Compositions and methods for alleviating conditions caused by abnormal subcutaneous deposition of adipose tissue or fat

Abstract

A method for alleviating a condition caused by abnormal subcutaneous deposition of adipose tissue or fat in a subject in need thereof, wherein an effective amount of a composition comprises: (i) a first active agent comprising a resveratrol compound, a curcumin compound, a quercetin compound, a puerarin compound, or a combination thereof; and (ii) a pharmaceutically acceptable carrier.

Description

Technical Field

[0001] Cross - Reference to Related Applications This application claims the benefit of the filing date of U.S. Provisional Patent Application No. 63 / 342,284, filed May 16, 2022, the entire contents of which are incorporated herein by reference.

[0002] The present disclosure relates to pharmaceutical compositions and their use for alleviation (e.g., treatment) of conditions caused by abnormal subcutaneous deposition of adipose tissue or fat. More specifically, the present disclosure relates to compositions comprising micelles formed by lipophilic and / or hydrophilic therapeutic agents and suitable surfactants for alleviating (e.g., treating) conditions caused by abnormal subcutaneous deposition of adipose tissue or fat.

Background Art

[0003] Lipoma is defined as a common subcutaneous tumor, often composed of adipocytes encapsulated by a thin layer of fibrotic cells. Clinically, lipomas can be present anywhere in the body and can even cause death if they grow in a life - threatening area. Lipomas are associated with various medical conditions, including Dercum's disease (adiposis dolorosa). Dercum's disease is a rare disorder characterized by chronic pain due to multiple lipomas in adipose tissue. Kucharz et al., Reumatologia 57(5):281 - 287(2019).

[0004] Dercum's disease is accompanied by long-term chronic and recurrent lipomas. There is no specific treatment for Dercum's disease. Treatment is directed at specific symptoms that are apparent in each individual and mainly focuses on alleviating the onset of characteristic pain. Patients have multiple painful lipomas or lipomatous tumors with abnormal accumulation of subcutaneous fat in the trunk and limbs, accompanied by spontaneous severe pain in that area, which persists for more than three months. Due to the above-mentioned severe chronic pain, patients are unable to lead a normal life. In addition, the symptoms do not spontaneously reduce or disappear, and painful lipomas may grow large in a short period, and new lipomas or fatty masses still grow even after surgical removal or liposuction. The cause of this disease has not yet been identified and is highly likely to be related to abnormal metabolism of adipose tissue.

[0005] According to statistics, currently, there are approximately 124,500 patients with Dercum's disease in the United States and approximately 240,000 patients in Europe. The incidence rate in women is about 5 to 30 times that in men. Currently, there are no commercially approved drugs or products for the treatment of Dercum's disease in the world, and the only things that can relieve symptoms are surgery or other drugs. Liposuction or surgical resection is a relatively common treatment method, but they have obvious side effects and high risks, and the postoperative recovery period is longer. Also, even after surgical removal or liposuction, new lipomas or lipomatous tumors will grow again.

[0006] Recently, various painkillers (analgesics) have been tried with limited effectiveness. Injections of corticosteroids are also used to treat individuals with Dercum's disease. However, in one case reported in the medical literature, the use of high-dose corticosteroids was related as a possible cause of the disease. Intravenous administration of the painkillers lidocaine and / or ketamine can provide temporary pain relief in some people.

[0007] Surgical excision of lipomas can temporarily relieve symptoms, but the occurrence of inflammation during and after surgery (part of the healing process) can induce the development of more lipomas in that area. Liposuction has been used as a symptomatic treatment for some individuals with Dercum's disease and can provide initial pain reduction and improvement in quality of life. These effects can decline over time.

[0008] Therefore, it is highly important to develop effective and safer therapies for relieving lipomas and treating lipoma-related diseases, with no scar care, reduced risk of infection, or minimized sequelae.

Summary of the Invention

[0009] The present disclosure is based, at least in part, on the development of pharmaceutical compositions comprising suitable therapeutic agents and surfactants that form micelles for use in alleviating (e.g., treating) conditions caused by abnormal subcutaneous deposition of adipose tissue or fat, such as lipomas, liposarcomas, lymphedema, and other such conditions known in the art or provided herein. For example, the exemplary compositions provided herein have successfully reduced the size of lipomas and alleviated pain associated with lipomas. See the following examples.

[0010] Accordingly, in one aspect, the present disclosure features a method for alleviating a condition caused by abnormal subcutaneous deposition of adipose tissue or fat in a subject. The method includes administering to a subject in need of treatment an effective amount of a composition comprising (a) an active agent (e.g., a resveratrol compound, a curcumin compound, a quercetin compound, a puerarin compound, or a combination thereof) and (b) a pharmaceutically acceptable carrier. In some instances, the resveratrol compound can be resveratrol. In other instances, the curcumin compound can be curcumin. Alternatively, or in addition, the quercetin compound can be quercetin and / or the puerarin compound can be puerarin.

[0011] The pharmaceutically acceptable carrier can be a pharmaceutically acceptable nonionic surfactant (e.g., Tween 80, polyoxyl 15 hydroxystearate (solutol HS 15), polyoxyethylene castor oil derivatives, or combinations thereof). Some preferred nonionic surfactants have a hydrophilic-lipophilic balance value (HLB value) greater than 10. In some embodiments, the weight ratio of the active agent to the nonionic surfactant can be from 1:5 to 1:500. The composition of the active agent and the nonionic surfactant can be in the form of micelles.

[0012] In other embodiments, the composition can further comprise additional micelles formed by a nonionic surfactant (e.g., as described above) and one or more hydrophilic therapeutic agents (e.g., green tea extract, epicatechin, epicatechin gallate, epigallocatechin, gallocatechin gallate, gallocatechin, catechin gallate, catechin, epigallocatechin gallate (EGCG), caffeine, carnitine, L-carnitine, synephrine, chlorogenic acid, and other hydrophilic drugs, or combinations thereof). The weight ratio of the hydrophilic therapeutic agent to the nonionic surfactant in the second micelle can also be from 1:5 to 1:500. Additionally, the weight ratio of the first active agent to the hydrophilic therapeutic agent can be from 30:1 to 1:10.

[0013] Any of the micelles contained in the compositions disclosed herein (e.g., those containing an active agent as disclosed herein) can have a diameter of less than 50 nm (e.g., from about 1 to about 50 nm, or from about 10 to 25 nm) and / or a polydispersity index (PDI) value of less than 0.4.

[0014] In some examples, the composition can be formulated for parenteral administration, such as injection, implantation, or transdermal administration. The composition formulated for injection can be in the form of a powder (e.g., lyophilized powder), a sterile suspension, an injection solution, an injectable emulsion, or an intravenous infusion. In some examples, the composition can be disposed in a microneedle device for injection. Alternatively, the composition can be formulated for transdermal administration, for example, in the form of an ointment, a lotion, a liniment, a cream, a gel, a bandage, an emulsion, a film, a patch, a compress, a poultice, a topical powder, or a topical solution.

[0015] In some embodiments, any of the methods disclosed herein can be carried out by administering any of the compositions disclosed herein via a parenteral route (e.g., topical administration or local injection). In some examples, the composition can be administered to a local site, such as to or near a lipoma or a liposarcoma. In some cases, the local site can be in the thigh, buttock, lower limb, pelvic region, or abdomen where lipomas or liposarcomas frequently occur. The composition can be administered to the subject one or more times depending on the size of the lipoma or liposarcoma to be treated.

[0016] In some embodiments, the condition for treatment by any of the methods disclosed herein can be a tumor of adipose tissue. In some examples, the tumor of adipose tissue can be a benign tumor, such as a lipoma. In some cases, the lipoma can be a nodular lipoma. In other cases, the lipoma can be a diffuse lipoma. In other examples, the tumor of adipose tissue can be a malignant tumor, such as a liposarcoma, Proteus syndrome, PTEN hamartoma syndrome, Gardner syndrome, familial multiple lipomatosis, Cowden syndrome, Madelung disease, painful lipoma, angiolipoma, lipomatosis, subcutaneous adipose tissue disease, adipose edema, rare adipose disorder (RAD), or soft tissue sarcoma.

[0017] In certain examples, the methods disclosed herein are for treating diseases associated with lipomas. Such diseases can be Dercum's disease. In other examples, the methods disclosed herein are for treating liposarcomas. In yet another example, the methods disclosed herein are for treating lymphedema.

[0018] Also provided are pharmaceutical compositions as disclosed herein for use in alleviating conditions caused by abnormal subcutaneous deposition of adipose tissue and / or fat (e.g., diseases associated with lipomas such as lipoma or Dercum's disease; or liposarcoma). Further, the present disclosure provides the use of any of the pharmaceutical compositions as disclosed herein for manufacturing a medicament for use in treating any of the target conditions as disclosed herein.

[0019] Details of one or more embodiments of the invention are set forth in the following description. Other features or advantages of the invention will become apparent from the following drawings and detailed description of several embodiments, as well as from the appended claims.

Brief Description of the Drawings

[0020] The following drawings form a part of this specification and are included to further demonstrate certain aspects of the present disclosure that can be better understood by reference to the drawings in combination with the detailed description of specific embodiments presented herein.

[0021]

Figure 1

Figures 2A - 2B

Figures 3A - 3B

Figures 4A - 4B

Mode for Carrying Out the Invention

[0022] Pharmaceutical compositions for alleviating (e.g., treating) conditions caused by abnormal subcutaneous deposition of adipose tissue or fat, including the diseases and disorders provided herein, and their therapeutic use are disclosed herein. The pharmaceutical compositions disclosed herein may include one or more active agents, which may be a resveratrol compound, a curcumin compound, a quercetin compound, a puerarin compound, or a combination thereof. The one or more active agents may form micelles (a first plurality of micelles) with a suitable pharmaceutically acceptable nonionic surfactant, such as those disclosed herein. In some embodiments, the pharmaceutical composition may further include a second plurality of micelles that may be formed by a suitable pharmaceutically acceptable nonionic surfactant and a hydrophilic agent as disclosed herein. Also provided herein is a method for alleviating (e.g., treating) a condition caused by abnormal subcutaneous deposition of adipose tissue or fat, such as a lipoma or liposarcoma, using any of the pharmaceutical compositions disclosed herein.

