[go: up one dir, main page]

WO2021257784A1 - Formulations de méloxicam injectables - Google Patents

Formulations de méloxicam injectables Download PDF

Info

Publication number
WO2021257784A1
WO2021257784A1 PCT/US2021/037753 US2021037753W WO2021257784A1 WO 2021257784 A1 WO2021257784 A1 WO 2021257784A1 US 2021037753 W US2021037753 W US 2021037753W WO 2021257784 A1 WO2021257784 A1 WO 2021257784A1
Authority
WO
WIPO (PCT)
Prior art keywords
mlx
formulation
metal
loaded
microparticles
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
PCT/US2021/037753
Other languages
English (en)
Inventor
Nicholas Karabin
Julia Rashba-Step
Zimeng WANG
Lesley C. RAUSCH-DERRA
Laman Alani
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Verte Therapeutics LLC
Original Assignee
Verte Therapeutics LLC
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Verte Therapeutics LLC filed Critical Verte Therapeutics LLC
Publication of WO2021257784A1 publication Critical patent/WO2021257784A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

Links

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
    • A61K9/19—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles lyophilised, i.e. freeze-dried, solutions or dispersions
    • 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
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/54—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame
    • A61K31/5415—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame ortho- or peri-condensed with carbocyclic ring systems, e.g. phenothiazine, chlorpromazine, piroxicam
    • 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
    • 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
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]

