Composition containing high-molecular polymer drug-loaded particle compound and application

Abstract

The invention provides a high-molecular polymer drug-loaded particle compound and a related method for reducing local fat, reducing body weight, preventing, treating and lightening skin color and melanin precipitation, and alleviating arthritis symptoms. The high-molecular polymer drug-loaded particle compound comprises at least one active ingredient and high-molecular polymer drug-loaded particles, and the high-molecular polymer drug-loaded particles are used as carriers of the active ingredients to coat the active ingredients so as to form the high-molecular polymer drug-loaded particle compound.

Description

TECHNICAL FIELD

[0001] The present application relates to a pharmaceutical composition, in particular, to a pharmaceutical composition for reducing local fat, reducing body weight, preventing or treating skin color lightening and melanin deposition, reducing skin lines or roughness, preventing or treating tumors, preventing or treating fat metabolism related diseases, and alleviating arthritic symptoms, by forming a polymer drug carrier particle complex by coating an active agent with a polymer drug carrier particle. BACKGROUND

[0002] I. Reducing local fat, reducing body weight, and treating obesity

[0003] In recent years, more and more people have raised their standards for self-health and body shape. Instead of simply losing weight, people now pay more attention to reducing local fat or sculpting curves. General weight loss methods, whether through diet or exercise, cannot reduce fat in specific single parts of the body. If you want to reduce fat in specific parts of the body (such as the waist, arms, and face), the current method for reducing local fat is mainly liposuction. However, liposuction can cause serious damage to nerves, blood vessels, and other body tissues, and has the risks of infection, excessive bleeding, prolonged anesthesia, and unpredictable fat embolism and anaphylaxis. In addition, liposuction can also cause serious bruising, swelling, severe pain, long recovery period, and unevenness of the liposuction area. Therefore, many consumers are affected by the side effects of liposuction, postoperative pain, or risks and give up.

[0004] Although some non-surgical local fat reduction pharmaceutical compositions or instruments can reduce some side effects, they mostly have poor efficacy and can cause other side effects, such as necrosis of surrounding normal cells, inflammation of surrounding tissues, and severe pain, and there are certain limitations on the implementation site. Therefore, there is still a great lack of a local fat reduction pharmaceutical composition that can effectively reduce local fat, reduce weight, treat obesity, and has lower side effects, better safety, and shorter recovery period.

[0005] II. Preventing and treating skin color lightening and melanin deposition

[0006] It is known that the color of the skin is mainly determined by the amount of melanin. Normally, melanin in the skin can serve as a natural protective barrier for the human body. The presence of melanin helps humans resist ultraviolet radiation and avoid the risk of photocarcinogenesis. On the contrary, excessive melanin pigmentation can cause many problems, such as age spots, freckles, dark spots, liver spots, and other unwanted pigment deposition on the skin, or pigment deposition during the wound healing process. Melanin is produced by melanocytes present in the epidermis, and the melanosome formed by the melanocytes is transferred to keratinocytes through the dendritic structure of the melanocytes.

[0007] Factors that stimulate melanin production include direct exposure to UV radiation or the action of melanocyte-stimulating hormones (a-MSH) secreted by keratinocytes, which in turn promote the enzymatic reaction of tyrosinase to produce melanin. The currently known mechanism of melanin production is through the action of tyrosinase enzyme to convert tyrosine through a multi-step reaction. Each step in the process involves the participation of tyrosinase. First, tyrosinase converts the tyrosine in the cell into L-DOPA, and then converts L-DOPA into L-dopaquinone, and continues to form intermediate products at each stage, including dopachrome, 5,6-dihydroxyindole and indole-5,6-quinone, through a series of reaction processes to ultimately produce melanin. Therefore, tyrosinase can be considered as the key enzyme responsible for regulating human melanization and melanin production, so regulating the activity of tyrosinase is currently the main research and development direction for reducing dark spots and promoting skin whitening. In addition, post-inflammatory hyperpigmentation (PIH) caused by skin inflammation due to injury is another reason for melanin production and transfer to keratinocytes. Generally, PIH can be divided into epidermal PIH and dermal PIH. When an inflammatory response occurs in the epidermis, melanocytes are stimulated by inflammatory factors, which promote the production of a large amount of melanin and transfer it to the surrounding keratinocytes. On the other hand, when the basal cell layer at the junction of the epidermis and the dermis is damaged by an inflammatory response, a large amount of melanin is ingested by melanophages in the dermis, resulting in a deeper dark brown or blue-gray deposit.

[0008] The whitening ingredients currently used to inhibit melanin production or lighten melanin include vitamin C derivatives and their salts, kojic acid, arbutin, ellagic acid, and hydroquinone, among many other ingredients proposed to inhibit melanin formation or reduce skin melanin deposition or lighten skin color.

[0009] The metal salts of vitamin C and the glycosylated derivatives are all by way of antioxidant, in the reaction process of tyrosinase, the intermediate product of melanin L-dopaquinone is reduced, to achieve the effect of inhibiting melanin production, vitamin C itself is safe and can prevent the formation of free radicals, but the stability is poor and easy to be oxidized, so the stability can be increased by combining with metal or glycosylation. Because tyrosinase is an oxidative enzyme with divalent copper ion as the active center, therefore the structure combined with copper ion or competing with tyrosinase is also developed to inhibit tyrosinase and block melanin production, and the representative substance of this kind is kojic acid. Another kind is to compete with the substrate of tyrosinase, such as arbutin, which can compete with tyrosine, so that the effect of tyrosinase is substantially reduced. Or use the free radicals generated by hydroquinone to directly produce cytotoxicity to melanocytes, but improper use may cause skin irritation, dermatitis, abnormal pigment deposition and skin hyperpigmentation.

[0010] Each component achieves the effect of whitening through different mechanisms, and also achieves the purpose of lightening skin color through different mechanisms, but the mechanisms of whitening include only blocking tyrosinase to reduce the production of melanin, blocking the transfer of melanin bodies from melanocytes to keratinocytes, inhibiting the activity of tyrosinase, promoting the metabolism of melanin in keratinocytes, or using preventive methods to isolate ultraviolet rays. In the past, various ingredients such as vitamin C, kojic acid, vitamin B group, etc. have been used to attempt to achieve the effect of depigmentation or whitening by intravenous injection, but such administration and whitening use have not obvious whitening effect and may also bring the risk of allergy. In addition, if the product is not completely sterilized or not completely disinfected during injection, there is a high risk of more serious side effects such as phlebitis, cellulitis, sepsis, etc.

[0011] III. Part about alleviating the symptoms of arthritis:

[0012] Degenerative arthritis most commonly occurs in the elderly, athletes who have long-term excessive weight bearing, or obese people. The disease can occur in any joint of the body, among which the knee joint and hip joint are the most common. Age and obesity are the most important risk factors for the disease, and modern people live longer, so almost everyone will be affected by some degree of degenerative arthritis as they age. Patients threatened by this disease will suffer from long-term swelling and pain and even loss of labor function.

[0013] Degenerative arthritis is a common joint disease, which is affected by multiple factors to synovial joints and extracellular matrix (ECM), resulting in fibrosis and loss of elasticity of cartilage, thinning and then fragmentation of the cartilage covering the outermost layer of bone, and even complete disappearance of the joint space, resulting in increased stress on the bone under the cartilage, and then causing bone sclerosis, necrosis, and cystic cavities, and finally causing pain and severe impact on mobility. Degenerative arthritis can be divided into primary arthritis and secondary arthritis. Primary arthritis is mainly related to aging, and secondary arthritis is related to mechanical compression (obesity), injury, metabolic disease or congenital anomaly. The main symptoms of degenerative arthritis include pain, stiffness, swelling and deformation. When the joint is active, an abnormal rubbing sound can often be heard.

[0014] See Figure 1 , Figure 1 is the classification of joint degeneration. Degenerative arthritis can be classified according to the degree of joint degeneration shown by the patient's X-ray film, which can be divided into 0-4 levels (Kellgren-Lawrence Grading Scale). The primary goal of current treatment of degenerative arthritis is to reduce joint pain and stiffness, and then to slow down the speed of disease progression. Mild patients can only improve by changing their lifestyle and physical therapy. Moderate patients need to be treated with drugs or hyaluronic acid injections. Severe patients need surgery. Therefore, how to effectively improve the incidence of degenerative arthritis and provide effective treatment methods is an important issue.

[0015] The painkillers commonly used to improve arthritis at this stage include three categories: acetaminophen, nonsteroidal anti-inflammatory drugs (NSAIDs), and COX-2 inhibitors. Acetaminophen is the first-line drug for pain relief, which can inhibit the secretion of prostaglandins. However, prostaglandins are also related to blood pressure regulation, blood clotting, gastric acid secretion and kidney function regulation, so interfering with prostaglandins will also affect the normal operation of the body's functions. On the other hand, when the dose of acetaminophen is too large, it will increase the risk of gastrointestinal bleeding and easily produce liver toxicity. Nonsteroidal anti-inflammatory drugs are used to inhibit cyclooxygenase COX-1 and COX-2, which have anti-inflammatory and analgesic effects. When COX-2 is inhibited, it will cause a decrease in prostaglandin I2 (Prostacyclin I2, PGI2) and produce anti-inflammatory and analgesic effects, but will promote platelet aggregation. Inhibition of COX-1 will damage the integrity of the gastrointestinal mucosa and affect renal blood flow, thereby producing side effects such as gastric ulcers or kidney failure.

