WO2021237039A1 - Compositions et méthodes pour la libération à long terme d'antagonistes de l'hormone de libération des gonadotropines (gnrh) - Google Patents

Compositions et méthodes pour la libération à long terme d'antagonistes de l'hormone de libération des gonadotropines (gnrh) Download PDF

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Publication number
WO2021237039A1
WO2021237039A1 PCT/US2021/033575 US2021033575W WO2021237039A1 WO 2021237039 A1 WO2021237039 A1 WO 2021237039A1 US 2021033575 W US2021033575 W US 2021033575W WO 2021237039 A1 WO2021237039 A1 WO 2021237039A1
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Prior art keywords
cetrorelix
composition
release
block copolymer
formulations
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PCT/US2021/033575
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English (en)
Inventor
Ravi Kacker
Mitchell S. Steiner
Jui-Chen LIN
Andrew Michael CERRO
Christopher A. Rhodes
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Veru Inc.
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Priority claimed from US16/880,309 external-priority patent/US20200282008A1/en
Application filed by Veru Inc. filed Critical Veru Inc.
Publication of WO2021237039A1 publication Critical patent/WO2021237039A1/fr

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    • 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
    • A61K9/06—Ointments; Bases therefor; Other semi-solid forms, e.g. creams, sticks, gels
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
    • A61K38/08—Peptides having 5 to 11 amino acids
    • A61K38/09—Luteinising hormone-releasing hormone [LHRH], i.e. Gonadotropin-releasing hormone [GnRH]; Related peptides
    • 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
    • A61K9/1629—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
    • A61P35/00—Antineoplastic agents

Definitions

  • the invention relates to compositions and methods for long term release of gonadotropin-releasing hormone (GnRH) antagonists and uses thereof. Specifically, the invention relates to polymer-based compositions and methods for controlled release of GnRH antagonists.
  • GnRH gonadotropin-releasing hormone
  • GnRH gonadotropin-releasing hormone
  • LHRH luteinizing hormone releasing hormone
  • FSH follicle stimulating hormone
  • GnRH agonist analogues that demonstrate greater relative potency for the secretion of LH and FSH.
  • a paradoxical clinical effect occurs when agonistic analogues are used continuously such that after the chronic, and relatively long period (2-3 weeks) of stimulation of the secretion of LH and FSH, there is actually an inhibition of LH and/or FSH release and consequent suppression of sex steroid production (testosterone and estrogen). ( Reissmann 2000). In certain medical conditions, however, an immediate and dose- dependent suppression of LH and FSH is desired.
  • GnRH antagonist analogues have been either successful or attempted for controlled ovarian stimulation for assisted reproductive techniques, uterine myoma, ovarian cancer, benign prostatic hyperplasia, and prostate cancer.
  • the major limitation for successful application of the GnRH antagonist analogue has been having only a short acting formulation where longer acting depot formulations would be more clinically advantageous for optimal drug compliance.
  • GnRH antagonist also called a LHRH antagonist
  • the invention relates to a long-term drug release composition
  • a long-term drug release composition comprising: a therapeutically effective amount of a GnRH antagonist in combination with a multi-block copolymer, wherein the composition releases the GnRH antagonist for a duration of at least six months.
  • the invention in another aspect, relates to a flowable composition, the composition comprising: (a) a multi -block copolymer; (b) a biocompatible polar aprotic solvent, wherein the biocompatible polar aprotic solvent is miscible to dispersible in aqueous medium or body fluid; and (c) a therapeutically effective amount of a GnRH antagonist, wherein the flowable composition releases the GnRH antagonist for a duration of at least four months.
  • the GnRH antagonist is cetrorelix, degarelix, ganirelix, ozarelix, taverelix, antarelix, or iturelix.
  • the multi-block copolymer is polyglycolide (PLG), polylactide (PLA), or poly-lactic co-glycolic acid (PLGA).
  • the invention relates to a composition for a long-term release of cetrorelix, the composition comprising a multi-block copolymer, a solvent, and a therapeutically effective amount of cetrorelix, and the release of cetrorelix duration is at least six months.
  • the invention in another aspect, relates to a method to extend the release of cetrorelix in a subject for a duration of at least six months.
  • the method comprising administering to the subject a composition comprising cetrorelix and a multi-block copolymer.
  • the multi block copolymer comprises poly-lactic co-glycolic acid (PLGA) in a lactide:glycolide molar ratio between 1:1, 1:0, and 0:1.
  • PLGA poly-lactic co-glycolic acid
  • cetrorelix is present in an amount of 5%-90% of the weight of the composition
  • the multi -block copolymer is present in an amount of 10%-50% of the weight of the composition.
  • the composition comprises cetrorelix and a multi-block copolymer, the multi-block copolymer comprising poly-lactic co-glycolic acid (PLGA) in a lactide:glycolide molar ratio of 3 : 1.
  • the composition comprises cetrorelix and a multi-block copolymer.
  • the multi-block copolymer comprising poly-lactic co-glycolic acid (PLGA) in a lactide:glycolide molar ratio of 5.67:15.
  • the invention in another aspect, relates to a method to maintain a therapeutic level of cetrorelix in a subject for a duration of at least six months.
  • the method comprising administering to the subject a composition comprising cetrorelix and a multi-block copolymer.
  • the multi-block copolymer comprising poly-lactic co-glycolic acid (PLGA) in a lactide:glycolide molar ratio between 1:1, 1:0 and 0:1.
  • PLGA poly-lactic co-glycolic acid
  • cetrorelix is present in an amount of 5%-90% by the weight of the composition
  • the multi-block copolymer is present in an amount of 10%-50% by the weight of the composition.
  • the invention relates to a composition
  • a composition comprising: a therapeutically effective amount of a GnRH antagonist in combination with a multi-block copolymer.
  • the multi-block copolymer comprises polyethyleneglycol(PEG)-PLGA-PEG, poly(3- hydroxy butyrate), PCL, poly(glycolide) (PLG), poly(lactide) (PLA), poly-lactic co-glycolic acid (PLGA) or a combination thereof.
  • the composition achieves a therapeutic effect within 24 hours and maintains therapeutic effect for at least 180 days.
  • GnRH antagonist is cetrorelix, degarelix, ganirelix, ozarelix, taverelix, antarelix, or iturelix.
  • the invention in another aspect, relates to a composition
  • a composition comprising: a therapeutically effective amount of a GnRH antagonist in combination with a multi-block copolymer.
  • the multi-block copolymer comprises randomly or non-alternatingly arranged hydrolysable segments.
  • each segment comprises pre-polymer A or pre-polymer B, and wherein the segments are operably linked to each other by a multifunctional chain extender.
  • the composition achieves a therapeutic effect within 24 hours and maintains therapeutic effect for at least 180 days.
  • the invention in another aspect, relates to a method for treating a disease or condition associated with gonadotropin-releasing hormone (GnRH).
  • the method comprising administering to a subject a composition of any of the above, or below, embodiments, thereby treating the disease in the subject.
  • the composition achieves a therapeutic effect within 24 hours and maintains therapeutic effect for at least 180 days.