Definitions

  • This invention relates to injectable meloxicam formulations for sustained release and to methods for preparations and uses thereof.
  • MLX Meloxicam
  • NSAID nonsteroidal anti-inflammatory drug
  • Meloxicam provides an analgesic effect without sedation or the addictive properties of narcotic analgesics.
  • the mean elimination half-life (tl/2) of meloxicam ranges from 15 hours to 20 hours, which makes it useful for lasting relief that narcotic analgesics do not provide.
  • the long half- life of meloxicam confers a long duration of action and thus requires less frequent dosing.
  • an injectable (e.g., intravenous, intramuscular, intraperitoneal, or subcutaneous) meloxicam formulation may provide a therapeutic amount of meloxicam over an extended period of time from a single injection for the treatment of acute pain and inflammation in animals.
  • the present invention provides injectable meloxicam formulations with sustained releases.
  • the present invention provides an injectable meloxicam formulation comprising Metal:Meloxicam (Metal:MLX)-loaded particles and a pharmaceutically acceptable carrier, excipient, or diluent, wherein said particles comprise a Metal:MLX complex dispersed in a polymer, wherein said polymer comprises a fatty acid, a triglyceride, polylactic acid (PLA), polyglycolic acid (PGA), poly(lactic-co-glycolic acid) (PGLA), polycaprolactone (PCL); sucrose acetate isobutyrate, poloxamer, glyceryl monooleate, PEG-PLA-PEG copolymer, or a derivative thereof.
  • Metal:MLX Metal:Meloxicam
  • said MetahMLX-loaded particles are Metal:MLX-loaded microparticles, MetahMLX-loaded nanoparticles, or a suspension containing MetahMLX-loaded microparticles or nanoparticles.
  • the suspension contains MetahMLX-loaded microparticles or nanoparticles.
  • the fatty acid is a long chain fatty acid.
  • the triglyceride is a medium chain triglyceride.
  • the formulation comprises meloxicam in an amount of from about 1 mg/mL to about 100 mg/mL.
  • the MetahMLX complex is a Zn:MLX complex.
  • the polymer comprises poly(lactic-co-glycolic acid) (PGLA).
  • the formulation comprises Zn:MLX-loaded PLGA microparticles or nanoparticles.
  • the Zn:MLX-loaded PLGA microparticles have a size of from about 10 ⁇ m to about 200 ⁇ m.
  • the Zn:MLX-loaded PLGA nanoparticles have a size of from about 20 nm to about 200 nm.
  • the formulation comprises meloxicam in an amount of from about 5 mg/mL to about 50 mg/mL.
  • the polymer comprises a triglyceride.
  • the triglyceride is tristearin.
  • the formulation of the invention comprises Zn:MLX- loaded tristearin microparticles.
  • the Zn:MLX-loaded tristearin microparticles have a size of from about 10 ⁇ m to about 200 ⁇ m in diameter.
  • the formulation of the invention comprises Zn:MLX-loaded tristearin nanoparticles.
  • the Zn:MLX-loaded tristearin nanoparticles have a size of from about 20 nm to about 200 nm.
  • the formulation in some embodiments, comprises meloxicam in an amount of from about 5 mg/mL to about 100 mg/mL. In other embodiments, the formulation comprises meloxicam in an amount of from about 20 mg/mL to about 50 mg/mL.
  • the formulation of the invention releases meloxicam for at least 5-60 days.
  • the present invention provides a method of treating pain or inflammation of osteoarthritis in a subject in need thereof, comprising administering a pharmaceutically effective amount of meloxicam by a formulation of the invention as described herein.
  • the subject is an animal.
  • the subject is a companion animal or an animal in a zoo.
  • the companion animal is a horse, a cat, a dog, or a ferret.
  • the subject is a dog.
  • the subject is an exotic animal, such as an animal in a zoo.
  • the present invention provides a method of preparing Metal.MLX-loaded particles in an injectable meloxicam formulation of the invention as described herein, comprising
  • step (iii) mixing the solution of the Metal:MLX complex of step (i) with the solution of the polymer of step (ii) to form an oil phase containing the Metal:MLX and the polymer;
  • step (iv) homogenizing the oil phase of step (iii) with an aqueous phase comprising polyvinylalcohol (PVA) in deionized water to form an emulsion;
  • PVA polyvinylalcohol
  • step (v) quenching the emulsion of step (iv) in deionized water to provide a microsphere suspension
  • the present invention provides a method of preparing Metal.MLX-loaded particles of the formulation of the invention as described herein, comprising
  • MetahMLX complex suspended in the melt polymer suspended in the melt polymer.
  • Figure 1 depicts a calibration curve generated for MLX quantitation.
  • Figure 2 provides a schematic representation of the process used to generate MLX-loaded tristearin microparticles.
  • Figure 3 depicts an in vitro release (IVR) profile of unwashed tristearin microparticles prepared on the 0.5 g scale.
  • Figure 4 depicts an in vitro release (IVR) profile of unwashed tristearin microparticles prepared on the 1.0 g scale.
  • Figure 5 depicts an in vitro release (IVR) profiles of unwashed and carbonate-bicarbonate buffer-washed tristearin microparticles prepared on the 1.0 g scale.
  • Figure 6 depicts an in vitro release (IVR) profiles of unwashed and carbonate-bicarbonate buffer-washed tristearin microparticles prepared on the 5.0 g scale.
  • Figure 7 depicts an in vitro release (IVR) profile for washed MLX-loaded tristearin microparticles utilized in Group 1 of Animal Study I.
  • Figure 8 depicts an in vitro release (IVR) profile for unwashed MLX-loaded tristearin microparticles utilized in Groups 2 & 3 of Animal Study I.
  • IVR in vitro release
  • Figure 9 depicts an overlay of averaged PK profiles of MLX-containing formulations utilized in Animal Study I.
  • Figure 10 depicts a schematic representation of the process for preparation of M 2+ :MLX complexes.
  • Figure 11 depicts a dissolution profile of Zn:MLX complexes prepared in carbonate- bicarbonate buffer (CBB) and methanol (MeOH). Solubility of MLX is included for reference.
  • Figure 12 depicts an in vitro release (IVR) profile for washed Zn:MLX-loaded tristearin microparticles utilized in Groups 1 & 3 of Animal Study II.
  • Figure 13 depicts an in vitro release (IVR) profile for unwashed Zn:MLX-loaded tristearin microparticles utilized in Groups 2 & 4 of Animal Study II.
  • IVR in vitro release
  • Figure 14 depicts an in vitro release (IVR) profile for washed MLX-loaded tristearin microparticles utilized in Group 5 of Animal Study II.
  • Figure 15 depicts averaged PK profiles for Groups 1-8 utilized in Animal Study II.
  • Figure 16 depicts a process diagram for preparation of Zn:MLX-loaded PLGA microparticles.
  • Figure 17 depicts an in vitro release (IVR) profde of development PLGA formulations at pH 7.4.
  • Figure 18 depicts an in vitro release (IVR) profile of development PLGA formulations at pH 9.0.
  • Figure 19 depicts an in vitro release (IVR) profile of washed MLX-loaded tristearin microparticles utilized in Group 1 and Group 3 of Animal Study III.
  • IVR in vitro release
  • Figure 20 depicts an in vitro release (IVR) profile of washed Zn:MLX-loaded tristearin microparticles utilized in Group 2 of Animal Study III.
  • IVR in vitro release
  • Figure 21 depicts an in vitro release (IVR) profile of Zn:MLX-loaded PLGA microparticles (Slower Releasing) utilized in Group 4 of Animal Study PI (39 °C, 25 mM sodium phosphate buffer pH 7.4 and Tris Buffer pH 9.0).
  • IVR in vitro release
  • Figure 22 depicts an in vitro release (IVR) profile of Zn:MLX-loaded PLGA microparticles (Fast Releasing) utilized in Group 5 of Animal Study III (39 °C, 25 mM sodium phosphate buffer pH 7.4 and Tris Buffer pH 9.0).
  • IVR in vitro release
  • Figure 23 depicts averaged PK profiles for Groups 1-5 utilized in Animal Study III.
  • the present invention provides a pharmaceutical formulation comprising meloxicam for injection with sustained releases.
  • the present invention provides injectable meloxicam formulations with sustained releases. It is surprising that the pharmaceutical formulations of the invention prolong the delivery of meloxicam and enhance the duration of action of the treatment of pain and inflammation in a subject, e.g., in a companion animal or an exotic animal, e.g., an animal in a zoo, and potentially reduce associated adverse events and hence enhance safety profile.
  • the present invention provides an injectable meloxicam formulation comprising Metal:Meloxicam ( Metal:MLX)-loaded particles and a pharmaceutically acceptable carrier, wherein said particles comprise a Metal:MLX complex dispersed in a polymer, wherein said polymer comprises a fatty acid, a triglyceride, polylactic acid (PLA), polyglycolic acid (PGA), poly(lactic-co-glycolic acid) (PGLA), polycaprolactone (PCL); sucrose acetate isobutyrate, poloxamer, glyceryl monooleate, PEG-PLA-PEG copolymer, or a derivative thereof.
  • Metal:MLX Metal:MLX
  • PGA polyglycolic acid
