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

Abstract

A composition for use in a method of alleviating a condition caused by aberrant subcutaneous deposition of adipose tissue or fat in a subject in need thereof, the composition comprising a first active agent comprising (i) a resveratrol compound, a curcumin compound, a quercetin compound, a puerarin compound, or a combination thereof, and (ii) a pharmaceutically acceptable carrier.

Description

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS

[0002] This application claims the benefit of the filing date of U.S. Provisional Application No. 63 / 342,284, filed on May 16, 2022, the entire contents of which are incorporated herein by reference. Technical Field

[0003] The present disclosure relates to pharmaceutical compositions and their use for alleviating 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, which are used to alleviate (e.g., treat) conditions caused by abnormal subcutaneous deposition of adipose tissue or fat. Background Art

[0004] Lipoma is defined as a common subcutaneous tumor composed of fat cells, usually encapsulated by a thin layer of fibrous tissue. Clinically, lipomas can be present in any part of the body and may even cause death if they grow in important areas. Lipoma is associated with a variety of medical conditions, including Dercum's disease (Adiposis dolorosa). Dercum's disease is a rare disease characterized by chronic pain caused by multiple lipomas in adipose tissue. Kucharz et al., Reumatologia 57(5):281-287(2019).

[0005] Derken's disease relates to long-term chronic and recurrent lipoma. There is no specific treatment for Derken's disease. Treatment is directed to the obvious specific symptoms in each individual body, and is mainly focused on alleviating characteristic pain attacks. The patient will suffer from multiple painful lipomas or fat masses, wherein there is an abnormal accumulation of subcutaneous fat on the trunk and limbs, with spontaneous severe pain in the region, and the pain lasts for more than 3 months. The above-mentioned severe chronic pain will prevent the patient from living a normal life. In addition, the symptoms will not spontaneously alleviate or disappear, and the painful lipoma may become larger in a short time, even after surgical excision or liposuction, new lipomas or fat masses will still grow. The cause of the disease has not yet been determined, and is likely to be related to adipose tissue metabolic disorders.

[0006] According to statistics, there are currently about 124,500 patients with Delken's disease in the United States and about 240,000 patients in Europe. The incidence rate in women is about 5 to 30 times that in men. At present, there are no drugs or products approved for the treatment of Delken's disease in the world, and only surgery or other drugs can alleviate the symptoms. Liposuction or surgical excision is a relatively common treatment method, but it has obvious side effects and high risks, and the postoperative recovery period is longer. Moreover, even with surgical excision or liposuction, new lipomas or fat masses will grow again.

[0007] Nowadays, various analgesics (painkillers) with limited effectiveness have been tried. Injection of corticosteroids has also been used to treat individuals with Derken's disease. However, in one case reported in the medical literature, the use of high-dose corticosteroids was considered a possible cause of the disease. Intravenous administration of the analgesics lidocaine and / or ketamine can temporarily relieve pain in some people.

[0008] Surgical removal of the lipoma may temporarily relieve symptoms, although the development of inflammation during and after surgery (part of the healing process) may cause more lipomas to develop in the area. Liposuction has been used as supportive treatment for some individuals with Derken's disease and can initially relieve pain and improve quality of life. These effects may decrease over time.

[0009] Therefore, it is extremely important to develop effective and safer therapies with no wound care, lower infection risk, or minimized sequelae for relieving lipomas and treating lipoma-related diseases. Summary of the invention

[0010] The present disclosure is based at least in part on the development of pharmaceutical compositions comprising suitable micelle-forming therapeutic agents and surfactants for alleviating (e.g., treating) conditions caused by abnormal subcutaneous deposition of adipose tissue or fat, such as lipomas, liposarcoma, lipedema, and other such conditions known in the art or provided herein. For example, the exemplary compositions provided herein successfully reduce the size of lipomas and alleviate the pain associated with lipomas. See the following examples.

[0011] Therefore, on the one hand, the present disclosure is characterized by a method for alleviating a condition caused by abnormal subcutaneous deposition of adipose tissue or fat in a subject. The method includes administering an effective amount of a composition to a subject in need of treatment, the composition including (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 cases, the resveratrol compound can be resveratrol. In other cases, the curcumin compound can be curcumin. Alternatively or additionally, the quercetin compound can be quercetin and / or the puerarin compound can be puerarin.

[0012] The pharmaceutically acceptable carrier can be a pharmaceutically acceptable nonionic surfactant (Tween 80, polyethylene glycol 15 hydroxystearate (solutol HS15), polyoxyethylene castor oil derivatives or combinations thereof). Some preferred nonionic surfactants have a hydrophilic-lipophilic balance (HLB value) greater than 10. In some embodiments, the weight ratio of the active agent to the nonionic surfactant can be 1:5-1:500. The composition of the active agent and the nonionic surfactant can be in the form of micelles.

[0013] In other embodiments, the composition can further include additional micelles formed from a nonionic surfactant (e.g., as described above) and one or more hydrophilic therapeutic agents (e.g., green tea extract, epicatechin, epicatechin gallate, epigallocatechin, epigallocatechin gallate, epigallocatechin, 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 1:5-1:500. In addition, the weight ratio of the first active agent to the hydrophilic therapeutic agent can be 30:1 to 1:10.

[0014] Any micelles contained in the compositions disclosed herein (e.g., micelles comprising an active agent as disclosed herein) may have a diameter of less than 50 nm (e.g., from about 1 to about 50 nm, or about 10-25 nm) and / or a polydispersity index (PDI) value of less than 0.4.

[0015] In some instances, the composition can be formulated for parenteral administration, for example, for injection, implantation or transdermal administration. The composition formulated for injection can be in the form of a powder (e.g., a freeze-dried powder), a sterile suspension, an injectable solution, an injectable emulsion, or an intravenous infusion. In some instances, the composition can be placed 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 dressing, an emulsion, a film, a patch, a poultice, a cataplasm, a topical solution, or a topical solution.

[0016] In some embodiments, any method disclosed herein can be carried out by parenteral route (e.g., topical application or local injection) application of any composition disclosed herein. In some instances, the composition can be applied to a local site, for example, located at or near a lipoma or liposarcoma. In some cases, the local site can be located at a thigh, buttocks, lower extremity, pelvis or abdomen, where lipomas or liposarcomas often occur. Depending on the size of a lipoma or liposarcoma, the composition can be applied to a subject once or multiple times for treatment.

[0017] In some embodiments, the condition treated by any method disclosed herein can be adipose tissue tumor. In some instances, adipose tissue tumor can be a benign tumor, such as a lipoma. In some cases, a lipoma can be a nodular lipoma. In other cases, a lipoma can be a diffuse lipoma. In other instances, adipose tissue tumor can be a malignant tumor, for example, liposarcoma, Proteus syndrome, PTEN hamartoma tumor syndrome, Gardner syndrome, familial multiple lipomatosis, Cowden syndrome, Madelung's disease, painful lipoma, angiolipoma, lipomatosis, subcutaneous adipose tissue disease, lipedema, rare adipose disorder (RAD) or soft tissue sarcoma.

[0018] In a specific example, the methods disclosed herein are used to treat diseases involving lipomas. Such diseases can be Dercum's disease. In other examples, the methods disclosed herein are used to treat liposarcoma. In still another example, the methods disclosed herein are used to treat lipedema.

[0019] Also provided herein is a pharmaceutical composition as disclosed herein for alleviating a condition caused by abnormal subcutaneous deposition of adipose tissue and / or fat (e.g., a lipoma or a disease associated with a lipoma, such as Derken's disease; or a liposarcoma). Further, the present disclosure provides the use of any pharmaceutical composition as disclosed herein in the preparation of a medicament for treating any target condition as disclosed herein.

[0020] The details of one or more embodiments of the invention are set forth in the following description. Other features and advantages of the invention will become apparent from the following drawings and the following detailed description of several embodiments and also from the appended claims. BRIEF DESCRIPTION OF THE DRAWINGS

[0021] The following drawings form part of this specification and are included to further illustrate certain aspects of the present disclosure, which may be better understood by referring to the drawings in combination with the detailed description of specific embodiments presented herein.

[0022] Figure 1 is a graph showing a comparative pain scale.

[0023] Figure 2A-2B Contains graphs showing the effectiveness in reducing lipoma size. Figure 2A : Average lipoma size. Figure 2B : Mean change in lipoma size.

[0024] Figure 3A-3B A graph showing the effect on pain relief is included. Figure 3A : Mean comparative pain scale scores. Figure 3B : Comparison of mean changes in pain scale scores.

[0025] Figure 4A-4B Contains graphs showing effectiveness in treating liposarcoma. Figure 4A : Cell viability (%). Figure 4B : Cytotoxicity against liposarcoma (%). DETAILED DESCRIPTION

[0026] Disclosed herein are pharmaceutical compositions and therapeutic uses thereof for alleviating (e.g., treating) the symptom (including diseases and conditions provided herein) caused by abnormal subcutaneous deposition of adipose tissue or fat. Pharmaceutical compositions disclosed herein may include one or more active agents, which may be resveratrol compounds, curcumin compounds, quercetin compounds, puerarin compounds or combinations thereof. The one or more active agents may form micelles (a first plurality of micelles) with suitable pharmaceutically acceptable nonionic surfactants, such as micelles disclosed herein. In certain embodiments, the pharmaceutical composition may further include a second plurality of micelles, which may be formed by suitable pharmaceutically acceptable nonionic surfactants and hydrophilic agents as disclosed herein. Also provided herein is a method for alleviating (e.g., treating) the symptom (e.g., lipoma or liposarcoma) caused by abnormal subcutaneous deposition of adipose tissue or fat using any pharmaceutical composition disclosed herein.