  • the invention relates to a composition, the composition comprising: a therapeutically effective amount of a GnRH antagonist in combination with a non-PLGA multi-block copolymer.
  • the multi-block copolymer is biodegradable.
  • the multi-block copolymer is a thermoplastic polyester that is substantially insoluble/stable in an aqueous medium or body fluid.
  • the multi-block copolymer is at least one of polyethylene glycol (PEG), PLG, PLA, polybutylene terephthalate (PBT), poly(epsilon-caprolactone) (PCL), dioxanone, butanediisocyanate, butanediol, polyoxyethylene, polypropylene, polyoxypropylene, polystyrene, poly methyl methacrylate.
  • PEG polyethylene glycol
  • PLG polyLG
  • PLA polybutylene terephthalate
  • PCL poly(epsilon-caprolactone)
  • dioxanone butanediisocyanate
  • butanediol polyoxyethylene
  • polypropylene polyoxypropylene
  • polystyrene polymethyl methacrylate
  • the invention in another aspect, relates to a flowable composition, the composition comprising: (a) a biodegradable thermoplastic polyester that is at least substantially insoluble/stable in aqueous medium or body fluid; (b) a biocompatible solvent, wherein the biocompatible solvent is miscible to dispersible in aqueous medium or body fluid; and (c) a therapeutically effective amount of a GnRH antagonist.
  • the invention in another aspect, relates to a flowable composition, the composition comprising: (a) a biodegradable thermoplastic polyester that is at least substantially insoluble/stable in aqueous medium or body fluid; (b) a biocompatible polar aprotic solvent, wherein the biocompatible polar aprotic solvent is miscible to dispersible in aqueous medium or body fluid; and (c) a therapeutically effective amount of a GnRH antagonist.
  • the thermoplastic polyester is a polylactide, a polyglycolide, a polycaprolactone, a copolymer thereof, a terpolymer thereof, or any combination thereof.
  • the solvent is N-methyl-2-pyrrolidone, 2- pyrrolidone, N,N-dimethylformamide, dimethyl sulfoxide, propylene carbonate, caprolactam, triacetin, benzyl benzoate, propylene glycol, or any combination thereof.
  • the flowable composition of the invention comprises a flowable delivery system such as an Atrigel® system comprising a copolymer, a water-soluble organic solvent, and a bioactive agent, for example, a GnRH antagonist.
  • the invention relates to a composition, the composition comprising: a therapeutically effective amount of a GnRH antagonist in combination with a multi-block copolymer, wherein the multi-block copolymer comprises polyethyleneglycol(PEG)-PLGA- PEG, poly(3-hydroxybutyrate), PCL, PLG, PLA, or a combination thereof.
  • the invention in another aspect, relates to a composition, the composition comprising: a therapeutically effective amount of a GnRH antagonist in combination with a multi-block copolymer, wherein the multi-block copolymer comprises randomly or non- alternatingly arranged hydrolysable segments, wherein each segment comprises pre-polymer A or pre polymer B, and wherein the segments are operably linked to each other by a multifunctional chain extender.
  • the repeating units of the multi-block copolymer can be the same subunit.
  • the multi-block copolymer is a phase separated multiblock copolymer, comprising: one or more segments of a linear soft biodegradable pre polymer A having a glass transition temperature (T g ) lower than 37°C.; and one or more segments of a linear hard biodegradable pre-polymer B having a melting point temperature (T m ) of 40-100°C.
  • the invention relates to the use of salt bridges or cyclization of the active agent either as a primary drug delivery technique or in combination with another drug delivery vehicle using compounds that include, but are not limited to, lanthionine, dicarba, hydrazine, or lactam bridges.
  • the invention relates to the use of micronization or stabilizing adjuvants for a long-term delivery of a GnRH antagonist.
  • the invention relates to the use of a solid-in-oil-in-water (S/O/W), a water-in-oil-in water (W/O/W), or a water-oil (W/O) production method for long term delivery of a GnRH antagonist.
  • the composition achieves a therapeutic effect within 24 hours and maintains therapeutic effect for at least 90 days for >95% percent of treated patients.
  • the composition is in the form of a hydrogel. In another particular embodiment, the composition is in the form of microspheres.
  • the composition of the invention is an injectable composition, which is administered with one injection or two injections administered concurrently or consecutively, with a total injection volume, for example, less than 4 ml. Injections may be subcutaneous or intramuscular.
  • the invention in another aspect, relates to a method for extending the release of a GnRH antagonist (e.g., cetrorelix) in a subject for a period ranging from about 1 month to about 6 months.
  • the method comprising administering to the subject a composition comprising cetrorelix and a multi -block copolymer.
  • the multi-block copolymer comprising poly-lactic co- glycolic acid (PLGA) in a lactide:glycolide molar ratio between 1:1, 1:0, and 0:1.
  • PLGA poly-lactic co- glycolic acid
  • cetrorelix is present in an amount of 5%-90% of the weight of the composition
  • the multi block copolymer is present in an amount of 10%-50% of the weight of the composition.
  • the invention in another aspect, relates to a method of maintaining a therapeutic level of a GnRH antagonist (e.g., cetrorelix) in a subject for a period ranging from about 1 month to about 6 months.
  • the method comprising administering to the subject a composition comprising cetrorelix and a polymer.
  • the polymer comprising poly-lactic co-glycolic acid (PLGA) in a lactide:glycolide molar ratio between 1:1, 1:0, and 0:1.
  • cetrorelix is present in an amount of 5%-90% of the weight of the composition, and the polymer is present in an amount of 10%-50% of the weight of the composition.
  • the composition of the invention has an encapsulation efficiency greater than 70% and a consistent release of the active agent from the drug delivery vehicle with no more than 25% variation.
  • the composition of the invention releases the active agent from the drug delivery vehicle with >85% intact in the active form over the entire duration of release.
  • Figure 1 shows in vitro release of cetrorelix (CRX) from microspheres (MSP) composed of different polymers and carriers.
  • Figure 2 shows in vitro release of cetrorelix (CRX) from microspheres (MSP) composed of different polymers loaded with cetrorelix prepared in 35% Acetic acid/65% FLO aqueous phase.
  • CRX cetrorelix
  • MSP microspheres
  • Figure 3 shows daily levels of cetrorelix release from microspheres composed of different polymers.
  • Figure 4A shows the morphology of cetrorelix coated 10CP10C20-D23 beads having 12.7% cetrorelix prepared using 65% Acetic Acid (HAc):25% water phase.
  • Figure 4B shows the morphology of cetrorelix coated 20CP15C50-D23 beads comprising 13.4% cetrorelix.
  • Figure 5 shows cetrorelix plasma concentration following administration of cetrorelix PLGA gel formulations to rats.
  • Figure 6A shows long term cetrorelix plasma concentration following administration to rats of two cetrorelix salt formulations as a suspension in water.
  • Figure 6B shows plasma concentration following administration to rats of two cetrorelix salt formulations as a suspension in water over the first 24 hours following administration (to show initial release).
  • Figure 7 A shows comparative cetrorelix plasma concentrations in rats for PLGA gel formulations and for cetrorelix salt formulations.