  • PGLA poly(lactic-co-glycolic acid)
  • PCL polycaprolactone
  • sucrose acetate isobutyrate poloxamer, glyceryl monooleate, PEG-PLA-PEG copolymer, or
  • the Metal:MLX-loaded particles are Metal:MLX-loaded microparticles, Metal:MLX-loaded nanoparticles, or a suspension containing Metal:MLX-loaded microparticles or nanoparticles.
  • the Metal:MLX-loaded particles are MetahMLX-loaded microparticles. In some embodiments, the Metal:MLX-loaded particles are MetahMLX-loaded nanoparticles. In some embodiments, the Metal:MLX-loaded particles are a suspension containing Metal:MLX-loaded microparticles or nanoparticles. In some embodiments, the suspension contains Metal:MLX-loaded microparticles or nanoparticles dispersed in a diluent containing excipients as described herein.
  • the Metal:MLX-loaded particles in the formulation of the invention have a size of from about 10 pm to about 100 ⁇ m. In some embodiments, the microparticles have a size of from about 20 ⁇ m to about 80 ⁇ m. In some embodiments, the microparticles have a size of from about 30 ⁇ m to about 80 ⁇ m.
  • the microparticles have a size of from about 20 ⁇ m to about 100 ⁇ m, or from about 30 ⁇ m to about 100 ⁇ m, or from about 40 ⁇ m to about 100 ⁇ m, or from about 10 ⁇ m to about 90 ⁇ m, or from about 10 ⁇ m to about 80 ⁇ m, or from about 10 ⁇ m to about 70 ⁇ m, or from about 10 ⁇ m to about 60 ⁇ m, or from about 10 ⁇ m to about 50 ⁇ m, or from about 10 ⁇ m to about 40 ⁇ m.
  • the Metal:MLX-loaded particles in the formulation of the invention have a size of from about 10 nm to about 1000 nm.
  • the nanoparticles have a size of from about 20 nm to about 800 nm.
  • the nanoparticles have a size of from about 20 nm to about 600 nm.
  • the nanoparticles have a size of from about 20 nm to about 500 nm.
  • the nanoparticles have a size of from about 20 nm to about 400 nm.
  • the nanoparticles have a size of from about 20 nm to about 300 nm.
  • the nanoparticles have a size of from about 20 nm to about 250 nm. In some embodiments, the nanoparticles have a size of from about 20 nm to about 200 nm. In some embodiments, the nanoparticles have a size of from about 20 nm to about 150 nm. In some embodiments, the nanoparticles have a size of from about 20 nm to about 100 nm.
  • the nanoparticles have a size of from about 100 nm to about 1000 nm, or from about 100 nm to about 800 nm, or from about 100 nm to about 700 nm, or from about 100 nm to about 600 nm, or from about 100 nm to about 500 nm, or from about 100 ⁇ m to about 400 nm, or from about 100 nm to about 300 nm, or from about 100 nm to about 250 nm, or from about 100 nm to about 200 nm.
  • the metal component in the Metal:MLX complex is a divalent metal component as known in the art, for example, Ca 2+ , Mg 2+ , Zn 2+ , Co 2+ , Cu 2+ , Mn 2+ , or Fe 2+ .
  • the metal component is Ca 2+ or Zn 2+ .
  • the Metal:MLX complex is a Zn:MLX complex, a Ca:MLX complex, or a Mg:MLX complex.
  • the Metal:MLX complex is a Zn:MLX complex.
  • the Metal:MLX complex has a metal component and a MLX component in a molar ratio of from about 10: 1 to about 1:10. In other embodiments, the Metal:MLX complex has a metal component and a MLX component in a molar ratio of from about 10: 1 to about
  • the Metal:MLX complex has a metal component and a MLX component in a molar ratio of from about 10:1 to about 1:1. In some embodiments, the Metal:MLX complex has a metal component and a MLX component in a molar ratio of from about 5: 1 to about 1: 10. In some embodiments, the Metal:MLX complex has a metal component and a MLX component in a molar ratio of from about 1: 1 to about 1: 10. In some embodiments, the Metal:MLX complex has a metal component and a MLX component in a molar ratio of from about 5:1 to about 1:5.
  • the Metal:MLX complex has a metal component and a MLX component in a molar ratio of from about 2:1 to about 1:2. In other embodiments, the Metal:MLX complex has a metal component and a MLX component in a molar ratio of about 1:7. In some embodiments, the Metal :MLX complex has a metal component and a MLX component in a molar ratio of about 1:6. In other embodiments, the Metal:MLX complex has a metal component and a MLX component in a molar ratio of about 1 :5. In other embodiments, the Metal:MLX complex has a metal component and a MLX component in a molar ratio of about 1:4.
  • the Metal:MLX complex has a metal component and a MLX component in a molar ratio of about 1:3. In other embodiments, the Metal:MLX complex has a metal component and a MLX component in a molar ratio of about 1 :2. In other embodiments, the Metal:MLX complex has a metal component and a MLX component in a molar ratio of about 1 : 1. In some embodiments, the Metal:MLX complex has a metal component and a MLX component in a molar ratio of about 7: 1. In some embodiments, the Metal:MLX complex has a metal component and a MLX component in a molar ratio of about 6: 1.
  • the Metal:MLX complex has a metal component and a MLX component in a molar ratio of about 5: 1. In some embodiments, the Metal:MLX complex has a metal component and a MLX component in a molar ratio of about 4: 1. In some embodiments, the Metal:MLX complex has a metal component and a MLX component in a molar ratio of about 3 : 1. In some embodiments, the Metal:MLX complex has a metal component and a MLX component in a molar ratio of about 2: 1. In certain embodiments, the Metal:MLX complex has a metal component and a MLX component in a molar ratio of about 1:1.
  • the term “MLX” refers to meloxicam.
  • the formulation of the invention comprises meloxicam in an amount of from about 1 mg/mL to about 100 mg/mL. In some embodiments, the formulation of the invention comprises meloxicam in an amount of from about 5 mg/mL to about 100 mg/mL. In some embodiments, the formulation of the invention comprises meloxicam in an amount of from about 5 mg/mL to about 90 mg/mL. In some embodiments, the formulation of the invention comprises meloxicam in an amount of from about 5 mg/mL to about 80 mg/mL.
  • the formulation of the invention comprises meloxicam in an amount of from about 5 mg/mL to about 70 mg/mL. In some embodiments, the formulation of the invention comprises meloxicam in an amount of from about 5 mg/mL to about 60 mg/mL. In some embodiments, the formulation of the invention comprises meloxicam in an amount of from about 5 mg/mL to about 50 mg/mL. In some embodiments, the formulation of the invention comprises meloxicam in an amount of from about 5 mg/mL to about 40 mg/mL. In some embodiments, the formulation of the invention comprises meloxicam in an amount of from about 5 mg/mL to about 30 mg/mL.
  • the formulation of the invention comprises meloxicam in an amount of from about 5 mg/mL to about 20 mg/mL. In other embodiments, the formulation comprises meloxicam in an amount of from about 10 mg/mL to about 50 mg/mL. In some embodiments, the formulation comprises meloxicam in an amount of from about 20 mg/mL to about 50 mg/mL. In some embodiments, the formulation comprises meloxicam in an amount of about 30 mg/mL to about 50 mg/mL. In other embodiments, the formulation comprises meloxicam in an amount of from about 10 mg/mL to about 40 mg/mL. In other embodiments, the formulation comprises meloxicam in an amount of from about 15 mg/mL to about 40 mg/mL.
  • the formulation comprises meloxicam in an amount of from about 20 mg/mL to about 40 mg/mL. In some embodiments, the formulation comprises meloxicam in an amount of from about 30 mg/mL to about 40 mg/mL. In some embodiments, the formulation comprises meloxicam in an amount of from about 30 mg/mL to about 45 mg/mL.
  • the formulation comprises meloxicam in an amount of from about 30 mg/mL to about 100 mg/mL. In some embodiments, the formulation comprises meloxicam in an amount of from about 30 mg/mL to about 90 mg/mL. In some embodiments, the formulation comprises meloxicam in an amount of about 30 mg/mL to about 80 mg/mL. In other embodiments, the formulation comprises meloxicam in an amount of from about 30 mg/mL to about 75 mg/mL. In some embodiments, the formulation comprises meloxicam in an amount of from about 30 mg/mL to about 70 mg/mL. In some embodiments, the formulation comprises meloxicam in an amount of about 30 mg/mL to about 60 mg/mL.
  • the formulation comprises meloxicam in an amount of about 20 mg/mL, about 25 mg/mL, about 30 mg/mL, about 35 mg/mL, or about 40 mg/mL, or any amount between the integers as aforementioned. In some embodiments, the formulation comprises meloxicam in an amount of about 30 mg/mL, about 35 mg/mL, about 40 mg/mL, or about 45 mg/mL, or about 50 mg/mL, or any amount between the integers as aforementioned.
  • the Metal:MLX complex such as Zn:MLX complex
  • Zn:MLX complex in the formulation of the invention, like free MLX, readily dissolves in many organic solvents, such as in N-Methyl-2- pyrrolidone (NMP) and dimethylformamide (DMF).
  • NMP N-Methyl-2- pyrrolidone
  • DMF dimethylformamide
