Method of preparing a pharmaceutical composition for treating and / or preventing edematous fibrosclerotic panniculopathy

Abstract

This invention provides a method for treating and / or preventing edematous fibroschisis of the fat membrane in an individual, comprising the step of administering an effective amount of a pharmaceutical composition to the individual. The pharmaceutical composition has a plurality of amphiphilic nanoparticles coated with one or more active ingredients, each amphiphilic nanoparticle being formed from a nonionic surfactant, a polymeric carrier, or a lipid carrier, wherein the hydrophilic-lipophilic balance (HLB) of the nonionic surfactant is greater than 9. The pharmaceutical composition is administered via a non-gastrointestinal route, such as by injection, microneedle, or implant, or via a topical or transdermal route.

Description

Technical Field

[0001] This application claims the benefit of priority to U.S. Provisional Patent Application No. 63 / 384,605, filed on November 22, 2022, the entirety of which is incorporated herein by reference.

[0002] The present invention relates to a composition for treating and / or preventing edematous fibrosclerotic panniculopathy (EFP), and more particularly, to a pharmaceutical composition comprising drug-containing micelles for improving EFP or inhibiting EFP formation in an individual. Prior Art

[0003] Edematous fibrosclerotic panniculopathy (EFP), also known as cellulite, female lipodystrophy, or focal lipodystrophy, is a morphological change in the skin and subcutaneous fat that commonly occurs on the buttocks, lower extremities, and abdomen. The pathogenesis of EFP involves expansion of subcutaneous fat, fibrosis of subcutaneous septa, skin laxity and atrophy, excess intracellular water-soluble matrix, and microvascular changes and inflammation in the connective tissue. These changes ultimately result in uneven, irregular, and "orange peel"-like appearance of the skin on the buttocks, lower extremities, and abdomen. While not life-threatening, EFP remains a cosmetic concern for many, particularly for the over 80% of postpubertal women who experience it.

[0004] Generally speaking, EFP has a negative impact on women's psychosocial well-being because it is directly and inevitably linked to appearance, self-esteem, and, consequently, happiness and social acceptance. EFP can lead to an unhealthy appearance and diminished self-confidence. According to Market Research Future (MRFR)'s comprehensive research report, "Cellulite Treatment Market Information by Cellulite Type, End Use and Treatment Procedure - Forecast till 2027," the market is projected to reach US$3.1621 billion by 2027, with a compound annual growth rate (CAGR) of 11.2%. This analysis indicates that market demand for EFP treatment is increasing.

[0005] The exact cause of EFP remains an unsolved question, but according to the inventors, it appears to be caused by the interaction between the connective tissue in the dermis, located below the skin's surface, and the underlying fat layer. EFP is more common in women because the fat cells and connective tissue in the skin are arranged vertically, with loose fibers between them. This structure causes the fat to bulge outward, creating the appearance of EFP. EFP severity is typically graded as follows: (i) Grade 0: No EFP; (ii) Grade 1: Smooth skin when standing, but with an orange peel appearance when sitting; (iii) Grade 2: Orange peel appearance when both standing and sitting; and (iv) Grade 3: Orange peel appearance with distinct raised and depressed areas when standing. Research over the past few decades has developed a variety of non-invasive and invasive methods for removing EFP.

[0006] For example, using massage cream is a common non-invasive method. However, because EFP is caused by the uneven accumulation of fat cells, and known massage creams can only act on the surface, their active ingredients are almost impossible to reach the subcutaneous tissue. Therefore, this method cannot effectively eliminate EFP.

[0007] On the other hand, invasive treatments include liposuction, radiofrequency therapy (RF), and laser therapy. Because EFP primarily occurs in the superficial fat and dermis, liposuction is not an effective treatment because, in addition to side effects, it can also cause scar tissue and uneven skin. RF heats the entire skin area evenly (through volumetric heating), also targeting the dermis and fat layers to achieve skin firming and wrinkle reduction. However, RF carries a high risk of skin burns, and the amount of heat applied to the patient must be carefully controlled throughout the treatment. Laser therapy requires local anesthesia, surgical incision creation, and catheter insertion. Specifically, laser therapy involves administering local anesthesia and making a small surgical incision to allow the catheter to be inserted beneath the skin. A low-energy laser beam from a laser probe is then used to break down and remove the underlying tissue. Other common treatments include acoustic wave therapy (AWT) and injections. However, most known treatments are expensive and have adverse side effects, such as inflammation, redness, pain, and bruising. Furthermore, these treatments lack sustained effectiveness. Existing topical medications, injections, and energy-based therapies can only improve the appearance of EFP but cannot eliminate or prevent its recurrence.

[0008] Therefore, the art still needs to provide safer and more sustainable methods for treating and / or preventing EFP. Summary of the Invention

[0009] In view of the shortcomings of the prior art, the present invention provides a pharmaceutical composition and its use for treating and / or preventing EFP. This pharmaceutical composition has the advantages of high stability, high bioavailability for adipose tissue, low side effects, and sustained release.

[0010] According to one embodiment, a pharmaceutical composition is provided for use in preparing a medicament for treating and / or preventing edematous fibrosclerotic lipopathy (EFP) in a subject. This use comprises administering an effective amount of the pharmaceutical composition to the subject, wherein the pharmaceutical composition comprises a plurality of amphiphilic nanoparticles encapsulating one or more active ingredients, each amphiphilic nanoparticle being formed from a nonionic surfactant, a polymeric carrier, or a lipid carrier, and the nonionic surfactant has a hydrophilic-lipophilic balance (HLB) greater than 9.

[0011] In one or more embodiments, the amphiphilic nanoparticles are a plurality of micelles or emulsions, which encapsulate one or more active ingredients and are formed by a non-ionic surfactant.

[0012] In one or more embodiments, the amphiphilic nanoparticles are a plurality of polymeric nanospheres or polymeric nanocapsules, which encapsulate one or more active ingredients and are formed by a polymer carrier.

[0013] In one or more embodiments, the amphiphilic nanoparticles are a plurality of liposomes that encapsulate one or more active ingredients and are formed by lipid carriers.

[0014] In one or more embodiments, each amphiphilic nanoparticle comprises a hydrophobic core and a hydrophilic outer membrane, wherein one or more active ingredients are encapsulated in the hydrophobic core, which is encapsulated in the hydrophilic outer membrane. The hydrophobic core is formed by the hydrophobic end groups of a nonionic surfactant, a polymer carrier, or a lipid carrier, and the hydrophilic outer membrane is formed by the hydrophilic end groups of a nonionic surfactant, a polymer carrier, or a lipid carrier.

[0015] In one or more embodiments, each amphiphilic nanoparticle comprises a hydrophilic core and a hydrophobic outer membrane, wherein one or more active ingredients are encapsulated in the hydrophilic core, which is encapsulated in the hydrophobic outer membrane. The hydrophilic core is formed by the hydrophilic end groups of a nonionic surfactant, a polymer carrier, or a lipid carrier, and the hydrophobic outer membrane is formed by the hydrophobic end groups of a nonionic surfactant, a polymer carrier, or a lipid carrier.

[0016] In one or more embodiments, the pharmaceutical composition is administered in a non-oral dosage form, such as parenteral administration via injection, microneedle, or implant, or topical or transdermal administration. Injectable dosage forms may include, but are not limited to, powder injections, freeze-dried injections, sterile suspensions, injectable solutions, injectable emulsions, and intravenous solutions. Topical or transdermal dosage forms may include, but are not limited to, ointments, lotions, liniments, creams, gels, dressings, emulsions, films, patches, poultices, cataplasms, topical powders, and topical solutions.

[0017] In one or more embodiments, the pharmaceutical composition is administered to the thigh, buttocks, lower extremities, pelvic region, or abdomen of a subject.

[0018] In one or more embodiments, the pharmaceutical composition is administered to a treatment area of ​​a subject, and the effective unit dose per unit area of ​​the treatment area injected is 0.01-50 mg / cm 2 , and the pharmaceutical composition is administered at least once.

[0019] In one or more embodiments, the pharmaceutical composition is administered to the treatment area of ​​the subject via microneedles or implants, and the effective unit dose per unit area of ​​the treatment area is 0.01-20 mg / cm 2 .

[0020] In one or more embodiments, the pharmaceutical composition is topically administered to a treatment area of ​​a subject, and the effective amount per unit area of ​​the treatment area is 0.5-20 mg / cm 2 .

[0021] In one or more embodiments, the pharmaceutical composition is administered to the treatment area of ​​the subject via a transdermal route, and the effective amount per unit area of ​​the treatment area is 0.5-50 mg / cm 2 .

[0022] In one or more embodiments, the effective amount of the pharmaceutical composition is 40-80 mg.

[0023] In one or more embodiments, the pharmaceutical composition is administered at least once.

[0024] In one or more embodiments, an effective amount is a dose sufficient to achieve at least one of the following efficacy endpoints: efficacy endpoint (a) a decrease in the depth of the treated area by at least 10%; efficacy endpoint (b) a decrease in the width of the treated area by at least 10%; efficacy endpoint (c) a decrease in the length of the treated area by at least 5%; efficacy endpoint (d) a decrease in the total volume of the treated area by at least 10%; efficacy endpoint (e) a decrease in the surface area of ​​the treated area by at least 10%.

