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WO2024151625A1 - Compositions de plga non toxiques et leurs procédés de fabrication et d'utilisation - Google Patents

Compositions de plga non toxiques et leurs procédés de fabrication et d'utilisation Download PDF

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Publication number
WO2024151625A1
WO2024151625A1 PCT/US2024/010868 US2024010868W WO2024151625A1 WO 2024151625 A1 WO2024151625 A1 WO 2024151625A1 US 2024010868 W US2024010868 W US 2024010868W WO 2024151625 A1 WO2024151625 A1 WO 2024151625A1
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Prior art keywords
plga
api
composition
glycofurol
spheres
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English (en)
Inventor
Barath RAMASUBRAMANIAN
Doug SOBEL
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Georgetown University
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Georgetown University
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Classifications

    • 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
    • A61K9/1629—Organic macromolecular compounds
    • A61K9/1641—Organic macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyethylene glycol, poloxamers
    • A61K9/1647—Polyesters, e.g. poly(lactide-co-glycolide)
    • 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
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
    • 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

Definitions

  • Poly(D,L-lactide-co-glycohde) copolymer (PLGA), a composition biodegradable compound made up of lactic acid and glycolic acid, is of great interest as a drug releasing system.
  • the polymer can release many kinds of substances when placed in the body and is FDA-approved for human use.
  • FDA-approved PLGA products include medications, growth factors, and hormones.
  • PLGA spheres are constructed with organic (volatile) solvents, most commonly chloroform and dichloromethane (DCM), which are deemed Class 2 (‘‘Solvents to Be Limited”) by the United States Pharmacopeia (USP) and are recommended to be limited to 60 and 600 ppm, respectively, by the International Conference of Harmonization (ICH) because of their inherent toxicity.
  • DCM chloroform and dichloromethane
  • glycofurol tetrahydrofurfuryl alcohol polyethylene glycol ether; also known as tetraglycol
  • Glycofurol is a good candidate as a PLGA solvent because it is a non-toxic solvent, biocompatible, and approved for human use.
  • preparing these spheres has met very limited success.
  • One drawback is that the duration of drug release has been short.
  • Another drawback has been extreme variability of drug releasing properties, even among drugs of similar lipophilicity. Allhenn et al., Pharm. Res. (2011) 28:563-571.
  • the PLGA compositions prepared according to the methods of the instant disclosure are formed with non-toxic glycofurol and without the need for toxic solvents such as chloroform and dichloromethane.
  • the present invention also provides compositions of various shapes and sizes comprising poly(D,L-lactide-co-glycolide) copolymer (PLGA) in glycofurol, and at least one active pharmaceutical ingredient (API), wherein the compositions are at least substantially free of toxic volatile solvents like chloroform, dichloromethane, and dioxane.
  • the PLGA compositions prepared in accordance with the methods have very reduced residual amounts of solvent, i.e., glycofurol, compared to existing methods, further reducing essentially to zero any potential toxicity attributable to the solvent used in their preparation.
  • PLGA compositions prepared in accordance with the methods described herein show extended release of drug as compared to existing methods.
  • An aspect of the instant disclosure is a method of making a composition comprising poly(D,L-lactide-co-glycolide) copolymer (PLGA), glycofurol, and at least one active pharmaceutical ingredient (API), comprising: suspending PLGA in glycofuroL thereby providing a polymer solution; combining at least one API with the polymer solution, thereby providing an API- polymer solution; and contacting the API-polymer solution with an aqueous phase or solution, thereby forming the composition.
  • PLGA poly(D,L-lactide-co-glycolide) copolymer
  • API active pharmaceutical ingredient
  • An aspect of the instant disclosure is a method of making a composition comprising poly(D,L-lactide-co-glycolide) copolymer (PLGA), glycofurol, and at least one active pharmaceutical ingredient (API) comprising: suspending PLGA in glycofurol, thereby providing a polymer solution; combining at least one API with the polymer solution, thereby providing an API- polymer solution; and combining the API-polymer solution with an aqueous solution, thereby forming the composition.
  • PLGA poly(D,L-lactide-co-glycolide) copolymer
  • API active pharmaceutical ingredient
  • the API-polymer is sprayed into the aqueous solution.
  • An aspect of the instant disclosure is a method of making a composition comprising poly(D,L-lactide-co-glycolide) copolymer (PLGA), glycofurol, and at least one active pharmaceutical ingredient (API): suspending PLGA in glycofurol, thereby providing a polymer solution; combining at least one API with the polymer solution, thereby providing an API- polymer solution; and pumping the API-polymer solution through a droplet generator into aqueous solution, wherein the droplet generator comprises a fine needle surrounded by an air jacket, thereby forming the composition.
  • PLGA poly(D,L-lactide-co-glycolide) copolymer
  • API active pharmaceutical ingredient
  • the fine needle consists of a 14s - 30s gauge needle.
  • An aspect of the instant disclosure is a method of making a composition comprising poly(D,L-lactide-co-glycolide) copolymer (PLGA), glycofurol, and at least one active pharmaceutical ingredient (API) comprising: suspending PLGA in glycofurol, thereby providing a polymer solution; combining at least one API with the polymer solution, thereby providing an API- polymer solution; placing the API-polymer solution into a mold having a desired shape and size; and placing the mold containing the API-polymer solution into an aqueous phase, thereby forming a composition comprising poly(D,L-lactide-co-glycolide) copolymer (PLGA), gly cofurol, and at least one API, wherein the composition has the desired shape and size of the mold.
  • PLGA poly(D,L-lactide-co-glycolide) copolymer
  • API active pharmaceutical ingredient
  • the composition is substantially free of dichloromethane.
  • the PLGA accounts for about 0.1% weight to about 50% weight of the polymer solution.
  • the API accounts for about 1 % weight to about 50% weight of the polymer solution.
  • An aspect of the instant disclosure is a composition
  • PLGA poly(D,L-lactide-co- glycolide copolymer
  • API active pharmaceutical ingredient
  • the composition is at least substantially free of dichloromethane.
  • An aspect of the instant disclosure is a composition comprising poly(D,L-lactide-co- glycolide) copolymer (PLGA) and at least one active pharmaceutical ingredient (API), wherein the composition is at least substantially free of dichloromethane.
  • PLGA poly(D,L-lactide-co- glycolide) copolymer
  • API active pharmaceutical ingredient
  • the composition comprises substantially spherical components, i.e.. takes the form of or is a sphere.
  • the composition takes the form of or is a microsphere.
  • the microsphere has a diameter of about 1 micrometer to about 1000 micrometers (pm).
  • the PLGA comprises alactide-to-glycolide ratio of about 100:0 to about 40:60. In certain embodiments, the PLGA comprises a lactide-to-glycolide ratio of about 40:60 to about 85: 15.
  • the PLGA comprises a lactide-to-glycolide ratio of about
  • the PLGA comprises a lactide-to-glycolide ratio of about
  • the PLGA comprises a lactide-to-glycolide ratio of about 40:60.
  • the PLGA has a molecular weight of about 2 kDa to about 2,000 kDa.
  • the PLGA accounts for about 0.1% weight to about 50% weight of the polymer solution.
  • the concentration of API in the polymer solution is about 0.1% to about 50%. In certain embodiments, the concentration of API in the polymer solution is about 0.1% to about 40% weight of the polymer solution. In certain embodiments, the API accounts for about 1% weight to about 50% weight of the polymer solution.
  • a further aspect of the instant disclosure is a pharmaceutical composition
  • a pharmaceutical composition comprising a composition of the disclosure and a pharmaceutically acceptable carrier.
  • the pharmaceutical composition can be formed by contacting a composition of the disclosure with a suitable pharmaceutically acceptable carrier.