  • the solution may exhibit an increased viscosity in comparison to the formulations containing Zn:MLX complexes suspended in either aqueous or oil-based diluents but show no issues with injectability.
  • the polymer for the injectable meloxicam formulations of the invention is a biodegradable, non-toxic polymer.
  • the polymer for the formulations of the invention has a concentration of from about 25 mg/mL to about 500 mg/mL.
  • the polymer has a concentration of from about 50 mg/mL to about 450 mg/mL.
  • the polymer has a concentration of from about 50 mg/mL to about 300 mg/mL.
  • the polymer has a concentration of from about 50 mg/mL to about 150 mg/mL.
  • the polymer has a concentration of from about 75 mg/mL to about 400 mg/mL.
  • the polymer has a concentration of from about 75 mg/mL to about 350 mg/mL. In some embodiments, the polymer has a concentration of from about 50 mg/mL to about 500 mg/mL. In other embodiments, the polymer has a concentration of from about 75 mg/mL to about 500 mg/mL. In some embodiments, the polymer has a concentration of from about 100 mg/mL to about 500 mg/mL. [0055] In some embodiments, the polymer has a concentration of from about 25 mg/mL to about
  • the polymer has a concentration of from about 25 mg/mL to about 400 mg/mL. In some embodiments, the polymer has a concentration of from about 25 mg/mL to about 350 mg/mL. In certain embodiments, the polymer has a concentration of about 100 mg/mL, 150 mg/mL, 200 mg/mL, or about 250 mg/mL, or any concentration between the integers as aforementioned. In some embodiments, the polymer has a concentration of about 300 mg/mL, 350 mg/mL, 400 mg/mL, about 450 mg/mL, or about 500 mg/mL, or any concentration between the integers as aforementioned.
  • Suitable polymer for the formulation of the invention includes, but is not limited to, polylactides, polyglycolides, polycaprolactones, polyanhydrides, polyamides, poly(amino acids), polyvinylpyrrolidone, polyethylene glycol, polyhydroxy cellulose, chitin, chitosan, alginate hyaluronic acid, gelatins; copolymers; polycaprolactones; sucrose acetate isobutyrate (SAIB).
  • SAIB sucrose acetate isobutyrate
  • the polymer comprises a triglyceride, a fatty acid, sucrose acetate isobutyrate, a poloxamer, glyceryl monooleate, thermogel, PEG-PLA-PEG copolymers, polylactic acid (PLA), polyglycolic acid (PGA), poly(lactic-co-glycolic acid) (PGLA), polycaprolactone (PCL), or a derivative thereof.
  • the triglyceride is a medium-chain triglyceride.
  • a “medium-chain triglyceride” refers to a triglyceride with two or three fatty acids having an aliphatic tail of 6 tol2 carbon atoms.
  • the fatty acid groups of the medium-chain triglyceride may include, but are not limited to, caproic acid, caprylic acid, capric acid, and lauric acid.
  • the fatty acid is a long-chain fatty acid.
  • a “long-chain fatty acid” is a fatty acid having a aliphatic tail of 13 to 21 carbon atoms.
  • the long-chain fat acid includes, but is not limited to myristic acid, palmitic acid, stearic acid, arachidic acid, oleic acid, palmitoleic acid, nervonic acid, linoleic acid, alpha-linolenic acid, arachidonic acid, and eicosapentaenoic acid.
  • thermogel is Poloxamer 188, Poloxamer F127, or a mixture thereof.
  • the polymer comprises poly(lactide-co-glycolide) (PLGA) or polylactide (PLA). In some embodiments, the polymer comprises poly(lactide-co-glycolide) (PLGA). In some embodiments, the LG ratio (lactide to glycolide ratio) of the PLGA is from about 85:15 to about 15:85 LG ratio In some embodiments, the LG ratio (lactide to glycolide ratio) of the PLGA is from about 75:25 to about 25:75. In some embodiments, the LG ratio (lactide to glycolide ratio) of the PLGA is from about 65:35 to about 35:65.
  • the LG ratio (lactide to glycolide ratio) of the PLGA is from about 50:50 to about 75:25 LG ratio.
  • the molecular weight of poly(lactide-coglycolide) is from about 10,000 Daltons to about 90,000 Daltons.
  • the molecular weight of the poly(lactide-co-glycolide) is from about 20,000 Daltons to about 80,000 Daltons, or from about 30,000 Daltons to about 70,000 Daltons.
  • PLGA refers to poly(lactic-co-glycolic acid) as known in the art, which is used interchangeably with poly(lactide-co-glycolide).
  • the polymer as used in the formulations of the invention is one of RESOMER® R polymers or RESOMER® RG polymers as known in the art.
  • RESOMER® R polymers refer to PLA/poly (D,L-lactide)-based biodegradable polymers for controlled release. These amorphous polymers may contain either acid or ester end groups. Degradation times of such polymers vary from as little as a few weeks or less to nine months or more. Inherent Viscosities (IV) can range from 0.15 to 0.75 dL/g, with molecular weights between 10,000 and 28,000 Daltons.
  • RESOMER® RG polymers refer to PLGA/poly (D,L-lactide-co-glycolide)-based bioresorbable excipients for controlled release. Designed for use with a range of complex parenteral drug products, these amorphous polymers are also available with either acid or ester end groups. Degradation times of such polymers can extend for up to 18 months or more. Inherent Viscosities (IV) can range from 0.09 to 1.7 dL/g, with molecular weights between 7,000 and 240,000 Daltons.
  • the Metal:MLX complex is a Zn:MLX complex.
  • the polymer comprises poly(lactide-co-glycolide) (PLGA).
  • the formulation comprises Zn:MLX-loaded PLGA microparticles,
  • the formulation comprises Zn:MLX-loaded
  • the Zn:MLX-loaded PLGA microparticles have a size of from about 10 ⁇ m to about 200 ⁇ m. In some embodiments, the microparticles have a size of from about 10 ⁇ m to about 100 ⁇ m. In some embodiments, the microparticles have a size of from about
  • the Zn:MLX-loaded PLGA nanoparticles have a size of from about 20 nm to about 200 nm. In some embodiments, the Zn:MLX-loaded PLGA nanoparticles have a size of from about 20 nm to about 150 nm. In some embodiments, the Zn:MLX- loaded PLGA nanoparticles have a size of from about 20 nm to about 100 nm. In some embodiments, the Zn:MLX-loaded PLGA nanoparticles have a size of from about 30 nm to about 80 nm.
  • the formulation in some embodiments, comprises meloxicam in an amount of from about 5 mg/mL to about 20 mg/mL.
  • the polymer comprises a triglyceride.
  • a triacylglycerol or triglyceride is an ester derived from glycerol and three fatty acid chains.
  • the three fatty acids can be the same fatty acid or a mixture of two or three different length of fatty acids.
  • the fatty acid chains may include any length and generally contain from about 4 to about 28 carbon atoms, or from about 8 to about 22 carbon atoms (e.g., about 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, or 22 carbon atoms).
  • the fatty acid is stearic acid, lauric acid, oleic acid, or palmitic acid.
  • the triacylglycerol or triglyceride includes, but is not limited to glyceryl tristearate, glyceryl tricaprate, glyceryl tricaproate, glyceryl tricaprylate, glyceryl tricaprylate, glyceryl trilaurate, glyceryl trilinoleate, glyceryl trioleate, glyceryl triundecanoate, glyceryl tricaprylate/caprate/laurate, glyceryl tricaprylate/caprate/linoleate, glyceryl tricaprylate/caprate/stearate.
  • the triacylglycerol is tristearin, trimyristin, tripahnitin, trilaurin, or trimargarine.
  • the triglyceride is tristearin.
  • the formulation of the invention comprises Zn:MLX-loaded tristearin microparticles, Zn:MLX-loaded tristearin nanoparticles, or a suspension containing Zn:MLX-loaded tristearin microparticles or nanoparticles.
  • the formulation of the invention comprises Zn:MLX-loaded tristearin microparticles.
  • the Zn:MLX-loaded tristearin microparticles have a size of from about 10 ⁇ m to about 200 ⁇ m.
  • the microparticles have a size of from about 10 ⁇ m to about 100 ⁇ m.
  • the microparticles have a size of from about 30 ⁇ m to about 80 ⁇ m.
  • the formulation of the invention comprises Zn:MLX-loaded tristearin nanoparticles.
  • the Zn:MLX-loaded tristearin nanoparticles have a size of from about 20 nm to about 200 nm.
  • the Zn:MLX-loaded tristearin nanoparticles have a size of from about 20 nm to about 150 nm.
  • the Zn:MLX-loaded tristearin nanoparticles have a size of from about 20 nm to about 100 nm.
  • the Zn:MLX-loaded tristearin nanoparticles have a size of from about 30 nm to about 80 nm.
  • the formulation in some embodiments, comprises meloxicam in an amount of from about 20 mg/mL to about 50 mg/mL.
  • the microparticles have a size of from about 10 ⁇ m to about 200 ⁇ m in diameter. In other embodiments, the microparticles have a size of from about 20 ⁇ m to about 100 ⁇ m in diameter. In certain embodiments, the microparticles have a size of from about 50 ⁇ m to about 100 ⁇ m in diameter.
  • tristearin refers to glyceryl tristearate.
