Composite drug particles and uses thereof

Abstract

Provided herein are particles comprising a compound having a steroid core structure, or a salt or ester thereof. Also provided herein are compositions comprising the particles, and methods of using the particles, for example, in methods for treating liver damage or for fat reduction.

Description

[Technical field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims priority to and the benefit of U.S. Provisional Patent Application No. 63 / 168,829, filed March 31, 2021, which is incorporated by reference in its entirety.

[0002] Provided herein are composite particles comprising a compound having a steroid core structure, or a salt or ester thereof. Also provided herein are compositions comprising the particles, and methods of using the particles, for example, in methods for treating liver damage or for fat reduction. [Background technology]

[0003] Compounds with a steroid backbone, such as bile acids and corticosteroids, are useful in treating a wide variety of disorders. However, solubilized forms of these drugs administered orally and subcutaneously can have limited efficacy and can produce undesirable side effects. Summary of the Invention

[0004] The present disclosure provides composite particles comprising a compound having a steroid core structure, or a salt or ester thereof, having at least one dimension having a length of at least 100 nm.

[0005] In some embodiments, the composite particles further comprise a transition metal ion. In some embodiments, the transition metal ion is selected from gold, silver, copper, platinum, palladium, nickel, and iron ions. In some embodiments, the transition metal ion is selected from gold, silver, copper, and iron ions. In some embodiments, the transition metal ion is a gold ion (e.g., an Au(III) ion) or an iron ion (e.g., an Fe(II) ion).

[0006] In some embodiments, the composite particles further comprise an acid, hi some embodiments, the acid is selected from hydrochloric acid and salicylic acid.

[0007] In some embodiments, the compound having a steroid core structure is testosterone, exemestane, formestane, mesterolone, fluoxymesterone, methyltestosterone, oxandrolone, oxymetholone, mestranol, norethindrone, danazol, gestrinone, levonorgestrel, lynestrenol, norgestrel, desogestrel, etonogestrel, tibolone, ethynodiol, cyproterone, megestrol, abiraterone, dienogest, mifepristone, drospirenone, spironolactone, estradiol, polyestradiol, estramustine, estrone, estropipate, progesterone, dydrogesterone, hydroxyprogesterone, medroxyprogesterone, segesterone, norelgestromin, norgestimate, cortisol, cortisone, fluorometholone, difluprednate, fludrocortisone, fluocinolone, loteprednol. , methylprednisolone, prednicarb, prednisolone, prednisone, triamcinolone, alclometasone, betamethasone, clobetasol, clobetasone, clocortolone, desoximetasone, dexamethasone, diflorasone, difluocortolone, fluticasone, halometasone, mometasone, rimexolone, amcinonide, budesonide, ciclesonide, deflazacort, desonide, flunisolide, fluticasone Selected from the group consisting of ocinonide, halcinonide, cholesterol, estradiol, hydrocortisone, diflucortolone, boldenone, nandrolone, altrenogest, stanozolol, osaterone, estriol, aglepristone, trilostane, flumethasone, deoxycorticosterone, alphaxalone, desoxycorticosterone, and isoflupredone, or a salt or ester thereof, or any combination thereof.

[0008] In some embodiments, the compound having a steroid core structure is a bile acid. In some embodiments, the bile acid is selected from cholic acid, deoxycholic acid, chenodeoxycholic acid, lithocholic acid, glycocholic acid, taurocholic acid, glycodeoxycholic acid, taurodeoxycholic acid, glycochenodeoxycholic acid, taurochenodeoxycholic acid, glycolithocholic acid, taurolithocholic acid, ursodeoxycholic acid, glycoursodeoxycholic acid, tauroursodeoxycholic acid, and obeticholic acid. In some embodiments, the bile acid is selected from cholic acid and deoxycholic acid. In some embodiments, the compound having a steroid core structure is a salt of a bile acid. In some embodiments, the salt of a bile acid is selected from sodium cholate, sodium deoxycholate, sodium ursodeoxycholic acid, and sodium chenodeoxycholic acid.

[0009] In some embodiments, the compound having a steroid core structure is a corticosteroid compound or a salt or ester thereof. In some embodiments, the corticosteroid compound is hydrocortisone, dexamethasone, beclomethasone, ciclesonide, clobetasol, clobetasone, desonide, desoxymethasone, desoxycorticosterone, dichlorisone, diflorasone, diflucortolone, fluclarolone, fludrocortisone, flumethasone, fluocinolone, fluocinonide, flucortine, fluocortolone, fluprednidene, flurandrenolone, halcinonide, halometasone, methylprednisolone, triamcinolone, cortisone, cortodoxone, flucetonide, The corticosteroid compound is selected from fluradrenalone, medrysone, alclometasone, amciafel, amcinafide, amcinonide, betamethasone, budesonide, chlorprednisone, clocortelone, clescinolone, difluprednate, flucloronide, flunisolide, fluoromethalone, fluperolone, fluprednisolone, hydrocortamate, meprednisone, mometasone, paramethasone, prednisolone, prednisone, prednicarbate, and tixocortol, or a salt or ester thereof. In some embodiments, the corticosteroid compound is selected from dexamethasone, methylprednisolone, and hydrocortisone, or a salt or ester thereof.

[0010] In some embodiments, the composite particles have at least one dimension having a length of at least 1 μm.

[0011] In some embodiments, the composite particles have a hexagonal prism shape. In some embodiments, the hexagonal prism has a diagonal length of 2.5 μm to 10 μm. In some embodiments, the hexagonal prism has a height of 2.5 μm to 6.5 μm.

[0012] In some embodiments, the composite particles have a rod shape. In some embodiments, the rods have a length between 2.5 μm and 100 μm. In some embodiments, the rods have a length between 10 μm and 50 μm.

[0013] In some embodiments, the particles consist essentially of (i) a compound having a steroid core structure, or a salt or ester thereof, and (ii) a transition metal ion, and / or an acid. In some embodiments, the particles consist essentially of a bile acid, or a salt or ester thereof, and a gold ion (e.g., Au(III) ion).

[0014] In some embodiments, the particles are essentially free of transition metal nanoparticles (eg, gold nanoparticles).

[0015] The present disclosure also provides a composition comprising a plurality of the composite particles described herein. In some embodiments, the composition further comprises a pharma- ceutically acceptable carrier.

[0016] The present disclosure also provides a method of making a plurality of composite particles, the method comprising the steps of: (a) providing a first solution comprising a transition metal salt in ethyl acetate; (b) mixing the first solution with water to form a first emulsion; (c) mixing the first emulsion with a second solution comprising a compound having a steroid core structure or a salt or ester thereof to form a final mixture, thereby forming the composite particles. Also provided is a method comprising:

[0017] The present disclosure also provides a method of making a plurality of composite particles, the method comprising the steps of: (a) providing a first solution comprising a compound having a steroid core structure, or a salt or ester thereof, in ethyl acetate; (b) combining the first solution with a transition metal salt to form a second solution; (c) mixing the second solution with water to form a first emulsion; (d) mixing the first emulsion with a solution of a compound having a steroid core structure or a salt or ester thereof in water to form a final mixture, thereby forming the composite particles. Also provided is a method comprising:

[0018] The present disclosure also provides a method of making a plurality of composite particles, the method comprising the steps of: (a) providing a first solution comprising a transition metal salt in water; (b) combining the first solution with ethyl acetate to form a first emulsion; (c) mixing the first emulsion with a solution of a compound having a steroid core structure or a salt or ester thereof in water to form a final mixture, thereby forming the composite particles. Also provided is a method comprising:

[0019] The present disclosure also provides a method of making a plurality of composite particles, the method comprising the steps of: (a) providing a first solution comprising an acid, a compound having a steroid core structure or a salt or ester thereof, and water; (b) combining the first solution with ethyl acetate to form a first emulsion; (c) mixing the first emulsion with a solution of an acid in water to form a final mixture, thereby forming the composite particles. Also provided is a method comprising:

[0020] The present disclosure also provides a method of making a plurality of composite particles, the method comprising the steps of: (a) providing a first solution comprising an acid in ethyl acetate; (b) combining the first solution with a second solution comprising a compound having a steroid core structure or a salt or ester thereof and water to form a first emulsion; (c) mixing the first emulsion with a third solution containing a compound having a steroid core structure or a salt or ester thereof and water to form a final mixture, thereby forming the composite particles. Also provided is a method comprising:

[0021] In some embodiments of the methods disclosed herein, the compound having a steroid core structure is a bile acid or a salt or ester thereof. In some embodiments, the compound having a steroid core structure is selected from sodium cholate, sodium deoxycholate, sodium ursodeoxycholate, and sodium chenodeoxycholate. In some embodiments, the compound having a steroid core structure is a corticosteroid compound or a salt or ester thereof. In some embodiments, the corticosteroid compound is selected from dexamethasone, methylprednisolone, and hydrocortisone, or a salt or ester thereof. In some embodiments, the transition metal salt is selected from gold(III) salts, silver(I) salts, copper(II) salts, platinum(II) salts, palladium(II) salts, nickel(II) salts, iron(II) salts, and iron(III) salts. In some embodiments, the transition metal salt is selected from gold(III) salts, silver(I) salts, copper(II) salts, and iron(II) salts. In some embodiments, the transition metal salt is gold(III) chloride or iron(II) sulfate.

[0022] In some embodiments of the methods disclosed herein, the method further comprises stirring the final mixture for about 15 seconds to about 15 minutes. In some embodiments, the method further comprises removing the solvent from the final mixture. In some embodiments, the method further comprises isolating the composite particles from the final mixture. In some embodiments, the method is carried out entirely at ambient temperature. In some embodiments, the final mixture does not contain a reducing agent.

[0023] The present disclosure also provides a method of treating a liver disease or a peroxisomal disease in a subject in need of treatment, comprising administering to the subject a therapeutically effective amount of a composition described herein (e.g., a composition comprising a plurality of composite particles described herein). In some embodiments, the liver disease is a bile acid synthesis disorder or primary biliary cholangitis. In some embodiments, the liver disease is a bile acid synthesis disorder resulting from a single enzyme deficiency. In some embodiments, the peroxisomal disease is a Zellweger spectrum disorder.

[0024] The present disclosure also provides a method for non-surgical removal of localized fatty deposits in a subject, comprising contacting the deposits with an effective amount of a composition described herein (e.g., a composition comprising a plurality of composite particles described herein).

[0025] The present disclosure also provides a method for reducing subcutaneous fat deposits in a subject in need thereof, the method comprising locally administering to the subcutaneous fat deposits of the subject an effective amount of a composition described herein (e.g., a composition comprising a plurality of composite particles described herein).

[0026] The present disclosure also provides a method of treating cancer in a subject in need thereof, comprising administering to the subject an effective amount of a composition described herein (e.g., a composition comprising a plurality of composite particles described herein). In some embodiments, the cancer is colorectal cancer or gastric cancer.

[0027] The present disclosure also provides a method of inhibiting the proliferation of cancer cells, comprising contacting the cells with an effective amount of a composition described herein (e.g., a composition comprising a plurality of composite particles described herein). In some embodiments, the cancer cells are colorectal cancer cells or gastric cancer cells.

[0028] The present disclosure also provides a method of treating a disorder selected from the group consisting of an endocrine disorder, a rheumatic disorder, a collagen disease, a skin disease, an allergic condition, an eye disease, a respiratory disease, a blood disorder, a neoplastic disease, a gastrointestinal disease, a nervous system disorder, an inflammatory disorder, and a renal disease, comprising administering to a subject a therapeutically effective amount of a composition described herein (e.g., a composition comprising a plurality of composite particles described herein).

[0029] The present disclosure also provides uses of the particles and compositions described herein (e.g., for the removal of localized fat deposits, for reducing subcutaneous fat deposits in a subject, for use in treating cancer such as colorectal cancer, for use in inhibiting the proliferation of cancer cells, for use in treating a disorder selected from endocrine disorders, rheumatic disorders, collagen diseases, skin diseases, allergic conditions, eye diseases, respiratory diseases, blood disorders, neoplastic diseases, gastrointestinal diseases, nervous system disorders, inflammatory disorders, and renal diseases, etc.). [Brief description of the drawings]

[0030] [Figure 1A] FIG. 2 shows a scanning electron microscopy (SEM) image of composite particles prepared with cholate (prepared with gold(III) chloride) as a compound having a steroid core structure. [Figure 1B] FIG. 2 shows a scanning electron microscopy (SEM) image of composite particles prepared with a compound having a steroid core structure: deoxycholate (prepared with gold(III) chloride). [Figure 1C] FIG. 2 shows a scanning electron microscopy (SEM) image of composite particles prepared with methylprednisolone (prepared with gold(III) chloride), a compound with a steroid core structure. [Figure 1D] FIG. 1 shows a scanning electron microscopy (SEM) image of composite particles prepared with a compound having a steroid core structure: hydrocortisone (prepared with gold(III) chloride). [Diagram 2] 1 shows energy dispersive spectroscopy (EDS) data for cholate / gold ion particles prepared according to the methods disclosed herein. [Diagram 3](A) Bright field microscopy image of rhodamine-loaded cholate particles containing gold ions, and (B) fluorescence microscopy image of the same rhodamine-loaded cholate particles. [Figure 4] Shown are SEM images (A) and EDS data (B) of composite particles prepared using dexamethasone phosphate and iron (II) sulfate heptahydrate. [Diagram 5] 1 shows degradation data for composite particles prepared with dexamethasone phosphate and iron (II) sulfate heptahydrate. [Figure 6A] 1 shows SEM images of composite particles prepared from hydrochloric acid and sodium cholate. [Figure 6B] 1 shows an SEM image of composite particles prepared from hydrochloric acid and sodium deoxycholate. [Figure 6C] 1 shows an SEM image of composite particles prepared from hydrochloric acid and sodium chenodeoxycholate. [Figure 6D] 1 shows an SEM image of composite particles prepared from hydrochloric acid and sodium ursodeoxycholate. [Figure 7] 1 shows SEM images of composite particles prepared from hydrochloric acid and methylprednisolone succinate (A), and hydrochloric acid and hydrocortisone succinate (B). [Figure 8A] 1 shows SEM images of composite particles prepared from salicylic acid and sodium cholate. [Figure 8B] 1 shows an SEM image of composite particles prepared from salicylic acid and sodium deoxycholate. [Figure 8C] 1 shows an SEM image of composite particles prepared from salicylic acid and methylprednisolone succinate. [Figure 8D] 1 shows an SEM image of composite particles prepared from salicylic acid and sodium chenodeoxycholate. [Figure 8E] 1 shows SEM images of composite particles prepared from salicylic acid and hydrocortisone succinate. [Figure 8F] 1 shows an SEM image of composite particles prepared from salicylic acid and sodium ursodeoxycholate. [Figure 9]1 shows UV-Vis spectroscopy data showing salicylic acid release from deoxycholate particles. [Figure 10A] FIG. 1 shows SEM images of cholate / gold ion particles when exposed to the degradation protocol detailed in Example 2: cholate / gold ion particles prepared according to the methods disclosed herein at days 0, 1, 3, 5, 10, and 15 of the degradation protocol. [Figure 10B] 1 shows SEM images of cholate / gold ion particles when exposed to the degradation protocol detailed in Example 2: comparative cholate / gold(0) nanoparticles prepared according to the method disclosed above at days 0, 1, 3, 5, 10, and 15 of the degradation protocol. [Figure 11] 1 shows data regarding the release of cholate from particles subjected to a degradation process. [Figure 12] 1 shows dynamic light scattering (DLS) data demonstrating the presence of gold nanoparticles following degradation of cholate particles prepared according to the methods disclosed above. [Figure 13] 1 shows UV-Vis spectroscopy data for detecting gold nanoparticles following degradation of deoxycholate particles prepared according to the methods disclosed herein and previously disclosed methods. [Figure 14] 1 shows images of samples subjected to the gold nanoparticle formation process. [Figure 15] 1 shows images of samples in which beef tallow was incubated with particles disclosed herein to produce cell lysis: (A) shows a negative control and a positive control, and (B) shows a negative control and a sample incubated with the indicated particles, with arrows pointing to lipid droplets in each case. [Figure 16] 1 shows the results of a cell viability assay when HT-29 colon cancer cells are incubated with composite particles as described herein. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0031] The present disclosure relates to particles that can be used for the controlled release of compounds having a steroid core structure or their salts.The particles can be used in various medical and dermatological treatments, such as the treatment of liver damage and the non-surgical removal of localized fatty deposits.The particles can also be used in the treatment of cancer or in methods of inhibiting the proliferation of cancer cells.

[0032] Previous work in the manufacture of composite particles has required the formation of transition metal (e.g., gold) nanoparticles to produce particles composed of bile salts. See, for example, International Patent Publication No. WO2021 / 011753. The nanoparticles were present in the sample as a result of a manufacturing process that reduced a transition metal precursor to form elemental transition metal nanoparticles in situ. A heating step was used to effect reduction of the transition metal ions, and the particles were formed in solution in parallel with the transition metal nanoparticles.

[0033] The composite particles disclosed herein do not include transition metal nanoparticles. Rather, the particles are produced from a solution containing either transition metal ions or an acid, and do not require a reduction step to template particle formation. Without wishing to be limited by theory, it is believed that the particles disclosed herein are formed as a result of establishing an appropriate pH in the solution or emulsion, which can be achieved using a solution of either an acid or a transition metal salt that forms an acidic solution when dissolved in water. In some embodiments (e.g., when transition metal ions are used), the particles can be formed as a result of complexation of the transition metal ion with a compound having a steroid backbone. The particles can be prepared in several ways, none of which include a reducing agent or a heating step such that transition metal nanoparticles are not formed.

[0034] composite particles In one aspect, the present disclosure provides a composite particle comprising a compound having a steroid core structure, or a salt or ester thereof, wherein at least one dimension has a length of at least 100 nm. In some embodiments, the particle further comprises a transition metal ion (e.g., from a transition metal salt). In some embodiments, the particle further comprises an acid.

[0035] The composite particles include compounds having the steroid core structures shown below, with conventional numbering of the perhydrocyclopenta[a]phenanthrene core. [ka]

[0036] The steroid core structure may be fully saturated as shown above, or may contain one or more double bonds. The core structure may contain one or more alkyl functional groups, for example, steroid compounds contain methyl groups at C10 and C13, and often an alkyl group (or functionalized alkyl group) at C17. The core structure may also contain one or more hydroxy or oxo groups, for example, steroids and sterols have an oxo or hydroxy group at C3.