  • Figure 7B shows comparative cetrorelix plasma concentrations in rats for PLGA gel formulations and for cetrorelix salt formulations.
  • Figure 8 shows comparative cetrorelix plasma concentrations in rats after dose normalization for PLGA gel formulations and for cetrorelix salt formulations.
  • Figure 9A shows rat serum testosterone levels following administration of PLGA gel formulations and for cetrorelix salt formulations over a 42 day period.
  • Figure 9B shows rat serum testosterone levels following administration of PLGA gel formulations and for cetrorelix salt formulations over the first 24 hours following administration.
  • Figure 10 shows cumulative cetrorelix in vitro release from PLGA gel formulations.
  • Figure 11 shows cumulative cetrorelix in vitro release from RG502H/RG752H (40% PLGA)-salt microsphere formulations compared to a PLGA gel formulation.
  • Figure 12 shows cumulative cetrorelix in vitro release from RG752H (40% PLGA) salt microsphere formulations compared to PLGA gel formulations.
  • Figure 13 shows cumulative cetrorelix in vitro release from RG502H/RG752H (40% PLGA)-salt microsphere formulations.
  • Figure 14 shows cetrorelix plasma concentration following administration to rats of cetrorelix PLGA gel formulations (VH-022-001, VH-023-002 and VH-024-001) for up to 119 days (17 weeks) and of cetrorelix salt formulations (Groups 4 and 5) for > 49 days (7 weeks).
  • the percent day 1 release ranged from 9 to 13% of the total cetrorelix release.
  • Figure 15A shows average rat serum testosterone levels following administration of various cetrorelix PLGA gel formulations (VH-022-001, VH-023-002 and VH-024-001) for up to 19 weeks and cetrorelix salt formulations (Groups 4 and 5).
  • PLGA gel formulations showed undetectable testosterone level for > 133 days (19 weeks).
  • Group 4 salt formulations showed undetectable testosterone level for greater than 1 week.
  • Figure 15B shows rat serum testosterone levels following administration of various cetrorelix gel formulations and salt formulations, as indicated in Figure 15 A, over the first week following administration, showing undetectable testosterone levels for all formulations after the first 24 hours.
  • Figures 16A and 16B show testosterone serum levels.
  • Figure 16A shows the testosterone serum level for several gel formulations in rats after 12 weeks.
  • Figure 16B is zoomed in for the 1 st day of Figure 16A showing undetectable testosterone levels after 24 hours.
  • Figure 17 shows cetrorelix levels in rats after 12 weeks for the gel formulations of Figure 16.
  • Figures 18A and 18B show serum cetrorelix data in dogs.
  • Figure 18A shows serum cetrorelix data for 19.9% RG752H, 30% RG752H, and 30% R202H solutions.
  • Figure 18B shows cetrorelix level 1 week prior to dosing.
  • LLOQ (ng/ml) 0.5.
  • Animal D0103 Group 2) vocalized and struggled during dose administration. As a result, the dose was delivered as 2 injections. The animal did receive the full dose as no formulation appeared to have been lost due to the animal struggling.
  • Figures 19A-19C show a comparison of rat and dog PK results for cetrorelix in gel formulations (up to 39 weeks).
  • Figure 19A shows 2 nd rat study results with cetrorelix levels above 1 ng/ml for up to 39 weeks.
  • Figure 19B shows 1 st dog study results with cetrorelix levels above 1 ng/ml for up to 26 weeks.
  • Figure 19C shows the formulation compositions and pharmacokinetic data for dogs and rats. Similar formulations show similar results in both species.
  • Figures 20A-20B show serum testosterone data.
  • Figure 20A shows serum testosterone data for 19.9% RG752H, 30% RG752H, and 30% R202H solutions.
  • Figure 20B shows testosterone level 1 week prior to dosing.
  • LLOQ (ng/ml) 0.01.
  • Figures 21A-21C show rat and dog study results for testosterone (up to 39 weeks).
  • Figure 21 A shows 2 nd rat study results with undetectable testosterone for greater than 30 weeks.
  • Figure 2 IB shows 1 st dog study results with undetectable testosterone for greater than 12 weeks.
  • Figure 21C shows the formulation data of the cetrorelix, the dosing of the experiment, the maximum serum concentration of the dose, and the area under the curve of the dose.
  • Figures 22A and 22B show 1 st dog study for group 1 (19.9% RG752H solution).
  • Figure 22A shows serum cetrorelix level.
  • Figure 22B shows serum testosterone level.
  • Figures 23A and 23B show 1 st dog study for group 2 (30% RG752H solution).
  • Figure 23A shows serum cetrorelix level.
  • Figure 23B shows serum testosterone level. These figures also show that testosterone level goes up once cetrorelix level drops less than 2 ng/mL.
  • Figures 24A and 24B show 1 st dog study for group 2 (30% R202H solution).
  • Figure 24A shows serum cetrorelix level.
  • Figure 24B shows serum testosterone level. These figures also show that testosterone level goes up once cetrorelix level drops less than 2 ng/mL.
  • the invention relates to a controlled release composition
  • a controlled release composition comprising a gonadotropin releasing hormone (GnRH) antagonist in combination with one or more polymers and/or salts.
  • GnRH antagonist and polymer composition may be stored in solution or suspension in a solvent suitable for both to create a stable formulation for storage in a prefilled syringe.
  • the composition may include any suitable a GnRH antagonist, known to one of skilled in the art.
  • GnRH is also known as follicle-stimulating hormone-releasing hormone (FSH-RH), luteinizing hormone-releasing hormone (LHRH), gonadoliberin, and by various other names, known to one of skilled in the art.
  • the GnRH antagonist is cetrorelix, abarelix, degarelix, ganirelix, ozarelix, taverelix, antarelix, or iturelix.
  • a composition comprising a therapeutically effective amount of a GnRH antagonist in combination with a multi-block copolymer.
  • the multi-block copolymer is polyglycolide (PLG), polylactide (PLA), or poly-(lactic co-gly colic acid) (PLGA).
  • the composition releases the GnRH antagonist for a long term.
  • the composition releases the GnRH antagonist for at least 180 days.
  • the composition release the GnRH antagonist (e.g., cetrorelix) for at least 120 days.
  • the composition achieves a therapeutic effect within 24 hours and maintains the therapeutic effect for at least 120 days.
  • the invention relates to a composition for a long-term release of cetrorelix.
  • the composition comprising a biodegradable multi-block copolymer, a solvent, and a therapeutically effective amount of cetrorelix, wherein the long-term release is a duration of at least six months.
  • the composition may have a release term of about three months, six months, nine months, or about 12 months.
  • the composition has a release term of about nine months or more.
  • composition comprising: a therapeutically effective amount of a GnRH antagonist in combination with a non-PLGA multi block copolymer, wherein the composition releases the GnRH antagonist for a long term.
  • Non- PLGA multi-block copolymer are well known in the art.