[0027] I. Pharmaceutical Compositions

[0028] The pharmaceutical composition disclosed herein includes one or more of a resveratrol compound, a curcumin compound, a quercetin compound, and a puerarin compound as an active agent to alleviate the condition caused by abnormal subcutaneous deposition of adipose tissue or fat, such as a lipoma or a liposarcoma. The active agent as disclosed herein can form micelles with a suitable nonionic surfactant, such as micelles (a first plurality of micelles) disclosed herein. The pharmaceutical composition disclosed herein can further include a second plurality of micelles formed by a hydrophilic agent and a suitable nonionic surfactant.

[0029] (A) Active agent

[0030] Exemplary active agents provided herein include resveratrol compounds, curcumin compounds, quercetin compounds, and puerarin compounds.

[0031] The resveratrol compound may have the structure of formula (I) or a salt thereof:

[0032] Where R 1 , R 2 , R 3 and R 4 Each of which is independently H, halo (e.g., F, Cl or Br), hydroxyl, alkyl, alkenyl, alkynyl, alkoxy, thiol and amine. In some embodiments, the resveratrol compound may have a structure of formula (Ia) or a salt thereof:

[0033] Where R 1 , R 2 and R 3 Each of is as defined above.

[0034] In one embodiment, the resveratrol compound is resveratrol (wherein R 1 -R 3 All of them are -OH, R 4 Alternatively, the resveratrol compound may have suitable substitutions at one or more suitable positions in resveratrol, as known to those skilled in the art.

[0035] The curcumin compounds disclosed herein may have the structure of formula (II) or a salt thereof:

[0036] Where R 1 , R 2 , R 3 and R 4 Each of is independently H, halo (e.g., F, Cl or Br), hydroxyl, alkyl, alkenyl, alkynyl, alkoxy, thiol and amine; Z' is CH2, NH, O or S; and Z' is CH2, NH, O or S. In some embodiments, the curcumin compound is a curcuminoid compound, such as curcumin, demethoxycurcumin or bisdemethoxycurcumin. In a specific example, the curcumin compound is curcumin. Alternatively, as known to those skilled in the art, the curcumin compound may have suitable substitutions at one or more suitable positions in curcumin.

[0037] In some embodiments, the Curcumin compound may have a structure of Formula (IIa) or a salt thereof:

[0038] Where R 1 , R 2 , R 3 and R 4 Each of is independently H, halo (e.g., F, Cl or Br), hydroxyl, alkyl, alkenyl, alkynyl, alkoxy, thiol and amine; X is CH2, NH, O or S; Y is CH3, NH2, OH or SH. In some embodiments, the curcumin compound is a curcuminoid compound, such as curcumin, demethoxycurcumin or bisdemethoxycurcumin. In a specific example, the curcumin compound is curcumin. Alternatively, as known to those skilled in the art, the curcumin compound may have suitable substitutions at one or more suitable positions in curcumin.

[0039] The quercetin compounds disclosed herein may have the structure of formula (III) or a salt thereof:

[0040] Where R 1 , R 2 , R 3 , R 4 and R5 Each of is independently H, halo (e.g., F, Cl or Br), hydroxyl, alkyl, alkenyl, alkynyl, alkoxy, thiol and amine; and X and Y are each independently CH2, NH, O or S. In a specific example, the quercetin compound is quercetin. Alternatively, as known to those skilled in the art, the quercetin compound may have suitable substitutions at one or more suitable positions in quercetin.

[0041] The puerarin compound disclosed herein may be a compound of formula (IV) or a salt thereof:

[0042] Where R 1 , R 2 , R 3 , R 4 , R 5 and R 6 Each of is independently H, halo (e.g., F, Cl or Br), hydroxyl, alkyl, alkenyl, alkynyl, alkoxy, thiol and amine; and X and Y are each independently CH2, NH, O or S. In some examples, the puerarin compound is puerarin. Alternatively, as known to those skilled in the art, the puerarin compound may have suitable substitutions at one or more suitable positions in puerarin.

[0043] "Alkyl" refers to a straight chain saturated non-cyclic monovalent hydrocarbon radical or a branched saturated non-cyclic monovalent hydrocarbon radical having from one to three carbon atoms connected to the rest of the molecule by a single bond, such as methyl, ethyl, n-propyl, or 1-methylethyl (isopropyl). Optionally substituted alkyl is an alkyl group optionally substituted, as valency permits, with one, two, three, four, or five substituents independently selected from the group consisting of halo, cyano, nitro, oxo, hydroxy, thio, or amino.

[0044] "Alkenyl" refers to a straight chain non-cyclic monovalent hydrocarbon radical or a branched non-cyclic monovalent hydrocarbon radical containing a carbon-carbon double bond, having two or three carbon atoms connected to the rest of the molecule by a single bond, such as ethenyl or propenyl. Optionally substituted alkenyl is an alkenyl radical optionally substituted, as valency permits, with one, two or three substituents independently selected from the group consisting of halo, cyano, nitro, hydroxy, thio or amino.

[0045] "Alkynyl" refers to a straight chain acyclic monovalent hydrocarbon radical or a branched acyclic monovalent hydrocarbon radical containing a triple bond and having two or three carbon atoms connected to the rest of the molecule by a single bond, such as ethynyl or propynyl. An optionally substituted alkynyl is an alkynyl radical optionally substituted with a substituent selected from the group consisting of halo, cyano, nitro, hydroxy, thio or amino.

[0046] "Alkoxy" refers to a group having the formula -ORa, wherein Ra is hydrogen or alkyl as defined above containing from one to three carbon atoms. The alkyl portion of the optionally substituted alkoxy is optionally substituted as defined above for an alkyl group.

[0047] "Amino" refers to a group having the formula -NRbRc, wherein Rb and Rc are each hydrogen or alkyl as defined above containing from one to three carbon atoms. The alkyl portion of the optionally substituted amino is optionally substituted as defined above for an alkyl group.

[0048] "Thiol" refers to a group having the formula -SRd, wherein Rd is hydrogen or an alkyl group as defined above containing from one to three carbon atoms. The alkyl portion of the optionally substituted thiol group is optionally substituted as defined above for an alkyl group.

[0049] As used herein, "hydrophilic" refers to one or more molecules having a hydrophilicity-lipophilicity balance greater than 10 (eg, using the Griffin method).

[0050] (B) Hydrophilic therapeutic agents

[0051] In some embodiments, the pharmaceutical compositions disclosed herein may further include one or more hydrophilic therapeutic agents as described herein, which may be beneficial for treating conditions caused by adipose tissue / fat deposits, compared to pharmaceutical compositions comprising only the active agents disclosed herein. The hydrophilic therapeutic agents may be effective in alleviating conditions as disclosed herein. Alternatively or additionally, the hydrophilic therapeutic agents may enhance the efficacy of the active agents, and / or reduce side effects associated with the active agents.

[0052] Hydrophilic therapeutic agents are water-soluble agents. Exemplary hydrophilic therapeutic agents include, but are not limited to, green tea extract; flavonoids, including flavonoids based on catechins (e.g., catechins, catechin gallates), gallocatechins (e.g., gallocatechins, gallocatechin gallates), epicatechins (e.g., epicatechins, epicatechin gallates), epigallocatechins (e.g., epigallocatechins, epigallocatechin gallates); xanthines, including methylxanthines (e.g., caffeine), carnitines, L-carnitine, synephrine, and chlorogenic acid. Combinations of the foregoing agents may also qualify as hydrophilic therapeutic agents used herein. Alternatively, other hydrophilic therapeutic agents may be combined with the present technology to help treat lipomas. In some embodiments, the hydrophilic therapeutic agent may be combined with a second nonionic surfactant, preferably to form micelles.

[0053] In some embodiments, the weight ratio of the active agent to the hydrophilic therapeutic agent is between 30:1 and 1:10, e.g., between 30:1 and 1:5, between 30:1 and 1:1, between 30:1 and 5:1, between 30:1 and 10:1, between 30:1 and 20:1, between 20:1 and 1:10, between 10:1 and 1:10, between 5:1 and 1:10, between 1:1 and 1:10, between 1:5 and 1:10, between 20:1 and 1:5, between 10:1 and 1:1, or between 5:1 and 1:1.

[0054] (C) Nonionic surfactant

[0055] Pharmaceutical compositions disclosed herein may include one or more nonionic surfactants that may form micelles with an active agent and / or a hydrophilic therapeutic agent as disclosed herein. The nonionic surfactants used in the present technology are at least beneficial in forming micelles in the composition. In some embodiments, micelles have the effect of encapsulating active agents and / or hydrophilic therapeutic agents.

