visits (Day 1) are scheduled to ensure that over the 8 week treatment period, weekly study drug administration for each subject occurs in a regular cycle, with doses of study drug administered on the same day each week (± 2 days).

On Study Procedures

Randomization and Treatment Visit (Day 1) Pre-dose (Day 1):

treatment sessions during the study. Pre-dose (Days 8. 15. 22. 29. 36. 43. 50 ± 2):

At each Treatment Visit, pre-dose procedures will be performed as per the Schedule of Events.

Prior to study drug being injected on the dosing day of each week, circumferential tape measurements of the treatment area, at the pre-marked levels in the treatment area will be made. The skin markings on the abdomen will be used to align an injection grid that will be used to guide the administration of the injections on the assigned dosing day each week. The treatment area will be standardized, and will involve 20 individual subcutaneous injections at each treatment visit.

In addition, on Day 29 ± 2, a standardized measurement of the treatment area using a digital 3-D photographic device will be made prior to the application of the temporary injection grid.

Post-dose (Days 8. 15. 22. 29. 36. 43. 50 ± 2):

On all treatment visits, the post-dose procedures will be performed as per the Schedule of Events. Subjects must remain in the clinic until the post- dose assessments have been completed and during this time concomitant medications and adverse events will be reviewed and recorded. Before leaving the clinic, subjects will be scheduled for their next visit. A subject will not be discharged from the clinic if, in the Investigator's opinion, the subject has experienced an adverse event that requires further in-clinic monitoring.

1 Week Post-Treatment Visit (Day 57 ± 2):

A week after the last study drug administration on Day 57 ± 2, patients will return to the clinic for their initial post-treatment visit. The study procedures will be performed as per the Schedule of Events.

On Day 57 ± 2 a standardized measurement of the treatment area using 3-D photography will be performed. Then, abdominal circumference

measurements using a tape measure at the pre-marked levels in the treatment area will be recorded.

Any abnormal laboratory tests that are clinically significant will be followed until resolution and/or repeated per protocol.

End of Studv Visit tf>av 78 ± 2) or Earlv Termination Visit:

Four weeks after the last study drug administration on Day 78 ± 2, patients will return to the clinic for their End of Study visit. The study procedures will be performed as per the Schedule of Events.

On Dav 78 ± 2 a standardized measurement of the treatment area using 3-D photography will be performed. Then, abdominal circumference measurements using a tape measure at the pre-marked levels in the treatment area will be recorded.

If a subject withdraws from the study early, and the Day 78 ± 2 End of Study Visit procedures have not been performed, these procedures should be performed prior to terminating the subject from the study.

Any abnormal laboratory tests that are clinically significant will be followed until resolution and/or repeated per protocol. Once the End of Study Visit procedures have been performed, the subject has completed the study.

Safety The following safety assessments will be performed at the designated time

Assessments points as specified in the protocol: (1) vital signs (systolic and diastolic blood pressure, heart rate, breathing rate and body temperature); (2) physical examinations; (3) clinical assessment of injection site reactions (local tolerability using the Injection Site Reaction Severity Scale); (4) clinical laboratory tests (hematology, serum chemistry, and urine dipstick analysis); (5) adverse events.

Safety parameters monitored during this study will be compared within each treatment group (i.e. changes from baseline) and between treatment groups.

Efficacy Efficacy assessments include: (1) circumferential measurements derived Assessments from analysis of standardized 3-D photographs of the treatment area; (2) manual tape circumferential measurement of the abdominal treatment area at the level of the umbilicus, and at other fixed levels in the treatment area; and, (3) volumetric changes in the treatment area derived from analysis of standardized 3-D photographs of the treatment area.

Study Endpoints The study endpoints will include both safety assessments and evaluations of efficacy of the four treatments being assessed. The study population will be evaluated for several objective efficacy assessments based on standard measurements of subcutaneous adipose tissue during this study, including: (1) manual tape circumferential measurement of the abdominal treatment area at the level of the umbilicus, and at other fixed levels in the treatment area; (2)circumferential measurements derived from analysis of

standardized 3-D photographs of the treatment area; and (3) volumetric changes in the treatment area derived from analysis of standardized 3-D photographs of the treatment area.

