Classifications

• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
  • A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
  • A61K31/57—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane or progesterone
  • A61K31/573—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane or progesterone substituted in position 21, e.g. cortisone, dexamethasone, prednisone or aldosterone
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
  • A61K31/575—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of three or more carbon atoms, e.g. cholane, cholestane, ergosterol, sitosterol
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K33/00—Medicinal preparations containing inorganic active ingredients
  • A61K33/24—Heavy metals; Compounds thereof
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K33/00—Medicinal preparations containing inorganic active ingredients
  • A61K33/24—Heavy metals; Compounds thereof
  • A61K33/26—Iron; Compounds thereof
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
  • A61K9/141—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers
  • A61K9/143—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers with inorganic compounds
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
  • A61K9/141—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers
  • A61K9/145—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers with organic compounds
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
  • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
  • A61K9/1605—Excipients; Inactive ingredients
  • A61K9/1611—Inorganic compounds
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
  • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
  • A61K9/1605—Excipients; Inactive ingredients
  • A61K9/1617—Organic compounds, e.g. phospholipids, fats
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
  • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
  • A61K9/1682—Processes
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
  • A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
  • A61K9/5005—Wall or coating material
  • A61K9/501—Inorganic compounds
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
  • A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
  • A61K9/5005—Wall or coating material
  • A61K9/5015—Organic compounds, e.g. fats, sugars
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P35/00—Antineoplastic agents
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Definitions

• composite particles comprising compounds having a steroid core structure, or salts or esters thereof. Also provided herein are compositions comprising the particles, and methods of using the particles, for example in methods of treating liver disorders or for fat reduction.
• Compounds having a steroid backbone such as bile acids and corticosteroids, are useful in treating a wide variety of disorders.
• oral and subcutaneous administration of solubilized versions of these drugs may have limited efficacy and may impose unwanted side effects.
• the present disclosure provides a composite particle comprising a compound having a steroid core structure, or a salt or ester thereof, wherein the composite particle has a length in at least one dimension of at least 100 nm.
• the composite particle further comprises transition metal ions.
• the transition metal ions are selected from gold, silver, copper, platinum, palladium, nickel, and iron ions.
• the transition metal ions are selected from gold, silver, copper, and iron ions.
• the transition metal ions are gold ions (e.g., Au(HI) ions) or iron ions (e.g., Fe(II) ions).
• the composite particle further comprises an acid.
• the acid is selected from hydrochloric acid and salicylic acid.
• the compound having a steroid core structure is selected from the group consisting of 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, nore
• the compound having a steroid core structure is a bile acid.
• the bile acid is selected from 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.
• the bile acid is selected from cholic acid and deoxycholic acid.
• the compound having a steroid core structure is a salt of a bile acid.
• the salt of the bile acid is selected from sodium cholate, sodium deoxy cholate, sodium ursodeoxycholate, and sodium chenodeoxycholate.
• the compound having a steroid core structure is a corticosteroid compound or a salt or ester thereof.
• the corticosteroid compound is selected from 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, fiuradrenalone, medrysone, alclometasone, amciafel, amcina
• the composite particle has a length in at least one dimension of at least 1 ⁇ m.
• the composite particle has a hexagonal prism shape.
• the hexagonal prism has a diagonal length of 2.5 ⁇ m to 10 pm.
• the hexagonal prism has a height of 2.5 pm to 6.5 pm.
• the composite particle has a rod shape.
• the rod has a length of 2.5 pm to 100 pm. In some embodiments, the rod has a length of 10 pm to 50 pm.
• the particle consists essentially of: (i) the compound having a steroid core structure or a salt or ester thereof, and (ii) transition metal ions and/or an acid.
• the particle consists essentially of a bile acid or salt or ester thereof and gold ions (e.g., Au(IH) ions).
• the particle is essentially free of transition metal nanoparticles
• the present disclosure also provides a composition comprising a plurality of composite particles described herein.
• the composition further comprises a pharmaceutically acceptable carrier.
• the present disclosure also provides a method of making a plurality of composite particles, comprising:
• the present disclosure also provides a method of making a plurality of composite particles, comprising:
• the present disclosure also provides a method of making a plurality of composite particles, comprising:
• the present disclosure also provides a method of making a plurality of composite particles, comprising:
• the present disclosure also provides a method of making a plurality of composite particles, comprising:
• the compound having a steroid core structure is a bile acid or a salt or an ester thereof.
• the compound having a steroid core structure is selected from sodium cholate, sodium deoxycholate, sodium ursodeoxycholate, and sodium chenodeoxycholate.
• the compound having a steroid core structure is a corticosteroid compound or a salt or an ester thereof.
• the corticosteroid compound is selected from dexamethasone, methylprednisolone, and hydrocortisone, or a salt or an ester thereof.
• the transition metal salt is selected from a gold(III) salt, a silver(I) salt, a copper(H) salt, a platinum(H) salt, a palladium(II) salt, a nickel(II) salt, an iron(II) salt, and an iron(III) salt.
• the transition metal salt is selected from a gold(III) salt, a silver(I) salt, a copper(II) salt, and an iron(II) salt.
• the transition metal salt is gold(III) chloride or iron(II) sulfate.
• the method further comprises a step of stirring the final mixture for about 15 seconds to about 15 minutes. In some embodiments, the method further comprises removing the solvents from the final mixture. In some embodiments, the method further comprises separating the composite particles from the final mixture. In some embodiments, the method is conducted entirely at ambient temperature. In some embodiments, the final mixture does not comprise a reducing agent.
• the present disclosure also provides a method of treating a liver disease or a peroxisomal disorder 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).
• a composition described herein e.g., a composition comprising a plurality of composite particles described herein.
• the liver disease is a bile acid synthesis disorder or primary biliary cholangitis.
• the liver disease is a bile acid synthesis disorder due to a single enzyme defect
• the peroxisomal disorder is a Zellweger spectrum disorder.
• the present disclosure also provides a method of non-surgical removal of a localized fat deposit in a subject, comprising contacting the deposit with an effective amount of a composition described herein (e.g., a composition comprising a plurality of composite particles described herein).
• a composition described herein e.g., a composition comprising a plurality of composite particles described herein.
• the present disclosure also provides a method of reducing a subcutaneous fat deposit in a subject in need thereof, comprising administering locally to the subcutaneous fat deposit in the subject an effective amount of a composition described herein (e.g., a composition comprising a plurality of composite particles described herein).
• a composition described herein e.g., a composition comprising a plurality of composite particles described herein.
• 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).
• a composition described herein e.g., a composition comprising a plurality of composite particles described herein.
• the cancer is colorectal cancer or gastric cancer.
• the present disclosure also provides a method of reducing 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).
• a composition described herein e.g., a composition comprising a plurality of composite particles described herein.
• the cancer cells are colorectal cancer cells or gastric cancer cells.
• the present disclosure also provides a method of treating a disorder selected from the group consisting of endocrine disorders, rheumatic disorders, collagen diseases, dermatologic diseases, allergic states, ophthalmic diseases, respiratory diseases, hematologic disorders, neoplastic diseases, gastrointestinal diseases, nervous system disorders, inflammatory disorders, and renal diseases, 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).
• a composition described herein e.g., a composition comprising a plurality of composite particles described herein.
• the present disclosure also provides uses of the particles and compositions described herein (e.g., use for removal of a localized fat deposit, use for reducing a subcutaneous fat deposit in a subject, use in the treatment of cancer such as colorectal cancer, use in reducing the proliferation of cancer cells, use in the treatment of disorders selected from endocrine disorders, rheumatic disorders, collagen diseases, dermatologic diseases, allergic states, ophthalmic diseases, respiratory diseases, hematologic disorders, neoplastic diseases, gastrointestinal diseases, nervous system disorders, inflammatory disorders, and renal diseases, etc.).
• cancer such as colorectal cancer
• disorders selected from endocrine disorders, rheumatic disorders, collagen diseases, dermatologic diseases, allergic states, ophthalmic diseases, respiratory diseases, hematologic disorders, neoplastic diseases, gastrointestinal diseases, nervous system disorders, inflammatory disorders, and renal diseases, etc.
• FIGS. 1A-1D show scanning electron microscopy (SEM) images of composite particles prepared with different compounds having a steroid core structure: (FIG. 1 A) cholate; (FIG. IB) deoxycholate; (FIG. 1C) methylprednisolone; and (FIG. ID) hydrocortisone; all prepared with gold(m) chloride.
• FIG. 2 shows energy-dispersive spectroscopy (EDS) data for cholate/gold ion particles prepared according to methods disclosed herein.
• EDS energy-dispersive spectroscopy
• FIGS. 3A-3B show: (FIG. 3A) a brightfield microscopy image of rhodamine-loaded cholate particles containing gold ions; and (FIG. 3B) a fluorescence microscopy image of the same rhodamine-loaded cholate particles.
• FIGS. 4A-4B show an SEM image (FIG. 4A) and EDS data (FIG. 4B) for composite particles prepared with dexamethasone phosphate and iron (II) sulfate heptahydrate.
• FIG. 5 shows degradation data for composite particles prepared with dexamethasone phosphate and iron (H) sulfate heptahydrate
• FIGS. 6A-6B show SEM images of composite particles prepared from hydrochloric acid and: (FIG. 6A) sodium cholate; (FIG. 6B) sodium deoxycholate; sodium chenodeoxycholate (FIG. 6C); and sodium ursodeoxycholate (FIG. 6D).
• FIGS. 7A-7B show SEM images of composite particles prepared from hydrochloric acid and: methylprednisolone succinate (FIG. 7 A); and hydrocortisone succinate (FIG. 7B).
• FIGS. 8A-8F show SEM images of composite particles prepared from salicylic acid and: (FIG. 8A): sodium cholate; (FIG. 8B) sodium deoxycholate; (FIG. 8C) methylprednisolone succinate; (FIG. 8D) sodium chenodeoxycholate; (FIG. 8E) hydrocortisone succinate; and (FIG. 8F) sodium ursodeoxycholate.
• FIG. 9 shows UV-visible spectrometry data demonstrating salicylic acid release from deoxycholate particles.
• FIGS. 10A-10B show SEM images of cholate/gold ion particles when exposed to a degradation protocol as detailed in Example 2: (FIG. 10A) cholate/gold ion particles prepared according to methods disclosed herein on days 0, 1, 3, 5, 10, and 15 of a degradation protocol; and (FIG. 10B) comparison cholate/gold(0) nanoparticle particles prepared according to a previously-disclosed method, on days 0, 1, 3, 5, 10, and 15 of a degradation protocol.
• FIG. 11 shows data for the release of cholate from particles subjected to a degradation process.
• FIG. 12 shows dynamic light scattering (DLS) data showing the presence of gold nanoparticles following degradation of cholate particles prepared according to a previously disclosed method.
• FIG. 13 shows UV-visible spectrometry data for the detection of gold nanoparticles following degradation of deoxycholate particles prepared according to a method disclosed herein, and deoxycholate particles prepared according to a previously disclosed method.
• FIG. 14 shows images of samples subjected to a gold nanoparticle formation process.
• FIGS. 15A-15B show images of samples in which beef fat was incubated with particles disclosed herein, resulting in cell lysis: (FIG. 15A) negative and positive controls; (FIG. 15B) negative control and samples incubated with the indicated particles; in each case, arrows point to lipid droplets.
• FIG. 16 shows results of cell viability assays when HT-29 colon cancer cells were incubated with composite particles described herein.
• the present disclosure relates to particles that may be used for controlled release of compounds having a steroid core structure, or their salts.
• the particles may be used for a variety of medical and dermatological treatments, such as treatments of liver disorders and for non- surgical removal of localized fat deposits.
• the particles can also be used for the treatment of cancer or in a method of reducing proliferation of cancer cells.