[0016] Therefore, currently used drugs for osteoarthritis only suppress pain and cannot address the underlying causes or sources of pain in the joints. They also cause side effects such as liver toxicity, gastrointestinal bleeding, ulcers, and kidney failure, placing a significant burden on the elderly, the primary group affected by osteoarthritis. While specific COX-2 inhibitors can reduce COX-2 and achieve better pain relief, they increase the risk of cardiovascular toxicity and offer little symptom improvement in patients with severe joint wear or aging. Glucosamine's analgesic and anti-inflammatory effects are poor, especially in elderly patients. Hyaluronic acid joint injections require an average of once a week; if injected continuously for more than five weeks, the risk of discomfort and infection increases significantly. Hyaluronic acid joint injections primarily increase joint lubrication to relieve pain but cannot directly reduce inflammatory factors in the joints. Current osteoarthritis drugs and treatments only address the symptoms, not the root cause. Therefore, the market still lacks a safer treatment or medication that can simultaneously reduce inflammation and pain with fewer side effects.

[0017] IV. Regarding reducing skin texture or skin roughness:

[0018] Skin ages gradually with age, and exposure to ultraviolet (UV) radiation accelerates this aging process. Recent studies have shown that age-related skin aging and UV-induced skin aging share some important commonalities at the molecular and biological level.

[0019] The skin, from the outside in, consists of the stratum corneum, epidermis, dermis, and subcutaneous tissue in that order. The epidermis is composed of epidermal cells that originate in the basal layer, the deepest part of the epidermis. After their formation, these cells gradually migrate outwards, constantly being replaced by new cells (a process known as epidermal cell turnover). The main causes of skin aging are known to be the reduced turnover of epidermal cells and the decrease in collagen present between fibroblasts in the dermis (ArchDermato 1. 2002; 138:1462-1470). Collagen is known to be the main component of the dermis. The maintenance of skin elasticity is affected by aging or damage from ultraviolet radiation, which reduces the amount of collagen in the skin, leading to a loss of elasticity and promoting wrinkle formation and skin aging. Furthermore, it is known that dryness causes thickening of the stratum corneum and epidermis, and slows down the shedding of the stratum corneum, contributing to the formation of shallow wrinkles (J. Dermatol. Sci. 2001; 27 Suppl 1: S19-25). While age spots and sagging skin are major symptoms of skin aging, wrinkle formation is the most significant factor. Therefore, various methods have been employed for wrinkle prevention. For example, methods that promote the synthesis of collagen fibers that support skin structure and prevent collagen loss. Furthermore, promoting skin hydration and maintenance, or the regeneration of stratum corneum and epidermal cells related to impaired function—that is, promoting the regeneration of the epidermis and stratum corneum (epidermal renewal)—is also an effective method for wrinkle prevention.

[0020] Currently, common wrinkle prevention methods on the market include topical cosmetics formulated with ingredients that moisturize the skin or maintain its elasticity. These cosmetics may contain, for example, mucopolysaccharides such as hyaluronic acid and chondroitin sulfate, or collagen, vitamins, amino acids, and ceramides.

[0021] Since it is particularly effective for preventing and improving skin aging with wrinkles as the main symptom, by increasing the amount of collagen in the dermis or promoting the renewal of the epidermis, there is a lack on the market of treatments or drugs that can simultaneously promote epidermal renewal, skin cell proliferation and inhibit skin aging, with low side effects and greater safety.

[0022] V. Section on the prevention and treatment of tumors:

[0023] Tumors are classified as benign or malignant. Benign tumors typically grow slowly, exhibiting an expansive growth pattern with a smooth surface. Although they may increase in size locally, compressing surrounding normal tissue, they do not invade adjacent normal tissue and are generally not fatal. Examples include uterine fibroids and subcutaneous tumors. Globally, malignant tumors (cancer) are the second leading cause of death after heart disease. Cancer is characterized by an increase in the number of abnormal or neoplastic cells originating from normal tissue. These cells proliferate to form a tumor mass; these neoplastic tumor cells invade adjacent tissues; and malignant cells are produced. These malignant cells eventually spread to local lymph nodes via the bloodstream or lymphatic system and then to distant sites through a process called metastasis. In cancerous conditions, cells proliferate under conditions where normal cells would not grow. Cancer itself manifests in various forms characterized by varying degrees of invasiveness and aggression, such as malignant lipomas.

[0024] VI. Section on the prevention and treatment of lipid metabolism-related diseases:

[0025] Obesity is not just a cosmetic issue; it is also a significant risk factor for diseases such as diabetes, fatty liver, high cholesterol, and high blood pressure. Dietary therapy, exercise therapy, and drug therapy have been proposed or implemented as methods for treating and preventing obesity. However, all these treatments can cause side effects such as malnutrition and motor dysfunction, as well as physical and mental suffering such as hunger and stress, making it difficult to maintain their effectiveness and even damaging to health.

[0026] In summary, the market still lacks a pharmaceutical composition that can effectively reduce local fat, reduce weight, treat obesity, prevent or treat skin discoloration and reduce melanin deposition, reduce skin texture or skin roughness, prevent or treat tumors, prevent or treat fat metabolism-related diseases, alleviate arthritis symptoms, and has low side effects and good safety. [Summary of the Invention]

[0027] This invention provides a composition and its preparation method for reducing localized fat, reducing weight, treating obesity, preventing or treating skin discoloration and reducing melanin deposition, reducing skin texture or roughness, preventing or treating tumors, preventing or treating lipid metabolism-related diseases, and alleviating arthritis symptoms. The composition comprises at least one active agent and polymeric drug-loaded particles, wherein the polymeric drug-loaded particles serve as a carrier for the active agent, encapsulating the active agent to form a polymeric drug-loaded particle complex.

[0028] Among them, polymer-loaded drug particles refer to a microstructure formed by a polymer, which is used as a carrier to encapsulate the active ingredient.

[0029] In some embodiments, the polymer refers to, for example, lactide-co-glycolide copolymer (PLGA), poly(L-lactide) (PLLA), poly-ε-caprolactone (PCL), polyglycolide (PGA), and polylactide (PLA).

[0030] In some embodiments, the polymer refers to a PEGylated component. This PEGylated component refers to a copolymer (PLA-PEG, PLGA-PEG, PLGA-PEG-PLGA, PLA-PEG-PLA, PEG-PCL, PCL-PEG-PCL, PEG-PLA-PEG, PEG-PLGA-PEG-PEG) formed by polyethylene glycol and, for example, poly(DL-lactide-co-glycolide) (PLGA), poly(L-lactide) (PLLA), poly-ε-caprolactone (PCL), polyglycolide (PGA), or polylactide (PLA).

[0031] In some embodiments, the composition further comprises a pharmaceutically acceptable aqueous solution.

[0032] In some embodiments, the composition further comprises a surfactant dissolved in a pharmaceutically acceptable aqueous solution.

[0033] In some embodiments, the composition further comprises hyaluronic acid dissolved in a pharmaceutically acceptable aqueous solution.

[0034] In some embodiments, the weight-average molecular weight of the polymer or the PEGylated component is 5,000 to 100,000 Da.

[0035] In some embodiments, the viscosity of the polymer or the PEGylated component is 0.25 to 0.80 dL / g (test conditions, for example, 0.5% (w / v), CHCl3, 25°C).

[0036] In some embodiments, the polymer is a poly(DL-lactide-co-glycolide) (PLGA), wherein the molar ratio of lactide to glycolide is 25:75 to 75:25.

[0037] In some embodiments, the pharmaceutically acceptable aqueous solution is water for injection, aqueous solution for injection, or physiological saline for injection.

[0038] In some embodiments, the surfactant is a nonionic surfactant.

[0039] In some embodiments, the nonionic surfactant is at least one or a combination of polysorbate 80 (Tween 80), propylene glycol, polyethylene glycol 600, polyoxyl 15-hydroxystearate (solutol HS 15), polyoxyethylene castor oil derivatives, polyoxyethylene derivatives, and other nonionic surfactants.

[0040] In some embodiments, the polyoxyethylene castor oil derivative is at least one of polyoxyethylene 35 castor oil (Cremophor ELP), polyoxyethylene 40 hydrogenated castor oil (Cremophor RH 40), and other polyoxyethylene castor oil derivatives, or a combination thereof.

[0041] In some embodiments, the composition contains 25-70% of an active agent and 30-75% of a polymer.

[0042] In some embodiments, the weight ratio of the active ingredient to the polymer is 1:1 to 1:30.

[0043] In some embodiments, the active ingredient is 5 to 30 percent by weight, based on 100 percent by weight of the total weight of the polymer-loaded drug particles; or, the drug loading rate of the polymer-loaded drug particles is 5 to 30 percent.

[0044] In some embodiments, the weight ratio of the polymer drug-loaded particles to the hyaluronic acid is 3:5 to 50:1; or, based on the weight of hyaluronic acid as 1 unit of weight, the total weight of the polymer and the active ingredient is 0.6 to 50 units of weight; or, based on the weight of hyaluronic acid as 1 unit of weight, the total weight of the polymer and the active ingredient is 0.6 to 50 units of weight.

[0045] In some embodiments, the composition further comprises an oil phase excipient, which is uniformly distributed in a pharmaceutically acceptable aqueous solution; wherein the oil phase excipient is at least one of unsaturated fatty acids, polyethylene glycol, glycerin, triglycerides, and other oil phase excipients, or a combination thereof.

[0046] In some embodiments, the unsaturated fatty acid is at least one or a combination of oleic acid, castor oil, sesame oil, cottonseed oil, soybean oil, safflower oil, and other unsaturated fatty acids; and the polyethylene glycol is at least one or a combination of polyethylene glycol 200 (PEG 200), polyethylene glycol 400 (PEG 400), polyethylene glycol 600 (PEG 600), and other polyethylene glycols.