[0023] I. Pharmaceutical Compositions The pharmaceutical compositions disclosed herein include one or more of a resveratrol compound, a curcumin compound, a quercetin compound, and a puerarin compound as active agents for alleviating conditions caused by abnormal subcutaneous deposition of adipose tissue or fat, such as lipoma or liposarcoma. Active agents as disclosed herein may form micelles (a first plurality of micelles) with a suitable nonionic surfactant such as those disclosed herein. The pharmaceutical compositions disclosed herein may further include a second plurality of micelles formed by a hydrophilic agent and a suitable nonionic surfactant.

[0024] (A) Active Agent Exemplary active agents provided herein include resveratrol compounds, curcumin compounds, quercetin compounds, and puerarin compounds.

[0025] A resveratrol compound may have the structure of formula (I) below or a salt thereof,

[0026]

Chemical formula

Chemical formula

[0027] In one example, the resveratrol compound is resveratrol (where R 1 -R 3 are all -OH and R 4 is -H). Alternatively, the resveratrol compound may have suitable substitutions at one or more suitable positions in resveratrol as known to those skilled in the art.

[0028] A curcumin compound as disclosed herein may have the structure of formula (II) below or a salt thereof,

Chemical formula

[0029] In some embodiments, the curcumin compound may have the structure of the following formula (IIa) or a salt thereof,

Chemical formula

[0030] The quercetin compound as disclosed herein may have the structure of the following formula (III) or a salt thereof,

Chemical formula

[0031] The puerarin compound as disclosed herein may be a compound of the following formula (IV) or a salt thereof,

Chemical formula

[0032] "Alkyl" refers to a straight-chain, saturated, acyclic, monovalent hydrocarbon radical or a branched, saturated, acyclic, monovalent hydrocarbon radical having 1 to 3 carbon atoms bonded to the rest of the molecule by a single bond, such as methyl, ethyl, n-propyl, or 1-methylethyl (iso-propyl). An optionally substituted alkyl radical is an alkyl radical optionally substituted by 1, 2, 3, 4, or 5 substituents independently selected from the group consisting of halo, cyano, nitro, oxo, hydroxyl, thio, or amino, as valency permits.

[0033] "Alkenyl" refers to a straight-chain, acyclic, monovalent hydrocarbon radical or a branched, acyclic, monovalent hydrocarbon radical having 2 or 3 carbon atoms containing a carbon-carbon double bond and bonded to the rest of the molecule by a single bond, such as ethenyl or propenyl. An optionally substituted alkenyl radical is an alkenyl radical optionally substituted by 1, 2, or 3 substituents independently selected from the group consisting of halo, cyano, nitro, hydroxyl, thio, or amino, as valency permits.

[0034] "Alkynyl" refers to a straight-chain, acyclic, monovalent hydrocarbon radical or a branched, acyclic, monovalent hydrocarbon radical having 2 or 3 carbon atoms containing a triple bond and bonded to the rest of the molecule by a single bond, such as ethynyl or propynyl. An optionally substituted alkynyl radical is an alkynyl radical optionally substituted by 1 substituent selected from the group consisting of halo, cyano, nitro, hydroxyl, thio, or amino.

[0035] "Alkoxy" refers to a radical of the formula -ORa, where Ra is hydrogen or an alkyl radical containing 1 to 3 carbon atoms as defined above. The alkyl portion of an optionally substituted alkoxy radical is optionally substituted for an alkyl radical as defined above.

[0036] "Amino" refers to a radical of the formula -NRbRc (wherein Rb and Rc are each hydrogen), or an alkyl radical containing 1 to 3 carbon atoms as defined above. The alkyl portion of an optionally substituted amino radical is optionally substituted for an alkyl radical as defined above.

[0037] "Thiol" refers to a radical of the formula -SRd (wherein Rd is hydrogen), or an alkyl radical containing 1 to 3 carbon atoms as defined above. The alkyl portion of an optionally substituted thiol radical is optionally substituted for an alkyl radical as defined above.

[0038] "Hydrophilic", as used herein, refers to one or more molecules having a hydrophilic-lipophilic balance greater than 10, for example, using the Griffin method.

[0039] (B) Hydrophilic therapeutic agent In some embodiments, the pharmaceutical compositions disclosed herein may further comprise one or more hydrophilic therapeutic agents as described herein, which may provide a benefit in the treatment of conditions caused by adipose tissue / adipose deposition, compared to pharmaceutical compositions containing only the active agents disclosed herein. The hydrophilic therapeutic agent may be effective in alleviating the conditions as disclosed herein. Alternatively, or in addition, the hydrophilic therapeutic agent may enhance the efficacy of the active agent and / or reduce the side effects associated with the active agent.

[0040] A hydrophilic therapeutic agent is a drug that is soluble in water. Exemplary hydrophilic therapeutic agents include, but are not limited to, flavonoids based on green tea extract, catechins (e.g., catechin, catechin gallate), gallocatechins (e.g., gallocatechin, gallocatechin gallate), epicatechins (e.g., epicatechin, epicatechin gallate), epigallocatechins (e.g., epigallocatechin, epigallocatechin gallate), xanthines including methylxanthines (e.g., caffeine), carnitine, L-carnitine, synephrine, and chlorogenic acid. Combinations of the aforementioned drugs may also be eligible as hydrophilic therapeutic agents used herein. Alternatively, other hydrophilic therapeutic agents may be combined with the present technology to assist in the treatment of lipomas. In some embodiments, the hydrophilic therapeutic agent may be combined with a second nonionic surfactant, preferably forming micelles.

[0041] In some embodiments, the weight ratio of the active agent to the hydrophilic therapeutic agent is from 30:1 to 1:10, such as from 30:1 to 1:5, from 30:1 to 1:1, from 30:1 to 5:1, from 30:1 to 10:1, from 30:1 to 20:1, from 20:1 to 1:10, from 10:1 to 1:10, from 5:1 to 1:10, from 1:1 to 1:10, from 1:5 to 1:10, from 20:1 to 1:5, from 10:1 to 1:1, or from 5:1 to 1:1.

[0042] (C) Nonionic surfactant The pharmaceutical compositions disclosed herein may include one or more nonionic surfactants that can form micelles with the active agents and / or hydrophilic therapeutic agents as disclosed herein. The nonionic surfactants used in the present technology are beneficial at least in the formation of micelles in the composition. In some embodiments, the micelles have the effect of encapsulating the active agent and / or hydrophilic therapeutic agent.

[0043] The nonionic surfactant used in any of the pharmaceutical compositions disclosed in this specification preferably has a hydrophilic-lipophilic balance (HLB) value exceeding 10. The nonionic surfactant is used in this technology at the ratios as described above. Exemplary nonionic surfactants include, but are not limited to, polysorbate 80 (Tween® 80), polyoxyl 15 hydroxystearate (Solutol® HS-15), polyoxyethylene castor oil derivatives (e.g., polyoxyl 35 castor oil (Kolliphor® ELP), polyoxyl 40 hydrogenated castor oil (Koliphor® RH40), and polyoxyl 60 hydrogenated castor oil (Cremophor® RH60), polyoxyethylene (12) glyceryl laurate (UNIGLY, ML-212), polyoxyl 20 stearate (Myrj™ S20), polyoxyl 40 stearate (Myrj™ S40), polyoxyl cetostearyl ether 12 (Kolliphor® CS12), and polyoxyl 12 cetostearyl ether 2 (Kolliphor® CS20).

[0044] In some cases, nonionic surfactants can be polyoxyethylene derivatives, which are also known as PEGylated excipients. In some examples, the polyoxyethylene derivatives are PEG castor oil derivatives, which are materials obtained by reacting various amounts of ethylene oxide with either castor oil or hydrogenated castor oil. Examples include PEG-35 castor oil and PEG-40 hydrogenated castor oil. In other examples, the polyoxyethylene derivatives are PEG esters, which can be produced by reacting polyethylene glycol with fatty acids. Examples include PEG-40 stearate and PEG-15 hydroxystearate. In some cases, the esters can be sorbitan fatty acid esters (e.g., PEG-20 sorbitan monooleate, PEG-40 sorbitan monooleate, PEG-60 sorbitan monooleate, PEG-80 sorbitan monooleate, PEG-20 sorbitan isostearate, PEG-30 sorbitan tetraoleate, PEG-40, -60 sorbitan tetraoleate, PEG-40 sorbitan diisostearate, or PEG-60 sorbitan tetrastearate), alkyl glycerides (e.g., PEG-8 caprylic / capric glyceride, PEG-32 hydrogenated palm glyceride, or PEG-32 lauroyl glyceride), or alkyl ethers (e.g., PEG-6 cetostearyl ether, PEG-12 cetostearyl ether, PEG-20 cetostearyl ether, PEG-10 cetyl ether, PEG-20 cetyl ether, PEG-4 lauryl ether, PEG-23 lauryl ether, PEG-2 oleyl ether, PEG-10 oleyl ether, PEG-20 oleyl ether, PEG-2 stearyl ether, PEG-10 stearyl ether, PEG-21 stearyl ether, or PEG-100 stearyl ether). In still other cases, the esters can be laurates (e.g., PEG-2 laurate, PEG-4 laurate, PEG-6 laurate, PEG-8 laurate.Lauric acid PEG-9-14, lauric acid PEG-20, lauric acid PEG-32-150, or lauric acid PEG-12 glyceryl), dilaurate (e.g., dilauric acid PEG-2, dilauric acid PEG-4, or dilauric acid PEG-6-150), or stearate (e.g., stearic acid PEG-2, stearic acid PEG-3, stearic acid PEG-4, isostearic acid PEG-4, stearic acid PEG-5-7, isostearic acid PEG-6-8, stearic acid PEG-8, stearic acid PEG-9, stearic acid PEG-10, isostearic acid PEG-10, isostearic acid PEG-12, stearic acid PEG-12-18, stearic acid PEG-20, stearic acid PEG-23-45, stearic acid PEG-40, stearic acid PEG-50, stearic acid PEG-100, stearic acid PEG-75-150, or palmitostearic acid PEG-6 and PEG-32), glyceryl stearate (e.g., glyceryl stearate / stearic acid PEG-40, glyceryl stearate / stearic acid PEG-100, stearic acid PEG-120 glyceryl, sesquistearic acid PEG-20 methyl glucose, or stearic acid PEG-25 propylene glycol), distearate (e.g., distearic acid PEG-2, distearic acid PEG-3-120, distearic acid PEG-150, or distearic acid PEG-175), hydroxystearate (e.g., hydroxystearic acid PEG-15) may be used.