Sample Size Initially 50 subjects per treatment group (total N=200) with observable Calc. abdominal subcutaneous adipose tissue (per the Inclusion Criteria) will be enrolled (and have signed an IC form and received at least one dose of study drug).

As the assumption of variability greatly affects the estimate for sample size, an interim review to assess the change from baseline in abdominal measurements will be conducted to assess the adequacy of the overall sample size relative to achieving the study objectives. After approximately 180 subjects have completed the study, an interim analysis of the primary efficacy results only will be conducted by an independent statistician. This analysis will be used only to confirm the adequacy of the planned sample size or to recommend enlarging the sample size to achieve adequate statistical power to detect the hypothesized difference between the SX, FP, and FP+SX treatment groups. If the re-estimate of the sample size results in a study size that is not practical to complete, Lithera will complete the study as originally designed (Shun et al., 2001). Statistical Descriptive statistical analyses will be presented for all efficacy and safety Analysis endpoints. Summary statistics will include counts and percentages for categorical variables and the number of subjects, mean, standard deviation (SD), median, minimum and maximum for continuous variables.

Continuous efficacy endpoints will be summarized by treatment group using descriptive statistics. Differences between treatment groups will be assessed using an ANCOVA with effects for treatment, site, and baseline.

Compliance This protocol was developed according to the guidelines of the

International Conference on

Statement Harmonisation (ICH) Good Clinical Practice (GCP) Guidelines E6 and 21

Code of Federal

Example 2: Pharmaceutical and Cosmetic Formulations

Subcutaneous Formulation

[0083] To prepare a parenteral pharmaceutical and/or cosmetic composition suitable for subcutaneous administration, a lipophilic glucocorticosteroid, such as fluticasone propionate, is dissolved in PEG 400 which is stabilized with polysorbate 80. Water is then added. This solution is stored in a single-use glass vial which is stored frozen and protected from light until dose preparation. When ready for use, the glucocorticosteroid solution is then diluted to a suitable concentration for subcutaneous administration using a diluent made of an aqueous solution of 20% PEG 400, 1% polysorbate 80, and sterile water for injection. Optionally, in certain embodiments, a co-solvent is used. In other embodiments, a co-solvent is not used. For example, in certain embodiments, a lipophilic, selective, long-acting beta agonist is lyophilized. Transcutaneous Formulation

[0084] Also provided herein is a transcutaneous formulation for administration to a patient, and methods of treatment provided herein, including for example methods for the reduction of adipose tissue, using the transcutaneous formulations provided herein. In some embodiments, a lipophilic glucocorticosteroid is formulated in a transcutaneous formulation which comprises about 0.5% to about 10%> by weight fluticasone or budesonide, about 1% to about 75% propylene glycol or isopropyl alcohol, and optionally other excipients including but not limited to transcutol, propyl gallate, water, and ethanol, wherein the total percent by weight is 100%). Example 3: Clinical Testing for Treatment of Graves' Ophthalmopathy with Compositions Comprising a Lipophilic Glucocorticosteroid

[0085] A non-limiting example of such a clinical testing for treatment of Graves'

Ophthalmopathy is as follows:

[0086] Patient Selection:

[0087] Patients are to be 18 years of age or above and have no hypersensitivity to the administered drugs. They are diagnosed with proptosis symptoms associated with Graves' Ophthalmopathy by ultrasonography or computerized tomography. In particular, patients are chosen with unilateral or bilateral proptosis edema of 3mm or more, with or without eyelid swelling. Patients may also exhibit diplopia, limitation of eye movement in extreme positions, and evident restriction of movement. Patients may have undergone thyroidectomy for hyperthyroidism. Other steroid therapies should be not used for treatment of hyperthyroidism. All studies are to be performed with institutional ethics committee approval and patient consent.

[0088] Study Design:

[0089] Test 1 : This is a multicenter, dose escalation study of the therapy of a lipophilic glucocorticosteroid such as fluticasone propionate in the treatment of thyroid eye disease.

Patients receive an injection administration of a parenteral composition of the drug daily.