[0037] In some embodiments, the compound having a steroid core structure is testosterone (e.g., testosterone enanthate, testosterone cypionate, or testosterone undecanoate), exemestane, formestane, mesterolone, fluoxymesterone, methyltestosterone, oxandrolone, oxymetholone, mestranol, norethindrone, danazol, gestrinone, levonorgestrel, lynestrenol, norgestrel, desogestrel, etonogestrel, tibolone, ethynodiol (e.g., ethynodiol diacetate), cyproterone, megestrol (e.g., megestrol acetate), abiraterone (e.g., abiraterone acetate), dienogest, mifepristone, drospirenone, spironolactone, estradiol, polyestradiol phosphate, estramustine (e.g., estramustine phosphate), estrone, estropipate, progesterone, dydrogesterone, Hydroxyprogesterone (e.g., hydroxyprogesterone caproate), medroxyprogesterone (e.g., medroxyprogesterone acetate), segesterone (e.g., segesterone acetate), norelgestromin, norgestimate, cortisol, cortisone, fluorometholone, difluprednate, fludrocortisone (e.g., fludrocortisone acetate), fluocinolone (e.g., fluocinolone acetonide), loteprednol (e.g., loteprednol etabonate), methylprednisolone (e.g., methylprednisolone acetate or methylprednisolone succinate), prednicarbate, prednisolone (e.g., prednisolone sodium phosphate or prednisolone acetate), prednisone, triamcinolone (e.g., triamcinolone acetonide or triamcinolone hexacetonide), alclometasone (e.g., alclometasone dipropionate),diproprionate), betamethasone (e.g., betamethasone sodium phosphate, betamethasone benzoate, betamethasone dipropionate, betamethasone valerate, or betamethasone acetate), clobetasol (e.g., clobetasol propionate), clobetasone (e.g., clobetasone butyrate), clocortolone (e.g., clocortolone pivalate), desoximetasone, dexamethasone (e.g., dexamethasone phosphate or dexamethasone sodium phosphate), diflorasone (e.g., diflorasone diacetate), difluocortolone, fluticasone (fluticasone propionate or fluticasone furoate), halometasone, mometasone (e.g., mometasone furoate), rimexolone, amcinonide, budesonide, ciclesonide, deflazacort, desonide, flunisolide , fluocinonide, halcinonide, cholesterol, estradiol valerate, hydrocortisone (e.g., hydrocortisone acetate, hydrocortisone buteprate, hydrocortisone butyrate, hydrocortisone succinate, or hydrocortisone valerate), diflucortolone (e.g., diflucortolone valerate), boldenone (e.g., boldenone undecylenate), nandrolone, altrenogest, stanozolol, osaterone (e.g., osaterone acetate), estriol, aglepristone, trilostane, flumethasone, deoxycorticosterone, alphaxalone, desoxycorticosterone (e.g., desoxycorticosterone pivalate), and isoflupredone (e.g., isoflupredone acetate), or any combination thereof.

[0038] In some embodiments, the composite particles include a compound having a steroid core structure, or a salt or ester thereof, in an amount of about 70% to about 99% by weight, or about 80% to about 95% by weight. For example, in some embodiments, the composite particles include a compound having a steroid core structure, or a salt or ester thereof, in an amount of about 70% by weight, 71% by weight, 72% by weight, 73% by weight, 74% by weight, 75% by weight, 76% by weight, 77% by weight, 78% by weight, 79% by weight, 80% by weight, 81% by weight, 82% by weight, 83% by weight, 84% by weight, 85% by weight, 86% by weight, 87% by weight, 88% by weight, 89% by weight, 90% by weight, 91% by weight, 92% by weight, 93% by weight, 94% by weight, 95% by weight, 96% by weight, 97% by weight, 98% by weight, or 99% by weight, or any range therebetween.

[0039] In some embodiments, the compound having a steroid core structure is a bile acid, or a salt or ester thereof. In such embodiments, the present disclosure provides a composite particle comprising a bile acid, or a salt or ester thereof, wherein at least one dimension has a length of at least 100 nm. In some embodiments, the complex further comprises a transition metal ion and / or an acid. In some embodiments, the present disclosure provides a composite particle comprising a bile acid, or a salt or ester thereof, and a gold ion (e.g., Au(III) ion) or an iron ion (e.g., Fe(II) ion). In some embodiments, the present disclosure provides a composite particle comprising a bile acid, or a salt or ester thereof, and an acid (e.g., hydrochloric acid or salicylic acid).

[0040] Bile acids are steroid acids found primarily in bile, including both primary bile acids synthesized in the liver and secondary bile acids synthesized from primary bile acids by bacteria in the colon. Bile acids and their salts help solubilize lipids in the small intestine and regulate liver, bile duct, and intestinal function; they have been proposed as therapeutic agents for treating a variety of conditions, including bile acid synthesis disorders and peroxisomal diseases, primary biliary cholangitis, primary sclerosing cholangitis, cardiometabolic diseases, gallstones and bile duct stones, nonalcoholic fatty liver disease, type 2 diabetes, human immunodeficiency virus type 1 (HIV-1), acute pancreatitis, and cancer.

[0041] Orally administered formulations of certain bile acids have been approved by the US Food and Drug Administration (FDA) for the treatment of various bile synthesis disorders and liver dysfunction. For example, cholic acid capsules have been approved for the treatment of bile acid synthesis disorders and peroxisomal diseases, and ursodeoxycholic acid tablets and obeticholic acid tablets have both been approved for the treatment of primary biliary cholangitis. However, oral administration of these agents may limit their bioavailability and may pose a risk of cytotoxicity through their membrane-disrupting properties. In addition, injectable deoxycholic acid has been approved by the US FDA for the destruction of fat cells to reduce moderate to severe submental fat. However, multiple injections are required for effective treatment. The formulation of bile acids in composite particles disclosed herein provides controlled or targeted delivery of bile acids that increases specificity while reducing side effects.

[0042] Bile acids may be conjugated with taurine or glycine. Exemplary bile acids include cholic acid, deoxycholic acid, chenodeoxycholic acid, lithocholic acid, glycocholic acid, taurocholic acid, glycodeoxycholic acid, taurodeoxycholic acid, glycochenodeoxycholic acid, taurochenodeoxycholic acid, glycolithocholic acid, taurolithocholic acid, ursodeoxycholic acid, glycoursodeoxycholic acid, and tauroursodeoxycholic acid. Bile acids also include semi-synthetic bile acids, such as obeticholic acid. In some embodiments, the bile acid is selected from cholic acid, deoxycholic acid, ursodeoxycholic acid, and chenodeoxycholic acid. In some embodiments, the bile acid is selected from cholic acid and deoxycholic acid. In some embodiments, the bile acid is cholic acid. In some embodiments, the bile acid is deoxycholic acid. In some embodiments, the composite particles comprise a combination of two or more bile acids or salts thereof.

[0043] The bile acid may be in the form of a salt. In some embodiments, the bile salt is a sodium salt or a potassium salt. In some embodiments, the bile salt is a sodium salt. Thus, in some embodiments, the particles comprise a bile salt selected from sodium cholate, sodium deoxycholate, sodium ursodeoxycholate, and sodium chenodeoxycholate. In some embodiments, the particles comprise a bile salt selected from sodium cholate and sodium deoxycholate. In some embodiments, the bile salt is sodium cholate. In some embodiments, the bile salt is sodium deoxycholate. In some embodiments, the bile salt is sodium ursodeoxycholate. In some embodiments, the bile salt is sodium chenodeoxycholate.

[0044] In some embodiments, the composite particles include bile acids or salts or esters thereof in an amount of about 70% to about 99% by weight, or about 80% to about 95% by weight. For example, in some embodiments, the composite particles include bile acids or salts or esters thereof in an amount of about 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% by weight, or any range therebetween.

[0045] In some embodiments, the compound having a steroid core structure is a corticosteroid or a salt or ester thereof. In such embodiments, the present disclosure provides a composite particle comprising a corticosteroid, or a salt or ester thereof, having at least one dimension having a length of at least 100 nm. In some embodiments, the composite particle further comprises a transition metal ion and / or an acid. In some embodiments, the present disclosure provides a composite particle comprising a corticosteroid, or a salt or ester thereof, and a gold ion (e.g., Au(III) ion) or an iron ion (e.g., iron(II) ion).

[0046] Corticosteroids are a class of steroid hormones produced in the adrenal cortex of vertebrates, as well as synthetic analogs of such hormones. The two main categories of corticosteroids are glucocorticoids and mineralocorticoids. These compounds are involved in a wide range of physiological processes, including stress response, immune response, and regulation of inflammation, carbohydrate metabolism, protein catabolism, blood electrolyte levels, and behavior.

[0047] Corticosteroids are generally divided into four classes: Group A (hydrocortisone-type), such as hydrocortisone (e.g., hydrocortisone acetate, hydrocortisone aceponate, hydrocortisone buteprate, hydrocortisone butyrate, hydrocortisone cypionate, or hydrocortisone succinate), cortisone (e.g., cortisone acetate), tixocortol (e.g., tixocortol pivalate), prednisolone, methylprednisolone (e.g., methylprednisolone succinate), and prednisone; Group B (acetonides and related compounds), such as amcinonide, budesonide, desonide, fluocinolone (e.g., fluocinolone acetonide), fluocinonide, halcinonide, and triamcinolone ( Group C (betamethasone type), such as beclomethasone, betamethasone, dexamethasone, fluocortolone, halometasone, and mometasone; and Group D (esters), such as Group D1 halogenated esters (alclometasone dipropionate, betamethasone dipropionate, betamethasone valerate, clobetasol propionate, clobetasone butyrate, fluprednidene acetate, and mometasone furoate), and Group D2 labile prodrug esters (ciclesonide, cortisone acetate, hydrocortisone aceponate, hydrocortisone acetate, hydrocortisone buteprate, hydrocortisone butyrate, hydrocortisone valerate, prednicarbate, and tixocortol pivalate). In some embodiments, the corticosteroid is hydrocortisone (e.g., hydrocortisone acetate, hydrocortisone aceponate, hydrocortisone buteprate, hydrocortisone butyrate, hydrocortisone cypionate, or hydrocortisone succinate), dexamethasone (e.g., dexamethasone phosphate), beclomethasone (e.g., beclomethasone dipropionate), ciclesonide, clobetasol (e.g., clobetasol propionate or clobetasol valerate), clobetasone (e.g., clobetasone butyrate), desonide, desoxymethasone, desoxycorticosterone (e.g., desoxycorticosterone acetate), dichlorisone, diflorasone (e.g., diflorasone diacetate), diflucortolone (e.g., diflucortolone valerate),fluadrenolone, fluclarolone (e.g. fluclarolone acetonide), fludrocortisone (e.g. fludrocortisone acetate), flumethasone (e.g. flumethasone pivalate), fluocinolone (e.g. fluocinolone acetonide), fluocinonide, flucortine (e.g. flucortine butyl ester), fluocortolone, fluprednidene (e.g. fluprednidene acetate), flurandrenolone, halcinonide, halometasone, methylprednisolone (e.g. methylprednisolone succinate), triamcinolone (e.g. triamcinolone acetonide), cortisone (e.g. cortisone acetate), cortodoxone, flucetonide, fluradrenaline (e.g. fluradrenaline acetonide), acetonide), medrysone, alclometasone (e.g., alclometasone dipropionate), amciafel, amcinafide, amcinonide, betamethasone (e.g., betamethasone dipropionate or betamethasone valerate), budesonide, chlorprednisone (e.g., chlorprednisone acetate), clocortelone, clesinolone, difluprednate, flucloronide, flunisolide, fluoromethalone, fluperolone, fluprednisolone, hydrocortamate, meprednisone, mometasone (e.g., mometasone furoate), paramethasone, prednisolone, prednisone, prednicarbate, and tixocortol (e.g., tixocortol pivalate). In some embodiments, the corticosteroid is selected from dexamethasone (e.g., dexamethasone phosphate), methylprednisolone (e.g., methylprednisolone succinate), and hydrocortisone (e.g., hydrocortisone succinate).

[0048] In some embodiments, the composite particles include a corticosteroid or salt or ester thereof in an amount of about 70% to about 99% by weight, or about 80% to about 95% by weight. For example, in some embodiments, the composite particles include a bile acid or salt or ester thereof in an amount of about 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% by weight, or any range therebetween.

[0049] The compounds having a steroid core structure may be in the form of a salt. For example, the compounds having a steroid core structure may be salted with a suitable cation, such as an alkali metal cation (e.g., sodium, lithium, potassium), an ammonium cation (e.g., NR4 + The steroid core structure may have one or more acidic moieties (e.g., carboxylates) capable of forming salts with, for example, 1,2,3,4,5,6,7,8,8,9,10,11,12,13,14,15,16,17,18,19 ...20,21,22,23,24,25,26,27,28,29,30,31,32,33,34,35,36,37,38,39,40,41,42,43,44,45,50,51,52,53,60,61,72,73,74,75,86,87,98,99,90,91,92,93,94,95,96,97,98,99,91,92,94,95,99,91,95,96,97,98,99,91,92,94,95,98,99,91,92,95,96,97,98,99,91,92,93,94,95,98,99,9 Compounds with a steroid core structure often have two adjacent hydroxy groups that can form a cyclic acetal to form an acetonide (eg, acetone, especially at the C16 and C17 positions).

[0050] In addition to the compound having a steroid core structure (or a salt or ester thereof), in some embodiments, the particle further comprises a transition metal ion. In some embodiments, the particle comprises a gold ion, a silver ion, a copper ion, a platinum ion, a palladium ion, a nickel ion, or an iron ion. In some embodiments, the particle comprises a gold ion, a silver ion, a copper ion, or an iron ion. In some embodiments, the particle comprises a gold (III) ion, a silver (I) ion, a copper (II) ion, a nickel (II) ion, a palladium (II) ion, a platinum (II) ion, an iron (II) ion, or an iron (III) ion. In some embodiments, the particle comprises a gold ion (e.g., a Au (III) ion) or an iron ion (e.g., a Fe (II) ion).

[0051] The transition metal ion may be present in the particle in an amount of about 1% to about 30% by weight, or about 5% to about 20% by weight. For example, in some embodiments, the composite particle includes the transition metal ion in an amount of about 1%, about 2%, about 3%, about 4%, about 5%, about 6%, about 7%, about 8%, about 9%, about 10%, about 11%, about 12%, about 13%, about 14%, about 15%, about 16%, about 17%, about 19%, about 20%, about 21%, about 22%, about 23%, about 24%, about 25%, about 26%, about 27%, about 28%, about 29%, or about 30% by weight, or any range therebetween.

[0052] In some embodiments, in addition to the compound having a steroid core structure (or a salt or ester thereof), the particle further comprises an acid. The acid can be an inorganic acid or an organic acid. Examples of suitable inorganic acids include, but are not limited to, hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, sulfurous acid, nitric acid, nitrous acid, phosphoric acid, and phosphorous acid. Examples of suitable organic acids include, but are not limited to, 2-acetyoxybenzoic, acetic, ascorbic, aspartic, benzoic, camphorsulfonic, cinnamic, citric, edetic, ethanedisulfonic, ethanesulfonic, fumaric, glucoheptonic, gluconic, glutamic, glycolic, hydroxymaleic, hydroxynaphthalenecarboxylic, isethionic, lactic, lactobionic, lauric, maleic, malic, methanesulfonic, mucic, oleic, oxalic, palmitic, pamoic, pantothenic, phenylacetic, phenylsulfonic, propionic, pyruvic, salicylic, stearic, succinic, sulfanilic, tartaric, tetrafluoroboric, toluenesulfonic, trifluoroacetic, trifluoromethanesulfonic, and valeric acid. In some embodiments, the acid is hydrochloric acid, hi some embodiments, the acid is salicylic acid.

[0053] In some embodiments, the particles disclosed herein are essentially free of transition metal nanoparticles (i.e., transition metal nanoparticles in which the transition metal is in the zero oxidation state (i.e., not a salt), e.g., gold nanoparticles). This feature distinguishes the particles disclosed herein from the aforementioned composite particles comprising compounds having a steroid core structure, such as those disclosed in International Patent Publication No. WO2021 / 011753, formed using a double emulsion method. As used herein, the phrase "essentially free" of transition metal nanoparticles means that the nanoparticles comprise less than 0.5% by weight of transition metal nanoparticles, or less than 0.2% by weight, or less than 0.1% by weight, or 0% by weight of transition metal nanoparticles. In some embodiments, the particles do not comprise any detectable amount of metal nanoparticles.

[0054] Composite particles can be prepared by a variety of methods. For example, in a first method for making a plurality of composite particles, the method comprises: (a) providing a first solution comprising a transition metal salt in ethyl acetate; (b) mixing the first solution with water to form a first emulsion; and (c) mixing the first emulsion with a second solution comprising a compound having a steroid core structure or a salt or ester thereof to form a final mixture, thereby forming the composite particles. Includes.

[0055] In a second method for making a plurality of composite particles, the method includes: (a) providing a first solution comprising a compound having a steroid core structure, or a salt or ester thereof, in ethyl acetate; (b) combining the first solution with a transition metal salt to form a second solution; (c) mixing the second solution with water to form a first emulsion; (d) mixing the first emulsion with a solution of a compound having a steroid core structure or a salt or ester thereof in water to form a final mixture, thereby forming the composite particles. Includes.

[0056] In a third method for making a plurality of composite particles, the method includes: (a) providing a first solution comprising a transition metal salt in water; (b) combining the first solution with ethyl acetate to form a first emulsion; (c) mixing the first emulsion with a solution of a compound having a steroid core structure or a salt or ester thereof in water to form a final mixture, thereby forming the composite particles. Includes.

[0057] In a fourth method for making a plurality of composite particles, the method includes: (a) providing a first solution comprising an acid, a compound having a steroid core structure or a salt or ester thereof, and water; (b) combining the first solution with ethyl acetate to form a first emulsion; (c) mixing the first emulsion with a solution of an acid in water to form a final mixture, thereby forming the composite particles. Includes.

[0058] In a fifth method for making a plurality of composite particles, the method includes: (a) providing a first solution comprising an acid in ethyl acetate; (b) combining the first solution with a second solution comprising a compound having a steroid core structure or a salt or ester thereof and water to form a first emulsion; (c) mixing the first emulsion with a third solution containing a compound having a steroid core structure or a salt or ester thereof and water to form a final mixture, thereby forming the composite particles. Includes.

[0059] In some embodiments of the first, second, and third methods, the transition metal salt is a gold(III) salt, a silver(I) salt, a copper(II) salt, a nickel(II) salt, a palladium(II) salt, a platinum(II) salt, an iron(II) salt, or an iron(III) salt. In some embodiments, the transition metal salt is a gold(III) salt. In some embodiments, the transition metal salt is gold(III) chloride. In some embodiments, the transition metal salt is an iron(II) salt. In some embodiments, the transition metal salt is iron(II) sulfate. In some embodiments, the transition metal salt is a silver(I) salt. In some embodiments, the transition metal salt is silver(I) nitrate. In some embodiments, the transition metal salt is a copper(II) salt. In some embodiments, the transition metal salt is copper(II) chloride.

[0060] In some embodiments of the first, second, third, fourth, and fifth methods, the compound having a steroid core structure is a bile acid or a salt or ester thereof. In some embodiments, the bile acid is selected from cholic acid, deoxycholic acid, chenodeoxycholic acid, lithocholic acid, glycocholic acid, taurocholic acid, glycodeoxycholic acid, taurodeoxycholic acid, glycochenodeoxycholic acid, taurochenodeoxycholic acid, glycolithocholic acid, taurolithocholic acid, ursodeoxycholic acid, glycoursodeoxycholic acid, tauroursodeoxycholic acid, and obeticholic acid. In some embodiments, the bile acid is selected from cholic acid, deoxycholic acid, ursodeoxycholic acid, and chenodeoxycholic acid. In some embodiments, the compound having a steroid core structure is a bile salt. In some embodiments, the bile salt is a sodium salt or a potassium salt. In some embodiments, the bile salt is a sodium salt. Thus, in some embodiments, the bile salt is selected from sodium cholate, sodium deoxycholate, sodium ursodeoxycholate, and sodium chenodeoxycholate. In some embodiments, the bile salt is selected from sodium cholate and sodium deoxycholate. In some embodiments, the bile salt is sodium cholate. In some embodiments, the bile salt is sodium deoxycholate. In some embodiments, the bile salt is sodium ursodeoxycholate. In some embodiments, the bile salt is sodium chenodeoxycholate.