[0025] In one or more embodiments, the effective amount is a dose sufficient to reduce the cellulite severity scale (CSS) grade of the EFP-affected area of ​​the subject by at least one grade, or to produce a significant change (significant change relative to baseline) in the total score of the Modified Hexsel Cellulite Severity Scale (mHSCC), or to achieve a one-grade improvement (compared to baseline) in the total score of the mHCSS.

[0026] In one or more embodiments, an effective amount is a dose sufficient to produce a significant change (a significant amount of change relative to baseline) in the total score of the mHCSS.

[0027] In one or more embodiments, an effective amount is a dose sufficient to achieve a 1-grade improvement (from baseline) in the total mHCSS score.

[0028] In one or more embodiments, the amphiphilic nanoparticles are a plurality of micelles formed by a non-ionic surfactant, the active ingredient is one or more fat-soluble compounds, and at least a portion of the fat-soluble compounds is encapsulated in the micelles.

[0029] In one or more embodiments, the nonionic surfactant comprises at least one selected from the group consisting of polysorbate 80 (also known as Tween 80, polyoxyethylene (20)-sorbitan monooleate), polyoxyl 15 hydroxystearate (also known as Solutol® HS 15), polyoxyethylene derivatives, and polyoxyethylene castor oil derivatives.

[0030] In one or more embodiments, the polymeric carrier has a molecular weight of 1000 g / mol to 1,000,000 g / mol and comprises at least one selected from the group consisting of acrylates (e.g., alkyl acrylates, methyl acrylates, ethyl acrylates, methacrylates, and ethyl acrylates polymers or copolymers thereof), cellulose or cellulose derivatives, polyvinyl alcohol (PVA), poly(lactic-co-glycolic acid) (PLGA), poly(L-lactide) (PLLA), poly(D-lactide) (PDLA), polyvinylpyrrolidone (PVP) or a carrier containing PVP as a monomer, polyethylene glycol (PEG) or a carrier containing PEG as a monomer, or any combination thereof.

[0031] In one or more embodiments, the lipid carrier comprises at least one selected from the group consisting of natural phospholipids (e.g., phosphatidylcholine (PC)), synthetic phospholipids (e.g., dipalmitoylphosphatidylcholine (DPPC), distearylphosphatidylcholine (DSPC), dipalmitoylethanolamine (DPPE), dioleoylphosphatidylcholine (DOPC), dioleoylphosphatidylglycerol (DOPG), phosphatidylethanolamine (PE), and sphingomyelin (SM)), and cholesterol.

[0032] In one or more embodiments, the active ingredient comprises one or more fat-soluble compounds, wherein the fat-soluble compound comprises at least one selected from the group consisting of curcumin, quercetin, puerarin, oxyresveratrol, resveratrol, and derivatives, metabolites, or isomers of the foregoing compounds.

[0033] In one or more embodiments, the active ingredient comprises one or more water-soluble compounds, the water-soluble compound comprising at least one selected from the group consisting of green tea extract, epigallocatechin gallate, epicatechin, epicatechin gallate, epigallocatechin, epigallocatechin gallate, gallocatechin, epigallocatechin gallate, catechin, epigallocatechin gallate (EGCG), caffeine, carnitine, L-carnitine, synephrine, and chlorogenic acid.

[0034] In one or more embodiments, the weight ratio of the active ingredient to the nonionic surfactant, polymer carrier or lipid carrier is in the range of 1:2 to 1:500.

[0035] In one or more embodiments, the concentration of the active ingredient in the pharmaceutical composition is in the range of 0.2 mg / g to 500 mg / g.

[0036] In one or more embodiments, the diameter of each amphiphilic nanoparticle is less than 200 nm, and the polydispersity index (PDI) of the amphiphilic nanoparticles is less than 0.4.

[0037] In one or more embodiments, the active ingredient comprises one or more fat-soluble compounds and one or more water-soluble compounds, wherein the fat-soluble compound comprises at least one selected from the group consisting of curcumin, quercetin, puerarin, oxyresveratrol, resveratrol, and derivatives, metabolites, or isomers of the foregoing compounds. The one or more water-soluble compounds include at least one selected from the group consisting of green tea extract, epigallocatechin gallate, epicatechin, epicatechin gallate, epigallocatechin, gallocatechin gallate, gallocatechin, catechin gallate, catechin, epigallocatechin gallate (EGCG), caffeine, carnitine, L-carnitine, synephrine, and chlorogenic acid.

[0038] In one or more embodiments, the weight ratio of the active ingredient to the nonionic surfactant, polymer carrier or lipid carrier is in the range of 1:2 to 1:500.

[0039] In one or more embodiments, the concentration of the fat-soluble compound in the pharmaceutical composition is in the range of 0.2 mg / g to 500 mg / g, and the concentration of the water-soluble compound in the pharmaceutical composition is in the range of 0.1 mg / g to 500 mg / g.

[0040] In one or more embodiments, the weight ratio of the fat-soluble compound to the water-soluble compound in the pharmaceutical composition is in the range of 30:1 to 1:10.

[0041] In one or more embodiments, the pharmaceutical composition further comprises at least one selected from the group consisting of a solvent, a co-solvent, a co-surfactant, a suspending agent, and an oil-phase excipient.

[0042] According to any embodiment, the pharmaceutical composition has therapeutic and preventive effects on EFP and can reduce adverse reactions and side effects, such as peripheral cell necrosis and inflammatory reactions. In some embodiments, the medical composition can be administered via direct injection, subcutaneous implant, intravenous injection, implantable infusion, cream, patch, or other transdermal route, without the need for any surgical intervention or device assistance. Simple diagram description

[0043] The following examples are intended to be illustrative and can be used to further understand the embodiments of the present invention. These examples should not be considered to limit the scope of the present invention in any way. FIG1 is a photograph showing the score of items using the light numerical description of the mHCSS according to the prior art; 2A to 2C are photographs showing the improvement in EFP of three human subjects after treatment with a curcumin-resveratrol combination pharmaceutical composition according to some embodiments; 3A and 3B are bar graphs showing the baseline mean mHCSS total score of each group of subjects, and the mean mHCSS total score at week 2 and week 4 of treatment with the Curcumin-Resveratrol combination pharmaceutical composition, according to some embodiments; FIG4A and FIG4B are photographs according to some embodiments, respectively showing the changes in EFP severity of two subjects after receiving a course of treatment with 40 mg of a curcumin-resveratrol composite pharmaceutical composition; FIG5 is a photograph showing the change in EFP severity of a subject receiving a 60 mg curcumin-resveratrol combination pharmaceutical composition according to some embodiments; and FIG6 is a photograph showing the change in EFP severity of subjects receiving 80 mg of the curcumin-resveratrol combination pharmaceutical composition according to some embodiments. Implementation Method

[0044] In a first aspect of the present invention, a pharmaceutical composition is provided for use in preparing a medicament for treating and / or preventing EFP in a subject. This use comprises the step of administering an effective amount of the pharmaceutical composition to the subject, wherein the pharmaceutical composition comprises a plurality of micelles and one or more fat-soluble or water-soluble compounds. The micelles are formed from a pharmaceutically acceptable nonionic surfactant having a hydrophilic-lipophilic balance (HLB) greater than 9, and at least a portion of the fat-soluble or water-soluble compound is encapsulated within the micelles.

[0045] In some embodiments, the pharmaceutical composition can be prepared according to the following steps: step (1a) dissolving a fat-soluble compound in an organic solvent to form a solution; step (2a) adding a nonionic surfactant to the solution and stirring the solution to volatilize the organic solvent; step (3a) after the organic solvent has completely volatilized, adding a pharmaceutically acceptable aqueous solution to obtain the pharmaceutical composition. Alternatively, in some embodiments, the pharmaceutical composition can be prepared according to the following steps: step (1b) dissolving a water-soluble compound in an aqueous solvent to form a solution; step (2b) adding a nonionic surfactant to the solution; step (3b) adding a pharmaceutically acceptable non-aqueous solution to obtain the pharmaceutical composition.

[0046] Specifically, in step (1a), the fat-soluble compound may include, but is not limited to, at least one selected from the group consisting of curcumin, quercetin, puerarin, oxidized resveratrol, resveratrol, and derivatives, metabolites, or isomers of the aforementioned compounds. This means that the fat-soluble compound encapsulated in the micelles may be curcumin, quercetin, puerarin, oxidized resveratrol, resveratrol, other fat-soluble therapeutic agents, derivatives, metabolites, or isomers of the aforementioned compounds, or any combination thereof. In a preferred embodiment, the fat-soluble compound comprises curcumin and resveratrol in a weight ratio of 4:1. The organic solvent may include, but is not limited to, a hydrophobic solvent, a hydrophilic solvent, other solvents having a boiling point below 100°C, or any combination thereof. Specifically, the hydrophobic solvent may include but is not limited to ether (e.g., diethyl ether, diethyl ether), or any combination thereof; the hydrophilic solvent may include but is not limited to ester (e.g., ethyl acetate), alcohol (e.g., methanol, ethanol, isopropanol, ethylene glycol), dimethylformamide (DMF), ketone (e.g., acetone), formaldehyde, acetonitrile, dimethyl sulfoxide (DMSO), or any combination thereof.