• transition metal e.g., gold
• nanoparticle formation to produce particles composed of bile salts. See, e.g., International Patent Publication No. WO 2021/011753.
• the nanoparticles were present in the sample as a result of the fabrication process, in which transition metal precursors were reduced to form elemental transition metal nanoparticles in situ.
• a heating step was used to effect reduction of the transition metal ions, and particles formed in solution alongside the transition metal nanoparticles.
• Composite particles disclosed herein do not include transition metal nanoparticles. Rather, the particles are fabricated from a solution containing either transition metal ions or an acid, and a reduction step is not required to template particle formation. Without wishing to be limited by theory, the particles disclosed herein are believed to form as a result of the establishment of an appropriate pH in the solution or emulsion, which can be achieved either using a solution of an acid or of a transition metal salt that forms an acidic solution when dissolved in water. In some embodiments, (e.g., when transition metal ions are used), particles may form as a result of formation of a complex between transition metal ions and a compound having a steroid backbone. The particles can be prepared in several ways, none of which involve a reducing agent or a heating step, such that transition metal nanoparticles do not form.
• the disclosure provides a composite particle comprising a compound having a steroid core structure, or a salt or ester thereof, wherein the composite particle has a length in at least one dimension of at least 100 nm.
• the particle further comprises transitional metal ions (e.g., from a transition metal salt).
• the particle further comprises an acid.
• the composite particles include a compound having a steroid core structure, as shown below, with the conventional numbering on the perhydrocyclopenta[a]phenanthrene core:
• the steroid core structure can be fully saturated as shown above, or can include one or more double bonds.
• the core structure can include one or more alkyl functional groups; for example, steroid compounds contain methyl groups at the CIO and C13 positions, and often contain an alkyl group (or a functionalized alkyl group) at Cl 7.
• the core structure can also include one or more hydroxy or oxo groups; for example, steroids and sterols have an oxo or hydroxy group at C3.
• the compound having a steroid core structure is selected from the group consisting of 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, drospiren
• testosterone e.g.
• the composite particles comprise the compound having a steroid core structure or salt or ester thereof in an amount of about 70 wt% to about 99 wt%, or about 80 wt% to about 95 wt%.
• the composite particles comprise the compound having a steroid core structure or salt or ester thereof in an amount of about 70 wt%, 71 wt%, 72 wt%, 73 wt%, 74 wt%, 75 wt%, 76 wt%, 77 wt%, 78 wt%, 79 wt%, 80 wt%, 81 wt%, 82 wt%, 83 wt%, 84 wt%, 85 wt%, 86 wt%, 87 wt%, 88 wt%, 89 wt%, 90 wt%, 91 wt%, 92 wt%, 93 wt%
• the compound having a steroid core structure is a bile acid, or a salt or ester thereof.
• the disclosure provides a composite particle comprising a bile acid, or a salt or ester thereof, wherein the composite particle has a length in at least one dimension of at least 100 nm.
• the composite further comprises transition metal ions and/or an acid.
• the disclosure provides a composite particle comprising a bile acid, or a salt or ester thereof, and gold ions (e.g., Au(III) ions) or iron ions (e.g., Fe(II) ions).
• the 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).
• Bile acids are steroid acids primarily found in bile, including both primary bile acids, which are synthesized by the liver, and secondary bile acids, which are synthesized from primary bile acids by bacteria in the colon. Bile acids and their salts help to solubilize lipids in the small intestine and regulate several hepatic, biliary, and intestinal functions; they have been proposed as therapeutic agents for treatment of different conditions including bile acid synthesis disorders and peroxisomal disorders, primary biliary cholangitis, primary sclerosing cholangitis, cardiometabolic diseases, gallstones and bile duct stones, non-alcoholic fatty liver disease, type-2 diabetes, human immunodeficiency virus type 1 (HIV-1), acute pancreatitis, and cancer.
• HAV-1 human immunodeficiency virus type 1
• Orally administered formulations of certain bile acids have been approved by the United States Food and Drug Administration (FDA) for treatment of different bile synthesis disorders and liver dysfunctions.
• FDA United States Food and Drug Administration
• cholic acid capsules are approved for treatment of bile acid synthesis disorders and peroxisomal disorders
• both ursodeoxycholic acid tablets and obeticholic acid tablets have been approved for treatment of primary biliary cholangitis.
• oral administration of these drugs may limit their bioavailability and can impose cytotoxicity risks through their membrane disruptive properties.
• injectable deoxycholic acid is approved by the U.S. FDA for destruction of fat cells to reduce moderate-to- severe fat below the chin.
• numerous injections are required for effective treatment.
• Formulation of bile acids in the composite particles disclosed herein provide controlled or targeted delivery of bile acids to increase specificity while lowering side effects.
• 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 semisynthetic bile acids, such as obeticholic acid.
• 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.
• the bile acid may be in the form of a salt.
• the bile acid salt is a sodium or potassium salt
• the bile acid salt is a sodium salt.
• the particle comprises a bile acid salt selected from sodium cholate, sodium deoxycholate, sodium ursodeoxycholate, and sodium chenodeoxycholate.
• the particle comprises a bile acid salt selected from sodium cholate and sodium deoxycholate.
• the bile acid salt is sodium cholate.
• the bile acid salt is sodium deoxycholate.
• the bile acid salt is sodium ursodeoxycholate.
• the bile acid salt is sodium chenodeoxycholate.
• the composite particles comprise the bile acid or salt or ester thereof in an amount of about 70 wt% to about 99 wt%, or about 80 wt% to about 95 wt%.
• the composite particles comprise the bile acid or salt or ester thereof in an amount of about 70 wt%, 71 wt%, 72 wt%, 73 wt%, 74 wt%, 75 wt%, 76 wt%, 77 wt%, 78 wt%, 79 wt%, 80 wt%, 81 wt%, 82 wt%, 83 wt%, 84 wt%, 85 wt%, 86 wt%, 87 wt%, 88 wt%, 89 wt%, 90 wt%, 91 wt%, 92 wt%, 93 wt%, 94 wt%, 95 wt%.
• the compound having a steroid core structure is a corticosteroid, or a salt or ester thereof.
• the disclosure provides a composite particle comprising a corticosteroid, or a salt or ester thereof, wherein the composite particle has a length in at least one dimension of at least 100 run.
• the composite particle further comprises transition metal ions and/or an acid.
• the disclosure provides a composite particle comprising a corticosteroid, or a salt or ester thereof, and gold ions (e.g., Au(III) ions) or iron ions (e.g., Fe(H) ions).
• 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.
• Corticosteroids are generally grouped into four classes: Group A (hydrocortisone type), including 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), including amcinonide, budesonide, desonide, fluocinolone (e.g., fluocinolone acetonide), fluocinonide, halcinonide, and triamcinolone (e.g., triamcinolone (
• the corticosteroid is selected from hydrocortisone (e.g., hydrocortisone acetate, hydrocortisone aceponate, hydrocortisone buteprate, hydrocortisone butyrate, hydrocortisone cypionate, or hydrocortisone succinate), dexamethasone (e.g., dexamethasone phosphate), beclometasone (e.g., beclometasone 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), diflucor
• the corticosteroid is selected from dexamethasone (e.g., dexamethasone phosphate), methylprednisolone (e.g., methylprednisolone succinate), and hydrocortisone (e.g., hydrocortisone succinate).
• dexamethasone e.g., dexamethasone phosphate
• methylprednisolone e.g., methylprednisolone succinate
• hydrocortisone e.g., hydrocortisone succinate
• the composite particles comprise the corticosteroid or salt or ester thereof in an amount of about 70 wt% to about 99 wt%, or about 80 wt% to about 95 wt%.
• the composite particles comprise the bile acid or salt or ester thereof in an amount of about 70 wt%, 71 wt%, 72 wt%, 73 wt%, 74 wt%, 75 wt%, 76 wt%, 77 wt%, 78 wt%, 79 wt%, 80 wt%, 81 wt%, 82 wt%, 83 wt%, 84 wt%, 85 wt%, 86 wt%, 87 wt%, 88 wt%, 89 wt%, 90 wt%, 91 wt%, 92 wt%, 93 wt%, 94 wt%, 95
• the compound having a steroid core structure can be in the form of a salt.
• the compound having a steroid core structure can have one or more acidic moieties (e.g., carboxylates), which can form a salt with a suitable cation, such as an alkali metal cation (e.g., sodium, lithium, potassium), an ammonium cation (e.g., NR ⁇ T, where each R is independently selected from hydrogen and an alkyl group), or the like.
• the salt is a sodium salt
• the compound having a steroid core structure also includes esters of steroid compounds. In such ester compounds, one or more hydroxy groups can be functionalized with an acyl group to form an ester.
• ester groups include acetate, adamantoate, benzoate, buteprate, butyrate, caproate, cypionate, enanthate, etabonate, furoate, hexanoate, linoleate, palmitate, pivalate, propionate, tebutate, succinate, undecanoate, undecylenate, valerate, and the like.
• the compound can also be in the form of a cyclic ketal, such as a cyclic acetal.
• the particles further comprise transition metal ions.
• the particles comprise gold, silver, copper, platinum, palladium, nickel, or iron ions.
• the particles comprise gold, silver, copper, or iron ions.
• the particles comprise gold(III) ions, silver(I) ions, copper(II) ions, nickelfU) ions, palladium(II) ions, platinum(II) ions, iron(H) ions, or ironflU) ions.
• the particles comprise gold ions (e.g., Au(HI) ions) or iron ions (e.g., Fe(n) ions).
• the transition metal ions may be present in the particles in an amount of about 1 wt% to about 30 wt%, or about 5 wt% to about 20 wt%.
• the composite particles comprise the transition metal ions in an amount of about 1 wt%, about 2 wt%, about 3 wt%, about 4 wt%, about 5 wt%, about 6 wt%, about 7 wt%, about 8 wt%, about 9 wt%, about 10 wt%, about 11 wt%, about 12 wt%, about 13 wt%, about 14 wt%, about 15 wt%, about 16 wt%, about 17 wt%, about 19 wt%, about 20 wt%, about 21 wt%, about 22 wt%, about 23 wt%, about 24 wt%, about 25 wt%, about 26 wt%, about 27 wt%, about 28 wt
• the particles in addition to the compound having a steroid cores structure (or salt or ester thereof), the particles further comprise an acid.
• the acid can be an inorganic acid or an organic acid.
• suitable inorganic acids include, but are not limited to: hydrochloric, hydrobromic, hydroiodic, sulfuric, sulfurous, nitric, nitrous, phosphoric, and phosphorous.
• 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, hydroxynaphthalene carboxylic, 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, trifluorome
• 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).
• 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 previously-described composite particles comprising a compound having a steroid core structure, such as those disclosed in International Patent Publication No. WO 2021/011753, which are formed using a double emulsion method.
• the phrase “essentially free of’ transition metal nanoparticles means that the nanoparticles include less than 0.5 wt% transition metal nanoparticles, or less than 0.2 wt%, or less than 0.1 wt%, or 0 wt% transition metal nanoparticles. In some embodiments, the particles do not include any detectable amount of metal nanoparticles.
• the composite particles can be prepared by a variety of methods.
• the method comprises:
• a second method for making a plurality of composite particles comprises:
• a third method for making a plurality of composite particles comprises:
• a fourth method for making a plurality of composite particles comprises: (a) providing a first solution comprising an acid, a compound having a steroid core structure or a salt or ester thereof, and water;
• a fifth method for making a plurality of composite particles comprises:
• the transition metal salt is a gold(IH) 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.
• the transition metal salt is a gold(III) salt
• the transition metal salt is gold(HI) chloride.
• the transition metal salt is an iron(II) salt. .
• the transition metal salt is iron(II) sulfate.
• the transition metal salt is a silver(I) salt.