[0061] In some embodiments of the first, second, third, fourth, and fifth methods, the compound having a steroid core structure is a corticosteroid compound or a salt or ester thereof. In some embodiments, the corticosteroid compound is selected from dexamethasone, methylprednisolone, and hydrocortisone, or an ester thereof. In some embodiments, the corticosteroid compound is dexamethasone or an ester thereof. In some embodiments, the corticosteroid compound is methylprednisolone or an ester thereof. In some embodiments, the corticosteroid compound is hydrocortisone or an ester thereof.

[0062] In some embodiments of the first, second, third, fourth, and fifth methods, the composite particles are formed immediately after the formation of the final mixture. In other embodiments, the first, second, and third methods further include a step of stirring the final mixture. In some embodiments, the final mixture is stirred for about 1 second to about 15 minutes, during which the composite particles are formed. For example, the stirring step can include stirring the final mixture for about 5 seconds, about 10 seconds, 15 seconds, about 30 seconds, about 45 seconds, about 60 seconds, about 2 minutes, about 3 minutes, about 4 minutes, about 5 minutes, about 6 minutes, about 7 minutes, about 8 minutes, about 9 minutes, about 10 minutes, about 11 minutes, about 12 minutes, about 13 minutes, about 14 minutes, or about 15 minutes.

[0063] The first, second, third, fourth, and fifth methods may further include a further step of separating the composite particles from the mixture. The separation step may include filtering using a filter with an appropriate pore size. The separation step may alternatively or additionally include centrifugation. For example, centrifugation (e.g., 100-5000 rpm, e.g., 100, 200, 300, 400, 500, 600, 700, 800, 900, 1000, 1500, 2000, 2500, 3000, 3500, 4000, 4500, or 5000 rpm) may effectively separate the composite particles from other components. The composite particles may be collected in a pellet by centrifugation.

[0064] In some embodiments of the first, second, third, fourth, and fifth methods, the method does not include a heating step. Compared to other methods of preparing composite particles containing metal nanoparticles that involve the use of a reducing agent to form transition metal nanoparticles and require a heating step to reduce transition metal ions to their elemental state, the methods disclosed herein do not require a reducing step and therefore do not require a heating step. In some embodiments of the first, second, and third methods, the method is carried out at ambient temperature.

[0065] Similarly, in the first, second, third, fourth, and fifth methods, the composition does not include a reducing agent (e.g., sodium citrate or sodium ascorbate), which is not necessary because the composite particles are formed without templating by the formation of transition metal nanoparticles.

[0066] In some embodiments, the method further comprises removing the solvent from the final mixture after the incubation step. The solvent can be removed using a variety of methods, such as evaporation at ambient temperature and pressure, or evaporation by heating, or evaporation under reduced pressure. In some embodiments, the solvent is removed by evaporation at ambient temperature and pressure.

[0067] Specific methods for making the composite particles disclosed herein are described in the Examples. In some embodiments, provided herein are particles produced by any of the above methods.

[0068] In some embodiments, the composite particles consist essentially of a compound having a steroid core structure, or a salt or ester thereof, and a transition metal ion. In some embodiments, the particles consist essentially of a bile acid, or a salt or ester thereof, and a gold ion, a silver ion, a copper ion, a platinum ion, a palladium ion, a nickel ion, or an iron ion. In some embodiments, the composite particles consist essentially of a bile acid, or a salt or ester thereof, and a gold ion, a silver ion, a copper ion, or an iron ion. In some embodiments, the composite particles consist essentially of a bile acid, or a salt or ester thereof, and a gold ion (e.g., an Au(III) ion) or an iron ion (e.g., an iron(II) ion). In some embodiments, the composite particles consist essentially of a corticosteroid, or a salt or ester thereof, and a transition metal ion. In some embodiments, the particles consist essentially of a corticosteroid, or a salt or ester thereof, and a gold ion, a silver ion, a copper ion, a platinum ion, a palladium ion, a nickel ion, or an iron ion. In some embodiments, the composite particles consist essentially of a corticosteroid, or a salt or ester thereof, and gold, silver, copper, or iron ions. In some embodiments, the composite particles consist essentially of a corticosteroid, or a salt or ester thereof, and gold ions (e.g., Au(III) ions) or iron ions (e.g., iron(II) ions). In such embodiments, the composite particles are free or substantially free of other components, such as small molecules, polymers, etc.

[0069] In some embodiments, the composite particles consist essentially of a compound having a steroid core structure, or a salt or ester thereof, and an acid. In some embodiments, the particles consist essentially of a bile acid, or a salt or ester thereof, and an acid selected from hydrochloric acid and salicylic acid. In some embodiments, the composite particles consist essentially of a corticosteroid, or a salt or ester thereof, and an acid. In some embodiments, the particles consist essentially of a corticosteroid, or a salt or ester thereof, an acid selected from hydrochloric acid and salicylic acid. In such embodiments, the composite particles are free or substantially free of other components, such as metal nanoparticles, metal ions, small molecules, polymers, etc.

[0070] In some embodiments, the composite particle does not include a polymer. For example, the composite particle does not include a polymer, such as a polyester, including poly(lactic-co-glycolic acid) (PLGA), or an anionic polymer, such as a polysaccharide (e.g., dextran sulfate, heparin, heparin sulfate, chondroitin sulfate, hyaluronic acid, or alginic acid), a nucleic acid polymer, etc. For example, in the composite particle of the present disclosure, the compound having a steroid core structure (e.g., bile acid or corticosteroid) is not bound to the polymer. In some embodiments, the composite particle does not include phosphatidylcholine.

[0071] In other embodiments, the particle may further comprise other components. For example, in some embodiments, the particle further comprises a targeting ligand. Targeting ligands are well known to those skilled in the art, and exemplary targeting ligands are described in Srinivasarao et al. "Ligand-Targeted Drug Delivery", Chem.Rev.2017,117(19),12133-12164 (herein incorporated by reference). Exemplary targeting ligands include antibodies against molecules expressed on cell surface, for example, certain lipoma cells are known to overexpress CD34, and anti-CD34 antibodies can be used as targeting ligands for these cells.

[0072] In other embodiments, the particles further comprise an additional therapeutic agent. Any suitable therapeutic agent can be used. Exemplary therapeutic agents include those described in Harrison's Principles of Internal Medicine, 20th Edition, Eds. JL Jameson et al., McGraw-Hill Education (2018); Physicians' Desk Reference, 71st Edition, PDR Network (2017); and Goodman & Gilman's The Pharmacological Basis of Therapeutics, 13 th Edition, Eds. L.L. Brunton et al., 2017; United States Pharmacopeia-The National Formulary, USP 42-NF 37, 2019, the contents of each of which are incorporated herein by reference.

[0073] The composite particles can be characterized by a wide variety of techniques. For example, the particles can be imaged using scanning electron microscopy (SEM) to determine their size and shape. The elemental composition can be confirmed using elemental analysis, for example, using energy dispersive spectroscopy (EDS) and / or X-ray photoelectron spectroscopy (XPS). The presence of bile acids can be further confirmed using techniques such as high performance liquid chromatography (HPLC), Fourier transform infrared (FTIR) spectroscopy, and nuclear magnetic resonance (NMR) spectroscopy.

[0074] In some embodiments, the composite particles have a hexagonal prism shape. Such particles can be characterized by their diagonal length, i.e., the length between two opposite vertices of a hexagon, and their height. In some embodiments, the composite particles have a hexagonal prism shape with an average diagonal length of about 2.5 μm to about 10 μm, or about 3.0 μm to about 9.0 μm (e.g., about 2.5, 3.0, 3.5, 4.0, 4.5, 5.0, 5.5, 6.0, 6.5, 7.0, 7.5, 8.0, 8.5, 9.0, 9.5, or 10 μm, or any range therebetween). In some embodiments, the composite particles have a hexagonal prism shape with an average height of about 2.5 μm to about 6.5 μm (e.g., about 2.5, 3.0, 3.5, 4.0, 4.5, 5.0, 5.5, 6.0, or 6.5 μm, or any range therebetween).

[0075] In some embodiments, the composite particles have a rod shape. In some embodiments, the composite particles have a rod shape with an average length of about 2.5 μm to about 100 μm, or about 10 μm to about 50 μm (e.g., about 2.5, 5.0, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, or 100 μm, or any range therebetween).

[0076] In some embodiments, the composite particles have a hexagonal sheet shape. Such particles can be characterized by the length of the long and short sides of the sheet. In some embodiments, the composite particles have a hexagonal sheet shape with an average long side length of about 10 μm to about 50 μm (e.g., about 10, 15, 20, 25, 30, 35, 40, 45, or 50 μm, or any range therebetween) and a short side length of 5 μm to 20 μm (e.g., about 5, 7.5, 10, 12.5, 15, 17.5, or 20 μm, or any range therebetween).

[0077] In some embodiments, the composite particles have a spherical shape. In some embodiments, the spheres have a diameter of 1 μm to 10 μm (e.g., about 1 μm, about 2 μm, about 3 μm, about 4 μm, about 5 μm, about 6 μm, about 7 μm, about 8 μm, about 9 μm, or about 10 μm, or any range therebetween).

[0078] composition In another aspect, the present disclosure provides a composition comprising a plurality of the composite particles described herein. In some embodiments, the composition further comprises a pharma- ceutically acceptable carrier.

[0079] As used herein, the term "pharmaceutically acceptable carrier" refers to a pharmaceutically acceptable substance, composition, or vehicle for administering an active agent described herein. Pharmaceutically acceptable carriers include any solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents, etc., that are compatible with the activity of the bile acid or its salt or ester and are physiologically acceptable to the subject. Some examples of substances which may function as pharma- ceutically acceptable carriers include: (i) sugars, such as lactose, glucose, and sucrose; (ii) starches, such as corn starch and potato starch; (iii) cellulose and its derivatives, such as sodium carboxymethylcellulose, methylcellulose, ethylcellulose, microcrystalline cellulose, and cellulose acetate; (iv) powdered tragacanth; (v) malt; (vi) gelatin; (vii) lubricants, such as magnesium stearate, sodium lauryl sulfate, and talc; (viii) excipients, such as cocoa butter and suppository wax; (ix) oils, such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil, and soybean oil; (x) glycols, such as propylene glycol; (xi) polysaccharides, such as cellulose acetate; Examples of suitable non-toxic compatible materials include glycerol, sorbitol, mannitol, and polyethylene glycol (PEG); (xii) esters, such as ethyl oleate and ethyl laurate; (xiii) agar; (xiv) buffers, such as magnesium hydroxide and aluminum hydroxide; (xv) alginic acid; (xvi) pyrogen-free water; (xvii) isotonic saline; (xviii) Ringer's solution; (xix) ethyl alcohol; (xx) pH buffers; (xxi) polyesters, polycarbonates, and / or polyanhydrides; (xxii) bulking agents, such as polypeptides and amino acids; (xxiii) serum components, such as serum albumin, HDL, and LDL; (xxiv) C2-C12 alcohols, such as ethanol; and (xxv) other non-toxic compatible materials used in pharmaceutical formulations. Wetting agents, coloring agents, release agents, coating agents, sweeteners, flavoring agents, fragrances, preservatives, and antioxidants may also be present in the formulation.

[0080] For the orally administered preparations described herein, pharma- ceutically acceptable carriers include, but are not limited to, pharma- ceutically acceptable excipients, such as inert diluents, disintegrants, binders, lubricants, sweeteners, flavorings, colorings, and preservatives.Suitable inert diluents include sodium and calcium carbonate, sodium and calcium phosphate, and lactose, while corn starch and alginic acid are suitable disintegrants.Binders can include starch and gelatin, while lubricants, if present, are generally magnesium stearate, stearic acid, or talc.If necessary, tablets can be coated with a material such as glyceryl monostearate or glyceryl distearate to delay absorption in the gastrointestinal tract.

[0081] The pharma- ceutically acceptable carrier may vary in the formulations described herein depending on the route of administration. The formulations described herein may be delivered via any mode of administration known to those skilled in the art. For example, the formulations described herein may be delivered systemically via oral and parenteral routes of administration, including, but not limited to, intravenous, intramuscular, intraperitoneal, intradermal, and subcutaneous. In some embodiments, the formulations described herein are in a form suitable for injection, particularly subcutaneous injection. In other embodiments, the formulations described herein are formulated for oral administration, for example, into tablets or capsules.

[0082] For parenteral administration, the preparations described herein can generally be formulated in a single injectable dosage form (solution, suspension, emulsion). Preparations suitable for injection include sterile aqueous solutions or dispersions. The carrier can be a solvent or dispersion medium containing, for example, water, a buffer solution (e.g., phosphate buffered saline), a polyol (e.g., glycerol, propylene glycol, liquid polyethylene glycol, etc.), a salt (e.g., sodium chloride), or a suitable mixture thereof. In some embodiments, the pharmaceutical carrier can be saline. In some embodiments, the pharmaceutical carrier can be a buffer solution (e.g., PBS). If necessary, the composition can also include a solubilizing agent and a local anesthetic, such as lignocaine, to ease pain at the site of the injection.

[0083] The formulations may also contain auxiliary substances such as wetting or emulsifying agents, pH buffering agents, gelling or viscosity enhancing additives, preservatives, coloring agents, etc., depending on the route of administration and the preparation desired. Standard texts such as "REMINGTON'S PHARMACEUTICAL SCIENCE", 17th edition, 1985 (incorporated herein by reference) can be consulted to prepare suitable formulations without undue experimentation. However, with respect to the formulations described herein, any vehicle, diluent, or additive used must be biocompatible with the active agent described herein. Those skilled in the art will recognize that the components of the formulation should be selected to be biocompatible with the active agent. This is either not a problem for those skilled in the art of chemical and pharmaceutical principles or can be easily avoided by reference to standard texts or simple experimentation (without undue experimentation).

[0084] For in vivo administration, the formulations described herein can be administered by a delivery device, such as a syringe.Accordingly, a further aspect described herein provides a delivery device comprising at least one chamber with an outlet, the at least one chamber containing a quantity of any formulation described herein, and the outlet providing an outlet for the formulation enclosed in the chamber.In some embodiments, the delivery device described herein can further comprise an actuator for controlling the release of the formulation through the outlet.Such a delivery device can be any device for facilitating the administration of any formulation described herein to a subject, for example, a syringe, a dry powder injector, a nasal spray, a nebulizer, or an implant such as a microchip for sustained or controlled release of any formulation described herein.

[0085] In some embodiments, the composition does not include phosphatidylcholine.

[0086] How to use The composite particles can be used in a variety of methods, such as, for example, methods of treating a disorder in a subject.

[0087] As used herein, the term "subject" includes humans and non-human animals. Exemplary human subjects include human patients with a disorder, e.g., a disorder described herein, or normal subjects. The term "non-human animals" includes all vertebrates, e.g., non-mammals (e.g., chickens, amphibians, reptiles), and mammals, e.g., non-human primates, domestic animals and / or agriculturally useful animals, e.g., horses, sheep, dogs, cats, cows, pigs, etc.

[0088] As used herein, the term "treat" or "treating" a subject with a disorder refers to administering a regimen, such as administering a particle or composition described herein, to a subject to cure, heal, alleviate, reduce, alter, treat, ameliorate, or improve at least one symptom of the disorder. Treating includes administering an amount effective to alleviate, alleviate, alter, treat, ameliorate, improve, or affect the disorder or a symptom of the disorder. Treatment may suppress the exacerbation or worsening of a symptom of the disorder.

[0089] Bile acids and their salts have been proposed as therapeutic agents for treating a variety of conditions, including disorders of bile acid synthesis and peroxisomal disorders (see, e.g., Klouwer et al. Orphanet J. Rare Dis., 2015, 10, 151; W. T. Elliot. Internal Medicine Alert, 2015, 37), primary biliary cholangitis (also known as primary biliary cirrhosis; see, e.g., Hirschfield et al. Gut, 2018, 67, 1568), primary sclerosing cholangitis (see, e.g., Mikov et al. Eur. J. Drug Metab. Pharmacokinet., 2006, 31, 237), cardiometabolic diseases (see, e.g., Ikemoto et al. Am. J. Physiol. Metab., 1997, 273, E37), gallstones and bile duct stones (see, e.g., Fini et al. al. J. Pharm. Sci. 85(9), 971; Lansford et al. Gut, 1974, 15, 48), nonalcoholic fatty liver disease (see, e.g., Quintero et al. J. Physiol. Biochem., 2014, 70, 667; Gabbi et al. Dig. Liver Dis., 2012, 44, 1018), type 2 diabetes (see, e.g., Gabbi 2012), human immunodeficiency virus type 1 (HIV-1) (see, e.g., Mikov 2006), acute pancreatitis (see, e.g., Mikov 2006), cancer (see, e.g., Goossens et al. Pharmacol. Ther. 203, 107396(2019); Zeng et al. Nutr. Cancer 62, 85-92(2009); Pardi et al. Gastroenterology 124,889-893(2003);Milovic et al.Eur.J.Clin.Invest.32,29-34(2002);Schlottmann et al.Cancer Res.60,4270-4276(2000);Sarenac et al. al.Front.Pharmacol.10:484(2019),doi:10.3389 / fphar.2019.00484), as well as removal of unwanted fat (Yagima Odo et al. Dermatologic Surg. 33, 178-189 (2007)). Bile acids and their salts are also useful for non-surgical removal of localized fat deposits in a subject. For example, deoxycholic acid injections have been approved by the U.S. FDA to improve the moderate to severe rounded or bulging appearance associated with submental fat in adults. However, many injections are required, with one single treatment involving up to 50 injections, and up to six single treatments may be required for effective treatment. Thus, it is contemplated that the composite particles disclosed herein provide a controlled release of bile acids or salts or esters thereof, thereby reducing the number of injections required for effective treatment.