[0047] In step (1b), the water-soluble compound may include, but is not limited to, at least one selected from the group consisting of green tea extract, epigallocatechin gallate, epicatechin, epicatechin gallate, epigallocatechin, epigallocatechin gallate, epigallocatechin gallate, epigallocatechin gallate, epigallocatechin gallate, catechin gallate, catechin, epigallocatechin gallate (EGCG), caffeine, carnitine, L-carnitine, synephrine, and chlorogenic acid. The aqueous solvent may include, but is not limited to, a hydrophilic solvent, other solvents having a boiling point below 100°C, or any combination thereof. Specifically, the hydrophilic solvent may include, but is not limited to, an ester (e.g., ethyl acetate), an alcohol (e.g., methanol, ethanol, isopropanol, ethylene glycol), dimethylformamide (DMF), a ketone (e.g., acetone), formaldehyde, acetonitrile, dimethylsulfoxide (DMSO), or any combination thereof.

[0048] In step (2a) and step (2b), the nonionic surfactant may include, but is not limited to, at least one selected from the group consisting of polysorbate 80 (Tween 80, polyoxyethylene (20)-sorbitan monooleate), polyoxyethylene-15 hydroxystearate (Solutol® HS 15; Kolliphor® HS 15), polyoxyethylene derivatives, and polyoxyethylene castor oil derivatives. This means that the nonionic surfactant used to form micelles may be Tween 80, Solutol® HS 15, polyoxyethylene castor oil derivatives, other nonionic surfactants having a hydrophilic-lipophilic balance (HLB) greater than 9, or any combination thereof. The polyoxyethylene castor oil derivative can be polyoxyethylene 35 castor oil (PEG-35 castor oil; Kolliphor® ELP; Cremophor® ELP), polyoxyethylene 40 hydrogenated castor oil (Cremophor® RH 40; Kolliphor® RH 40), or any combination thereof.

[0049] The weight ratio of the fat-soluble compound to the nonionic surfactant is in the range of 1:2 to 1:500. In one or more embodiments, the weight ratio of the fat-soluble compound to the nonionic surfactant is in the range of 1:20 to 1:150. The concentration of the fat-soluble compound in the pharmaceutical composition is in the range of 0.2 mg / g to 500 mg / g, the diameter of each micelle is less than 50 nm, and the polydispersity index (PDI) of the micelles is less than 0.4.

[0050] Alternatively, the weight ratio of the water-soluble compound to the nonionic surfactant is in the range of 1:2 to 1:500, the concentration of the water-soluble compound in the pharmaceutical composition is in the range of 0.1 mg / g to 500 mg / g, the diameter of each micelle is less than 50 nm, and the polydispersity index (PDI) of the micelles is less than 0.4.

[0051] In step (3a), the pharmaceutically acceptable aqueous solution may be, but is not limited to, water for injection, an aqueous solution for injection, or normal saline. The pharmaceutically acceptable aqueous solution may further contain one or more local anesthetics, antioxidants, or other water-soluble agents (e.g., green tea extract). The weight ratio of the fat-soluble compound to the pharmaceutically acceptable aqueous solution is in the range of 1:400 to 3:50.

[0052] In step (3b), the pharmaceutically acceptable non-aqueous solution may be, but is not limited to, benzene, ethanol, ether, carbon disulfide, or acetone. The pharmaceutically acceptable non-aqueous solution may further contain one or more local anesthetics, antioxidants, or other fat-soluble agents (e.g., curcumin). The weight ratio of the fat-soluble compound to the pharmaceutically acceptable non-aqueous solution is in the range of 1:400 to 3:50.

[0053] Local anesthetics may include, but are not limited to, amides, para-aminobenzoic acid esters, aminoethers, or any combination thereof. The amide may be dibucaine, lidocaine, mepivacaine HCl, bupivacaine HCl, pyrrocaine HCl, prilocaine HCl, digacaine, oxethazaine, or any combination thereof. The para-aminobenzoic acid ester may be butacaine, dimethocaine, tutocaine, or any combination thereof. The aminoether may be quinisocaine, pramocaine, or any combination thereof. Antioxidants may include, but are not limited to, beta-carotene, lutein, lycopene, bilirubin, vitamin A, vitamin C (ascorbic acid), vitamin E, uric acid, nitric oxide, nitroxide, pyruvate, catalase, superoxide dismutase, glutathione peroxidases, N-acetyl cysteine, naringenin, other oxidation inhibitors, or any combination thereof.

[0054] In some embodiments, the pharmaceutical composition may include one or more fat-soluble compounds or one or more water-soluble compounds, and at least a portion of the fat-soluble compounds and the water-soluble compounds are encapsulated in micelles. In this embodiment, the pharmaceutical composition can be prepared according to the following steps: step (1) dissolving the fat-soluble compound and the water-soluble compound in an organic solvent to form a solution; step (2) adding a non-ionic surfactant to the solution and stirring the solution to volatilize the organic solvent; step (3) after the organic solvent is completely volatilized, adding a pharmaceutically acceptable aqueous solution to obtain the pharmaceutical composition. The organic solvent may include but is not limited to a hydrophobic solvent, a hydrophilic solvent, other solvents with a boiling point below 100°C, or any combination thereof. Specifically, the hydrophobic solvent may include but is not limited to ether (e.g., diethyl ether, diethyl ether) or any combination thereof. The hydrophilic solvent may include, but is not limited to, esters (e.g., ethyl acetate), alcohols (e.g., methanol, ethanol, isopropanol, ethylene glycol), dimethylformamide (DMF), ketones (e.g., acetone), formaldehyde, acetonitrile, dimethyl sulfoxide (DMSO), or any combination thereof.

[0055] The fat-soluble compound may include, but is not limited to, at least one member selected from the group consisting of curcumin, quercetin, puerarin, oxidized resveratrol, resveratrol, and derivatives, metabolites, or isomers of the foregoing compounds. In one or more embodiments, the fat-soluble compound comprises curcumin and resveratrol in a weight ratio of 4:1. The weight ratio of the fat-soluble compound to the nonionic surfactant ranges from 1:2 to 1:500. In one or more embodiments, the weight ratio of the fat-soluble compound to the nonionic surfactant ranges from 1:20 to 1:150. The concentration of the fat-soluble compound in the pharmaceutical composition ranges from 0.2 mg / g to 500 mg / g. The water-soluble compound may include, but is not limited to, at least one member selected from the group consisting of green tea extract, epigallocatechin gallate, epicatechin, epicatechin gallate, epigallocatechin, epigallocatechin gallate, epigallocatechin, epigallocatechin gallate, catechin gallate, catechin, epigallocatechin gallate (EGCG), caffeine, carnitine, L-carnitine, synephrine, and chlorogenic acid. The weight ratio of the water-soluble compound to the nonionic surfactant is in the range of 1:5 to 1:500, the concentration of the water-soluble compound in the pharmaceutical composition is in the range of 0.1 mg / g to 500 mg / g, and the weight ratio of the fat-soluble compound to the water-soluble compound in the pharmaceutical composition is in the range of 30:1 to 1:10.

[0056] In some embodiments, the pharmaceutical composition may further comprise at least one agent selected from the group consisting of a solvent, a cosolvent, a cosurfactant, a suspending agent, an oil-phase excipient, and an antimicrobial drug. This means that the pharmaceutical composition may further comprise a solvent, a cosolvent, a cosurfactant, a suspending agent, an oil-phase excipient, an antimicrobial drug, or any combination thereof. A solvent can be any substance, typically a liquid, that can dissolve one or more substances to produce a solution and / or form micelles. A cosolvent is used to increase the solubility of the compound encapsulated in the micelles. A cosolvent may include, but is not limited to, polyethylene glycol, propylene glycol, ethanol, other cosolvents that increase the solubility of lipid-soluble or water-soluble compounds, or any combination thereof. Specifically, polyethylene glycol may be PEG 200, PEG 400, PEG 600, or any combination thereof. A cosurfactant is a chemical substance added to a surfactant to improve its performance. This means that a cosurfactant is a secondary surfactant used in conjunction with the primary surfactant. Co-surfactants may include, but are not limited to, ethanol, propylene glycol, polyethylene glycol (PEG), or any combination thereof. Suspending agents are used to reduce the sedimentation of micelles or the compound encapsulated therein. Suspending agents may include, but are not limited to, sodium alginate, glycerol, sodium carboxymethylcellulose, mannitol, other suspending agents that reduce the sedimentation of micelles or fat-soluble or water-soluble compounds encapsulated therein, or any combination thereof. Oil-phase excipients are used to increase the stability of the pharmaceutical composition and / or increase the solubility of the encapsulated compound. Oil-phase excipients may include, but are not limited to, unsaturated fatty acids, glycerol, triglycerides, other oil-phase excipients that increase the stability of micelles and / or increase the solubility of fat-soluble or water-soluble compounds, or any combination thereof. Specifically, unsaturated fatty acids may include, but are not limited to, oleic acid, castor oil, sesame oil, cottonseed oil, soybean oil, safflower oil, corn oil, or any combination thereof. Triglycerides may include, but are not limited to, medium-chain triglycerides. Antimicrobials can be defined as natural or synthetic substances that can kill microorganisms, such as bacteria, fungi and algae, or inhibit the growth of microorganisms. This means that antimicrobials are therapeutic substances used to prevent or treat microbial infections. Antimicrobials can be, but are not limited to, antibacterial agents, antibiotics, antivirals, antifungals and antiparasitics.