Patients who do not achieve proptosis improvement or partial or complete response but who have stable disease after 1 week of therapy will receive an additional 1 week of therapy at a higher dose than what is originally assigned. Cohorts of 3-6 patients receive escalating doses of the drug until the maximum tolerated dose (MTD) is determined. The MTD is defined as the dose preceding that at which 2 of 3 or 2 of 6 patients experience dose-limiting toxicity.

[0090] Test 2: This is a randomized, multicenter study. The study length is 60 days. Patients are randomized to 1 of 18 treatment groups. For group 1, patients are given fluticasone or a salt thereof alone daily at MTD. For Group 2, patients are given fluticasone or a salt thereof on every other day. For Group 3, patients are given fluticasone or a salt thereof once a week. Groups 4-6 have the same dosing regime as 1-3 except the dosage is at one-fourth MTD. Groups 7-9 also have the same dosing regime as 1-3 except the dosage is at one-tenth MTD. In addition to the treatment groups, a control group is left untreated.

[0091] Endpoint Assessment:

[0092] Patients are assessed for reduction of proptosis and decrease of orbital fat volume and extraocular muscles at the conclusion of the study. Improvement in eyelid closure and ocular movement is also assessed. A 20% reduction within 60 days is presumed as a positive outcome. Example 4: Effects of a Lipophilic Glucocorticosteroid when injected SC in the rat inguinal fat pad

[0093] The effects of fluticasone propionate on the inguinal fat pad weight of rats were evaluated following their SC injection into the inguinal fat pad. Mature male Sprague-Dawley rats weighing approximately 500 g were lightly anesthetized with 4% isoflurane. Test article injections (drug vehicle, different doses of fluticasone propionate) were injected SC into the right inguinal fat pad in a volume of 0.4 mL. An equal volume of drug vehicle was injected into the left inguinal fat pad. Rats received an injection comprising doses of 0.003 μg, 0.03 μg, 0.3 μg, or 3 μg in each fat pad on 3 consecutive days. Approximately 24 hours after the last injection, rats were anesthetized, sacrificed and the right and left fat pads harvested and weighed. The change in fat pad weight (Right vs. Left) was calculated and expressed as a percent change in inguinal fat pad weight (% change IFP = (Right side - Left side) x 100/Left side).

[0094] The injection of fluticasone propionate into the rat inguinal fat pad produced a dose- related reduction in fat pad weight (Figure 1). Staining and histological evaluation of the tissue showed a reduction in fat cell number and size (data not shown).

Example 5: Study of pharmacokinetics and bioavailability of Lipophilic

Glucocorticosteroid in minipigs

[0095] Plasma concentrations of fluticasone (in all instances fluticasone indicates fluticasone propionate) were monitored in a male and a female Gottingen minipig after single intravenous (IV) bolus and subcutaneous (SC) administration of fluticasone propionate. The doses were 0.1, 0.3, and 1 μg/kg for fluticasone propionate SC, and 0.3 μg/kg for fluticasone propionate IV. A total of 4 fluticasone propionate treatments were given with each administration separated by at least a 3-day washout period. The test article was administered by either intravenous (IV) or subcutaneous (SC) bolus injection. Fluticasone propionate was formulated using 20% PEG 400/1% Tween 80 in 0.9% saline varied concentrations and prepared fresh on each treatment day. The study design is presented in Table 1 below.

[0096] Table 1: Study design of the pharmacokinetics and bioavailability of fluticasone propionate in minipigs Administration Dose Dose Volume Dose Solution Number of

Injection #

Route g/k ) (niL/kg) Cone ^ /mL) Animals

1 SC 1.0 0.05 20 1/sex

2 SC 0.3 0.05 6 1/sex

3 SC 0.1 0.05 2 1/sex

4 IV 0.3 0.05 6 1/sex

[0097] The IV dose was administered into the marginal ear vein by slow bolus (1 minute, 0.0167 hr), whereas the SC dose for fluticasone was administered as a bolus injection into an area along the back where there was a longitudinal fat depot. Each dose was separated by at least a 3-day washout period. Blood samples (approximately 4 mL) were collected via the brachiocephalic plexus at pre-dose and at 2, 5, 10, 20, 30, and 45 min, and at 1, 2, 4, 8, and 24 hr post-dose. Blood samples were placed in tubes containing K2-EDTA as the anticoagulant. Samples were processed to plasma by centrifugation under refrigeration and stored frozen at approximately -70°C (±15°C) until analysis.