  • the present invention provides an injectable meloxicam formulation comprising Metal:Meloxicam ( Metal:MLX)-loaded particles and a pharmaceutically acceptable carrier, wherein said particles comprise the Metal:MLX complex dispersed in a polymer, and wherein said polymer comprises a triglyceride, a fatty acid, sucrose acetate isobutyrate, a poloxamer, glyceryl monooleate, thermogel, PEG-PLA-PEG copolymers, poly lactic acid (PLA), poly glycolic acid (PGA), poly (lactic-co-gly colic acid) (PGLA), polycaprolactone (PCL), or a derivative thereof.
  • Metal:Meloxicam Metal:MLX
  • a pharmaceutically acceptable carrier wherein said particles comprise the Metal:MLX complex dispersed in a polymer, and wherein said polymer comprises a triglyceride, a fatty acid, sucrose acetate isobutyrate, a poloxamer, gly
  • the present invention provides an injectable meloxicam formulation comprising MetakMeloxicam ( Metal:MLX)-loaded particles and a pharmaceutically acceptable carrier, wherein said particles comprise the Metal:MLX complex dispersed in a polymer, and wherein the polymer comprises a triglyceride, polylactic acid (PLA), polyglycolic acid (PGA), poly(lactic-co-glycolic acid) (PGLA), or a derivative thereof.
  • PLA polylactic acid
  • PGA polyglycolic acid
  • PGLA poly(lactic-co-glycolic acid)
  • the pharmaceutically acceptable carrier or diluent or excipient in the formulations of the invention is suitable for injection.
  • the pharmaceutically acceptable carrier or diluent or excipient is well known to those skilled in the art.
  • the pharmaceutically acceptable carrier, excipient, or diluent for the formulations of the invention is substantially inert so that it does not interact with the microparticles described herein and is non-toxic so that it does not negatively impact the patient. It may be a solid or a liquid, or mixtures thereof.
  • the pharmaceutically acceptable carrier or diluent or excipient for the formulation of the invention includes, but is not limited to, a sugar (e.g., lactose, mannitol, sucrose, dextrose), a cellulosic material (e.g. microcrystalline cellulose), an acrylate (e.g. polymethylacrylate), calcium carbonate, magnesium oxide, or mixtures thereof.
  • the pharmaceutically acceptable carrier, excipient, or diluent comprises sodium carboxymethylcellulose (CMC), Kolliphor P188, mannitol, cottonseed oil, or HPMC.
  • the pharmaceutically acceptable carrier comprises sodium carboxymethylcellulose or hydroxypropyl methyl cellulose, poloxamers, various surfactants in aqueous solutions,
  • the carrier, excipient, or diluent may comprise sterile water, though other ingredients may be included, such as ingredients that aid solubility or for preservation. Injectable solutions may also be prepared in which case appropriate stabilizing agents may be employed. Administration may, for example, be intravenous, intra-arterial, intrathecal, intramuscular, intraperitoneal, subcutaneous, or intramuscular. In some embodiments, the formulation of the invention is administered by subcutaneous injection or intraperitoneal injection.
  • the formulation of the invention releases meloxicam for at least 10- 30 days. In some embodiments, the formulation of the invention releases meloxicam for at least 10 days, at least 15 days, at least 20 days, at least 25 days, or at least 30 days. In some embodiments, the formulation of the invention releases meloxicam for at least 15 days. In some embodiments, the formulation of the invention releases meloxicam for at least 30 days. In some embodiments, the formulation of the invention releases meloxicam for at least 15-30 days. In some embodiments, the formulation of the invention releases meloxicam for at least 20-30 days.
  • the formulation of the invention comprising Metal:MLX-loaded microparticles demonstrates that the burse release (i.e. initial release; e.g., Cmax at 0-1 day) for meloxicam is significantly reduced relative to free MLX-loaded microparticles.
  • Cmax is the maximum serum concentration of drug, e.g., meloxicam, which occurs during the period of release which is monitored.
  • the Cmax may occur at from about 7 days to about 30 days, for example, about 7 days, 10 days, 15 days, 20 days, 25 days, or 30 days, or about two weeks, three weeks, four weeks, five weeks, 6 weeks, or 7 weeks post administration and can occur at any integer day or week in between.
  • the injectable meloxicam formulation of the invention as disclosed herein is unexpectedly stable and effective. It exhibits distinct advantages of long shelf life for the stability of the injectable formulation and sustained release of meloxicam to reduce the frequency of dosing.
  • the formulation of the invention has a shelf life of at least 1 year, or at least 1.5 years, or at least 2 years.
  • the formulation, optionally lyophilized can be kept at a low temperature (e.g., at about -5 °C or about -15 °C) to extend its shelf life.
  • the present invention provides a method of treating pain or inflammation of osteoarthritis in a subject in need thereof, comprising administering a pharmaceutically effective amount of meloxicam by a formulation of the invention as described herein.
  • the subject is an animal.
  • the subject is a companion animal, or an exotic animal, or an animal in a zoo.
  • the companion animal is a horse, a cat, a dog, or a ferret.
  • the subject is a dog.
  • the subject is a cat.
  • the subject is an animal in a zoo.
  • the formulation releases meloxicam for at least 5 days to 60 days.
  • the formulation releases meloxicam for at least 10-30 days, or at least 10-45 days, or at least 10-60 days, or at least 20-60 days. In some embodiments, the formulation releases meloxicam for at least 10 days, at least 15 days, at least 20 days, at least 25 days, or at least 30 days or any days between the integers as aforementioned. In other embodiments, the formulation releases meloxicam for at least 15 days. In certain embodiments, the formulation releases meloxicam for at least 30 days. In some embodiments, the formulation is administered by subcutaneous injection. In other embodiments, the formulation is administered by intraperitoneal injection.
  • meloxicam in the formulation of the invention is administered at a dose of 1-10 mg per day, 3-26 mg per day, 3-60 mg per day, 3-16 mg per day, 3-30 mg per day, 10- 26 mg per day, 10- 100 mg per day, 15-60 mg per day, 15-100 mg per day, 25-100 mg per day, 50- 100 mg per day, 50-200 mg per day, 100-200 mg per day, 100-250 mg per day.
  • meloxicam in the formulation of the invention is administered at a dosage of 10 mg per day. In one embodiment, meloxicam in the formulation of the invention as described herein is administered at a dosage of 15 mg per day. In one embodiment, meloxicam in the formulation of the invention as described herein is administered at a dosage of 20 mg per day. In one embodiment, meloxicam in the formulation of the invention as described herein is administered at a dosage of 25 mg per day. In one embodiment, meloxicam in the formulation of the invention as described herein is administered at a dosage of 30 mg per day. In one embodiment, meloxicam in the formulation of the invention as described herein is administered at a dosage of 35 mg per day.
  • meloxicam in the formulation of the invention as described herein is administered at a dosage of 40 mg per day. In one embodiment, meloxicam in the formulation of the invention as described herein is administered at a dosage of 50 mg per day. In one embodiment, meloxicam in the formulation of the invention as described herein is administered at a dosage of 67.5 mg per day. In one embodiment, meloxicam in the formulation of the invention as described herein is administered at a dosage of 75 mg per day. In one embodiment, meloxicam in the formulation of the invention as described herein is administered at a dosage of 80 mg per day. In one embodiment, meloxicam in the formulation of the invention as described herein is administered at a dosage of 100 mg per day. In one embodiment, meloxicam in the formulation of the invention as described herein is administered at a dosage of 125 mg per day. In one embodiment, meloxicam in the formulation of the invention as described herein is administered at a dosage of 250 mg per day.
  • the method of the invention may comprise administering meloxicam by the formulation of the invention as described herein at various dosages.
  • meloxicam by the formulation of the invention as described herein may be administered at a dosage of 3 mg, 10 mg, 30 mg, 40 mg, 50 mg, 80 mg, 100 mg, 120 mg, 125 mg, 200 mg, or 250 mg per day.
  • meloxicam in the formulation of the invention may be administered at a dose of 0.1 mg/kg.
  • meloxicam in the formulation of the invention may administered at a dose of from 0.2 to 100 mg/kg, or from 1 to 100 mg/kg, or from 5 to 100 mg/kg, or from 10 to 100 mg/kg, or from 5 to 75 mg/kg, or from 5 to 50 mg/kg, or from 10 to 50 mg/kg, or from 10 to 300 mg/kg.
  • meloxicam in the formulation of the invention may administered at a dose of 0.2 mg/kg, 0.3 mg/kg, 1 mg/kg, 3 mg/kg, 5 mg/kg, 7.5 mg/kg, 10 mg/kg, 15 mg/kg, 20 mg/kg, 25 mg/kg, 30 mg/kg, 35 mg/kg, 40 mg/kg, 45 mg/kg, 50 mg/kg, 55 mg/kg, 60 mg/kg, 65 mg/kg, 70 mg/kg, 75 mg/kg, 80 mg/kg, 85 mg/kg, 90 mg/kg, 95 mg/kg, or 100 mg/kg.