[0056] The hydrophilic-lipophilic balance (HLB) value of the nonionic surfactant used in any of the pharmaceutical compositions disclosed herein is preferably greater than 10. The ratios of nonionic surfactants used in the present technology are as described above. Exemplary nonionic surfactants include, but are not limited to, polysorbate 80 ( 80), polyethylene glycol 15 hydroxystearate ( HS-15), polyoxyethylene castor oil derivatives (e.g., polyethylene glycol 35 castor oil ( ELP), Macrogol 40 hydrogenated castor oil ( RH40) and Macrogol 60 hydrogenated castor oil ( RH60), polyoxyethylene (12) glyceryl laurate (UNIGLY ML-212), polyethylene glycol 20 stearate (Myrj TM S20), polyethylene glycol 40 stearate (Myrj TM S40), polyethylene glycol 12 cetearyl ether ( CS12) and PEG-20 cetearyl ether ( CS20).

[0057] In some cases, nonionic surfactants can be polyoxyethylene derivatives, also referred to as PEGylated excipients. In some instances, polyoxyethylene derivatives are PEG castor oil derivatives, which are materials obtained by reacting different amounts of ethylene oxide with castor oil or hydrogenated castor oil. Examples include PEG-35 castor oil and PEG-40 hydrogenated castor oil. In other instances, polyoxyethylene derivatives are PEG esters, which can be manufactured by reacting polyethylene glycol with fatty acids. Examples include PEG-40 stearate and PEG-15 hydroxystearate. In some cases, the ester can be a sorbitan fatty acid ester (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), an alkyl glyceride (e.g., 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), an alkyl glyceride (e.g., PEG-80 glyceryl stearate, PEG-12 hydrogenated palm glycerides, PEG-20 cetearyl 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 ester can be a laurate (e.g., PEG-2 laurate, PEG-4 laurate, PEG-6 laurate, PEG-8 laurate, PEG-9-14 laurate, PEG-20 laurate, PEG-32-150 laurate, or PEG-12 glyceryl laurate), a dilaurate (e.g., PEG-2 dilaurate, PEG-4 dilaurate, or PEG-6-150 dilaurate), or a stearate (e.g., PEG-2 stearate, PEG-3 stearate, PEG-4 stearate, PEG-4 isostearate, PEG-5-7 stearate, PEG-6-8 isostearate, PEG-8 stearate, PEG-9 stearate, PEG-10 stearate, PEG-10 isostearate, PEG-12 isostearate , PEG-12-18 stearate, PEG-20 stearate, PEG-23-45 stearate, PEG-40 stearate, PEG-50 stearate, PEG-100 stearate, PEG-75-150 stearate, or PEG-6 and PEG-32 palmitoyl stearate), glyceryl stearate (e.g., glyceryl stearate / PEG-40 stearate, glyceryl stearate / PEG-100 stearate, PEG-120 glyceryl stearate, PEG-20 methyl glucose sesquistearate, or PEG-25 propylene glycol stearate), distearate (e.g., PEG-2 distearate, PEG-3-120 distearate, PEG-150 distearate, or PEG-175 distearate), hydroxystearate (e.g., PEG-15 hydroxystearate).

[0058] In some cases, the nonionic surfactant can 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).

[0059] Additional examples of nonionic surfactants include PEG-15 cocoamine, vitamin E polyethylene glycol succinate, PEG-75 lanolin, and PEG-120 methyl glucose dioleate.

[0060] (D) Micelles and their preparation

[0061] Any pharmaceutical composition in the pharmaceutical composition can include micelles formed by the first nonionic surfactant and one or more active agents as disclosed herein, the one or more active agents such as resveratrol compounds (e.g., resveratrol), curcumin compounds (e.g., curcumin), quercetin compounds (e.g., quercetin), puerarin compounds (e.g., puerarin) or combinations thereof. If the pharmaceutical composition further includes one or more hydrophilic therapeutic agents as disclosed herein, the pharmaceutical composition can further include a second nonionic surfactant, which forms micelles with the hydrophilic therapeutic agent. In this case, the pharmaceutical composition can 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 instances, the first and second nonionic surfactants are the same. In other instances, the first nonionic surfactant is different from the second nonionic surfactant.

[0062] In some embodiments, the micelles may include the nonionic surfactant and the active agent in a suitable weight ratio, which produces a suitable particle size and / or a suitable polydispersity index (PDI) value. For example, a suitable weight ratio between the active agent and the nonionic surfactant may be in the range of about 1:5-1:500, such as between about 1:5-1:8, between about 1:5-1:10, between about 1:5-1:20, between about 1:5-1:40, between about 1:5-1:100, between 1:5-1:150, between 1:5-1:200, between 1:5-1:300, between 1:5-1:400, between 1:5-1:500. , between about 1:8-1:10, between about 1:8-1:20, between about 1:8-1:40, between about 1:8-1:100, between 1:8-1:150, between 1:8-1:200, between 1:8-1:300, between 1:8-1:400, between 1:8-1:500, between about 1:10-1:20, between about 1:10-1:40, between about 1:10-1:100, between 1:1 0-1:150, between 1:10-1:200, between 1:10-1:300, between 1:10-1:400, between 1:10-1:500, between about 1:20-1:40, between about 1:20-1:100, between 1:20-1:150, between 1:20-1:200, between 1:20-1:300, between 1:20-1:400, between 1:20-1:500, between about 1: 40-1:100, between 1:40-1:150, between 1:40-1:200, between 1:40-1:300, between 1:40-1:400, between 1:40-1:500, between 1:100-1:150, between 1:100-1:200, between 1:100-1:300, between 1:100-1:400, between 1:100-1:500, or between 1:150-1:500. It is reported that micelles formed at a suitable weight ratio between an active agent as disclosed herein and a nonionic surfactant will result in a suitable particle size (e.g., less than 50 nm) and a suitable PDI value (e.g., <0.4). See U.S. Pat. No. 10,610,496, the relevant disclosure of which is incorporated by reference for the subject matter and purposes cited herein.

[0063] In some embodiments, the pharmaceutical composition may further include micelles (the second plurality of micelles) formed by a nonionic surfactant as disclosed herein and one or more hydrophilic therapeutic agents in the hydrophilic therapeutic agent as also disclosed herein. Similar to the first plurality of micelles, the hydrophilic therapeutic agent and the nonionic surfactant may be in a suitable weight ratio to produce 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 1:5-1:500, for example, between about 1:5-1:8, between about 1:5-1:10, between about 1:5-1:20, between about 1:5-1:40, between about 1:5-1:100, between 1:5-1:150, between 1:5-1:200, between 1:5-1:300, between 1:5-1:400, between 1:5-1:500. , between about 1:8-1:10, between about 1:8-1:20, between about 1:8-1:40, between about 1:8-1:100, between 1:8-1:150, between 1:8-1:200, between 1:8-1:300, between 1:8-1:400, between 1:8-1:500, between about 1:10-1:20, between about 1:10-1:40, between about 1:10-1:100, between 1:1 0-1:150, between 1:10-1:200, between 1:10-1:300, between 1:10-1:400, between 1:10-1:500, between about 1:20-1:40, between about 1:20-1:100, between 1:20-1:150, between 1:20-1:200, between 1:20-1:300, between 1:20-1:400, between 1:20-1:500, between about 1: between 1:40-1:100, between 1:40-1:150, between 1:40-1:200, between 1:40-1:300, between 1:40-1:400, between 1:40-1:500, between 1:100-1:150, between 1:100-1:200, between 1:100-1:300, between 1:100-1:400, between 1:100-1:500 or between 1:150-1:500.

[0064] In some embodiments, the particle size (diameter) of the first plurality of micelles, the second plurality of micelles, or both may be less than 50 nm. In some instances, the particle size may be in the range of about 1 nm to about 50 nm. In some instances, the particle size may be in the range of about 10 nm to about 25 nm. Unless otherwise stated, the particle size disclosed herein refers to the actual size (diameter) of the micelles in the micelle population. For example, if the particle size of the smallest micelle in the population is 10 nm, and the particle size of the largest micelle in the population is 50 nm, the particle size range of the population is 10 nm to 50 nm.

[0065] 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) less than 50 nm.

[0066] Alternatively or additionally, the polydispersity index of the first plurality of micelles, the second plurality of micelles, or both can 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 can 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.

[0067] Any micelle in the micelle disclosed herein can be prepared by conventional methods or as disclosed herein. An example is provided below. An appropriate amount of 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 (e.g., at 150-500rpm) at a suitable temperature until the active agent or hydrophilic therapeutic agent as disclosed herein is completely dissolved in the solvent to form a solution. An appropriate amount of a pharmaceutically acceptable nonionic surfactant (e.g., a nonionic surfactant disclosed herein) can be added to the solution. The resulting mixture can be stirred (e.g., at 100-300rpm) at a suitable temperature to volatilize the solvent. Once the solvent is completely volatilized, an appropriate amount of a pharmaceutically acceptable aqueous solution (e.g., normal saline) can be added to the mixture to produce micelles encapsulated with an active agent or a hydrophilic agent. The resulting particles can be filtered through a suitable filter (eg, a 0.2 μm filter), and the filtered solution including the drug-containing micelles can be stored in a refrigerator in the dark for future use.

[0068] Additional details regarding micelle preparation of the present technology can be found in U.S. Patent No. 10,610,496, the relevant disclosure of which is incorporated herein by reference for the subject matter and purposes cited herein.