[0090] Corticosteroids have been used in a variety of conditions, such as endocrine disorders (e.g., hypercalcemia associated with primary or secondary adrenal insufficiency, congenital adrenal hyperplasia, nonsuppurative thyroiditis, or cancer), rheumatic disorders (e.g., rheumatoid arthritis (including juvenile rheumatoid arthritis), ankylosing spondylitis, acute and subacute bursitis, osteoarthritic synovitis, acute nonspecific tenosynovitis, posttraumatic osteoarthritis, psoriatic arthritis, epicondylitis, or acute gouty arthritis), collagen diseases (e.g., during exacerbations or as maintenance therapy for systemic lupus erythematosus, systemic dermatomyositis (polymyositis), or acute rheumatic carditis), skin disorders (e.g., bullous dermatitis herpetiformis).herpetiformis), severe erythema multiforme (Stevens-Johnson syndrome), severe seborrheic dermatitis, exfoliative dermatitis, mycosis fungoides, pemphigus, or severe psoriasis), allergic conditions (e.g., seasonal or perennial allergic rhinitis, drug hypersensitivity reactions, serum sickness, contact dermatitis, bronchial asthma, or atopic dermatitis), eye diseases (e.g., severe acute and chronic allergic and inflammatory processes involving the eye and ocular adnexa, e.g., allergic marginal corneal ulcers, ophthalmic zonule herpes, anterior ocular inflammation, diffuse posterior uveitis and choroiditis, sympathetic ophthalmia, keratitis, optic neuritis, allergic conjunctivitis, chorioretinitis, uveitis and ocular inflammatory conditions refractory to topical steroids, or iritis and iridocyclitis), respiratory diseases (e.g., symptomatic sarcoidosis, beryllium disease, Löffler syndrome, fulminant or disseminated pulmonary tuberculosis, aspiration pneumonitis, chronic obstructive pulmonary disease (COPD), allergic bronchopulmonary aspergillosis, asthma, hypersensitivity pneumonitis, and organizing pneumonia). idiopathic bronchiolitis obliterans, idiopathic eosinophilic pneumonia, idiopathic pulmonary fibrosis, or Pneumocystis carinii pneumonia), blood disorders (e.g., idiopathic thrombocytopenic purpura, secondary thrombocytopenia, acquired (autoimmune) hemolytic anemia, erythroblastopenia (red blood anemia), congenital (erythroid) aplastic anemia, Diamond-Blackfan anemia, or pure red cell aplasia), neoplastic diseases (e.g., leukemia and lymphoma in adults, or acute leukemia in children), gastrointestinal diseases (e.g., ulcerative colitis, Corticosteroids are used to treat acute episodes of chronic enteritis, regional enteritis, or Crohn's disease, nervous system disorders (e.g., acute exacerbations of multiple sclerosis), inflammatory disorders, renal disease (e.g., to induce diuresis or relief of proteinuria in nephrotic syndrome, idiopathic or due to lupus erythematosus), as well as other conditions (e.g., tuberculous meningitis with subarachnoid or urgency block when combined with appropriate antituberculous chemotherapy, trichinellosis with neurological or myocardial disorders). Corticosteroids are often used to treat severe allergies or skin diseases, asthma, and arthritis.

[0091] Other compounds having a steroid core structure are also used to treat a wide variety of disorders. For example, listed below are compounds having a steroid core structure and the disorders they are used to treat in humans. In some embodiments, the composite particles described herein include the indicated compounds, and the disclosure provides methods of using such particles to treat the indicated disorders and / or for:

[0092] Testosterone (testosterone, testosterone enanthate, and testosterone cypionate forms): Metastatic breast cancer; delayed puberty; hypogonadotropic hypogonadism (congenital or acquired); primary hypogonadism (congenital or acquired); hormone therapy in transgender men (female to male);

[0093] Testosterone Undecanoate: Metastatic breast cancer; delayed puberty; hypogonadotropic hypogonadism (congenital or acquired); primary hypogonadism (congenital or acquired); hormone therapy in transgender men (female to male);

[0094] Exemestane: Breast cancer; First-line adjuvant treatment of estrogen receptor-positive early breast cancer in postmenopausal women; Risk reduction of invasive breast cancer in postmenopausal women;

[0095] Formestane: Treatment of advanced breast cancer in postmenopausal women;

[0096] Mesterolone: ​​Androgen deficiency; hypogonadism; infertility; delayed puberty;

[0097] Fluoxymesterone: metastatic breast cancer (female); delayed puberty (male); primary or hypogonadotropic hypogonadism (male);

[0098] Methyltestosterone: metastatic breast cancer (female); delayed puberty (male); primary or hypogonadotropic hypogonadism (male);

[0099] Oxandrolone: ​​Weight gain (adjunctive therapy); Severe burns (adjunctive therapy);

[0100] Oxymetholone: ​​Anemia; Fanconi anemia;

[0101] Mestranol (with norethindrone): Abnormal uterine bleeding; dysmenorrhea; menstrual bleeding (menorrhagia); pain associated with endometriosis; polycystic ovary syndrome (PCOS) in women with menstrual irregularities and hirsutism / acne;

[0102] Norethindrone: Abnormal uterine bleeding; secondary amenorrhea; contraception; endometriosis;

[0103] Danazol: Endometriosis; prevention of hereditary angioedema (HAE); cyclic breast pain (mastalgia) associated with benign breast disorders; refractory immune thrombocytopenia;

[0104] Gestrinone: Endometriosis;

[0105] Levonorgestrel: Contraception; heavy menstrual bleeding; endometrial hyperplasia;

[0106] Lynestrenol: Prevention of pregnancy; treatment of frequent menstruation, menorrhagia, irregular uterine bleeding, primary and secondary amenorrhea or oligomenorrhea; treatment of benign breast disease; treatment of endometrial cancer; adjunct to estrogen therapy in peri- and postmenopausal women to prevent endometrial hyperplasia; treatment of endometriosis; suppression of ovulation, ovulatory pain, or menstruation, or dysmenorrhea; delaying the onset of menstruation;

[0107] Norgestrel (administered with ethinyl estradiol): Contraception; abnormal uterine bleeding; dysmenorrhea; hirsutism; menstrual bleeding (menorrhagia); pain associated with endometriosis; polycystic ovary syndrome (PCOS) in women with menstrual irregularities and hirsutism / acne;

[0108] Desogestrel: Contraception; abnormal uterine bleeding; dysmenorrhea; hirsutism; menstrual bleeding (menorrhagia); polycystic ovary syndrome (PCOS) in women with menstrual irregularities and hirsutism / acne;

[0109] Etonogestrel: Contraception;

[0110] Tibolone: ​​Treatment of symptoms associated with menopause; Prevention of postmenopausal osteoporosis in high-risk women with contraindications or intolerance to first-line therapy;

[0111] Ethynodiol Diacetate (administered with ethinyl estradiol): Contraception; abnormal uterine bleeding; dysmenorrhea; hirsutism; menstrual bleeding (menorrhagia); pain associated with endometriosis; polycystic ovary syndrome (PCOS) in women with menstrual irregularities and hirsutism / acne;

[0112] Cyproterone: Prostate cancer; hormone therapy for transgender women (male to female); paraphilias;

[0113] Megestrol acetate: Anorexia or cachexia; breast cancer; endometrial cancer; treatment of cancer-related cachexia;

[0114] Abiraterone acetate: metastatic prostate cancer;

[0115] Dienogest: Endometriosis;

[0116] Mifepristone: To suppress hyperglycemia secondary to hypercortisolism in adult patients with type 2 diabetes or impaired glucose tolerance, and endogenous Cushing's syndrome who have failed surgery or are not surgical candidates; Medical termination of intrauterine pregnancy up to 70 days gestation, in combination with misoprostol; Early abortion;

[0117] Drospirenone: Contraception;

[0118] Spironolactone: Ascites due to cirrhosis; heart failure with reduced ejection fraction; hypertension; primary hyperaldosteronism; acne vulgaris in women; heart failure with preserved ejection fraction; heart failure with reduced ejection fraction; hirsutism in women; hormone therapy in transgender women (male to female); post-myocardial infarction complicated by reduced ejection fraction;

[0119] Estradiol: metastatic breast cancer; hypoestrogenism (women); prevention of osteoporosis (women); advanced prostate cancer; vasomotor symptoms associated with menopause; vulvovaginal atrophy associated with menopause; functional hypothalamic amenorrhea with low bone density (young adult women); hormone therapy in transgender women (male to female);

[0120] Polyestradiol phosphate: Palliative treatment of inoperable advanced prostate cancer;

[0121] Megestrol: Anorexia or cachexia; breast cancer; endometrial cancer; treatment of cancer-related cachexia;

[0122] Estramustine: Prostate cancer (metastatic castration-resistant);

[0123] Estramustine phosphate: Prostate cancer;

[0124] Estrone: Vulvovaginal atrophy;

[0125] Estropipate: Hypoestrogenism in women; Prevention of osteoporosis; Vasomotor symptoms due to menopause; Vulvovaginal atrophy due to menopause;

[0126] Progesterone: Prevention of endometrial hyperplasia in non-hysterectomized postmenopausal women receiving conjugated estrogens; treatment of secondary amenorrhea; treatment of amenorrhea or abnormal uterine bleeding due to hormonal imbalance in the absence of organic lesions such as submucosal fibroids or uterine cancer; as part of assisted reproductive technologies (ART) for infertile women with progesterone deficiency; to support embryo implantation and early pregnancy by supplementing the corpus luteum as part of ART for infertile women; to reduce the risk of recurrent spontaneous preterm birth;

[0127] Dydrogesterone: Treatment of various conditions caused by progesterone deficiency;

[0128] Hydroxyprogesterone caproate: To reduce the risk of preterm birth in women with a singleton pregnancy and a history of singleton spontaneous preterm birth; for the treatment of advanced (stage III or IV) uterine adenocarcinoma; for the management of amenorrhea (primary and secondary) and abnormal uterine bleeding due to hormonal imbalance in the absence of organic lesions (e.g., submucosal fibroids or uterine carcinoma); as a test for endogenous estrogen production; for the production and shedding of the secretory endometrium;

[0129] Medroxyprogesterone acetate: Abnormal uterine bleeding; secondary amenorrhea; contraception; prevention of endometrial hyperplasia; endometrial cancer; endometriosis; acute abnormal uterine bleeding; endometrial hyperplasia; hot flashes; paraphilia / hypersexuality;

[0130] Segesterone acetate (administered with ethinyl estradiol): Contraception;

[0131] Norelgestromin (administered with ethinyl estradiol): Contraception; Polycystic ovary syndrome (PCOS) in women with menstrual irregularities and hirsutism / acne;

[0132] Norgestimate (administered with estradiol): Prevention of osteoporosis; vasomotor symptoms associated with menopause; vulvovaginal atrophy associated with menopause;

[0133] Norgestimate (administered with ethinyl estradiol): Acne vulgaris; Contraception; Abnormal uterine bleeding; Dysmenorrhea; Hirsutism; Menstrual bleeding (menorrhagia); Polycystic ovary syndrome (PCOS) in women with menstrual irregularities and hirsutism / acne;

[0134] Cortisol:Allergic conditions: Control of severe or refractory allergic conditions refractory to adequate trials of conventional therapy in drug hypersensitivity reactions, perennial or seasonal allergic rhinitis, serum sickness, transfusion reactions, or acute noninfectious laryngeal edema (epinephrine is the drug of choice);Dermatological conditions: Atopic dermatitis; Bullous herpetiform dermatitis; Contact dermatitis; Exfoliative dermatitis; Exfoliative erythroderma; Pemphigus; Severe erythema multiforme (Stevens-Johnson syndrome); Severe psoriasis; Severe seborrheic dermatitis; Mycosis fungoides;Edematous conditions: Idiopathic or erythematous To induce diuresis or to alleviate proteinuria in nephrotic syndrome without uremia due to cystic fibrosis; endocrine disorders: acute adrenal insufficiency; congenital adrenal hyperplasia; hypercalcemia associated with cancer; nonsuppurative thyroiditis; primary or secondary adrenal insufficiency; preoperative and in cases of severe trauma or illness, in patients with known adrenal insufficiency or when adrenal reserve is in doubt; shock unresponsive to conventional therapy when adrenal insufficiency is present or suspected; gastrointestinal disorders: in ulcerative colitis and regional enteritis To get patients through critical periods of disease;Blood disorders: Acquired (autoimmune) hemolytic anemia; Congenital (erythroid) aplastic anemia (Diamond-Blackfan anemia); Erythroblastopenia (red cell anemia); Adult immune thrombocytopenia (formerly known as idiopathic thrombocytopenic purpura); Pure red cell aplasia; Some cases of secondary thrombocytopenia;Oncologic diseases: Palliative management of leukemia and lymphoma (adults); Acute leukemia in children;Nervous system: Cerebral edema following primary or metastatic brain tumors or craniotomy;Ophthalmic diseases: Severe acute and chronic allergies involving the eye allergic and inflammatory processes, such as allergic conjunctivitis; allergic marginal corneal ulcers; anterior segment inflammation; chorioretinitis; diffuse posterior uveitis and choroiditis; herpes zoster ophthalmicus; iritis and iridocyclitis; keratitis; optic neuritis; sympathetic ophthalmia; other ocular inflammatory conditions refractory to topical corticosteroids; respiratory diseases: aspiration pneumonitis; bronchial asthma; berylliosis; fulminant or disseminated pulmonary tuberculosis when combined with appropriate antituberculous chemotherapy; idiopathic eosinophilic pneumonia; Löffler's syndrome (uncontrollable by other methods); symptomatic sarcoidosis;Rheumatic disorders: acute and subacute bursitis, acute gouty arthritis, acute nonspecific tenosynovitis, ankylosing spondylitis, epicondylitis, post-traumatic osteoarthritis, psoriatic arthritis, rheumatoid arthritis, e.g. juvenile rheumatoid arthritis, osteoarthritis synovitis, as adjunctive therapy for short-term administration; acute rheumatic carditis, dermatomyositis (polymyositis), temporal arteritis, and as exacerbation or maintenance therapy of systemic lupus erythematosus; Other: trichinellosis with neurological or myocardial impairment; tuberculous meningitis with subarachnoid block or impending block when combined with appropriate antituberculous chemotherapy; in-hospital cardiac arrest; septic shock; thyroid storm;

[0135] Cortisone (in the form of cortisone and cortisone acetate): Allergic conditions: Control of severe or refractory allergic conditions resistant to adequate trials of conventional treatment for atopic dermatitis, bronchial asthma, contact dermatitis, drug hypersensitivity reactions, seasonal or perennial allergic rhinitis, and serum sickness; Skin disorders: Bullous herpetiform dermatitis, exfoliative dermatitis, mycosis fungoides, pemphigus, severe erythema multiforme (Stevens-Johnson syndrome), severe psoriasis, severe seborrheic dermatitis; Endocrine disorders: Congenital adrenal hyperplasia, hypercalcemia associated with cancer, ulcerative colitis, nonsuppurative thyroiditis, primary or secondary adrenal cortex;gastrointestinal diseases: ulcerative colitis and regional enteritis to get patients through critical periods of disease;blood disorders: acquired (autoimmune) hemolytic anemia, congenital (erythroid) aplastic anemia, erythroblastopenia (red blood cell [RBC] anemia), adult immune thrombocytopenia (formerly known as idiopathic thrombocytopenic purpura), secondary thrombocytopenia in adults;neoplastic diseases: palliative management of leukemia and lymphoma in adults;acute leukemia in children;eye diseases: eye and severe acute and chronic allergic and inflammatory processes involving the ocular adnexa (e.g. allergic conjunctivitis, allergic peripheral corneal ulcers, anterior segment inflammation, chorioretinitis, diffuse posterior uveitis and choroiditis, keratitis, herpes zoster ophthalmicus, iritis and iridocyclitis, optic neuritis, sympathetic ophthalmia); renal diseases: to induce diuresis or relief of proteinuria in nephrotic syndrome without uremia, either idiopathic or caused by lupus erythematosus; respiratory diseases: aspiration pneumonitis, beryllium disease, appropriate anti-inflammatory drugs. Fulminant or disseminated pulmonary tuberculosis when used in combination with tuberculosis chemotherapy, Löffler's syndrome not otherwise controllable, symptomatic sarcoidosis; rheumatic disorders: acute and subacute bursitis; acute gouty arthritis; acute nonspecific tenosynovitis; ankylosing spondylitis; epicondylitis: post-traumatic osteoarthritis; psoriatic arthritis; rheumatoid arthritis (RA), e.g. juvenile rheumatoid arthritis (some cases require low-dose maintenance therapy); and as adjunctive short-term therapy in osteoarthritic synovitis (to survive an acute episode or exacerbation).As maintenance therapy during exacerbations in acute rheumatic carditis, systemic dermatomyositis (polymyositis), and some cases of systemic lupus erythematosus; others: tuberculous meningitis with subarachnoid block or impending block when combined with appropriate antituberculous chemotherapy; trichinellosis with neurological or myocardial impairment;

[0136] Fluorometholone: ​​Eye inflammation: Treatment of steroid-responsive inflammation of the palpebral and bulbar conjunctiva, cornea, and anterior segment of the eye;

[0137] Difluprednate: Inflammation / Pain: Treating inflammation and pain after ophthalmic surgery; Uveitis: Treating endogenous anterior uveitis;

[0138] Fludrocortisone (in the form of fludrocortisone acetate): Primary adrenal insufficiency; Classic congenital adrenal hyperplasia; Idiopathic orthostatic hypotension; Septic shock;

[0139] Fluocinolone (fluocinolone acetonide form): Body oils: For the treatment of moderate to severe atopic dermatitis in pediatric patients 3 months of age and older; For the treatment of atopic dermatitis in adults; Creams, ointments, and topical solutions: For the relief of inflammatory and pruritic symptoms of corticosteroid-responsive dermatitis; Scalp oils: For the treatment of psoriasis of the scalp in adults; Shampoos: For the treatment of seborrheic dermatitis of the scalp; For the relief of chronic ear canal eczema; Diabetic macular edema; Uveitis;

[0140] Loteprednol (loteprednol etabonate form): Ocular inflammatory conditions (0.5% suspension): Treatment of ocular inflammation, anterior segment inflammation anticipated to respond to topical corticosteroid therapy; Postoperative inflammation / pain (0.38% gel; 0.5% suspension / ointment / gel; 1% suspension): Treatment of postoperative inflammation and pain following ophthalmic surgery; Seasonal allergic conjunctivitis (0.2% suspension): Temporary relief of signs and symptoms of seasonal allergic conjunctivitis;

[0141] Methylprednisolone (methylprednisolone acetate and methylprednisolone succinate forms): Oral, intramuscular (acetate or succinate), and intravenous (succinate only) administration: Anti-inflammatory or immunosuppressant in the treatment of various diseases, such as blood disorders (e.g. immune thrombocytopenia, warm autoimmune hemolytic anemia), allergic diseases, gastrointestinal diseases (e.g. Crohn's disease, ulcerative colitis), inflammatory diseases, neoplastic diseases, neurological diseases (e.g. multiple sclerosis), rheumatic diseases (e.g. antineutrophil cytoplasmic antibody-associated vasculitis, dermatomyositis / polymyositis, giant cell arteritis, gout [acute flare ], giant cell arteritis, mixed cryoglobulinemia syndrome, polyarteritis nodosa, rheumatoid arthritis, systemic lupus erythematosus), and / or autoimmune origin; Intra-articular or soft tissue administration (acetate only): Gout (acute flare), acute and subacute bursitis, acute nonspecific tenosynovitis, epicondylitis, rheumatoid arthritis, and / or osteoarthritis synovitis; Intralesional administration (acetate only): Alopecia areata; discoid lupus erythematosus; keloids; focal hypertrophic, infiltrative, inflammatory lesions of granuloma annulare, lichen planus, lichen simplex chronicus (neurodermatitis), and psoriatic plaques; and diabetic necrobiosis lipoidica. May be useful in cystic tumors of the aponeurosis or tendon (ganglion);moderate to severe acute respiratory distress syndrome;heart transplant: antibody-mediated rejection;chronic obstructive pulmonary disease;management of post-mortem organ donors;acute graft-versus-host disease;in-hospital cardiac arrest;severe / refractory nausea and vomiting in pregnancy;adjuvant treatment of moderate to severe disease with Pneumocystis pneumonia;metastatic castration-resistant prostate cancer;