  • non-PLGA multi-block copolymer examples include, for example, but are not limited to, polyethyleneglycol (PEG), PLG, PLA, polybutylene terephthalate (PBT), poly(epsilon-caprolactone) (PCL), dioxanone, butanediisocyanate, butanediol polyoxyethylene, polypropylene, polyoxypropylene, polystyrene, poly methyl methacrylate, or a block copolymer which additionally incorporates one more novel amphiphilic, hydrophilic, or hydrophobic component.
  • PEG polyethyleneglycol
  • PLG polybutylene terephthalate
  • PCL poly(epsilon-caprolactone)
  • dioxanone butanediisocyanate
  • butanediol polyoxyethylene polypropylene
  • polyoxypropylene polyoxypropylene
  • polystyrene polymethyl methacrylate
  • a non- PLGA block polymer comprises a blend of two or more multi-block copolymer types capable of releasing therapeutically effective amount of GnRH antagonists.
  • the composition is a flowable composition capable of forming an in situ implant in a subject.
  • the composition includes a biodegradable thermoplastic multi -block copolymer, a biocompatible solvent; and a GnRH antagonist.
  • the invention in another aspect, relates to a flowable composition, the composition comprising: (a) a biodegradable thermoplastic multi -block copolymer that is at least substantially insoluble/stable in aqueous medium or body fluid; (b) a biocompatible polar aprotic solvent, wherein the biocompatible polar aprotic solvent is miscible to dispersible in aqueous medium or body fluid; and (c) a therapeutically effective amount of cetrorelix.
  • biodegradable thermoplastic multi-block copolymer can be substantially insoluble/stable in aqueous medium or body fluid.
  • Biodegradable thermoplastic multi-block copolymer are well known in the art and fully described in U.S. Patents 6,565,874; 5,324,519; 4,938,763; 5,702,716; 5,744,153; and 5,990,194, which are incorporated by reference herein in their entirety.
  • biodegradable thermoplastic multi-block copolymer is a polyester, for example, including but not limited to, a polylactide, a polyglycolide, a polycaprolactone, a copolymer thereof, a terpolymer thereof, or any combination thereof.
  • biodegradable thermoplastic multi-block copolymer present in the composition may depend upon one or more desired properties of the controlled release implant.
  • biodegradable thermoplastic polyesters examples are well known in the art and fully described in U.S. Patent 6,565,874.
  • the suitable biodegradable thermoplastic polyester is 1 : 1 poly (DL-lactide-co-glycolide) having a carboxy terminal group or is 3:1 poly (DL-lactide-co-glycolide) with a carboxy terminal group that is protected.
  • Other suitable copolymers known to one of skilled in the art, can also be used.
  • the PLGA multi-block copolymers in the compositions of the present invention may have lactide:glycolide weight ratio ranging from about 1:1 to about 1:0.
  • the lactide to glycolide ratio is about, 1:1, 11:9, 3:2, 13:7, 7:3, 3:1, 4:1, 5.67:1, 9:1, or 20:1.
  • the PLGA polymers the compositions of the present invention may comprise a mixture of two or more PLGA multi-block copolymers each having a different glycolide and lactide fractions.
  • the mixture may include a first PLGA polymer having equal amount of glycolide and lactide (RG502H) and a second PLGA polymer having 25% glycolide and 75% lactide (RG752H).
  • the proportions of the first PLGA polymer and the second PLGA polymer may vary, for example the ratio of RG502H to RG752H can range from about 1:0 to about 0:1.
  • the amount of biodegradable thermoplastic multi-block copolymer, in the composition can be any suitable amount, known to one of skilled in the art.
  • the amount, in the composition may range from about 10 wt. % to about 80 wt. %; from about 20 wt. % to about 60 wt. %; from about 25 wt. % to about 55 wt. %; from about 30 wt. % to about 50 wt. %; or from about 35 wt. % to about 45 wt. %.
  • the amount is approximately 10, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, or 80 wt. %.
  • the molecular weight of biodegradable thermoplastic polymer, in the composition can be any suitable molecular weight, known to one of skilled in the art.
  • the molecular weight may range from about 10,000 to about 50,000; from about 15,000 to about 45,000; from about 20,000 to about 40,000; or from about 20,000 to about 30,000. In a particular embodiment, the molecular weight is approximately 10,000, 15,000, 20,000, 25,000, 30,000, 35,000, 40,000, 45,000, or 50,000.
  • the biodegradable thermoplastic polyester has an average molecular weight ranging from about 15,000 to about 45,000 or from about 20,000 to about 35,000.
  • the biocompatible solvent can be a biocompatible solvent.
  • the biocompatible solvent can be a biocompatible polar aprotic solvent.
  • the solvent is miscible to dispersible in aqueous medium or body fluid.
  • Suitable polar aprotic solvents are well known in the art and fully described in, for example, in Aldrich Handbook of Fine Chemicals and Laboratory Equipment, Milwaukee, Wis. (2000) and U.S. Patents 6,565,874, 5,324,519; 4,938,763; 5,702,716; 5,744,153; and 5,990,194.
  • the solvent of the invention diffuses into body fluid so that the flowable composition coagulates or solidifies.
  • the solvent of the invention is biodegradable.
  • the solvent of the invention is biocompatible.
  • the solvent of the invention is non-toxic.
  • suitable polar aprotic solvents include polar aprotic solvents having an amide group, an ester group, a carbonate group, a ketone, an ether, a sulfonyl group, or a combination thereof.
  • the polar aprotic solvent is N-methyl-2-pyrrolidone, 2-pyrrolidone, N,N-dimethylformamide, N,N-dimethylacetamide, dimethyl sulfoxide, propylene carbonate, caprolactam, triacetin, benzyl benzoate, propylene glycol, or any combination thereof.
  • the polar aprotic solvent is N-methyl-2-pyrrolidone.
  • the polar aprotic solvent can be present in any suitable amount.
  • the type and amount of biocompatible polar aprotic solvent present in the composition may depend upon the desired properties of the controlled release implant. In a particular embodiment, the type and amount of biocompatible polar aprotic solvent influences the initial release rate and the length of time in which the GnRH antagonist is released from the controlled release implant.
  • the solvent may be present at the concentration ranging from about 10% to about 30% (w/w).
  • the cetrorelix may be present at a concentration ranging from about 5% to about 90% (w/w).
  • cetrorelix may be present in an amount of about 50 mg to about 300 mg or 50 mg to about 150 mg per dosage.
  • the composition may further comprise a salt, i.e., a salt of the GnRH antagonist (e.g., cetrorelix).
  • a salt include but are not limited to calcium pamoate (Ca pamoate), sodium pamoate (Na pamoate) and calcium citrate (Ca citrate).
  • the cetrorelix may be present as a salt, i.e., cetrorelix salt.
  • salts include, but are not limited to, sulfate, citrate, acetate, oxalate, chloride, bromide, iodide, nitrate, bisulfate, phosphate, acid phosphate, carbonate, bicarbonate, isonicotinate, lactate, salicylate, acid citrate, tartrate, oleate, tannate, pantothenate, bitartrate, ascorbate, succinate, maleate, gentisinate, fumarate, gluconate, glucaronate, saccharate, formate, benzoate, glutamate, methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate, camphorsulfonate, and pamoate.