[0069] (E) Pharmaceutical Composition

[0070] Any of the active agent, optionally the hydrophilic therapeutic agent, and the nonionic surfactant that can form micelles with the active agent and optionally the hydrophilic therapeutic agent can be formulated into a pharmaceutical composition for use in the therapeutic applications disclosed herein.

[0071] The pharmaceutical composition to be used in the present method may include a pharmaceutically acceptable carrier, excipient or stabilizer in the form of a lyophilized formulation or aqueous solution. (Remington: The Science and Practice of Pharmacy, 20th edition (2000) Lippincott Williams and Wilkins, ed. KE Hoover). Acceptable carriers, excipients or stabilizers are nontoxic to the recipient at the dosages and concentrations used, and may include buffers such as phosphates, citrates and other organic acids; antioxidants, including ascorbic acid and methionine; preservatives (such as octadecyldimethylbenzyl ammonium chloride; hexamethonium chloride; benzalkonium chloride, benzethonium chloride; phenol, butyl alcohol or benzyl alcohol; alkyl parabens such as methyl or propyl paraben; catechol; resorcinol; cyclohexanol; 3-pentanol; and m-cresol); 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®. TM 、PLURONICS TM or polyethylene glycol (PEG).

[0072] In other examples, the pharmaceutical compositions described herein can be formulated in a sustained release format. Suitable examples of sustained release formulations include a semipermeable matrix of a solid hydrophobic polymer containing the antibody, the matrix being in the form of a shaped article (e.g., a film or microcapsule). Examples of sustained release matrices include polyesters, hydrogels (e.g., poly(2-hydroxyethyl-methacrylate) or poly(vinyl alcohol)), polylactic acid (U.S. Pat. No. 3,773,919), copolymers of L-glutamic acid and 7-ethyl-L-glutamate, non-degradable ethylene-vinyl acetate, such as LUPRON DEPOT TM (Injectable microspheres composed of lactic acid-glycolic acid copolymer and leuprolide acetate) and other degradable lactic acid-glycolic acid copolymers, sucrose acetate isobutyrate and poly-D-(-)-3-hydroxybutyric acid.

[0073] Pharmaceutical compositions to be used for in vivo administration must be sterile. This is easily achieved, for example, by filtering through a sterile filtration membrane. The therapeutic antibody composition is usually placed in a container with a sterile access port, for example, an intravenous solution bag or a vial with a stopper that can be pierced by a hypodermic injection needle.

[0074] The pharmaceutical compositions described herein can be in unit dosage form, 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 by an appropriate route, such as oral, parenteral, topical, rectal, buccal, vaginal or via an implanted reservoir.

[0075] Sterile injectable compositions (e.g., sterile injectable aqueous or oily suspensions) can be formulated using suitable dispersants or wetting agents (e.g., polysorbate 80) and suspending agents according to techniques known in the art. Sterile injectable preparations can also be sterile injectable solutions or suspensions in nontoxic parenterally acceptable diluents or solvents, for example in the form of solutions in 1,3-butanediol. 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 suspension media (e.g., synthetic mono- or di-glycerides). Fatty acids (e.g., oleic acid) and their glyceride derivatives can be used to prepare injectables, as can natural pharmaceutically acceptable oils, such as olive oil or castor oil, particularly in their polyoxyethylated forms. These oil solutions or suspensions can also contain long-chain alcohol diluents or dispersants, or carboxymethyl cellulose or similar dispersants. For the purposes of formulation, other commonly used surfactants (such as Tween or Span) or other similar emulsifying agents or bioavailability enhancers which are commonly used in the manufacture of pharmaceutically acceptable solid, liquid, or other dosage forms may also be used.

[0076] In some embodiments, the compositions described herein can be formulated into topical preparations, such as creams, lotions, or gels for topical application. Such creams, lotions, or gels can be formulated using ingredients known in the art to be suitable for topical medications.

[0077] The carrier in the pharmaceutical composition must be "acceptable" in the sense of being compatible with the active ingredients of the formulation (and preferably, capable of stabilizing it) and not harmful to the subject to be treated. For example, solubilizers (such as cyclodextrins) or more solubilizers that form more soluble complexes with the oxadiazole compound can be used as pharmaceutical carriers for delivery of the oxadiazole compound. Examples of other carriers include colloidal silicon dioxide, magnesium stearate, sodium lauryl sulfate, and D&C Yellow No. 10.

[0078] In some embodiments, the pharmaceutical compositions disclosed herein may further include 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, nitroxoxide, pyruvate, catalase, superoxide dismutase, glutathione peroxidase, N-acetylcysteine, and naringenin, or a combination thereof.

[0079] II. Methods for Alleviating Conditions Caused by Abnormal Subcutaneous Deposition of Adipose Tissue and / or Fat

[0080] In some aspects, provided herein are methods for using any of the pharmaceutical compositions disclosed herein to alleviate (eg, treat) a condition caused by abnormal subcutaneous deposition of adipose tissue and / or fat.

[0081] In some embodiments, the condition caused by abnormal subcutaneous deposition of adipose tissue and / or fat can be an adipose tissue tumor, which can result in abnormal deposition of fat under fat cells / tissue (adipose tissue) and / or skin spots (subcutaneous). In some instances, the adipose tissue tumor can be benign, such as a lipoma. In other instances, the adipose tissue tumor can be malignant, such as a liposarcoma.

[0082] (A) Lipoma and lipoma-related diseases

[0083] Lipomas are benign fatty tumors that form between the skin and the underlying muscle. Lipomas can develop anywhere in the body where fat cells are present. The neck, shoulders, armpits, and thighs are common locations where lipomas will appear. Depending on their location, lipomas can be classified into three subtypes: subcutaneous lipoma, intermuscular lipoma, and visceral lipoma.

[0084] Lipomas can be associated with a variety of medical conditions, such as Derken's disease (adiposis dolorosa), Gardner's syndrome, familial multiple lipomatosis (hereditary multiple lipomatosis), Madelung's disease (multiple symmetrical lipomatosis), painful lipomas, angiolipomas, lipomatosis, subcutaneous adipose tissue disease, lipedema and rare fat disorders (RAD), panniculitis, Weber-Christian disease, progressive lipodystrophy or other diseases / symptoms associated with fat lesions. Some of these diseases may cause serious symptoms, such as swelling, severe pain or even psychiatric problems.

[0085] In some embodiments, the subject suitable for treatment disclosed herein can be a human patient with at least one lipoma. Such human patients may also suffer from adipose disorders, subcutaneous adipose tissue diseases, lipedema, rare adipose disorders (RAD), skin diseases, lipid metabolism disorders or metabolic diseases. Alleviating lipomas by any of the methods disclosed herein is expected to be beneficial for treating such diseases and disorders.

[0086] In some instances, provided herein is a method for treating Derken's disease (DD) using any of the compositions disclosed herein. DD, also known as adiposity dolorosa, painful lipomatosis, or Ander's syndrome, is a rare condition characterized by chronic pain caused by multiple lipomas in adipose tissue. The disease is often accompanied by many associated symptoms, such as weakness, fatigue, depression, and dementia. Painful adipose tissue can be diffuse and systemic, or concentrated in palpable lipomas. The most common locations of involvement are the limbs, trunk, pelvic region, and buttocks.

[0087] DD patients can usually be diagnosed by exclusion, and imaging helps DD diagnosis. Patients with Dercum's disease usually suffer from severe pain of their adipose tissue deposition, which usually becomes more intense during the progression of the disease. Such pain is particularly frequent in the abdomen and buttocks, upper arms and outer thighs, and sometimes also occurs in the knees and elbows. Even minimal stimulation (e.g., slight contact, airflow, friction of clothing or bedding, temperature changes) can cause severe discomfort. This can also lead to psychosocial problems. The diagnosis of Dercum's disease should be based on clinical examination and after excluding relevant differential diagnoses. A 2012 publication (Hansson E, Svensson H, Brorson H. Review of Dercum's disease and proposal of diagnostic criteria, diagnostic methods, classification and management).) Two main criteria were formulated: obesity and chronic pain (>3 months) in hyperplastic / hypertrophic adipose tissue. There are no clear histological or instrumental (imaging) diagnostic criteria.

[0088] The differential diagnosis and comorbidities of DD are summarized in Table 1. Table 2 lists the four subtypes based on their morphological appearance and distribution pattern.

[0089] Table 1: Differential diagnosis and comorbidities of Derken's disease

[0090] Differential diagnosis and comorbidities of Derken's disease Fibromyalgia Lipedema, lipolymphedema, elephantiasis Cushing's disease, Cushing syndrome Multiple symmetrical lipomas Neurofibromatosis type I Panniculitis (traumatic, autoimmune, infectious) (Deep) erythematous sarcoidosis, erythema nodosum Somatization depression (with obesity) Drugs, drug effects, or drug withdrawal Peripheral neuropathy Mucinoses Granulomatous disorders (infectious or autoinflammatory)

[0091] Table 2: Classification of Derken's disease

[0092]

[0093] There is currently a lack of effective treatment for patients with Derken's disease because there is no effective long-term treatment. The management of Derken's disease usually involves pain control by oral medication or direct injection or surgical excision. Surgical interventions (e.g., liposuction and lipectomy) have different results. It has been shown that lidocaine injected directly into lipomas can only provide short-term pain relief.