[0142] Prednicarbate: Dermatitis;

[0143] Prednisolone (in the form of prednisolone sodium phosphate and prednisolone acetate); Corneal injuries: treatment of acute chemical injuries of the cornea; Ocular inflammatory conditions: treatment of ocular inflammation, anterior segment inflammation expected to respond to topical corticosteroid therapy; Allergy conditions: control of severe or refractory allergic conditions refractory to adequate trials of conventional therapy in asthma, atopic dermatitis, drug hypersensitivity reactions, seasonal or perennial allergic rhinitis, and serum sickness; Skin disorders: bullous herpetiform dermatitis; contact dermatitis; exfoliative erythroderma; exfoliative dermatitis; mycosis fungoides; pemphigus; severe erythroderma multiforme plaques (Stevens-Johnson syndrome); severe psoriasis; severe seborrheic dermatitis; endocrine disorders: congenital adrenal hyperplasia; hypercalcemia associated with cancer; nonsuppurative thyroiditis; primary or secondary adrenal insufficiency; gastrointestinal disorders: during acute episodes of Crohn's disease or ulcerative colitis; blood disorders: acquired (autoimmune) hemolytic anemia; congenital (erythroid) aplastic anemia (Diamond-Blackfan anemia); erythroblastopenia (red blood anemia); immune thrombocytopenia (formerly known as idiopathic thrombocytopenic purpura); pure red cell aplasia; secondary thrombocytopenia; neoplastic disorders: acute Treatment of chronic leukemia and aggressive lymphoma; Nervous system: acute exacerbation of multiple sclerosis; cerebral edema following primary or metastatic brain tumors, craniotomy, or head trauma; Eye disorders: allergic conjunctivitis; allergic peripheral corneal ulcer; anterior segment inflammation; chorioretinitis; diffuse posterior uveitis and choroiditis; herpes zoster ophthalmicus; iritis and iridocyclitis; keratitis; optic neuritis; sympathetic ophthalmia; uveitis and other ocular inflammatory conditions refractory to topical corticosteroids; Renal disorders: diuresis or slowing of proteinuria in nephrotic syndrome without uremia, either idiopathic or due to lupus erythematosus to induce harmony;respiratory diseases: acute exacerbation of chronic obstructive pulmonary disease (COPD);allergic bronchopulmonary aspergillosis;aspiration pneumonitis;asthma;beryllium disease;fulminant or disseminated pulmonary tuberculosis when combined with appropriate antituberculous chemotherapy;hypersensitivity pneumonitis;idiopathic bronchiolitis obliterans with organizing pneumonia;idiopathic eosinophilic pneumonia;idiopathic pulmonary fibrosis;Löffler's syndrome (unmanageable by other means);Pneumocystis carinii pneumonia (PCP) with hypoxemia occurring in HIV-positive individuals receiving treatment with appropriate anti-PCP antibiotics;symptomatic sarcoidosis;Rheumatic Disorders: Short-term supplementation in acute and subacute bursitis, acute gout flares, acute nonspecific tenosynovitis, ankylosing spondylitis, epicondylitis, rheumatic polymyalgia / temporal arteritis, post-traumatic osteoarthritis, psoriatic arthritis, relapsing polychondritis, rheumatoid arthritis (including juvenile rheumatoid arthritis), osteoarthritic synovitis, acute rheumatic carditis, systemic lupus erythematosus, dermatomyositis / polymyositis, Sjogren's syndrome, and certain cases of vasculitis. As adjuvant therapy;Other: acute or chronic solid organ rejection; trichinellosis with neurological or myocardial damage; tuberculous meningitis with subarachnoid block or impending block, tuberculosis with mediastinal lymphadenopathy causing respiratory distress, tuberculosis with pleural or pericardial effusion (when treating tuberculous complications, use appropriate antituberculous chemotherapy); alcoholic hepatitis (severe); asthma exacerbation; Bell's palsy; chronic obstructive pulmonary disease (COPD) (acute exacerbation);

[0144] Prednisone: Anti-inflammatory or immunosuppressant in the treatment of various diseases, such as allergic diseases, blood diseases (e.g. immune thrombocytopenia, warm autoimmune hemolytic anemia), skin diseases, gastrointestinal diseases, inflammatory diseases, eye diseases, neoplastic diseases, rheumatic diseases (e.g. acute gout flare, vasculitis, dermatomyositis, mixed cryoglobulinemia syndrome, polyarteritis nodosa, polymyositis, polymyalgia rheumatica, rheumatoid arthritis, systemic lupus erythematosus), autoimmune diseases, nervous system diseases (e.g. acute exacerbation of multiple sclerosis), kidney diseases, respiratory diseases, endocrine disorders (e.g. primary or secondary adrenocorticoid deficiency); solid organ rejection (acute / chronic); primary Bell's palsy; acute exacerbation of chronic idiopathic urticaria; Duchenne muscular dystrophy; treatment of giant cell arteritis; treatment of acute graft-versus-host disease; autoimmune hepatitis; treatment of minimal change disease; multiple myeloma (untreated; transplant ineligible); myasthenia gravis crisis; acute pericarditis; adjunctive treatment of moderate to severe disease of Pneumocystis pneumonia, metastatic prostate cancer; Takayasu's arteritis; subacute thyroiditis; pulmonary tuberculosis;

[0145] Triamcinolone (triamcinolone acetonide form): Allergic rhinitis; upper respiratory tract allergies; adjunct to antibiotics (empiric treatment) for acute bacterial rhinosinusitis; chronic rhinosinusitis; alopecia areata; discoid lupus erythematosus; keloids; focal hypertrophic, infiltrative, inflammatory lesions of granuloma annulare, lichen planus, lichen simplex chronicus (neurodermatitis), and psoriatic plaques; diabetic necrobiosis lipoidica; cystic tumors of the aponeurosis or tendon (ganglion); allergic conditions: severe or refractory allergic conditions refractory to adequate trials of conventional therapy in asthma control, drug hypersensitivity reactions, perennial or seasonal allergic rhinitis, serum sickness, or transfusion reactions; skin disorders: atopic dermatitis, bullous herpetiform dermatitis, contact dermatitis, exfoliative erythroderma, mycosis fungoides, pemphigus, or severe erythema multiforme (Stevens-Johnson syndrome), vulvar dermatitis, psoriasis, seborrheic dermatitis; endocrine disorders: primary or secondary adrenal insufficiency, congenital adrenal hyperplasia, hypercalcemia associated with cancer, or nonsuppurative thyroiditis; gastrointestinal disorders: Crohn's disease or ulcerative colitis to get patients through critical periods of disease; blood disorders Harm: some cases of acquired (autoimmune) hemolytic anemia, Diamond-Blackfan anemia, pure red cell aplasia, and secondary thrombocytopenia; neoplastic diseases: palliative management of leukemia and lymphoma; nervous system: acute exacerbations of multiple sclerosis; cerebral edema following primary or metastatic brain tumors or craniotomy; ophthalmic diseases: sympathetic ophthalmia, temporal arteritis, uveitis, and ocular inflammatory conditions refractory to topical corticosteroids; renal diseases: to induce diuresis or relief of proteinuria in idiopathic nephrotic syndrome or caused by lupus erythematosus; respiratory diseases: beryllium in the treatment of: fulminant or disseminated pulmonary tuberculosis when used in combination with appropriate antituberculous chemotherapy, idiopathic eosinophilic pneumonia, symptomatic sarcoidosis; rheumatic disorders: acute pain flares; acute rheumatic carditis; ankylosing spondylitis; psoriatic arthritis; as adjunctive therapy for short-term administration in rheumatoid arthritis, e.g. juvenile rheumatoid arthritis; treatment of dermatomyositis, polymyositis, and systemic lupus erythematosus; other: trichinosis with neurological or myocardial impairment; tuberculous meningitis with subarachnoid or urgency block when used in combination with appropriate antituberculous chemotherapy; aphthous stomatitis;

[0146] Alclometasone (alclometasone dipropionate form): Steroid-responsive dermatitis;

[0147] Betamethasone (betamethasone, betamethasone sodium phosphate, betamethasone benzoate, betamethasone dipropionate, betamethasone valerate, and betamethasone acetate forms):Allergic conditions: Control of severe or refractory allergic conditions resistant to adequate trials of conventional therapy in asthma, atopic dermatitis; contact dermatitis, drug hypersensitivity reactions, perennial or seasonal allergic rhinitis, serum sickness, transfusion reactions;Dermatological disorders: bullous herpetiform dermatitis, exfoliative erythroderma, mycosis fungoides, pemphigus, severe erythema multiforme (Stevens-Johnson syndrome);Endocrine disorders: congenital adrenal hyperplasia, hypercalcemia associated with cancer, nonsuppurative thyroiditis.Synthetic analogs may be used in combination with mineralocorticoids, where applicable; mineralocorticoid supplementation is particularly important during infancy; gastrointestinal diseases: during acute episodes in regional enteritis and ulcerative colitis; blood disorders: acquired (autoimmune) hemolytic anemia, Diamond-Blackfan anemia, pure red cell aplasia, some cases of secondary thrombocytopenia; neoplastic diseases: palliative management of leukemia and lymphoma; nervous system: acute exacerbations of multiple sclerosis; cerebral edema following primary or metastatic brain tumors or craniotomy; ophthalmic diseases: sympathetic ophthalmia, temporal arteritis, uveitis and ocular inflammatory states refractory to topical corticosteroids; renal diseases: to induce diuresis or relief of proteinuria in idiopathic nephrotic syndrome or due to lupus erythematosus; respiratory diseases: beryllium disease, fulminant or disseminated pulmonary tuberculosis when combined with appropriate antituberculous chemotherapy, idiopathic acidophilic pulmonary tuberculosis. pneumonia, symptomatic sarcoidosis; rheumatic disorders: acute gout flares; acute rheumatic carditis; ankylosing spondylitis; psoriatic arthritis; short-term adjunctive therapy in rheumatoid arthritis, e.g. juvenile rheumatoid arthritis (some cases require low-dose maintenance therapy); treatment of dermatomyositis, polymyositis, and systemic lupus erythematosus; other: trichinellosis with neurological or myocardial involvement, intrathecal when used with appropriate antituberculous chemotherapy. Tuberculous meningitis with block or impending block; short-term adjunctive therapy in acute gout flares, acute and subacute bursitis, acute nonspecific tenosynovitis, epicondylitis, rheumatoid arthritis, and osteoarthritis synovitis; alopecia areata; discoid lupus erythematosus; keloids; focal hypertrophic, infiltrative, inflammatory lesions of granuloma annulare, lichen planus, lichen simplex chronicus (neurodermatitis), and psoriatic plaques; treatment of diabetic necrobiosis lipoidica; promotion of fetal lung maturation;

[0148] Betamethasone valerate and betamethasone dipropionate combination: Dermatitis: Relief of inflammatory and pruritic symptoms of corticosteroid-responsive dermatitis; Dermatitis of the scalp: Relief of inflammatory and pruritic symptoms of corticosteroid-responsive dermatitis of the scalp; Plaque psoriasis (spray; patch): Treatment of mild to moderate plaque psoriasis in patients aged 18 years and older;

[0149] Clobetasol (clobetasol propionate form): Steroid-responsive dermatitis;

[0150] Clobetasone (clobetasone butyrate form): Dermatitis: Management of topical eczema, as well as dermatitis, including atopic eczema and irritant and allergic contact dermatitis;

[0151] Clocortolone (pivalate form of clocortolone): Steroid-responsive dermatitis;

[0152] Desoximetasone: Relief of inflammatory and pruritic symptoms of corticosteroid-responsive dermatitis; treatment of plaque psoriasis;

[0153] Dexamethasone (dexamethasone, dexamethasone phosphate, and dexamethasone sodium phosphate forms): Oral, intravenous, or intramuscular injection: Anti-inflammatory or immunosuppressive agent in the treatment of various diseases, e.g., allergic diseases, blood diseases (e.g., immune thrombocytopenia), skin diseases, neoplastic diseases, rheumatic diseases, autoimmune diseases, nervous system diseases, renal diseases, and respiratory origin; Primary or secondary adrenocorticoid deficiency (not first choice); Management of shock, cerebral edema, and as a diagnostic agent; Intra-articular or soft tissue injection: Osteoarthritis synovitis, rheumatoid arthritis, acute and subacute bursitis, acute gouty arthritis, epicondylitis, acute nonspecific tenosynovitis. , and as adjunctive therapy for short-term administration in post-traumatic osteoarthritis;Intralesional injection: Keloids; focal hypertrophic, infiltrative, inflammatory lesions of lichen planus, psoriatic plaques, granuloma annulare, and lichen simplex chronicus (neurodermatitis);Discoid lupus erythematosus;Diabetic necrobiosis lipoidica;Alopecia areata;and cystic tumors of the aponeurosis or tendon (ganglion);Off-label use: Acute mountain sickness / high altitude cerebral edema;Antiemetic regimens: Prevention of nausea and vomiting associated with chemotherapy;Antiemetic regimens: Prevention of nausea and vomiting associated with radiation therapy;Acute exacerbation of asthma;Treatment of coronavirus disease 2019 (COVID-19);Promotion of fetal lung maturation;Prevention of neurological complications of meningitis (bacterial);Multiple myeloma;

[0154] Diflorasone (diflorasone diacetate form): Dermatitis: Treatment of inflammatory and pruritic symptoms of corticosteroid-responsive dermatitis;

[0155] Difluocortolone: ​​Acute and chronic skin conditions: Treatment of acute and chronic skin conditions that respond to the anti-inflammatory, antipruritic, and anti-allergic properties of topical corticosteroids;

[0156] Fluticasone (fluticasone propionate and fluticasone furoate forms): Asthma; chronic obstructive pulmonary disease; eosinophilic esophagitis (oral); allergic rhinitis; nasal polyps; nonallergic rhinitis; upper respiratory tract allergies; adjunct to antibiotics for acute bacterial rhinosinusitis (empiric treatment); chronic rhinosinusitis; relief of viral rhinosinusitis symptoms; dermatitis;

[0157] Halometasone: Treatment of steroid-responsive skin disorders;

[0158] Mometasone (mometasone furoate form): Corticosteroid-responsive dermatitis; Allergic rhinitis (seasonal and perennial); Nasal congestion associated with seasonal rhinitis; Nasal polyps; Seasonal allergic rhinitis (prophylaxis); Chronic rhinosinusitis; Adjunctive treatment of rhinosinusitis (acute); Treatment of rhinosinusitis (acute, mild to moderate, uncomplicated); Asthma;

[0159] Rimexolone: ​​Ocular inflammatory conditions: Treatment of postoperative inflammation after ophthalmic surgery; Treatment of anterior uveitis;

[0160] Amcinonide: Relief of inflammatory and pruritic symptoms of corticosteroid-responsive dermatitis;

[0161] Budesonide: Ulcerative colitis; Allergic rhinitis; Upper respiratory tract symptoms: Relief of symptoms of hay fever or other upper respiratory tract allergies (e.g., nasal congestion, runny nose, itchy nose, sneezing); Nasal polyps; Rhinitis; Adjunct to antibiotics for acute bacterial rhinosinusitis (empiric treatment); Chronic rhinosinusitis; Asthma; Chronic obstructive pulmonary disease (acute exacerbation); Chronic obstructive pulmonary disease (stable phase); Eosinophilic esophagitis; Mild to moderate Crohn's disease; Microscopic (lymphocytic and collagenous) colitis;

[0162] Ciclesonide: Seasonal and perennial allergic rhinitis; adjunct to antibiotics for acute bacterial rhinosinusitis (empiric treatment); chronic rhinosinusitis; asthma;

[0163] Deflazacort: Duchenne muscular dystrophy;

[0164] Desonide: Atopic dermatitis; Corticosteroid-responsive dermatitis;

[0165] Flunisolide: Asthma; rhinitis; adjunct to antibiotics for acute bacterial rhinosinusitis (empiric treatment); chronic rhinosinusitis; nonallergic rhinitis; symptomatic relief of viral rhinosinusitis;

[0166] Fluocinonide: Inflammatory and pruritic skin conditions;

[0167] Halcinonide: Steroid-responsive dermatitis;

[0168] Cholesterol: Prevention / treatment of vitamin and mineral deficiencies;

[0169] Estradiol valerate: metastatic breast cancer; hypoestrogenism (women); prevention of osteoporosis (women); advanced prostate cancer; vasomotor symptoms associated with menopause; vulvovaginal atrophy associated with menopause; functional hypothalamic amenorrhea with low bone density (young adult women); hormone therapy in transgender women (male to female);

[0170] Hydrocortisone (hydrocortisone, hydrocortisone acetate, hydrocortisone buteprate, hydrocortisone butyrate, hydrocortisone succinate, and hydrocortisone valerate forms): Anal and vulvar pruritus; Corticosteroid-responsive dermatitis (e.g., atopic dermatitis, contact dermatitis, vulvar dermatitis, psoriasis, seborrheic dermatitis); Hemorrhoids; Ulcerative colitis; Stasis dermatitis; Desquamative inflammatory vaginitis; Allergic conditions: Control of severe or refractory allergic conditions refractory to adequate trials of conventional therapy in drug hypersensitivity reactions, perennial or seasonal Nodular allergic rhinitis, serum sickness, transfusion reactions, or acute noninfectious laryngeal edema; Skin diseases: atopic dermatitis; bullous herpetiform dermatitis; contact dermatitis; exfoliative dermatitis; exfoliative erythroderma; pemphigus; severe erythema multiforme (Stevens-Johnson syndrome); severe psoriasis; severe seborrheic dermatitis; mycosis fungoides; Edematous conditions: to induce diuresis or relief of proteinuria in nephrotic syndrome without uremia, idiopathic or due to lupus erythematosus; Endocrine disorders: acute adrenal insufficiency; congenital adrenal hyperplasia; hypercalcemia associated with cancer; nonsuppurative thyroiditis; primary or Secondary adrenal insufficiency; preoperatively and in cases of severe trauma or illness, in patients with known adrenal insufficiency or when adrenal reserve is in doubt; shock unresponsive to conventional therapy when adrenal insufficiency is present or suspected; gastrointestinal diseases: ulcerative colitis and regional enteritis to get patients through critical periods of disease; blood disorders: acquired (autoimmune) hemolytic anemia; congenital (erythroid) aplastic anemia (Diamond-Blackfan anemia); erythroblastopenia (red blood anemia); immune thrombocytopenia in adults (formerly known as idiopathic thrombocytopenic purpura) (formerly known as erythroblastic aplasia); some cases of secondary thrombocytopenia; neoplastic diseases: palliative management of leukemia and lymphoma (adults); acute leukemia in children; nervous system: cerebral edema following primary or metastatic brain tumors or craniotomy; ophthalmic diseases: severe acute and chronic allergic and inflammatory processes involving the eye, e.g. allergic conjunctivitis; allergic marginal corneal ulcers; anterior segment inflammation; chorioretinitis; diffuse posterior uveitis and choroiditis; herpes zoster ophthalmicus; iritis and iridocyclitis; keratitis; optic neuritis; sympathetic ophthalmia; other ocular inflammatory conditions refractory to topical corticosteroids;Respiratory diseases: aspiration pneumonitis; bronchial asthma; berylliosis; fulminant or disseminated pulmonary tuberculosis when combined with appropriate antituberculous chemotherapy; idiopathic eosinophilic pneumonia; Löffler's syndrome (uncontrollable by other means); symptomatic sarcoidosis; Rheumatic disorders: acute and subacute bursitis, acute gouty arthritis, acute nonspecific tenosynovitis, ankylosing spondylitis, epicondylitis, post-traumatic osteoarthritis, psoriatic arthritis, rheumatoid arthritis, e.g. As adjunctive therapy for short-term administration in chronic rheumatoid arthritis and osteoarthritis synovitis; as maintenance therapy during exacerbations of acute rheumatic carditis, dermatomyositis (polymyositis), temporal arteritis, and systemic lupus erythematosus; other: trichinellosis with neurological or myocardial impairment; tuberculous meningitis with subarachnoid or impending block when combined with appropriate antituberculous chemotherapy; in-hospital cardiac arrest; septic shock; thyroid storm;

[0171] Triamcinolone hexacetonide: For the symptomatic treatment of subacute and chronic inflammatory joint diseases, including synovitis, tendonitis, bursitis, epicondylitis, rheumatoid arthritis (RA), juvenile idiopathic arthritis (JIA), osteoarthritis, or post-traumatic arthritis; and

[0172] Diflucortolone valerate: Acute and chronic skin diseases.