[0045] In some cases, the nonionic surfactant may be a castor oil derivative (e.g., PEG-35 castor oil or PEG-40 castor oil) or a hydrogenated castor oil (e.g., PEG-40 hydrogenated castor oil, PEG-54 hydrogenated castor oil, or PEG-60 hydrogenated castor oil).

[0046] Additional examples of nonionic surfactants include PEG-15 cocoamine, polyethylene glycol vitamin E succinate, PEG-75 lanolin, and PEG-120 methyl glucose dioleate.

[0047] (D) Micelles and their preparation Any of the pharmaceutical compositions may include micelles formed by a first nonionic surfactant as disclosed herein and one or more active agents such as a resveratrol compound (e.g., resveratrol), a curcumin compound (e.g., curcumin), a quercetin compound (e.g., quercetin), a puerarin compound (e.g., puerarin), or a combination thereof. If the pharmaceutical composition further includes one or more hydrophilic therapeutic agents as disclosed herein, the pharmaceutical composition may further include a second nonionic surfactant that forms micelles with the hydrophilic therapeutic agent. In that case, the pharmaceutical composition may include a first plurality of micelles formed by the first nonionic surfactant and the active agent and a second plurality of micelles formed by the second nonionic surfactant and the hydrophilic therapeutic agent. In some examples, the first nonionic surfactant and the second nonionic surfactant are the same. In other examples, the first nonionic surfactant is different from the second nonionic surfactant.

[0048] In some embodiments, the micelles can include a nonionic surfactant and an active agent in a suitable weight ratio that results in a suitable particle size and / or a suitable polydispersity index (PDI) value. For example, suitable weight ratios between the active agent and the nonionic surfactant can range from about 1:5 to 1:500, such as about 1:5 to 1:8, about 1:5 to 1:10, about 1:5 to 1:20, about 1:5 to 1:40, about 1:5 to 1:100, 1:5 to 1:150, 1:5 to 1:200, 1:5 to 1:300, 1:5 to 1:400, 1:5 to 1:500, about 1:8 to 1:10, about 1:8 to 1:20, about 1:8 to 1:40, about 1:8 to 1:100, 1:8 to 1:150, 1:8 to 1:200, 1:8 to 1:300, 1:8 to 1:400, 1:8 to 1:500, about 1:10 to 1:20, about 1:10 to 1:40, about 1:10 to 1:100, 1:10 to 1:150, 1:10 to 1:200, 1:10 to 1:300, 1:10 to 1:400, 1:10 to 1:500, about 1:20 to 1:40, about 1:20 to 1:100, 1:20 to 1:150, 1:20 to 1:200, 1:20 to 1:300, 1:20 to 1:400, 1:20 to 1:500, about 1:40 to 1:100, 1:40 to 1:150, 1:40 to 1:200, 1:40 to 1:300, 1:40 to 1:400, 1:40 to 1:500, 1:100 to 1:150, 1:100 to 1:200, 1:100 to 1:300, 1:100 to 1:400, 1:100 to 1:500, or 1:150 to 1:500. Micelles formed at suitable weight ratios between the active agent and the nonionic surfactant as disclosed herein have been reported to result in suitable particle sizes (e.g., less than 50 nm) and suitable PDI values (e.g., less than 0.4). See U.S. Patent No. 10,610,496, the relevant disclosure of which is incorporated herein by reference for the subject matter and purposes referenced herein.

[0049] In some embodiments, the pharmaceutical composition may further comprise micelles (second plurality of micelles) formed by a nonionic surfactant as disclosed herein and one or more of the hydrophilic therapeutic agents as also disclosed herein. Similar to the first plurality of micelles, the hydrophilic therapeutic agent to nonionic surfactant may be in a suitable weight ratio that results in a suitable particle size and / or PDI value. For example, the weight ratio between the hydrophilic therapeutic agent and the nonionic surfactant may be in the range of about 1:5 to 1:500, such as about 1:5 to 1:8, about 1:5 to 1:10, about 1:5 to 1:20, about 1:5 to 1:40, about 1:5 to 1:100, 1:5 to 1:150, 1:5 to 1:200, 1:5 to 1:300, 1:5 to 1:400, 1:5 to 1:500, about 1:8 to 1:10, about 1:8 to 1:20, about 1:8 to 1:40, about 1:8 to 1:100, 1:8 to 1:150, 1:8 to 1:200, 1:8 to 1:300, 1:8 to 1:400, 1:8 to 1:500, about 1:10 to 1:20, about 1:10 to 1:40, about 1:10 to 1:100, 1:10 to 1:150, 1:10 to 1:200, 1:10 to 1:300, 1:10 to 1:400, 1:10 to 1:500, about 1:20 to 1:40, about 1:20 to 1:100, 1:20 to 1:150, 1:20 to 1:200, 1:20 to 1:300, 1:20 to 1:400, 1:20 to 1:500, about 1:40 to 1:100, 1:40 to 1:150, 1:40 to 1:200, 1:40 to 1:300, 1:40 to 1:400, 1:40 to 1:500, 1:100 to 1:150, 1:100 to 1:200, 1:100 to 1:300, 1:100 to 1:400, 1:100 to 1:500, or 1:150 to 1:500.

[0050] In some embodiments, the first plurality of micelles, the second plurality of micelles, or both may have a particle size (diameter) of less than 50 nm. In some examples, the particle size may be in the range of about 1 nm to about 50 nm. In some examples, the particle size may be in the range of about 10 nm to about 25 nm. Unless otherwise indicated, the particle sizes disclosed herein refer to the actual size (diameter) of the micelles in the micelle population. For example, if the smallest micelle in the population has a particle size of 10 nm and the largest micelle in the population has a particle size of 50 nm, the particle size of the population is in the range of 10 nm to 50 nm.

[0051] In some embodiments, at least 50% (e.g., 60%, 70%, 80%, 90% or more) of the particles in the first plurality of micelles, the second plurality of micelles, or both have a particle size (diameter) of less than 50 nm.

[0052] Alternatively, or in addition, the polydispersity index of the first plurality of micelles, the second plurality of micelles, or both may be less than 0.6, e.g., less than 0.5, less than 0.4, less than 0.3, less than 0.2, or less than 0.1. In some examples, the polydispersity index of the first plurality of micelles, the second plurality of micelles, or both may be in the range of 0 to 0.6, e.g., 0.1 to 0.6, 0.2 to 0.6, 0.3 to 0.6, 0.4 to 0.6, 0.5 to 0.6, 0.1 to 0.5, 0.2 to 0.5, 0.3 to 0.5, 0.4 to 0.5, 0.1 to 0.4, 0.2 to 0.4, 0.3 to 0.4, 0.1 to 0.3, 0.2 to 0.3, or 0.1 to 0.2.

[0053] Any of the micelles disclosed herein can be prepared by conventional methods or as disclosed herein. An example is provided below. A suitable amount of an active agent or hydrophilic therapeutic agent can be mixed with a suitable solvent (e.g., alcohol (e.g., methanol, ethanol, propanol), acetonitrile, chlorinated solvent (e.g., dichloromethane, chloroform), diethyl ether, and ethyl acetate), and the mixture can be stirred at a suitable temperature (e.g., 150 - 500 rpm) until the active agent or hydrophilic therapeutic agent is completely dissolved in the solvent to form a solution. A suitable amount of a pharmaceutically acceptable nonionic surfactant (e.g., those disclosed herein) can be added to the solution. The resulting mixture can be stirred at a suitable temperature (e.g., 100 - 300 rpm) to evaporate the solvent. When the solvent is completely evaporated, a suitable amount of a pharmaceutically acceptable aqueous solution (e.g., physiological saline) can be added to the mixture to produce micelles encapsulating the active agent or hydrophilic agent. The resulting particles can be filtered through a suitable filter (e.g., a 0.2 μm filter), and the filtered solution containing the drug-containing micelles can be stored in the dark in a refrigerator for later use.

[0054] Additional details regarding the preparation of the micelles of the present technology can be found in U.S. Patent No. 10,610,496, the relevant disclosure of which is incorporated by reference for the subject matter and purposes referenced herein.

[0055] (E) Pharmaceutical composition Any of the active agent, optionally hydrophilic therapeutic agent, and nonionic surfactant, which can form micelles with an active agent and optionally a hydrophilic therapeutic agent, can be formulated into a pharmaceutical composition for use in the therapeutic uses disclosed herein.