  • Yet a further aspect of the instant disclosure is a method of treating or preventing a disease, disorder, or condition, comprising administering to a subject in need thereof an effective amount of a composition comprising poly(D,L-lactide-co-glycolide) copolymer (PLGA) glycofurol, and at least one active pharmaceutical ingredient (API), wherein the composition is substantially free of dichloromethane, and wherein the API is therapeutically effective for treating or preventing the disease, disorder, or condition.
  • PLGA poly(D,L-lactide-co-glycolide) copolymer
  • API active pharmaceutical ingredient
  • the disease, disorder, or condition is selected from the group comprising of cancer, autoimmune disease, transplant rejection, allergy, asthma, anemia, viral infection, bacterial infection, fungal infection, genetic disorder, infertility, pregnancy, and any combination thereof.
  • the subject is an animal.
  • the subject is a human.
  • the subject is a plant and the disease, disorder, or condition is selected from the group consisting of tumor, viral infection, bacterial infection, fungal infection, genetic disorder, and any combination thereof.
  • the API is any substance or combination of substances, including any organic or inorganic substances, which are capable of exerting pharmacological activity or otherwise have effect in the diagnosis, cure, mitigation, treatment, or prevention of disease or condition in a subj ect.
  • the API is selected from the group comprising of anti-inflammatory agents, anti-angiogenic agents, anti-cancer agents, anti-viral agents, anti-bacterial agents, anti-fungal agents, anti-hypertensive agents, hormones, insulin, clotting factors, cytokines, growth factors, enzymes, other polypeptides, and any combination thereof.
  • FIG. 1 depicts a PLGA droplet generator appartus used in Example 1. Shown are Syringe S, Syringe Pump D, Flow Regulator F, and Pump P, where dl is the distance between the needle tip and the air flow tube and d2 is the distance between the needle tip and the surface of the double-distilled water (ddELO).
  • FIG. 2A is a photomicrographic image of glycofurol formulated spheres prepared with 20% PLGA and 16.089% (w/w) dexamethasone load.
  • FIG. 2B is a graph depicting size distribution of glycofurol formulated compositions determined by software image measurements (ImageJ).
  • FIG. 3 A - FIG. 3D are HPLC chromatograms of the following preparations: FIG. 3A, PLGA without dexamethasone (DEX).
  • FIG 3B dexamethasone (DEX) alone at a concentration of 2 pg mL' 1 .
  • FIG. 3C dexamethasone-loaded PLGA spheres at one week.
  • FIG. 3D dexamethasone-loaded PLGA spheres at 5 weeks.
  • FIG. 4A - FIG. 4B are graphs depicting results of an Alamar Blue assay to determine cytotoxicity of PLGA spheres made from dichlormethane (DCM) and glycofurol (Glyc) on splenocytes (FIG. 4A) and fibroblasts (FIG. 4B).
  • DCM dichlormethane
  • Glyc glycofurol
  • FIG. 5 is a graph depicting cumulative drug release (percent) over time from PLGA compositions constructed with either 20% or 5% PLGA and 20% dexamethasone in glycofurol. * indicates p ⁇ 0.05. ** indicates pO.OOOl.
  • FIG. 6 is a graph depcting accumulated drug release (percent) over time from PLGA compositions made from a 20% PLGA solution constructed with a drug load with 20% and 1% dexamethasone in glycofurol.
  • FIG. 7 is a graph depicting accumulated drug release (percent) over time from 20% drug (DEX) in 20% PLGA spheres made from glycofurol and di chlormethane (DCM). * indicates p ⁇ 0.05, ** indicates p ⁇ 0.001.
  • FIG. 8 is a graph depicting percent water diffusion into PLGA spheres constructed with either glycofurol or dichlormethane (DCM) as a solvent with a PLGA concentration of 20% and drug (dexamethasone) of 20%. ** indicates p ⁇ 0.005.
  • FIG. 9 is a graph depicting accumulated release (percent) over time of lipophilic dexamethsone (DEX) and hydrophilic dexamethasone salt (DSP) from PLGA compositions.
  • DEX lipophilic dexamethsone
  • DSP hydrophilic dexamethasone salt
  • FIG. 10 is a graph depicting accumulated release (percent) over time of Enbrel from 20% and 30% PLGA glycofurol formulated compositions.
  • FIG. 11 is a graph depicting accumulated release (percent) over time of tacrolimus and rapamycin from 30% PLGA glycofurol formulated compositions.
  • FIG. 12 is a graph depicting accumulated release (percent) over time of lenalidomide and hydrocortisone (HC) from 20% PLGA glycofurol formulated compositions.
  • FIG. 13 is a graph depicting accumulated release (percent) over time of heparin from 20% PLGA (75:25) glycofurol formulated compositions.
  • FIG. 14 is a graph depicting accumulated release (percent) over time of tafacinib from PLGA glycofurol formulated compositions.
  • FIG. 16A is a graph depicting accumulated release (percent) over time of 20% rabbit IgG (RIgG) from 20%, 30%, and 40% PLGA glycofurol formulated compositions, with and without titanium dioxide (TiCh). X-axis, days; Y-axis, accumulated release (percent).
  • FIG. 16B is a graph depicting accumulated release (percent) over time of 20% dexamethasone from 20%, 30%, and 40% PLGA glycofurol formulated compositions, with and without titanium dioxide (TiCh). X-axis, days; Y-axis, accumulated release (percent).
  • FIG. 17 is a graph depicting accumulated release (percent) over time of 1%, 5%, and 20% rapamycin from 20% PLGA (75:25) glycofurol formulated compositions.
  • FIG. 18 is a graph depicting the effect of lactide:glycolide ratio of PLGA on drug release characteristics for 20% lipophilic dexamethasone (DEX), 20% PLGA in glycofurol formulated compositions.
  • DEX lipophilic dexamethasone
  • FIG. 19A is a graph depicting the effect of molecular weight of PLGA on drug release characteristics for 20% lipophilic dexamethasone (DEX), 20% 50:50 PLGA in glycofurol formulated compositions.
  • DEX lipophilic dexamethasone
  • FIG. 19B is a graph depicting the effect of molecular weight of PLGA on drug release characteristics for 20% lipophilic dexamethasone (DEX), 20% 50:50 PLGA in glycofurol formulated compositions.
  • DEX lipophilic dexamethasone
  • FIG. 20A is a graph depicting the effect of polymer concentration on release of rapamycin from PLGA (75:25) glycofurol formulated compositions.
  • FIG. 20B is a graph depicting the effect of polymer concentration on release of dexamethasone (DEX) from PLGA (75:25) glycofurol formulated compositions.
  • DEX dexamethasone
  • FIG. 21 is a graph depicting the effect of different concentrations of drug in polymer solution on release rate of non-peptide drugs dexamethasone (Dex), hydrocortisone (HC), rapamycin, and lenalidomide from PLGA 20% glycofurol formulated compositions.
  • Dex dexamethasone
  • HC hydrocortisone
  • rapamycin rapamycin
  • lenalidomide from PLGA 20% glycofurol formulated compositions.
  • FIG. 22 is a graph depicting the effect of different concentrations of drug in polymer solution on release rate of non-peptide drugs rapamycin and tacrolimus from 30% PLGA glycofurol formulated compositions.
  • FIG. 23 is a graph depicting the effect of different concentrations of drug in polymer solution (5% vs. 20%) on release of non-peptide drug tofacitinib from 20% PLGA glycofurol formulated compositions.
  • FIG. 24 is a graph depicting the effect of different concentrations of drug in polymer solution (1% vs. 5% vs. 20%) on release of peptide drug Enbrel from 20% PLGA glycofurol formulated compositions.
  • FIG. 25 is a graph depicting the effect of different concentrations of drug in polymer solution (1% vs. 5% vs. 20%) and polymer concentration (20% vs. 30%) on release of peptide drug Enbrel from PLGA glycofurol formulated compositions.