[0047] In some embodiments, the composition is used to prepare joint injections, subcutaneous injections, subcutaneous implants, subcutaneous implants, implantable infusions, or transdermal dosage forms, including but not limited to topical liquids, ointments, gels, gels, or patches.

[0048] In some embodiments, the active ingredient comprises at least one of curcumin, curcumin derivatives, curcumin metabolites, resveratrol, oxidized resveratrol, resveratrol derivatives, and resveratrol metabolites.

[0049] Pharmaceutically acceptable carriers can be pharmaceutically acceptable and PEGylated or unPEGylated polymers (e.g., poly(DL-lactide-co-glycolide) (PLGA), poly(L-lactide) (PLLA), poly-ε-caprolactone (PCL), polyglycolide (PGA), and polylactide (PLA).

[0050] In other embodiments, the composition may further comprise a polyethylene glycol-modified or unpolyglycolic nonionic surfactant (e.g., as described above) and one or more hydrophilic therapeutic agents.

[0051] Any polymeric drug-loaded particles included in the compositions disclosed herein (e.g., those comprising active agents as disclosed herein) may have a diameter of less than 35 μm, 500 nm, or 50 nm (e.g., about 1 to about 50 nm, or about 10 to 25 nm), and / or a polydispersity index (PDI) value of less than 0.4. In some embodiments, the particle size of such polymeric drug-loaded particles is 3 to 500 nm. In some embodiments, the particle size of the polymeric drug-loaded particle complex is 1 to 35 μm.

[0052] In some embodiments, any of the methods disclosed herein may be implemented by administering any of the compositions disclosed herein via a parenteral route (e.g., topical application or local injection). In some embodiments, the composition may be applied to a local site. In some embodiments, the local site may be in areas such as the thigh, buttocks, or lower extremities; in some embodiments, the local site may be in areas where fat, lipomas, or liposarcomas frequently occur (e.g., the thigh, buttocks, lower extremities, pelvic region, or abdomen); the composition may be applied to an individual once or multiple times.

[0053] In one embodiment, the polymer chain carries cationic or anionic groups, or does not carry cationic or anionic groups.

[0054] The present invention also provides the use of a composition for preparing a drug for application to a local subcutaneous site of an individual to reduce the amount of fat in that local subcutaneous site.

[0055] The present invention further provides the use of a composition for preparing a medicament for application to a local subcutaneous site of an individual to reduce the individual's weight.

[0056] The present invention further provides a use of the composition for preparing a medicament for application to a local subcutaneous site on an individual to treat obesity.

[0057] The present invention further provides a use of the composition for preparing a drug that inhibits melanin production or deposition.

[0058] The present invention further provides a use of the composition for preparing a medicament that reduces skin texture or skin roughness.

[0059] The present invention further provides the use of the composition for preparing a medicament to relieve the degree of joint inflammation. In one embodiment, the joint inflammation is arthritis. In another embodiment, the joint inflammation is osteoarthritis.

[0060] The present invention further provides a method for preparing a composition, comprising: The active ingredient and the polymer are mixed and filtered through a filter membrane. The particles remaining on the filter membrane are the polymer-loaded drug particle complex described herein.

[0061] Details of one or more embodiments of the present invention are set forth in the description below. Other features or advantages of the invention will become apparent from the following figures and detailed descriptions of several embodiments, as well as from the appended claims. [Attached Image Description]

[0062] Figure 1 Grading of joint degeneration.

[0063] Figure 2 Appearance of curcumin lactide-glycol copolymer (PLGA) particles with an average particle size of 5 μm under an optical microscope.

[0064] Figure 3 Appearance of curcumin lactide-glycol copolymer (PLGA) particles with an average particle size of 12 μm under an optical microscope.

[0065] Figure 4 Appearance of curcumin lactide-glycol copolymer (PLGA) particles with an average particle size of 20 μm under an optical microscope.

[0066] Figure 5 Image of resveratrol lactide-glycol copolymer (PLGA) particles under an optical microscope.

[0067] Figure 6 Graph showing in vitro drug release rate data of curcumin lactide-glycolide copolymer (PLGA) particles.

[0068] Figure 7 Tissue section results of the normal control group.

[0069] Figure 8 Tissue section results of the negative control group.

[0070] Figure 9 Tissue section results of the ARTZDispo injection group.

[0071] Figure 10 Tissue section results of the injection group containing curcumin microcells and hyaluronic acid (OT-00CH injection group).

[0072] Figure 11 Tissue section results of the injection group (OT-00PCH injection group) containing curcumin lactide-glycol copolymer (PLGA) particles and hyaluronic acid.

Detailed Implementation Methods

[0073] This article discloses pharmaceutical compositions and their therapeutic uses for reducing local fat, reducing weight, preventing or treating skin discoloration and reducing melanin deposition, reducing skin texture or skin roughness, preventing or treating tumors, preventing or treating lipid metabolism-related diseases, and alleviating arthritis symptoms.

[0074] Pharmaceutical Composition

[0075] The pharmaceutical compositions disclosed herein may comprise one or more active agents, which may be curcumin, a curcumin derivative, a curcumin metabolite, resveratrol, resveratrol oxidase, a resveratrol derivative, or a resveratrol metabolite, or a combination thereof. The one or more active agents may form a first plurality of polymer-loaded drug-eluting particle complexes with at least one suitable pharmaceutically acceptable polymer, such as those disclosed herein. In some embodiments, the pharmaceutical composition may further comprise a second plurality of polymer-loaded drug-eluting particle complexes. In some embodiments, the pharmaceutical composition may further comprise a third plurality of polymer-loaded drug-eluting particle complexes. The first polymer-loaded drug-eluting particle complexes contain at least one or a combination of curcumin, curcumin derivatives, and curcumin metabolites; the second polymer-loaded drug-eluting particle complexes contain at least one or a combination of resveratrol, oxidized resveratrol, resveratrol derivatives, and resveratrol metabolites; and the third polymer-loaded drug-eluting particle complexes contain (1) at least one or a combination of curcumin, curcumin derivatives, and curcumin metabolites, and (2) at least one or a combination of resveratrol, oxidized resveratrol, resveratrol derivatives, and resveratrol metabolites.

[0076] In some embodiments, the pharmaceutical composition may be formed from a suitable pharmaceutically acceptable polymer, an active agent, and a pharmaceutically acceptable aqueous solution as disclosed herein.

[0077] Pharmaceutical Composition

[0078] The pharmaceutical compositions disclosed herein comprise one or more curcumin, curcumin derivatives, curcumin metabolites, resveratrol, resveratrol monoxide, resveratrol derivatives, or resveratrol metabolites as active agents, for the purpose of reducing localized fat, reducing weight, preventing or treating skin discoloration and reducing melanin deposition, reducing skin texture or skin roughness, preventing or treating tumors, preventing or treating lipid metabolism-related diseases, and alleviating arthritis symptoms. The active agents disclosed herein may form first polymer-loaded drug-eluting particle complexes, second polymer-loaded drug-eluting particle complexes, and / or third polymer-loaded drug-eluting particle complexes with suitable polymers such as those disclosed herein.

[0079] (A)Active ingredients

[0080] Exemplary active ingredients provided herein include resveratrol compounds and curcumin compounds. Resveratrol compounds may have the structure of chemical formula (I) or salts thereof:

[0081] Where R 1 R 2 R 3 and R 4 Each is independently H, a halogen (e.g., F, Cl, or Br), a hydroxyl group, an alkyl group, an alkenyl group, an alkoxy group, a thiol group, or an amine group. In some embodiments, the resveratrol compound may have the structure of chemical formula (Ia) or a salt thereof:

[0082] Where R 1 R 2 and R 3 Each is as defined above. In one embodiment, the resveratrol compound is resveratrol (having R... 1 –R 3 All are hydroxyl groups, R 4 (e.g., -H). Alternatively, as is well known to those skilled in the art, resveratrol compounds may have suitable substitutions at one or more suitable positions of resveratrol.

[0083] The curcumin compounds disclosed herein can have the structure of chemical formula (II) or its salts:

[0084] Where R 1 R 2 R 3 and R 4Each is independently H, a halogen (e.g., F, Cl, or Br), a hydroxyl group, an alkyl group, an alkenyl group, an alkoxy group, a thiol group, or an amine group; Z is CH2, NH, O, or S; and Z' is CH2, NH, O, or S. In some embodiments, the curcumin compound is a curcuminoid, such as curcumin, demethoxycurcumin, or bisdemethoxycurcumin. In specific embodiments, the curcumin compound is curcumin. Alternatively, as is well known to those skilled in the art, the curcumin compound may have suitable substitutions at one or more suitable positions of curcumin.

[0085] In some embodiments, the curcumin compound may have the structure of chemical formula (IIa) or a salt thereof:

[0086] Where R 1 R 2 R 3 and R 4 Each is independently H, a halogen (e.g., F, Cl, or Br), a hydroxyl, an alkyl, an alkenyl, an alkoxy, a thiol, or an amine; X is CH2, NH, O, or S; and Y is methyl (CH3), amino (NH2), hydroxyl (OH), or thiol (SH). In some embodiments, the curcumin compound is a curcuminoid, such as curcumin, demethoxycurcumin, or dedimethoxycurcumin. In specific embodiments, the curcumin compound is curcumin. Alternatively, as is well known to those skilled in the art, the curcumin compound may have suitable substitutions at one or more suitable positions of curcumin.