[0056] The pharmaceutical composition used in this method may include a pharmaceutically acceptable carrier, excipient, or stabilizer in the form of a lyophilized formulation or an aqueous solution. (Remington: The Science and Practice of Pharmacy 20th Ed. (2000) Lippincott Williams and Wilkins, Ed. K. E. Hoover). The acceptable carrier, excipient, or stabilizer is non-toxic to the recipient at the dosages and concentrations used, and includes buffers such as phosphates, citrates, and other organic acids; antioxidants including ascorbic acid and methionine; preservatives (octadecyl dimethyl benzyl ammonium chloride; hexamethonium chloride; benzalkonium chloride, benzetonium chloride; phenol, butyl, or benzyl alcohol; alkyl parabens such as methyl or propyl paraben; catechol; resorcinol; cyclohexanol; 3-pentanol; and m-cresol, etc.); low molecular weight (less than about 10 residues) polypeptides; proteins such as serum albumin, gelatin, or immunoglobulins; hydrophilic polymers such as polyvinylpyrrolidone; amino acids such as glycine, glutamine, asparagine, histidine, arginine, or lysine; monosaccharides, disaccharides, and other carbohydrates including glucose, mannose, or dextran; chelating agents such as EDTA; sugars such as sucrose, mannitol, trehalose, or sorbitol; salt-forming counterions such as sodium; metal complexes (e.g., Zn-protein complexes); and / or nonionic surfactants such as TWEEN (trademark), PLURONICS (trademark), or polyethylene glycol (PEG).

[0057] In other examples, the pharmaceutical compositions described herein can be formulated in a sustained release format. Suitable examples of sustained release preparations include semipermeable matrices of solid hydrophobic polymers containing the antibody, and the matrix is in the form of a shaped article, such as a film or microcapsule. Examples of sustained release matrices include polyesters, hydrogels (e.g., poly(2-hydroxyethyl-methacrylate), or poly(vinyl alcohol)), polylactides (U.S. Patent No. 3,773,919), copolymers of L-glutamic acid and 7-ethyl-L-glutamate, non-degradable ethylene-vinyl acetate, degradable lactic acid-glycolic acid copolymers such as LUPRON DEPOT™ (injectable microspheres composed of lactic acid-glycolic acid copolymer and leuprolide acetate), sucrose acetate isobutyrate, and poly-D-(-)-3-hydroxybutyric acid.

[0058] Pharmaceutical compositions used for in vivo administration must be sterile. This can be readily accomplished, for example, by filtration through sterile filtration membranes. Therapeutic antibody compositions are generally placed in a container having a sterile access port, such as an intravenous solution bag or vial having a stopper penetrable by a hypodermic needle.

[0059] The pharmaceutical compositions described herein can be in unit dosage forms such as tablets, pills, capsules, powders, granules, solutions, or suspensions, or suppositories for oral, parenteral, or rectal administration, or for administration by inhalation or insufflation. For example, such pharmaceutical compositions can be formulated in a manner suitable for administration via a suitable route, such as oral, parenteral, topical, rectal, buccal, vaginal, or via an implantable reservoir.

[0060] Sterile injectable compositions, for example, sterile aqueous or oleaginous suspensions, can be formulated according to techniques known in the art using suitable dispersing or wetting agents (such as polysorbate 80) and suspending agents. Sterile injectable preparations can be, for example, sterile injectable solutions or suspensions in a non-toxic parenterally acceptable diluent or solvent such as a solution in 1,3 - butanediol. Among the acceptable vehicles and solvents that can be used are mannitol, water, Ringer's solution, and isotonic sodium chloride solution. In addition, sterile fixed oils are conventionally used as solvents or suspending media (such as synthetic mono - or diglycerides). Fatty acids such as oleic acid and its glyceride derivatives are useful in the preparation of injectables, as are natural pharmaceutically acceptable oils such as olive oil or castor oil, especially their polyoxyethylated versions. These oil solutions or suspensions can also contain long - chain alcohol diluents or dispersing agents, or carboxymethyl cellulose or similar dispersing agents. Other commonly used surfactants, such as Tweens or Spans or other similar emulsifying agents or bioavailability enhancers (commonly used in the manufacture of pharmaceutically acceptable solid, liquid, or other dosage forms), can also be used for the purpose of formulation.

[0061] In some embodiments, the compositions described herein can be formulated as topical preparations, for example, as creams, lotions, or gels for topical application. Such creams, lotions, or gels can be formulated using components known in the art to be suitable for topical dosing.

[0062] A carrier in a pharmaceutical composition is "acceptable" in that it is compatible with (preferably, capable of stabilizing) the active ingredient of the formulation and must not be harmful to the subject being treated. For example, solubilizing agents such as cyclodextrins that form more soluble complexes with oxadiazole compounds, or additional solubilizing agents, can be utilized as pharmaceutical carriers for the delivery of oxadiazole compounds. Examples of other carriers include colloidal silicon dioxide, magnesium stearate, sodium lauryl sulfate, and D&C Yellow No. 10.

[0063] In some embodiments, the pharmaceutical compositions disclosed herein may further comprise an antioxidant. Examples include, but are not limited to, beta-carotene, lutein, lycopene, bilirubin, vitamin A, vitamin C (ascorbic acid), vitamin E, uric acid, nitric oxide, nitrogen oxides, pyruvate, catalase, superoxide dismutase, glutathione peroxidase, N-acetylcysteine, and naringenin, or combinations thereof.

[0064] II. Method for alleviating conditions caused by abnormal subcutaneous deposition of adipose tissue and / or fat In some aspects, provided herein are methods for alleviating (e.g., treating) conditions caused by abnormal subcutaneous deposition of adipose tissue and / or fat using any of the pharmaceutical compositions disclosed herein.

[0065] In some embodiments, the condition caused by abnormal subcutaneous deposition of adipose tissue and / or fat can be a tumor of adipose tissue, which can result in abnormal deposition of adipocytes / tissue (adipose tissue) and / or fat under the skin spots (subcutaneous). In some examples, the tumor of adipose tissue can be benign, e.g., lipoma. In other examples, the tumor of adipose tissue can be malignant, e.g., liposarcoma.

[0066] (A). Lipoma and diseases associated with lipoma A lipoma is a benign tumor of fat formed between the skin and the underlying muscle. Lipomas can grow anywhere in the body where fat cells are present. The neck, shoulders, underarms, and thighs are common locations where lipomas tend to develop. Depending on their location, lipomas can be classified into three subtypes: subcutaneous lipoma, intermuscular lipoma, and visceral lipoma.

[0067] Lipomas can be associated with various medical conditions, such as Dercum's disease (adiposis dolorosa), Gardner's syndrome, familial multiple lipomatosis (hereditary multiple lipomatosis), Madelung's disease (multiple symmetric lipomatosis), painful lipomas, angiolipomas, lipomatosis, subcutaneous adipose tissue disorders, lipedema, and rare adipose disorders (RAD), panniculitis, Weber-Christian disease, progressive lipodystrophy, or other diseases / conditions associated with adipose lesions. Some of such disorders can result in severe symptoms such as swelling, intense pain, or even mental problems.

[0068] In some embodiments, a subject suitable for the treatment disclosed herein can be a human patient having at least one lipoma. Such a human patient can also have an adipose disorder, a subcutaneous adipose tissue disorder, lipedema, a rare adipose disorder (RAD), a skin disorder, a lipid metabolism disorder, or a metabolic disorder. Alleviating a lipoma by any of the methods disclosed herein is expected to be beneficial for the treatment of such diseases and disorders.

[0069] In some examples, a method for treating Dercum's disease (DD) is provided herein using any of the compositions disclosed herein. DD, also known as adiposis dolorosa, adiposis dolorosa lipomatosis, or Ander's syndrome, is a rare disorder characterized by chronic pain due to multiple lipomas in adipose tissue. This disease is often accompanied by a number of related symptoms such as debilitation, fatigue, depression, and dementia. The painful adipose tissue can be diffuse or systemic, or concentrated in palpable lipomas. The most commonly affected sites are the extremities, trunk, pelvic region, and buttocks.

[0070] Patients with DD can often be diagnosed by exclusion, and imaging can be helpful in the diagnosis of DD. Patients with Dercum's disease are typically troubled by severe pain in their adipose tissue deposits, which often becomes more intense over the course of the disease. Such pain is frequently seen especially in the abdomen and buttocks, upper arms, and outer thighs, and sometimes also in the knees and elbows. Even minor stimuli (e.g., light touch, ventilation, rubbing against clothing or bedding, temperature changes) can cause severe discomfort. This can also lead to psychosocial problems. The diagnosis of Dercum's disease should be made based on clinical examination after excluding related differential diagnoses. Two main criteria were established in the 2012 publication (Hansson E, Svensson H, Brorson H. Review of Dercum’s disease and proposal of diagnostic criteria, diagnostic methods, classification and management.): obesity and chronic pain (more than 3 months) in hyperplastic / hypertrophic adipose tissue. There are no clear histological or instrumental (imaging) diagnostic criteria.

[0071] Table 1 below summarizes the differential diagnosis of DD and related co-morbidities. Table 2 lists four subtypes based on their morphological appearance and distribution pattern.

Table 1

Table 2

[0072] Effective treatments for patients with Dercum's disease are currently lacking because there are no effective long-term treatments. The management of Dercum's disease typically involves pain control by oral medications or direct injection or surgical removal. Surgical interventions (e.g., liposuction and adipose tissue resection) have variable outcomes. Direct injection of lidocaine into lipomas has been shown to provide only short-term pain relief.

[0073] (B). Liposarcoma and diseases associated with liposarcoma Liposarcoma is a rare type of malignant tumor that develops in adipose tissue. Liposarcoma is a type of soft tissue sarcoma. Liposarcoma can occur in adipocytes anywhere in the body. Typically, liposarcoma occurs in older individuals, but can occur in any age group. The symptoms of liposarcoma depend on the part of the body where the malignant tumor forms. For example, liposarcoma in the arms and legs can cause one or more of the symptoms of a mass in the subcutaneous tissue of the affected limb, pain, swelling, and weakness. Liposarcoma in the abdomen can cause abdominal pain, abdominal distension, earlier satiety during meals, constipation, and / or bloody stools. Current treatments for liposarcoma usually involve surgery to remove the malignant tumor. Other treatments such as radiation therapy may also be used.