[0057] The pharmaceutical composition can be further formulated so that it can be administered to a subject in the form of an injection, microneedle, implant, transdermal patch, cream, lotion, diffuser, gel, ointment or suspension.

[0058] The subject can be a mammal (e.g., a human). The pharmaceutical composition can be administered to a localized area of ​​the subject (e.g., an area affected by EFP). The margins of the localized area can be determined by the surgeon. The pharmaceutical composition can be administered subcutaneously. In one or more embodiments, the pharmaceutical composition can be administered 1-10 mm below the subcutaneous tissue.

[0059] In some embodiments, the subject is a human subject, and the pharmaceutical composition can be administered subcutaneously to the thigh (e.g., the posterior and lateral thigh), buttocks, lower limbs, pelvic region, abdomen, or other areas of the body affected by EFP.

[0060] The pharmaceutical composition can be administered via any conventional non-oral dosage form via a non-digestive administration route, which may include injection, microneedle, implant, topical administration route, transdermal administration route or any non-intestinal administration route.

[0061] In some embodiments, the pharmaceutical composition is formulated as an injectable composition and can be administered to a subject via injection, microneedle, or implant. For example, the pharmaceutical composition can be administered subcutaneously to the treatment area of ​​a human subject. During each treatment session, the injection volume per unit area of ​​the treatment area is 0.01-50 mg / cm². In one or more embodiments, during each treatment session, the injection volume per unit area of ​​the treatment area is 1-2 mg / cm². The distance between each injection site can be at least 0.5 cm. The number of injection sites can vary depending on the body area.

[0062] In some embodiments, the pharmaceutical composition is formulated as a composition for topical or transdermal administration and can be topically or transdermally administered to a subject, for example, topically administering the pharmaceutical composition to a treatment area of ​​a human subject, with a dose per unit area of ​​the treatment area being 0.5-20 mg / cm 2 .

[0063] The subject may receive at least one treatment course. To achieve the desired effect, the pharmaceutical composition may be administered once every other day, at least once a week, at least once every two weeks, at least once a month, or at least once per treatment course. In this embodiment, there is no limit to the number of treatment courses, and treatment courses may be continued until a significant improvement in EFP is observed.

[0064] In some embodiments, the effective amount can be a dose sufficient to achieve at least one of the following therapeutic efficacy indicators: (a) a reduction in the depth of the treated area by at least 10%; (b) a reduction in the width of the treated area by at least 10%; (c) a reduction in the length of the treated area by at least 5%; (d) a reduction in the total volume of the treated area by at least 10%; or (e) a reduction in the surface area of ​​the treated area by at least 10%. In some embodiments, the effective amount can be a dose sufficient to reduce the severity of cellulite in the EFP-affected area of ​​the subject by at least one grade, or to produce a significant change (a significant change from baseline) in the total mHCSS score, or to achieve a one-grade improvement (from baseline) in the total mHCSS score.

[0065] In a second aspect of the present invention, another pharmaceutical composition is provided for use in preparing a medicament for treating and / or preventing EFP in a subject. This use comprises administering an effective amount of the pharmaceutical composition to the subject, wherein the pharmaceutical composition comprises a plurality of amphiphilic nanoparticles encapsulating one or more active ingredients, each amphiphilic nanoparticle being formed from a nonionic surfactant, a polymeric carrier, or a lipid carrier, wherein the nonionic surfactant has a hydrophilic-lipophilic balance (HLB) greater than 9.

[0066] In some embodiments, the amphiphilic nanoparticles are micelles or emulsions that encapsulate one or more active ingredients and are formed by a non-ionic surfactant.

[0067] In some embodiments, the amphiphilic nanoparticles are polymeric nanospheres or polymeric nanocapsules, which encapsulate one or more active ingredients and are formed by a polymer carrier.

[0068] In some embodiments, the amphiphilic nanoparticles are liposomes, which encapsulate one or more active ingredients and are formed by lipid carriers.

[0069] In some embodiments, each amphiphilic nanoparticle has a hydrophobic core and a hydrophilic outer membrane. One or more active ingredients are encapsulated in the hydrophobic core, which is encapsulated in the hydrophilic outer membrane. The hydrophobic core is formed by the hydrophobic end groups of a nonionic surfactant, a polymer carrier, or a lipid carrier, and the hydrophilic outer membrane is formed by the hydrophilic end groups of a nonionic surfactant, a polymer carrier, or a lipid carrier.

[0070] In some embodiments, each amphiphilic nanoparticle has a hydrophilic core and a hydrophobic outer membrane. One or more active ingredients are encapsulated in the hydrophilic core, which is encapsulated in the hydrophobic outer membrane. The hydrophilic core is formed by the hydrophilic end groups of a nonionic surfactant, a polymer carrier, or a lipid carrier, and the hydrophobic outer membrane is formed by the hydrophobic end groups of a nonionic surfactant, a polymer carrier, or a lipid carrier.

[0071] In some embodiments, the amphiphilic nanoparticles are micelles formed by a non-ionic surfactant, and the active ingredient is one or more fat-soluble compounds and / or water-soluble compounds.

[0072] In some embodiments, the nonionic surfactant comprises at least one member selected from the group consisting of polysorbate 80 (Tween 80, polyoxyethylene (20)-sorbitan monooleate), polyoxyethylene-15 hydroxystearate (e.g., Solutol® HS 15), polyoxyethylene derivatives, and polyoxyethylene castor oil derivatives.

[0073] In some embodiments, the polymeric carrier has a molecular weight of 1000 g / mol to 1,000,000 g / mol. The polymeric carrier comprises at least one selected from the group consisting of acrylates (e.g., alkyl acrylates, methyl acrylates, ethyl acrylates, methacrylates, and ethyl acrylates polymers or copolymers thereof), cellulose or cellulose derivatives, polyvinyl alcohol (PVA), poly(lactic-co-glycolic acid) (PLGA), polyvinylpyrrolidone (PVP) or carriers containing PVP as a monomer, polyethylene glycol (PEG) or carriers containing PEG as a monomer, or any combination thereof.

[0074] In some embodiments, the lipid carrier comprises at least one member selected from the group consisting of natural phospholipids (e.g., phosphatidylcholine (PC)), synthetic phospholipids (e.g., dipalmitoylphosphatidylcholine (DPPC), distearylphosphatidylcholine (DSPC), dipalmitoylethanolamine (DPPE), dioleoylphosphatidylcholine (DOPC), dioleoylphosphatidylglycerol (DOPG), phosphatidylethanolamine (PE), sphingomyelin (SM), and cholesterol.

[0075] The pharmaceutical composition can be prepared according to the following steps: step (ia) dissolving the active ingredient in an organic solvent to form a solution; step (iia) adding a nonionic surfactant to the solution and stirring the solution to volatilize the organic solvent; and step (iiia) after the organic solvent has completely evaporated, adding a pharmaceutically acceptable aqueous solution to obtain the pharmaceutical composition. Alternatively, in some embodiments, the pharmaceutical composition can be prepared according to the following steps: step (ib) dissolving a water-soluble compound in an aqueous solvent to form a solution; step (iib) adding a nonionic surfactant to the solution; and step (iiib) adding a pharmaceutically acceptable non-aqueous solution to obtain the pharmaceutical composition.

[0076] Specifically, in step (ia), the active ingredient may include one or more fat-soluble compounds. These fat-soluble compounds may include, but are not limited to, at least one selected from the group consisting of curcumin, quercetin, puerarin, oxidized resveratrol, resveratrol, and derivatives, metabolites, or isomers of the foregoing compounds. This means that the fat-soluble compound encapsulated in the hydrophobic core of the amphiphilic nanoparticles may be curcumin, quercetin, puerarin, oxidized resveratrol, resveratrol, other fat-soluble therapeutic agents, derivatives, metabolites, or isomers of the foregoing compounds, or any combination thereof. In one or more embodiments, the pharmaceutical composition comprises fat-soluble compounds including curcumin and resveratrol in a weight ratio of 4:1. The organic solvent may include, but is not limited to, a hydrophobic solvent, a hydrophilic solvent, other solvents with a boiling point below 100°C, or any combination thereof. Specifically, the hydrophobic solvent may include but is not limited to ether (e.g., diethyl ether, diethyl ether) or any combination thereof; the hydrophilic solvent may include but is not limited to ester (e.g., ethyl acetate), alcohol (e.g., methanol, ethanol, isopropanol, ethylene glycol), dimethylformamide (DMF), ketone (e.g., acetone), formaldehyde, acetonitrile, dimethyl sulfoxide (DMSO) or any combination thereof.