  • FIG. 26A is a graph depicting the effect of different concentrations of drug in polymer solution (5% vs. 20%) on release of peptide drug heparin from 20% PLGA (75:25) glycofurol formulated compositions.
  • FIG. 26B is a graph depicting the effect of different concentrations of drug in polymer solution (1% vs. 5% vs. 20%) and polymer concentration (20% vs. 30%) on release of peptide drug heparin from PLGA (75:25) glycofurol formulated compositions.
  • X-axis days; Y-axis, accumulated release percent.
  • FIG. 27 is a graph depicting the effect of different concentrations of drug in polymer solution (5% vs. 20%) on release of the peptide drug Abatacept from 20% PLGA glycofurol formulated compositions.
  • FIG. 28 is a graph depicting the effect of different concentrations of drug in polymer solution (5% vs. 20%) on release of rabbit IgG from 20% PLGA glycofurol formulated compositions. Data for 5% dexamethasone (Dex) is shown for comparison. X-axis, days; Y- axis, accumulated release percent.
  • FIG. 29 is a graph depicting peptide and non-peptide drug release from PLGA formulations with gycofurol. All drugs at 20% load; all PLGA 20% glycofurol formulated compositions. X-axis, days; Y-axis, accumulated release percent.
  • FIG. 30 is a graph depicting the effect of 1% T1O2 on release of dexamethasone from glycofurol formulated compositions X-axis, days; Y-axis, accumulated release percent.
  • FIG. 31 is a graph depicting the effects of PLGA polymer concentration (20% vs. 30% vs. 40%) and T1O2 (1% or none) on release of 5% dexamethasone (Dex). X-axis, days; Y-axis, accumulated release percent.
  • FIG. 32 is a graph depicting the effects of PLGA polymer concentration (20% vs. 30% vs. 40%) and TiCh (1% or none) on release of 20% rabbit IgG (RIgG) from glycofurol formulated compositions.
  • FIG. 33 is a graph depicting the effects of PLGA polymer concentration (20% vs 30% vs 40%) and T1O2 (1% or none) on release of 5% rabbit IgG (RIgG) from glycofurol formulated compositions.
  • X-axis days; Y-axis, accumulated release percent.
  • FIG. 34 is a graph depicting accumulated release of dexamethasone (DEX) (1% vs 20%), rapamycin (RAP) (1% vs. 20%), and Enbrel (1% vs. 20%) from 20% PLGA compositions.
  • DEX dexamethasone
  • RAP rapamycin
  • Enbrel 1% vs. 20%
  • FIG. 35A is a graph depicting the effect on proliferation of ConA- or lipopolysaccharide (LPS)-stimulated splenocytes of dexamethasone (DEX) (1 % vs. 20%), rapamycin (RAP) (1% vs. 20%), and Enbrel (1% vs. 20%) released from 20% PLGA glycofurol formulated compositions.
  • DEX dexamethasone
  • RAP rapamycin
  • Enbrel 1% vs. 20% released from 20% PLGA glycofurol formulated compositions.
  • FIG. 35B is a graph depicting the effect on proliferation of Con-A- or lipopolysaccharide (LPS)-stimulated splenocytes of dexamethasone (DEX) (1% vs. 20%), rapamycin (RAP) (1% vs. 20%), and Enbrel (1% vs. 20%) released from 20% PLGA glycofurol formulated compositions
  • DEX dexamethasone
  • RAP rapamycin
  • Enbrel 1% vs. 20% released from 20% PLGA glycofurol formulated compositions
  • Data is for days 14-16.
  • FIG. 35C is a graph depicting the effect on proliferation of Con-A- or lipopolysaccharide (LPS)-stimulated splenocytes of dexamethasone (DEX) (1% vs. 20%), rapamycin (RAP) (1% vs. 20%), and Enbrel (1% vs. 20%) released from 20% PLGA glycofurol formulated compositions.
  • DEX dexamethasone
  • RAP rapamycin
  • Enbrel 1% vs. 20% released from 20% PLGA glycofurol formulated compositions.
  • Data is for days 21-23.
  • Y-axis net absorbance.
  • FIG. 35D is a graph depicting the effect on proliferation of Con-A- or lipopolysaccharide (LPS)-stimulated splenocytes of dexamethasone (DEX) (1% vs. 20%), rapamycin (RAP) (1% vs. 20%). and Enbrel (1% vs. 20%) released from 20% PLGA glycofurol formulated compositions. Data is for days 42-45. Y-axis, net absorbance.
  • DEX dexamethasone
  • RAP rapamycin
  • Enbrel 1% vs. 20%
  • FIG. 36A is a graph depicting accumulated release of immunoglobulin from PLGA glycofurol formulated PLGA composition shaped as rods.
  • FIG. 36B is a graph depicting accumulated release of rapamycin from PLGA- gly cofurol formulated PLGA composition shaped as rods.
  • FIG. 37 is a graph depicting accumulated release of dexamethasone from PLGA- glycofurol formulated PLGA microspheres produced by an electrospray technique.
  • FIG. 38 is a graph depicting accumulated release of sodium citrate, an inorganic molecule, from PLGA microspheres using a glycofurol technique.
  • Glycofurol is represented by the structure where n is an integer > 1 .
  • the molecular weight of glycofurol will vary in accordance with the value(s) of n.
  • Glycofurol is readily available from any of a variety of commercial suppliers.
  • Biocompatible, biodegradable polymers suitable for controlled drug delivery are known in the art and include polylactic acid (PLA), polygly colic acid (PGA), poly(lactic-co-glycolic acid) (PLGA). polycaprolactone (PCL), polyhydroxyalkanoate (PHA), poly(lactic acid)- poly(ethylene oxide) (PLA-PEG), polyanhydrides, poly(ester anhydrides), polymethylmethacrylate (PMMA), poly(2-hydroxyethyl methacrylate) (pHEMA), poly caprolactone (PCL), cellulose acetate, chitosan, and copolymers and blends thereof.
  • PLA polylactic acid
  • PGA polygly colic acid
  • PLGA poly(lactic-co-glycolic acid)
  • PCL polycaprolactone
  • PHA polyhydroxyalkanoate
  • PMMA poly(ester anhydrides
  • PMMA polymethylmethacrylate
  • pHEMA poly(2-hydroxyethyl methacrylate)
  • PLGA a particularly exemplary polymer for controlled delivery’ of drugs
  • PLGA is well-described in the art and is readily available from any of a variety of commercial suppliers.
  • lactide to glycolide used for the polymerization, different forms of PLGA can be obtained; these are usually identified in regard to the molar ratio of the monomers used (e.g., PLGA 75:25 identifies a copolymer whose composition is 75% lactic acid and 25% glycolic acid).
  • a ‘"composition” or “composite” refers to generally a solid structure of various shapes and sizes, including but not limited to cube, cuboid, triangular, or cylindrical, configurations.
  • a “microsphere” refers to a generally spherical solid structure having a diameter of about 1 pm to about 999 pm.
  • the diameter of a microsphere may be somewhat less than about 1 pm, e.g., about 0.01 pm (10 nm) to about 0.99 pm.
  • the diameter of a microsphere may be somewhat greater than about 999 pm, e.g., about 1000 pm (1 mm) to about 10,000 pm.
  • anti-inflammatory agent refers to any pharmaceutically acceptable agent capable of reducing an inflammatory response in a mammal.
  • Anti-inflammatory agents include corticosteroids, non-steroidal anti-inflammatory drugs (NSAIDs), anti-leukotrienes, and immune-selective anti-inflammatory derivatives (ImSAIDs).