[0074] Liposarcoma can be associated with various medical conditions, such as soft tissue sarcoma, lipomatous hemangiopericytoma.

[0075] In some examples, methods for treating liposarcoma are provided herein using any of the compositions disclosed herein. Liposarcoma is classified as a malignant tumor due to its potential to recur locally and metastasize to other areas of the body. The severity of the disease depends on the subtype of liposarcoma and the presenting stage of the primary tumor. Liposarcoma can occur in various parts of the body, but is most frequently seen in the extremities, particularly the thigh. Liposarcoma can also grow in the dorsal part of the abdomen in an area called the "retroperitoneum," where there is a large amount of space, so tumors of considerable size and weight can be substantially hidden. Some individuals with liposarcoma may be asymptomatic in the early stages, but as the tumor grows and progresses to the later stages, it can compress other tissues and cause pain.

[0076] The specific genetic causes of liposarcoma have not yet been identified, but studies suggest that liposarcoma occurs in adipocytes that have lost their ability to mature or have stopped regulating growth. Liposarcoma has been found to occur more often in middle-aged men aged 50 - 65 years compared to women and is extremely rare in children.

[0077] Most patients diagnosed with liposarcoma are not noticed during the early stages of the disease until the tumor grows to a size large enough to compress adjacent tissues, causing pain or functional impairment, without any initial symptoms. In some cases, it may be noticed by touching a deep-seated tumor. Liposarcoma, like all other malignant tumors, can present with non-specific symptoms such as fever, chills, fatigue, night sweats, and weight loss. When the tumor is located in the retroperitoneal region, it can present with specific symptoms in the abdomen, including abdominal or flank pain, swelling, and constipation, or a feeling of fullness earlier than expected after meals.

[0078] The most important step in the diagnosis of liposarcoma involves undergoing a biopsy of the suspected tumor. A biopsy is the removal of tissue from the tumor for microscopic evaluation to determine whether the tissue has characteristics specific to the tumor. Many of these tumors are deeply embedded in the body, so imaging such as ultrasound can be used to guide the placement of a needle into the tumor and ensure the specific collection of a tissue sample from that tumor.

[0079] Liposarcoma can also be diagnosed by imaging the body with either computed tomography (CT) or magnetic resonance imaging (MRI). CT is important in using multiple X-ray measurements to create an image of the body and determine the location of the tumor and its relationship to surrounding tissues. MRI is another method of imaging liposarcoma and can show the characteristics of the tumor itself, which can be useful in the diagnostic differences between benign and malignant soft tissue tumors. [Table 3]

[0080] Table 3 lists five subtypes of liposarcoma: well-differentiated, dedifferentiated, myxoid, round cell, and pleomorphic. The well-differentiated type is less invasive and tends to be a large, painless tumor found in deep tissues and the retroperitoneum. The myxoid, round cell, and pleomorphic types tend to be in the arms and legs, while dedifferentiation tends to be in the retroperitoneum and is often associated with the well-differentiated subtype. Specifically, pleomorphic liposarcoma is a very rare subtype with a high recurrence rate and poor outcome rate.

[0081] (C). Treatment of conditions caused by abnormal subcutaneous deposition of adipose tissue and / or fat To practice the methods disclosed herein, an effective amount of the pharmaceutical composition described herein can be administered to a subject (e.g., a human) in need of treatment via a suitable route such as parenteral administration or topical administration (e.g., topical injection or topical application). Subjects (e.g., humans) who would benefit from such administration include patients having lipoma or liposarcoma, or patients suspected of having lipoma or liposarcoma. In some examples, the methods disclosed herein are directed to treating Dercum's disease in human patients. In other examples, the methods disclosed herein are directed to treating liposarcoma.

[0082] Of the patients with Dercum's disease, four subgroups of the patient population are particularly suitable for the described treatment and are described below.

[0083] Subgroup type I refers to the generalized diffuse type of lipoma. The lipomas of this subgroup may have ill-defined borders but are diffusely distributed in adipose tissue. Lipomas are associated with a pain response at a high frequency.

[0084] Subgroup II is the generalized nodular type of lipoma. Nodular lipomas are generally present in adipose tissue and are generally associated with a pain response in adipose tissue and lipomas. In addition, this subgroup type can result in multiple lipomas.

[0085] Subgroup III is the localized nodular type of lipoma. This subgroup generally results in multiple lipomas that are characteristically painful specifically in lipomas.

[0086] Subgroup IV is the juxta-articular type of lipoma. This type of lipoma is frequently an adipose tissue tumor of the medial knee or elbow.

[0087] As used herein, "effective amount" refers to the amount of each active agent necessary to provide a therapeutic effect to a subject, either alone or in combination with one or more other active agents. The determination of whether the amount of an antibody has achieved a therapeutic effect will be apparent to one of ordinary skill in the art. The effective amount will vary depending on individual patient parameters including the particular condition being treated, the severity of the condition, age, health status, size, gender, and weight, the duration of the treatment, the nature of any concomitant therapy (if any), the particular route of administration, and similar factors within the knowledge and expertise of the medical practitioner. These factors are well known to those of ordinary skill in the art and can be addressed with routine experimentation only. In general, it is preferred to use the maximum dosage of the individual components or combinations thereof, i.e., the highest safe dosage in accordance with sound medical judgment.

[0088] Empirical considerations such as half-life generally contribute to the determination of dosage. For example, antibodies that are compatible with the human immune system, such as humanized or fully human antibodies, can be used to extend the half-life of the antibody and prevent the antibody from being attacked by the host immune system. The frequency of administration can be determined and adjusted over the course of therapy and generally is not essential but is based on the treatment and / or suppression and / or improvement and / or retardation of the target disease / disorder. Alternatively, sustained continuous release formulations of the antibody may be appropriate. Various formulations and devices for achieving sustained release are known in the art.

[0089] For the purposes of the present disclosure, the appropriate dosage of a pharmaceutical composition as described herein depends on the particular active agent employed and optionally a hydrophilic agent, the type and severity of the disease / disorder, whether the composition is administered for prophylactic or therapeutic purposes, past therapies, the patient's medical history and response to the active agent, and the judgment of the attending physician. Typically, a clinician administers the pharmaceutical composition disclosed herein until a dosage that achieves the desired result is reached. In some embodiments, the desired result is a reduction or elimination of lipoma or liposarcoma, or a alleviation of at least one symptom associated with a disease associated with lipoma (e.g., pain) or a disease associated with liposarcoma. The method of determining whether the dosage has brought about the desired result will be apparent to those of skill in the art. The particular dosage regimen used in the methods described herein, i.e., the dosage, timing, and repetition, depends on the particular subject and that subject's medical history. The treatment efficacy against the target disease / disorder can be determined by methods well known in the art.

[0090] As used herein, the term "treating" refers to applying or administering a composition comprising one or more active agents to a subject having a target disease or disorder, a symptom of a disease / disorder, or a predisposition to a disease or disorder, for the purpose of treating, curing, alleviating, reducing, modifying, correcting, ameliorating, improving, or acting on the disorder, symptom of the disease, or predisposition to the disease or disorder.

[0091] Relieving a target disease or disorder includes delaying the development or progression of the disease, reducing the severity of the disease, or extending the survival period. Relieving a disease or extending the survival period does not necessarily require a curative result. As used herein, "delaying" the development of a target disease or disorder means deferring, inhibiting, decelerating, suppressing, stabilizing, and / or postponing the progression of the disease. This delay can be of various lengths of time depending on the disease history and / or the individual receiving the treatment. A method of delaying or relieving the development of a disease, or delaying the onset of a disease, is a method that reduces the probability of developing one or more symptoms of the disease within a given time frame and / or reduces the degree of those symptoms within a given time frame as compared to not using the method. Such comparisons are typically based on clinical trials using a sufficient number of subjects to give statistically significant results.

[0092] "Development" or "progression" of a disease means the initial symptoms of the disease and / or subsequent progression. The development of a disease is detectable and determinable using standard clinical techniques well known in the art. However, development can also refer to progression that is undetectable. For the purposes of the present disclosure, development or progression refers to the biological course of the symptoms. "Development" includes occurrence, recurrence, and onset. As used herein, "onset" or "occurrence" of a target disease or disorder includes initial onset and / or recurrence.

[0093] Using conventional methods known to those of ordinary skill in the medical art, a pharmaceutical composition can be administered to a subject depending on the type of disease being treated or the site of the disease. The composition can also be administered via other conventional routes, for example, parenterally, topically, or via an implantable reservoir. The term "parenteral" as used herein includes subcutaneous, intradermal, intravenous, intramuscular, intra-articular, intra-arterial, intra-synovial, intrasternal, intramedullary, intralesional, and intracranial injection or infusion techniques. In addition, it can be administered to a subject via an injectable depot administration route, such as using 1, 3, or 6-month depot injection or biodegradable materials and methods.

[0094] In one embodiment, the pharmaceutical compositions disclosed herein are administered via site-specific or targeted local delivery techniques. Examples of site-specific or targeted local delivery techniques include various implantable depot sources or local delivery catheters of the composition, such as infusion catheters, indwelling catheters, or needle catheters, synthetic grafts, adventitial wraps, shunts and stents, or other implantable devices, site-specific carriers, direct injection, or direct application. See, for example, PCT Publication No. WO00 / 53211 and U.S. Patent No. 5,981,568.

[0095] In some examples, the pharmaceutical compositions disclosed herein are administered to a subject by injection, such as intramuscular (IM) injection, subcutaneous (SC) injection, intravenous (IV) injection, intraosseous injection, epidural injection, intradermal (ID) injection, or any other injection modality.