[0098] Sample Analysis: Plasma samples were analyzed for fluticasone using qualified liquid chromatography/mass spectrometry/mass mass spectrometry (LC/MS/MS) methods. The lower limit of quantitation (LLOQ) was 5.00 pg/mL for fluticasone.

[0099] Data Analysis: Noncompartmental pharmacokinetic parameters were calculated using WinNonlin 5.2 software, NCA model 202, IV infusion input for the IV data and NCA model 200, extravascular input for the SC data (Pharsight Corporation, Mountain View, CA).

Individual plasma concentrations for each animal were used in the calculation of

pharmacokinetic parameters. Nominal collection times and doses were used in the calculations. The area under the plasma concentration-time curve (AUC) was calculated using linear trapezoidal approximation (linear/log interpolation). Concentration values below the assay limit of quantitation were set to zero for calculations. The maximum plasma concentration (C_max) and the time of its occurrence (T_max) were verified by inspection. The half-life (t½) values were calculated using the last 3 plasma concentrations with nonzero values, if data permitted. Other calculations were done using Microsoft Excel® XP. The bioanalytical and pharmacokinetic data were reported to 3 significant figures.

[00100] Results: The determined pharmacokinetic parameters are shown in Table 2 below.

[00101] Table 2: Pharmacokinetic parameters CL

AUCinf Vss

Dose Tmax Cmax t½ tlast (niL/

Analyte Route Sex (Pg'hr/ (niL/

g/k ) (hr) (pg/mL) (hr) (hr) hr/

ml.) kg)

kg) F

Fluticasone SC 0.1 Fe 0.167 10.2 19.0 1.03 1.00 NA NA NA

Fluticasone SC 0.1 M 0.0833 55.1 46.3 1.10 2.00 NA NA NA

Fluticasone SC 0.3 Fe 0.0833 56.4 164 5.31 8.00 NA NA 0.706

Fluticasone SC 0.3 M 0.750 35.9 146 NR 4.00 NA NA 0.918

Fluticasone SC 1 Fe 0.333 61.0 768 15.3 24.0 NA NA NA

Fluticasone SC 1 M 0.0333 249 512 2.36 8.00 NA NA NA

Fluticasone IV 0.3 Fe 0.0333 332 232 3.29 8.00 1290 4030 NA

Fluticasone IV 0.3 M 0.0333 21 1 159 1.39 4.00 1890 3160 NA

AUCi_nf = area under the curve at infinite time, CL = plasma clearance, F = bioavailability, Fe = female, M = male, NA = not applicable, t_last = time of last measurable plasma concentration,

V_ss = volume of distribution at steady state. SC for fluticasone = single site SC injection,. Male

= animal 1-0771 , female = animal 2-0623

[00102] There were no apparent (consistent) gender differences in the SC PK of fluticasone propionate. Fluticasone propionate Tmax values ranged from 0.0833 to 0.75 hours, indicating that fluticasone propionate is rapidly absorbed following SC administration. Increases in Cmax following SC administration of fluticasone propionate were dose-dependent. The fluticasone propionate IV elimination half-life averaged 2.34 hours. In general, the t½ of fluticasone propionate following SC administration was dose-dependent, ranging from 1.03 hours at 0.1 μg/kg to 15.3 hours at 1 μg/kg. Mean bioavailability of fluticasone propionate (0.3 and 1 μg/kg) administered SC ranged from 70.6 to 99.3%. The mean partition ratio (Cmax SC/Cmax IV) for fluticasone was 0.36.

Example 6: Testing for Aesthetic Treatment of Cheek Contour Defects with Compositions Comprising a Lipophilic Glucocorticosteroid

[00103] A non-limiting example of such a clinical testing for aesthetic treatment of cheek contour defects such as chipmunk cheeks is as follows: [00104] Patient Selection:

[00105] Patients are to be 18 years of age or above and have no hypersensitivity to the administered drugs. Other steroid therapies should be not used. All studies are to be performed with institutional ethics committee approval and patient consent.