  • the invention is a method of preparing a flowable composition, the method comprising: mixing a biodegradable thermoplastic multi-block copolymer, a biocompatible solvent; and a GnRH antagonist. The mixing is performed for a sufficient period of time effective to form the flowable composition for use as a controlled release implant.
  • the invention is an implant formed in situ by the process of injecting the composition of the invention to a subject; allowing the solvent, in the composition, to dissipate to produce a solid biodegradable implant.
  • the invention is a method of forming an implant in situ in a subject, the method comprising the steps of: injecting the composition of the invention to a subject; and allowing the solvent, in the composition, to dissipate to produce a solid biodegradable implant.
  • the flowable composition of the invention comprises a flowable delivery system such as an Atrigel® system comprising a multi-block copolymer, a water- soluble organic solvent, and a bioactive agent, for example, a GnRH antagonist.
  • a flowable delivery system such as an Atrigel® system comprising a multi-block copolymer, a water- soluble organic solvent, and a bioactive agent, for example, a GnRH antagonist.
  • ATRIGEL® is a registered Trademark of Tolmar Pharmaceuticals, Fort Collins, CO. found in H. B. Ravivarapu, K. L. Moyer, R. L. Dunn, International Journal of Pharmaceutics, 194 (2000) 181-191, which is incorporated in its entirety.
  • ATRIGEL® unless otherwise specified, comprises PLGA dissolved in l-methyl-2-pyrrolidinone (NMP).
  • the invention relates to a controlled release composition
  • a gonadotropin releasing hormone (GnRH) antagonist e.g., cetrorelix
  • GnRH gonadotropin releasing hormone
  • the inventor relates to a multi-block copolymer composition having a gonadotropin-releasing hormone (GnRH) antagonist (e.g., cetrorelix) as a bioactive agent.
  • GnRH gonadotropin-releasing hormone
  • the multi-block copolymer compositions are well known and fully described in U.S. Patents 8,481,651; 8,674,032; 8,674,033; and 9,364,442 and U.S. Application Publications 2013/0209568; 2013/0273284; and 2014/0199385, and PCT International Application Publications W02005068533; W02004007588; W02012005594; and WO2013015685, all of which are incorporated by reference herein in their entirety.
  • the multi-block copolymer comprises one or more hydroly sable segments. In one embodiment, the multi-block copolymer comprises one or more randomly arranged hydrolysable segments. In another embodiment, the multi-block copolymer comprises one or more non-randomly arranged hydroly sable segments. In yet another embodiment, the multi block copolymer comprises one or more altematingly arranged hydrolysable segments. In yet another embodiment, the multi-block copolymer comprises one or more non-alternatingly arranged hydrolysable segments.
  • the segments can be randomly and non-retematingly connected to each other by multi-functional chain extenders.
  • the multi-block copolymer is amorphous at human body conditions.
  • the multi-block copolymer has a glass transition temperature below body temperature at human body conditions.
  • the multi-block copolymer includes pre-polymer A, pre-polymer B, or a combination thereof.
  • pre-polymers A and B are composed of different monomers.
  • pre-polymers A and B are composed of the same monomers but in a different amount.
  • the pre-polymers are composed of the same monomers but with a different initiator in order to obtain the multi -block copolymers of the present invention.
  • the multi-block copolymer is comprised of pre-polymers A and B which are the same monomer with the same initiators.
  • Pre-polymers A and B can be selected in such a way that the segments would exhibit significantly different properties, for example, but not limited to thermal, degradation and hydrophilic properties.
  • the pre -polymers A or B may comprise a hydrolysable polyester, poly ether ester, polycarbonate, polyester carbonate, polyanhydride or copolymers thereof.
  • the pre-polymers can be derived from cyclic monomers such as lactide (L, D or L/D), glycolide, e-caprolactone, d-valerolactone, trimethylene carbonate, tetramethylene carbonate, l,5-dioxepane-2-one, 1,4- dioxane-2-one (para-dioxanone) or cyclic anhydrides (oxepane-2,7-dione).
  • the pre-polymer includes an ester linkage.
  • pre-polymer includes a carbonate linkage.
  • pre-polymer includes an anhydride linkage.
  • pre-polymer optionally comprises a polyether group.
  • polyether is present as an additional pre-polymer.
  • pre-polymer comprises a reaction product of an ester forming monomer.
  • the ester forming monomer can be selected from the group consisting of diols, dicarboxylic acids and hydroxycarboxylic acids.
  • pre-polymer comprises reaction products of at least one suitable cyclic monomer with at least one non-cyclic initiator.
  • the non-cyclic initiator can be selected from the group consisting of diols, dicarboxylic acids and hydroxycarboxylic acids.
  • cyclic monomers include, but are not limited to, glycolide, lactide (L, D or DL), e-caprolactone, d-valerolactone, trimethylene carbonate, tetramethylene carbonate, 1 ,4-dioxane-2-one (para-dioxanone), l,5-dioxepane-2-one and cyclic anhydrides.
  • the pre-polymer comprises at least two different cyclic monomers.
  • pre-polymer comprises glycolide and e-caprolactone in a 1:1 weight ratio.
  • pre-polymer comprises glycolide and lactide in a 1 : 1 weight ratio.
  • non-cyclic initiator examples include, but are not limited to, succinic acid, glutaric acid, adipic acid, sebacic acid, lactic acid, glycolic acid, hydroxybutyric acid, ethylene glycol, diethylene glycol, 1,4-butanediol and 1,6-hexanediol.
  • polyether groups include, but are not limited to, PEG (polyethylene glycol), PEG-PPG (polypropylene glycol), PTMG (polytetramethylene ether glycol) and combinations thereof.
  • the polyether group is PEG.
  • PEG can be an initiator for ring-opening polymerization.
  • PEG with any suitable molecular weight can be used, for example, a molecular weight between 150-40000.
  • each of pre polymers A and B has a number average molecular weight between 300 and 30000.
  • the composition comprises a polyethylene glycol (PEG).
  • PEG polyethylene glycol
  • Any suitable PEG known to one of skilled in the art can be used.
  • PEG is polyethylene glycol 200, polyethylene glycol 300, or methoxy polyethylene glycol 350.
  • the chain-extender of the invention can be any suitable multifunctional chain extender, known to one of skilled in the art.
  • the pre-polymers are linked by the di functional chain-extender.
  • di-functional chain-extender include, for example, but are not limited to, a diisocyanate chain-extender, a diacid and a diol compound.
  • the amount of pre-polymer, in the composition can be any suitable amount, known to one of skilled in the art.
  • the amount, in the composition may be of about 10-90 wt. %.
  • the intrinsic viscosity also may vary depending on one or more desired properties.
  • the intrinsic viscosity is larger than about 0.1 dl/g and less than about 6 dl/g. In one embodiment, the intrinsic viscosity lies between about 0.2-4 dl/g, more preferably between 0.4-2 dl/g.
  • phase separated multi block copolymers may refer to a system, for example, a copolymer having two or more different pre -polymers, of which at least two are incompatible with each other at temperatures of 40°C or below (when kept at body conditions).