• the transition metal salt is silver(I) nitrate.
• the transition metal salt is a copper(II) salt In some embodiments, the transition metal salt is copper(II) chloride.
• the compound having a steroid core structure is a bile acid or a salt or ester thereof.
• 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.
• the bile acid is selected from cholic acid, deoxycholic acid, ursodeoxycholic acid, and chenodeoxycholic acid.
• the compound having a steroid core structure is a bile acid salt.
• the bile acid salt is a sodium or potassium salt.
• the bile acid salt is a sodium salt Accordingly, in some embodiments, the bile acid salt is selected from sodium cholate, sodium deoxycholate, sodium ursodeoxycholate, and sodium chenodeoxycholate.
• the bile acid salt is selected from sodium cholate and sodium deoxycholate.
• the bile acid salt is sodium cholate.
• the bile acid salt is sodium deoxycholate.
• the bile acid salt is sodium ursodeoxycholate.
• the bile acid salt is sodium chenodeoxycholate.
• the compound having a steroid core structure is a corticosteroid compound or a salt or ester thereof.
• the corticosteroid compound is selected from dexamethasone, methylprednisolone, and hydrocortisone, or an ester thereof.
• the corticosteroid compound is dexamethasone or an ester thereof.
• the corticosteroid compound is methylprednisolone or an ester thereof.
• the corticosteroid compound is hydrocortisone or an ester thereof.
• the composite particles form immediately upon formation of the final mixture.
• the first, second, and third methods further comprise a step of stirring a final mixture.
• the final mixture is stirred for about 1 second to about 15 minutes, during which time the composite particles form.
• the stirring step may comprise 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.
• the first, second, third, fourth, and fifth methods may further comprise an additional step of separating the composite particles from the mixture.
• the separating step can include filtering using a filter having an appropriate pore size.
• the separating step may alternatively or additionally include centrifugation.
• centrifugation e.g., at 100-5000 rpm, such as 100, 200, 300, 400, 500, 600, 700, 800, 900, 1000, 1500, 2000, 2500, 3000, 3500, 4000, 4500, or 5000 rpm
• the composite particles may be recovered in the pellet from the centrifugation.
• the method does not comprise a heating step.
• the methods disclosed herein do not require a reduction step, and accordingly no heating step is required.
• the methods are conducted at ambient temperature.
• the compositions do not include a reducing agent (e.g., sodium citrate or sodium ascorbate).
• a reducing agent is not necessary as the composite particles form without being templated by the formation of transition metal nanoparticles.
• 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 with heating, or evaporation under reduced pressure. In some embodiments, the solvent is removed by evaporation at ambient temperature and pressure.
• the composite particles consist essentially of a compound having a steroid core structure, or the salt or ester thereof, and transition metal ions.
• the particle consists essentially of a bile acid or salt or ester thereof and gold, silver, copper, platinum, palladium, nickel, or iron ions.
• the composite particles consist essentially of a bile acid or a salt or ester thereof, and gold, silver, copper, or iron ions.
• the composite particles consist essentially of a bile acid or a salt or ester thereof, and gold ions (e g., Au(III) ions) or iron ions (e.g., iron(II) ions).
• the composite particles consist essentially of a corticosteroid, or a salt or ester thereof, and transition metal ions.
• the particle consists essentially of a corticosteroid, or a salt or ester thereof, and gold, silver, copper, platinum, palladium, nickel, or iron ions.
• the composite particles consist essentially of a corticosteroid, or a salt or ester thereof, and gold, silver, copper, or iron ions.
• the composite particles consist essentially of a corticosteroid, or a salt or ester thereof, and gold ions (e.g., Auflll) ions) or iron ions (e.g., iron(II) ions).
• the composite particles do not include, or are substantially free of, other components such as small molecules, polymers, and the like.
• the composite particles consist essentially of a compound having a steroid core structure, or the salt or ester thereof, and an acid.
• the particle consists essentially of a bile acid or salt or ester thereof and an acid selected from hydrochloric acid and salicylic acid.
• the composite particles consist essentially of a corticosteroid, or a salt or ester thereof, and an acid.
• the particle consists essentially of a corticosteroid, or a salt or ester thereof, an acid selected from hydrochloric acid and salicylic acid.
• the composite particles do not include, or are substantially free of, other components such as metal nanoparticles, metal ions, small molecules, polymers, and the like.
• the composite particles do not include a polymer.
• the composite particles do not include polymers such as polyesters, including poly(lactic-co-glycolic acid) (PLGA), or anionic polymers such as polysaccharides (e.g., dextran sulfate, heparin, heparin sulfate, chondroitin sulfate, hyaluronic acid, or alginic acid), nucleic acid polymers, and the like.
• the compound having the steroid core structure e.g., the bile acid or the corticosteroid
• the composite particles do not include phosphatidylcholine.
• the particles may further comprise other components.
• the particles further include a targeting ligand.
• Targeting ligands are well-known to those skilled in the art; exemplary targeting ligands are described by Srinivasarao et al. “Ligand-Targeted Drug Delivery,” Chem. Rev. 2017, 117(19), 12133-12164, which is incorporated herein by reference.
• Exemplary targeting ligands include antibodies to molecules that are expressed on cell surfaces; for example, certain lipoma cells are known to overexpress CD34, and an anti-CD34 antibody could be used as a targeting ligand for those cells.
• the particles further include 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. J. L. Jameson et al, McGraw-Hill Education (2016); Physicians' Desk Reference, 71 st 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.
• the composite particles can be characterized by a wide variety of techniques. For example, particles can be imaged using scanning electron microscopy (SEM) to determine their size and shape.
• SEM scanning electron microscopy
• the elemental composition can be confirmed using elemental analysis, for example using energy-dispersive spectroscopy (EDS) and/or X-ray photoelectron spectroscopy (XPS).
• EDS energy-dispersive spectroscopy
• XPS X-ray photoelectron spectroscopy
• the presence of the bile acid can further be confirmed using techniques such as high- performance liquid chromatography (HPLC), Fourier-transform infrared (FUR) spectroscopy, and nuclear magnetic resonance (NMR) spectroscopy.
• HPLC high- performance liquid chromatography
• FUR Fourier-transform infrared
• NMR nuclear magnetic resonance
• 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 the hexagon, as well as their height. In some embodiments, the composite particles have a hexagonal prism shape with an average diagonal length of about 2.5 pm to about 10 pm, or about 3.0 pm to about 9.0 pm (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,
• the composite particles have a hexagonal prism shape with an average height of about 2.5 pm to about 6.5 pm (e.g., about 2.5, 3.0, 3.5, 4.0, 4.5, 5.0, 5.5, 6.0, or 6.5 pm, or any range therebetween).
• the composite particles have a rod shape.
• the composite particles have a rod shape with an average length of about 2.5 pm to about 100 pm, or about 10 pm to about 50 pm (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 pm, or any range therebetween).
• 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.
• the composite particles have a hexagonal sheet shape with an average long side length of about 10 pm to about 50 pm (e.g., about 10, 15, 20, 25, 30, 35, 40, 45, or 50 pm, or any range therebetween), and a short side length of 5 pm to 20 pm (e.g., about 5, 7.5, 10, 12.5, 15,
• the composite particles have a spherical shape.
• the sphere has a diameter of 1 pm to 10 pm (e.g., about 1 pm, about 2 pm, about 3 pm, about 4 pm, about 5 pm, about 6 pm, about 7 pm, about 8 pm, about 9 pm, or about 10 pm, or any range therebetween).
• the disclosure provides a composition comprising a plurality of the composite particles described herein.
• the compositions further comprise a pharmaceutically acceptable carrier.
• the term “pharmaceutically acceptable carrier” refers to a pharmaceutically-acceptable material, composition or vehicle for administration of an active agent described herein.
• Pharmaceutically acceptable carriers include any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents, and the like which are compatible with the activity of the bile acid or salt or ester thereof and are physiologically acceptable to the subject.
• materials that can serve as pharmaceutically-acceptable carriers include: (i) sugars, such as lactose, glucose and sucrose; (ii) starches, such as com starch and potato starch; (iii) cellulose, and its derivatives, such as sodium carboxymethyl cellulose, methylcellulose, ethyl cellulose, microcrystalline cellulose and cellulose acetate; (iv) powdered tragacanth; (v) malt; (vi) gelatin; (vii) lubricating agents, such as magnesium stearate, sodium lauryl sulfate and talc; (viii) excipients, such as cocoa butter and suppository waxes; (ix) oils, such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, com oil and soybean oil; (x) glycols, such as propylene glycol; (xi) polyols, such as glycerin, sorbitol, mannito
• pharmaceutically acceptable carriers include, but are not limited to pharmaceutically acceptable excipients such as inert diluents, disintegrating agents, binding agents, lubricating agents, sweetening agents, flavoring agents, coloring agents and preservatives.
• suitable inert diluents include sodium and calcium carbonate, sodium and calcium phosphate, and lactose, while com starch and alginic acid are suitable disintegrating agents.
• Binding agents may include starch and gelatin, while the lubricating agent, if present, will generally be magnesium stearate, stearic acid or talc. If desired, the tablets may be coated with a material such as glyceryl monostearate or glyceryl distearate, to delay absorption in the gastrointestinal tract.
• compositions described herein can vary in a formulation described herein, depending on the administration route.
• the formulations described herein can be delivered via any administration mode known to a skilled practitioner.
• the formulations described herein can be delivered in a systemic manner, via administration routes such as, but not limited to, oral and parenteral, including intravenous, intramuscular, intraperitoneal, intradermal, and subcutaneous.
• the formulations described herein are in a form that is suitable for injection, particularly subcutaneous injection.
• the formulations described herein are formulated for oral administration, such as a tablet or a capsule.
• a formulation described herein can be generally formulated in a unit dosage injectable form (solution, suspension, emulsion).
• the formulations suitable for injection include sterile aqueous solutions or dispersions.
• the carrier can be a solvent or dispersing medium containing, for example, water, buffers (e.g., phosphate buffered saline), polyol (for example, glycerol, propylene glycol, liquid polyethylene glycol, and the like), salts (e.g., sodium chloride), or suitable mixtures thereof.
• the pharmaceutical carrier can be a saline solution.
• the pharmaceutical carrier can be a buffered solution (e.g., PBS).
• the composition may also include a solubilizing agent and a local anesthetic such as lignocaine to ease pain at the site of the injection.
• the formulations can also contain auxiliary substances such as wetting or emulsifying agents, pH buffering agents, gelling or viscosity enhancing additives, preservatives, colors, and the like, depending upon the route of administration and the preparation desired.
• Standard texts such as “REMINGTON'S PHARMACEUTICAL SCIENCE,” 17th edition, 1985, incorporated herein by reference, may be consulted to prepare suitable preparations, without undue experimentation.
• any vehicle, diluent, or additive used should have to be biocompatible with the active agents described herein.
• the components of the formulations should be selected to be biocompatible with respect to the active agent. This will present no problem to those skilled in chemical and pharmaceutical principles, or problems can be readily avoided by reference to standard texts or by simple experiments (not involving undue experimentation).
• the formulations described herein can be administered with a delivery device, e.g., a syringe.
• a delivery device e.g., a syringe.
• an additional aspect described herein provides for delivery devices comprising at least one chamber with an outlet, wherein the at least one chamber comprises a pre-determined amount of any formulation described herein and the outlet provides an exit for the formulation enclosed inside the chamber.
• a delivery device described herein can further comprise an actuator to control release of the formulation through the outlet.
• Such delivery device can be any device to facilitate the administration of any formulation described herein to a subject, e.g., a syringe, a dry powder injector, a nasal spray, a nebulizer, or an implant such as a microchip, e.g., for sustained-release or controlled release of any formulation described herein.
• compositions do not include phosphatidylcholine.