[0087] (B) Polymers

[0088] The pharmaceutical compositions disclosed herein may comprise one or more polymers that can form polymeric drug-loaded particle complexes with active agents and / or hydrophilic therapeutic agents as disclosed herein. For example, the polymer may be poly(DL-lactide-co-glycolide) (PLGA), poly(L-lactide) (PLLA), poly-ε-caprolactone (PCL), polyglycolic acid (PGA), or polylactide (PLA), and the polymer may form polymeric drug-loaded particle complexes with active agents and / or hydrophilic therapeutic agents as disclosed herein.

[0089] Alternatively, the pharmaceutical compositions disclosed herein may comprise one or more PEGylated ingredients, such as PLA-PEG, PLGA-PEG, PLGA-PEG-PLGA, PLA-PEG-PLA, PEG-PCL, PCL-PEG-PCL, PEG-PLA-PEG, PEG-PLGA-PEG, and the PEGylated ingredient may form a liposome complex with an active agent and / or a hydrophilic therapeutic agent as disclosed herein.

[0090] The polymers used in this technology are at least conducive to the formation of polymer-loaded drug particles in the composition. In some embodiments, the polymer-loaded drug particles have the function of encapsulating active ingredients and / or hydrophilic therapeutic agents.

[0091] Hydrophilic therapeutic agents (such as green tea extract, epicatechin, epicatechingallate, epigallocatechin, catechin, caffeine, carnitine, L-carnitine, synephrine, chlorogenic acid) and other hydrophilic drugs, or combinations thereof. The weight ratio of the active ingredient to the hydrophilic therapeutic agent is between 30:1 and 1:10.

[0092] Any pharmaceutical composition disclosed herein may further comprise a nonionic surfactant. In some embodiments, the nonionic surfactant used has a hydrophilic-lipophilic balance (HLB) value greater than 10. The nonionic surfactant is used in this technology in the proportions described above. The nonionic surfactant may be a castor oil derivative or a polyoxyethylene derivative, the latter also known as a pegylated excipient. In some embodiments, the polyoxyethylene derivative is a polyethylene glycol castor oil derivative; exemplary nonionic surfactants include, but are not limited to, polysorbate 80, polyoxyethylene 15-hydroxystearate, polyoxyethylene castor oil derivatives (e.g., polyoxyethylene 35-castor oil, polyoxyethylene 40-hydrogenated castor oil, and polyoxyethylene 60-hydrogenated castor oil), polyoxyethylene (12) glyceryl laurate (also known as polyethylene glycol (12) glyceryl laurate) (UNIGLY ML-212), and polyoxyethylene 20-stearate (also known as polyethylene glycol 20-stearate). TM S20), Polyoxyethylene 40 Stearate (also known as Polyethylene Glycol 40 Stearate (Myrj) TM S40), Polyoxyethylene 12 Cetearyl Ether (also known as polyethylene glycol 12 cetearyl ether) CS 12), and polyoxyethylene 20 cetearyl ether (also known as polyethylene glycol 20 cetearyl ether). CS 20).

[0093] (C) Polymer drug-loaded particles and their preparation

[0094] (D-1) Preparation of polymer-loaded drug-particle complexes

[0095] The steps for preparing a drug-loaded polymer complex include at least the following: (S110) The active ingredient, the polymer, and the solvent for the first emulsification are mixed and stirred uniformly to obtain an oil-phase solution; and (S120) At a speed of 1000 to 3000 rpm, the oil phase solution and an aqueous phase solution are uniformly mixed and emulsified for 2 to 4 hours to obtain a polymer-loaded drug particle complex, wherein the aqueous phase solution includes an emulsion stabilizer.

[0096] In some embodiments, step (S110) further includes a second emulsifying solvent, and step (S110) involves mixing the active ingredient, the polymer, the first emulsifying solvent, and the second emulsifying solvent, and stirring them uniformly to obtain the oil phase solution.

[0097] In some embodiments, step (S120) includes at least the following steps: (S121) Under a rotational speed of 1000–3000 rpm, the oil phase solution and an aqueous phase solution are uniformly mixed and emulsified for 2–4 hours, wherein the aqueous phase solution includes an emulsification stabilizer; and (S122) Filter with a 2-5 μm filter membrane. The particles remaining on the filter membrane are the polymer drug-loaded particle complex described in (S120).

[0098] In some embodiments, in step (S110), the solvent for the first emulsification is at least one or a combination of diethyl ether, benzene, chloroform, methyl acetate, ethyl acetate, dichloromethane, hexane, methanol, ethanol, acetone, and other organic solvents.

[0099] In some embodiments, in step (S120), the emulsifying stabilizer is at least one or a combination of polyvinyl alcohol (PVA), Polysorbate 20 (Tween 20), Polysorbate 80 (Tween 80), Poloxamer 188, and other emulsifying stabilizers.

[0100] In some embodiments, in step (S110), the solvent for the second emulsification is at least one or a combination of diethyl ether, benzene, chloroform, methyl acetate, ethyl acetate, dichloromethane, hexane, methanol, ethanol, acetone, and other organic solvents.

[0101] In some embodiments, the polymer is a poly(DL-lactide-co-glycolide); PLGA, and the specifications of the PLGA are, for example, as shown below: L / G ratio end group I.V range Molecular weight range (kDa) 50 / 50 ESTER 0.15-0.25 15-30 50 / 50 COOH 0.40-0.55 40-67 75 / 25 COOH 0.08-0.2 5-10 50 / 50 COOH 0.25-0.40 15-30 50 / 50 COOH 0.15-0.25 5-20

[0102] Wherein, IV range represents the intrinsic viscosity, expressed in dL / g. The intrinsic viscosity range of this lactide-glycolic acid copolymer (PLGA) is 0.08–0.80 dL / g.

[0103] (D-2) Determination of the mass of polymer particle complex

[0104] Particle size measurement: The particle size of the polymer drug-loaded particle complex was measured using an optical microscope, its associated charge-coupled device (CCD), and imaging software. Twenty-five particles were randomly sampled from each field of view, for a total of 75 particles from three fields of view. The average particle size and standard deviation were calculated.

[0105] Drug loading rate test: The polymer-loaded drug-particle complex was lyophilized. 1 mg of the lyophilized sample was dissolved in 1 mL of DMSO solvent, and the drug loading rate was quantitatively analyzed using high-performance liquid chromatography (HPLC; e.g., HPLC-UV).

[0106] (D-3) Preparation of a pharmaceutical composition comprising a polymer-loaded drug-eluting particle complex.

[0107] This experiment utilizes a polymer-loaded drug-particle complex to prepare a first pharmaceutical composition, and utilizes the polymer-loaded drug-particle complex and hyaluronic acid to prepare a second pharmaceutical composition.

[0108] (D-3-1) The steps for preparing the first pharmaceutical composition are as follows: (S100) Obtain a polymer drug-loaded particle complex, the polymer drug-loaded particle complex comprising a polymer drug-loaded particle formed of a polymer and an active ingredient encapsulated in the polymer drug-loaded particle. (S200) The polymer-loaded drug-particle complex, a surfactant, and a first pharmaceutically acceptable aqueous solution are mixed, wherein the hydrophilic-lipophilic balance value (HLB value) of the surfactant is greater than 10. In some embodiments, after step (S200), the following step is further included:

[0109] (S300) Add to a second pharmaceutically acceptable aqueous solution.

[0110] In some embodiments, after step (S200), the following step is further included:

[0111] (S300) Add a suspending agent.

[0112] In some embodiments, the suspending agent is used to increase the viscosity and stability of the dosage form, or to replace other functions of hyaluronic acid.

[0113] In some embodiments, the first or second pharmaceutically acceptable aqueous solution comprises at least one or a combination of water for injection, aqueous solution for injection, physiological saline for injection, and other pharmaceutically acceptable aqueous solutions.

[0114] The first or second pharmaceutically acceptable aqueous solution contains a water-soluble drug.

[0115] In some embodiments, the first or second pharmaceutically acceptable aqueous solution contains a local anesthetic.

[0116] In some embodiments, the local anesthetic is at least one of amides, para-aminobenzoic acid esters, and amino ethers, or a combination thereof.

[0117] In some embodiments, the first or second pharmaceutically acceptable aqueous solution contains an antioxidant.

[0118] In some embodiments, the first or second pharmaceutically acceptable aqueous solution contains an antibacterial agent.

[0119] In some embodiments, the antibacterial agent is at least one of phenolic antibacterial agents, alcoholic antibacterial agents, hydroxyphenyl ester antibacterial agents, and thimerosal, or a combination thereof.

[0120] (D-3-2) The steps for preparing the second pharmaceutical composition are as follows: (S1000) Obtain a polymer drug-loaded particle complex, the polymer drug-loaded particle complex comprising a polymer drug-loaded particle formed of a polymer and an active ingredient encapsulated in the polymer drug-loaded particle. (S2000) The polymer drug-loaded particle complex, a surfactant, a third pharmaceutically acceptable aqueous solution, and hyaluronic acid are mixed, wherein the hydrophilic-lipophilic balance value (HLB value) of the surfactant is greater than 10.

[0121] In some embodiments, after step (S2000), the following step is further included: (S3000) Add to a fourth-grade pharmaceutically acceptable aqueous solution.

[0122] In some embodiments, the polymer-loaded drug particles are uniformly suspended in an aqueous solution acceptable to the third drug.

[0123] In some embodiments, the third or fourth pharmaceutically acceptable aqueous solution comprises at least one or a combination of water for injection, aqueous solution for injection, physiological saline for injection, and other pharmaceutically acceptable aqueous solutions.

[0124] In some embodiments, the surfactant is a nonionic surfactant.

[0125] In some embodiments, the weight ratio of the polymer drug-loaded particles to the hyaluronic acid is 3:5 to 50:1; or, based on the weight of hyaluronic acid as 1 unit of weight, the total weight of the polymer and the active ingredient is 0.6 to 50 units of weight; or, based on the weight of hyaluronic acid as 1 unit of weight, the total weight of the polymer and the active ingredient is 0.6 to 50 units of weight.