[0077] In step (ib), the active ingredient may include one or more water-soluble compounds. The water-soluble compounds may include, but are not limited to, at least one selected from the group consisting of green tea extract, epigallocatechin gallate, epicatechin, epicatechin gallate, epigallocatechin, epigallocatechin gallate, epigallocatechin gallate, epigallocatechin gallate, epigallocatechin gallate, catechin gallate, catechin, epigallocatechin gallate (EGCG), caffeine, carnitine, L-carnitine, synephrine, and chlorogenic acid. The aqueous solvent may include, but is not limited to, a hydrophilic solvent, other solvents with a boiling point below 100°C, or any combination thereof. Specifically, the hydrophilic solvent may include, but is not limited to, esters (e.g., ethyl acetate), alcohols (e.g., methanol, ethanol, isopropanol, ethylene glycol), dimethylformamide (DMF), ketones (e.g., acetone), formaldehyde, acetonitrile, dimethylsulfoxide (DMSO), or any combination thereof.

[0078] In step (iia), the nonionic surfactant may include, but is not limited to, at least one selected from the group consisting of polysorbate 80 (Tween 80, polyoxyethylene (20)-sorbitan monooleate), polyoxyethylene-15 hydroxystearate (Solutol® HS 15; Kolliphor® HS 15), polyoxyethylene derivatives, and polyoxyethylene castor oil derivatives. This means that the nonionic surfactant used to form micelles may be Tween 80, Solutol® HS 15, polyoxyethylene castor oil derivatives, other nonionic surfactants having a hydrophilic-lipophilic balance (HLB) greater than 9, or any combination thereof. The polyoxyethylene castor oil derivative can be polyoxyethylene 35 castor oil (PEG-35 castor oil; Kolliphor® ELP; Cremophor® ELP), polyoxyethylene 40 hydrogenated castor oil (Cremophor® RH 40; Kolliphor® RH 40), or any combination thereof.

[0079] The weight ratio of the fat-soluble compound to the nonionic surfactant is in the range of 1:2 to 1:500. In one or more embodiments, the weight ratio of the fat-soluble compound to the nonionic surfactant is in the range of 1:20 to 1:150. The concentration of the fat-soluble compound in the pharmaceutical composition is in the range of 0.2 mg / g to 500 mg / g. Each amphiphilic nanoparticle has a diameter of less than 200 nm, and the polydispersity index (PDI) of the amphiphilic nanoparticles is less than 0.4.

[0080] Alternatively, in some embodiments, the weight ratio of the water-soluble compound to the nonionic surfactant is in the range of 1:2 to 1:500. The concentration of the water-soluble compound in the pharmaceutical composition is in the range of 0.1 mg / g to 500 mg / g. The diameter of each micelle is less than 50 nm, and the micelle polydispersity index (PDI) is less than 0.4.

[0081] In step (iiia), the pharmaceutically acceptable aqueous solution may include, but is not limited to, water for injection, an aqueous solution for injection, or normal saline. The pharmaceutically acceptable aqueous solution may further contain one or more local anesthetics, antioxidants, or other water-soluble agents (e.g., green tea extract). The weight ratio of the fat-soluble compound to the pharmaceutically acceptable aqueous solution is in the range of 1:400 to 3:50.

[0082] In step (iiib), the pharmaceutically acceptable non-aqueous solution may be, but is not limited to, benzene, ethanol, ether, carbon disulfide, or acetone. The pharmaceutically acceptable non-aqueous solution may further contain one or more local anesthetics, antioxidants, or other fat-soluble agents (e.g., curcumin). The weight ratio of the fat-soluble compound to the pharmaceutically acceptable non-aqueous solution is in the range of 1:400 to 3:50.

[0083] Local anesthetics may include, but are not limited to, amides, para-amine benzoates, amino ethers, or any combination thereof. The amide may be dibucaine, lidocaine, mepivacaine hydrochloride, bupivacaine hydrochloride, procaine hydrochloride, prilocaine hydrochloride, digacaine, oxazepam, or any combination thereof. The para-amine benzoate may be butacaine, dimethocaine, or tutocaine, or any combination thereof. The amino ether may be quinicaine, pramoxine, or any combination thereof. Antioxidants may include, but are not limited to, β-carotene, lutein, lycopene, bilirubin, vitamin A, vitamin C (ascorbic acid), vitamin E, uric acid, nitric oxide, nitrogen oxide, pyruvate, catalase, superoxide dismutase, glutathione peroxidase, N-acetylcysteine, naringenin, other oxidation inhibitors, or any combination thereof.

[0084] In some embodiments, the active ingredient may include one or more fat-soluble compounds and one or more water-soluble compounds, which are coated on amphiphilic nanoparticles. In this embodiment, the pharmaceutical composition can be prepared according to the following steps: step (i') dissolving the fat-soluble compound and the water-soluble compound in an organic solvent to form a solution; step (ii) adding a nonionic surfactant to the solution and stirring the solution to volatilize the organic solvent; and step (iii) after the organic solvent has completely evaporated, adding a pharmaceutically acceptable aqueous solution to obtain the pharmaceutical composition. The organic solvent may include, but is not limited to, a hydrophobic solvent, a hydrophilic solvent, other solvents with a boiling point below 100°C, or any combination thereof. Specifically, the hydrophobic solvent may include, but is not limited to, an ether (e.g., diethyl ether, diethyl ether), or any combination thereof; the hydrophilic solvent may include, but is not limited to, an ester (e.g., ethyl acetate), an alcohol (e.g., methanol, ethanol, isopropyl alcohol, ethylene glycol), dimethylformamide (DMF), a ketone (e.g., acetone), formaldehyde, acetonitrile, dimethyl sulfoxide (DMSO), or any combination thereof.

[0085] The fat-soluble compound may include at least one member selected from the group consisting of curcumin, quercetin, puerarin, oxidized resveratrol, resveratrol, and derivatives, metabolites, or isomers of the foregoing compounds. In one or more embodiments, the fat-soluble compound comprises curcumin and resveratrol in a weight ratio of 4:1. The weight ratio of the fat-soluble compound to the nonionic surfactant ranges from 1:2 to 1:500. In one or more embodiments, the weight ratio of the fat-soluble compound to the nonionic surfactant ranges from 1:20 to 1:150. The concentration of the fat-soluble compound in the pharmaceutical composition ranges from 0.2 mg / g to 500 mg / g. The water-soluble compound may include, but is not limited to, at least one member selected from the group consisting of green tea extract, epigallocatechin gallate, epicatechin, epicatechin gallate, epigallocatechin, epigallocatechin gallate, epigallocatechin, epigallocatechin gallate, catechin gallate, catechin, epigallocatechin gallate (EGCG), caffeine, carnitine, L-carnitine, synephrine, and chlorogenic acid. The weight ratio of the water-soluble compound to the nonionic surfactant is in the range of 1:5 to 1:500, the concentration of the water-soluble compound in the pharmaceutical composition is in the range of 0.1 mg / g to 500 mg / g, and the weight ratio of the fat-soluble compound to the water-soluble compound in the pharmaceutical composition is in the range of 30:1 to 1:10.

[0086] In some embodiments, the pharmaceutical composition may further comprise at least one agent selected from the group consisting of a solvent, a cosolvent, a cosurfactant, a suspending agent, an oil-phase excipient, and an antimicrobial drug. This means that the pharmaceutical composition may further comprise a solvent, a cosolvent, a cosurfactant, a suspending agent, an oil-phase excipient, an antimicrobial drug, or any combination thereof. A solvent can be any substance, typically a liquid, that can dissolve one or more substances to produce a solution and / or form micelles. A cosolvent is used to increase the solubility of the compound encapsulated in the micelles. Cosolvents may include, but are not limited to, polyethylene glycol, propylene glycol, ethanol, other cosolvents that increase the solubility of lipid-soluble or water-soluble compounds, or any combination thereof. Specifically, polyethylene glycol may be PEG 200, PEG 400, PEG 600, or any combination thereof. A cosurfactant is a chemical substance added to a surfactant to improve its performance. This means that a cosurfactant is a secondary surfactant used in combination with the primary surfactant. Co-surfactants may include, but are not limited to, ethanol, propylene glycol, polyethylene glycol (PEG), or any combination thereof. Suspending agents are used to reduce the sedimentation of micelles or the compound encapsulated therein. Suspending agents may include, but are not limited to, sodium alginate, glycerol, sodium carboxymethylcellulose, mannitol, other suspending agents that reduce the sedimentation of micelles or fat-soluble or water-soluble compounds encapsulated therein, or any combination thereof. Oil-phase excipients are used to increase the stability of the pharmaceutical composition and / or increase the solubility of the encapsulated compound. Oil-phase excipients may include, but are not limited to, unsaturated fatty acids, glycerol, triglycerides, other oil-phase excipients that increase the stability of micelles and / or increase the solubility of fat-soluble or water-soluble compounds, or any combination thereof. Specifically, unsaturated fatty acids may include, but are not limited to, oleic acid, castor oil, sesame oil, cottonseed oil, soybean oil, safflower oil, corn oil, or any combination thereof. Triglycerides may include, but are not limited to, medium-chain triglycerides. Antimicrobials can be defined as natural or synthetic substances that kill or inhibit the growth of microorganisms, such as bacteria, fungi, and algae. This means that antimicrobials are therapeutic substances used to prevent or treat microbial infections. Antimicrobials can include, but are not limited to, antibacterials, antibiotics, antivirals, antifungals, and antiparasitics.