  • the formulation of the invention is prepared for once daily administration. In another embodiment, the formulation of the invention is prepared for more than once daily administration, for example, twice daily, or three times daily, etc.
  • the MetahMLX complex can be prepared under aqueous conditions or under non-aqueous conditions.
  • MLX and a metal salt, such as zinc acetate at a 2:1 molar ratio in hot methanol (65 - 75 °C).
  • the recovered solids ranged from 88% to 93% MLX, which aligns with the calculated percentage of 91% for complexes exhibiting a 2:1 ratio of MLX to Zn.
  • the preparation of MetahMLX complex can be conducted under aqueous conditions based on protocols for protein complexation as known in the art (e.g., Yordanova, et al. Sci Rep 8, 11280 (2016); Qian, et al. int. J. Pharm.
  • CBB carbonate-bicarbonate buffer
  • the Metal:MLX-loaded microparticles and the formulations comprising the same can be prepared by processes known in the art (e.g., Cai, et al. Osteoarthr. Cartil. 10, 692-706 (2002); Nafissi etal. Egyptian journal of pharmaceutical research: IJPR 10(2) : 203-9 (2011); Yin etal. Chem Pharm Bull (Tokyo). 56(2): 156-161 (2008)).
  • the Metal:MLX-loaded microparticles and the formulations of the invention can be prepared by methods as illustrated in Figure 16 and the examples as described herein.
  • the present invention provides a method of preparing MetahMLX-loaded particles in the formulation of the invention as described herein, comprising
  • step (iii) mixing the solution of the Metal:MLX complex of step (i) with the solution of the polymer of step (ii) to form an oil phase containing the Metal:MLX and the polymer;
  • step (iv) homogenizing the oil phase of step (iii) with an aqueous phase comprising polyvinylalcohol (PVA) in deionized water to form an emulsion;
  • PVA polyvinylalcohol
  • step (v) quenching the emulsion of step (iv) in deionized water to provide a microsphere suspension
  • the Metal:MLX-loaded particles of step (vi) are MetahMLX-loaded microparticles, Metal:MLX-loaded nanoparticles, or a suspension containing MetahMLX-loaded microparticles or nanoparticles.
  • the term "suspension” refers to a dispersion of particles in which a liquid excipient forms a continuous liquid phase in which the solid form of Metal:MLX particles dispersed or suspended.
  • the liquid excipient or suspending agent
  • the liquid excipient comprises HPC (hydroxypropyl cellulose), HPMC, or sodium methylcellulose.
  • the first organic solvent is dimethylformamide.
  • the second organic solvent is methylene chloride.
  • the Metal:MLX complex is a Zn:MLX complex.
  • the polymer is poly(lactic-co-glycolic acid) (PGLA).
  • the Metal:MLX-loaded microparticles are Zn:MLX-loaded PLGA microparticles.
  • the method of the invention further comprises a step of adding the pharmaceutically acceptable carrier, excipient, or diluent.
  • the pharmaceutically acceptable carrier, excipient, or diluent comprises CMC, P188, or mannitol.
  • the present invention provides a method of preparing MetahMLX-loaded particles in the formulation of the invention as described herein, comprising
  • the Metal:Meloxicam (Metal:MLX)-loaded particles of step (e) are Metal :Meloxicam ( Metal:MLX)-loaded microparticles or MetahMeloxicam ( Metal:MLX)-loaded nanoparticles.
  • the solid Metal:MLX complex in the method of the invention comprises from about 1% to about 25% w/w of the solid mixture of step (a). In other embodiments, the solid polymer comprises from about 75% to about 99% w/w of the solid mixture of step (a). [0097] In some embodiments, the homogenizing of step (b) is carried out by vortexing.
  • the melted polymer suspension is prepared by vortexing to suspend the solid Metal:MLX complex in the melt polymer.
  • the method of the invention further comprises a step of sieving the Metal-MLX particles after step (e).
  • the Metal:MLX complex in the method of the invention is a Zn:MLX complex.
  • the polymer is a triglyceride.
  • the triglyceride is tristearin.
  • the Metal:MLX-loaded particles are Zn:MLX-loaded tristearin microparticles or nanoparticles.
  • Tristearin-based formulations were suspended in DMSO and incubated for 30 minutes at 85°C. Upon tristearin melting, solutions were vortexed and aliquoted to microcentrifuge tubes. Aliquots were subsequently centrifuged at 10,000 rpm for 5 min to separate solid and liquid fractions. An aliquot of the liquid fraction was transferred to an HPLC vial for quantitation.
  • IVR studies were conducted by immersing MLX-containing formulations in 25 mM sodium phosphate buffer (pH 7.4). Formulations were agitated within an air incubator maintained at 39°C. At pre-determined timepoints, a 1 mL aliquot was recovered and centrifuged at 10,000 rpm for 5 min to separate the IVR media from the suspended formulation. An 800 ⁇ L aliquot was collected from the supernatant and transferred to an HPLC vial for quantitation.
  • Example 1 Microparticles for Formulations of Invention [00109] Tristearin Granulation
  • Tristearin granulation was explored to embed MLX within the tristearin matrix. Granulation permitted the preparation of tristearin microparticles with mean diameters measuring tens of microns and containing MLX at an actual drug loading of 4 - 5%.
  • Figure 2 provides a schematic representation of the process used to generate MLX-loaded tristearin microparticles. [00111] Microparticle Washing
  • MLX-containing tristearin microparticles were washed with carbonate-bicarbonate buffer (pH 9). The washing procedure showed a limited effect on the burst observed in vitro but did slow the rate of MLX release.
  • MLX-containing tristearin microparticles prepared at the 1.0 g scale exhibited comparable drug loading to microparticles prepared at the 0.5 g scale.
  • the particles prepared at the 1.0 g exhibited a reduction in their burst release at the 24 h timepoint from -68% to -51%. Further, washing the microparticles with CBB (pH 9) demonstrated that MLX release could be further slowed.
  • Figure 4 depicts an in vitro release (IVR) profile of unwashed tristearin microparticles prepared on the 1.0 g scale.
  • Figure 5 depicts an in vitro release (IVR) profiles of unwashed and carbonate-bicarbonate buffer-washed tristearin microparticles prepared on the 1.0 g scale.
  • MLX-containing tristearin microparticles prepared on the 5.0 g scale exhibited both comparable loading and IVR in comparison to MLX-containing microparticles prepared on the 1.0 g scale.
  • Figure 6 depicts an in vitro release (IVR) profiles of unwashed and carbonate-bicarbonate buffer-washed tristearin microparticles prepared on the 5.0 g scale.
  • ISP In situ Precipitating
  • PLGA-based in situ precipitating (ISP) gels represent a simple (solution of polymer and API in acceptable organic solvent) and potentially cost-effective (limited processing) strategy for achieving sustained release.
  • the PLGA (Resomer 504H) utilized in the development of ISP gels was sourced from Evonik Corporation (201 Evonik Road Theodore, AL 36582). ISP PLGA gels containing MLX were successfully prepared in vitro.
  • Example 2 Formulations for Animal Study I [00124] Five formulations were prepared for Animal Study I. Formulation compositions upon reconstitution are listed in Table 2.
  • Table 2 Description of formulations utilized in Animal Study I.
  • MLX meloxicam
  • CMC sodium carboxymethylcellulose
  • HPMC hydroxypropyl methyl cellulose.
  • Washed tristearin microparticles exhibited comparable burst to unwashed tristearin formulations but a reduced rate of release in vitro. Washed tristearin microparticles were selected for Animal Study I and administered utilizing an aqueous diluent containing CMC and HPMC. [00128] Microparticles exhibited a mean diameter of ⁇ 80 ⁇ m and exhibited an IVR profile comparable to similarly prepared R&D formulations. Figure 7 depicts an in vitro release (IVR) profile for washed MLX-loaded tristearin microparticles utilized in Group 1 of Animal Study I.
  • IVR in vitro release
  • Unwashed tristearin microparticles were selected for Animal Study I. Due to the limited solubility of MLX in oil, unwashed tristearin microparticles were administered utilizing two oil- based diluents.
  • Microparticles exhibited a mean diameter of ⁇ 85 ⁇ m and a slightly increased burst in comparison to their CBB-washed counterparts.
  • Figure 8 depicts an in vitro release (IVR) profile for unwashed MLX-loaded tristearin microparticles utilized in Groups 2 & 3 of Animal Study I.
  • Table 4 Size characteristics of MLX-loaded tristearin microparticles utilized in Groups 2 & 3 of Animal Study I [00134] ISP PLGA Gel
  • Temperature Sensitive Poloxamer 407 Gel [00137] Temperature Sensitive Poloxamer 407 Gel [00137] MLX-containing poloxamer 407 gels were investigated in rodents. The temperature sensitive poloxamer gels were the most difficult formulation to administer in Animal Study I due to the discomfort felt by the rodents (i.e. writhing, tensing, etc.).