[0126] The third or fourth pharmaceutically acceptable aqueous solution contains a water-soluble drug.

[0127] In some embodiments, the third or fourth pharmaceutically acceptable aqueous solution contains a local anesthetic.

[0128] In some embodiments, the local anesthetic is at least one of amides, para-aminobenzoic acid esters, and amino ethers, or a combination thereof.

[0129] In some embodiments, the third or fourth pharmaceutically acceptable aqueous solution contains an antioxidant.

[0130] In some embodiments, the third or fourth pharmaceutically acceptable aqueous solution contains an antibacterial agent.

[0131] In some embodiments, the antibacterial agent is at least one of phenolic antibacterial agents, alcoholic antibacterial agents, hydroxyphenyl ester antibacterial agents, and thimerosal, or a combination thereof.

[0132] The results show that the polymer-loaded curcumin particles of the present invention can significantly reduce the amount of curcumin needed, significantly increase its biological effects, and improve its therapeutic index. Furthermore, the aqueous solution formulation of the polymer-loaded curcumin particles exhibits high stability. Ultimately, this allows the polymer-loaded curcumin particles of the present invention to better achieve the various effects described in this invention. The high stability of the polymer-loaded curcumin particles of the present invention solves the problems of poor water solubility and low stability.

[0133] The results show that the polymer-loaded resveratrol particles of the present invention can significantly reduce the dosage of resveratrol, significantly increase its biological effects, and improve its therapeutic index. Furthermore, the aqueous solution formulation of the polymer-loaded resveratrol particles exhibits high stability. Ultimately, the polymer-loaded resveratrol particles of the present invention can better achieve the various efficacy claims of this invention. The high stability of the polymer-loaded resveratrol particles of the present invention solves the problems of poor water solubility and low stability.

[0134] In some embodiments, the curcumin drug with polymer-loaded particles prepared by the present invention is composed of 0.0001-5% curcumin and 95-100% polymer-loaded particle carrier.

[0135] In some embodiments, the resveratrol drug with polymer-loaded particles prepared by the present invention is composed of 0.0001-5% resveratrol and 95-100% polymer-loaded particle carrier.

[0136] Additional details regarding the preparation of the polymer drug-loaded particles of the present invention can be found in published patents PCT / CN2018 / 073897 or CN107213136B, the relevant disclosures of which are incorporated herein by reference for the purposes of this document.

[0137] In some embodiments, the polymer-loaded drug-eluting particle complex disclosed in this invention can be used to reduce local fat, reduce weight, prevent and treat skin discoloration and melanin deposition, reduce skin texture or skin roughness, prevent and treat tumors, prevent and treat lipid metabolism-related diseases and / or alleviate arthritis symptoms. In some embodiments, the polymer-loaded drug-eluting particles further comprise at least one of the following: 1,2-dimyristoyl-sn-glycero-3-phosphocholine (DMPC), 1,2-dimyristoyl-sn-glycero-3-phosphoglycerol (DMPG), or DMPC / DMPG. In some embodiments, the polymer-loaded drug particles further comprise at least one of the following lysophosphatidylglycerols: lysophosphatidylcholine, lauroyl-lysophosphatidylcholine, myristoyl-lysophosphatidylcholine, palmitoyl-lysophosphatidylcholine, stearoyl-lysophosphatidylcholine, arachidoyl-lysophosphatidylcholine, oleoyl-lysophosphatidylcholine, linoleic acid oleoyl-lysophosphatidylcholine, linolenic acid oleoyl-lysophosphatidylcholine, or erucic acid oleoyl-lysophosphatidylcholine. In some embodiments, curcumin accounts for 2-9% by weight in the polymer-loaded drug particle complex. In some embodiments, resveratrol accounts for 2-9% by weight in the polymer-loaded drug particle complex.

[0138] In other embodiments, the pharmaceutical compositions described herein may be formulated into sustained-release forms. Suitable embodiments of sustained-release preparations include semipermeable matrices of solid hydrophobic polymers containing antibodies, in the form of shaped articles, such as films or microcapsules. Examples of sustained-release matrices include polyesters, hydrogels (e.g., poly(2-hydroxyethyl-methacrylate) or poly(vinyl alcohol)), polylactides (US Patent No. 3,773,919), copolymers of L-glutamic acid and 7ethyl-L-glutamate, non-degradable ethylene-vinyl acetate, and degradable lactic acid-glycolic acid copolymers, such as LUPRONDEPOT. TM (Injectable microspheres composed of lactic acid-glycolic acid copolymer and leuprolide acetate), sucrose acetate isobutyrate, and poly-D-(-)-3-hydroxybutyric acid.

[0139] The pharmaceutical compositions described herein may be in unit dose 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 may be formulated in a manner suitable for administration by a suitable route, such as oral, parenterally, topically, rectal, buccally, vaginally, or via an implanted reservoir. General Technology

[0140] Unless otherwise stated, the practice of this disclosure will employ conventional techniques from molecular biology (including recombinant technologies), microbiology, cell biology, biochemistry, and immunology, which are within the scope of the art. Based on the foregoing description, those skilled in the art will be able to make the most of this invention. Therefore, the detailed descriptions below should be considered illustrative only and not in any way limiting the remainder of this disclosure. All publications cited herein are incorporated by reference for the purposes or subject matter of this citation.

[0141] Example 1: Effects of polymer-loaded drug-eluting particle complex on subcutaneous fat mass and body weight in rats

[0142] Preparation method of active ingredient polymer-loaded drug particle complex: The active ingredient-loaded polymer drug-eluting particle complex solution of this embodiment was prepared using the method disclosed in this case, comprising the active ingredient, a polymer (e.g., PLGA), cholesterol, and DMPE-PEG-200. The presence and size of the polymer drug-eluting particle complex were then confirmed using a particle size analyzer.

[0143] The active ingredient is curcumin or resveratrol.

[0144] The experiment was conducted using rats. First, 20 rats were fed a high-fat diet to induce subcutaneous fat accumulation until their body weight reached 330 ± 10 g. Then, the rats were randomly divided into four groups: a control group, a saline group, a PEG group, and a polymer-loaded drug-eluting particle complex group, with five rats in each group, ensuring no statistically significant difference in body weight among the groups. The body weight of each rat was recorded and defined as its "pre-experimental body weight." Then, the drug was administered as follows.

[0145] The active ingredient saline solution, the active ingredient PEG solution, and the active ingredient polymer drug-loaded particle complex solution were injected into the subcutaneous fat layer of the inguinal region of rats in the saline group, PEG group, and polymer drug-loaded particle complex group, respectively. Each injection dose was a fixed weight of mg of active ingredient per kilogram of body weight. The control group was given the same volume of saline solution in the same way.

[0146] The injection sites were the lower inguinal fat of rats, with injections on both the left and right sides on average. One injection was given on each of the 1st, 2nd, 3rd and 4th days of the experiment. During the experiment, rats were fed a high-fat diet continuously, and their weight changes were recorded daily. Water intake and food intake were recorded once a week. The experiment lasted for 14 days, and the rats were sacrificed with carbon dioxide on the 15th day.

[0147] Record the weight of each rat, defining it as the "post-experiment weight" for each rat. Subtract the "pre-experiment weight" from the "post-experiment weight" for each rat to obtain the "total weight gain". Divide the total weight gain of each group of rats by the total weight gain of the control group rats to obtain the "relative total weight gain".

[0148] Subcutaneous fat was collected from both sides of the lower groin of rats and weighed. The amounts of subcutaneous fat from both sides were summed to calculate the total amount of subcutaneous fat in the lower groin. The amount of subcutaneous fat in the lower groin of each group of rats was divided by the amount of subcutaneous fat in the lower groin of the control group rats to obtain the "relative weight of subcutaneous fat in the lower groin".

[0149] Data are presented as mean ± SD and analyzed using one-way ANOVA. Statistical results are expressed by symbols or letters. Different symbols or letters indicate statistical differences between groups (p < 0.05), while the same symbol or letter indicates no statistical difference between groups (p > 0.05).

[0150] Local fat assay results showed that direct injection of the active ingredient into the subcutaneous fat layer at the application site did not reduce fat (local fat) at the application site. There was no significant difference in the relative weight of subcutaneous fat in the inguinal region between the PEG group and the control group; however, there was a significant difference in the relative weight of subcutaneous fat in the inguinal region between the polymer-loaded drug-particle complex group and the control group (p<0.05).

[0151] The weight loss experiment showed that direct application of the active ingredient did not reduce body weight. There was no significant difference in body weight between the PEG group and the control group; however, there was a significant difference in body weight between the polymer-loaded drug-particle complex group and the control group (p<0.05).

[0152] The above experiments show that directly injecting the active ingredient into the subcutaneous fat layer of the application site cannot reduce fat (localized fat) or weight. Injecting an active ingredient composition with added excipient PEG (a common solubilizer) into the subcutaneous fat layer of the application site also fails to reduce fat (localized fat) or weight. However, encapsulating the active ingredient in polymer-loaded drug particles before injection into the subcutaneous fat layer of the application site significantly reduces both fat (localized fat) and weight. Therefore, polymer-loaded drug particle encapsulation significantly enhances the effectiveness of active ingredients in reducing subcutaneous fat (localized fat) and weight at the application site.