[0096] In some cases, the pharmaceutical composition is injected into or near the lipoma site in the subject. In other examples, the pharmaceutical composition is for topical administration.

[0097] In some cases, a pharmaceutical composition as disclosed herein is administered to a subject in an amount (a therapeutically effective amount) sufficient to reduce the size of a lipoma or liposarcoma via injection at the lipoma site or liposarcoma site (the lipoma site or liposarcoma site or in the vicinity thereof). The injection volume of the pharmaceutical composition can be determined according to the diameter of the lipoma or liposarcoma. For example, a therapeutically effective amount of the pharmaceutical composition can contain about 1 to 25 mg (e.g., about 1 to 5 mg, about 5 to 10 mg, about 10 to 15 mg, about 15 to 20 mg, or about 20 to 25 mg) of the active agent per injection for each minimal-sized lipoma having a diameter of about 1.0 to 2.0 cm. In another example, a therapeutically effective amount of the pharmaceutical composition can contain about 2.5 to 60 mg (e.g., about 2.5 to 10 mg, about 10 to 20 mg, about 20 to 30 mg, about 30 to 40 mg, about 40 to 50 mg, or about 50 to 60 mg) of the active agent per injection for each small-sized lipoma or liposarcoma having a diameter of about 2.0 to 3.5 cm. In yet another example, a therapeutically effective amount of the pharmaceutical composition can contain about 10 to 200 mg (e.g., about 10 to 50 mg, about 50 to 100 mg, about 100 to 150 mg, or about 150 to 200 mg) of the active agent per injection for each medium-sized lipoma or liposarcoma having a diameter of about 3.5 to 5.0 cm. In other examples, a therapeutically effective amount of the pharmaceutical composition can contain about 30 to 300 mg of the active agent per injection for each large-sized lipoma or liposarcoma having a diameter greater than 5 cm (e.g., about 5 to 6 cm). In other examples, a therapeutically effective amount of the pharmaceutical composition can contain at least about 45 mg of the active agent per injection for each extra-large-sized lipoma or liposarcoma having a diameter greater than 6 cm.

[0098] Any of the pharmaceutical compositions can be administered to the subject at least once, depending on the size of the lipoma or liposarcoma to be treated.

[0099] In one embodiment, the pharmaceutical composition is administered to a subject by topical administration. In some cases, a therapeutically effective amount of the composition may contain an active agent of about 0.5 to 5 mg / cm2 (e.g., about 0.5 to 1 mg / cm2, about 1 to 2 mg / cm2, about 2 to 3 mg / cm2, about 3 to 4 mg / cm2, or about 4 to 5 mg / cm2).

[0100] Any of the pharmaceutical compositions may be administered to a subject as disclosed herein in an amount sufficient to achieve one or more of the following results, as measured by lipoma site analysis: (a) reducing the diameter of the lipoma by at least 2 mm or 5%, (b) reducing the height of the lipoma by at least 2 mm or 5%, (c) reducing the total volume of the lipoma by at least 10%, and (d) reducing the surface area of the lipoma by at least 5%.

[0101] Any of the pharmaceutical compositions may be administered to a subject as disclosed herein in an amount sufficient to achieve one or more of the following results, as measured by liposarcoma site analysis: (a) reducing the diameter of the liposarcoma by at least 2 mm or 5%, (b) reducing the height of the liposarcoma by at least 2 mm or 5%, (c) reducing the total volume of the liposarcoma by at least 10%, and (d) reducing the surface area of the liposarcoma by at least 5%.

[0102] Alternatively, or in addition, any of the pharmaceutical compositions may be administered to a subject in need of treatment via a suitable route of administration in an amount sufficient to reduce at least one level of pain score according to a comparative pain scale.

[0103] In some embodiments, any of the pharmaceutical compositions may be administered to a subject in need of treatment via a suitable route of administration in an amount sufficient to improve the total score by at least 1 point according to the QOL evaluated by the 36-Item Short Form Survey (SF-36) and the Psychological General Well Being Index (PGWBI).

[0104] III. Kit for use in treating conditions caused by abnormal subcutaneous deposition of adipose tissue and / or fat The present disclosure also provides a kit for use in treating or alleviating a condition caused by abnormal subcutaneous deposition of adipose tissue and / or fat (e.g., lipoma or liposarcoma, or a target disease associated with lipoma or liposarcoma, e.g., those described herein (e.g., DD)). The present disclosure also provides a kit for use in treating or alleviating liposarcoma or a target disease associated with liposarcoma, e.g., those described herein. Such a kit may comprise one or more containers containing the pharmaceutical compositions disclosed herein. In some cases, the pharmaceutical composition may be used concomitantly with a second therapeutic agent.

[0105] In some embodiments, the kit may comprise instructions for use for use according to any of the methods described herein. The instructions included may include instructions for administration of the pharmaceutical composition and optionally a second therapeutic agent for treating, delaying the onset of, or alleviating lipoma or liposarcoma or a target disease related to those described herein. The kit may further comprise instructions for selecting a suitable individual for treatment, e.g., by applying a diagnostic method as described herein, based on whether the individual has lipoma or liposarcoma or a target disease.

[0106] Instructions for use related to the use of the pharmaceutical compositions disclosed herein generally include information regarding dosage, dosing schedule, and route of administration for the intended treatment. The container may be a unit dose, a bulk package (e.g., a multi-dose package), or a sub-unit dose. Instructions for use attached to the kits of the invention are typically instructions described on a label or package insert (e.g., a paper sheet included in the kit), although machine-readable instructions (e.g., instructions carried on a magnetic or optical storage disk) are also acceptable.

[0107] The label or package insert indicates that the composition is used for treating, delaying the onset of, and / or alleviating lipoma or liposarcoma or related diseases, such as DD or liposarcoma. Instructions for use for carrying out any of the methods described herein may be provided.

[0108] The kit of the present invention is in a suitable package. Suitable packages include, but are not limited to, vials, bottles, flasks, flexible packaging (e.g., sealed Mylar or plastic bags), etc. Also contemplated are packages for use in combination with certain devices, such as inhalers, nasal administration devices (e.g., atomizers), or infusion devices such as mini pumps. The kit may have a sterile access port (e.g., the container may be a vial having a stopper penetrable by an intravenous solution bag or a hypodermic needle). The container may also have a sterile access port (e.g., the container may be a vial having a stopper penetrable by an intravenous solution bag or a hypodermic needle).

[0109] The kit may optionally provide additional components such as buffers and interpretive information. Usually, the kit includes a container, and a label or package insert on or associated with the container. In some embodiments, the present invention provides a product comprising the contents of the kit described above.

[0110] General techniques In the practice of the present disclosure, unless otherwise indicated, conventional techniques within the skill of the art are used in molecular biology (including recombinant techniques), microbiology, cell biology, biochemistry, and immunology. Such techniques are described in Molecular Cloning: A Laboratory Manual, second edition (Sambrook, et al., 1989) Cold Spring Harbor Press; Oligonucleotide Synthesis (M.J. Gait, ed. 1984); Methods in Molecular Biology, Humana Press; Cell Biology: A Laboratory Notebook (J.E. Cellis, ed., 1989) Academic Press; Animal Cell Culture (R.I. Freshney, ed. 1987); Introuction to Cell and Tissue Culture (J.P. Mather and P.E. Roberts, 1998) Plenum Press; Cell and Tissue Culture: Laboratory Procedures (A. Doyle, J.B. Griffiths, and D.G. Newell, eds. 1993 - 8) J.Wiley and Sons; Methods in Enzymology (Academic Press, Inc.); Handbook of Experimental Immunology (D.M. Weir and C.C. Blackwell, eds.); Gene Transfer Vectors for Mammalian Cells (J.M. Miller and M.P. Calos, eds., 1987); Current Protocols in Molecular Biology (F.M. Ausubel, et al. eds. 1987); PCR: The Polymerase Chain Reaction, (Mullis, et al., eds. 1994); Current Protocols in Immunology (J.E. Coligan et al., eds., 1991); Short Protocols in Molecular Biology (Wiley and Sons, 1999); Immunobiology (C.A. Janeway and P. Travers, 1997); Antibodies (P. Finch, 1997); Antibodies: a practice approach (D. Catty., ed., IRL Press, 1988 - 1989); Monoclonal antibodies: a practical approach (P. Shepherd and C. Dean, eds., Oxford University Press, 2000); Using antibodies: a laboratory manual (E. Harlow and D. Lane (Cold Spring Harbor Laboratory Press, 1999); The Antibodies (M. Zanetti and J.D. Capra, eds. Harwood Academic Publishers, 1995); DNA Cloning: A practical Approach, Volumes I and II (D.N. Glover ed. 1985); Nucleic Acid Hybridization (B.D. Hames & S.J. Higgins eds. (1985)); Transcription and Translation (B.D. Hames & S.J. Higgins, eds. (1984)); Animal Cell Culture (R.I. Freshney, ed. (1986)); Immobilized Cells and Enzymes (lRL Press, (1986)); and are well described in the literature such as B. Perbal, A practical Guide To Molecular Cloning (1984); F.M. Ausubel et al. (eds.).

[0111] Without further elaboration, it is believed that those skilled in the art can make maximum use of the present invention based on the above description. Therefore, the following specific embodiments should be construed as merely illustrative and in no way limit the remainder of the present disclosure. All publications cited herein are incorporated by reference for the purposes or subject matter referred to herein.

[0112] Example 1: Preparation of Curcumin-Containing Micelles and Evaluation of Their Properties Exemplary curcumin-containing partial micelle formulations and micelle formulations were prepared as follows.