  • Corticosteroids include, without limitation, prednisone, prednisolone, methylprednisolone, cortisol (hydrocortisone), cortisone, beclometasone, betamethasone, and dexamethasone.
  • NSAIDs include, without limitation, aspirin, ibuprofen, naproxen, fenoprofen, ketoprofen, indomethacin, tolmetin, sulindac, diclofenac, etodolac, ketorolac, piroxicam, meloxicam, tenoxicam, droxicam, and lomoxicam.
  • Anti-leukotrienes include, without limitation, montelukast, zafirlukast, pranlukast, and 5 -lipoxygenase inhibitors, such as zileuton.
  • the phrase “substantially free”’ means at least 80% free. In some embodiments, the phrase “substantially free” means at least 81% free. In some embodiments, the phrase “substantially free” means at least 82% free. In some embodiments, the phrase “substantially free” means at least 83% free. In some embodiments, the phrase “substantially free” means at least 84% free. In some embodiments, the phrase “substantially free” means at least 85% free. In some embodiments, the phrase “substantially free” means at least 86% free. In some embodiments, the phrase “substantially free” means at least 87% free. In some embodiments, the phrase “substantially free” means at least 88% free.
  • the phrase “substantially free” means at least 89% free. In some embodiments, the phrase “substantially free” means at least 90% free. In some embodiments, the phrase “substantially free” means at least 91% free. In some embodiments, the phrase “substantially free” means at least 92% free. In some embodiments, the phrase “substantially free” means at least 93% free. In some embodiments, the phrase “substantially free” means at least 94% free. In some embodiments, the phrase “substantially free” means at least 95% free. In some embodiments, the phrase “substantially free” means at least 96% free. In some embodiments, the phrase “substantially free” means at least 97% free. In some embodiments, the phrase “substantially free” means at least 98% free. In some embodiments, the phrase “substantially free” means at least 99% free. In some embodiments, the phrase “substantially free” means 100% free.
  • Class 2 solvents are show n in Table 1, where PDE refers to permitted daily exposure.
  • compositions such as but not limited to a sphere or microsphere comprising poly(D,L-lactide-co-glycolide) copolymer (PLGA), glycofurol and at least one active pharmaceutical ingredient (API), wherein the microsphere is substantially free of dichloromethane.
  • PLGA poly(D,L-lactide-co-glycolide) copolymer
  • API active pharmaceutical ingredient
  • Such compositions can be prepared, for example, using the methods disclosed herein.
  • the glycofurol content of the liquid portion of the polymer solution is approximately 60-100% although 80-100 % is best.
  • the microsphere has a diameter of about 1 to about 1000 micrometers (pm). In certain embodiments, the microsphere has a diameter of about 1 to about 500 pm. In certain embodiments, the microsphere has a diameter of about 1 to about 250 pm. In certain embodiments, the microsphere has a diameter of about 1 to about 100 pm. In certain embodiments, the microsphere has a diameter of about 1 to about 50 pm. In certain embodiments, the microsphere has a diameter of about 1 to about 10 pm. In certain embodiments, the microsphere has a diameter of about 1 pm.
  • the microsphere has a diameter of about 10 to about 1000 pm.
  • the microsphere has a diameter of about 10 to about 500 pm. In certain embodiments, the microsphere has a diameter of about 10 to about 250 pm. In certain embodiments, the microsphere has a diameter of about 10 to about 100 pm. In certain embodiments, the microsphere has a diameter of about 10 to about 50 pm. In certain embodiments, the microsphere has a diameter of about 10 to about 20 pm. In certain embodiments, the microsphere has a diameter of about 10 pm.
  • the microsphere has a diameter of about 25 to about 1000 pm. In certain embodiments, the microsphere has a diameter of about 25 to about 500 pm. In certain embodiments, the microsphere has a diameter of about 25 to about 250 pm. In certain embodiments, the microsphere has a diameter of about 25 to about 100 pm. In certain embodiments, the microsphere has a diameter of about 25 to about 50 pm. In certain embodiments, the microsphere has a diameter of about 25 pm.
  • the microsphere has a diameter of about 50 to about 1000 pm. In certain embodiments, the microsphere has a diameter of about 50 to about 500 pm. In certain embodiments, the microsphere has a diameter of about 50 to about 250 pm. In certain embodiments, the microsphere has a diameter of about 50 to about 200 pm. In certain embodiments, the microsphere has a diameter of about 50 to about 100 pm. In certain embodiments, the microsphere has a diameter of about 50 pm.
  • the microsphere has a diameter of about 100 to about 1000 pm. In certain embodiments, the microsphere has a diameter of about 100 to about 500 pm. In certain embodiments, the microsphere has a diameter of about 100 to about 250 pm. In certain embodiments, the microsphere has a diameter of about 100 to about 200 pm. In certain embodiments, the microsphere has a diameter of about 100 pm.
  • the microsphere has a diameter of about 200 to about 1000 pm. In certain embodiments, the microsphere has a diameter of about 200 to about 500 pm. In certain embodiments, the microsphere has a diameter of about 200 to about 250 pm. In certain embodiments, the microsphere has a diameter of about 200 pm.
  • the microsphere has a diameter of about 250 to about 1000 pm. In certain embodiments, the microsphere has a diameter of about 250 to about 500 pm. In certain embodiments, the microsphere has a diameter of about 250 pm. In certain embodiments, the microsphere has a diameter of about 500 to about 1000 m. In certain embodiments, the microsphere has a diameter of about 500 pm.
  • the microsphere has a diameter of about 1000 pm.
  • the PLGA compositions can be molded to different shapes and sizes.
  • the PLGA composition comprises a lactide:glycolide ratio of 100:0 to 30:60 with 40:60 to 85:15 as an exemplary ratio.
  • the PLGA composition comprises a lactide:glycolide ratio of 50:50. In certain embodiments, the PLGA composition comprises a lactide:glycolide ratio > 60:40. In certain embodiments, the PLGA comprises a lactide:glycolide ratio > 65:35. In certain embodiments, the PLGA composition comprises a lactide:glycolide ratio > 70:30. In certain embodiments, the PLGA composition comprises a lactide:glycolide ratio > 75:25. In certain embodiments, the PLGA composition comprises a lactide:glycolide ratio equal to about 75:25. In certain embodiments, the PLGA composition comprises a lactide:glycolide ratio equal to 75:25.
  • the PLGA has a molecular weight of about 2.0 kDa to about 2,000 kDa. In certain embodiments, the PLGA has a molecular weight of about 10-75 kDa. In certain embodiments, the PLGA has a molecular weight of about 20-75 kDa. In certain embodiments, the PLGA has a molecular weight of about 30-75 kDa. In certain embodiments, the PLGA has a molecular weight of about 40-75 kDa. In certain embodiments, the PLGA has a molecular weight of about 50-75 kDa. In certain embodiments, the PLGA has a molecular weight of about 60-75 kDa. In certain embodiments, the PLGA has a molecular weight of about 70-75 kDa. In certain embodiments, the PLGA has a molecular weight of about 75 kDa.
  • the PLGA has a molecular weight of about 10-65 kDa (1-300 kDa). In certain embodiments, the PLGA has a molecular weight of about 20-65 kDa. In certain embodiments, the PLGA has a molecular weight of about 30-65 kDa. In certain embodiments, the PLGA has a molecular weight of about 40-65 kDa. In certain embodiments, the PLGA has a molecular weight of about 50-65 kDa. In certain embodiments, the PLGA has a molecular weight of about 60-65 kDa. In certain embodiments, the PLGA has a molecular weight of about 65 kDa.
  • the PLGA has a molecular weight of about 10-55 kDa. In certain embodiments, the PLGA has a molecular weight of about 20-55 kDa. In certain embodiments, the PLGA has a molecular weight of about 30-55 kDa. In certain embodiments, the PLGA has a molecular weight of about 40-55 kDa. In certain embodiments, the PLGA has a molecular weight of about 50-55 kDa. In certain embodiments, the PLGA has a molecular weight of about 55 kDa.