[0153] Example 2: Effects of polymer-loaded drug-eluting particle complex on the prevention and treatment of skin discoloration and melanin deposition

[0154] Example 2-1: Experiment on inhibiting melanin production (melanin production was induced before drug administration)

[0155] This embodiment tests the effects of physiological saline solution, active ingredient PEG solution, and active ingredient polymer-loaded particle complex solution (as described in Example 1) on their ability to inhibit melanin production. First, mouse melanoma cells B16-F10 were used. Five experimental groups were established: a control group (α-MSH), arbutin, physiological saline group, PEG group, and polymer-loaded particle complex group. Each experiment was repeated three times, and the melanin content of each group was measured.

[0156] Mouse melanoma cells B16-F10 were seeded into 6-well plates and cultured for 24 hours. Afterward, α-MSH was added and the cells were treated for 30 minutes. Except for the control group, each group was further treated with arbutin, physiological saline solution, PEG solution of the active ingredient, or a polymer-loaded drug-eluting particle complex solution of the active ingredient, respectively. After 48 hours of culture, cells were collected by centrifugation for 5 minutes, and the cells were rehydrated. The samples were then heated for 1.5 hours after thorough mixing. After cooling, the samples were analyzed using a multi-functional microplate analyzer. The M2e Multimode Microplate Reader measures absorbance at a wavelength of 475 nanometers (nm) and calculates the melanin production inhibition rate.

[0157] The experimental results showed that the active ingredient polymer-loaded particle complex had a significantly better inhibitory effect on melanin than physiological saline solution and active ingredient PEG solution, and its inhibitory effect was also significantly better than arbutin. In other words, the active ingredient polymer-loaded particle complex can effectively reduce melanin production. Example 2-2: Experiment on inhibition of tyrosinase activity (inducing melanin production before drug administration)

[0158] This embodiment evaluates and compares the ability of physiological saline solution, active ingredient PEG solution, and active ingredient polymer-loaded particle complex solution to inhibit tyrosinase activity by measuring the amount of L-DOPA converted to dopaquinone in Example 1. This embodiment uses mouse melanoma cells B16-F10, with five experimental groups: control group (α-MSH), arbutin, physiological saline group, PEG group, and polymer-loaded particle complex group. The tyrosinase enzyme activity of each group was measured.

[0159] Mouse melanoma cells B16-F10 were seeded into 6-well plates and cultured for 24 hours. After 30 minutes of treatment with α-MSH, except for the control group, each group was further cultured for 48 hours with arbutin, physiological saline solution, active ingredient PEG solution, or active ingredient polymer drug-loaded particle complex solution, respectively. Cells were then collected with Trypsin-EDTA and washed with PBS. Tyrosinase protein in the cells was extracted and quantified. After quantification, L-DOPA was mixed and the absorbance was measured at a wavelength of 405 nm using a microplate analyzer. The measurement was performed for one hour, and the absorbance was recorded every 10 minutes.

[0160] The results showed that the active ingredient polymer-loaded particle complex solution had a significantly better ability to inhibit tyrosinase activity than physiological saline solution and active ingredient PEG solution, and was also significantly better than arbutin. Example 3: Preparation of curcumin lactide-glycolide copolymer (PLGA) particles of various sizes

[0161] Curcumin-lactide-glycol copolymer (PLGA) particles of various sizes were prepared using curcumin, PLGA, ethyl acetate, and ethanol.

[0162] (4-1) Steps for preparing curcumin lactide-glycol copolymer (PLGA) particles with an average particle size of 5 μm: (S110') Mix 175 mg curcumin, 800 mg PLGA, and 50 mL ethyl acetate (reagent grade; an example of an ethyl acetate solvent for primary emulsification) and stir thoroughly to obtain an oil phase solution; and (S120') includes the following steps: (S121') At a speed of 1000-3000 rpm, the oil phase solution is uniformly mixed with 500 mL of aqueous phase solution, and emulsification is carried out at a speed of 1000-3000 rpm for 2-4 hours, wherein the aqueous phase solution contains 0.1-0.2% polyvinyl alcohol (PVA; polyvinyl alcohol is an example of an emulsion stabilizer); (S122) Filter with a 2-5 μm filter membrane. The particles left on the filter membrane are the curcumin lactide-glycol copolymer (PLGA) particles with an average particle size of 5 μm (abbreviated as 5 μm PLGA / curcumin).

[0163] In this specific embodiment, the weight ratio of curcumin to lactide-glycolic acid copolymer (PLGA) is 175 mg: 800 mg, that is, the weight ratio of curcumin to lactide-glycolic acid copolymer (PLGA) is approximately 1:4.57; or, that is, the weight ratio of curcumin to lactide-glycolic acid copolymer (PLGA) is approximately 1:5.

[0164] (4-2) Steps for preparing curcumin lactide-glycol copolymer (PLGA) particles with an average particle size of 12 μm: (S110”) Mix 300 mg curcumin, 800 mg PLGA, 37.5 mL ethyl acetate (reagent grade; ethyl acetate is an example of a solvent for the first emulsification), and 2.5 mL ethanol (an example of a solvent for the second emulsification), and stir thoroughly to obtain an oil phase solution; and (S120) includes the following steps: (S121”) At a speed of 1000 to 3000 rpm, the oil phase solution is uniformly mixed with 500 mL of aqueous phase solution, and emulsification is carried out at a speed of 1000 to 3000 rpm for 2 to 4 hours, wherein the aqueous phase solution contains 0.1 to 0.2% polyvinyl alcohol (PVA, an example of an emulsion stabilizer); (S122”) is filtered through a 2-5 μm filter membrane. The particles remaining on the filter membrane are the curcumin lactide-glycolide copolymer (PLGA) particles with an average particle size of 12 μm (abbreviated as 12 μm PLGA / curcumin).

[0165] In this specific embodiment, the weight ratio of curcumin to lactide-glycolic acid copolymer (PLGA) is 300 mg: 800 mg, that is, the weight ratio of curcumin to lactide-glycolic acid copolymer (PLGA) is approximately 1:2.67; or, that is, the weight ratio of curcumin to lactide-glycolic acid copolymer (PLGA) is 1:3.

[0166] (4-3) Steps for preparing curcumin lactide-glycol copolymer (PLGA) particles with an average particle size of 20 μm: (S110”') Mix 240 mg curcumin, 800 mg PLGA, 30 mL ethyl acetate (an example of a solvent for the first emulsification), and 2 mL ethanol (an example of a solvent for the second emulsification), and stir thoroughly to obtain an oil phase solution; and (S120”’) includes the following steps: (S121”') At a rotation speed of 800–3000 rpm, the oil phase solution is uniformly mixed with 500 mL of aqueous phase solution, and emulsification is carried out at a rotation speed of 800–3000 rpm for 2–4 hours, wherein the aqueous phase solution contains 0.1–0.2% polyvinyl alcohol (PVA, as an example of an emulsion stabilizer); and (S122”’) Filtered with a 2-5 μm filter membrane, the particles left on the filter membrane are the curcumin lactide-glycol copolymer (PLGA) particles with an average particle size of 20 μm (abbreviated as 20 μm PLGA / curcumin).

[0167] In this specific embodiment, the weight ratio of curcumin to lactide-glycolic acid copolymer (PLGA) is 240 mg: 800 mg, that is, the weight ratio of curcumin to lactide-glycolic acid copolymer (PLGA) is approximately 1:3.33; or, that is, the weight ratio of curcumin to lactide-glycolic acid copolymer (PLGA) is approximately 1:3. Example 4: Preparation of resveratrol lactide-glycolide copolymer (PLGA) particles

[0168] Resveratrol-lactide-glycol copolymer (PLGA) particles were prepared using resveratrol, lactide-glycol copolymer (PLGA), ethyl acetate, and acetone.

[0169] Steps for preparing resveratrol-lactide-glycol copolymer (PLGA) particles: (SS110') 160 mg resveratrol (an example of a polyphenolic compound), 800 mg PLGA, 15 mL ethyl acetate (reagent grade; an example of an ethyl acetate solvent for the first emulsification), and 10 mL acetone (an example of an acetone solvent for the second emulsification) are mixed and stirred until a uniform oil phase solution is obtained; and (SS120') includes the following steps: (SS121') The oil phase solution is uniformly mixed with 400 mL of aqueous phase solution at a speed of 1000 to 3000 rpm, and emulsification is carried out at a speed of 1000 to 3000 rpm for 2 to 4 hours, wherein the aqueous phase solution contains 0.1 to 0.2% polyvinyl alcohol (PVA, an example of an emulsion stabilizer); (SS122) is filtered through a 2-5 μm filter membrane. The particles remaining on the filter membrane are the resveratrol lactide-glycol copolymer (PLGA) particles (abbreviated as PLGA / resveratrol). Example 5: Determination of the mass of lactide-glycolic acid copolymer (PLGA) particles

[0170] The particle size of curcumin lactide-glycol copolymer (PLGA) particles and resveratrol lactide-glycol copolymer (PLGA) particles was measured using an optical microscope, its matching charge-coupled device (CCD), and imaging software.

[0171] Curcumin lactide-glycolic acid copolymer (PLGA) particles and resveratrol lactide-glycolic acid copolymer (PLGA) particles were lyophilized. 1 mg of the lyophilized sample was dissolved in 1 mL of DMSO solvent, and the drug loading was quantitatively analyzed using high-performance liquid chromatography (HPLC; e.g., HPLC-UV).

[0172] Please see Figure 2 , 3 4, 5 and Table 1. Figure 2 The image is obtained by observing curcumin lactide-glycol copolymer (PLGA) particles with an average particle size of 5 μm using an optical microscope. Figure 3 The image is obtained by observing curcumin lactide-glycol copolymer (PLGA) particles with an average particle size of 12 μm using an optical microscope. Figure 4 The image is obtained by observing curcumin lactide-glycol copolymer (PLGA) particles with an average particle size of 20 μm using an optical microscope. Figure 5 These are images obtained by observing resveratrol lactide-glycol copolymer (PLGA) particles using an optical microscope. Table 1 shows the particle size and drug loading rate of curcumin or resveratrol after PLGA coating.