[0113] (a) Curcumin-ELP Partial Micelle Formulation 20 g of polyoxyl 35 castor oil (Kolliphor® ELP, also known as Cremophor® ELP) was mixed with an appropriate amount of physiological saline for injection to a total weight of 100 g. The solution was thoroughly mixed to completely dissolve the ELP, and a 20% ELP solution was obtained. 400 mg of curcumin was mixed with an appropriate amount of the 20% ELP solution to a total weight of 80 g. The solution was thoroughly mixed to completely dissolve the curcumin, and a curcumin ELP partial micelle formulation having a curcumin concentration of about 5 mg / mL and an ELP concentration of about 20% (by weight) was obtained. The weight ratio of curcumin to ELP was about 1:40.

[0114] (b) Curcumin-ELP Micelle Formulation 450 mg of curcumin was mixed with 80 - 140 mL of dichloromethane and stirred at 150 - 500 rpm at room temperature until the curcumin was completely dissolved. 18 g of polyoxyl 35 castor oil (Kolliphor® ELP, also known as Cremophor® ELP) was added to the solution and stirred thoroughly at 100 - 300 rpm to evaporate the dichloromethane. When the dichloromethane was completely evaporated, physiological saline was slowly added to a total volume of 90 mL, and the solution was thoroughly mixed to obtain a curcumin-ELP solution having a curcumin concentration of 5 mg / mL and an ELP concentration of about 20% (by weight%). The weight ratio of curcumin to ELP in the resulting solution was 1:40.

[0115] (c) Curcumin-HS-15 partial micelle formulation 20 g of polyoxyl 15 hydroxystearate (Kolliphor® HS-15 (HS-15)) was mixed with an appropriate amount of physiological saline for injection up to a total weight of 100 g. The solution was mixed well to completely dissolve HS-15, and a 20% HS-15 solution was obtained. 400 mg of curcumin was mixed with an appropriate amount of the 20% HS-15 solution up to a total weight of 80 g. The solution was mixed well to completely dissolve curcumin, and a curcumin HS-15 partial micelle formulation having a curcumin concentration of about 5 mg / mL and an HS-15 concentration of about 20% (wt%) was obtained. The weight ratio of curcumin to HS-15 was about 1:40.

[0116] (d) Curcumin-HS-15 micelle formulation 500 mg of curcumin was mixed with 80 - 140 mL of dichloromethane and stirred at 150 - 500 rpm at room temperature until curcumin was completely dissolved. 20 g of polyoxyl 15 hydroxystearate (Kolliphor® HS-15 (HS-15)) was added and stirred at 100 - 300 rpm to evaporate dichloromethane. When dichloromethane was completely evaporated, physiological saline was slowly added up to a total volume of 100 g. The solution was mixed well to form drug-containing micelles, and a curcumin HS-15 micelle formulation having a curcumin concentration of about 5 mg / mL and an HS-15 concentration of about 20% (wt) was obtained. The weight ratio of curcumin to HS-15 was about 1:40.

[0117] The curcumin-ELP partial micelle formulation (a), curcumin-HS-15 partial micelle formulation (c), curcumin-ELP micelle formulation (b), and curcumin-HS-15 micelle formulation (d) were analyzed by a particle size analyzer to determine the presence of micelles and, if present, the size of the particles. The results showed that both the curcumin-ELP partial micelle formulation and the curcumin-HS-15 partial micelle formulation exhibited curcumin precipitates, indicating a low number of curcumin-containing micelles. In contrast, the curcumin-ELP micelle formulation and the curcumin-HS-15 micelle formulation were transparent without any layering (showing no curcumin precipitation) and had a high number of curcumin-containing micelles.

[0118] In addition, the particle sizes (indicated by the average diameter) of the micelles in the curcumin-ELP partial micelle formulation, curcumin-HS-15 partial micelle formulation, curcumin-ELP micelle formulation, and curcumin-HS-15 micelle formulation were 13.16 ± 0.18 nm, 13.18 ± 1.45 nm, 12.43 ± 0.40 nm, and 11.46 ± 0.41 nm, respectively, and the PDI values were 0.22 ± 0.03, 0.18 ± 0.05, 0.28 ± 0.05, and 0.18 ± 0.04.

[0119] Further details can be found in US10,610,496, and the related disclosure is incorporated herein by reference for the subject matter and purposes referred to herein.

[0120] Example 2: Method for Treating Dercum's Disease (DD) Dercum's disease (DD) is a chronic and recurrent severe rare disease. DD patients typically have multiple lipomas or lipomatous tumors with abnormal accumulation of subcutaneous fat on the trunk and limbs, and may be accompanied by spontaneous severe pain at the affected site, which can last for more than three months. Due to the severe chronic pain, patients are often unable to lead a normal life.

[0121] The symptoms of DD usually do not disappear spontaneously, and the lipomas or lipomatous masses may grow large in a short period of time.

[0122] Currently, there are approximately 124,500 patients with Dercum's disease in the United States and approximately 240,000 DD patients in Europe. The incidence of DD in women is about 5 to 30 times that in men. Currently, there are no commercially approved drugs or products for the treatment of Dercum's disease worldwide. Current treatment approaches for DD include surgery and drugs to relieve symptoms. Liposuction or surgical excision are relatively common treatment methods, but they are associated with side effects and high risks and require a long postoperative recovery period. Even after surgical removal or liposuction, in most cases, new lipomas or lipomatous tumors will grow again.

[0123] This example illustrates an exemplary clinical trial to evaluate the safety and efficacy of a curcumin-containing composition as an example in human patients (including both male and female patients) with nodular Dercum's disease (DD).

[0124] Eligible participants have at least 4 painful and clearly defined lipomas of an appropriate size selected as the treatment area. Each enrolled participant receives one or more treatment courses at the assigned dose for the participant injected into the treatment area.

[0125] The injection volume per lipoma is based on the size of the lipoma (determined by ultrasound). The total dose for multiple lipomas in each treatment is based on the size and number of lipomas. The dosing scheme is presented in Table 4 below.

Table 4

[0126] The subject should lie down during administration. The composition can be administered to the subject via needles and syringes of any size according to the operating requirements. After confirming the injection area, use a marker to mark the injection spot. The needle should be inserted beside the injection marker so that the ink does not migrate into the tissue. Insert the needle into the adipose tissue of each lipoma identified to administer the composition evenly. After completing the administration for one lipoma, if bleeding is observed, apply pressure to each injection site for 10 - 20 seconds to minimize the condition. Immediately after the injection is completed, a moisturizer or topical antibiotic cream is sent to the injection site, especially at the edge of the injection area, which helps to spread the drug evenly. Before rubbing, confirm that there is no bleeding around the injection area. If bleeding occurs, use a wound dressing to cover the bleeding site and apply pressure to stop the bleeding. Use the base of the hand to massage each injection site for about 60 seconds. Since there is injection fluid under the thin skin, small lumps may appear. Rub the lumps until the drug spreads evenly. Since continuous massage may cause adverse events related to inflammation, the subject should be careful not to massage themselves after discharge.

[0127] Results: Five patients (A, B, C, D, and E) were treated according to the above treatment conditions. Each patient received a maximum of two injections. If the lipoma disappeared after the first injection, no additional injection was given to the patient.

[0128] The lipoma size and pain scale in each of the five patients were examined at the following stages: V2 (BL): Baseline, before treatment V3: Second treatment (if the lipoma disappeared after the first treatment, the second treatment was not performed) V4: Four weeks after the last treatment V5: Eight weeks after the last treatment

[0129] The size of the lipoma was measured by ultrasound, the volume was calculated, and the pain was evaluated using a comparative pain scale (0 - 10 points, where a higher score indicates more severe pain), as illustrated in Figure 1 below. Also, reference is made to the comparative pain scale chart provided at 123rf.com / photo_61431492_stock-vector-faces-pain-scale-doctors-pain-assessment-scale-comparative-pain-scale-chart-faces-pain-rating-tool-v.html (cited in August 2018), and the relevant disclosure is incorporated by reference for the subject matter and purposes referred to herein. The treatment dosage administered to each patient and the number of lipomas are provided in Table 5 below.

Table 5

[0130] The average lipoma size and average lipoma change for each patient before and after treatment are shown in Figures 2A and 2B, respectively. The average comparative pain scale score and average change in the comparative pain scale score for each patient before and after treatment are shown in Figures 3A and 3B, respectively.

[0131] The results obtained from this study indicate that the average lipoma size of all patients was significantly reduced after treatment. As an example, the lipoma of one patient (Patient C) disappeared after the injection treatment.

[0132] Furthermore, all patients experienced a significant decrease (e.g., elimination) in the comparative pain scale score after treatment.

[0133] In summary, the results obtained from the clinical study indicate that the composition used herein containing curcumin is effective in reducing the size of lipomas or eliminating lipomas and alleviating pain scores in DD patients. The results also suggest that the composition disclosed herein will provide benefits in the treatment of lipomas and related diseases, as well as other conditions caused by abnormal subcutaneous deposition of adipose tissue or fat, such as liposarcoma and related diseases.

[0134] Example 3: Treatment of Liposarcoma SW872 is a human malignant liposarcoma cell line isolated from the connective tissue of a male with liposarcoma. Histopathological evaluation reported an undifferentiated malignant tumor consistent with liposarcoma.

[0135] Liposarcoma is a rare and heterogeneous soft tissue malignant tumor with a poor prognosis and a significant impact on mortality. Liposarcoma is the second most common soft tissue invasive malignant tumor, with at least 30 cases per million people per year in the United States.

[0136] In particular, there are still limitations in the diagnosis of patients with soft tissue liposarcoma due to the cell type of the malignant tumor, tumor size, and anatomical location. Currently, the treatment options for liposarcoma patients are chemotherapy, radiotherapy, and surgery, but the favorable response to conventional treatment of liposarcoma is still not satisfactory. Therefore, there is still a need for new, non-toxic, and more effective therapeutic agents that meet the needs of liposarcoma patients. To date, there is no effective treatment for liposarcoma, while surgical resection is a valuable treatment with many adverse effects.