[0173] Compounds having a steroid core structure are also used to treat a wide variety of disorders in animals. For example, listed below are compounds having a steroid core structure and the disorders they are used to treat in animal subjects, such as dogs, cats, horses, pigs, and cows. In some embodiments, the composite particles described herein comprise the indicated compounds, and the present disclosure provides methods of using such particles in animal subjects to treat the indicated disorders and / or for:

[0174] Testosterone: Dogs - Testosterone-responsive urinary incontinence in neutered males; Dermatitis: Bilateral alopecia. Cats - Testosterone-responsive urinary incontinence in neutered males;

[0175] Boldenone (Boldenone Undecylenate Form): Horses - As an adjunct to the treatment of debilitated horses where improvement in weight, coat condition, or general body condition is desired;

[0176] Nandrolone: ​​Stimulates erythropoiesis in general veterinary patients - in patients with certain anemias (e.g., secondary to renal failure, aplastic anemia);

[0177] Altrenogest: Horses - suppress estrus or maintain pregnancy in the absence of progestin. Pigs - synchronize estrus. Dogs - luteal phase defect; prevention of premature birth;

[0178] Methyltestosterone: Female dogs - Treatment of estrogen-dependent tumors; pseudopregnancy; hormone-dependent alopecia. Male dogs - Decreased libido; testosterone-responsive incontinence; certain hormone-induced alopecia. Cats - Hormone-dependent alopecia; increased libido;

[0179] Stanozolol: Horses - improve appetite, promote weight gain, and increase strength and energy; treatment of chronic osteoarthritis. Dogs - improve appetite, promote weight gain, and increase strength and energy; collapse of the trachea. Cats - improve appetite, promote weight gain, and increase strength and energy;

[0180] Mibolerone: Female dogs - prevention of estrus;

[0181] Danazol: Dogs - Treatment of immune-mediated thrombocytopenia and hemolytic anemia in dogs. Cats - Autoimmune hemolytic anemia and thrombocytopenia;

[0182] Osaterone acetate: Male dogs - benign prostatic hyperplasia;

[0183] Spironolactone: Dogs - Potassium-sparing diuretic or adjunctive treatment of heart failure;

[0184] Estradiol: Horses - Enhancement of estrous behavior and receptivity in ovariectomized mares. Dogs -

[0185] Estrogen-responsive urinary incontinence;Abortion. Feline-Abortion. Bovine-Abortion;

[0186] Megestrol (in the form of megestrol acetate): Female dogs - for delaying estrus and relieving pseudopregnancy; Male dogs - benign prostatic hyperplasia. Cats - many skin and behavior-related conditions;

[0187] Estriol: Female dogs Estrogen-responsive urinary incontinence in ovariohysterectomized female dogs;

[0188] Aglepristone: Dogs - abortion; pyometra complex. Cats - progesterone-dependent mammary hyperplasia;

[0189] Medroxyprogesterone (medroxyprogesterone acetate form): Dogs - progestin-responsive dermatitis; aggressive behavior; long-term reproductive control; treatment of dwarfism in young German Shepherds; short-term treatment of benign prostatic hyperplasia; luteal phase insufficiency. Cats - sexually dimorphic behavioral problems such as wandering, male-male aggression, spraying, and mounting; feline psychogenic dermatitis and alopecia;

[0190] Trilostane: Canine - Treatment of pituitary-dependent hyperadrenocorticism (PDH) and hyperadrenocorticism associated with adrenal cortical tumors (HAC).

[0191] Cortisone (in the form of cortisone acetate): Dogs - oral treatment of hypoadrenocorticism;

[0192] Fluorometholone: ​​In general veterinary patients - treatment of inflammation of the palpebral and bulbar conjunctiva, cornea, and anterior segment of the eye (blepharitis, conjunctivitis, keratitis, anterior uveitis);

[0193] Difluprednate: In general animal patients - to treat inflammation following ocular trauma or cataract surgery, or to treat general inflammatory conditions of the anterior segment of the eye (conjunctivitis, keratitis, anterior uveitis);

[0194] Fludrocortisone (fludrocortisone acetate form): Small animals - Treatment of hypoadrenocorticism (Addison's disease); adjunctive therapy in hyperkalemia;

[0195] Loteprednol: In general veterinary patients - treatment of inflammatory conditions of the palpebral and bulbar conjunctiva, cornea, and anterior segment of the eye (blepharitis, conjunctivitis, keratitis, anterior uveitis);

[0196] Methylprednisolone (in the form of methylprednisolone acetate and methylprednisolone succinate): Replacement of glucocorticoid activity in general veterinary patients - in patients with adrenal insufficiency; anti-inflammatory; immunosuppressant;

[0197] Prednisolone / Prednisone (treated as a bioequivalent): General veterinary patients - replacement or supplementation for glucocorticoid deficiency secondary to adrenal insufficiency (e.g., relative adrenal insufficiency associated with septic shock); Anti-inflammatory; Immunosuppressant; Anti-tumor agent.

[0198] Triamcinolone (triamcinolone acetonide form): General animal patients - unifocal (e.g. footpad) or multifocal lesions for relatively short periods of time;

[0199] Betamethasone: General veterinary patients - for relatively short periods of time for unifocal (e.g. footpad) or multifocal lesions; Horses - intra-articular injections to treat painful and inflamed joints; Dogs - induction of premature labor;

[0200] Dexamethasone: General veterinary patient - diagnostic agent to test for hyperadrenocorticism; replacement or supplementation for glucocorticoid deficiency secondary to hypoadrenocorticism (e.g., relative adrenal insufficiency associated with septic shock); anti-inflammatory agent; immunosuppressant; anti-tumor agent;

[0201] Flumethasone: Horses - musculoskeletal conditions resulting from inflammation without permanent structural changes, e.g. bursitis, brachial arthritis, osteophytes, and myositis; allergic conditions such as hives and insect bites. Dogs - musculoskeletal conditions resulting from inflammation of muscles or joints and attached structures without permanent structural changes, e.g. arthritis, osteoarthritis, disc syndrome, and myositis; certain acute and chronic dermatitis of various etiologies (helps to control the itching, irritation, and inflammation associated with these conditions); allergic conditions such as hives and insect bites. Cats - certain acute and chronic dermatitis of various etiologies (helps to control the itching, irritation, and inflammation associated with these conditions);

[0202] Fluticasone (in the form of fluticasone propionate): Horses - recurrent airway obstruction or inflammatory airway disease. Dogs - chronic cough. Cats - feline asthma;

[0203] Mometasone (mometasone furoate form): General veterinary patients - for unifocal (e.g. footpad) or multifocal lesions for relatively short periods of time;

[0204] Rimexolone: ​​General animal patients - symptomatic relief of corticosteroid-responsive inflammatory conditions of the palpebral and bulbar conjunctiva, cornea, and anterior segment of the eye (e.g., allergic conjunctivitis, acne rosacea, superficial punctate keratitis, iritis, and cyclitis). Horses - treatment of uveitis;

[0205] Budesonide: Small animals - Treatment of inflammatory bowel disease; Dermatitis; Corticosteroid-responsive dermatitis;

[0206] Deoxycorticosterone: Dogs - Parenteral treatment of adrenal insufficiency (Addison's disease). Cats - Parenteral treatment of adrenal insufficiency (Addison's disease);

[0207] Alfaxalone: ​​Dogs - induction and maintenance of anesthesia, and maintenance with inhaled anesthetics after induction of anesthesia. Cats - induction and maintenance of anesthesia, and maintenance with inhaled anesthetics after induction of anesthesia;

[0208] Hydrocortisone: In general animal patients - for relatively short periods of time for unifocal (e.g., footpad) or multifocal lesions; when acute glucocorticoid / mineralocorticoid effects are desired (e.g., acute adrenal insufficiency; severe associated corticosteroid failure [CIRCI]); inflammatory conjunctivitis;

[0209] Desoxycorticosterone (in the form of desoxycorticosterone pivalate): In dogs - treatment of hypoadrenocorticism (Addison's disease); In cats - treatment of hypoadrenocorticism (Addison's disease); and

[0210] Isoflupredone acetate: Horse - anti-inflammatory and immunosuppressive; Pig - anti-inflammatory and immunosuppressive; Bovine - anti-inflammatory and immunosuppressive.

[0211] Thus, in one aspect, the present disclosure provides a method of treating a liver disease or peroxisomal disease in a subject in need of treatment, comprising administering to the subject a therapeutically effective amount of a plurality of composite particles described herein, e.g., a pharmaceutical composition comprising a plurality of composite particles described herein (e.g., a composite particle comprising a bile acid or a salt or ester thereof).

[0212] For example, in one aspect, the present disclosure provides a method of treating a liver disease in a subject in need of treatment, comprising administering to the subject a therapeutically effective amount of a plurality of composite particles described herein, e.g., a pharmaceutical composition comprising a plurality of composite particles described herein (e.g., a composite particle comprising a bile acid or a salt or ester thereof). In some embodiments, the liver disease is a bile acid synthesis disorder. In some embodiments, the liver disease is a bile acid synthesis disorder caused by a single enzyme deficiency. For example, in some embodiments, the single enzyme deficiency in the bile acid synthesis disorder is 3β-hydroxy-Δ5-C27-steroid oxidoreductase deficiency, α-methylacyl-CoA racemase (AMACR) deficiency, amino acid N-acyltransferase deficiency, bile acid CoA ligase deficiency, cholesterol 7α-hydroxylase deficiency, Δ4-3-oxosteroid 5β-reductase deficiency, oxysterol 7α-hydroxylase deficiency, sterol 27-hydroxylase deficiency (cerebrotendinous xanthomatosis), or trihydroxycholestanoic acid CoA oxidase deficiency. In other embodiments, the liver disease is selected from primary biliary cholangitis, primary sclerosing cholangitis, bile duct stones, and nonalcoholic fatty liver disease, hi some embodiments, the liver disease is primary biliary cholangitis.

[0213] In some embodiments, the present disclosure provides a method of treating a peroxisomal disease in a subject in need of treatment, comprising administering to the subject a therapeutically effective amount of a plurality of composite particles described herein, such as a pharmaceutical composition comprising a plurality of composite particles described herein. In some embodiments, the peroxisomal disease is a Zellweger spectrum disorder. Zellweger spectrum disorders are a group of autosomal recessive disorders caused by mutations in the PEX gene that encodes peroxins, and this spectrum includes Zellweger syndrome, neonatal adrenoleukodystrophy, and infantile Refsum's disease. In some embodiments, the subject suffers from a Zellweger spectrum disorder with symptoms of liver disease, steatorrhea, or complications due to reduced absorption of fat-soluble vitamins.

[0214] In some embodiments, the present disclosure provides a method of treating a disorder selected from cardiometabolic disease, gallstones, type 2 diabetes, human immunodeficiency virus type 1 (HIV-1), and acute pancreatitis, comprising administering to a subject a therapeutically effective amount of a plurality of composite particles described herein, e.g., a pharmaceutical composition comprising a plurality of composite particles described herein (e.g., a composite particle comprising a bile acid or a salt or ester thereof).

[0215] In one aspect, the disclosure provides a method of non-surgical removal of localized fatty deposits in a subject, comprising contacting the deposits with an effective amount of a plurality of composite particles described herein, e.g., a pharmaceutical composition comprising a plurality of composite particles described herein (e.g., composite particles comprising a bile acid or a salt or ester thereof). In some embodiments, the subject has localized fatty deposits and desires to remove the deposits. In some embodiments, the localized fatty deposits are located in the submandibular region of the subject. In some embodiments, the localized fatty deposits are located in the abdominal region of the subject. In some embodiments, the deposits are contacted with the composition by subcutaneous injection.

[0216] In one aspect, the disclosure provides a method of reducing subcutaneous fat deposits in a subject in need thereof, comprising locally administering an effective amount of a pharmaceutical composition comprising a plurality of composite particles as described herein, such as a plurality of composite particles as described herein (e.g., composite particles comprising a bile acid or a salt or ester thereof). In some embodiments, the subject has subcutaneous fat deposits and desires to remove the deposits. In some embodiments, the subcutaneous fat deposits are located in the submandibular region of the subject. In some embodiments, the subcutaneous fat deposits are located in the abdominal region of the subject. In some embodiments, the deposits are contacted with the composition by subcutaneous injection. In some embodiments, the subcutaneous fat deposits are associated with a condition selected from the group consisting of obesity, fat redistribution syndrome, eyelid fat herniation, lipoma, Dercum's disease, lipodystrophy, buffalo hump lipodystrophy, neck and back fat, visceral adiposity, breast hypertrophy, adiposity, diffuse body fat around the trunk and arms, and fat deposits associated with cellulite.

[0217] In some embodiments, the present disclosure provides a method of treating cancer in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a plurality of composite particles described herein, such as a pharmaceutical composition comprising a plurality of composite particles described herein (e.g., a composite particle comprising a bile acid or a salt or ester thereof). In some embodiments, the cancer is selected from colorectal cancer, cervical cancer, gastric cancer, and liver cancer. In some embodiments, the cancer is colorectal cancer.

[0218] In some embodiments, the present disclosure provides a method of inhibiting the proliferation of cancer cells, comprising contacting the cells with an effective amount of a plurality of composite particles described herein, such as a pharmaceutical composition comprising a plurality of composite particles described herein (e.g., a composite particle comprising a bile acid or a salt or ester thereof). In some embodiments, the cancer cells are selected from colorectal cancer cells, cervical cancer cells, gastric cancer cells, and liver cancer cells. In some embodiments, the cancer cells are colorectal cancer cells.

[0219] In some embodiments, the present disclosure provides a method of treating a disorder in a subject selected from the group consisting of an endocrine disorder, a rheumatic disorder, a collagen disease, a skin disease, an allergic condition, an eye disease, a respiratory disease, a blood disorder, a neoplastic disease, a gastrointestinal disease, a nervous system disorder, an inflammatory disorder, and a renal disease, comprising administering to the subject a therapeutically effective amount of a plurality of composite particles described herein, e.g., a pharmaceutical composition comprising a plurality of composite particles described herein (e.g., a composite particle comprising a corticosteroid or a salt or ester thereof).

[0220] In some embodiments, the present disclosure provides a method of treating a respiratory disease in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a plurality of composite particles as described herein, e.g., a pharmaceutical composition comprising a plurality of composite particles as described herein (e.g., a composite particle comprising a corticosteroid or a salt or ester thereof). In some embodiments, the respiratory disease is selected from asthma, croup, chronic obstructive pulmonary disease (COPD), bronchitis, and pneumonia (e.g., interstitial pneumonia).

[0221] The disclosed method includes administration of an "effective amount" or a "therapeutically effective amount" of the composite particle. As used herein, both terms refer to an amount effective at the dosage and duration necessary to achieve the desired result. A therapeutically effective amount of a composition can be determined by one skilled in the art and may vary depending on factors such as the disease state, age, sex, and weight of the individual, as well as the ability of the composition to elicit a desired response in the individual. A therapeutically effective amount is also one in which any toxic or adverse effects of the compound (e.g., a component of the composite particle or composition) are outweighed by the therapeutically beneficial effects. For example, a therapeutically effective amount of the composite particles described herein may be from about 1 mg / kg to about 1000 mg / kg, from about 5 mg / kg to about 950 mg / kg, from about 10 mg / kg to about 900 mg / kg, from about 15 mg / kg to about 850 mg / kg, from about 20 mg / kg to about 800 mg / kg, from about 25 mg / kg to about 750 mg / kg, from about 30 mg / kg to about 700 mg / kg, from about 35 mg / kg to about 650 mg / kg, from about 40 mg / kg to about 600 mg / kg, , about 45 mg / kg to about 550 mg / kg, about 50 mg / kg to about 500 mg / kg, about 55 mg / kg to about 450 mg / kg, about 60 mg / kg to about 400 mg / kg, about 65 mg / kg to about 350 mg / kg, about 70 mg / kg to about 300 mg / kg, about 75 mg / kg to about 250 mg / kg, about 80 mg / kg to about 200 mg / kg, about 85 mg / kg to about 150 mg / kg, and about 90 mg / kg to about 100 mg / kg.

[0222] The disclosed method may further include administering one or more additional therapeutic agents to the subject. The composite particles and the additional therapeutic agent(s) may be administered to the subject simultaneously or sequentially. In some embodiments, the additional therapeutic agent(s) may be administered in the same composition as the composite particles. In other embodiments, there may be an interval between the administration of the additional therapeutic agent(s) and the composite particles. In some embodiments, administering the additional therapeutic agent with the composite particles may allow for lower doses of the other therapeutic agents and / or administration at less frequent intervals. When used in combination with one or more other active ingredients, the composite particles and the other active ingredients may be used in lower doses than when each is used alone.

[0223] For example, the method can further include administering to the subject an additional therapeutic agent, wherein the additional therapeutic agent is selected from an anti-inflammatory agent, an analgesic agent, a chemotherapeutic agent, and a bile acid or a salt thereof.

[0224] Suitable anti-inflammatory agents for use with the disclosed compositions and methods can include both steroidal and non-steroidal anti-inflammatory agents. Suitable steroidal anti-inflammatory agents include, but are not limited to, corticosteroids such as hydrocortisone, dexamethasone, dexamethasone phosphate, beclomethasone dipropionate, clobetasol valerate, desonide, desoxymethasone, desoxycorticosterone acetate, dichlorisone, diflorasone diacetate, diflucortolone valerate, fluadrenolone, fluclarolone acetonide, fludrocortisone, fludrocortisone acetate, Flumethasone pivalate, fluocinolone acetonide, fluocinonide, flucortine butyl ester, fluocortolone, fluprednidene acetate, flurandrenolone, halcinonide, hydrocortisone, hydrocortisone acetate, hydrocortisone butyrate, methylprednisolone, triamcinolone, triamcinolone acetonide, cortisone, cortodoxone, flucetonide, difluorosone diacetate diacetate), fluradrenaline acetonide, medrysone, amciafer, amcinafide, betamethasone and the remainder of its esters, chlorprednisone, chlorprednisone acetate, clocortelone, clesinolone, dichlorisone, difluprednate, flucloronide, flunisolide, fluoromethalone, fluperolone, fluprednisolone, hydrocortisone valerate, hydrocortisone cyclopentylpropionate, hydrocortamate, meprednisone, paramethasone, prednisolone, prednisone, beclomethasone dipropionate, betamethasone dipropionate, and mixtures thereof. Pharmaceutically acceptable salts and esters of these agents may also be used.