[0094] (B) Liposarcoma and liposarcoma-related diseases

[0095] Liposarcoma is a rare type of malignant tumor that occurs in fatty tissue. Liposarcoma is a type of soft tissue sarcoma. Liposarcoma can start in fat cells anywhere in the body. Liposarcoma usually appears in older people; however, it can occur in any age group. The symptoms of liposarcoma depend on the part of the body where the malignancy forms. For example, liposarcoma in the arms and legs may cause one or more of the following symptoms: a mass of tissue growing under the skin, pain, swelling, and weakness in the affected limb. Liposarcoma in the abdomen can cause abdominal pain, abdominal swelling, feeling full faster when eating, constipation, and / or blood in the stool. Current treatments for liposarcoma usually involve surgery to remove the malignancy. Other treatments, such as radiation therapy, may also be used.

[0096] Liposarcomas can be associated with various medical conditions, such as soft tissue sarcomas, lipomatous hemangiopericytoma.

[0097] In some instances, a method for treating liposarcoma using any of the compositions disclosed herein is provided herein. Liposarcoma is classified as a malignant tumor because it is likely to recur locally and spread to other areas of the body. The severity of the disease depends on the subtype of liposarcoma and the stage of appearance of the primary tumor. It can appear in various locations throughout the body, although it is most often found in the limbs, especially the thighs. It can also grow in an area called the "retroperitoneum" in the back of the abdomen, in which a tumor of significant size and weight can be effectively hidden due to the huge space. Some individuals with liposarcoma may have no symptoms in the early stages, but as the tumor grows and progresses to the later stages, it can potentially compress other tissues and cause pain.

[0098] The specific genetic cause of liposarcoma has not been determined, although research has proposed that it begins in fat cells that have lost their ability to mature or grow unregulated. Liposarcomas are found more often in middle-aged men aged 50-65 years than in women and are very rare in children.

[0099] Most patients diagnosed with liposarcoma do not have any early symptoms and will go unnoticed during the initial stages of the disease until the tumor has grown to a large enough size to compress adjacent tissues and cause pain or decreased function. Sometimes, it is noticed as a deep mass that cannot be felt. Like all other malignancies, liposarcoma can present with nonspecific symptoms such as fever, chills, fatigue, night sweats, and weight loss. If the tumor is retroperitoneal in location, it may present with specific symptoms in the abdomen, including abdominal or flank pain, swelling, and constipation or a feeling of being full sooner than expected after eating.

[0100] The most critical step in the diagnosis of liposarcoma involves taking a biopsy of the mass in question. A biopsy is performed when tissue is removed from the tumor so that it can be evaluated under a microscope to assess whether the tissue has tumor-specific characteristics. Because many of these tumors are deeply embedded in the body, imaging such as ultrasound may be used to guide the position of the needle relative to the mass and ensure that the tissue sample is being taken specifically from said mass.

[0101] Liposarcomas can also be diagnosed by imaging the body with computed tomography (CT) or magnetic resonance imaging (MRI). CT uses multiple X-ray measurements to create an image of the body, and this is important for assessing the location of the mass and its relationship to surrounding tissue. MRI is another imaging modality for liposarcoma, and it can show the characteristics of the mass itself, which may help to diagnostically distinguish between benign and malignant soft tissue masses.

[0102] Table 3: Classification of liposarcoma

[0103]

[0104] Table 3 lists the five subtypes of liposarcoma: well-differentiated, dedifferentiated, myxoid, round cell, and pleomorphic. The well-differentiated types are less invasive and tend to be large, painless masses found in deeper tissues and the retroperitoneum. The myxoid, round cell, and pleomorphic types tend to be in the arms and legs, while the dedifferentiated tend to be in the retroperitoneum and are often associated with the well-differentiated types. In particular, pleomorphic liposarcoma is the least common subtype with a high recurrence rate and poor outcome.

[0105] (C) Treatment of conditions caused by abnormal subcutaneous deposition of adipose tissue and / or fat

[0106] In order to practice the methods disclosed herein, an effective amount of the pharmaceutical composition described herein can be administered to a subject (e.g., a person) in need of treatment by a suitable route such as parenteral administration or topical administration (e.g., local injection or topical administration). Subjects (e.g., people) benefiting from such administration include patients suffering from lipoma or liposarcoma or suspected of suffering from lipoma or liposarcoma. In some instances, the methods disclosed herein are intended to treat Derken's disease in human patients. In other instances, the methods disclosed herein are intended to treat liposarcoma.

[0107] Among patients suffering from Derken's disease, there are four subgroups of patient populations that are particularly suitable for the treatments described and are described below.

[0108] Subgroup I refers to diffuse lipomas of the generalized type. Lipomas in this subgroup may not be clearly demarcated but are diffusely distributed throughout the adipose tissue. Lipomas are often associated with a pain response.

[0109] Subgroup II is systemic nodular lipoma. Nodular lipomas are usually present in adipose tissue and are usually associated with pain responses in adipose tissue and lipomas. Additionally, this subgroup type may lead to multiple lipomas.

[0110] Subgroup III is localized nodular lipoma. This subtype usually results in multiple lipomas that are specifically painful in the lipomas.

[0111] Subgroup IV is the juxtaarticular lipoma. This type of lipoma is often a tumor of fatty tissue on the inside of the knee or on the elbow.

[0112] As used herein, "effective amount" refers to the amount of each active agent required to give a subject a therapeutic effect, either alone or in combination with one or more other active agents. It will be apparent to those skilled in the art to determine whether a certain amount of antibody achieves a therapeutic effect. As recognized by those skilled in the art, the variation in effective amount depends on the specific condition being treated, the severity of the condition, individual patient parameters (including age, physical condition, body shape, sex and weight), the duration of treatment, the nature of concurrent therapy (if any), specific routes of administration, and similar factors within the knowledge and expertise of health practitioners. These factors are well known to those of ordinary skill in the art and can be solved only by routine experiments. It is generally preferred to use the maximum dose of the individual components or their combinations, i.e., the highest safe dose according to reasonable medical judgment.

[0113] Empirical considerations such as half-life will generally help determine dosage. For example, antibodies compatible with the human immune system such as humanized antibodies 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's immune system. The frequency of administration can be determined and adjusted during therapy, and is generally but not necessarily based on the treatment and / or suppression and / or relief and / or delay of the target disease / disorder. Alternatively, a sustained continuous release formulation of the antibody may be appropriate. Various preparations and devices for achieving sustained release are known in the art.

[0114] For the purposes of this disclosure, the appropriate dosage of the pharmaceutical compositions as described herein will depend on the specific active agent and optionally the hydrophilic agent employed, the type and severity of the disease / disorder, whether the composition is administered for preventive or therapeutic purposes, previous therapy, the patient's clinical history and response to the active agent, and the discretion of the attending physician. Typically, a clinician will administer the pharmaceutical compositions disclosed herein until a dosage is reached that achieves the desired result.

[0115] In some embodiments, the desired result is to reduce or eliminate lipomas or liposarcomas, or to alleviate at least one symptom associated with a lipoma-related disease (e.g., pain) or a liposarcoma-related disease. Methods for determining whether a dose produces a desired result will be apparent to those skilled in the art. The specific dosing regimen (i.e., dosage, timing, and repetition) used in the methods described herein will depend on the specific subject and the subject's medical history. The therapeutic efficacy of the target disease / disorder can be evaluated by methods well known in the art.

[0116] As used herein, the term "treat" refers to applying or administering a composition comprising one or more active agents to a subject suffering from a target disease or condition, symptoms of a disease / condition, or susceptibility to a disease / condition, with the purpose of curing, rehabilitating, alleviating, altering, remedying, improving, ameliorating, or affecting the condition, symptoms of a disease, or susceptibility to a disease or condition.

[0117] Relieve target disease / illness and comprise delaying the development or progress of disease or reducing disease severity or prolonging life span.Relieve disease or prolong life span do not necessarily need curative results.As used herein, "delaying" the development of target disease or illness means to postpone, hinder, slow down, slow down, stabilize and / or delay the progress of disease.This delay can have different time lengths, depending on the disease treated and / or individual medical history.Delay or alleviate disease development or delay the method of disease onset is to reduce the possibility of one or more symptoms of disease development in a given time frame and / or reduce the degree of symptom in a given time frame compared with not using the method.This type of comparison is usually based on clinical research, using many subjects that are enough to give statistically significant results.

[0118] "Development" or "progression" of a disease means the initial manifestation and / or subsequent progression of the disease. The progression of a disease may be detectable and can be assessed using standard clinical techniques as are well known in the art. However, progression also refers to progression that may not be detectable. For purposes of this disclosure, development or progression refers to the biological course of symptoms. "Development" encompasses occurrence, recurrence, and onset. As used herein, "onset" or "occurrence" of a target disease or condition encompasses initial onset and / or recurrence.

[0119] According to the disease type to be treated or the disease site, the conventional method known to those of ordinary skill in the medical field can be used to apply the pharmaceutical composition to the experimenter. This composition can also be used by other conventional routes, for example, parenteral administration, by topical application or by implantable reservoir administration. As used herein, the term "parenteral" comprises subcutaneous, intracutaneous, intravenous, intramuscular, intraarticular, intraarterial, intrasynovial, intrasternal, intrathecal, intralesional and intracranial injection or infusion techniques. In addition, it can be applied to the experimenter by injectable reservoir administration route, as using 1 month, 3 months or 6 months reservoir injectable or biodegradable materials and methods.