[00106] Study Design:

[00107] Test 1 : This is a multicenter, dose escalation study of the therapy of fluticasone or a salt thereof such as fluticasone propionate, a lipophilic glucocorticosteroid in the aesthetic treatment of cheek contour defects. Patients receive an injection administration of a parenteral composition of the drug daily. Patients who do not achieve reduction of buccal or subcutaneous cheek fat after 1 week of therapy will receive an additional 1 week of therapy at a higher dose than what is originally assigned. Cohorts of 3-6 patients receive escalating doses of the drug until the maximum tolerated dose (MTD) is determined. The MTD is defined as the dose preceding that at which 2 of 3 or 2 of 6 patients experience dose-limiting toxicity.

[00108] Test 2: This is a randomized, multicenter study. The study length is 60 days.

Patients are randomized to 1 of 18 treatment groups. For group 1, patients are given fluticasone or a salt thereof alone daily at MTD. For Group 2, patients are given fluticasone or a salt thereof on every other day. For Group 3, patients are given fluticasone or a salt thereof once a week. Groups 4-6 have the same dosing regime as 1-3 except the dosage is at one-fourth MTD. Groups 7-9 also have the same dosing regime as 1-3 except the dosage is at one-tenth MTD. In addition to the treatment groups, a control group is left untreated.

[00109] Endpoint Assessment:

[00110] Patients are assessed for reduction of subcutaneous cheek fat or decrease of buccal fat volume at the conclusion of the study.

[00111] The examples and embodiments described herein are for illustrative purposes only and various modifications or changes are included within the spirit and purview of this application and scope of the appended claims. All publications, patents, and patent applications cited herein are hereby incorporated by reference for all purposes.

Claims

WHAT IS CLAIMED IS:

1. An injectable formulation for regional adiposity reduction consisting essentially of:

(a) active ingredient that consists essentially of an adipose tissue-reducing amount of one or more lipophilic glucocorticosteroids, or salts, solvates, or polymorphs thereof; and

(b) one or more subcutaneously acceptable inactive ingredients.

2. An injectable formulation for regional adiposity reduction consisting of:

(a) active ingredient that consists essentially of an adipose tissue-reducing amount of one or more lipophilic glucocorticosteroids, or salts, solvates, or polymorphs thereof; and

(b) one or more subcutaneously acceptable inactive ingredients.

3. An injectable formulation for regional adiposity reduction comprising:

(a) active ingredient that consists essentially of an adipose tissue-reducing amount of one or more lipophilic glucocorticosteroids, or salts, solvates, or polymorphs thereof; and

(b) one or more subcutaneously acceptable inactive ingredients.

4. A cosmetic method for reducing adiposity in a human patient comprising subcutaneously administering a pharmaceutical formulation suitable for subcutaneous injection consisting essentially of:

(a) active ingredient that consists essentially of an adipose tissue-reducing amount of one or more lipophilic glucocorticosteroids, or salts, solvates, or polymorphs thereof; and

(b) one or more subcutaneously acceptable inactive ingredients.

5. A cosmetic method for reducing adiposity in a human patient comprising subcutaneously administering a pharmaceutical formulation suitable for subcutaneous injection consisting of:

(a) active ingredient that consists essentially of an adipose tissue-reducing amount of one or more lipophilic glucocorticosteroids, or salts, solvates, or polymorphs thereof; and

(b) one or more subcutaneously acceptable inactive ingredients.

6. A cosmetic method for reducing adiposity in a human patient comprising subcutaneously administering a pharmaceutical formulation suitable for subcutaneous injection comprising:

(a) active ingredient that consists essentially of an adipose tissue-reducing amount of one or more lipophilic glucocorticosteroids, or salts, solvates, or polymorphs thereof; and

(b) one or more subcutaneously acceptable inactive ingredients.

7. A cosmetic method for inducing lipo lysis in a human patient comprising subcutaneously administering a pharmaceutical formulation suitable for subcutaneous injection comprising: (a) active ingredient that consists essentially of an adipose tissue-reducing amount of one or more lipophilic glucocorticosteroids, or salts, solvates, or polymorphs thereof; and

(b) one or more subcutaneously acceptable inactive ingredients.