[0137] The experimental groups and concentrations of the test substances for each group are provided in Table 6 below.

Table 6

[0138] SW872 Tumor Cytotoxicity Assay (MTT Assay): SW872 cells were seeded at a density of 1×10 5 cells / well. The next day, after the cells were confluent, different concentrations of the test substance were added and allowed to act for 48 hours, then the MTT medium was replaced and the reaction was carried out in an incubator at 37°C for 2 hours.

[0139] After removing the supernatant, DMSO was added to redissolve the purple crystals, and the maximum absorbance value O.D.570nm and the background value O.D.630nm were measured with an ELASA reader. First, the absorbance value of each group was subtracted from the background value, and the data was expressed as [100% - (A 570nm - A 630nm ) / A ビヒクル *100%]. Using this data, the cytotoxic effects of test substances at different concentrations on SW872 cells can be compared.

[0140] Results: The cell viability (%) and cytotoxicity (%) of liposarcoma in test substances at different concentrations on SW872 cells are shown in Table 7 and Table 8, and Figures 4A and 4B, respectively. According to the test results, DDTA can significantly reduce the number of SW872 tumor cells starting from 1.6 ppm, reduce 53.9% of tumor cells at 6.4 ppm, and eliminate more than 99% of tumor cells at 25.6 ppm, and it was found that almost complete removal effect can be achieved. Further analysis results show that the IC50 of SW872 liposarcoma tumor cells showing DDTA is about 5.6 ppm.

Table 7

Table 8

[0141] Other Embodiments All of the features disclosed in this specification can be combined in any combination. Each feature disclosed in this specification can be replaced by alternative features that serve the same, equivalent, or similar purpose. Therefore, unless otherwise specified, each feature disclosed is only an example of a general series of equivalents or similar features.

[0142] From the above description, those skilled in the art can easily identify the essential features of the present invention and, without departing from its spirit and scope, make various changes and modifications to the present invention and adapt it to various uses and conditions. Therefore, other embodiments are also within the scope of the claims.

[0143] Equivalents Although some embodiments of the present invention are described and illustrated herein, those skilled in the art will readily envision various other means and / or structures for performing the functions described herein and / or for obtaining one or more of the results and / or advantages, and each such variation and / or modification is considered to be within the scope of the embodiments of the present invention described herein. More generally, those skilled in the art will understand that all parameters, dimensions, materials, and configurations described herein are exemplary, and that actual parameters, dimensions, materials, and / or configurations will depend on the particular one or more uses for which the teachings of the present invention are employed. Those skilled in the art will be able to ascertain many equivalents to the specific embodiments of the present invention described herein using only routine experimentation. Accordingly, the foregoing embodiments are presented by way of example only, and it is to be understood that within the scope of the appended claims and their equivalents, embodiments of the present invention may be practiced otherwise than as specifically described and claimed. Embodiments of the present invention disclosed herein are directed to each and every individual feature, system, article, material, kit, and / or method described herein. Additionally, any combination of two or more such features, systems, articles, materials, kits, and / or methods is included within the scope of the present invention disclosed herein if such features, systems, articles, materials, kits, and / or methods are not mutually inconsistent.

[0144] All definitions, as defined and used herein, are to be understood to control the dictionary definitions, definitions in incorporated references, and / or ordinary meaning of the defined terms.

[0145] All references, patents, and patent applications disclosed in this specification are incorporated by reference for the subject matter to which each is cited, and in some cases, may include the entire document.

[0146] The indefinite articles "a" and "an", as used herein in the specification and claims, should be understood to mean "at least one" unless the contrary is clearly indicated.

[0147] The phrase "and / or", as used herein in the specification and claims, should be understood to mean "either or both" of the elements so conjoined, i.e., elements that are conjunctively present in some cases and disjunctively present in other cases. Multiple elements listed with "and / or" should be construed in the same manner, i.e., as "one or more" of the elements so conjoined. Other elements other than those specifically identified by the "and / or" clause may optionally be present, whether or not related to those specifically identified elements. Thus, by way of non-limiting example, a reference to "A and / or B", when used with open-ended language such as "comprising", may refer in one embodiment to only A (optionally including elements other than B), in another embodiment to only B (optionally including elements other than A), and in yet another embodiment to both A and B (optionally including other elements), etc.

[0148] As used herein in the specification and claims, "or" should be understood to have the same meaning as "and / or" as defined above. For example, when separating items in a list, "or" or "and / or" is to be construed as inclusive, i.e., including at least one of a number of elements or a list of elements, but also including two or more, and optionally including additional items not in the list. Only terms that clearly indicate the contrary, such as "only one of", "exactly one of", or "consisting of" when used in the claims, refer to exactly one element out of a number of elements or a list of elements. In general, the term "or" as used herein is to be construed as indicating an exclusive alternative (i.e., "either one or the other, but not both") only when preceded by exclusive terms such as "either", "one of", "only one of", or "exactly one of". "Consisting essentially of" shall have its ordinary meaning as used in the field of patent law when used in the claims.

[0149] As used herein in the specification and claims, the phrase "at least one" with respect to a list of one or more elements should be understood to mean at least one element selected from any one or more of the elements in the list of elements, but does not necessarily include at least one of each element specifically recited within the list of elements, nor does it exclude any combination of elements in the list of elements. This definition also allows for the possibility that elements other than those specifically identified within the list of elements referred to by the phrase "at least one" may optionally be present, whether or not they are related to those specifically identified elements. Thus, by way of non-limiting example, "at least one of A and B" (or, equivalently, "at least one of A or B", or, equivalently "at least one of A and / or B") can, in one embodiment, refer to at least one A (optionally including two or more A's) with no B present (and optionally including elements other than B), in another embodiment, can refer to at least one B (optionally including two or more B's) with no A present (and optionally including elements other than A), and in yet another embodiment, can refer to at least one A (optionally including two or more A's), and at least one B (optionally including two or more B's) (and optionally including other elements), and so forth.

[0150] Also, it should be understood that, unless the contrary is clearly indicated, in any method claimed herein that includes two or more steps or acts, the order of the steps or acts of the method is not necessarily limited to the order in which the steps or acts of the method are recited.

Claims

1. A pharmaceutical composition for use in alleviating a condition caused by abnormal subcutaneous deposition of adipose tissue or fat in a subject, wherein the pharmaceutical composition comprises (i) a first activator comprising a resveratrol compound, a curcumin compound, a quercetin compound, a puerarin compound, or a combination thereof, and (ii) a pharmaceutically acceptable carrier.

2. The pharmaceutical composition according to claim 1, wherein the resveratrol compound is resveratrol, the curcumin compound is curcumin, the quercetin compound is quercetin, and / or the puerarin compound is puerarin.

3. The pharmaceutical composition according to claim 1, wherein the pharmaceutically acceptable carrier comprises a first pharmaceutically acceptable nonionic surfactant having a hydrophilic-lipophilic balance value (HLB value) of 10 or more.

4. The pharmaceutical composition according to claim 3, wherein the first pharmaceutically acceptable nonionic surfactant comprises polyoxyl stearate 40, polyoxyl 20 cetostearyl ether, Tween 80, polyoxyl hydroxystearate 15 (solutol HS 15), polyoxyethylene derivatives, polyoxyethylene castor oil derivatives, or a combination thereof.

5. The pharmaceutical composition according to claim 3, wherein the first activator forms a first plurality of micelles with the first pharmaceutically acceptable nonionic surfactant.

6. The pharmaceutical composition according to claim 3, wherein the weight ratio of the first activator in the composition to the first pharmaceutically acceptable nonionic surfactant is 1:2 to 1:

500.

7. The pharmaceutical composition according to claim 5, wherein the micelles in the first plurality of micelles have a diameter in the range of about 1 nm to about 200 nm and / or a polydispersity index (PDI) value of less than 0.

4.

8. The pharmaceutical composition according to any one of claims 1 to 7, wherein the composition is in the form of a parenteral dosage form, and optionally, the composition is formulated for injection, transplantation, or transdermal administration.

9. The pharmaceutical composition according to any one of claims 1 to 7, wherein the condition is a tumor of adipose tissue.

10. The pharmaceutical composition according to claim 9, wherein the tumor of the adipose tissue is a benign tumor.

11. The pharmaceutical composition according to claim 10, wherein the tumor of the adipose tissue is a lipoma.

12. The pharmaceutical composition according to claim 11, wherein the lipoma is a nodular lipoma or a diffuse lipoma.

13. The pharmaceutical composition according to claim 9, wherein the tumor of the adipose tissue is a malignant tumor, which is optionally liposarcoma, Proteus syndrome, PTEN hamartoma syndrome, Gardner syndrome, familial multiple lipomatosis, Cowden syndrome, Madelung disease, painful lipoma, angiolipoma, lipomatosis, subcutaneous adipose tissue disease, lipodysedema, rare lipopathy (RAD), or soft tissue sarcoma.

14. The pharmaceutical composition according to any one of claims 1 to 7, wherein the condition is Darkum disease or fatty edema.

15. The pharmaceutical composition according to any one of claims 1 to 7, wherein the subject is a human patient having the condition described above, or a human patient suspected of having the condition described above.

16. The pharmaceutical composition according to any one of claims 1 to 7, wherein the composition is administered to the subject by a parenteral route.

17. The pharmaceutical composition according to any one of claims 1 to 7, wherein the composition is administered to the subject at a local site.

18. The pharmaceutical composition according to claim 17, wherein the composition is administered to the subject topically or by injection.

19. The pharmaceutical composition according to claim 17, wherein the local area is located in or near a site where adipose tissue or subcutaneous fat deposition occurs.

20. The pharmaceutical composition according to claim 19, wherein the local site is located in or near a lipoma or liposarcoma.

Images