  • the pre-polymers do not form a homogeneous mixture when combined as a physical mixture or chemical mixture.
  • phase separated multi block copolymers are well known in the art and fully described in U.S. Patents 9,364,442 and 8,674,033, and PCT International Application Publications W02012005594 and, W02004007588.
  • the phase-separated quality of the copolymers of the present invention is reflected in the profile of the glass transition temperature (Tg), melting temperature (Tm), or a combination thereof.
  • the phase-separated copolymers are characterized by at least two-phase transitions, each of which is related to (but not necessarily identical to) the corresponding Tg or Tm values of the prepolymers which are comprised in the copolymer.
  • the multi-block copolymer is a phase separated multiblock copolymer, comprising: one or more segments of a pre-polymer A (e.g., a linear soft biodegradable pre-polymer A) having a glass transition temperature (T g ) lower than 37°C; and one or more segments of a pre-polymer B (e.g., a linear hard biodegradable pre-polymer B) having a melting point temperature (T m ) ranging from about 40 °C to about 100°C.
  • a pre-polymer A e.g., a linear soft biodegradable pre-polymer A
  • T g glass transition temperature
  • T m melting point temperature
  • the invention relates to a composition, the composition comprising: a therapeutically effective amount of a cetrorelix in combination with a multi-block copolymer, wherein the multi-block copolymer comprises randomly or non-alternatingly arranged hydrolysable segments, wherein each segment comprises pre -polymer A or pre-polymer B, and wherein the segments are operably linked to each other by a multifunctional chain extender.
  • the multi-block copolymer is a phase separated multiblock copolymer, comprising: one or more segments of a linear soft biodegradable pre-polymer A having a glass transition temperature (T g ) lower than 37 °C; and one or more segments of a linear hard biodegradable pre-polymer B having a melting point temperature (T m ) of 40-100°C.
  • T g glass transition temperature
  • T m melting point temperature
  • the multi -block copolymer compositions may be in any suitable form, for example, in the form of implant, microspheres, microrods, microparticles, injectable gel formulation, coatings or membranes or devices, or any other form known in the art.
  • the composition forms of a hydrogel.
  • the composition is in the form of microspheres.
  • the microspheres are loaded with a GnRH antagonist (e.g., cetrorelix) and without salt.
  • the invention relates to the use of salt bridges or cyclization of the active agent either as a primary drug delivery technique or in combination with another drug delivery vehicle using compounds that include, but are not limited to, lanthionine, dicarba, hydrazine, or lactam bridges.
  • salt bridges for linking through non-covalent bonds are well known in the art and fully described in PCT International application publications WO2009/155257 and WO 2012/163519, which are incorporated by reference herein in their entirety.
  • the invention relates to the use of micronization or stabilizing adjuvants for a long-term delivery of a GnRH antagonist.
  • Micronization techniques are well known in the art and fully described, for example, in PCT International Application Publication WO2011/034514 and U.S. Application Publication US2014/0219954, all of which are incorporated by reference herein in their entirety.
  • Stabilizing adjuvants are also well known in the art and fully described, for example, in U.S. Patent 7,611,709, which is incorporated by reference herein in its entirety.
  • the invention relates to the use of a solid-in-oil-in-water (S/O/W), a water-in-oil-in water (W/O/W), or a water-oil (W/O) production method for long term delivery of a GnRH antagonist.
  • S/O/W solid-in-oil-in-water
  • W/O/W water-in-oil-in water
  • W/O water-oil
  • the composition achieves a therapeutic effect within 24 hours and maintains therapeutic effect for at least 180 days in, for example, >95% percent of treated patients. In another embodiment, the composition achieves a therapeutic effect within 24 hours and maintains therapeutic effect for at least 133 days in, for example, >95% percent of treated patients. In alternate embodiments, the composition achieves a therapeutic effect within 7 days and maintains the therapeutic effect for at least 90 days in, for example, >95% percent of treated patients.
  • microspheres for sustained release of therapeutically active agents and methods of their preparations are well known in the art (see e.g. U.S. Patent Nos. 6,458,387 and 9,381,159 which are incorporated by reference herein in their entirety).
  • the microspheres typically comprise a matrix formed of biodegradable polymer.
  • the inner matrix diffuses through the outer surface under appropriate conditions.
  • the outer surface not only enables aqueous fluids to enter the microsphere, but also enables solubilized drug and polymer to exit the microsphere.
  • the microspheres are made to release drug and polymer from the interior of the microsphere when placed in an appropriate aqueous medium, such as body fluids or a physiologically acceptable buffer under physiological conditions over a prolonged period of time, thereby providing sustained release of a drug.
  • the microspheres are made to release a drug without an initial burst or rapid drug release.
  • the microspheres have a generally uniform size (substantially spherical) and shape, with each preparation having a narrow size distribution. Microspheres range in size from about 0.5 microns to about 100 microns, depending upon the fabrication conditions. The characteristics of the microspheres may be altered during preparation by manipulating the water-soluble polymer concentration, reaction temperature, pH, concentration of therapeutic agent, crosslinking agent, and/or the length of time the macromolecule is exposed to the crosslinking agent and/or the energy source. In one example, microspheres are suitable for oral or parenteral administration; mucosal administration; ophthalmic administration; intravenous, subcutaneous, intra articular, or intramuscular injection; administration by inhalation; or topical administration.
  • the microsphere size is between 20-90 pm. In another embodiment the microsphere size is between 30-80 pm. In another embodiment the microsphere size is between 45-70 pm.
  • the amount of polymer matrix, in the microsphere composition can be any suitable amount, known to one of skilled in the art.
  • the amount in the microsphere composition may range from about 10 wt. % to about 50 wt. %; from about 20 wt. % to about 40 wt. %; from about 25 wt. % to about 35 wt . %. In a particular embodiment, the amount is approximately 10, 20, 25, 30, 35, 40, 45, or 50 wt. %.
  • the amount of therapeutic molecule in the microsphere ranges from about 1 wt. % to about 90 wt. %, from about 1 wt. % to about 40 wt. %, from about 3 wt. % to about 30 wt. %, from about 5 wt. %. to about 20 wt. %, from about 10 wt. %. to about 15 wt. %. In a particular embodiment, the amount is approximately 1, 3, 5, 7, 9 10, 1520, 25, 30, 35, 40, 45, 50, 60, 70, 80, or 90 wt. %.
  • the therapeutic molecule is loaded between 5% and 20% weight/weight. In another embodiment the therapeutic molecule is loaded between 7% and 13 % weight/weight.
  • the C max (maximum concentration in the blood stream) is between 100 ng/ml and 400 ng/ml, or between 200 ng/ml and 350 ng/ml. More preferably between 275 ng/ml and 325 ng/ml.
  • the area under the curve (the curve of the drug concentration in blood plasma vs. time) (AUC) is between 10000 ng/mL*hr and 30000 ng/mL*hr. In another embodiment the AUC is between 12500 ng/mL*hr and 25000 ng/mL*hr. In another embodiment the AUC is between 15000 ng/mL*hr and 20000ng/mL*hr.