  • CBB carbonate-bicarbonate buffer
  • Results Aqueous conditions could be successfully used to form zinc:meloxicam complexes (Zn:MLX). Anywhere from 85% to 100% of the MLX added could be recovered within the resulting precipitate.
  • Figure 10 depicts a schematic representation of the process to create M 2+ :MLX complexes.
  • ISP PLGA gels containing Zn:MLX were prepared in vitro.
  • a wash procedure was instituted to better emulate the tristearin microparticles that would be prepared via microencapsulation. Washing MLX-loaded tristearin microparticles resulted in the slowest MLX release in vitro, and a similar result was expected through washing Zn:MLX-loaded microparticles.
  • Washed MLX-loaded tristearin microparticles were identified as the most attractive formulation from Animal Study I based on its PK profile. The formulation was included in Animal Study II to investigate the release profile achieved when administering the formulation at the concentration to be used in the target species.
  • Microparticles exhibited a mean diameter of 76 ⁇ m and exhibited an IVR profile comparable to the washed MLX-loaded tristearin microparticles prepared for Animal Study I.
  • Microparticles administered in aqueous diluent (CMC/HPMC) were significantly easier to inject in comparison the Zn:MLX-loaded tristearin microparticles administered in aqueous (HPMC alone) diluent.
  • Figure 14 depicts an in vitro release (IVR) profile for washed MLX-loaded tristearin microparticles utilized in Group 5 of Animal Study II.
  • Zn:MLX complexes were prepared via methanol reflux. Complexes were 93% MLX by mass (as determined by HPLC) and showed comparable dissolution profiles in vitro to previously prepared complexes. The suspended Zn:MLX formulations demonstrated the best injectability behavior.
  • ISP PLGA gels were incorporated into Animal Study II to explore whether MLX complexation with zinc could reduce the burst observed from ISP gels utilized in Animal Study
  • Figure 15 depicts averaged PK profiles for Groups 1-8 utilized in Animal Study II.
  • a flow diagram of the process used for Zn:MLX-loaded PLGA microparticles is depicted in Figure 16.
  • DMF dimethylformamide
  • DCM dichloromethane
  • PVA polyvinyl alcohol
  • OAV oil in water
  • MS microsphere
  • CBB carbonate-bicarbonate buffer
  • DI deionized water.
  • Manufacturing and processing conditions can be utilized to tailor the physical characteristics and IVR of PLGA microparticles.
  • One process parameter investigated was the manufacturing concentration of PLGA in organic solvent during microsphere formation.
  • the oil phase utihzed in the emulsion preparation consisted of a co-solvent system of dimethylformamide (DMF) and dichloromethane (DCM). Keeping the mass of PLGA constant, the volume of DCM within the cosolvent system was altered, permitting the PLGA concentration in oil phase to be varied.
  • IVR- altering microsphere characteristics, including particle diameter and density, are known to be influenced by the PLGA concentration in the oil phase. As such, formulations were investigated at high and low concentrations of PLGA (250 mg/mL versus 167 mg/mL) for microsphere manufacturing.
  • the polymer utilized for PLGA microparticle preparation is known to influence the IVR of the resulting formulation.
  • Two PLGA polymers, Resomer 504H and Resomer 752H, that vary in their lactide to glycolide ratio (LG ratio) were investigated. While Resomer 504H exhibits a 50:50 LG ratio, Resomer 752H exhibits a 75:25 LG ratio. This shift in the LG ratio is expected to increase the hydrophobicity of the matrix and slow down the IVR attributed to polymer degradation.
  • PLGA microparticles prepared utilizing Resomer 752H exhibited comparable drug loading (28.8%) and size characteristics (53 ⁇ m) to the microparticles prepared using Resomer 504H under similar manufacturing conditions.
  • a comparison of the process and microparticle characteristics is provided in Table 12 and Table 13.
  • Figure 17 depicts an in vitro release (IVR) profile of development PLGA formulations at pH 7.4.
  • Figure 18 depicts an in vitro release (IVR) profile of development PLGA formulations at pH 9.0.
  • Example 6 Formulations for Animal Study III [00184] The objective of Animal Study III was to investigate the release of MLX in the target species, dogs.
  • Washed MLX-loaded Tristearin Microparticles [00187] Washed MLX-loaded tristearin microparticles, tested in both Animal Study I and II, were selected for in vivo testing in Animal Study III. The formulation was selected due to the favorable PK profile observed for Group 2 in Animal Study I (Diluent: Cottonseed Oil).
  • Microparticles exhibited a mean diameter of 98 pm and exhibited an IVR profile comparable to the washed MLX-loaded tristearin microparticles prepared for Animal Study P, albeit with a lower burst. Microparticles were administered using either cottonseed oil (Group 1) or 5% aluminum monostearate in cottonseed oil (Group 3).
  • Figure 19 depicts an in vitro release (IVR) profile of washed MLX-loaded tristearin microparticles utilized in Group 1 and Group 3 of Animal Study PI.
  • Table 15 Particle size characteristics of washed MLX-loaded tristearin microparticles utilized in Animal Study III
  • Microparticles exhibited a mean diameter of 95 ⁇ m and exhibited an IVR profile comparable to the washed Zn:MLX-loaded tristearin microparticles prepared for Animal Study II. Microparticles were administered using 0.5% HPMC and 50 mg/mL Mannitol.
  • Figure 20 depicts an in vitro release (IVR) profile of washed Zn:MLX-loaded tristearin microparticles utilized in Group 2 of Animal Study III.
  • Table 17 provides particle size characteristics of Zn:MLX-loaded PLGA microparticles (Slower Releasing) utilized in Animal Study III.
  • Figure 21 depicts an in vitro release (IVR) profile of Zn:MLX-loaded PLGA microparticles (Slower Releasing) utilized in Group 4 of Animal Study III (39 °C, 25 mM sodium phosphate buffer pH 7.4 and Tris Buffer pH 9.0).
  • Zn:MLX-loaded PLGA Microparticles (Faster Releasing) [00195] From the prepared PLGA formulations, Lot No. 83109-01 was selected because of its drug loading (29%) and its IVR profile. Lot No. 83109-01 exhibited the fastest release in vitro and was selected to help establish the lower bound of potential PLGA release durations. Table 18 provides particle size characteristics of Zn:MLX-loaded PLGA microparticles (Faster Releasing) utilized in Animal Study III.
  • Figure 22 depicts an In vitro release (IVR) profile of Zn:MLX-loaded PLGA microparticles (Fast Releasing) utilized in Group 5 of Animal Study III (39 °C, 25 mM sodium phosphate buffer pH 7.4 and Tris Buffer pH 9.0).
  • IVR In vitro release
  • Tristearin microparticles loaded with MLX (Groups 1 and 3) exhibited high burst release. Both formulations achieved a maximum MLX plasma concentration that exceeded 1,450 ng/mL 24 hours post-administration. The average MLX plasma concentration for Group 1 and Group 3 exceeded the minimum efficacious concentration through the 5-day and 6-day timepoints, respectively.
  • the similarity between the average PK profiles of Group 1 and Group 3 suggests that the addition of excipients aimed at altering the viscoelastic properties of the oil diluent (i.e. oil gellators like aluminum monostearate) has limited impact.
  • Tristearin microparticles loaded with the Zn:MLX complex (Group 2) were administered using an aqueous solution of HPMC. The formulation achieved a maximum MLX plasma concentration of approximately 800 ng/mL 96 hours post-administration. The average MLX plasma concentration for Group 2 exceeded the minimum efficacious concentration through the 6-day timepoint.
  • PLGA microparticles loaded with the Zn:MLX complex (Groups 4 and 5) were administered using an aqueous solution of PI 88 and CMC. The formulation administered for Group 4 (previously referred to as the “slower releasing” PLGA microparticles) achieved a maximum MLX plasma concentration of approximately 280 ng/mL 72 hours post-administration.
  • the formulation administered for Group 5 achieved a maximum MLX plasma concentration of approximately 380 ng/mL 48 hours postadministration.
  • the PLGA-based formulations demonstrated that the burst release for MLX could be significantly reduced. But neither prototype formulation was able to achieve an MLX plasma concentration that exceeded the minimum efficacious concentration during the course of the study.
  • Figure 23 depicts averaged PK profiles for tested formulations including Groups 4 and 5. [00199] Zn:MLX complexation allowed drug loading within PLGA microparticles to exceed 25%.
  • the PLGA-based formulations demonstrated the characteristics for the control of MLX release, and further demonstrated extended release of meloxicam in vivo.