[0087] The pharmaceutical composition can be further formulated so that it can be administered to a subject in the form of an injection, cream, lotion, spread, gel, ointment or suspension.

[0088] The subject can be a mammal (e.g., a human). The pharmaceutical composition can be administered to a localized area of ​​the subject (e.g., an area affected by EFP). The margins of the localized area can be determined by the surgeon. The pharmaceutical composition can be administered subcutaneously. In one or more embodiments, the pharmaceutical composition can be administered 1-10 mm below the subcutaneous tissue.

[0089] In some embodiments, the subject is a human subject, and the pharmaceutical composition is administered subcutaneously to the thigh (e.g., the posterior and lateral thigh), buttocks, lower limbs, pelvic region, abdomen, or other areas of the body affected by EFP.

[0090] The pharmaceutical composition can be administered via any conventional non-oral dosage form via a non-digestive administration route, which may include injection, microneedle, implant, topical administration route, transdermal administration route or any non-intestinal administration route.

[0091] In some embodiments, the pharmaceutical composition is formulated as an injectable composition and administered to a subject by injection, for example, by subcutaneous injection of the pharmaceutical composition into the treatment area of ​​a human subject. During each treatment session, the injection volume per unit area of ​​the treatment area is 0.01-50 mg / cm². In one or more embodiments, during each treatment session, the injection volume per unit area of ​​the treatment area is 0.5-2 mg / cm². The distance between each injection site can be at least 0.5 cm. The number of injection sites can vary depending on the body area.

[0092] In some embodiments, the pharmaceutical composition is formulated as a composition for topical administration and is topically administered to a subject, for example, the pharmaceutical composition is topically administered to a treatment area of ​​a human subject, with a dose per unit area of ​​the treatment area being 0.5-20 mg / cm 2 .

[0093] The subject may receive at least one treatment course. To achieve the desired effect, the pharmaceutical composition may be administered once every other day, at least once a week, at least once every two weeks, at least once a month, or at least once per treatment course. In this embodiment, there is no limit to the number of treatment courses, and treatment courses may be continued until a significant improvement in EFP is observed.

[0094] In the present invention, an effective amount may be a dose sufficient to achieve at least one of the following therapeutic indicators: (a) a reduction in the depth of the treated area by at least 10%; (b) a reduction in the width of the treated area by at least 10%; (c) a reduction in the length of the treated area by at least 5%; (d) a reduction in the total volume of the treated area by at least 10%; or (e) a reduction in the surface area of ​​the treated area by at least 10%. In some embodiments, an effective amount may be a dose sufficient to reduce the cellulite severity level of the EFP-affected area of ​​the individual by at least one grade, or to produce a significant change (significant change from baseline) in the total mHCSS score, or to achieve a one-grade improvement (compared to baseline) in the total mHCSS score.

[0095] Example

[0096] Example 1: Component Analysis of Pharmaceutical Compositions

[0097] The pharmaceutical composition was allowed to stand for at least 20 minutes. If no separation occurred, the composition was subjected to particle size analysis.

[0098] A particle size analyzer is used to test whether the pharmaceutical composition contains micelles or amphiphilic nanoparticles. If the particle size measured by the particle size analyzer is less than 50 nm and the polydispersity index (PDI) is less than 0.4, the pharmaceutical composition solution is clear and transparent when observed with the naked eye, and a beam of light is observed when the laser is irradiated on the pharmaceutical composition solution, then the pharmaceutical composition contains micelles or amphiphilic nanoparticles.

[0099] If micelles or amphiphilic nanoparticles are present in a pharmaceutical composition, the pharmaceutical composition is a pharmaceutical composition according to an embodiment of the present invention, which is used for treating and / or preventing EFP.

[0100] In one or more embodiments, if the pharmaceutical composition does not separate and does not settle after standing, the pharmaceutical composition is a preferred pharmaceutical composition of the present invention.

[0101] Example 2: Preparation of curcumin-resveratrol compound pharmaceutical composition

[0102] Preparation of a curcumin-resveratrol compound pharmaceutical composition (e.g., a pharmaceutical composition comprising micelles or amphiphilic nanoparticles encapsulating curcumin and resveratrol):

[0103] Combine 0.2 g of resveratrol, 0.8 g of curcumin, and 150 mL to 200 mL of dichloromethane. Stir at room temperature at 150 to 500 rpm until the resveratrol and curcumin are completely dissolved. Add 40 g of Kolliphor® ELP (hereinafter referred to as ELP) and stir at 100 to 300 rpm until the dichloromethane evaporates. After the dichloromethane has completely evaporated, slowly add normal saline for injection to a total volume of 200 mL and stir evenly to obtain a curcumin-veratrol ELP solution. The curcumin-veratrol ELP solution contains micelles, with a combined concentration of curcumin and veratrol of 5 mg / mL and an ELP concentration of 20%. The weight ratio of curcumin, veratrol, and ELP is 4:1:200.

[0104] Example 3: Effect of the compound pharmaceutical composition on improving EFP in human subjects

[0105] In this example, three subjects of all genders and ages were recruited who suffered from moderate or severe edematous fibrosclerosing panniculopathy (EFP). These subjects had at least one EFP-affected area in at least the thighs, buttocks, lower extremities, pelvic region, and / or abdomen. During the subject screening process, the cellulite severity score was used to determine the local area to be treated with the drug combination and the severity of the EFP.

[0106] EFP severity was analyzed based on the mHCSS, as described by Hexsel, DM et al., “A validated photonumeric cellulite severity scale.” Journal of the European Academy of Dermatology and Venereology: JEADV, 23(5), 523–528.

[0107] The mHCSS is a validated and objective comprehensive EFP assessment scale. As shown in Figure 1, the mHCSS is an alpha-light digital scale that comprehensively considers the scores of three clinically important EFP components: (A) the number of noticeable pits, (B) the depth of pits, and (C) the appearance of the skin surface. Each component is rated from 0 to 3, and their respective ratings are explained below.

[0108] Item (A) Number of visible depressions: Visually inspect the local area to be inspected and assign corresponding scores based on the number of visible depressions. The scores are assigned as follows: 0 points for no depressions; 1 point for a small number (1 to 4 visible depressions); 2 points for a moderate number (5 to 9 visible depressions); and 3 points for a large number (10 or more visible depressions).

[0109] Item (B) Depth of depression: Perform a visual inspection of the local area to be examined. It is recommended to compare it with the image of the severity of cellulite shown in Figure 1. Assess the depth of the depression and assign a corresponding score. The score is assigned as follows: 0 points for no depression; 1 point for superficial depression; 2 points for moderate deep depression; 3 points for severe deep depression.

[0110] Item (C) Skin Surface Appearance: Perform a visual inspection of the local area to be examined. It is recommended that the area be compared with the image of cellulite severity shown in Figure 1. Evaluate the different morphological patterns of skin surface changes and assign corresponding scores. The scores are assigned as follows: 0 points for no raised areas; 1 point for an "orange peel" appearance; 2 points for a "cottage cheese" appearance; and 3 points for a "mattress" appearance.

[0111] The scores for the three aforementioned items are summed to obtain a total score, which is used to categorize the severity of EFP into mild, moderate, or severe. As shown in Table 1 below, a total score of 0 (Grade 0) indicates no EFP, a total score of 1 to 3 (Grade 1) indicates mild EFP, a total score of 4 to 6 (Grade 2) indicates moderate EFP, and a total score of 7 to 9 (Grade 3) indicates severe EFP.

[0112] Table 1: Classification of cellulite severity levels according to mHSCC. grade Total cellulite severity score (mHSCC total score) EFP severity Level 0 0 points none Level 1 1 to 3 points Mild Level 2 4 to 6 points Moderate Level 3 7 to 9 points severe

[0113] Preparation of a curcumin-resveratrol compound pharmaceutical composition: A curcumin-resveratrol compound pharmaceutical composition was prepared as described in Example 2, wherein the total concentration of curcumin and resveratrol was 5 mg / mL, and the weight ratio of curcumin to resveratrol was 4:1.

[0114] According to the following steps, the curcumin-resveratrol compound pharmaceutical composition is administered to a subject in the form of an injection.