• the composite particles can be used in a variety of methods, such as a methods of treating a disorder in a subject.
• the term “subject ' ’ includes human and non-human animals.
• exemplary human subjects include a human patient having a disorder, e.g. , a disorder described herein, or a normal subject.
• non-human animals includes all vertebrates, e.g. , nonmammals (such as chickens, amphibians, reptiles) and mammals, such as non-human primates, domesticated and/or agriculturally useful animals, e.g. , horse, sheep, dog, cat, cow, pig, etc.
• the term “treat” or “treating” a subject having a disorder refers to subjecting the subject to a regimen, e.g., the administration of a particle or a composition described herein, such that at least one symptom of the disorder is cured, healed, alleviated, relieved, altered, remedied, ameliorated, or improved. Treating includes administering an amount effective to alleviate, relieve, alter, remedy, ameliorate, improve or affect the disorder or the symptoms of the disorder. The treatment may inhibit deterioration or worsening of a symptom of a disorder.
• Bile acids and their salts have been proposed as therapeutic agents for treatment of different conditions including bile acid synthesis disorders and peroxisomal disorders (see, e.g., Klouwer etal. OrphanetJ. 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 etal. Eur. J. Drug Metab.
• Type-2 diabetes see, e.g., Gabbi 2012
• human immunodeficiency virus type 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 etal. Nutr. Cancer 62, 85-92 (2009); Pardi et al. Gastroenterology 124, 889-893 (2003); Milovic etal. Eur. J. Clin. Invest. 32, 29-34 (2002); Schlottmann et al. Cancer Res.
• Bile acids and salts thereof are also useful for the non- surgical removal of a localized fat deposit in a subject.
• deoxycholic acid injections have been approved by the U.S. FDA for improving the appearance of moderate to severe convexity or fullness associated with submental fat in adults.
• many injections are needed, with a single treatment including up to 50 injections, and up to six single treatments may be needed for effective treatment. Accordingly, it is contemplated that the composite particles disclosed herein provide controlled release of the bile acid or salt or ester thereof, which reduces the number of injections required for effective treatment.
• Corticosteroids are used to treat a variety of conditions, including endocrine disorders (e.g., primary or secondary adrenocortical insufficiency, congenital adrenal hyperplasia, nonsuppurative thyroiditis, or hypercalcemia associated with cancer), rheumatic disorders (e.g., rheumatoid arthritis (including juvenile rheumatoid arthritis), ankylosing spondylitis, acute and subacute bursitis, synovitis of osteoarthritis, acute nonspecific tenosynovitis, post-traumatic osteoarthritis, psoriatic arthritis, epicondylitis, or acute gouty arthritis), collagen diseases (e.g., during an exacerbation or as maintenance therapy in systemic lupus erythematosus, systemic dermatomyositis (polymyositis), or acute rheumatic carditis), dermatologic diseases (e.g., bullous endocrine
• Testosterone Teestosterone, testosterone enanthate, and testosterone cypionate forms: Breast cancer, metastatic; delayed puberty; Hypogonadism, hypogonadotropic (congenital or acquired); Hypogonadism, primary (congenital or acquired); Hormone therapy for transgender males (female-to-male);
• Testosterone undecanoate Breast cancer, metastatic; Delayed puberty;
• hypogonadotropic congenital or acquired
• Hypogonadism primary (congenital or acquired)
• Hormone therapy for transgender males female-to-male
• Exemestane Breast cancer; First-line adjuvant treatment of estrogen receptor-positive early breast cancer in postmenopausal women; Risk reduction for invasive breast cancer in postmenopausal women;
• Formestane Treatment of advanced breast cancer in postmenopausal women;
• Mesterolone Androgen deficiency; hypogonadism; infertility; delayed puberty;
• Fluoxymesterone Breast cancer, metastatic (females); Delayed puberty (males);
• hypogonadism primary or hypogonadotrophic (males);
• Methyltestosterone Breast cancer, metastatic (females); Delayed puberty (males); Hypogonadism, primary or hypogonadotropic (males);
• Oxandrolone Weight gain (adjunctive therapy); Bums, severe (adjunctive therapy);
• Oxymetholone Anemia; Fanconi anemia;
• Dysmenorrhea Menstrual bleeding (menorrhagia); Pain associated with endometriosis; Polycystic ovary syndrome (PCOS) in women with menstrual irregularities and hirsutism/acne; [00117] Norethindrone: Abnormal uterine bleeding; Amenorrhea, secondary; Contraception; Endometriosis;
• Danazol Endometriosis; Hereditary angioedema (HAE), prophylaxis; Cyclic breast pain (mastalgia) associated with benign breast disorders; Immune thrombocytopenia, refractory;
• Gestrinone Endometriosis
• Levonorgestrel Contraception; Heavy menstrual bleeding; Endometrial hyperplasia;
• Lynestrenol Prevention of pregnancy; treatment of polymenorrhea, menorrhagia, metrorrhagia, primary and secondary amenorrhea or oligomenorrhea; treatment of benign breast disease; treatment of endometrial carcinoma; adjunct to estrogen therapy in peri- and postmenopausal women to prevent endometrial hyperplasia; treatment of endometriosis; suppression of ovulation, ovulation pain or menstruation, or dysmenorrhea; to postpone the onset of menstruation;
• 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;
• Desogestrel Contraception; Abnormal uterine bleeding; Dysmenorrhea; Hirsutism; Menstrual bleeding (menorrhagia); Polycystic ovary syndrome (PCOS) in women with menstrual irregularities and hirsutism/acne;
• Tibolone Treatment of symptoms associated with menopause; prevention of postmenopausal osteoporosis in high-risk women with contraindications or an intolerance to first-line therapy;
• 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;
• PCOS Polycystic ovary syndrome
• Cyproterone Prostate cancer; Hormone therapy for transgender females (male-to- female); Paraphilia;
• Megestrol acetate Anorexia or cachexia; Breast cancer; Endometrial cancer; Treatment of cancer-related cachexia;
• Mifepristone To control hyperglycemia occurring secondary to hypercortisolism in adult patients with endogenous Cushing syndrome who have type 2 diabetes mellitus or glucose intolerance and who failed surgery or who are not surgical candidates; Medical termination of intrauterine pregnancy through 70 days gestation, in combination with misoprostol; Early pregnancy loss;
• Drospirenone Contraception
• Spironolactone Ascites due to cirrhosis; Heart failure with reduced ejection fraction;
• Hypertension Primary hyperaldosteronism; Acne vulgaris, females; Heart failure with preserved ejection fraction; Heart failure with reduced ejection fraction; Hirsutism, females; Hormone therapy for transgender females, male-to-female; Post myocardial infarction, complicated by reduced ejection fraction;
• Estradiol Breast cancer, metastatic; Hypoestrogenism (female); Osteoporosis prevention (female); Prostate cancer, advanced; Vasomotor symptoms associated with menopause; Vulvar and vaginal atrophy associated with menopause; Functional hypothalamic amenorrhea with low bone density (young adult females); Hormone therapy for transgender females (male-to-female);
• Megestrol Anorexia or cachexia; Breast cancer; Endometrial cancer; Treatment of cancer-related cachexia;
• Estramustine Prostate cancer (metastatic castration-resistant);
• Estramustine phosphate Prostate Cancer
• Estrone Vulvar and vaginal atrophy
• Estropipate Hypoestrogenism, female; Osteoporosis prevention; Vasomotor symptoms due to menopause; Vulvar and vaginal atrophy due to menopause;
• Progesterone Prevention of endometrial hyperplasia in nonhysterectomized, postmenopausal women who are receiving conjugated estrogens; treatment of secondary amenorrhea; Treatment of amenorrhea or abnormal uterine bleeding due to hormonal imbalance in the absence of organic pathology, such as submucous fibroids or uterine cancer; Part of assisted reproductive technology (ART) for infertile women with progesterone deficiency; To support embryo implantation and early pregnancy by supplementation of corpus luteal function as part of ART for infertile women; Reduce the risk of recurrent spontaneous preterm birth;
• ART assisted reproductive technology
• Dydrogesterone Treatment of various conditions caused by progesterone deficiencies
• Hydroxyprogesterone caproate To reduce the risk of preterm birth in women with a singleton pregnancy who have a history of singleton spontaneous preterm birth; Treatment of advanced (stage III or IV) uterine adenocarcinoma; management of amenorrhea (primary and secondary) and abnormal uterine bleeding due to hormonal imbalance in the absence of organic pathology (e.g., submucous fibroids or uterine cancer); as a test for endogenous estrogen production; production of secretory endometrium and desquamation;
• Medroxyprogesterone acetate Abnormal uterine bleeding; Amenorrhea, secondary; Contraception; Endometrial hyperplasia prevention; Endometrial carcinoma; Endometriosis; Abnormal uterine bleeding, acute; Endometrial hyperplasia; Hot flashes;
• Norgestimate (administered with estradiol): Osteoporosis prevention; Vasomotor symptoms associated with menopause; Vulvar and vaginal atrophy associated with menopause; [00148] 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; [00149] Cortisol: Allergic states-.
• Atopic dermatitis bullous dermatitis herpetiformis; contact dermatitis; exfoliative dermatitis; exfoliative erythroderma; pemphigus; severe erythema multiforme (Stevens-Johnson syndrome); severe psoriasis; severe seborrheic dermatitis; mycosis fungoides; Edematous states.- To induce diuresis or remission of proteinuria in the nephrotic syndrome, without uremia, of the idiopathic type or that due to lupus erythematosus; Endocrine disorders.
• autoimmune hemolytic anemia congenital (erythroid) hypoplastic anemia (Diamond Blackfan anemia); erythroblastopenia (RBC anemia); immune thrombocytopenia (formerly known as idiopathic thrombocytopenic purpura) in adults; pure red cell aplasia; select cases of secondary thrombocytopenia; Neoplastic diseases-. Palliative management of leukemias and lymphomas (adults); acute leukemia of childhood; Nervous system-. Cerebral edema associated with primary or metastatic brain tumor, or craniotomy; Ophthalmic diseases-.
• Severe acute and chronic allergic and inflammatory processes involving the eye such as allergic conjunctivitis; allergic corneal marginal ulcers; anterior segment inflammation; chorioretinitis; diffuse posterior uveitis and choroiditis; herpes zoster ophthalmicus; ulceris and iridocyclitis; keratitis; optic neuritis; sympathetic ophthalmia; other ocular inflammatory conditions unresponsive to topical corticosteroids; Respiratory diseases-.
• Trichinosis with neurologic or myocardial involvement; tuberculous meningitis with subarachnoid block or impending block when used concurrently with appropriate antituberculous chemotherapy; In-hospital cardiac arrest; Septic shock; Thyroid storm;
• Cortisone Cortisone and cortisone acetate forms: Allergic stales. Control of severe or incapacitating allergic conditions intractable to adequate trials of conventional treatment of atopic dermatitis, bronchial asthma, contact dermatitis, drug hypersensitivity reactions, seasonal or perennial allergic rhinitis, and serum sickness; Dermatologic diseases; Bullous dermatitis herpetiformis, 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, nonsuppurative thyroiditis, primary or secondary adrenocortical; Gastrointestinal diseases: To tide the patient over a critical period of the disease in regional enteritis and ulcerative colitis; Hematologic disorders; Acquired (autoimmune) hemolytic anemia, congenital (erythroid) hypoplastic anemia, erythroblastopenia (red blood cell [RBC] anemia), immune thrombocytopenia (formerly known as idiopathic thrombocytopenic purpura) in adults, secondary thrombocytopenia in adults; Neoplastic diseases.