[0120] In one embodiment, the pharmaceutical compositions disclosed herein are administered by site-specific or targeted local delivery techniques. Examples of site-specific or targeted local delivery techniques include various implantable reservoir sources or local delivery catheters (such as infusion catheters, indwelling catheters or needle catheters, synthetic grafts, adventitial wraps, shunts and stents or other implantable devices) of the composition; site-specific carriers; direct injection or direct application. See, for example, PCT Publication No. WO 00 / 53211 and U.S. Patent No. 5,981,568.

[0121] 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 form of injection.

[0122] In some cases, the pharmaceutical composition is injected into the subject at or near the site of the lipoma. In other examples, the pharmaceutical composition is used for local administration.

[0123] In some cases, the pharmaceutical composition as disclosed herein is administered to the subject by injection at the lipoma site or liposarcoma site (at or near the lipoma site or liposarcoma site) in an amount (therapeutically effective amount) sufficient to reduce the size of the lipoma or liposarcoma. The injection volume of the pharmaceutical composition can be determined according to the diameter of the lipoma or liposarcoma. For example, the pharmaceutical composition of the therapeutically effective amount can contain about 1 mg to 25 mg (e.g., about 1 mg to 5 mg, about 5 mg to 10 mg, about 10 mg to 15 mg, about 15 mg to 20 mg or about 20 mg to 25 mg) of an active agent each time it is injected into each extremely small size lipoma, which means that the diameter of the lipoma is about 1.0 cm to 2.0 cm. In another example, a therapeutically effective amount of the pharmaceutical composition may contain about 2.5 mg to 60 mg (e.g., about 2.5 mg to 10 mg, about 10 mg to 20 mg, about 20 mg to 30 mg, about 30 mg to 40 mg, about 40 mg to 50 mg, or about 50 mg to 60 mg) of active agent per injection into each small-sized lipoma or liposarcoma, which refers to a lipoma or liposarcoma having a diameter of about 2.0 cm to 3.5 cm. In yet another example, a therapeutically effective amount of the pharmaceutical composition may contain about 10 mg to 200 mg (e.g., about 10 mg to 50 mg, about 50 mg to 100 mg, about 100 mg to 150 mg, or about 150 mg to 200 mg) of active agent per injection into each medium-sized lipoma or liposarcoma, which refers to a lipoma or liposarcoma having a diameter of about 3.5 cm to 5.0 cm. In other examples, a therapeutically effective amount of the pharmaceutical composition may contain about 30 mg to 300 mg of active agent per injection into each large-sized lipoma or liposarcoma, which means that the diameter of the lipoma or liposarcoma is greater than 5 cm (e.g., about 5-6 cm). In other examples, a therapeutically effective amount of the pharmaceutical composition may contain about at least 45 mg of active agent per injection into each extremely large-sized lipoma or liposarcoma, which means that the diameter of the lipoma or liposarcoma is greater than 6 cm.

[0124] Any of the pharmaceutical compositions may be administered to a subject at least once, depending on the size of the lipoma or liposarcoma being treated.

[0125] In one embodiment, the pharmaceutical composition is applied to a subject by topical administration. In some cases, a therapeutically effective amount of the composition may contain 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) of an active agent.

[0126] Any of the pharmaceutical compositions can 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 a lipoma by at least 2 mm or 5%; (b) reducing the height of a lipoma by at least 2 mm or 5%; (c) reducing the total volume of a lipoma by at least 10%; and (d) reducing the surface area of ​​a lipoma by at least 5%.

[0127] Any of the pharmaceutical compositions can 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%.

[0128] Alternatively or additionally, 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 pain scores by at least one level according to a comparative pain rating scale.

[0129] 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 one point based on QOL assessed by the 36-item Short Form Survey (SF-36) and Psychological Global Well-Being (PGWBI).

[0130] III. Kits for use in treating conditions caused by abnormal subcutaneous deposition of adipose tissue and / or fat

[0131] The present disclosure also provides kits for use in treating or alleviating conditions caused by abnormal subcutaneous deposition of adipose tissue and / or fat (e.g., lipoma or liposarcoma or target diseases associated with lipoma or liposarcoma, such as the diseases described herein (e.g., DD)). The present disclosure also provides kits for use in treating or alleviating liposarcoma or target diseases associated with liposarcoma (e.g., diseases described herein). Such kits may include one or more containers, the one or more containers including a pharmaceutical composition disclosed herein. In some cases, the pharmaceutical composition may be used together with a second therapeutic agent.

[0132] In some embodiments, the kit may include instructions for use in any of the methods described herein. The included instructions may include a description of the administration of the pharmaceutical composition and, optionally, a second therapeutic agent to treat, delay the onset of, or alleviate a target disease associated with a lipoma or liposarcoma, or a disease as described herein. The kit may further include a description of selecting an individual suitable for treatment based on identifying whether the individual has a lipoma or liposarcoma or a target disease, for example, using a diagnostic method as described herein.

[0133] Instructions related to the use of the pharmaceutical compositions disclosed herein typically include information about dosage, dosing regimen, and route of administration for the intended treatment. The container may be a unit dose, bulk package (e.g., multi-dose package), or subunit dose. The instructions provided in the kit of the present invention are typically written instructions on a label or package insert (e.g., paper included in the kit), but machine-readable instructions (e.g., instructions carried on a magnetic or optical storage disk) are also acceptable.

[0134] The label or package insert indicates that the composition is used to treat, delay the onset of, and / or alleviate a lipoma or liposarcoma or a related disease, such as DD or liposarcoma.Instructions may be provided for practicing any of the methods described herein.

[0135] The kit of the present invention is in suitable packaging. Suitable packaging includes, but is not limited to, vials, bottles, jars, flexible packaging (e.g., sealed Mylar or plastic bags), etc. It is also contemplated that packaging used in combination with a specific device (e.g., an inhaler, a nasal application device (e.g., a nebulizer), or an infusion device (e.g., a mini pump)). The kit can have a sterile access port (e.g., the container can be an intravenous solution bag or a vial with a stopper that can be pierced by a hypodermic injection needle). The container can also have a sterile access port (e.g., the container can be an intravenous solution bag or a vial with a stopper that can be pierced by a hypodermic injection needle).

[0136] The kit may optionally provide additional components such as buffer and interpretative information. Typically, the kit includes a container and a label or package insert located on or associated with the container. In some embodiments, the invention provides an article of manufacture comprising the contents of the kit described above.

[0137] General techniques

[0138] The practice of the present disclosure will employ, unless otherwise indicated, conventional techniques of molecular biology (including recombinant techniques), microbiology, cell biology, biochemistry, and immunology, which are within the skill of the art. Such techniques are fully explained in the following literature, such as: Molecular Cloning: A Laboratory Manual, 2nd Edition (Sambrook et al., 1989) Cold Spring Harbor Press; Oligonucleotide Synthesis (MJ Gait ed. 1984); Methods in Molecular Biology (Humana Press); Cell Biology: A Laboratory Notebook (JE Cellis ed., 1989) Academic Press; Animal Cell Culture (RI Freshney ed. 1987); Introduction to Cell and Tissue Culture (JPather and PE Roberts, 1998) Plenum Press; Cell and Tissue Culture: Laboratory Procedures (JP Cellis ed., 1998) Academic Press; Procedures (A. Doyle, JB Griffiths and DG Newell, eds. 1993-8) John 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 (FMAusubel et al., ed., 1987); PCR: The Polymerase Chain Reaction, (Mullis et al., ed., 1994); Current Protocols in Immunology (J.E. Coligan et al., ed., 1991); Short Protocols in Molecular Biology (Wiley and Sons, 1999); Immunobiology (CA 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, ed., Oxford University Press, 1994); =The Antibodies: A Laboratory Manual (E. Harlow and D. Lane (Cold Spring Harbor Laboratory Press, 1999)); The Antibodies (M. Zanetti and JD Capra, eds. Harwood Academic Publishers, 1995); DNA Cloning: A Practical Approach, Volumes I and II (DN Glover, ed. 1985); Nucleic Acid Hybridization (BD Hames and SJ Higgins, eds. (1985)); Transcription and Translation (BD Hames and SJ Higgins, eds. (1984)); Animal Cell Culture (RI Cell Culture).Freshney, ed. (1986); Immobilized Cells and Enzymes (IRL Press, (1986)); and B. Perbal, A Practical Guide To Molecular Cloning (1984); FM Ausubel et al. (eds.).

[0139] Without further elaboration, it is believed that those skilled in the art can utilize the present invention to the greatest extent based on the above description. Therefore, the following specific examples should be interpreted as being merely illustrative and not limiting the remainder of the present disclosure in any way. All disclosures cited herein are incorporated by reference for the purpose or subject matter of this reference.

[0140] Example 1: Preparation and characterization of curcumin-containing micelles

[0141] Exemplary curcumin-containing partial micellar formulations and micellar formulations were prepared as follows.