[0115] Step (a) determining the severity of EFP on one lateral thigh of a subject and marking one or more treatment areas with a marker; step (b) identifying and marking one or more injection points in the treatment area; step (c) injecting the pharmaceutical composition into the adipose tissue at the injection point, specifically, inserting the injection needle next to the injection point marked in step (b) to prevent ink transfer into the tissue; step (d) pressing the injection point for 10 to 20 seconds to stop bleeding; step (e) after stopping bleeding, injecting the pharmaceutical composition into the next injection point until all marked injection points have been injected; step (f) applying a moisturizer or topical antimicrobial cream and massaging the treatment area with the base of the palm for approximately 60 seconds until the pharmaceutical composition is evenly distributed in the treatment area; and step (g) repeating the aforementioned steps on the other lateral thigh of the subject.

[0116] In this embodiment, each subject was injected with a unit dose of 2 mg / cm2, with a total dose of 80-160 mg of the curcumin-resveratrol compound pharmaceutical composition.

[0117] The severity of EFP in the subjects was assessed before treatment (treatment day 1) and after treatment (treatment day 14).

[0118] Please refer to FIG. 2A to FIG. 2C , which are photographs according to some embodiments, showing the degree of improvement in EFP of human subjects during treatment with the curcumin-resveratrol composite pharmaceutical composition.

[0119] The results in Figures 2A to 2C show that after two weeks of treatment, the subjects' total mHCSS scores on their thighs were significantly reduced. Specifically, the cellulite severity level decreased by at least one level based on the total mHCSS score of the treated area. For example, as shown in Figure 2A , the cellulite severity level on Subject 1's right thigh decreased from Level 3 (total mHCSS score of 9) to Level 2 (total mHCSS score of 4), while the cellulite severity level on their left thigh decreased from Level 3 (total mHCSS score of 7) to Level 1 (total mHCSS score of 3). Similarly, as shown in Figure 2B , the cellulite severity level on Subject 2's right thigh decreased from Level 3 (total mHCSS score of 9) to Level 2 (total mHCSS score of 6), while the cellulite severity level on their left thigh decreased from Level 2 (total mHCSS score of 6) to Level 1 (total mHCSS score of 3). As shown in Figure 2C, the severity level of cellulite on the right thigh of subject 3 decreased from grade 3 (total mHCSS score of 7) to grade 1 (total mHCSS score of 3), while the severity level of cellulite on the left thigh decreased from grade 3 (total mHCSS score of 7) to grade 2 (total mHCSS score of 5).

[0120] In addition, analysis of the treatment area results showed that the curcumin-resveratrol compound pharmaceutical composition can achieve at least one of the following therapeutic indicators: therapeutic indicator (a) the depth of the treated area is reduced by at least 10%; therapeutic indicator (b) the width of the treated area is reduced by at least 10%; therapeutic indicator (c) the length of the treated area is reduced by at least 5%; therapeutic indicator (d) the total volume of the treated area is reduced by at least 10%; and therapeutic indicator (e) the surface area of ​​the treated area is reduced by at least 10%.

[0121] Example 4: Effective Dosage of a Compound Pharmaceutical Composition for Improving EFP in Human Subjects

[0122] In this example, 12 subjects were selected. The screening criteria were: female subjects aged 18 to 64 years, weighing greater than or equal to 50 kg, with a total mHCSS score of greater than or equal to 4 and less than or equal to 8 on the screening day and before treatment (day 1), good skin condition at the treatment site, and a healthy general health (e.g., normal liver, kidney, cardiovascular, coagulation, and immune functions, normal blood sugar levels, and no infectious diseases or cancer). Furthermore, as described in Example 3, the severity of EFP at the local site to be treated with the drug combination was analyzed based on the mHCSS.

[0123] Preparation of a curcumin-resveratrol compound pharmaceutical composition: A curcumin-resveratrol compound pharmaceutical composition was prepared as described in Example 2, wherein the total concentration of curcumin and resveratrol was 5 mg / mL, and the weight ratio of curcumin to resveratrol was 4:1.

[0124] The subjects were randomly divided into three groups, Group 1, Group 2 and Group 3, with 4 subjects in each group. In Group 1, the subject's treatment area was injected with a unit dose of 1 mg / cm2 per unit area, with a total dose of 40 mg of the Curcumin-Resveratrol compound pharmaceutical composition; in Group 2, the subject's treatment area was injected with a unit dose of 1.5 mg / cm2 per unit area, with a total dose of 60 mg of the Curcumin-Resveratrol compound pharmaceutical composition; in Group 3, the subject's treatment area was injected with a unit dose of 2 mg / cm2 per unit area, with a total dose of 80 mg of the Curcumin-Resveratrol compound pharmaceutical composition.

[0125] On the first day of the treatment, the curcumin-resveratrol compound pharmaceutical composition was applied to the outer thighs of both sides of the subjects. On the second and fourth weeks of the treatment, the appearance of the outer thighs of both sides of the subjects was observed and their total mHCSS scores were recorded. The curcumin-resveratrol compound pharmaceutical composition is administered to a subject according to the following steps: step (a) determining the severity of EFP on the outer thigh of one side of the subject and marking one or more treatment areas with a marker; step (b) identifying and marking one or more injection points in the treatment area; step (c) injecting the pharmaceutical composition into the fatty tissue at the injection point, specifically, inserting the injection needle next to the injection point marked in step (b) to prevent ink transfer into the tissue; step (d) pressing the injection point for 10 to 20 seconds to stop bleeding; step (e) after stopping bleeding, injecting the pharmaceutical composition into the next injection point until all marked injection points have been injected; step (f) applying a moisturizer or topical antimicrobial cream and massaging the treatment area with the base of the palm for approximately 60 seconds until the pharmaceutical composition is evenly distributed in the treatment area; and step (g) repeating the aforementioned steps on the outer thigh of the subject's other side.

[0126] In this example, the primary efficacy endpoint was the change in mHCSS total score from baseline at Weeks 2 and 4 of treatment; the secondary efficacy endpoint was the percentage of thighs of subjects who achieved a 1-grade improvement (compared to baseline) based on the mHCSS total score at Weeks 2 and 4 of treatment.

[0127] Please refer to Table 2, Figures 3A, and 3B. Regarding the primary efficacy endpoint, all three groups demonstrated a significant reduction in the mHCSS total score compared to baseline at Week 2, as shown in Table 2 and Figure 3A. Similar results were also observed at Week 4, as shown in Table 2 and Figure 3B. In Table 2, the n value represents the number of treatment areas (e.g., eight treatment areas were located on both lateral thighs for four subjects).

[0128] Table 2: mHCSS total score and its change Group Unit dose (mg / cm2) n mHCSS total score (mean ± SD) Total score change (mean ± SD) Baseline Week 2 Week 4 Week 2 Week 4 1 1.0 8 6.88±1.13 4.63±0.74 4.75±0.71 -2.25±0.89 -2.13±0.84 2 1.5 8 6.13±1.64 4.88±1.81 4.63±1.77 -1.25±1.04 -1.50±0.93 3 2.0 8 7.75±0.71 5.75 ±0.5 5.13±1.13 -2.00±0.93 -2.63±1.51

[0129] Please refer to Table 3 for the secondary efficacy outcome measure, which shows the percentage of thighs achieving a one-grade improvement (from baseline) in the mHCSS total score at Weeks 2 and 4 of treatment. In Groups 1 and 2, three of eight lateral thighs in each group showed significant improvement at Week 2 of treatment; the number of improved thighs increased further at Week 4. In Group 3, seven of eight lateral thighs showed significant improvement at Week 2 of treatment. These results also demonstrate that the curcumin-resveratrol combination can significantly improve EFP severity in a single treatment course (or single injection).

[0130] Table 3: Percentage of Thighs Subjects Achieving at Least 1 Grade Improvement Group n Unit dose (mg / cm2) Week 2 Week 4 1 8 1.0 37.5% (3 / 8) 50.0% (4 / 8) 2 8 1.5 37.5% (3 / 8) 62.5% (5 / 8) 3 8 2.0 87.5% (7 / 8) 87.5% (7 / 8)

[0131] Please refer to Figures 4A and 4B . Figures 4A and 4B are photographs from some embodiments showing changes in EFP severity in two subjects from Group 1 (total dose 40 mg, unit dose 1.0 mg / cm²) after treatment with the curcumin-resveratrol combination pharmaceutical composition. In the upper left photographs of Figures 4A and 4B , the raised area on the lateral thigh is marked with a red line, the depressed area with a green line, and the injection point with a white dot. As shown in Figures 4A and 4B , the mHCSS total score (or EFP severity) in the treated area of ​​the subjects' lateral thighs significantly decreased (or EFP severity significantly improved) at weeks 2 and 4 of treatment.

[0132] Please refer to Figure 5, which is a photograph from some embodiments showing the change in EFP severity in a subject in Group 2 (total dose 60 mg, unit dose 1.5 mg / cm²) after treatment with the curcumin-resveratrol combination pharmaceutical composition. In the upper left photograph of Figure 5, the raised area on the lateral thigh is marked with a red line, the depressed area with a green line, and the injection point with a white dot. As shown in Figure 5, the mHCSS total score in the treated area of ​​the subject's lateral thigh significantly decreased (or EFP severity significantly improved) at weeks 2 and 4 of treatment.