  • the PLGA has a molecular weight of about 10-45 kDa. In certain embodiments, the PLGA has a molecular weight of about 20-45 kDa. In certain embodiments, the PLGA has a molecular weight of about 30-45 kDa. In certain embodiments, the PLGA has a molecular w eight of about 40-45 kDa. In certain embodiments, the PLGA has a molecular w eight of about 45 kDa.
  • the PLGA has a molecular weight of about 10-35 kDa. In certain embodiments, the PLGA has a molecular weight of about 20-35 kDa. In certain embodiments, the PLGA has a molecular weight of about 30-35 kDa. In certain embodiments, the PLGA has a molecular w eight of about 35 kDa.
  • the PLGA has a molecular weight of about 10-25 kDa. In certain embodiments, the PLGA has a molecular weight of about 20-25 kDa. In certain embodiments, the PLGA has a molecular weight of about 25 kDa.
  • the PLGA concentration within the polymer solution is 1%- 50%. In certain embodiments, the PLGA concentration within the polymer solution is 15-40%.
  • the API accounts for 0. 1 to 50% of the polymer solution. In certain embodiments, the API accounts for 1 to 30% of the polymer solution.
  • the API is selected from the group consisting of antiinflammatory agents, anti-angiogenic agents, anti-cancer agents, anti-viral agents, antibacterial agents, anti-fungal agents, anti-hypertensive agents, hormones, insulin, clotting factors, cytokines, growth factors, enzymes, other polypeptides, and any combination thereof.
  • a pharmaceutical composition comprising a microsphere as disclosed herein and a pharmaceutically acceptable carrier.
  • the pharmaceutical composition generally includes a therapeutically effective amount of the API or combination of APIs.
  • pharmaceutically acceptable carrier relates to carriers or excipients, which are generally non-toxic. Examples of such excipients are, but are not limited to, saline. Ringer’s solution, dextrose solution, Hanks’ solution, and water for injection. Non-aqueous excipients such as fixed oils and ethyl oleate may also be used.
  • compositions ty pically are sterile and stable under the conditions of manufacture and storage.
  • the composition can be formulated as a solution, suspension, dispersion, gel, or other ordered structure suitable to high drug concentration.
  • suitable aqueous and non-aqueous carriers which may be employed in the pharmaceutical compositions of the invention include water, ethanol, polyols (such as glycerol, propylene glycol, polyethylene glycol, and the like), and suitable mixtures thereof, vegetable oils, such as olive oil, and injectable organic esters, such as ethyl oleate.
  • Proper fluidity can be maintained, for example, by the use of coating materials, such as lecithin, by the maintenance of the required particle size in the case of dispersions, and by the use of surfactants.
  • the pharmaceutical compositions may also contain adjuvants such as preservatives, wetting agents, emulsifying agents and dispersing agents. Prevention of presence of microorganisms may be ensured both by sterilization procedures and by the inclusion of various antibacterial and antifungal agents, for example, paraben, chlorobutanol, phenol, sorbic acid, and the like. It may also be desirable to include isotonicity agents, such as sugars, polyalcohols such as mannitol, sorbitol, glycerol or sodium chloride in the compositions.
  • adjuvants such as preservatives, wetting agents, emulsifying agents and dispersing agents. Prevention of presence of microorganisms may be ensured both by sterilization procedures and by the inclusion of various antibacterial and antifungal agents, for example, paraben, chlorobutanol, phenol, sorbic acid, and the like. It may also be desirable to include isotonicity agents, such as sugars, polyalcohol
  • antioxidants may also be included, for example (1) water-soluble antioxidants, such as ascorbic acid, cysteine hydrochloride, sodium bisulfate, sodium metabisulfite, sodium sulfite and the like; (2) oil-soluble antioxidants, such as ascorbyl palmitate, bufy dated hydroxyanisole (BHA), butylated hydroxy toluene (BHT), lecithin, propyl gallate, alpha-tocopherol, and the like; and (3) metal chelating agents, such as citric acid, ethylenediamine tetraacetic acid (EDTA), sorbitol, tartaric acid, phosphoric acid, and the like.
  • water-soluble antioxidants such as ascorbic acid, cysteine hydrochloride, sodium bisulfate, sodium metabisulfite, sodium sulfite and the like
  • oil-soluble antioxidants such as ascorbyl palmitate, bufy dated hydroxyanisole (BHA), butylated hydroxy toluen
  • Sterile injectable solutions can be prepared by incorporating the compositions in the required amount in an appropriate solvent or other carrier with one or a combination of ingredients, e.g., as enumerated above, as required, followed by sterilization microfiltration.
  • dispersions are prepared by incorporating the active compound into a sterile vehicle that contains a basic dispersion medium and the required other ingredients, e.g., from those enumerated above.
  • exemplary methods of preparation are vacuum drying and freeze-drying (lyophilization) that yield a powder of the active ingredient plus any additional desired ingredient from a previously sterile-filtered solution thereof.
  • the pharmaceutical composition can be prepared with carriers that will further protect the compositions against rapid release, such as a controlled release formulation, including implants, transdermal patches, and encapsulated (e.g., microencapsulated or macroencapsulated) deliver ⁇ ' systems.
  • a controlled release formulation including implants, transdermal patches, and encapsulated (e.g., microencapsulated or macroencapsulated) deliver ⁇ ' systems.
  • Biodegradable, biocompatible polymers can be used, such as ethylene vinyl acetate, polyanhydrides, polyglycolic acid, collagen, polyorthoesters, and poly lactic acid. Methods for the preparation of such formulations are generally known to those skilled in the art. See, e.g.. Sustained and Controlled Release Drug Delivery Systems, J. R. Robinson, ed., Marcel Dekker, Inc., New York, 1978.
  • compositions can be administered with medical devices known in the art.
  • Dosage regimens are adjusted to provide the optimum desired response (e.g., a therapeutic response). For example, a single bolus may be administered, several divided doses may be administered over time, or the dose may be proportionally reduced or increased as indicated by the exigencies of the therapeutic situation.
  • the pharmaceutical composition can be conveniently formulated in single unit doses.
  • the pharmaceutical composition is generally administered parenterally, locally, or orally.
  • parenteral administration and “administered parenterally” as used herein mean modes of administration other than enteral and topical administration, usually by injection or infusion, and include, without limitation, intravenous, intraperitoneal, subcutaneous, intramuscular, intraarterial, intrathecal, intracapsular, intraorbital (intraocular), intracardiac, intradermal, transtracheal, subcuticular, intraarticular, subcapsular, subarachnoid, intraspinal, epidural, intracistemal, intratumoral, peritumoral, intracavitary', intrahepatic, intracranial, intralumenal, and intravesical injection and infusion.
  • the pharmaceutical composition can be formulated for administration to a subject by any suitable route of administration.
  • routes of administration can include, for example, intravenous, subcutaneous, intraperitoneal, intraorbital (intraocular), intratumoral, peritumoral, intracavitary, intrahepatic, intracranial, intralumenal, and intravesical.
  • the pharmaceutical composition is formulated for intravenous administration. In certain embodiments, the pharmaceutical composition is formulated for subcutaneous administration. IV. Methods of Making
  • An aspect of the disclosure is a method of making compositions comprising poly(D,L- lactide-co-glycolide) copolymer (PLGA), glycofurol and at least one active pharmaceutical ingredient (API), wherein the microsphere is substantially free of dichloromethane.
  • the method comprises: suspending PLGA in glycofurol, thereby providing a polymer solution; combining API to the polymer solution, thereby providing an API-polymer solution; and pumping the API-polymer solution through a droplet generator into water, wherein the droplet generator comprises a fine needle surrounded by an air jacket, thereby forming the composition.