• FluoromethoIone Ocular inflammation; Treatment of steroid-responsive inflammation of the palpebral and bulbar conjunctiva, cornea, and anterior segment of the eye; [00152] Difluprednate: Inflammation/pain: Treatment of inflammation and pain following ocular surgery; Uveitis: Treatment of endogenous anterior uveitis;
• Fludrocortisone (Fludrocortisone acetate form): Adrenal insufficiency, primary; Congenital adrenal hyperplasia, classic; Idiopathic orthostatic hypotension; Septic shock; [00154] Fluocinolone (fluocinolone acetonide form): Body oil: Treatment of moderate to severe atopic dermatitis in pediatric patients >3 months; treatment of atopic dermatitis in adults; Cream, ointment, topical solution: Relief of inflammatory and pruritic manifestations of corticosteroid-responsive dermatoses; Scalp oil: Treatment of psoriasis of the scalp in adults; Shampoo: Treatment of seborrheic dermatitis of the scalp; Relief of chronic eczematous external otitis; Diabetic macular edema; Uveitis;
• Loteprednol (Loteprednol etabonate form): Ophthalmic inflammatory conditions (0.5% suspension); Treatment of ocular, anterior segment inflammation that is expected to be responsive to topical corticosteroid therapy; Postoperative inflammation/pain (0.38% gel; 0.5% suspension/ointment/gel; 1% suspension): Treatment of postoperative inflammation and pain following ocular surgery; Seasonal allergic conjunctivitis (0.2% suspension): Temporary relief of signs and symptoms of seasonal allergic conjunctivitis;
• Methylprednisolone (methylprednisolone acetate and methylprednisolone succinate forms): Oral, IM (acetate or succinate), and IV (succinate only) administration; Antiinflammatory or immunosuppressant agent in the treatment of a variety of diseases, including those of hematologic (e.g., immune thrombocytopenia, warm autoimmune hemolytic anemia), allergic, gastrointestinal (e.g., Crohn disease, ulcerative colitis), inflammatory, neoplastic, neurologic (e.g., multiple sclerosis), rheumatic (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 ery
• cystic tumor of an aponeurosis or tendon ganglia
• Acute respiratory distress syndrome moderate to severe
• Cardiac transplant Antibody-mediated rejection
• Chronic obstructive pulmonary disease Deceased organ donor management
• Graft-vs- host disease acute; In-hospital cardiac arrest; Nausea and vomiting of pregnancy, severe/refiactory
• Pneumocystis pneumonia adjunctive therapy for moderate to severe disease
• Prostate cancer metastatic, castration-resistant
• Prednisolone (Prednisolone sodium phosphate and prednisolone acetate forms):
• Corneal injury Treatment of acute chemical injury of the cornea; Ophthalmic inflammatory conditions. Treatment of ocular, anterior segment inflammation that is expected to be responsive to topical corticosteroid therapy; Allergic states. Control of severe or incapacitating allergic conditions intractable to adequate trials of conventional treatment in asthma, atopic dermatitis, drug hypersensitivity reactions, seasonal or perennial allergic rhinitis, and serum sickness; Dermatologic diseases-.
• Congenital adrenal hyperplasia hypercalcemia associated with cancer; nonsuppurative thyroiditis; primary or secondary adrenocortical insufficiency; GI diseases; During acute episodes of Crohn disease or ulcerative colitis; Hematologic disorders; Acquired (autoimmune) hemolytic anemia; congenital (erythroid) hypoplastic anemia (Diamond-Blackfan anemia); erythroblastopenia (RBC anemia); immune thrombocytopenia (formerly known as idiopathic thrombocytopenic purpura), pure red cell aplasia; secondary thrombocytopenia; Neoplastic diseases; Treatment of acute leukemia and aggressive lymphomas; Nervous system: Acute exacerbations of multiple sclerosis; cerebral edema associated with primary or metastatic brain tumor, craniotomy, or head injury; Ophthalmic diseases; Allergic conjunctivitis; allergic corneal marginal ulcers; anterior segment inflammation; chorioretinitis; diffuse posterior uveitis and choroid
• COPD chronic obstructive pulmonary disease
• Prednisone Anti-inflammatory or immunosuppressant agent in the treatment of a variety of diseases, including allergic, hematologic (e.g., immune thrombocytopenia, warm autoimmune hemolytic anemia), dermatologic, GI, inflammatory, ophthalmic, neoplastic, rheumatic (e.g., acute gout flare, vasculitis, dermatomyositis, mixed cryoglobulinemia syndrome, polyarteritis nodosa, polymyositis, polymyalgia rheumatica, rheumatoid arthritis, systemic lupus erythematosus), autoimmune, nervous system (e.g., acute exacerbations of multiple sclerosis), renal, respiratory (e.g., asthma), and endocrine (e.g., primary or secondary adrenocorticoid deficiency); solid organ rejection (acute/chronic); Bell palsy, new onset
• Triamcinolone Triamcinolone acetonide form: Allergic rhinitis; Upper respiratory allergies; Acute bacterial rhinosinusitis, adjunct to antibiotics (empiric treatment); Chronic rhinosinusitis; Alopecia areata; discoid lupus erythematosus; keloids; localized hypertrophic, infiltrated, inflammatory lesions of granuloma annulare, lichen planus, lichen simplex chronicus (neurodermatitis), and psoriatic plaques; necrobiosis lipoidica diabeticorum; cystic tumors of an aponeurosis or tendon (ganglia); Allergic states.
• Atopic dermatitis bullous dermatitis herpetiformis, contact dermatitis, exfoliative erythroderma, mycosis fungoides, pemphigus, or severe erythema multiforme (Stevens-Johnson syndrome), vulvar dermatitis, psoriasis, seborrheic dermatitis; Endocrine disorders-.
• GI diseases To tide the patient over a critical period of disease in Crohn disease or ulcerative colitis; Hematologic disorders-. Acquired (autoimmune) hemolytic anemia, Diamond-Blackfan anemia, pure red cell aplasia, select cases of secondary thrombocytopenia; Neoplastic diseases-.
• Nervous system Acute exacerbations of multiple sclerosis; cerebral edema associated with primary or metastatic brain tumor or craniotomy; Ophthalmic diseases: Sympathetic ophthalmia, temporal arteritis, uveitis, and ocular inflammatory conditions unresponsive to topical corticosteroids; Renal diseases: To induce diuresis or remission of proteinuria in idiopathic nephrotic syndrome or that is caused by lupus erythematosus; Respiratory diseases: Berylliosis, fulminating or disseminated pulmonary tuberculosis when used concurrently with appropriate antituberculous chemotherapy, idiopathic eosinophilic pneumonias, symptomatic sarcoidosis; Rheumatic disorders: As adjunctive therapy for short-term administration in acute gout flares; acute rheumatic carditis; ankylosing spondylitis
• Alclometasone (Alclometasone diproprionate form): Steroid-responsive dermatosis;
• Betamethasone (Betamethasone, betamethasone sodium phosphate, betamethasone benzoate, betamethasone dipropionate, betamethasone valerate, and betamethasone acetate forms): Allergic states: Control of severe or incapacitating allergic conditions intractable to adequate trials of conventional treatment in asthma, atopic dermatitis, contact dermatitis, drug hypersensitivity reactions, perennial or seasonal allergic rhinitis, serum sickness, transfusion reactions; Dermatologic diseases: Bullous dermatitis herpetiformis, 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 conjunction with mineralocorticoids where applicable; in infancy mineralocorticoid supplementation is of particular importance; Gastrointestinal diseases-. During acute episodes in regional enteritis and ulcerative colitis; Hematologic disorders-. Acquired (autoimmune) hemolytic anemia, Diamond- Blackfan anemia, pure red cell aplasia, selected cases of secondary thrombocytopenia;
• Neoplastic diseases Palliative management of leukemias and lymphomas; Nervous system; Acute exacerbations of multiple sclerosis; cerebral edema associated with primary or metastatic brain tumor or craniotomy; Ophthalmic diseases; Sympathetic ophthalmia, temporal arteritis, uveitis and ocular inflammatory conditions unresponsive to topical corticosteroids; Renal diseases; To induce diuresis or remission of proteinuria in idiopathic nephrotic syndrome or that due to lupus erythematosus; Respiratory diseases; Berylliosis, fulminating or disseminated pulmonary tuberculosis when used concurrently with appropriate antituberculous chemotherapy, idiopathic eosinophilic pneumonias, symptomatic sarcoidosis; Rheumatic disorders; Adjunctive therapy for short-term administration in acute gout flares; acute rheumatic carditis; ankylosing s
• Betamethasone valerate and Betamethasone diproprionate administered together Dermatoses; Relief of inflammatory and pruritic manifestations of corticosteroid-responsive dermatoses; Dermatoses of the scalp; Relief of inflammatory and pruritic manifestations of corticosteroid-responsive dermatoses of the scalp; Plaque psoriasis (spray; patch) ; Treatment of mild to moderate plaque psoriasis in patients 18 years and older;
• Clobetasol (Clobetasol propionate form): Steroid-responsive dermatoses; [00165] Clobetasone (Clobetasone butyrate form): Dermatitis 1 . Management of localized eczema and dermatitis including atopic eczema and irritant and allergic contact dermatitis;
• Clocortolone (Clocortolone pivalate form): Steroid-responsive dermatoses;
• Desoximetasone Relief of inflammation and pruritic symptoms of corticosteroidresponsive dermatoses; Plaque psoriasis treatment;
• Dexamethasone (Dexamethasone, dexamethasone phosphate, and dexamethasone sodium phosphate forms): Oral, IV, or IM injection 1 .
• Anti-inflammatory or immunosuppressant agent in the treatment of a variety of diseases including those of allergic, hematologic (e.g., immune thrombocytopenia), dermatologic, neoplastic, rheumatic, autoimmune, nervous system, renal, and respiratory origin; primary or secondary adrenocorticoid deficiency (not first line); management of shock, cerebral edema, and as a diagnostic agent; Intra-articular or soft tissue injection 1 .