[0133] Please refer to Figure 6, which is a photograph from some embodiments showing the change in EFP severity in a subject in Group 3 (total dose 80 mg, unit dose 2.0 mg / cm²) after treatment with the curcumin-resveratrol combination pharmaceutical composition. In the upper left photograph of Figure 6, the raised area on the lateral thigh is marked with a red line, the depressed area with a green line, and the injection point with a white dot. As shown in Figure 6, the mHCSS total score in the treated area of ​​the subject's lateral thigh significantly decreased (or EFP severity significantly improved) at weeks 2 and 4 of treatment.

[0134] Definition of terms

[0135] In this application, the term "curcumin" refers to curcumin extracted from natural plants or commercially available curcumin. In one or more embodiments, the curcumin has a purity of 90% to 100% (wt%).

[0136] In this application, the term "resveratrol" refers to resveratrol extracted from natural plants or commercially available resveratrol. In one or more embodiments, the resveratrol has a purity of 90% to 100% (wt%).

[0137] In this case, the term "green tea extract" includes a mixture of green tea components extracted by any solvent and any extraction method, a commercially available green tea extract, a mixture containing at least 45% epigallocatechin gallate (EGCG), or commercially available EGCG.

[0138] In this case, the term "nonionic surfactant" refers to a compound having a hydrophilic end and a hydrophobic end (such as a lipophilic end), which includes polysorbate 80 (Tween 80; polyoxyethylene (20)-sorbitan monooleate), polyoxyethylene-15 hydroxystearate (Solutol® HS 15; Kolliphor® HS 15), polyoxyethylene 35 castor oil (PEG-35 castor oil; Kolliphor® ELP; Cremophor® ELP), polyoxyethylene 40 hydrogenated castor oil (Cremophor® RH 40; Kolliphor® RH 40), or other polyoxyethylene castor oil derivatives, or any combination thereof.

[0139] In this application, the term "micelle" refers to a microstructure formed by a surfactant. Each surfactant has a hydrophilic end and a hydrophobic end. The surfactants can be arranged with the hydrophilic end facing outward and the hydrophobic end facing inward, or with the hydrophobic end facing outward and the hydrophilic end facing inward. In one or more embodiments, the microstructure is spherical, spherical-like, or other shaped.

[0140] In this case, the term "amphiphilic nanoparticles" refers to micelles or emulsions formed by non-ionic surfactants and encapsulating one or more active ingredients, polymeric nanospheres or polymeric nanocapsules formed by polymer carriers and encapsulating one or more active ingredients, or liposomes formed by lipid carriers and encapsulating one or more active ingredients.

[0141] In this case, the term "non-settling" means that there is no sediment observable to the naked eye.

[0142] In this case, the term "edematous fibrosclerotic panniculopathy (EFP)" can refer to cellulite, female lipodystrophy, or focal lipodystrophy, all of which are related to changes in the morphology of the skin and subcutaneous fat, and are commonly found on the buttocks, lower limbs, and abdomen.

[0143] In this application, the term "effective amount" refers to a therapeutically and / or prophylactically effective dose. A therapeutically effective dose is a dose sufficient to effectively reduce the depth, width, length, volume, or surface area of ​​the EFP-affected area by a desired ratio, or a dose sufficient to effectively reduce the severity of cellulite in the EFP-affected area by at least one grade, or a dose sufficient to produce a significant change (a significant change from baseline) in the mHCSS total score in the EFP-affected area, or a dose that achieves a one-grade improvement (compared to baseline) in the mHCSS total score. A prognostically effective dose is a dose sufficient to effectively prevent or delay the formation of EFP.

[0144] The term "injection" includes all types of injections, such as subcutaneous (SC), intravenous (IV), intraosseous, epidural, intradermal (ID) or any other form of injection.

[0145] The terms "a" and "an" include one or more than one, and the term "or" refers to a non-exclusive "or" unless otherwise specified. It should be understood that the terms and expressions used herein (unless otherwise defined) are for descriptive purposes only and not for purposes of limitation. Furthermore, all publications, patents, and patent documents cited in this application are incorporated herein by reference in their entirety, meaning that this application incorporates by reference the entire contents of each document. In the event of a discrepancy between the usages of this application and those incorporated by reference, the usage in the incorporated document shall be deemed supplementary to that of this application; in the event of conflicting usages, the usage in this application shall prevail.

[0146] The foregoing description is merely a preferred embodiment of the present invention and should not be used to limit the scope of the present invention. That is, all equivalent variations and modifications made within the scope of the present invention are intended to be covered by the present invention. Furthermore, when interpreting the present invention, all terms should be interpreted in the broadest possible manner consistent with the context. Specifically, the terms "include," "comprising," and "having" should be interpreted as referring to elements, components, or steps in a non-exclusive manner, indicating that the referenced elements, components, or steps may be present or employed, or may be combined with other elements, components, or steps not expressly referenced.

[0147] The terms "one embodiment," "an embodiment," "an example," etc., used herein, indicate that the described embodiment may include specific features, structures, or characteristics, but not every embodiment necessarily includes those specific features, structures, or characteristics. Furthermore, these terms do not necessarily refer to the same embodiment. When a specific feature, structure, or characteristic is described in one embodiment, it is assumed that the specific feature, structure, or characteristic has a related effect in other embodiments, even if not explicitly described.

[0148] In the preparation methods described herein, steps may be performed in any order without departing from the principles of the invention, unless a time or sequence of operations is explicitly stated. In the claims, when a step is described as being performed first and then other steps, it is intended that the first step be performed before any other steps. However, the other steps may be performed in any suitable order unless the order is further stated in the other steps.

[0149] none

Claims

1. Use of a composition for preparing a drug for reducing or improving the severity grade of edematous fibrosclerotic panniculopathy (EFP) in an individual; the composition comprising: a plurality of amphiphilic nanoparticles; wherein, Each of the amphiphilic nanoparticles is coated with one or more lipophilic compounds, the one or more lipophilic compounds comprising at least one selected from the group consisting of curcumin and resveratrol; and each of the amphiphilic nanoparticles is a nanoparticle formed from a pharmaceutically acceptable nonionic surfactant, and the pharmaceutically acceptable nonionic surfactant has a hydrophilic-lipophilic balance (HLB) greater than 9; wherein the drug is an injection, a microneedle or an implant, or is administered via a local route or a transdermal route.

2. The use as described in claim 1, wherein the drug is applied to the individual’s thigh, buttocks, lower limbs, pelvic region or abdomen.

3. The use as described in claim 1, wherein the drug is the injectable drug, and when the drug is applied to a treatment area of ​​the individual, the effective unit dose is 0.01-50 mg per square centimeter (0.01-50 mg / cm2).

4. The use as described in claim 1, wherein the drug is the microneedle or the implant, and when the drug is applied to a treatment area of ​​the individual, the effective unit dose is 0.01-20 mg per square centimeter (0.01-20 mg / cm2).

5. The use as described in claim 1, wherein the drug is applied to a treatment area of ​​the individual via the local route of administration, and the effective amount applied to the treatment area per unit area is 0.5-20 mg / cm2.

6. The use as described in claim 1, wherein the drug is administered to a treatment area of ​​the individual via the transdermal route, and the effective amount per unit area of ​​the treatment area is 0.5-50 mg / cm².

7. The use as described in claim 1, wherein the amphiphilic nanoparticles are a plurality of microcells formed by the nonionic surfactant.

8. The use as claimed in claim 1, wherein the nonionic surfactant comprises at least one, or a combination thereof, selected from the group consisting of polysorbate 80, polyoxyethylene 15-hydroxystearate, polyoxyethylene derivatives, and polyoxyethylene castor oil derivatives.

9. The use as described in claim 1, wherein the weight ratio of the one or more lipophilic compounds to the nonionic surfactant is in the range of 1:2 to 1:

500.

10. The use as claimed in claim 1, wherein the concentration of the one or more fat-soluble compounds in the composition is in the range of 0.2 mg / g to 500 mg / g.

11. The use as claimed in claim 1, wherein the composition further comprises one or more water-soluble compounds comprising at least one selected from the group consisting of green tea extract, epigallocatechin gallate, epicatechin, epicatechingallate, epigallocatechin, gallatechingallate, gallatechin, catechingallate, catechin, epigallocatechin gallate (EGCG), caffeine, carnitine, L-carnitine, synephrine, and chlorogenic acid.

12. The use as described in claim 1, wherein the diameter of each of the amphiphilic nanoparticles is less than 200 nm, or the polydispersity index (PDI) of the amphiphilic nanoparticles is less than 0.

4.

13. The use as claimed in claim 11, wherein the concentration of the one or more fat-soluble compounds in the composition is in the range of 0.2 mg / g to 500 mg / g, or the concentration of the one or more water-soluble compounds in the composition is in the range of 0.1 mg / g to 500 mg / g.

14. The use as described in claim 11, wherein the weight ratio of the one or more fat-soluble compounds to the one or more water-soluble compounds in the composition is in the range of 30:1 to 1:

10.

15. The use as claimed in claim 1, wherein the composition further comprises at least one selected from the group consisting of a solvent, a co-solvent, a co-surfactant, a suspending agent and an oil phase excipient.

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