  • the amount of cetrorelix released after one-and-a-half months is between 5% and 25% of the total amount of cetrorelix. In another embodiment the amount of cetrorelix released at this time is between 10% and 20% of the total amount of cetrorelix. In another embodiment the amount of cetrorelix released is between 12% and 15% of the total amount of cetrorelix.
  • the polymer is loaded at 15%-45% weight/weight. In another embodiment the polymer is loaded at 25%-35% weight/weight.
  • the composition of the invention is an injectable composition, which is administered with one injection or two injections administered either concurrently or consecutively, with a total injection volume of less than 4 mL.
  • the injection may be subcutaneous or intramuscular.
  • the GnRH antagonist and polymer may be stored in solution or suspension in a solvent suitable to create a stable formulation for storage in a prefilled syringe.
  • the syringe may contain a GnRH antagonist, such as cetrorelix, in an amount of about 50 mg to about 300 mg or about 50 mg to about 150 mg.
  • the invention also relates to a kit, wherein the kit comprising: the composition of the invention.
  • composition of the invention is prepared with over 75% encapsulation/incorporation efficiency, and exhibits consistent release of the active agent from the drug delivery vehicle with no more than 25% variation.
  • composition of the invention releases the active agent from the drug delivery vehicle with >85% intact over the entire duration of release.
  • the invention relates to a method of extending release of a pharmaceutical agent (e.g. cetrorelix) in a subject for a period ranging from about 1 month to about 6 months or about 1 month to about 9 months or greater than 9 months.
  • the method comprising administering to the subject a composition of the invention (e.g. microspheres or gel).
  • the invention relates to a method of extending the release of a pharmaceutical agent (e.g. cetrorelix) in a subject for a period of at least 90 days, the method comprising administering to the subject a composition of the invention (e.g. microspheres).
  • the invention relates to a method of maintaining an effective level of a therapeutic agent (e.g. cetrorelix) in a subject for a period ranging from about 1 month to about 6 months or from about 1 month to about 9 months or greater than 9 months.
  • the method comprising administering to the subject a composition of the invention (e.g. microspheres or gel).
  • the invention relates to a method of maintaining an effective level of a therapeutic agent (e.g. cetrorelix) in a subject for a period at least 90 days, the method comprising administering to the subject a composition of the invention (e.g. microspheres).
  • the invention relates to a method for treating a disease or condition associated with GnRH, the method comprising administering a therapeutically effective amount of the composition of the invention, thereby treating the disease in the subject.
  • compositions of the present invention for treatment of conditions or diseases as described herein vary depending upon many different factors, including means of administration, target site, physiological state of the patient, whether the patient is human or an animal, other medications administered, and whether treatment is prophylactic or therapeutic.
  • the patient is a human, however non-human mammals, including transgenic mammals, can also be treated.
  • Treatment dosages may be titrated using routine methods known to those of skill in the art to optimize safety and efficacy.
  • compositions of the invention may include a “therapeutically effective amount.”
  • a “therapeutically effective amount” refers to an amount effective, at dosages and for periods of time necessary, to achieve the desired therapeutic result.
  • a therapeutically effective amount of a molecule may vary according to factors such as the disease state, age, sex, and weight of the individual, and the ability of the molecule to elicit a desired response in the individual.
  • a therapeutically effective amount is also one in which any toxic or detrimental effects of the molecule are outweighed by the therapeutically beneficial effects.
  • compositions of the invention described herein can be used to treat any GnRH associated disease or condition that could be treated by GnRH antagonist in humans or animals.
  • treatments, for diseases or conditions treated by the compositions of the invention include, for example, but are not limited to, suppression of testosterone production, as well as suppression of the hormones FSH and/or LH for the treatment of prostate cancer, especially hormone sensitive prostate cancer, and benign prostatic hyperplasia, directly blocking GnRH receptors on prostate cells for treatment of prostate cancer and benign prostatic hyperplasia, controlled ovarian stimulation for assisted reproductive techniques, treatment of uterine myoma, suppression of ovarian function while undergoing chemotherapy, treatment of breast cancer, treatment of ovarian cancer, male contraception, and female contraception.
  • the terms “treat” and “treatment” refer to therapeutic treatment, including prophylactic or preventative measures, wherein the object is to prevent or slow down (lessen) an undesired physiological change associated with a disease or condition.
  • Beneficial or desired clinical results include, but are not limited to, alleviation of symptoms, diminishment of the extent of a disease or condition, stabilization of a disease or condition (/. ⁇ ? ., where the disease or condition does not worsen), delay or slowing of the progression of a disease or condition, amelioration or palliation of the disease or condition, and remission (whether partial or total) of the disease or condition, whether detectable or undetectable.
  • Treatment can also mean prolonging survival as compared to expected survival if not receiving treatment.
  • Those in need of treatment include those already with the disease or condition as well as those prone to having the disease or condition or those in which the disease or condition is to be prevented.
  • the methods of treatment described herein can be used to treat any suitable mammal, including primates, such as monkeys and humans, horses, cows, cats, dogs, rabbits, elk, deer and rodents such as rats and mice.
  • the mammal to be treated is human.
  • administering to a subject is not limited to any particular delivery system and may include, without limitation, parenteral (including subcutaneous, intravenous, intramedullary, intraarticular, intramuscular, or intraperitoneal injection).
  • composition of the invention may be administered parenterally (e.g., intravenous, subcutaneous, intraperitoneal, and intramuscular). Further, the composition of the invention may be administered by intravenous infusion or injection. The composition of the invention may be administered by intramuscular or subcutaneous injection. In some embodiments, the composition of the invention may be administered surgically.
  • a "composition” refers to any composition that contains a pharmaceutically effective amount of one or more active ingredients (e.g., a GnRH antagonist). The composition, when administered to a subject (human or animal) induces a desired pharmacological and/or physiologic effect by local and/or systemic action.
  • subject refers to an animal, for example a human, to whom treatment, including prophylactic treatment, with the pharmaceutical composition according to the present invention, is provided.
  • subject refers to human and non-human animals.
  • non-human animals and “non-human mammals” are used interchangeably herein and include all vertebrates, e.g., mammals, such as non-human primates, (particularly higher primates), sheep, dog, rodent, (e.g. mouse or rat), guinea pig, goat, pig, cat, rabbits, cows, horses and non mammals such as reptiles, amphibians, chickens, and turkeys.
  • Poly(DL-lactide-co-glycolide) with 1 : 1 ratio of lactide to glycolide is dissolved in a suitable solvent to prepare an Atrigel® polymer solution. This solution is then filled into a syringe with a female luer lock fitting.
  • Each GnRH antagonist (ozarelix, degarelix, cetrorelix, or ganirelex) is then dissolved in water or other solvents and filled into a syringe with a male luer- lock fitting.
  • the two syringes Prior to administration, the two syringes are coupled, and the contents are mixed back and forth between the two syringes for multiple cycles. After thorough mixing, the formulation is drawn back into the syringe with the male coupling.
  • the two syringes are separated and a needle is attached.
  • the contents of the syringe is then subcutaneously injected into subjects.