• Keloids localized hypertrophic, infiltrated, inflammatory lesions of lichen planus, psoriatic plaques, granuloma annulare, and lichen simplex chronicus (neurodermatitis); discoid lupus erythematosus; necrobiosis lipoidica diabeticorum; alopecia areata; and cystic tumors of an aponeurosis or tendon (ganglia); Off-Label Use; Acute mountain sickness/high-altitude cerebral edema; Antiemetic regimens: chemotherapy-associated nausea and vomiting, prevention; Antiemetic regimens: radiation therapy-associated nausea and vomiting, prevention; Asthma, acute exacerbation; Coronavirus disease 2019 (COVID-19), treatment; Fetal lung maturation, acceleration of; Meningitis (bacterial), prevention of neurologic complications; Multiple myeloma;
• Diflorasone Dermatoses; Treatment of inflammation and pruritic symptoms of corticosteroid-responsive dermatoses;
• Difluocortolone Acute and chronic skin disease; Treatment of acute and chronic skin diseases responsive to the anti-inflammatory, antipruritic, and antiallergic effects of topical corticosteroids;
• Fluticasone Fluticasone (Fluticasone propionate and fluticasone furoate forms): Asthma; Chronic obstructive pulmonary disease; Eosinophilic esophagitis (oral); Allergic rhinitis; Nasal polyps; Nonallergic rhinitis; Upper respiratory allergies; Acute bacterial rhinosinusitis, adjunct to antibiotics (empiric treatment); Chronic rhinosinusitis; Viral rhinosinusitis symptomatic relief; Dermatoses;
• Halometasone Treatment of steroid responsive skin disorders
• Mometasone (Mometasone furoate form): Corticosteroid-responsive dermatoses; Allergic rhinitis (seasonal and perennial); Nasal congestion associated with seasonal rhinitis; Nasal polyps; Seasonal allergic rhinitis (prophylaxis); Chronic rhinosinusitis; Rhinosinusitis, adjunctive treatment (acute); Rhinosinusitis, treatment (acute, mild to moderate, uncomplicated); Asthma;
• Rimexolone Ophthalmic inflammatory conditions-. Treatment of postoperative inflammation following ocular surgery; treatment of anterior uveitis;
• Budesonide Ulcerative colitis; Allergic rhinitis; Upper respiratory symptoms-. Relief of symptoms of hay fever or other upper respiratory allergies (e.g., nasal congestion, runny nose, itchy nose, sneezing); Nasal polyps; Rhinitis; Acute bacterial rhinosinusitis, adjunct to antibiotics (empiric treatment); Chronic rhinosinusitis; Asthma; Chronic obstructive pulmonary disease (acute exacerbation); Chronic obstructive pulmonary disease (stable); Eosinophilic esophagitis; Crohn disease, mild to moderate; Microscopic (lymphocytic and collagenous) colitis;
• Ciclesonide Seasonal and perennial allergic rhinitis; Acute bacterial rhinosinusitis, adjunct to antibiotics (empiric treatment); Chronic rhinosinusitis; Asthma;
• Deflazacort Duchenne muscular dystrophy
• Desonide Atopic dermatitis; Corticosteroid-responsive dermatoses;
• Flunisolide Asthma; Rhinitis; Acute bacterial rhinosinusitis, adjunct to antibiotics
• Fluocinonide Inflammatory and pruritic dermatologic conditions
• Halcinonide Steroid-responsive dermatoses
• Estradiol valerate Breast cancer, metastatic; Hypoestrogenism (female); Osteoporosis prevention (female); Prostate cancer, advanced; Vasomotor symptoms associated with menopause; Vulvar and vaginal atrophy associated with menopause; Functional hypothalamic amenorrhea with low bone density (young adult females); Hormone therapy for transgender females (male-to-female);
• Hydrocortisone Hydrocortisone (Hydrocortisone, hydrocortisone acetate, hydrocortisone buteprate, hydrocortisone butyrate, hydrocortisone succinate, and hydrocortisone valerate forms): Anal and genital pruritus, external; Corticosteroid-responsive dermatoses (e.g., atopic dermatitis, contact dermatitis, vulvar dermatitis, psoriasis, seborrheic dermatitis); Hemorrhoids; Ulcerative colitis; Stasis dermatitis; Vaginitis, desquamative inflammatory; Allergic states-.
• Corticosteroid-responsive dermatoses e.g., atopic dermatitis, contact dermatitis, vulvar dermatitis, psoriasis, seborrheic dermatitis
• Hemorrhoids Ulcerative colitis
• autoimmune hemolytic anemia congenital (erythroid) hypoplastic anemia (Diamond Blackfan anemia); erythroblastopenia (RBC anemia); immune thrombocytopenia (formerly known as idiopathic thrombocytopenic purpura) in adults; pure red cell aplasia; select cases of secondary thrombocytopenia; Neoplastic diseases: Palliative management of leukemias and lymphomas (adults); acute leukemia of childhood; Nervous system: Cerebral edema associated with primary or metastatic brain tumor, or craniotomy; Ophthalmic diseases: Severe acute and chronic allergic and inflammatory processes involving the eye, such as allergic conjunctivitis; allergic corneal marginal ulcers; anterior segment inflammation; chorioretinitis; diffuse posterior uveitis and choroiditis; herpes zoster ophthalmicus; ulceris and iridocyclitis; keratitis; optic neuritis; sympathetic ophthalm
• Aspiration pneumonitis bronchial asthma; berylliosis; fulminating or disseminated pulmonary tuberculosis when used concurrently with appropriate antituberculous chemotherapy; idiopathic eosinophilic pneumonias; Loeffler syndrome (not manageable by other means); symptomatic sarcoidosis; Rheumatic disorders.
• Triamcinolone hexacetonide Symptomatic treatment of subacute and chronic inflammatory joint diseases including: synovitis, tendinitis, bursitis, epicondylitis, rheumatoid arthritis (RA), juvenile idiopathic arthritis (JIA), osteoarthritis, or post-traumatic arthritis; and [00187] Diflucortolone valerate: Acute and chronic skin disease.
• Compounds having steroid core structures are also used in treating a wide variety of disorders in animals.
• listed below are compounds having steroid core structures, and disorders they are used to treat in veterinary subjects, including dogs, cats, horses, swine, and cattle.
• the composite particles described herein comprise the indicated compounds, and the disclosure provides a method of using such particles to treat the indicated disorders and/or for the following purposes in veterinary subjects:
• Testosterone Dogs - Testosterone-responsive urinary incontinence in neutered males; Dermatitis: bilateral alopecia. Cats - Testosterone-responsive urinary incontinence in neutered males;
• Boldenone (Boldenone undecylenate form): Horses - as an aid for treating debilitated horses when an improvement in weight, haircoat, or general physical condition is desired; [00191] Nandrolone: General Veterinary Patients - .stimulate erythropoiesis in patients with certain anemias (e.g., secondary to renal failure, aplastic anemias);
• Altrenogest Horses - To suppress estrus or maintain pregnancy when progestin deficient. Swine - Synchronize estrus. Dogs - Luteal deficiency; prevent premature delivery; [00193] Methyltestosterone: Female dogs - Treatment of estrogen-dependent tumors; Pseudopregnancy; Hormonal-dependent alopecias. Male dogs - Deficient libido; Testosteroneresponsive incontinence; Certain hormonal alopecias. Cats - Hormonal-dependent alopecias; Increasing libido;
• Mibolerone Female dogs - Estrus prevention
• Danazol Dogs - Treatment of canine immune-mediated thrombocytopenia and hemolytic anemia. Cats - Autoimmune hemolytic anemia and thrombocytopenia;
• Osaterone acetate Male dogs - Benign prostatic hypertrophy
• Spironolactone Dogs - Potassium sparing diuretic or for adjunctive treatment for heart failure;
• Estradiol Horses - Enhancing estrus behavior and receptivity in ovariectomized mare. Dogs -
• Megestrol (Megestrol acetate form): Female dogs - For postponement of estrus & the alleviation of false pregnancy; Male dogs - Benign prostatic hypertrophy. Cats - Many dermatologic & behavior-related conditions;
• Estriol Female dogs estrogen-responsive urinary incontinence in ovariohysterectomized female dogs;
• Aglepristone Dogs - Pregnancy termination; Pyometra complex. Cats - Progesteronedependent mammary hyperplasia;
• Medroxyprogesterone (Medroxyprogesterone acetate form): Dogs - Progestinresponsive dermatitis; aggressive behaviors; long-term reproductive control; treatment of young German shepherd dwarfs; short-term treatment of benign prostatic hypertrophy; luteal insufficiency. Cats - Sexually dimorphic behavior problems such as roaming, inter-male aggressive behaviors, spraying, and mounting; Feline psychogenic dermatitis and alopecia;
• Trilostane Dogs - Treatment of pituitary-dependent hyperadrenocorticism (PDH) and for the treatment of hyperadrenocorticism (HAC) associated with adrenocortical tumors (AT).
• PDH pituitary-dependent hyperadrenocorticism
• HAC hyperadrenocorticism
• AT adrenocortical tumors
• Cortisone Cortisone acetate forms: Dogs - Oral treatment of hypoadrenocorticism;
• FluoromethoIone General Veterinary Patients - Treatment of inflammation of the palpebral and bulbar conjunctiva, cornea, and anterior segment of the globe (blepharitis, conjunctivitis, keratitis, anterior uveitis);
• Difluprednate General Veterinary Patients - Treatment of inflammation following ocular injury or cataract surgery or to treat generalized inflammatory conditions of the anterior segment (conjunctivitis, keratitis, anterior uveitis);
• Fludrocortisone (Fludrocortisone acetate form): Small Animals - Treatment of hypoadrenocorticism (Addison’s disease); Adjunctive therapy in hyperkalemia;
• Loteprednol General Veterinary Patients - Treatment of inflammatory conditions of the palpebral and bulbar conjunctiva, cornea, and anterior segment of the globe (blepharitis, conjunctivitis, keratitis, anterior uveitis);
• Methylprednisolone (methylprednisolone acetate and methylprednisolone succinate forms): General Veterinary Patients - Replacement of glucocorticoid activity in patients with adrenal insufficiency; Anti-inflammatory agent; Immunosuppressant;
• Prednisolone/Prednisone (Treated as bioequivalents): General Veterinary Patient - Replacement or supplementation (e.g., relative adrenal insufficiency associated with septic shock) for glucocorticoid deficiency secondary to hypoadrenocorticism; Anti-inflammatory agent; Immunosuppressant; Antineoplastic agent.
• Triamcinolone Triamcinolone acetonide form
• Betamethasone General Veterinary Patients - Focal (e.g., pedal) or multifocal lesions for relatively short durations; Horses - intra-articular injection for treating pain and inflamed joints. Dogs - Induce premature labor;
• Dexamethasone General Veterinary Patients - Diagnostic agent to test for hyperadrenocorticism; Replacement or supplementation (e.g., relative adrenal insufficiency associated with septic shock) for glucocorticoid deficiency secondary to hypoadrenocorticism; Anti-inflammatory agent; Immunosuppression; Antineoplastic agent; [00217] Flumethasone: Horses - Musculoskeletal conditions due to inflammation, where permanent structural changes do not exist, such as bursitis, carpitis, osselets, and myositis; Allergic states such as urticaria (hives) and insect bites.
• Fluticasone (Fluticasone propionate form): Horses - Recurrent airway obstruction or inflammatory airway disease. Dogs - Chronic cough. Cats - Feline asthma;
• Mometasone (Mometasone furoate form): General Veterinary Patient - Focal (e.g., pedal) or multifocal lesions and for relatively short durations;
• Rimexolone General Veterinary Patients - Symptomatic relief of corticosteroidresponsive inflammatory conditions of the palpebral and bulbar conjunctiva, cornea, and anterior segment of the globe (e.g., allergic conjunctivitis, acne rosacea, superficial punctate keratitis, ulceris, and cyclitis). Horses - Treatment of uveitis;
• Budesonide Small Animals - Treatment of inflammatory intestinal diseases; dermatitis; Corticosteroid-responsive dermatoses;
• Deoxycorticosterone Dogs - Parenteral treatment of adrenocortical insufficiency (Addison’s disease). Cats - Parenteral treatment of adrenocortical insufficiency (Addison’s disease);
• Alfaxalone Dogs - Induction and maintenance of anesthesia and for induction of anesthesia followed by maintenance with an inhalant anesthetic. Cats - Induction and maintenance of anesthesia and for induction of anesthesia followed by maintenance with an inhalant anesthetic;
• Hydrocortisone General Veterinary Patient - Focal (e.g., pedal) or multifocal lesions for relatively short durations; When an acute glucocorticoid/mineralocorticoid effect is desired (e.g., acute adrenal insufficiency; critical illness-related corticosteroid insufficiency [CIRCI]); Inflammatory conjunctivitis; [00225] Desoxycorticosterone (Desoxycorticosterone pivalate form): Dogs - Treatment of hypoadrenocortdespite (Addison’s disease). Cats - Treatment of hypoadrenocorticism (Addison’s disease); and
• Isoflupredone acetate Horses - Anti-inflammatory & immunosuppressive effects; Swine - Anti-inflammatory & immunosuppressive effects; Cattle - Anti-inflammatory & immunosuppressive effects.
• the disclosure provides a method of treating a liver disease or a peroxisomal disorder 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 (e.g., composite particles comprising a bile acid or a salt or ester thereof).
• 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).
• the 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, such as 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).
• 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).
• the liver disease is a bile acid synthesis disorder.
• the liver disease is a bile acid synthesis disorder due to a single enzyme defect.