  • the fine needle is a 22s gauge (0.00625inch inner diameter) or finer (smaller inner diameter) needle.
  • the method can be used to make PLGA spheres with the non-toxic solvent glycofurol, and these compositions are capable of releasing any of a wide variety of different kinds of drugs or substances for 6-12 months (or more).
  • the PLGA polymer sy stem can be customized to release any of a number of different substances, both hydrophobic and hydrophilic, such as drugs (e.g., steroids, antibodies, medications for cancer, inflammatory disease, pain relief, tissue rejection, genetic materials such as DNA, etc.).
  • additives such as titanium dioxide can be incorporated into the compositions to slow further the release of drug or substance from the compositions.
  • the drug-laden PLGA compositions can be coated or surrounded, completely or partially, with gels to extend duration of release and alter the solvent and aqueous phases.
  • An aspect of the disclosure is a method of treating or preventing a disease, disorder, or condition, comprising administering to a subject in need thereof an effective amount of a PLGA composition comprising poly(D,L-lactide-co-glycolide) copolymer (PLGA) in glycofurol, and at least one active pharmaceutical ingredient (API), wherein the composition is free of dichloromethane, and wherein the API is therapeutically effective for treating or preventing the disease, disorder, or condition.
  • PLGA composition comprising poly(D,L-lactide-co-glycolide) copolymer (PLGA) in glycofurol, and at least one active pharmaceutical ingredient (API), wherein the composition is free of dichloromethane, and wherein the API is therapeutically effective for treating or preventing the disease, disorder, or condition.
  • PLGA composition comprising poly(D,L-lactide-co-glycolide) copolymer (PLGA) in glycofurol, and at least one active pharmaceutical ingredient
  • an “effective amount” refers to an amount that is sufficient to achieve a desired outcome or result.
  • a “therapeutically effective amount” refers to an amount that is sufficient to achieve a desired biological or therapeutic outcome or result.
  • terapéuticaally effective means capable of achieving a desired therapeutic outcome or result.
  • “treat” or “treating” refers to reducing, ameliorating, or slowing or halting progression of at least one objective or subjective sign, symptom, or characteristic of a particular disease or condition of a subject. In certain embodiments, “treat” or “treating” refers to reducing, ameliorating, or slowing or halting progression of at least one objective sign, symptom, or characteristic of a particular disease or condition of a subject by a measurable degree or amount. In certain embodiments, “treat” or “treating” refers to reducing, ameliorating, or slowing or halting progression of at least one objective or subjective sign, symptom, or characteristic of a particular disease or condition of a subject or group of subjects by a statistically significant degree or amount.
  • preventing refers to at least substantially blocking the development or occurrence of a disease, disorder, condition, or event. In certain embodiments, “preventing” refers to blocking the development or occurrence of a disease, disorder, condition, or event.
  • the pharmaceutical composition can be administered to a subject by any suitable route of administration.
  • routes of administration can include, for example, intravenous, subcutaneous, intraperitoneal, intraorbital (intraocular), intratumoral, peritumoral, intracavitary, intrahepatic. intracranial, intralumenal, and intravesical.
  • the route of administration is intravenous.
  • the route of administration is subcutaneous.
  • the route of administration is intratumoral.
  • the pharmaceutical composition can be administered as a bolus injection. In certain embodiments, the pharmaceutical composition can be administered as an infusion. In certain embodiments, the pharmaceutical composition is administered only once. In certain other embodiments, the pharmaceutical composition is administered more than just once. In the case of repeat dosing, the dosing frequency can be determined by a health professional based on considerations such as the condition to be treated, the overall condition of the subject being treated (e.g., age, general health, sex, body weight), the route of administration or site of the pharmaceutical composition, and response of the condition to the treatment.
  • the dosing frequency can be determined by the subject being treated based on considerations such as the condition to be treated, the overall condition of the subject being treated (e.g., age, general health, sex, body weight), and response of the condition to the treatment.
  • the method can further include administration of one or more additional agents useful in the treatment of the disease, disorder, or condition.
  • Such one or more additional agents can be administered to the subject before, simultaneously, or following administration of the compositions or pharmaceutical composition of the instant disclosure. Additionally, such one or more additional agents can be administered to the subject by the same or different route of administration of the compositions or pharmaceutical composition of the instant disclosure.
  • the disease, disorder, or condition is selected from the group comprising of cancer, autoimmune disease, diabetes mellitus (type 1 or type 2), transplant rejection, allergy, asthma, anemia, glaucoma, benign prostatic hypertrophy, addiction, viral infection, bacterial infection, fungal infection, genetic disorder, hypertension, infertility, pregnancy, and any combination thereof.
  • the disease, disorder, or condition is cancer.
  • the disease, disorder, or condition is an autoimmune disease.
  • the disease, disorder, or condition is diabetes mellitus.
  • the disease, disorder, or condition is transplant rejection.
  • the disease, disorder, or condition is allergy’.
  • the disease, disorder, or condition is asthma.
  • the disease, disorder, or condition is anemia.
  • the disease, disorder, or condition is glaucoma. In certain embodiments, the disease, disorder, or condition is benign prostatic hypertrophy.
  • the disease, disorder, or condition is addiction.
  • the disease, disorder, or condition is viral infection.
  • the disease, disorder, or condition is bacterial infection.
  • the disease, disorder, or condition is fungal infection.
  • the disease, disorder, or condition is a genetic disorder.
  • the disease, disorder, or condition is hypertension.
  • the disease, disorder, or condition is infertility.
  • the disease, disorder, or condition is pregnancy.
  • a ‘subject” refers to an animal.
  • a “subject” refers to a mammal, including but not limited to mice, rats, hamsters, guinea pigs, rabbits, cats, dogs, pigs, goats, sheep, horses, cows, non-human primates, and humans.
  • a “subject” is a human.
  • a “subject” refers to a plant.
  • the present invention is further illustrated by the following non-limiting example.
  • Example 1 Microsphere preparation with glycofurol.
  • PLGA with lactide:glycolide ratio of 75:25 and molecular weight of 66,000-107,000 Daltons was obtained from Sigma Aldrich, Product # P1941).
  • the solvent, Tetraglycol BioXtra (glycofurol) was obtained from Sigma Aldrich, Product #T3396).
  • Dexamethasone, 98% was obtained from Alfa Aesar, Product #A17590.
  • PLGA spheres were prepared by a phase inversion technique using an air-driven droplet generator device (FIG. 1).
  • PLGA was suspended in glycofurol at concentrations of either 1, 5, or 20% w/v and placed on a shaker at 150 rpm for 24 h at room temperature to ensure complete dissolution.
  • Dexamethasone was added to the polymer solution at concentrations of 1% and 20% (wt/wt PLGA).
  • the PLGA-gly cofurol solution was pumped via Hamilton 100 pL syringe, through a Hamilton syringe pump, to a droplet generator (made from solution dropped from a needle surrounded by an air jacket into distilled deionized water to allow phase inversion which quickly resulted in the formation of PLGA compositions.
  • PLGA spheres remained in water for 30 min to ensure complete phase inversion. After collected by fdtration, spheres were washed twice with distilled, deionized water, and lyophilized and then stored at -20°C prior to use.
  • PLGA compositions can be created by spraying the polymer solution containing the API into aqueous solution to form smaller microspheres and nanospheres.
  • the spraying mechanism can be mechanical or can be facilitated using an electrostatic field to create polymer jets.
  • PLGA was first dissolved in glycofurol at concentration of either 1%, 5% or 20% w/v. and placed on a shaker at 150 rpm for 24 hours, at room temperature to ensure complete dissolution.