[0173] Figure 2 As shown in Table 1, particle size analysis and drug loading rate analysis were performed on the curcumin lactide-glycol copolymer (PLGA) particles with an average particle size of 5 μm. The measured average particle size was 5 ± 3 μm and the average drug loading rate was 21.5%. Figure 3As shown in Table 1, particle size analysis and drug loading rate analysis were performed on the curcumin lactide-glycol copolymer (PLGA) particles with an average particle size of 12 μm. The measured average particle size was 13 ± 5 μm and the average drug loading rate was 24.4%. Figure 4 As shown in Table 1, particle size analysis and drug loading rate analysis were performed on the curcumin lactide-glycol copolymer (PLGA) particles with an average particle size of 20 μm. The measured average particle size was 20 ± 8 μm and the average drug loading rate was 20.67%. Figure 5 As shown in Table 1, the particle size and drug loading of the resveratrol lactide-glycolic acid copolymer (PLGA) particles were analyzed. The average particle size was 15±5μm and the average drug loading was 10.5%.

[0174] Depend on Figure 2 , 3 As can be seen from 4, 5 and Table 1, the average particle size of the various lactide-glycolic acid copolymer (PLGA) particles prepared is 1 to 35 μm, and the drug loading rate is 5 to 30%. Therefore, the various lactide-glycolic acid copolymer (PLGA) particles prepared meet the quality specifications of this application regarding the preferred particle size and preferred drug loading rate.

[0175] Table 1. Particle size and drug loading rate of curcumin or resveratrol after PLGA coating Example 6: In vitro drug release test of curcumin lactide-glycolic acid copolymer (PLGA) particles. The curcumin lactide-glycolic acid copolymer (PLGA) particles with an average particle size of 20 μm obtained in step (S124”') were freeze-dried and weighed for later use in this example. The experiment was divided into 3 groups: control group (PLGA+PBS), surfactant group (PLGA+ELP), and surfactant-hyaluronic acid group (PLGA+ELP+HA).

[0176] Curcumin lactide-glycolic acid copolymer (PLGA) particles were mixed with phosphate-buffered saline (PBS) to obtain the control group test solution. Curcumin lactide-glycolic acid copolymer (PLGA) particles were mixed with a PBS solution containing polyoxyethylene 35 castor oil to obtain the surfactant group test solution. Curcumin lactide-glycolic acid copolymer (PLGA) particles were mixed with a PBS solution containing polyoxyethylene 35 castor oil and hyaluronic acid to obtain the surfactant-hyaluronic acid group test solution.

[0177] Each of the above test solutions was added to PBS and mixed until the final volume was sufficient to simulate the volume of synovial fluid in a normal joint cavity, thus obtaining the test substances for each group.

[0178] After preparation, the sample was left to stand at room temperature for 8 weeks, and samples were taken once a week starting from week 0, for a total of 9 time points.

[0179] Sampling procedures for the control group and surfactant group: Centrifuge the test substances of the control group and surfactant group for 3 minutes during weeks 0-8, and collect the supernatant to obtain samples from different time points of the control group or surfactant group. Mix the supernatant with DMSO evenly, filter it through a PTFE filter, and then use a high-performance liquid chromatography (HPLC) system. Chromatography, HPLC; e.g. High Performance Liquide The filtrate was analyzed using HPLC-DAD (Chromatography / Diode Array Detector), and the curcumin concentration in the supernatant was deduced to obtain the curcumin concentration in the sample. For the control group and surfactant group, PBS was added after each supernatant collection to maintain drug release from the PLGA-loaded particles at a fixed volume.

[0180] In this embodiment, since the supernatant is diluted with DMSO, the method to back-calculate the curcumin concentration in the supernatant is to multiply the curcumin concentration in the filtrate by the dilution ratio.

[0181] Sampling steps for surfactant and hyaluronic acid components:

[0182] Sampling procedure for Week 0: First, centrifuge the surfactant and hyaluronic acid test materials for Week 0, and collect the supernatant to obtain the sample of the surfactant and hyaluronic acid group for Week 0. Dissolve the supernatant in DMSO and make up to a fixed volume, then filter it through a PTFE filter. Analyze the filtrate using high performance liquid chromatography (HPLC; for example, High Performance Liquid Chromatography / Diode Array Detector, HPLC-DAD) and deduce the curcumin concentration in the supernatant to obtain the curcumin concentration in the sample.

[0183] Sampling Procedure for Weeks 1-8: During weeks 1-8, the surfactant and hyaluronic acid test substances were centrifuged for 3 minutes, and the supernatant was collected to obtain the surfactant and hyaluronic acid samples for weeks 1-8. The supernatant was then uniformly mixed with DMSO and filtered through PTFE. The curcumin content in the filtrate was analyzed using high-performance liquid chromatography (HPLC; e.g., High Performance Liquid Chromatography / Diode Array Detector, HPLC-DAD), and the curcumin concentration in the supernatant was deduced to obtain the curcumin concentration in the surfactant and hyaluronic acid samples for weeks 1-8. The curcumin release amount of each sample was calculated using the following formula:

[0184] Curcumin release (%) = (curcumin concentration in sample / final curcumin concentration in test substance) × 100%.

[0185] Please see Figure 6 , Figure 6 This is a graph showing the in vitro drug release rate data of curcumin lactide-glycolic acid copolymer (PLGA) particles. In the 8-week in vitro drug release test, the control group's PLGA particles did not release curcumin, indicating that PBS could not induce the release of curcumin from PLGA particles. In the surfactant group, the curcumin release rate reached only 7.7% at the end of week eight, showing that while the surfactant could induce the release of curcumin from PLGA particles, the release effect was poor. In the surfactant and hyaluronic acid group, the PLGA particles released curcumin slowly and steadily, and the curcumin release rate reached 46.1% at the end of week eight, indicating that the combination of surfactant and hyaluronic acid could achieve an appropriate release and sustained-release effect for curcumin. Example 7: Preparation of a pharmaceutical composition containing curcumin lactide-glycolic acid copolymer (PLGA) particles

[0186] The preparation steps are as follows: (S100') Obtain curcumin lactide-glycolide copolymer (PLGA) particles with an average particle size of 20 μm obtained in step (S124”'), which will be used in this experiment; (S200') Mix 150 mg curcumin lactide-glycol copolymer (PLGA) particles, 300 mg polyoxyethylene 35 castor oil (Cremophor ELP, an example of a surfactant), and 0.5 mL physiological saline for injection (an example of a second pharmaceutically acceptable aqueous solution); (S300') Add injectable physiological saline (a third example of a medically acceptable aqueous solution) to bring the total volume to 3 mL. Example 8: Preparation of a pharmaceutical composition comprising curcumin lactide-glycolic acid copolymer (PLGA) particles and hyaluronic acid

[0187] The preparation steps are as follows: (S1000') Obtain curcumin lactide-glycolide copolymer (PLGA) particles with an average particle size of 20 μm obtained in step (S124”'), which will be used in this experiment; (S2000') Mix 150 mg curcumin lactide-glycol copolymer (PLGA) particles, 300 mg polyoxyethylene 35 castor oil (Cremophor ELP; an example of a surfactant), 0.5 mL physiological saline for injection (an example of a pharmaceutically acceptable aqueous solution), and 2 g of 1.5% hyaluronic acid aqueous solution (preparation method: mix 0.03 g of hyaluronic acid with an appropriate amount of physiological saline for injection to make a total mass of 2 g). (S3000') Add injectable physiological saline (example of a medically acceptable aqueous solution) to bring the total volume to 3 mL.

[0188] In this specific embodiment, the weight ratio of the curcumin lactide-glycolic acid (PLGA) particles (an example of drug-loaded lactide-glycolic acid (PLGA) particles) with an average particle size of 20 μm to the hyaluronic acid is 150 mg: 0.03 g, that is, 5:1. Alternatively, with the weight of hyaluronic acid as 1 unit of weight, the total weight of the lactide-glycolic acid (PLGA) and the curcumin is 5 units of weight. Example 9: A pharmaceutical composition containing curcumin microcells and hyaluronic acid, or containing curcumin polylactic acid. - An animal study evaluating the efficacy of a pharmaceutical composition of polyglycolic acid (PLGA) particles and hyaluronic acid in improving cartilage tissue in osteoarthritis.

[0189] To evaluate the therapeutic effects of ARTZDispo, a joint injection prepared from a pharmaceutical composition containing curcumin microcells and hyaluronic acid (code-named OT-00CH), and a joint injection prepared using the pharmaceutical composition of the present invention containing curcumin lactide-glycolic acid copolymer (PLGA) particles and hyaluronic acid (code-named OT-00PCH) on osteoarthritis, the inventors conducted the following experiments and evaluated them using joint tissue staining.

[0190] Twenty-five rats were divided into five groups: a normal control group, a negative control group, an ARTZDispo injection group, an injection group containing curcumin microcells and hyaluronic acid (OT-00CH injection group), and an injection group containing curcumin lactide-glycolic acid (PLGA) particles and hyaluronic acid (OT-00PCH injection group), with five rats in each group.

[0191] The detailed administration methods and experimental designs for each group are shown in Table 5.

[0192] First, on day 0 of the experiment, a fixed weight of sodium monoiodoacetate (MIA) was injected into the left knee joint of rats in the negative control group, the ARTZDispo injection group, the injection group containing curcumin microcells and hyaluronic acid (OT-00CH injection group), and the injection group containing curcumin lactide-glycolic acid copolymer (PLGA) particles and hyaluronic acid (OT-00PCH injection group) to induce osteoarthritis. Osteoarthritis was not induced in the normal control group.