• the single enzyme defect in the bile acid synthesis disorder is a 3 ⁇ -hydroxy-A5-C27-steroid oxidoreductase deficiency, alpha-methylacyl-CoA racemase (AMACR) deficiency, amino acid N-acyltransferase deficiency, bile acid CoA ligase deficiency, cholesterol 7a-hydroxylase deficiency, A4-3 -oxosteroid 5 ⁇ - reductase deficiency, oxysterol 7ct-hydroxylase deficiency, sterol 27-hydroxylase deficiency (cerebrotendinous xanthomatosis), or trihydroxycholestanoic acid CoA oxidase deficiency.
• AMACR alpha-methylacyl-CoA racemase
• amino acid N-acyltransferase deficiency amino acid N-acyltransferase deficiency
• the liver disease is selected from primary biliary cholangitis, primary sclerosing cholangitis, bile duct stones, and non-alcoholic fatty liver disease. In some embodiments, the liver disease is primary biliary cholangitis.
• the disclosure provides a method of treating a peroxisomal disorder 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.
• the peroxisomal disorder is a Zellweger spectrum disorder. Zellweger spectrum disorders are a group of autosomal recessive genetic disorders caused by mutations in PEX genes that encode peroxins; subdivisions of the spectrum are Zellweger syndrome, neonatal adrenoleukodystrophy, and infantile Refsum disease.
• the subject is suffering from a Zellweger spectrum disorder with manifestations of liver disease, steatorrhea, or complications from decreased fat soluble vitamin absorption.
• the 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 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., composite particles comprising a bile acid or a salt or ester thereof).
• 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).
• the disclosure provides a method of non-surgical removal of a localized fat deposit in a subject, comprising contacting the deposit 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., composite particles comprising a bile acid or a salt or ester thereof).
• 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).
• the subject has a localized fat deposit and desires to remove the deposit.
• the localized fat deposit is located in the submental region of the subject
• the localized fat deposit is located in the abdominal region of the subject.
• the deposit is contacted with the composition by subcutaneous injection.
• the disclosure provides a method of reducing a subcutaneous fat deposit in a subject in need thereof, comprising administering locally to the subcutaneous fat deposit in the subject 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., composite particles comprising a bile acid or a salt or ester thereof).
• 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).
• the subject has a subcutaneous fat deposit and desires to remove the deposit.
• the subcutaneous fat deposit is located in the submental region of the subject.
• the subcutaneous fat deposit is located in the abdominal region of the subject.
• the deposit is contacted with the composition by subcutaneous injection.
• the subcutaneous fat deposit is associated with a condition selected from the group consisting of obesity, fat redistribution syndrome, eyelid fat herniation, lipomas, Dercum's disease, lipodystrophy, buffalo hump lipodystrophy, dorsocervical fat, visceral adiposity, breast enlargement, hyperadiposity, diffused body fat around trunk and arms, and fat deposits associated with cellulite.
• the 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., composite particles comprising a bile acid or a salt or ester thereof).
• 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).
• the cancer is selected from colorectal cancer, cervical cancer, gastric cancer, and liver cancer.
• the cancer is colorectal cancer.
• the disclosure provides a method of reducing 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., composite particles comprising a bile acid or a salt or ester thereof).
• 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).
• the cancer cells are selected from colorectal cancer, cervical cancer, gastric cancer, and liver cancer cells.
• the cancer cells are colorectal cancer cells.
• the disclosure provides a method of treating a disorder in a subject, wherein the disorder is selected from the group consisting of endocrine disorders, rheumatic disorders, collagen diseases, dermatologic diseases, allergic states, ophthalmic diseases, respiratory diseases, hematologic disorders, neoplastic diseases, gastrointestinal diseases, nervous system disorders, inflammatory disorders, renal diseases, 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., composite particles comprising a corticosteroid or a salt or ester thereof).
• a pharmaceutical composition comprising a plurality of composite particles described herein (e.g., composite particles comprising a corticosteroid or a salt or ester thereof).
• the 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 described herein, such as a pharmaceutical composition comprising a plurality of composite particles described herein (e.g., composite particles comprising a corticosteroid or a salt or ester thereof).
• a respiratory disease is selected from asthma, croup, chronic obstructive pulmonary disease (COPD), bronchitis, and pneumonia (e.g., interstitial pneumonia).
• the disclosed methods involve administration of an “effective amount” or a “therapeutically effective amount” of the composite particles.
• an “effective amount” or a “therapeutically effective amount” of the composite particles refers to an amount effective, at dosages and for periods of time necessary, to achieve the desired result.
• a therapeutically effective amount of the composition may be determined by a person skilled in the art and may vary according to factors such as the disease state, age, sex, and weight of the individual, and 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 detrimental effects of a compound (e.g., a component of the composite particles or the compositions) are outweighed by the therapeutically beneficial effects.
• a therapeutically effective amount of the composite particles described herein may be about 1 mg/kg to about 1000 mg/kg, about 5 mg/kg to about 950 mg/kg, about 10 mg/kg to about 900 mg/kg, about 15 mg/kg to about 850 mg/kg, about 20 mg/kg to about 800 mg/kg, about 25 mg/kg to about 750 mg/kg, about 30 mg/kg to about 700 mg/kg, about 35 mg/kg to about 650 mg/kg, 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.
• the disclosed methods may further comprise a step of 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.
• the additional therapeutic agent or agents may be administered in the same composition as the composite particles.
• administration of an additional therapeutic agent with the composite particles may allow lower doses of the other therapeutic agents and/or administration at less frequent intervals.
• the composite particles and the other active ingredients may be used in lower doses than when each is used singly.
• the methods may further comprise a step of administering an additional therapeutic agent to the subject, wherein the additional therapeutic agent is selected from antiinflammatory agents, analgesics, chemotherapy agents, and bile acids or salts thereof.
• Anti-inflammatory agents suitable for use with the disclosed compositions and methods can include both steroidal anti-inflammatory agents and non-steroidal antiinflammatory 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, fluosinolone acetonide, fluocinonide, flucortine butylester, fluocortolone, fluprednidene (fluprednylidene)acetate, flurandreno
• Suitable non-steroidal 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, benorylate, trilisate, safapryn, solprin, diflunisal, and fendosal; acetic acid derivatives, such as diclofenac, fenclofenac, indomethacin, sulindac, tolmetin, isoxepac, furofenac, tiopinac, zidometacin, acematacin, fentiazac, zomepiract, clidanac, oxepinac, and felbinac; fenamates, such as mefenamic, meclofenamic, flufenamic, niflumic, and tolfenamic;
• Analgesics may reduce discomfort due to inflammation, particularly after parenteral administration (e.g., subcutaneous injection) of a composition of the disclosure.
• Suitable analgesics include, but are not limited to, injectable local amine and ester anesthetics, such as lidocaine, mepivacaine, bupivacaine, procaine, chloroprocaine, etidocaine, prilocaine and tetracaine. Mixtures of these analgesics, as well as the pharmaceutically acceptable salts and esters or these agents, may also be used.
• Bile acids or salts thereof may also be used in combination with the composite particles.
• the separately administered bile acid or salt or ester thereof may be the same as or different from the bile acid or salt or ester thereof that is 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.
• obeticholic acid is often used in combination with ursodeoxycholic acid for treatment of primary biliary cholangitis.
• the methods further comprise administration of ursodeoxycholic acid.
• the methods further comprise administration of obeticholic acid.
• the composite particles may be used in combination with a chemotherapy agent.
• exemplary chemotherapy agents include those listed in the “A to Z List of Cancer Drugs” published by the National Cancer Institute.
• Microparticle Characterization Microparticles were imaged with brightfield and scanning electron microscopy (SEM) (JEOL JSM-7800FLV) microscopes. Fluorescent images of the particles were acquired using an inverted Nikon Microscope and via fluorescent lamps and a TRITC/CY3 filter. For the SEM imaging, the samples were dried on a glass slide and coated with carbon and imaged with both secondary scattered and backscattered probes. Energy- dispersive spectroscopy (EDS) analyses were used to characterize the elemental composition of the particles.
• SEM brightfield and scanning electron microscopy
• EDS Energy- dispersive spectroscopy
• EDS analysis was performed on the microparticles by an Oxford XMaxN 80 mm 2 silicon-drift energy-dispersive X-ray spectrometer.
• Dynamic light scattering (DLS) was used to determine the hydrodynamic diameter of particles and zeta potential (ZP) was used to determine particle surface charge.
• DLS and ZP analyses were performed on the particles with a Malvern Nano-ZS zetasizer.
• Method 1 10 mg gold(III) chloride was dissolved in 1 mL ethyl acetate. This ethyl acetate solution was emulsified with 2 mL water via vortexing for 15 seconds. The resulting oil/water emulsion was added to 10 mL of a 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. Particles were isolated via centrifugation at 2000 rpm for 5 minutes.
• Method 2 Excess sodium cholate ( ⁇ 5 mg) was added to 1 mL ethyl acetate. Due to the low solubility of sodium cholate in ethyl acetate, the solution was centrifuged down to form a pellet of excess sodium cholate, and the supernatant was collected. 10 mg gold(m) chloride was added to the collected ethyl acetate/sodium cholate supernatant solution, and the resulting solution was emulsified with 2 mL water via vortexing for 15 seconds.
• the resulting oil/water emulsion was added to 10 mL of a 0.3 wt% sodium cholate solution in a 100 mL beaker, and the mixture was stirred at 300 rpm. Composite particles appeared immediately. Particles were isolated via centrifugation at 2000 rpm for 5 minutes.
• Method 3 10 mg gold(III) chloride was dissolved in 4 mL water. This solution was emulsified with 1 mL ethyl acetate via vortexing for 15 seconds. The resulting oil/water emulsion was added to 10 mL of a 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. Particles were isolated via centrifugation at 2000 rpm for 5 minutes.
• FIGS. 1 A-1D SEM images of the particles are shown in FIGS. 1 A-1D.
• FIG. 1 A shows SEM images of the cholate particles prepared according to Method 1, at 1500x magnification (top) and 8500x magnification (bottom);
• FIG. IB shows SEM images of the deoxycholate particles prepared according to Method 1, at 1700x magnification (top) and lOOOOx magnification (bottom);
• FIG. 1C shows SEM images of the methylprednisolone particles prepared according to Method 1, at lOOOx magnification (top) and 3700x magnification (bottom);
• FIG. ID shows SEM images of the hydrocortisone particles prepared according to Method 1, at 450x magnification (top) and 1700x magnification (bottom).
• EDS data for the particle shown in the lower panel of FIG. 1 A is shown in FIG. 2.
• This particle is primarily composed of carbon and oxygen, with trace amounts of gold, sodium, and chlorine.
• the large silicon peak is due to the signal obtained from the silicon wafer on which the sample is mounted.
• the data confirm that gold is contained within the particles.
• Rhodamine B-loaded cholate particles were prepared according to Method 1 , with 3 mg rhodamine B introduced in the oil phase of the oil/water emulsion (i.e. the solution of gold(HI) chloride and ethyl acetate). Images of the resulting particles are shown in FIG. 3A (brightfield microscopy image at 40x magnification); and FIG. 3B (the same particles fluorescing when exposed to light at 546 nm, confirming that rhodamine B was loaded in to the hexagonal cholate/gold ion particles). Rhodamine B loaded particles were also prepared by adding the rhodamine B to the water phase of the oil/water emulsion.
• Method 1 5-10 mg iron(II) sulfate heptahydrate was dissolved in 50 pL water. This solution was added to 10 mL of a 0.5 wt% solution of dexamethasone phosphate sodium salt in water with stirring at 500 rpm. Stirring was continued for 15 minutes, with particles beginning to form soon after stirring began. Particles were isolated via centrifugation at 15000 rpm for 5 minutes. The pellet was resuspended in water and the centrifugation was repeated 3 more times to wash the particles.