  • DEX was added to the polymer solution at concentrations of 1% and 20% (wt./wt. PLGA).
  • the applied voltage used was 10 kV, nozzle internal diameter 0.25 mm, the collecting distance and flow rate were fixed at 15 cm and 0.1 ml/h. respectively.
  • the PLGA/drug solution was pumped using syringe pump.
  • the positive electrode was connected to needle and collector was connected to earth. This results in a cone jet that appears, followed by evaporation of the solvent during the jet process and formation of PLGA microspheres at the collector.
  • the PLGA/ API constructs can be made into shapes other than spheres by placing the polymer solution containing the API into molds and immersing molds in the aqueous solution to form various shapes and sizes of the drug-laden polymer.
  • PLGA was first dissolved in Glycofurol at concentration of either 1%, 5% or 20% w/v. and placed on a shaker at 150 rpm for 24 hours, at room temperature to ensure complete dissolution.
  • DEX was added to the polymer solution at concentrations of 1% and 20% (wt./wt. PLGA).
  • the PLGA/drug solution is placed inside a 5 ml dispenser syringe and expelled from the tip onto a silicone mold (size/shape customizable, usually rod-shaped molds between 5 and 20 mm). The mold is then immersed in an aqueous solution to facilitate phase inversion. After 5 min. The formed polymer is removed from the mold and is allowed to sit in the aqueous solution for another 5 min to complete the phase inversion process resulting in a polymer scaffold.
  • PBS phosphate buffered saline
  • Dexamethasone-loaded microsphere formulations were prepared using an oil-in-water (o/w) emulsion solvent extraction/ evaporation technique.
  • the PLGA polymer was dissolved in dichloromethane at 20% w/v and dexamethasone was dispersed in this solution at 20% w/w.
  • This organic phase was then slowly added to 10 mL of PVA solution (1% (w/v), average MW 30-70 kDa) under constant mechanical stirring at 250 rpm.
  • the emulsion was then transferred to 125 mL of an aqueous polyvinyl alcohol (PVA) solution (0.1% (w/v), MW 30-70 kDa) and stirred at 250 rpm under vacuum for 2.5 hours to evaporate the solvent and harden the compositions.
  • PVA polyvinyl alcohol
  • the compositions were then washed three times with 10 mL deionized water, collected by centrifugation, lyophilized and stored at 4°C until further use.
  • C57BL/6 mouse spleen cells (1 x 10 5 ), isolated using Ficoll-Paque density gradient and mixed with Con A 2 pg/mL, or C57BL/6 mouse embryonic fibroblasts (1 x 10 5 ), served as target cells.
  • PLGA compositions (10 mg, 3 batches) were dissolved in 0.9 mL dimethylsulfoxide (DMSO) in a glass tube for 1 hour, followed by the addition of 3 mL of 0.05 M HC1 for another 1 hour.
  • Drug content was determined using spectrophotometric analysis. The encapsulation efficiency was calculated.
  • the theoretical drug load is the maximum drug load of the PLGA.
  • Encapsulation efficiency % (EE) actual drua load — x 100% theoretical drug load
  • the average diameters of microsphere shaped compositions were analyzed by software image measurement (NIH, ImageJ) (29/27).
  • the density and porosity values of the PLGA spheres were measured in triplicate by a liquid displacement methodology. Forty PLGA spheres were immersed in a volume measuring device containing a known volume (VI) of water. The sample was allowed to stand for 10 min and the new volume was then recorded as V2. The volume difference. (V2-V 1), represented the total volume of the PLGA spheres.
  • the porosity of the PLGA (tp) expressed as percentage (%) was calculated by:
  • Lyophilized PLGA compositions were weighed to obtain the dry weight (wl).
  • the solidification time (ti), the time required for phase inversion to complete, was assessed and compared in 20% PLGA, 10% PLGA, 5% PLGA and 1% PLGA spheres (n 12/group) not containing drug by determining the required time for spheres to turn opaque once the generated droplet entered the aqueous phase.
  • some PLGA spheres were taken out of the aqueous phase immediately after turning opaque and some were maintained in the aqueous phase for another 5, 10, or 15 min. Following routine processing, sphere hardness was compared in all groups.
  • PLGA spheres of varying sizes and morphology resulting from various polymer concentration, polymer-drug mixture flow rate, air flow rate, and d2. *indicates the parameters selected for preparing PLGA spheres for the drug elution experiments.
  • PLGA compositions were spherical (FIG. 2A) and had a mean diameter of 397.38 pm ( ⁇ 32.43 SE) (FIG. IB).
  • the drug encapsulation efficiency within the glycofurol spheres was significantly greater than that in DCM spheres, 80.45% and 72.25% respectively.
  • the burst over the first day was also significantly lower in the glycofurol spheres than in DCM spheres.
  • the hardness of the DCM and glycofurol PLGA spheres (n 30) made with 20% PLGA were compared by measuring the compressive modulus.
  • High Performance Liquid Chromatography was performed to determine if the dexamethasone molecule released from the spheres is denatured over time (FIG. 3).
  • Dexamethasone had a retention time of 9.99 min. There was a sharp DEX peak at 1 w eek that was not altered over time. There was no secondary breakdown peak(s) even by 5 weeks.
  • the mean glycofurol content of compositions made from 20% PLGA was 6.26 mg ( ⁇ 1.78 SE) per 100 mg of PLGA compositions.
  • compositions prepared with dichloromethane or glycofurol were assessed and compared by measuring the effect of different quantities of each type of spheres has on the proliferation (or viability) of fibroblasts or Con A-stimulated mononuclear spleen cells (FIG. 4).
  • the proliferation of spleen cells and fibroblasts decreased dose- dependently with the number of incubated DCM-constructed spheres (FIG. 4).
  • all doses of glycofurol-constructed PLGA spheres caused no decrease in viability of fibroblasts and spleen cells.
  • Spheres with 20% PLGA had lower mean cumulative dexamethasone release at every time point. The duration of drug release was also longer in the 20 % PLGA than 5% PLGA spheres (FIG. 5).
  • dexamethasone concentration on drug release from 20% PLGA compositions is depicted in FIG. 6.
  • the drug bursts in the 20% dexamethasone and 1 % dexamethasone compositions were similar, 5.99% and 4.91%, respectively.
  • both the 1% and the 20% dexamethasone-made spheres there was no lag phase after the drug burst.
  • Table 5 Comparision of time to 25%, 50%, and 75% release of spheres made from 20% PLGA in glycofurol with 20% and 1% dexamethasone (DEX). * indicates p ⁇ 0.001.
  • the pattern of drug release included a small decline in drug release rate from 48-68 days in the 20% dexamethasone spheres and a smaller decline of drug release from 60-75 days in the 1% dexamethasone spheres.
  • the 1% dexamethasone spheres exhibited a zero-order fit while the 20% dexamethasone spheres did not, with a mean R 2 of 0.971 (0.015) (range 0.96-0.98) vs 0.884 (.033) (range 0.85-0.93) (p ⁇ 0.0002).
  • Table 6 Comparison of kinetic models of release for 20% dexamethasone (DEX) vs 1% DEX f and J are the best fit models for 20% Dex and 1% Dex respectively. * and ** are p ⁇ 0.005 and p ⁇ 0.008, respectively, when compared to the best fit model(s).
  • the accumulated dexamethasone release over time was compared in 320-380 pm in diameter PLGA microsphere made with glycofurol and DCM.
  • Table 7 Comparision of time to 25%, 50%, 75% and 80% release of spheres made from DCM and glycofurol with 20% dexamethasone drug load and 20% PLGA concentration.
  • the time to 25, 50, and 75% release of releasable drug was faster in the DCM-prepared spheres (Table 8).
  • 50% of releasable drug was release within 12 days in DCM spheres as compared to 71 days in the Tetraglycol spheres.