[0225] Suitable nonsteroidal anti-inflammatory agents include, but are not limited to, oxicams such as piroxicam, isoxicam, tonexicam, sudoxicam, and CP-14,304; salicylates such as salicylic acid, aspirin, disalcid, benorate, trilysate, safapryn, solprin, diflunisal, and fendosal; acetic acid derivatives such as diclofenac, fenclofenac, indomethacin, sulindac, tolmetin, isoxepac, furofenac, tiopinac, zidometacin, acematacin, fentiazac, zomepiract, clidanac, oxalate ... Sepinac and felbinac; fenamates such as mefenamic acid, meclofenamic acid, flufenamic acid, niflumic acid and tolfenamic acid; propionic acid derivatives such as ibuprofen, naproxen, benoxaprofen, flurbiprofen, ketoprofen, fenoprofen, fenbufen, indoprofen, pirprofen, carprofen, oxaprozin, pranoprofen, miloprofen, tioxaprofen, suprofen, alminoprofen and thiaprofenic; and pyrazoles such as phenybutazone, oxyphenbutazone, feprazone, azapropazone and trimethasone; and mixtures thereof. Pharmaceutically acceptable salts and esters of these drugs can also be used.

[0226] Analgesics can reduce the discomfort caused by inflammation, especially after parenteral administration (e.g., subcutaneous injection) of the composition of the present disclosure. Suitable analgesics include, but are not limited to, injectable amine-type and ester-type local anesthetics, such as lidocaine, mepivacaine, bupivacaine, procaine, chloroprocaine, etidocaine, prilocaine, and tetracaine. Mixtures of these analgesics, as well as pharma- ceutically acceptable salts and esters, or these agents, can also be used.

[0227] Bile acids or their salts may also be used in combination with the composite particles. The bile acids or their salts or esters administered separately may be the same or different from the bile acids or their salts or esters present in the composite particles. Exemplary bile acids include cholic acid, deoxycholic acid, chenodeoxycholic acid, lithocholic acid, glycocholic acid, taurocholic acid, glycodeoxycholic acid, taurodeoxycholic acid, glycochenodeoxycholic acid, taurochenodeoxycholic acid, glycolithocholic acid, taurolithocholic acid, ursodeoxycholic acid, glycoursodeoxycholic acid, and tauroursodeoxycholic acid. For example, obeticholic acid is often used in combination with ursodeoxycholic acid to treat primary biliary cholangitis. Thus, in some embodiments, when the composite particles include obeticholic acid, the method further includes administration of ursodeoxycholic acid. In other embodiments, when the composite particle comprises ursodeoxycholic acid, the method further comprises administration of obeticholic acid.

[0228] In some embodiments, the composite particles may be used in combination with a chemotherapeutic agent. Exemplary chemotherapeutic agents include those listed in the "A to Z List of Cancer Drugs" published by the National Cancer Institute.

[0229] The following examples further illustrate aspects of the present disclosure but, of course, should not be construed as in any way limiting its scope. EXAMPLES

[0230] Materials and Methods Unless otherwise indicated, all materials were purchased from Sigma-Aldrich and used as received.

[0231] Characterization of microparticles: Microparticles were imaged with bright field and scanning electron microscopy (SEM) (JEOL JSM-7800FLV) microscopes. Fluorescent images of the particles were acquired using a Nikon inverted microscope with a fluorescent lamp and a TRITC / CY3 filter. For SEM imaging, samples were dried on glass slides, coated with carbon, and imaged with both secondary scattering and backscattering probes. Energy dispersive spectroscopy (EDS) analysis was used to characterize the elemental composition of the particles. EDS analysis was performed with an Oxford XMaxN 80mm microscope on the microparticles. 2 The particle size distribution was measured by a Silicon Drift Energy Dispersive X-ray Spectrometer (SDS-PAGE). Dynamic Light Scattering (DLS) was used to measure the hydrodynamic diameter of the particles and Zeta Potential (ZP) was used to measure the surface charge of the particles. DLS and ZP analysis was performed on the particles using a Malvern Nano-ZS Zetasizer.

[0232] Example 1: Preparation of composite particles with gold ions Method 1: 10 mg of gold(III) chloride was dissolved in 1 mL of ethyl acetate. The ethyl acetate solution was emulsified with 2 mL of water by vortexing for 15 seconds. The resulting oil / water emulsion was added to 10 mL of 0.3 wt% sodium cholate solution in a 100 mL beaker, and the mixture was stirred at 300 rpm. Composite particles appeared after 1-3 minutes of stirring. The particles were isolated by centrifugation at 2000 rpm for 5 minutes.

[0233] Method 2: Excess sodium cholate (approximately 5 mg) was added to 1 mL of ethyl acetate. Due to the low solubility of sodium cholate in ethyl acetate, the solution was centrifuged to pellet the excess sodium cholate and the supernatant was collected. 10 mg of gold(III) chloride was added to the collected ethyl acetate / sodium cholate supernatant and the resulting solution was emulsified with 2 mL of water by vortexing for 15 seconds. The resulting oil / water emulsion was added to 10 mL of 0.3 wt % sodium cholate solution in a 100 mL beaker and the mixture was stirred at 300 rpm. Composite particles appeared immediately. The particles were isolated by centrifugation at 2000 rpm for 5 minutes.

[0234] Method 3: 10 mg of gold(III) chloride was dissolved in 4 mL of water. This solution was emulsified with 1 mL of ethyl acetate by vortexing for 15 s. The resulting oil / water emulsion was added to 10 mL of 0.3 wt % sodium cholate solution in a 100 mL beaker, and the mixture was stirred at 300 rpm. Composite particles appeared after 1-3 min of stirring. The particles were isolated by centrifugation at 2000 rpm for 5 min.

[0235] In addition to the sodium cholate particles prepared according to methods 1-3 above, particles were also prepared according to method 1 where sodium cholate was replaced with sodium deoxycholate, methylprednisolone sodium succinate, and hydrocortisone sodium succinate.

[0236] SEM images of the particles are shown in Figures 1A-1D. Specifically, Figure 1A shows SEM images of cholate particles prepared according to method 1 at 1500x magnification (top) and 8500x magnification (bottom); Figure 1B shows SEM images of deoxycholate particles prepared according to method 1 at 1700x magnification (top) and 10000x magnification (bottom); Figure 1C shows SEM images of methylprednisolone particles prepared according to method 1 at 1000x magnification (top) and 3700x magnification (bottom); Figure 1D shows SEM images of hydrocortisone particles prepared according to method 1 at 450x magnification (top) and 1700x magnification (bottom).

[0237] EDS data for the particle shown in the bottom panel of Figure 1A is shown in Figure 2. The particle is composed primarily of carbon and oxygen with traces of gold, sodium, and chlorine. The large silicon peak is due to the signal obtained from the silicon wafer on which the sample was mounted. The data confirms that gold is contained within the particle.

[0238] Rhodamine B-loaded cholate particles were prepared by introducing 3 mg of Rhodamine B into the oil phase of an oil / water emulsion (i.e., a solution of gold(III) chloride and ethyl acetate) according to method 1. Images of the resulting particles are shown in Figure 3A (bright field microscope image at 40x magnification) and Figure 3B (the same particles but fluorescing when exposed to 546 nm light, confirming that Rhodamine B was loaded onto the hexagonal cholate / gold ion particles). Rhodamine B-loaded particles were also prepared by adding Rhodamine B to the water phase of an oil / water emulsion.

[0239] Example 2: Preparation of composite microparticles with iron ions Method 1: 5-10 mg of iron(II) sulfate heptahydrate was dissolved in 50 μL of water. This solution was added to 10 mL of 0.5 wt % aqueous solution of dexamethasone phosphate sodium salt while stirring at 500 rpm. Stirring was continued for 15 min, and particles began to form shortly after stirring began. The particles were isolated by centrifugation at 15000 rpm for 5 min. The pellet was resuspended in water and the centrifugation was repeated three more times to wash the particles.

[0240] Method 2: 10 mg of iron(II) sulfate heptahydrate was dissolved in 50 μL of water. This solution was vortexed in 1 mL of ethyl acetate for 15 seconds. To this mixture, 2 mL of 1 wt % aqueous solution of dexamethasone sodium phosphate was added, and the mixture was vortexed for 15 seconds. To this mixture, 10 mL of 0.5 wt % aqueous solution of dexamethasone sodium phosphate was added, followed by mixing. Stirring at 500 rpm was carried out for 5-15 minutes, and particles began to form immediately after stirring began. The particles were isolated by centrifugation at 15,000 rpm for 5 minutes. The pellet was resuspended in water, and the centrifugation was repeated three more times to wash the particles.

[0241] A representative SEM image of the particle is shown in FIG. 4A. Specifically, FIG. 4A shows an SEM image at 100,000 times magnification of dexamethasone particles prepared according to method 1. EDS data for the particle shown in FIG. 4A is shown in FIG. 4B. The particle is composed of carbon and oxygen with traces of iron. The large silicon peak is due to the signal obtained from the silicon wafer on which the sample was placed. The large gold peak is due to the signal obtained from the gold coated particles for SEM imaging. The data confirms that iron is contained within the particle.

[0242] Dynamic light scattering (DLS) data for particles prepared according to method 1 using 5 mg or 10 mg of ferrous sulfate heptahydrate showed average particle sizes of 165 nm and 205 nm, respectively. The zeta potential for particles prepared according to method 1 using 5 mg or 10 mg of ferrous sulfate heptahydrate was measured and found to be -25.9 mV and -16.2 mV, respectively. These data suggest that the surface charge of the particles can be tuned by adjusting the iron ion concentration.

[0243] Dexamethasone release from particles prepared according to Method 1 was assessed by suspending 6.9 mg of particles in 42 mL of phosphate buffered saline (PBS) and rotating the mixture at 37 °C for 26 h. Samples of the liquid were collected and analyzed by UV-Vis spectroscopy in comparison to dexamethasone standards (either 1 μg / mL dexamethasone phosphate or 8 μg / mL dexamethasone phosphate). The data are shown in Figure 5. Absorbance at approximately 230-260 nm indicates release of dexamethasone into solution.

[0244] Rhodamine B-loaded dexamethasone particles were prepared by introducing 2 mg of rhodamine B into 50 μL of a water / ferrous sulfate heptahydrate solution according to Method 1. The particles were pink in color and fluorescent, similar to the cholate / gold ion particles described in Example 1, indicating that rhodamine was loaded onto the particles.

[0245] Example 3: Preparation of composite microparticles with acid Bile salts / HCl particles. Hydrochloric acid was added to water until the pH was 2, then 50 mg of bile salts (sodium cholate, sodium deoxycholate, sodium ursodeoxycholate, or sodium chenodeoxycholate) was added to 2 mL of water at pH 2 and vortexed until the solution was clear. 2 mL of this solution was added to 1 mL of ethyl acetate and the mixture was vortexed for 15 seconds. To this emulsion, 10 mL of water was added at pH 3 (adjusted with HCl). Particle formation required additional mixing at 300 rpm for 1-2 minutes. SEM images of particles formed using sodium cholate, sodium deoxycholate, sodium chenodeoxycholate, and sodium ursodeoxycholate are shown in Figure 6A, Figure 6B, Figure 6C, and Figure 6D, respectively. EDS data for sodium chenodeoxycholate and sodium ursodeoxycholate particles showed peaks only for carbon, oxygen, and silicon (with Si peaks arising from the Si wafer the sample was mounted on).

[0246] Corticosteroid / HCl particles. Hydrochloric acid was added to water until the pH was 3, then 50 mg of the corticosteroid compound (methylprednisolone succinate or hydrocortisone succinate) was added to 2 mL of water at pH 3 and vortexed until the solution was clear. 2 mL of this solution was added to 1 mL of ethyl acetate and the mixture was vortexed for 15 seconds. To this emulsion, 10 mL of water at pH 2 (adjusted with HCl) was added. Particle formation required additional stirring at 300 rpm for 1-2 minutes. SEM images of particles formed using methylprednisolone succinate and hydrocortisone succinate are shown in Figure 7A and Figure 7B, respectively. EDS data for these particles showed peaks only for carbon, oxygen, and silicon (with Si peaks arising from the Si wafer the sample was mounted on) and, notably, no chlorine was detected.

[0247] Bile salt or corticosteroid / salicylic acid particles. 5-6 mg of salicylic acid was dissolved in 1 mL of ethyl acetate. To this solution, 1 wt% of a bile salt or corticosteroid (sodium cholate, sodium deoxycholate, methylprednisolone succinate, hydrocortisone succinate, sodium ursodeoxycholate, or sodium chenodeoxycholate) was added and the mixture was vortexed for 15 seconds. This emulsion was added to 10 mL of the same bile salt or corticosteroid solution (sodium cholate, sodium deoxycholate, methylprednisolone succinate, hydrocortisone succinate, sodium ursodeoxycholate, or sodium chenodeoxycholate) at 0.3 wt%. Particle formation required additional stirring at 300 rpm for 1 min. SEM images of particles formed using sodium cholate, sodium deoxycholate, methylprednisolone succinate, sodium chenodeoxycholate, hydrocortisone succinate, and sodium ursodeoxycholate are shown in Figures 8A, 8B, 8C, 8D, 8E, and 8F, respectively. The EDS data for the methylprednisolone succinate, sodium chenodeoxycholate, hydrocortisone succinate, and sodium ursodeoxycholate particles showed peaks only for carbon, oxygen, and silicon (from the Si wafer on which the samples were mounted).

[0248] Salicylic acid release from deoxycholate particles was measured by UV-Vis spectroscopy measuring absorbance at 296 nm. Deoxycholate particles were completely degraded by dropwise addition of 0.1 M NaOH, and the absence of particles was visually confirmed by light microscopy at 40x magnification. The data is shown in Figure 9.

[0249] Example 4: Degradation Assay Sodium cholate-based particles were prepared according to method 1 of Example 1 using 15 mg of gold(III) chloride. For comparison, particles were prepared using a double emulsion method with a reducing agent that reduced gold ions to gold nanoparticles that served as templates for particle formation (see International Patent Application Publication No. WO2021 / 011753). After preparation, the particles were suspended in deionized water at a concentration of 10 mg particles / mL of water, mixed well by vortexing, and stirred continuously on a rotating platform at 37°C. At 24-hour intervals, samples were centrifuged at 15,000 rpm for 5 minutes and the supernatant was collected before resuspending the particles in deionized water to the original volume. The collected supernatant was analyzed for released cholate molecules using a bile acid assay kit (Sigma-Aldrich catalogue no. MAK309).

[0250] The particles were collected and imaged by SEM on days 0, 1, 3, 5, 10, and 15. The images are shown in Figures 10A-10B, where Figure 10A shows an image of cholate / gold ion particles prepared according to method 1 of Example 1, and Figure 10B shows an image of cholate / gold(0) nanoparticles prepared according to WO2021 / 011753. These images show that the particles have similar degradation characteristics. In Figure 10A, the magnifications are 11000x, 12000x, 9500x, 11000x, 10000x, and 9000x on days 0, 1, 3, 5, 10, and 15, respectively. In FIG. 10B, the magnifications are 12,000x, 14,000x, 5,500x, 11,000x, 11,000x, and 11,000x on days 0, 1, 3, 5, 10, and 15, respectively.

[0251] Data showing the release of cholate from degraded particles is shown in Figure 11. Particles produced according to Method 1 disclosed herein (with gold(III) ions) were shown to release active cholate molecules in a similar manner and to a similar extent compared to previously characterized gold(0) nanoparticle-templated cholate particles.

[0252] Example 5: Detection of Gold Nanoparticles To compare the cholate particles produced according to the methods disclosed herein (Method 1 according to Example 1) with cholate particles containing gold nanoparticles (e.g., particles disclosed in WO2021 / 011753), both particles were degraded by suspending 20 mg of particles in 2 mL of 95% ethanol. The sample was mixed well to ensure complete degradation of all particles, and then centrifuged at 15,000 rpm for 10 minutes to isolate any gold nanoparticles that may have been released. The supernatant was removed and the sample was resuspended in water, pipetting up and down to aid in resuspension of the nanoparticles. The sample was then vortexed for 30 seconds to mix well. The washing step was repeated again, and then the sample was pipetted into a cuvette and analyzed by dynamic light scattering (DLS). No particles were detected in the sample of degraded particles prepared according to Method 1 of Example 1, confirming the absence of gold nanoparticles. In contrast, gold nanoparticles were detected in the sample prepared according to WO2021 / 011753. The DLS readout for this sample is shown in Figure 12 and shows a sharp peak at approximately 170 nm, which corresponds to the diameter of the particles present in solution, suggesting the presence of gold nanoparticles in this size range.

[0253] As an additional method, deoxycholate particles produced by each method were also degraded by dropwise addition of 0.1 M NaOH, and the absence of particles was visually confirmed by optical microscopy at 40x magnification. The absorbance of both degraded particles was measured by UV-Vis spectroscopy. The UV-Vis spectroscopy data for these samples is shown in FIG. 13. No gold nanoparticles were detected in the sample of degraded particles prepared according to Method 1 of Example 1, as there was no significant peak between wavelengths of 350 nm and 800 nm, thereby confirming the absence of gold nanoparticles. In contrast, gold nanoparticles were detected in the sample prepared according to WO2021 / 011753, with a peak at 548 nm.

[0254] Example 6: Detection of gold ions To confirm the presence of gold ions in the particle matrix of particles prepared according to Example 1 (e.g., by Method 1), the particles were decomposed by suspending them in 250 μL of deionized water and then adding 1 μL of 1 M NaOH in increments until the particles were completely dissolved. The sample was mixed thoroughly by vortexing after each addition of NaOH. 44 μL of NaOH solution was required to completely decompose the sample such that no particles were visible under an optical microscope at 40x magnification. This decomposition product was then used in the gold nanoparticle generation process. If gold(III) ions are present in the decomposition solution, then gold nanoparticles should be formed upon the addition of a reducing agent and heat. Assuming 1 wt% gold ions in the particle matrix, 17.6 mg of particles (assuming 0.176 mg gold ions and 17.424 mg cholate) were subjected to the decomposition. For comparison, individual solutions were prepared with 17.424 mg of cholate and 0.05-0.5 mg of gold ions (specifically 0.05 mg, 0.1 mg, 0.25 mg, 0.3 mg, and 0.5 mg) dissolved in water. In each sample, the gold ions were reduced to gold nanoparticles by adding 0.94 mg of sodium citrate as a reducing agent and heating at 80 °C for 10 min. The total volume of each sample was 1.89 mL.