Landscapes

  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Engineering & Computer Science (AREA)
  • Epidemiology (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Rheumatology (AREA)
  • Molecular Biology (AREA)
  • Dermatology (AREA)
  • Pain & Pain Management (AREA)
  • Biophysics (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Organic Chemistry (AREA)
  • Medicinal Preparation (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

La présente invention concerne des formulations de méloxicam injectables pour une libération prolongée ainsi que des méthodes pour des préparations et des utilisations de celles-ci.
PCT/US2021/037753 2020-06-18 2021-06-17 Formulations de méloxicam injectables Ceased WO2021257784A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US202063040658P 2020-06-18 2020-06-18
US63/040,658 2020-06-18

Publications (1)

Publication Number Publication Date
WO2021257784A1 true WO2021257784A1 (fr) 2021-12-23

Family

ID=79268398

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/US2021/037753 Ceased WO2021257784A1 (fr) 2020-06-18 2021-06-17 Formulations de méloxicam injectables

Country Status (1)

Country Link
WO (1) WO2021257784A1 (fr)

Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20040229038A1 (en) * 2003-03-03 2004-11-18 Elan Pharma International Ltd. Nanoparticulate meloxicam formulations
WO2007150075A2 (fr) * 2006-06-23 2007-12-27 Elan Pharma International Limited Compositions comprenant du meloxicam nanoparticulaire et de l'hydrocodone à libération contrôlée
US20090269390A1 (en) * 2008-04-25 2009-10-29 Medtronic, Inc. Medical devices, polymers, compositions, and methods for delivering a haloacetate
US20100316725A1 (en) * 2009-05-27 2010-12-16 Elan Pharma International Ltd. Reduction of flake-like aggregation in nanoparticulate active agent compositions
US20120160944A1 (en) * 2009-04-24 2012-06-28 Aaron Dodd Method for the production of commercial nanoparticle and micro particle powders
US20130017239A1 (en) * 2010-03-24 2013-01-17 Lipotec S.A. Lipid nanoparticle capsules
WO2018094253A1 (fr) * 2016-11-18 2018-05-24 Pacira Pharmaceuticals, Inc. Formulations de liposomes multivésiculaires à microparticules de complexe de méloxicam de zinc et leurs procédés de fabrication

Patent Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20040229038A1 (en) * 2003-03-03 2004-11-18 Elan Pharma International Ltd. Nanoparticulate meloxicam formulations
WO2007150075A2 (fr) * 2006-06-23 2007-12-27 Elan Pharma International Limited Compositions comprenant du meloxicam nanoparticulaire et de l'hydrocodone à libération contrôlée
US20090269390A1 (en) * 2008-04-25 2009-10-29 Medtronic, Inc. Medical devices, polymers, compositions, and methods for delivering a haloacetate
US20120160944A1 (en) * 2009-04-24 2012-06-28 Aaron Dodd Method for the production of commercial nanoparticle and micro particle powders
US20100316725A1 (en) * 2009-05-27 2010-12-16 Elan Pharma International Ltd. Reduction of flake-like aggregation in nanoparticulate active agent compositions
US20130017239A1 (en) * 2010-03-24 2013-01-17 Lipotec S.A. Lipid nanoparticle capsules
WO2018094253A1 (fr) * 2016-11-18 2018-05-24 Pacira Pharmaceuticals, Inc. Formulations de liposomes multivésiculaires à microparticules de complexe de méloxicam de zinc et leurs procédés de fabrication

Similar Documents

Publication Publication Date Title
Dinarvand et al. Effect of surfactant HLB and different formulation variables on the properties of poly-D, L-lactide microspheres of naltrexone prepared by double emulsion technique
Yeo et al. Control of encapsulation efficiency and initial burst in polymeric microparticle systems
EP3906918B1 (fr) Procédés et compositions associées à des nanosupports synthétiques comprenant de la rapamycine dans un état super-saturé stable
Luan et al. Influence of the poly (lactide-co-glycolide) type on the leuprolide release from in situ forming microparticle systems
Johansen et al. Improving stability and release kinetics of microencapsulated tetanus toxoid by co-encapsulation of additives
CN1224380C (zh) 减少微颗粒中残留有机溶剂的方法和所述微颗粒在制备药物中的用途
CN112972388B (zh) 卡利拉嗪释放制剂
WO2010119455A2 (fr) Composition pharmaceutique injectable à libération prolongée
CN107683133A (zh) 包含聚合物‑脂质混杂微粒的药物递送组合物
CN115484931A (zh) 与合成纳米载体相关的方法和组合物
Ansary et al. Preparation, characterization and in vitro release study of BSA-loaded double-walled glucose-poly (lactide-co-glycolide) microspheres
WO2021257784A1 (fr) Formulations de méloxicam injectables
US11110061B2 (en) Microspherical sustained-release injection containing escitalopram and method for preparing same
KR102383448B1 (ko) 락트산 또는 글리콜산을 포함하는 미립구형 서방출 제제 및 그의 제조방법
CA2654113A1 (fr) Formulations a liberation prolongee d'inhibiteurs de l'aromatase
US20240216280A1 (en) Microsphere formulations comprising nalmefene andmethods for making and using the same
JP2024507528A (ja) ルラシドンを含むミクロスフェア製剤ならびにその製造方法および使用方法
WO2019079095A2 (fr) Composition et procédé de production d'une préparation à libération prolongée de rispéridone
HK40051607A (en) Cariprazine release formulations
WO2025096848A1 (fr) Particules polymères biodégradables contrôlées par le ph pour la libération entretenue d'espèces chargées positivement
HK40051607B (zh) 卡利拉嗪释放制剂
KR20200087594A (ko) 레티노익산을 포함하는 미립구형 서방출 제제 및 그의 제조방법
Samein et al. Preparation and Characterization of Biodegradable Microspheres Containing Sertraline Hydrochloride
Vysloužil et al. Vliv formulačních a procesních parametrů na vlastnosti PLGA mikročástic s řízeným uvolňováním léčiva
KR20030024103A (ko) 상전이 현상을 이용한 약물전달용 생분해성 고분자미소구의 제조방법

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 21825492

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 21825492

Country of ref document: EP

Kind code of ref document: A1