• Method 2 10 mg iron(II) sulfate heptahydrate was dissolved in 50 ⁇ L water. This solution was vortexed into 1 mL ethyl acetate for 15 seconds. To this mixture was added 2 mL of a 1 wt% solution of dexamethasone phosphate sodium salt in water, and this mixture was vortexed for 15 seconds. To this mixture was added 10 mL of a 0.5 wt% solution of dexamethasone phosphate sodium salt in water followed by mixing. Stirring at 500 rpm was conducted for 5-15 minutes, with particles beginning to form soon after stirring began. Particles were isolated via centrifugation at 15000 rpm for 5 minutes. The pellet was resuspended in water and the centrifugation was repeated 3 more times to wash the particles.
• FIG. 4A An SEM image of a representative particle is shown in FIG. 4A.
• FIG. 4A shows an SEM image of the dexamethasone particles prepared according to Method 1, at 100,000x magnification.
• EDS data for the particle shown in FIG. 4A is shown in FIG. 4B.
• This particle is composed of carbon and oxygen, with trace amounts of iron.
• the large silicon peak is due to the signal obtained from the silicon wafer on which the sample is mounted.
• the large gold peak is due to the signal obtained from gold coating particles for SEM imaging. The data confirm that iron is contained within the particles.
• Dynamic light scattering (DLS) data for particles prepared according to Method 1 using 5 mg or 10 mg iron sulfate heptahydrate showed that the mean particle diameter was 165 nm and 205 nm respectively.
• Zeta potential was determined for particles prepared according to Method 1 using 5 mg or 10 mg iron sulfate heptahydrate, and was found to be -25.9 mV and - 16.2 mV respectively.
• Dexamethasone release from particles prepared according to Method 1 was evaluated by suspending 6.9 mg particles in 42 mL phosphate-buffered saline (PBS) and rotating the mixture at 37 C for 26 hours. Samples of the liquid were collected and analyzed by UV-visible spectrometry compared to dexamethasone standards (either 1 pg/mL dexamethasone phosphate or 8 pg/mL dexamethasone phosphate. The data are shown in FIG. 5. The absorbance between about 230-260 nm shows the release of dexamethasone into the solution.
• PBS phosphate-buffered saline
• Rhodamine B-loaded dexamethasone particles were prepared according to Method 1, with 2 mg rhodamine B introduced in the 50 pL water/iron (II) sulfate heptahydrate solution. The particles were pink in color and fluoresced, similar to the cholate/gold ion particles described in Example 1, suggesting that the particles were loaded with rhodamine.
• Bile Salt/BCl Particles Hydrochloric acid was added to water until a pH of 2, and then 50 mg of a bile acid salt (sodium cholate, sodium deoxycholate, sodium ursodeoxycholate, or sodium chenodeoxycholate) was added to 2 mL of pH 2 water and the solution was vortexed until 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 was added 10 mL water at pH 3 (adjusted with HC1). Further stirring at 300 rpm for 1-2 minutes was required for particle formation.
• a bile acid salt sodium cholate, sodium deoxycholate, sodium ursodeoxycholate, or sodium chenodeoxycholate
• FIGS. 6A, 6B, 6C, and 6D SEM images of particles formed using sodium cholate, sodium deoxycholate, sodium chenodeoxycholate, and sodium ursodeoxycholate are shown in FIGS. 6A, 6B, 6C, and 6D, respectively.
• EDS data for the sodium chenodeoxycholate and sodium ursodeoxycholate particles showed peaks only for carbon, oxygen, and silicon (with the Si peak resulting from the Si wafer on which the sample is mounted).
• Corticosteroid/HCI Particles Corticosteroid/HCI Particles. Hydrochloric acid was added to water until a pH of 3, and then 50 mg of a corticosteroid compound (methylprednisolone succinate or hydrocortisone succinate) was added to 2 mL of pH 3 water and the solution was vortexed until 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 was added 10 mL water at pH 2 (adjusted with HC1). Further stirring at 300 rpm for 1-2 minutes was required for particle formation.
• a corticosteroid compound methylprednisolone succinate or hydrocortisone succinate
• FIGS. 7 A and 7B SEM images of particles formed using methylprednisolone succinate and hydrocortisone succinate are shown in FIGS. 7 A and 7B, respectively. EDS data for these particles showed peaks only for carbon, oxygen, and silicon (with the Si peak resulting from the Si wafer on which the sample is mounted); notably, chlorine was not detected.
• Bile Salt or Corticosteroid/Salicylic Acid Particles 5-6 mg salicylic acid was dissolved in 1 mL ethyl acetate. To this solution was added a 1 wt% bile acid 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.
• corticosteroid sodium cholate, sodium deoxycholate, methylprednisolone succinate, hydrocortisone succinate, sodium ursodeoxycholate, or sodium chenodeoxycholate
• This emulsion was added to 10 mL of a 0.3 wt% solution of the same bile acid salt or corticosteroid (sodium cholate, sodium deoxycholate, methylprednisolone succinate, hydrocortisone succinate, sodium ursodeoxycholate, or sodium chenodeoxy cholate). Further stirring at 300 rpm for 1 minute was required for particle formation. SEM images of particles formed using sodium cholate, sodium deoxycholate, methylprednisolone succinate, sodium chenodeoxycholate, hydrocortisone succinate, and sodium ursodeoxycholate are shown in FIGS. 8A, 8B, 8C, 8D, 8E, and 8F, respectively.
• 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 sample is mounted).
• Salicylic acid release from the deoxycholate particles was determined by UV-vis spectrometry, measuring the absorbance at 296 nm.
• the deoxycholate particles were fully degraded by dropwise addition of 0. IM NaOH and particle absence was visually confirmed by light microscopy at 40x magnification. Data are shown in FIG. 9.
• Sodium cholate-based particles were prepared according to Method 1 in Example 1, using 15 mg gold(m) chloride.
• particles were prepared using a double emulsion method with a reducing agent the reduce the gold ions to gold nanoparticles, which serve as a template for particle formation (see International Patent Publication No. WO 2021/011753).
• the particles were suspended in deionized water at a concentration of 10 mg particles / mL water, were well mixed via vortexing, and were continuously agitated on a rotating platform at 37 °C.
• FIGS. 10A-10B Images are shown in FIGS. 10A-10B, with FIG. 10A showing images of cholate/gold ion particles prepared according to Method 1 in Example 1, and FIG. 10B showing images of cholate/gold(0) nanoparticle particles prepared according to WO 2021 /011753. The images show that the particles have similar degradation characteristics.
• magnifications are 1 lOOOx, 12000x, 9500x, llOOOx, lOOOOx, and 9000x for days 0, 1, 3, 5, 10, and 15, respectively.
• magnifications are 12000x, 14000x, 5500x, l lOOOx, llOOOx, and llOOOx for days 0, 1, 3, 5, 10, and 15, respectively.
• FIG. 11 Data showing release of cholate salt from the degraded particles is shown in FIG. 11.
• the particles fabricated according to Method 1 disclosed herein (with gold(III) ions) were shown to release active cholate molecules in a similar manner and at a similar order of magnitude when compared to the previously-characterized gold(O) nanoparticle templated cholate particles.
• deoxycholate particles fabricated by each method were also degraded by dropwise addition of 0.1 M NaOH and particle absence was visually confirmed by light microscopy at 40x magnification.
• the absorbance of the both degraded particles was measured by UV-visible spectrometry.
• the UV-visible spectrometry data for these samples is shown in FIG. 13.
• No gold nanoparticles were detected in the sample of the degraded particles prepared according to Method 1 in Example 1, since there was no significant peak between 350 nm and 800 nm wavelengths, confirming the absence of any gold nanoparticles.
• gold nanoparticles were detected with a peak at 548 run in the sample prepared according to WO 2021/011753.
• particles were degraded by suspending them in 250 ⁇ L deionized water, and then adding 1 M NaOH in 1 ⁇ L increments to fully dissolve the particles. Samples were thoroughly mixed via vortexing after each addition of NaOH. 44 pL of the NaOH solution were required to fully degrade the sample such that no particles were visible on a light microscope at 40x magnification. The degradation products were then used in a gold nanoparticle production process. If gold(III) ions are present in the degradation solution, addition of a reducing agent and heat should result in gold nanoparticle formation.
• Human umbilical vein endothelial cells will be cultured into 12- well plates which were pre-treated with gelatin, glutaraldehyde, and glycine as previously described (Charoenphol etal. Biomaterials. 2010; 31(6): 1392-1402). After reaching confluency, the cells will be incubated with 1 ml of either bile acid solutions (e.g., cholate and deoxycholate solutions) of different concentrations, or a suspension of composite particles of known concentrations for different time-points at 37 °C and 5% CO2.
• bile acid solutions e.g., cholate and deoxycholate solutions
• the treatment solution/suspension will be removed from the wells, the cells will be washed with warm IX phosphate buffered saline (PBS) and incubated with 1 ml of the 1:25 dilution of MTS assay cell titer (Promega, WI) in IX PBS at 37 °C and 5% CO2 for 2 hours until the appearance of the orange color in the untreated control wells.
• the absorbance will be then measured at 490 ran, and each condition will be repeated in triplicate.
• the percentage of the cell viability will be quantified via subtracting the background cell titer absorbance from the absorbance of the desired point and dividing it by the average signal of the untreated cells after subtracting the background.
• the capability of the particle formulation to kill fat cells will be tested by incubating them with primary subcutaneous human adipocytes.
• the primary subcutaneous human adipocytes cultured in 96- well plates will be purchased from a commercial supplier (e.g., Zen- Bio, Research Triangle, NC).
• 150 ⁇ l of the media will be removed from each well, and the cells will be incubated at 37 °C and 5% CO2.
• 150 pl of the salt solution or particle suspension of the known concentration in FBS free RPMI-medium will be incubated for a known time-point.
• the treatment solution will be aspirated, the cells will be washed with warm PBS, and 150 pl of a 1:25 dilution in IX PBS of MTS assay cell titer (purchased from Promega Corporation, Madison, WI) will be added to each well. Plates will be incubated at 37 °C and 5% CO2 for 3 hours or until the appearance of the orange color in the untreated control wells and the absorbance will be measured at 490 nm. The cell viability will be quantified via subtracting the background cell titer absorbance from the absorbance of the desired point and dividing it by the average signal of the untreated cells after subtracting the background.
• the cells will be incubated with different concentrations of bile acid (e.g., sodium cholate and sodium deoxycholate) in RPMI media.
• bile acid e.g., sodium cholate and sodium deoxycholate
• In vivo lipolysis assays will be performed via subcutaneous injection of rhodamine- loaded composite particles (e.g., deoxy cholate particles) into the inguinal fat pads of genetically obese mice alongside the salt solution and vehicle control.
• Genetically obese mice will be anesthetized using isoflurane, shaved, and subcutaneously injected with a suspension of rhodamine-loaded particles (e.g., deoxycholate particles) or a solution of cholate or deoxycholate salt in saline (25 mg/mL), or vehicle control into their right inguinal fat pad. 100 pL of pure saline will be injected into the left fat pad of the animals as the control.
• the weight and appearance of the animals will be tracked over the course of two weeks.
• One group of the animals will receive a second dosage of particles on Day 7.
• the animals will be euthanized, the right and left fat pad of the animals were removed, weighed, and fixed in 10% formalin solution overnight
• Histology slides of the samples will be prepared via paraffin embedding and standard hematoxylin and eosin staining. The histology slides will be analyzed by blindfolded physicians and the digital scans will be analyzed using QuPath software.
• HT-29 colon cancer cells (ATCC® HTB38TM) were purchased from American Type
• the percentage of the cell viability was quantified via determining which percentage of cells showed neither Annexin V staining (an indicator of cellular apoptosis) nor PI staining (necrosis or late stage apoptosis). Data are shown in FIG. 15, and show reductions in cell viability particularly for the acid-containing particles.

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