8. A method for the aesthetic treatment of contour defects comprising bulging in a human

patient (for example, abdominal bulging), said method comprising subcutaneously administering a formulation suitable for subcutaneous injection comprising:

(a) active ingredient that consists essentially of an adipose tissue-reducing amount of one or more lipophilic glucocorticosteroids, or salts, solvates, or polymorphs thereof; and

(b) one or more subcutaneously acceptable inactive ingredients.

9. A method for treating thyroid eye disease by contacting a targeted fat deposit in the eye with a composition comprising:

(a) active ingredient that consists essentially of an adipose tissue-reducing amount of one or more lipophilic glucocorticosteroids, or salts, solvates, or polymorphs thereof; and

(b) one or more subcutaneously acceptable inactive ingredients.

10. The method or formulation of any of claims 1-9 wherein the glucocorticosteroid is

fluticasone or a salt, solvate, or polymorph thereof.

11. The method or formulation of any of claims 1-10 wherein the glucocorticosteroid is

fluticasone propionate or fluticasone furoate.

12. The method or formulation of claim 11 wherein the glucocorticosteroid is fluticasone

propionate.

13. The method or formulation of claim 12 wherein the formulation comprises a weekly dose of fluticasone propionate in an amount that is between about 50 ng to about 25 μg.

14. The method or formulation of claim 12 wherein the formulation is administered to a patient once per week at a single session dose of fluticasone propionate that is between about 50 ng to about 25 μg.

15. The method or formulation of claim 12 wherein the formulation is formulated to contain between about 50 ng to about 25 μg of fluticasone propionate that is further formulated to be administered to a patient once every two weeks.

16. The method or formulation of claim 12 wherein the formulation is formulated to contain between about 50 ng to about 25 μg of fluticasone propionate that is further formulated to be administered to a patient once per month.

17. The method or formulation of claim 12 wherein the formulation comprises at least two sub- doses of fluticasone propionate wherein each sub- dose is in an amount that is between about 5 ng to about 20 μg.

18. The method or formulation of claim 12 wherein the formulation provides a mean blood plasma C_max of fluticasone propionate that is equal to or less than about 100 pg/mL when administered to a patient.

19. The method or formulation of claim 12 wherein the formulation provides a mean blood plasma C_max of fluticasone propionate that is equal to or less than about 50 pg/mL when administered to a patient.

20. The method or formulation of claim 12 wherein the formulation provides a mean blood plasma C_max of fluticasone propionate that is equal to or less than about 10 pg/mL when administered to a patient.

21. The method or formulation of any claims 1-9 wherein the glucocorticosteroid selectively partitions into adipose tissue relative to blood plasma when administered to a patient.

22. The method or formulation of claim 12 wherein a partition ratio of between about 0.01 to about 0.4 is provided when the glucocorticosteroid is administered subcutaneously.

23. The method or formulation of claim 12 wherein a partition ratio of between about 0.1 to about 0.2 is provided when the glucocorticosteroid is administered subcutaneously.

24. The method or formulation of any of claims 1-9 wherein the formulation provides a partition ratio of the glucocorticosteroid that is at least about four times lower than the partition ratio of budesonide.

25. The method or formulation of any of claims 1-9 wherein the at least one subcutaneously acceptable inactive ingredient is a co-solvent.

26. The method or formulation of any of claims 1-9 wherein the co-solvent is selected from polyethylene glycol, tert-butyl alcohol, and polysorbate.

27. The method of any of claims 4-8 wherein the administration comprises at least one injection into a submental region of the patient, an abdominal region of the patient, a hip region of the patient, a thigh region of the patient, a buttocks region of the patient, a back region of the patient, an upper arm region of the patient or a chest region of the patient.

28. The method of claim 27 wherein the administration comprises at least one injection into the submental area of the patient.

29. The method of claim 27 wherein the administration comprises at least one injection into the abdominal region of the patient.

0. The method or formulation of claims 1-9 wherein the injectable formulation is substantially free of a lipophilic long-acting selective beta-2 adrenergic receptor agonist.