  • the DCM prepared spheres released all of its releasable drug within 42 days as compared to >110 days in the Tetraglycol spheres when the experiment was terminated.
  • Table 8 Comparision of time to 25%, 50%, and 75% release of spheres made from 5% PLGA and 20% PLGA in glycofurol having a dexamethasone drug load of 20%.
  • the optimal device settings were determined to construct PLGA compositions wi th 20% PLGA were: a solvent/drug (pump) flow rate of 5 pL min' 1 , a 35 gauge needle, air flow rate of 30 LPM, a dl of 2.5 mm and a d2 of 25 mm.
  • PLGA spheres prepared with organic solvents such as dimethylchloride (DCM) has been toxicity on the surrounding tissue and the degrading effect on the drug payload.
  • DCM dimethylchloride
  • results disclosed herein also indicated that PLGA compositions made with DCM were toxic to spleen cells and fibroblasts in vitro.
  • PLGA spheres made with glycofurol were non-toxic, having no inhibitory effect on either of these ty pes of target cell, a significant advantage for using glycofurol-constructed spheres disclosed herein.
  • Hickey observed the dexamethasone molecule released from PLGA spheres constructed with DCM degraded within just a week of in vitro incubation. Their HPLC studies revealed a second peak, representing degraded dexamethasone that increased over time. In contrast, the glycofurol-constructed spheres caused no dexamethasone degradation even after 5 weeks of incubation.
  • glycofurol is considered non-toxic ⁇ it seems reasonable to keep the amount of solvent within the spheres as low as possible.
  • the residual amount of glycofurol within the spheres presented here was 5.71 mg/ 100 mg, far less than the 14-16.9 mg/100 mg found in previously described glycofurol PLGA spheres prepared by methods different from the method disclosed herein. This surprisingly low residual amount may be further reduced by utilizing standard methods such as dialysis.
  • Microspheres in the art were constructed with glycofurol using an emulsion extraction method and incorporated three substances, Ritonavir, Lopinavir, and Sudan III, with a reported maximal duration of release of only 4 h, 20 h, and 18 days, respectively.
  • PLGA nanospheres in the art were made using interfacial polymer deposition method with glycofurol and then loaded Paclitaxel by adsorption on to the spheres. However, it was reported that all drug was released by' 7 days. Using a phase separation method, nanospheres were constructed in the art with glycofurol incorporating lysozy me or TGF-P w ith a total duration of drug release of only 10 days and 20 days respectively.
  • Drug release from PLGA spheres are described to generally occur in three phases.
  • An initial short drug burst over the first 24 hours is thought to be due to drug release from the surface or just below the surface of the microsphere.
  • a minimal drug release for 2-3 or more weeks usually occurs, called a lag phase, which is thought to be due to drug diffusing from the core of the sphere to the surface.
  • Spheres with very short duration of drug release may not demonstrate this lag phase.
  • the lag phase is frequently followed by a third phase of a more rapid rate of drug release sometimes occurring at a constant (zeroorder kinetics) induced by the (hydrolytic) breakdown of the PLGA.
  • glycofurol-constructed spheres have a relatively small bursts of 5% to 6% as compared to the 18% to 65% burst in previously reported dexamethasone spheres constructed with dichloromethane. This small burst may be clinically helpful to avoid a large bolus of drug.
  • the small burst that we observed could be due to a small amount of drug on the sphere surface (which may be related to the speed these spheres formed) and/or a very slow time for the drug near the surface of the spheres to diffuse through the pores to the surface.
  • the increased dexamethasone release after the slowdown may not be due to dexamethasone transfer from the core but solely due to hydrolytic degradation of PLGA which then starts the last phase of drug release, a phase of brisk extended drug release at zeroorder kinetics in both the 1% and 20% dexamethasone spheres.
  • the release/diffusion mechanism was assessed by calculating the diffusion exponent A and erosion exponent B derived from the nonlinear-fitted Kopchas model.
  • the calculated value of A and B indicated that both factors, diffusion and erosion, are responsible for drug release.
  • An extended duration of drug release from implanted compositions may be critical in treating chronic inflammation and disease such as cancer, chronic inflammatory bowel disease, arthritis, chronic abscess, and AIDS.
  • the duration of dexamethasone release from our 1 % and 20% dexamethasone compositions was approximately 6 months, far longer than the duration of active release of previously reported dexamethasone-laden PLGA spheres.
  • alterations to the methodology to prepare spheres described herein, such as encasing the compositions in gels may further improve and extend the release of drug.
  • the spheres made with DCM had far shorter duration of drug release than spheres made with glycofurol.
  • the time to 50% drug release was 12 days vs 71 days in DCM and glycofurol spheres, respectively (p ⁇ 0.01 ).
  • sphere size was the main reason for the long duration of drug release from our spheres.
  • Panyam found that a 10-fold increase in PLGA sphere size may have no effect on rates of sphere degradation. Panyam J et al., J Control Release 92(1 -2): 173 (2003).
  • the kinetics of release are also more clinically advantageous with a unique lack of a lag phase after the burst, and a prolonged constant drug release rate particularly in the spheres made with 1 % dexamethasone.

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  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Chemical & Material Sciences (AREA)
  • Biophysics (AREA)
  • Molecular Biology (AREA)
  • Dermatology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention concerne des constructions de copolymère de poly(D, L-lactide-co-glycolide) (PLGA) et des compositions préparées à l'aide de glycofurol de solvant non toxique. Les constructions de PLGA et les compositions comprennent des quantités résiduelles très faibles de glycofurol et présentent une libération inattendue in vitro et in vivo de médicaments incorporés dans celles-ci. L'invention concerne également des procédés de fabrication et d'utilisation des constructions de PLGA et des compositions et des compositions pharmaceutiques les comprenant.
PCT/US2024/010868 2023-01-10 2024-01-09 Compositions de plga non toxiques et leurs procédés de fabrication et d'utilisation Ceased WO2024151625A1 (fr)

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Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20020064547A1 (en) * 1998-03-19 2002-05-30 Rey T. Chern Liquid polymeric compositions for controlled release of bioactive substances
US20100098735A1 (en) * 2006-10-05 2010-04-22 Rajesh Jain Injectable depot compositions and its process of preparation
US20220096504A1 (en) * 2019-01-30 2022-03-31 Diamond Therapeutics Inc. Methods and compositions comprising a 5ht receptor agonist for the treatment of psychological, cognitive, behavorial, and/or mood disorders
WO2022093722A1 (fr) * 2020-10-27 2022-05-05 Pts Consulting, Llc Composition injectable liquide de donepezil

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20020064547A1 (en) * 1998-03-19 2002-05-30 Rey T. Chern Liquid polymeric compositions for controlled release of bioactive substances
US20100098735A1 (en) * 2006-10-05 2010-04-22 Rajesh Jain Injectable depot compositions and its process of preparation
US20220096504A1 (en) * 2019-01-30 2022-03-31 Diamond Therapeutics Inc. Methods and compositions comprising a 5ht receptor agonist for the treatment of psychological, cognitive, behavorial, and/or mood disorders
WO2022093722A1 (fr) * 2020-10-27 2022-05-05 Pts Consulting, Llc Composition injectable liquide de donepezil

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
AUBERT-POUESSEL ET AL.: "Preparation of PLGA Microparticles by an Emulsion-Extraction Process Using Glycofurol as Polymer Solvent", PHARMACEUTICAL RESEARCH, vol. 21, no. 12, December 2004 (2004-12-01), pages 2384 - 2391, XP019370681, Retrieved from the Internet <URL:https://link.springer.com/article/10.1007/s11095-004-7693-3> [retrieved on 20240308], DOI: 10.1007/s11095-004-7693-3 *

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