  • a total injection volume would be less than 4 mL per syringe and per injection.
  • the GnRH antagonist composition may achieve a therapeutic effect within 24 hrs and maintain therapeutic effect for at least 90 days in >95% percent of treated patients.
  • the composition is prepared with an encapsulation efficiency of over 70% and may allow for consistent release of the active agent from the drug delivery vehicle with no more than 25% variation.
  • the composition may release the active agent from the drug delivery vehicle with >85% intact over the entire duration of release.
  • a multi-block copolymer is provided.
  • Each GnRH antagonist (ozarelix, degarelix, cetrorelix, or ganirelex) is loaded into the multi-block copolymer.
  • the formulation may be in the form of microspheres.
  • the formulation would be subcutaneously injected into subjects.
  • a total injection volume would be less than 4 mL.
  • the GnRH antagonist composition may achieve a therapeutic effect within 24 hours and maintain therapeutic effect for at least 90 days in >95% percent of treated patients.
  • the composition may allow for consistent release of the active agent from the drug delivery vehicle with no more than 25% variation plus an encapsulation efficiency of over 70%.
  • the composition may release the active agent from the drug delivery vehicle with >85% intact over the entire duration of release.
  • MSP microspheres
  • IVR cetrorelix in vitro release
  • cetrorelix salt compositions were prepared in formulations using 40% total PLGA (1:1 RG502H and RG752H) or 40% RG752S (ester end capped), with NMP or DMSO as polymer solvent (Table 9) were tested.
  • AUC for 20 mg/kg dose was assumed to be 123,620 and AUC for 5 mg/kg dose (ng/mL *hr) was assumed to be 30,905.
  • the calculations based on the above assumptions results in estimated percentage of cetrorelix released (up to 119 days) ranging from 9 to 13% of the amount initially present in the gel. (See Table 11).
  • FIG. 16A shows the testosterone level in rats at 12 weeks.
  • the formulations found within Table 13 were injected in rats and then the testosterone was measured at 0, 1, 2, 8 and 24 hours and then daily until the end of the first week and then biweekly until week 4 and then weekly thereafter.
  • Figure 16B the level of testosterone dropped below 1 ng/ml within 8 hours and the level was maintained over 12 weeks with no formulations showing break through (elevated testosterone).
  • Figure 17 shows the cetrorelix levels in the 2 nd rat study over the same 12-week period.
  • the levels of cetrorelix were all above 2 ng/ml which is the level required to inhibit testosterone production.
  • Figure 19 compares the cetrorelix data from the 1 st dog trials to the 2 nd rat trial up to 39 weeks. All three formulations injected into the rats had quantifiable levels of cetrorelix after 39 weeks as shown in Figure 19A. Similarly, Figure 19B shows that the three formulations injected into the dogs in the first trial had quantifiable levels of cetrorelix after 26 weeks. The pharmacokinetic data is tabulated in Figure 19C.
  • FIG. 20A shows the levels of testosterone the dogs had within each group. All the dogs had quantifiable levels of testosterone one week prior to injection, as shown in Figure 20B, but after the injection the animals only had a sustained quantifiable level of testosterone starting at week 8 and some of the animals did not have a quantifiable level of testosterone even after 26 weeks.
  • Figure 21 compares the data from the 2 nd rat and 1 st dog study results for testosterone levels. Figure 21A shows that the rats did not have a resurgence of testosterone for any of the formulations until week 26. Whereas Figure 21B shows that the dogs started to regain testosterone after week 6, but it did take several weeks for the animals to regain the levels they had before the cetrorelix injection. The data is tabulated in Figure 20A.
  • Figure 22A shows the level of cetrorelix for the 19.9% RG752H solution formulation in the 1st dog trial.
  • the serum level of cetrorelix stayed above 2 ng/ml until at least week 4 and for one animal up to week 14.
  • Figure 22B shows the corresponding measured level of serum testosterone for the same animals. As long as the cetrorelix level was above 2 ng/ml, the testosterone level was below the quantifiable limit for all three animals. Once cetrorelix level drops below 2 ng/ml the testosterone level increased.
  • Figure 23A shows the level of cetrorelix for the 30% RG752H solution formulation in the 1 st dog trial.
  • the serum level of cetrorelix stayed equal to or greater than 2 ng/ml until at least week 4 and for one animal until week 14.
  • Figure 23B shows the corresponding measured level of serum testosterone for the same animals. As long as the cetrorelix level was above 2 ng/ml the testosterone level was below the quantifiable limit for all three animals. Once cetrorelix level drops below 2 ng/ml the testosterone level increased.
  • Figure 24A shows the level of cetrorelix for the 30% R202H solution formulation in the 1 st dog trial.
  • the serum level of cetrorelix stayed above 2 ng/ml until at least week 13 and for one animal even after 26 week the level still was above 2 ng/ml.
  • Figure 24B shows the corresponding measured level of serum testosterone for the same animals. As long as the cetrorelix level was above 2 ng/ml the testosterone level was below the quantifiable limit for all three animals. Once cetrorelix level drops below 2 ng/ml the testosterone level increased. Therefore, the animal whose level of cetrorelix did not dip below 2 ng/ml did not experience an increase in testosterone even after 26 weeks.
  • a subject is injected with a depot injection, usually subcutaneously that deposits the drug in a localized mass that is gradually absorbed by the surrounding tissue.
  • the depot injection has a consistent release of the drug over a sustained period.
  • Cetrorelix in any of the formulations described herein, is injected subcutaneously as a depot, and the drug releases over at least 90 days. There is an immediate suppression of testosterone, without a concurrent surge upon the initial or repeated injection of the formulation of cetrorelix.
  • the subjects will have their blood taken every week to have the serum levels of cetrorelix and testosterone analyzed. Every 3 weeks, biopsies are performed to ascertain the size of the adenocarcinoma of the prostate. It is assumed that as long as the level of cetrorelix is above 2 ng/ml the levels of testosterone within the subject would be extremely low, which will cause the adenocarcinoma to shrink and the tumor to go into remission.

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Abstract

L'invention concerne des compositions et des méthodes pour la libération à long terme d'antagonistes de l'hormone de libération des gonadotropines (GnRH), et leurs utilisations. Plus particulièrement, l'invention concerne des compositions polymères et des méthodes pour la libération régulée d'antagonistes de la GnRH.
PCT/US2021/033575 2020-05-21 2021-05-21 Compositions et méthodes pour la libération à long terme d'antagonistes de l'hormone de libération des gonadotropines (gnrh) WO2021237039A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US16/880,309 US20200282008A1 (en) 2017-01-31 2020-05-21 COMPOSITIONS AND METHODS FOR LONG TERM RELEASE OF GONADOTROPIN-RELEASING HORMONE (GnRH) ANTAGONISTS
US16/880,309 2020-05-21

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US20180250354A1 (en) * 2017-01-31 2018-09-06 Veru Inc. COMPOSITIONS AND METHODS FOR LONG TERM RELEASE OF GONADOTROPIN-RELEASING HORMONE (GnRH) ANTAGONISTS
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