[0193] The following are the administration methods for rats that underwent sodium monoiodide-induced osteoarthritis for 14 days after treatment: negative control group, ARTZDispo injection group, OT-00CH injection group containing curcumin microcells and hyaluronic acid, and OT-00PCH injection group containing curcumin lactide-glycolic acid copolymer (PLGA) particles and hyaluronic acid.

[0194] Normal control group: No medication was administered.

[0195] Negative control group: No medication was administered.

[0196] ARTZDispo injection group: ARTZDispo injection was administered into the left knee joint cavity of rats on days 15, 22, and 29 of the experiment.

[0197] The injection group containing curcumin microcells and hyaluronic acid (OT-00CH injection group): On days 15, 22 and 29 of the experiment, the pharmaceutical composition containing curcumin microcells and hyaluronic acid was injected into the left knee joint cavity of rats. The injection dose was the same as that of the joint injection group.

[0198] The injection group containing curcumin lactide-glycolide copolymer (PLGA) particles and hyaluronic acid (OT-00PCH injection group): On day 15 of the experiment, the pharmaceutical composition containing curcumin lactide-glycolide copolymer (PLGA) particles with an average particle size of 20 μm and hyaluronic acid prepared in Example 9 of the present invention was injected into the left knee joint cavity of rats. The injection dose was the same as that of the joint injection group.

[0199] Among them, the ARTZDispo injection group, OT-00CH injection group, and OT-00PCH injection group all contained the same concentration of hyaluronic acid; the OT-00CH injection group and the OT-00PCH injection group contained the same dose of curcumin; the OT-00PCH injection group contained PLGA / curcumin sustained-release drug particles, and the average particle size of the PLGA drug-loaded particles was 20±8μm.

[0200] On day 57 of the experiment (6 weeks after drug administration), rats in each group were sacrificed, and their left knee joints were sectioned for histological examination. The histopathological examination was then performed using hematoxylin and eosin staining (H&E stain) to evaluate the efficacy of each test substance in treating osteoarthritis.

[0201] Please refer to the tissue section results. Figures 7-11 .

[0202] For the tissue section results of the normal control group, please refer to [link / reference]. Figure 7 . Figure 7 The results showed that in normal control rats that had not undergone MIA-induced osteoarthritis, the joint cavity was intact, the knee joint cartilage membrane was smooth and neat, and there was no damage to the articular cartilage or inflammatory cell infiltration.

[0203] For the tissue section results of the negative control group, please refer to [link / reference]. Figure 8 . Figure 8 The results showed that the left knee joint of rats in the negative control group, which underwent MIA-induced osteoarthritis but received no treatment, exhibited significant damage, with roughened articular cartilage surfaces, destroyed chondrocytes, cartilage breakage, and suspected inflammatory cell infiltration in the cartilage tissue. In other words, the joints of the negative control rats showed moderate damage, indicating that this experiment successfully induced the pathological symptoms of osteoarthritis in rats.

[0204] For the tissue section results of the ARTZDispo injection group, please refer to [link to relevant documentation]. Figure 9 . Figure 9The results showed that the treatment regimen of injecting ARTZDispo (1 mg / rat) into the left knee joint cavity on days 15, 22, and 29 after MIA-induced osteoarthritis did not improve the pathological changes of osteoarthritis. Pathological interpretation results in both this group and the negative control group indicated moderate damage. The stained sections revealed multiple irregularities and perichondrial tears on the articular cartilage surface, indicating that the ARTZDispo injection could not improve or alleviate the symptoms of osteoarthritis.

[0205] For tissue section results of the injection group containing curcumin microcells and hyaluronic acid (OT-00CH injection group), please refer to [link to relevant documentation]. Figure 10 . Figure 10 The results showed that, after MIA-induced osteoarthritis, the treatment method of injecting the pharmaceutical composition containing curcumin microcells and hyaluronic acid of this invention into the left knee joint cavity on days 15, 22, and 29 of the experiment significantly improved the pathological characteristics of osteoarthritis, and the section staining results showed mild damage. Compared with the negative control group or the ARTZDispo injection group, the articular cartilage surface of rats in this group was more intact and smooth, with less cartilage damage, chondrocyte erosion, or inflammatory cell infiltration (p<0.05), indicating that it can significantly improve or alleviate the various symptoms of osteoarthritis.

[0206] For tissue section results of the injectable group (OT-00PCH injection group) containing curcumin lactide-glycolic acid copolymer (PLGA) particles and hyaluronic acid, please refer to [link to relevant documentation]. Figure 11 . Figure 11 The results showed that, following MIA-induced osteoarthritis, the treatment method of injecting the pharmaceutical composition of this invention, containing curcumin lactide-glycolic acid copolymer (PLGA) particles and hyaluronic acid into the left knee joint cavity on day 15 of the experiment significantly improved the severity of osteoarthritis symptoms. The staining results of the tissue sections in this group showed mild damage. Compared with the negative control group or the ARTZDispo group, the articular cartilage surface was more intact and smooth, with less cartilage breakage, chondrocyte erosion, or inflammatory cell infiltration (p<0.05), indicating a significant improvement or alleviation of various symptoms of osteoarthritis.

[0207] All features disclosed in this specification can be combined in any combination. Each feature disclosed in this specification can be replaced by an alternative feature that achieves the same, equivalent, or similar purpose. Therefore, unless otherwise expressly stated, each disclosed feature is merely an example of a general series of equivalent or similar features.

[0208] As described above, those skilled in the art can easily grasp the essential characteristics of this invention, and various changes and modifications can be made to adapt it to various uses and situations without departing from the spirit and scope of the invention. Therefore, other embodiments are also within the scope of this claim. Equivalents

[0209] As used in the specification and claims, the term "and / or" should be understood to mean "any one or both" of the so-called connected components, that is, components that are common in some cases and separate in others. Multiple components listed with "and / or" should be interpreted in the same way, that is, "one or more" of the so-called connected components. Other components may optionally be present, whether or not they are related to those specifically identified by the "and / or" subordinate clause. Thus, as a non-limiting example, when used in conjunction with open-ended language such as "comprising," reference to "A and / or B" may, in one embodiment, contain only A (optionally including components other than B); in another embodiment, contain only B (optionally including components other than A); in yet another embodiment, contain both A and B (optionally including other components), and so on.

[0210] 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 items are listed separately, "or" or "and / or" should be interpreted as included, that is, including at least one, but also including more than one or some of the listed items. Generally, the word "or" as used herein should only be interpreted as an alternative to exclusivity (i.e., "one or the other, but not both") when preceding exclusive terms such as "any," "one of," "only one," or "exactly one." When used in the claims, "consisting mainly of" should have the ordinary meaning as it is used in the field of patent law.

[0211] It should also be understood that, unless there is an explicit indication to the contrary, in any method that includes more than one step or action in the claims herein, the order of the steps or actions of the method is not necessarily limited to the order in which the steps or actions of the method are described.

Claims

1. A composition comprising a high molecular weight polymeric drug-loaded particle complex; the high molecular weight polymeric drug-loaded particle complex comprising: a microstructure formed by a high molecular weight polymer; and an active ingredient encapsulated in the microstructure; the active ingredient comprising at least one of curcumin, curcumin derivative, curcumin metabolite, resveratrol, oxidized resveratrol, resveratrol derivative, and resveratrol metabolite; wherein the active ingredient is non-synthetic or synthetic. the high molecular weight polymer is poly(lactide-co-glycolide) (PLGA), poly-L-lactide (PLLA), polycaprolactone (PCL), polyglycolide (PGA), polylactide (PLA), or a polyethylene glycolated component; wherein the polyethylene glycolated component is PLA-PEG, PLGA-PEG, PLGA-PEG-PLGA, PLA-PEG-PLA, PEG-PCL, PCL-PEG-PCL, PEG-PLA-PEG, or PEG-PLGA-PEG. the high molecular weight polymer has a weight average molecular weight of 5000-100000 Da; or the high molecular weight polymer has a viscosity of 0.25-0.80 dL / g I; or the high molecular weight polymer is poly(lactide-co-glycolide) (PLGA) and the molar ratio of lactide to glycolide is 25:75-75:

25.

2. The composition of claim 1, wherein, the composition further comprises a surfactant; wherein the surfactant is preferably a non-ionic surfactant, and preferably the non-ionic surfactant is at least one of polysorbate 80, propylene glycol, polyethylene glycol 600, polyoxyl 15-hydroxystearate, polyoxyl castor oil derivatives, polyoxyethylene derivatives, and other non-ionic surfactants, or a combination thereof.

3. The composition of claim 1 or 2, wherein, the high molecular weight polymeric drug-loaded particle complex has a particle size of 1-50 μm.

7. Use of the composition of any one of claims 1-6 for the manufacture of a product for application to a local subcutaneous site of an individual to reduce the amount of fat at the local subcutaneous site, to reduce the body weight of the individual, or to treat obesity.

4. The composition of any one of claims 1-3, wherein, 8. Use of the composition of any one of claims 1-6 for the manufacture of a product for reducing melanin, skin lines, or skin roughness.

5. The composition of any one of claims 1-4, wherein, 9. Use of the composition of any one of claims 1-6 for the manufacture of a medicament for alleviating the degree of inflammation of a joint.

6. The composition of any one of claims 1-5, wherein, 10. Use of the composition of any one of claims 1-6 for the manufacture of a medicament for preventing or treating a tumor or a disease related to fat metabolism. ​ ​ ​ ​

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