[0142] (a) Curcumin-ELP partial micellar preparation

[0143] 20g of polyethylene glycol 35 castor oil ( ELP, also known as ELP) is mixed with an appropriate amount of normal saline for injection to a total weight of 100g. The solution is mixed thoroughly to completely dissolve the ELP to obtain a 20% ELP solution. 400mg of Curcumin is mixed with an appropriate amount of 20% ELP solution to a total weight of 80g. The solution is mixed thoroughly to completely dissolve the Curcumin to obtain a Curcumin ELP partial micellar preparation having a Curcumin concentration of about 5mg / mL and an ELP concentration of about 20% (by weight). The weight ratio of Curcumin to ELP is about 1:40.

[0144] (b) Curcumin-ELP micelle preparation

[0145] 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 polyethylene glycol 35 castor oil ( ELP, also known as ELP) was added to the solution and stirred at 100-300 rpm to volatilize the dichloromethane. Once the dichloromethane was completely volatilized, normal saline was slowly added to a total volume of 90 mL, and the solution was fully mixed to obtain a curcumin-ELP solution having a curcumin concentration of 5 mg / mL and an ELP concentration of about 20% (wt%). The weight ratio of curcumin to ELP in the resulting solution was 1:40.

[0146] (c) Curcumin-HS-15 partial micellar preparation

[0147] 20 g of polyethylene glycol 15 hydroxystearate ( HS-15 (HS-15)) was mixed with an appropriate amount of normal saline for injection to a total weight of 100 g. The solution was mixed thoroughly to completely dissolve HS-15 to obtain a 20% HS-15 solution. 400 mg of curcumin was mixed with an appropriate amount of 20% HS-15 solution to a total weight of 80 g. The solution was mixed thoroughly to completely dissolve curcumin to obtain a curcumin HS-15 partial micellar preparation having a curcumin concentration of about 5 mg / mL and a HS-15 concentration of about 20% (wt%). The weight ratio of curcumin to HS-15 was about 1:40.

[0148] (d) Curcumin-HS-15 micellar preparation

[0149] 500 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. 20 g of polyethylene glycol 15 hydroxystearate ( HS-15 (HS-15)) and stirred at 100-300 rpm to volatilize dichloromethane. Once the dichloromethane is completely volatilized, normal saline is slowly added to a total volume of 100 g. The solution is fully mixed to form drug-containing micelles to obtain a curcumin HS-15 micellar preparation having a curcumin concentration of about 5 mg / mL and a HS-15 concentration of about 20% (by weight). The weight ratio of curcumin to HS-15 is about 1:40.

[0150] Curcumin-ELP partial micellar preparation (a), curcumin-HS-15 partial micellar preparation (c), curcumin-ELP micellar preparation (b) and curcumin-HS-15 micellar preparation (d) are analyzed by particle size analyzer to determine the presence of micelle, and if present, the size of particle is determined. Result shows that both curcumin-ELP partial micellar preparation and curcumin-HS-15 partial micellar preparation show curcumin precipitate, and the number of micelle containing curcumin is less. In contrast, curcumin-ELP micellar preparation and curcumin-HS-15 micellar preparation are transparent, without any stratification (indicating that there is no curcumin precipitation), and the number of micelle containing curcumin is more.

[0151] In addition, the particle sizes (expressed as average diameter) of micelles in the Curcumin-ELP partial micelle preparation, Curcumin-HS-15 partial micelle preparation, Curcumin-ELP micelle preparation and Curcumin-HS-15 micelle preparation 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, respectively.

[0152] Further details may be found in US 10,610,496, the relevant disclosure of which is incorporated by reference for the subject matter and purposes referred to herein.

[0153] Example 2: Method for treating Derkern's disease (DD)

[0154] Delken's disease (DD) is a chronic and relapsing severe rare disease. DD patients usually suffer from multiple lipomas or fatty masses, in which there are abnormal accumulations of subcutaneous fat on the trunk and limbs, which can be accompanied by spontaneous severe pain in the affected area and can last for more than 3 months. Severe chronic pain often prevents patients from leading a normal life.

[0155] Symptoms of DD will not usually disappear spontaneously, and the lipoma or fatty mass may grow larger over a short period of time.

[0156] It is estimated that there are currently about 124,500 patients with Delken's disease in the United States and about 240,000 patients with DD in Europe. The incidence of DD in women is about 5 to 30 times that of men. Currently, there are no approved drugs or products for curing Delken's disease in the world. Current treatments for DD include surgical operations and drugs for alleviating symptoms. Liposuction or surgical excision is a relatively common treatment method, but it is associated with side effects and high risks, and requires a long postoperative recovery period. Even after surgical excision or liposuction, new lipomas or fat masses will grow again in most cases.

[0157] This example illustrates an exemplary clinical trial to evaluate the safety and efficacy of a composition containing curcumin in human patients (including both male and female patients) suffering from nodular Delken's disease (DD) as an example.

[0158] Eligible participants had at least 4 appropriately sized, painful, and well-defined lipomas that were selected as treatment areas. Each enrolled participant received one or more treatment sessions in which their assigned dose was injected into the treatment area.

[0159] The injection volume per lipoma is based on lipoma size (as determined by ultrasound). The total dose for multiple lipomas in each treatment is based on lipoma size and number of lipomas. The dosing regimen is presented in Table 4 below.

[0160] Table 4: Dosage regimen

[0161]

[0162] The subject should lie down during the application. The composition can be applied to the subject by a needle and syringe of any size according to the requirements of the operation. After confirming the injection area, use a marker to mark the injection point. The needle should be inserted next to the injection mark to avoid ink transfer into the tissue. Insert the needle into the adipose tissue of each identified lipoma to evenly apply the composition. After completing the application for one lipoma, if bleeding is observed, apply pressure to each injection site for 10-20 seconds to minimize the symptoms. Just after the injection is completed, massage the injection site with a moisturizer or topical antibiotic cream, especially the edge of the injection area, to help the drug spread evenly. Before rubbing, make sure there is no bleeding around the injection area. If bleeding is ongoing, cover the bleeding site with a wound dressing and apply pressure to stop the bleeding. Use the heel of the palm of the hand to massage each injection site for approximately 60 seconds. Because the injection solution is located under the thin skin, very small blocks may appear. Rub the blocks until the drug is evenly spread. Remind the subject not to self-massage after discharge, because continuous massage may cause inflammation-related AEs.

[0163] result:

[0164] Five patients (A, B, C, D and E) were treated according to the above treatment conditions. Each patient was given up to two injections. When the patient's lipoma disappeared after the first injection, no additional injections were given to the patient.

[0165] The lipoma size and pain scale were examined in each of the five patients at the following stages:

[0166] V2(BL): Baseline, before treatment

[0167] V3: Secondary treatment (if the lipoma disappears after the first treatment, no secondary treatment is performed)

[0168] V4: 4 weeks after the last treatment

[0169] V5: 8 weeks after last treatment

[0170] The size of the lipoma was measured by ultrasound and the volume was calculated. The pain was assessed by a comparative pain scale (0-10 points, with higher scores indicating more severe pain). Figure 1 The comparative pain scale is shown. See also the comparative pain scale 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, the relevant disclosure of which is incorporated by reference for the subject matter and purposes cited herein. The treatment dose and number of lipomas for each patient are provided in Table 5 below:

[0171] Table 5: Participant dose and number of lipomas

[0172] Participant Number C E A D B dose Low Low high high high Volume per injection (mL) 2 2 3 3 3 The number of lipomas 4 8 5 8 6

[0173] The average lipoma size and average lipoma change before and after treatment for each patient are shown in Figure 2A and Figure 2B The mean comparative pain scale score and the mean change in the comparative pain scale score before and after treatment for each patient are shown in Figure 3A and Figure 3B middle.

[0174] The results obtained from this study showed that the average lipoma size of all patients had been significantly reduced after treatment. For example, the lipoma of one patient (patient C) disappeared after injection treatment.

[0175] Furthermore, all patients had a significant reduction (eg, elimination) in their comparative pain scale scores following treatment.

[0176] In summary, the results obtained from the clinical studies show that the compositions including Curcumin used herein are effective in reducing the size of lipomas or eliminating lipomas, and reducing pain scores in DD patients. The results also indicate that the compositions disclosed herein will be beneficial in treating lipomas and related diseases, as well as other conditions also caused by abnormal subcutaneous deposition of adipose tissue or fat, such as liposarcoma and related diseases.

[0177] Example 3: Treatment of liposarcoma

[0178] SW872 is a human malignant liposarcoma cell line isolated from the connective tissue of a male with liposarcoma. Histopathological evaluation reported an undifferentiated malignancy consistent with liposarcoma.

[0179] Liposarcoma is a rare and heterogeneous soft tissue malignancy with a significant impact on mortality and a poor prognosis. Liposarcoma is the second most common invasive soft tissue malignancy with an incidence of at least 30 cases per million people per year in the United States.

[0180] It is noteworthy that there are still limitations in diagnosing patients with soft tissue liposarcoma due to the malignancy of cell type, tumor size and anatomical location. Currently, the options for treating liposarcoma patients are chemotherapy, radiotherapy and surgery, but the favorable response to conventional treatments for liposarcoma is still unsatisfactory. Therefore, there is still a need for new, non-toxic and more effective therapeutic agents to meet the needs of liposarcoma patients. To date, there is no effective treatment for liposarcoma, and surgical resection is only the golden treatment with many adverse reactions.