[0255] Images of the sample are provided in FIG. 13. The color of the solution before and after heating was used as an indicator of gold nanoparticle formation, with a color change from colorless to deep red indicating the reduction of gold ions to gold nanoparticles. No color change was observed before heating, suggesting that no nanoparticles were formed in the absence of heat (as expected). After heating, the solution developed a red color, with a darker color developing in the comparative sample with a higher initial concentration of gold(III) ions. The sample containing decomposed particles prepared according to Method 1 in Example 1 showed a red color, indicating the formation of nanoparticles, thereby confirming the presence of gold(III) ions in the solution resulting from the decomposition of the particles.

[0256] Example 7: Cytolysis assay Human umbilical vein endothelial cells (HUVECs) are cultured in 12-well plates pretreated with gelatin, glutaraldehyde, and glycine as previously described (Charoenphol et al. Biomaterials. 2010;31(6):1392-1402). After reaching confluence, the cells are incubated with 1 ml of either different concentrations of bile acid solutions (e.g., cholate and deoxycholate solutions) or suspensions of composite particles of known concentrations for different periods of time at 37°C and 5% CO2. After the desired period, the treatment solutions / suspensions are removed from the wells, the cells are washed with warm 1x phosphate buffered saline (PBS) and incubated with 1 ml of a 1:25 dilution of MTS assay cell titer (Promega, WI) in 1x PBS for 2 hours at 37°C and 5% CO2 until an orange color appears in the untreated control wells. The absorbance is then measured at 490 nm and each condition is repeated in triplicate. Percent cell viability is quantified by subtracting the background cell titer absorbance from the absorbance at the desired time point and dividing by the average signal of untreated cells after background subtraction.

[0257] Example 8: Tallow lysis assay The ability of the particle formation to kill fat cells was tested by incubating the particles with beef tallow tissue. 0.15 g of beef tallow tissue was incubated with 1 mg / mL of deoxycholate particles in 1×PBS. The particles were prepared by various methods, such as gold nanoparticle-containing particles (see WO2021 / 011753), gold ion-containing particles, and particles made with either HCl or salicylic acid. 1×PBS was used as a negative control, and 1% sodium deoxycholate solution in 1×PBS was used as a positive control. The mixture was incubated on a rotator at 37° C. for 3 hours.

[0258] Lipolysis was observed qualitatively by the presence of lipid droplets in the sample tubes. Images of the tubes with arrows pointing to visible droplets are shown in Figures 14A and 14B. No lipid droplets were observed in the PBS control tube.

[0259] Example 9: Further lysis assays The ability of the particle formulations to kill adipocytes is tested by incubating the adipocytes with primary subcutaneous human adipocytes. Primary subcutaneous human adipocytes cultured in 96-well plates are purchased from a commercial supplier (e.g., Zen-Bio, Research Triangle, NC). Upon arrival, 150 μl of medium is removed from each well and the cells are incubated at 37° C. and 5% CO2. For lysis assays, 150 μl of a known concentration of salt solution or particle suspension in FBS-free RPMI medium is incubated for a known period of time. The treatment solution is then aspirated, the cells are washed with warm PBS, and 150 μl of a 1:25 dilution of MTS assay cell titer (purchased from Promega Corporation, Madison, WI) in 1×PBS is added to each well. The plates are incubated at 37° C. and 5% CO2 for 3 hours or until an orange color appears in the untreated control wells, and the absorbance is measured at 490 nm. Cell viability is quantified by subtracting the background cell titer absorbance from the absorbance at the desired time point and dividing by the average signal of untreated cells after background subtraction.

[0260] For control experiments, cells are incubated with various concentrations of bile acids (eg, sodium cholate and sodium deoxycholate) in RPMI medium.

[0261] Example 10: In vivo dissolution of mouse adipose tissue In vivo lipolysis assays are performed by subcutaneously injecting rhodamine-loaded composite particles (e.g., deoxycholate particles) into the inguinal fat pad of genetically obese mice in parallel with saline and vehicle controls. Genetically obese mice are anesthetized using isoflurane, shaved, and a suspension of rhodamine-loaded particles (e.g., deoxycholate particles), or a solution of cholate or deoxycholate in saline (25 mg / mL), or a vehicle control, is subcutaneously injected into the right inguinal fat pad of the mice. 100 μL of pure saline is injected into the left fat pad of the animals as a control. The weight and appearance of the animals are followed for 2 weeks. One group of animals receives a second dose of particles on day 7. After 14 days, the animals are euthanized and the left and right fat pads of the animals are excised, weighed, and fixed overnight in 10% formalin solution. Histology slides of the samples are prepared by paraffin embedding and standard hematoxylin and eosin staining. The histology slides are analyzed by a blinded investigator and the digital scans are analyzed using QuPath software.

[0262] Example 11: Cancer cell lysis assay HT-29 colon cancer cells (ATCC® HTB38™) were purchased from the American Type Culture Collection (ATCC) and cultured in 24-well plates until confluence was reached. Each well was incubated for 24 hours with a specific concentration of deoxycholate microparticles (1000 μM deoxycholate / well) in 1000 μl of McCoy's 5A medium. The concentration of 1000 M was the theoretical maximum assuming that all particles were immediately dissolved in the well. All particle types, including gold nanoparticle-containing particles (see WO2021 / 011753), gold ion-containing particles, and particles manufactured using either HCl or salicylic acid, were prepared in parallel with an untreated control. All wells were then washed with warm PBS and their viability was quantified using Annexin V / Propidium Iodide (PI) staining and flow cytometry. The percentage of cell viability was quantified by determining the percentage of cells that showed neither Annexin V staining (indicative of cell apoptosis) nor PI staining (necrosis or late stage apoptosis). The data are presented in Figure 15 and show a decrease in cell viability, especially for acid-containing particles.

[0263] All references cited in this specification, including publications, patent applications, and patents, are herein incorporated by reference to the same extent as if each reference was individually and specifically indicated to be incorporated by reference and is hereby incorporated by reference in its entirety as if each reference was individually and specifically indicated to be incorporated by reference.

[0264] In the context of the description of the invention (particularly in the context of the claims which follow), use of the terms "a," "an," and "the," as well as "at least one," and similar referents, should be construed to encompass both the singular and the plural, unless otherwise indicated herein or clearly contradicted by context. Use of the term "at least one" followed by a list of one or more items (e.g., "at least one of A and B") should be construed to mean one item selected from the listed items (A or B) or any combination of two or more of the listed items (A and B), unless otherwise indicated herein or clearly contradicted by context. The terms "comprising," "having," "including," and "containing" should be construed as open-ended terms (i.e., meaning "including, but not limited to"), unless otherwise indicated. The recitation of ranges of values ​​herein is intended to serve merely as a shorthand method of individually referring to each separate value falling within the range, unless otherwise indicated herein, and each separate value is incorporated herein as if it were individually recited herein. All methods described herein can be performed in any suitable order, unless otherwise indicated herein or clearly contradicted by context. Any examples provided herein, or the use of exemplary language (e.g., "etc.") are merely intended to better illustrate the invention, and are not intended to limit the scope of the invention unless otherwise claimed. No language in this specification should be construed as indicating any non-claimed element as essential to the practice of the invention.

[0265] Preferred embodiments of the present invention are described herein, including the best mode known to the inventors for carrying out the invention. Variations of these preferred embodiments will become apparent to those skilled in the art upon reading the foregoing description. The inventors anticipate that such variations will be utilized by those skilled in the art as appropriate, and the inventors intend for the invention to be practiced otherwise than as specifically described herein. Accordingly, this invention includes all modifications and equivalents of the subject matter recited in the claims appended hereto as permitted by applicable law. Moreover, this invention encompasses any combination of the above-described elements in all possible variations thereof unless otherwise indicated herein or clearly contradicted by context.

Claims

1. A composite particle comprising a compound having a steroid core structure, or a salt or ester thereof, the composite particle having a length of at least 100 nm in at least one dimension.

2. The composite particle of claim 1 further comprising a transition metal ion.

3. 3. The composite particle of claim 2, wherein the transition metal ions are selected from gold, silver, copper, platinum, palladium, nickel, and iron ions.

4. The composite particle of claim 3 , wherein the transition metal ions are selected from gold, silver, copper, and iron ions.

5. The composite particle according to claim 3 , wherein the transition metal ion is a Au(III) ion or a Fe(II) ion.

6. The composite particle of claim 1 further comprising an acid.

7. The composite particle of claim 1 further comprising an acid.

8. The composite particle of claim 7 , wherein the acid is selected from hydrochloric acid and salicylic acid.

9. The compound having a steroid core structure is preferably testosterone, exemestane, formestane, mesterolone, fluoxymesterone, methyltestosterone, oxandrolone, oxymetholone, mestranol, norethindrone, danazol, gestrinone, levonorgestrel, lynestrenol, norgestrel, desogestrel, etonogestrel, tibolone, ethynodiol, cyproterone, megestrol, abiraterone, dienogest, mifepristone, drospirenone, spironolactone, estradiol, polyestradiol, estramustine, estrone, estropipate, progesterone, dydrogesterone, hydroxyprogesterone, medroxyprogesterone, segesterone, norelgestromin, norgestimate, cortisol, cortisone, fluorometholone, difluprednate, fludrocortisone, fluocinolone, loteprednol, methylpred Nisolone, prednicarbate, prednisolone, prednisone, triamcinolone, alclometasone, betamethasone, clobetasol, clobetasone, clocortolone, desoximetasone, dexamethasone, diflorasone, difluocortolone, fluticasone, halometasone, mometasone, rimexolone, amcinonide, budesonide, ciclesonide, deflazacort, desonide, flunisolide, fluocinonide, halcinonide, cholesterol, es The composite particle according to any one of claims 1 to 8, which is selected from the group consisting of traziol, hydrocortisone, diflucortolone, boldenone, nandrolone, altrenogest, stanozolol, osaterone, estriol, aglepristone, trilostane, flumethasone, deoxycorticosterone, alphaxalone, desoxycorticosterone, and isoflupredone, or a salt or ester thereof, or any combination thereof.

10. The composite particle according to any one of claims 1 to 8, wherein the compound having a steroid core structure is a bile acid.

11. The composite particle of claim 10, wherein the bile acid is selected from cholic acid, deoxycholic acid, chenodeoxycholic acid, lithocholic acid, glycocholic acid, taurocholic acid, glycodeoxycholic acid, taurodeoxycholic acid, glycochenodeoxycholic acid, taurochenodeoxycholic acid, glycolithocholic acid, taurolithocholic acid, ursodeoxycholic acid, glycoursodeoxycholic acid, tauroursodeoxycholic acid, and obeticholic acid.

12. The composite particle according to claim 10, wherein the bile acid is selected from cholic acid and deoxycholic acid.

13. The composite particle according to any one of claims 1 to 8, wherein the compound having a steroid core structure is a salt of a bile acid.

14. 14. The composite particle of claim 13, wherein the salt of the bile acid is selected from sodium cholate, sodium deoxycholate, sodium ursodeoxycholate, and sodium chenodeoxycholate.

15. The composite particle according to any one of claims 1 to 8, wherein the compound having a steroid core structure is a corticosteroid compound, or a salt or ester thereof.

16. The corticosteroid compound may be hydrocortisone, dexamethasone, beclomethasone, ciclesonide, clobetasol, clobetasone, desonide, desoxymethasone, desoxycorticosterone, dichlorisone, diflorasone, diflucortolone, fluclarolone, fludrocortisone, flumethasone, fluocinolone, fluocinonide, flucortine, fluocortolone, fluprednidene, flurandrenolone, halcinonide, halometasone, methylprednisolone, triamcinolone, cortisone, cortodoxone, fluse 16. The composite particle of claim 15, wherein the compound is selected from the group consisting of tonide, fluradrenaline, medrysone, alclometasone, amciafer, amcinafide, amcinonide, betamethasone, budesonide, chlorprednisone, clocortelone, clesinolone, difluprednate, flucloronide, flunisolide, fluoromethalone, fluperolone, fluprednisolone, hydrocortamate, meprednisone, mometasone, paramethasone, prednisolone, prednisone, prednicarbate, and tixocortol, or a salt or ester thereof.

17. 17. The composite particle of claim 16, wherein the corticosteroid compound is selected from dexamethasone, methylprednisolone, and hydrocortisone, or salts or esters thereof.

18. The composite particle of any one of claims 1 to 17, wherein the composite particle has a length of at least 1 µm in at least one dimension.

19. The composite particle according to any one of claims 1 to 18, wherein the particle has a hexagonal columnar shape.

20. The composite particle according to claim 19, wherein the hexagonal prism has a diagonal length of 2.5 μm to 10 μm.

21. The composite particle according to claim 19 or 20, wherein the hexagonal column has a height of 2.5 μm to 6.5 μm.

22. The composite particle according to any one of claims 1 to 18, wherein the particle has a rod shape.

23. 23. The composite particle of claim 22, wherein the rod has a length of between 2.5 μm and 100 μm.

24. 24. The composite particle of claim 22 or claim 23, wherein the rod has a length of between 10 μm and 50 μm.

25. 25. The composite particle of any one of claims 1 to 24, wherein the particle consists essentially of (i) a compound having a steroid core structure, or a salt or ester thereof, and (ii) a transition metal ion, and / or an acid.

26. 26. The composite particle of any one of claims 1 to 25, wherein the particle is essentially free of transition metal nanoparticles.

27. A composition comprising a plurality of composite particles according to any one of claims 1 to 26.

28. 30. The composition of claim 27, further comprising a pharma- ceutically acceptable carrier.

29. A method for producing a plurality of composite particles according to any one of claims 1 to 28, comprising the steps of: (a) providing a first solution comprising a transition metal salt in ethyl acetate; (b) mixing the first solution with water to form a first emulsion; (c) mixing the first emulsion with a second solution comprising a compound having a steroid core structure or a salt or ester thereof to form a final mixture, thereby forming the composite particles. A method comprising:

30. A method for producing a plurality of composite particles according to any one of claims 1 to 28, comprising the steps of: (a) providing a first solution comprising a compound having a steroid core structure, or a salt or ester thereof, in ethyl acetate; (b) combining the first solution with a transition metal salt to form a second solution; (c) mixing the second solution with water to form a first emulsion; (d) mixing said first emulsion with a solution of a compound having a steroid core structure or a salt or ester thereof in water to form a final mixture, thereby forming said composite particles. A method comprising:

31. A method for producing a plurality of composite particles according to any one of claims 1 to 28, comprising the steps of: (a) providing a first solution comprising a transition metal salt in water; (b) combining the first solution with ethyl acetate to form a first emulsion; (c) mixing said first emulsion with a solution of a compound having a steroid core structure or a salt or ester thereof in water to form a final mixture, thereby forming said composite particles. A method comprising:

32. A method for producing a plurality of composite particles according to any one of claims 1 to 28, comprising the steps of: (d) providing a first solution comprising an acid, a compound having a steroid core structure or a salt or ester thereof, and water; (e) combining the first solution with ethyl acetate to form a first emulsion; (f) mixing the first emulsion with a solution of an acid in water to form a final mixture, thereby forming the composite particles. A method comprising:

33. A method for producing a plurality of composite particles according to any one of claims 1 to 28, comprising the steps of: (d) providing a first solution comprising an acid in ethyl acetate; (e) mixing the first solution with a second solution comprising a compound having a steroid core structure or a salt or ester thereof and water to form a first emulsion; (f) mixing the first emulsion with a third solution comprising a compound having a steroid core structure or a salt or ester thereof and water to form a final mixture, thereby forming the composite particles. A method comprising:

34. The method of any one of claims 29 to 33, wherein the compound having a steroid core structure is a bile acid or a salt or ester thereof.

35. 35. The method of claim 34, wherein the compound having a steroid core structure is selected from sodium cholate, sodium deoxycholate, sodium ursodeoxycholate, and sodium chenodeoxycholate.

36. 34. The method of any one of claims 29 to 33, wherein the compound having a steroid core structure is a corticosteroid compound, or a salt or ester thereof.

37. 37. The method of claim 36, wherein the corticosteroid compound is selected from dexamethasone, methylprednisolone, and hydrocortisone, or salts or esters thereof.

38. 32. The method of any one of claims 29 to 31, wherein the transition metal salt is selected from gold(III) salts, silver(I) salts, copper(II) salts, platinum(II) salts, palladium(II) salts, nickel(II) salts, iron(II) salts, and iron(III) salts.

39. 32. The method of any one of claims 29 to 31, wherein the transition metal salt is selected from gold(III) salts, silver(I) salts, copper(II) salts, and iron(II) salts.

40. 33. The method of any one of claims 29 to 32, wherein the transition metal salt is gold(III) chloride or iron(II) sulfate.

41. 41. The method of any one of claims 29 to 40, further comprising the step of stirring the final mixture for about 15 seconds to about 15 minutes.

42. The method of any one of claims 29 to 41, further comprising removing the solvent from the final mixture.

43. The method of any one of claims 29 to 42, further comprising separating the composite particles from the final mixture.

44. A method according to any one of claims 29 to 43, wherein the method is carried out entirely at ambient temperature.

45. The method of any one of claims 29 to 44, wherein the final mixture does not contain a reducing agent.

46. 29. The composition of claim 27 or claim 28 for treating a liver disease or a peroxisomal disorder in a subject in need of such treatment.

47. 47. The composition of claim 46, wherein the liver disease is a bile acid synthesis disorder or primary biliary cholangitis.

48. 47. The composition of claim 46, wherein the liver disease is a bile acid synthesis disorder caused by a single enzyme deficiency.

49. 47. The composition of claim 46, wherein the peroxisomal disease is a Zellweger spectrum disorder.

50. 29. A composition according to claim 27 or claim 28 for non-surgical removal of localised fat deposits in a subject by contacting said deposits.

51. 29. A composition as described in claim 27 or claim 28 for reducing subcutaneous fat deposits in a subject in need of reduction by administering locally to the subcutaneous fat deposits of said subject.

52. 29. The composition of claim 27 or claim 28 for treating cancer in a subject in need of treatment.

53. 53. The composition of claim 52, wherein the cancer is selected from colorectal cancer and gastric cancer.

54. The composition according to claim 27 or 28, for suppressing the proliferation of cancer cells by contacting the composition with cancer cells.

55. 55. The composition of claim 54, wherein the cancer cells are selected from colorectal cancer cells and gastric cancer cells.

56. The composition of claim 27 or claim 28 for treating a disorder selected from the group consisting of endocrine disorders, rheumatic disorders, collagen diseases, skin diseases, allergic conditions, eye diseases, respiratory diseases, blood disorders, neoplastic diseases, gastrointestinal diseases, nervous system disorders, inflammatory disorders, and renal diseases.

57. Use of a particle or composition according to any of claims 1 to 28.

58. Use of a particle or composition according to any of claims 1 to 28 in the manufacture of a medicament for removing localised fatty deposits.

59. 29. Use of a particle or composition according to any one of claims 1 to 28 in the manufacture of a medicament for treating a disease selected from liver disease, peroxisomal disease, cancer, endocrine disorder, rheumatic disorder, collagen disease, skin disease, allergic condition, eye disease, respiratory disease, blood disorder, neoplastic disease, gastrointestinal disease, nervous system disorder, inflammatory disorder, and renal disease.

Images