[0181] The experimental groups and the test substance concentrations for each group are provided in Table 6 below:

[0182] Table 6: Experimental groups

[0183]

[0184] SW872 tumor cell cytotoxicity assay (MTT assay):

[0185] 1×10 5 SW872 cells were seeded at an amount of 10 cells / well. After the cells were full on the next day, the test substances at different concentrations were added to act for 48 hours, and then the MTT medium was replaced and the action was performed in a 37° C. incubator for 2 hours.

[0186] After removing the supernatant, DMSO was added to redissolve the purple crystals, and the maximum absorbance value OD570nm and the background value OD630nm were measured with an ELASA reader. First, the absorbance value of each group was subtracted from the background value, and the data were expressed as [100%-(A 570 nm -A 630 nm ) / A 媒剂 *100%]. This data can be used to compare the cytotoxic effects of different concentrations of the test substances on SW872 cells.

[0187] result:

[0188] The cell viability (%) and cytotoxicity (%) of the test substances at different concentrations on SW872 cells are shown in Tables 7 and 8, respectively. Figure 4A and Figure 4B The test results found that DDTA could significantly reduce the number of SW872 tumor cells starting at 1.6ppm, reduce 53.9% of tumor cells at 6.4ppm, and eliminate more than 99% of tumor cells at 25.6ppm, achieving almost complete removal. The results of additional analysis showed that the IC50 of DDTA for SW872 liposarcoma tumor cells was about 5.6ppm.

[0189] Table 7: Cell viability (%)

[0190] Group Medium DDTA-1 DDTA-2 DDTA-3 DDTA-4 DDTA-5 DDTA-6 DDTA-7 average value 100.0 97.5 95.7 93.8 76.0 46.1 23.0 0.9 SD 0.6 1.9 1.7 2.1 0.6 2.3 0.8 0.0

[0191] Table 8: Cytotoxicity of liposarcoma (%)

[0192] Group Medium DDTA-1 DDTA-2 DDTA-3 DDTA-4 DDTA-5 DDTA-6 DDTA-7 average value 0.0 2.5 4.3 6.2 24.0 53.9 77.0 99.1 SD 0.6 1.9 1.7 2.1 0.6 2.3 0.8 0.0

[0193] Other embodiments

[0194] All of the features disclosed in this specification may be combined in any combination. Each feature disclosed in this specification may be replaced by an alternative feature for the same, equivalent or similar purpose. Therefore, unless otherwise expressly stated, each feature disclosed is merely an example of a general series of equivalent or similar features.

[0195] Through the above description, those skilled in the art can easily determine the essential characteristics of the present invention, and can make various changes and modifications to the present invention to adapt it to various uses and conditions without departing from its spirit and scope. Therefore, other embodiments are also within the scope of the claims.

[0196] Equivalent

[0197] Although several embodiments of the present invention have been described and shown herein, a person of ordinary skill in the art will readily conceive of various other ways and / or structures for performing functions and / or obtaining results and / or one or more of the advantages described herein, and each of such variations and / or modifications is considered to be within the scope of the embodiments of the present invention described herein. More generally, a person of ordinary skill in the art will readily understand that all parameters, dimensions, materials, and configurations described herein are meant to be exemplary, and that actual parameters, dimensions, materials, and / or configurations will depend on one or more specific applications for using the teachings of the present invention. Using only routine experiments, a person of ordinary skill in the art will recognize or be able to determine many equivalents of the specific embodiments of the present invention described herein. Therefore, it should be understood that the foregoing embodiments are presented only by way of example, and within the scope of the appended claims and their equivalents, embodiments of the present invention may be practiced in a manner different from that specifically described and claimed. The embodiments of the present invention disclosed herein relate to each individual feature, system, article, material, kit, and / or method described herein. In addition, any combination of two or more such features, systems, articles, materials, kits and / or methods is included within the scope of the present invention of the present disclosure if such features, systems, articles, materials, kits and / or methods are not mutually inconsistent.

[0198] It should be understood that all definitions, as defined and used herein, control over dictionary definitions, definitions in documents incorporated by reference, and / or ordinary meanings of the defined terms.

[0199] All references, patents, and patent applications disclosed herein are incorporated by reference for the subject matter in which each is cited, which, in some cases, may be the entire document.

[0200] Unless expressly indicated to the contrary, the indefinite articles "a" and "an" as used herein in the specification and claims should be understood to mean "at least one".

[0201] As used herein in the specification and claims, the phrase "and / or" should be understood to mean "either one or both" of the elements so combined, i.e., the elements exist together in some cases and separately in other cases. Multiple elements listed with "and / or" should be interpreted in the same manner, i.e., "one or more elements" of the elements so combined. In addition to the elements specifically identified by the "and / or" clause, other elements may optionally be present, whether related or unrelated to those specifically identified. Therefore, as a non-limiting example, in one embodiment, when used in conjunction with open-ended language such as "including", a reference to "A and / or B" may refer only to A (optionally including elements other than B); in another embodiment, only to B (optionally including elements other than A); in yet another embodiment, to both A and B (optionally including other elements); etc.

[0202] 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 the items in the list, "or" or "and / or" should be interpreted as inclusive, i.e., including at least one element in a plurality of elements or element lists, but also including more than one element and optionally other unlisted items. Only explicitly indicating the opposite term (such as "only one" or "just one") or when used in the claims, "consisting of..." will refer to including exactly one element in many elements or element lists. Usually, as used herein, when previously being an exclusive term (such as "any one of...", "one of...", "only one of..." or "just one of..."), the term "or" should only be interpreted as indicating exclusive alternatives (that is, "one or another, but not both"). When used in the claims, "mainly consisting of..." should have the common meaning as used in the field of patent law.

[0203] 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 elements in the list of elements, but not necessarily including at least one element of each and every element specifically listed in the list of elements, and not excluding any combination of elements in the list of elements. This definition also allows that elements other than the elements specifically identified in the list of elements referred to by the phrase "at least one" may optionally be present, whether related or unrelated to those elements specifically identified. Thus, as a non-limiting example, in one embodiment, "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") may refer to at least one optionally containing more than one A, without B (and optionally containing elements other than B); in another embodiment, may refer to at least one optionally containing more than one B, without A (and optionally containing elements other than A); in yet another embodiment, may refer to at least one optionally containing more than one A, and optionally containing more than one B (and optionally containing other elements); etc.

[0204] It should also be understood that in any method claimed herein that includes more than one step or action, the order of the steps or actions of the method is not necessarily limited to the order of the steps or actions of the method as recited unless explicitly stated to the contrary.

Claims

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

2. The method of 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 method according to claim 1 or claim 2, wherein the pharmaceutically acceptable carrier comprises a first pharmaceutically acceptable nonionic surfactant having a hydrophilic-lipophilic balance (HLB value) greater than 10.

4. The method of claim 3, wherein the first pharmaceutically acceptable nonionic surfactant comprises polyethylene glycol 40 stearate, polyethylene glycol 20 cetearyl ether, Tween 80, polyethylene glycol 15 hydroxystearate (solutol HS15), a polyoxyethylene derivative, a polyoxyethylene castor oil derivative, or a combination thereof.

5. The method of claim 3 or claim 4, wherein the first active agent forms a first plurality of micelles with the first pharmaceutically acceptable non-ionic surfactant.

6. The method according to any one of claims 3 to 5, wherein the weight ratio of the first active agent to the first pharmaceutically acceptable non-ionic surfactant in the composition is 1:2-1:

500.

7. The method of any one of claims 5 to 6, 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 less than 0.

4.

8. The method according to any one of claims 1 to 7, wherein the composition is in the form of a non-oral dosage form, optionally wherein the composition is formulated for injection, implantation or transdermal administration.

9. The method of any one of claims 1 to 8, wherein the condition is an adipose tissue tumor.

10. The method of claim 9, wherein the adipose tissue tumor is a benign tumor, optionally a lipoma.

11. The method of claim 10, wherein the adipose tissue tumor is a lipoma, and the lipoma is a nodular lipoma or a diffuse lipoma.

12. The method of claim 9, wherein the adipose tissue tumor is a malignant tumor, optionally a liposarcoma, Proteus syndrome, PTEN hamartoma tumor syndrome, Gardner syndrome, familial multiple lipomatosis, Cowden syndrome, Madelung's disease, painful lipoma, angiolipoma, lipomatosis, subcutaneous adipose tissue disease, lipedema, rare adipose disorder (RAD), or soft tissue sarcoma.

13. The method of any one of claims 1 to 7, wherein the condition is Dercum's disease or lipedema.

14. The method of any one of claims 1 to 13, wherein the subject is a human patient suffering from or suspected of suffering from the condition.

15. The method according to any one of claims 1 to 14, wherein the composition is administered to the subject parenterally.

16. The method of any one of claims 1 to 15, wherein the composition is administered to the subject at a local site.

17. The method of claim 16, wherein the composition is administered to the subject topically or by injection.

18. The method of claim 16 or claim 17, wherein the local site is located at or near a site where adipose tissue or fat is deposited subcutaneously.

19. The method of claim 18, wherein the local site is at or near a lipoma or liposarcoma.

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