EP4661840A2 - Formulations polymériques de dégarelix - Google Patents

Formulations polymériques de dégarelix

Info

Publication number
EP4661840A2
EP4661840A2 EP24710302.1A EP24710302A EP4661840A2 EP 4661840 A2 EP4661840 A2 EP 4661840A2 EP 24710302 A EP24710302 A EP 24710302A EP 4661840 A2 EP4661840 A2 EP 4661840A2
Authority
EP
European Patent Office
Prior art keywords
composition
degarelix
less
nmp
kda
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.)
Pending
Application number
EP24710302.1A
Other languages
German (de)
English (en)
Inventor
John Downing
Bennet HARDING
Dileep JANAGAM
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.)
Tolmar International Ltd
Original Assignee
Tolmar International Ltd
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 Tolmar International Ltd filed Critical Tolmar International Ltd
Publication of EP4661840A2 publication Critical patent/EP4661840A2/fr
Pending 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
    • A61K9/0012—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
    • 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
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/02—Inorganic compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/22—Heterocyclic compounds, e.g. ascorbic acid, tocopherol or pyrrolidones
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/34—Macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyesters, polyamino acids, polysiloxanes, polyphosphazines, copolymers of polyalkylene glycol or poloxamers
    • 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
    • A61K9/0024—Solid, semi-solid or solidifying implants, which are implanted or injected in body tissue

Definitions

  • Degarelix acts by directly blocking GnRH action on the pituitary by competitively and reversibly binding to GnRH receptors and produces a fast suppression of testosterone with no initial surge or minimal surge.
  • the currently marketed drug-delivery technology for degarelix in the United States and Europe e.g., FIRMAGON® (degarelix for injection), Ferring Pharmaceuticals Inc. or Ferring GmbH
  • FIRMAGON® degarelix for injection
  • Ferring Pharmaceuticals Inc. or Ferring GmbH has significant limitations, including administration of a starting dose given as two high volume injections (3 mL each), followed by maintenance doses administered as a single high volume injection (1 x 4 mL) every 28 days.
  • degarelix is supplied as a powder (lyophilized, contained mannitol as a bulking agent), and once it is reconstituted with water the degarelix molecules aggregate and cross-link in a gel-forming network, resulting in a hydrogel. Because of its self-aggregation property and chemical instability in aqueous media, it has to be separated out from the aqueous vehicle and needs to be kept in a dried form by lyophilization. Therefore, it needs to be reconstituted at the time of administration. Since the rate and extent of self-aggregation/gel formation of peptide in aqueous media is concentration dependent, it is challenging to prepare a ready-to-inject formulation of degarelix for injection.
  • degarelix is manufactured by aseptic processing and involves multiple steps for reconstitution.
  • an injectable drug formulation of degarelix in a single syringe system that is ready-to-inject, and provides in a single injection, extended-release of a therapeutically effective amount of degarelix for more than a month within a low injection volume ( ⁇ 2.5 mL or 2 mL).
  • a composition comprising a therapeutically effective amount of degarelix or a pharmaceutically acceptable salt thereof.
  • the composition comprises a biodegradable polymer; and a biocompatible solvent, wherein the composition is formulated for subcutaneous injection into a subject; wherein a single dose of the composition is about 2.5 mL or less, or about 2.0 mL or less; and upon injection into the subject, the composition forms an in situ depot that releases the degarelix or pharmaceutically acceptable salt thereof over a time period of from about 1 month to about 6 months.
  • the in situ depot releases the degarelix or pharmaceutically acceptable salt thereof over a time period selected from the group consisting of: at least about 1 month, at least about 1.5 months, at least about 2 months, at least about 2.5 months, at least about 3 months, at least about 3.5 months, at least about 4 months, at least about 4.5 months, and at least about 5 months.
  • the pharmaceutically acceptable salt of the degarelix is selected from degarelix acetate, degarelix citrate, degarelix pamoate, degarelix palmitate, and degarelix mesylate.
  • the biodegradable polymer comprises monomer residues selected from the group consisting of lactide, glycolide, caprolactone, p- dioxanone, trimethylene carbonate, thylene oxide, propylene oxide, sebacic anhydride, diketene acetals/diols, and combinations thereof.
  • the biodegradable polymer comprises lactide and glycolide monomer residues. In one aspect, a molar ratio of the lactide to glycolide monomer residues is from about 45:55 to about 99:1.
  • a molar ratio of the lactide to glycolide monomer residues is from about 50:50 to about 90:10.
  • the biodegradable polymer comprises: lactide monomer residues and monomer residues selected from the group consisting of ⁇ - caprolactone, trimethylene carbonate, and combinations thereof.
  • a molar ratio of the lactide monomer residues to the ⁇ -caprolactone and/or trimethylene carbonate monomer residues is from about 10:90 to about 90:10.
  • a molar ratio of the lactide monomer residues to the ⁇ -caprolactone and/or trimethylene carbonate monomer residues is from about 25:75 to about 75:25. In yet another aspect, a molar ratio of the lactide monomer residues to the ⁇ -caprolactone and/or trimethylene carbonate monomer residues is about 75:25.
  • the biodegradable polymer comprises at least one carboxylic acid end group, at least one hydroxyl end group, or at least one hydroxy end group and is substantially free of terminal carboxy end groups.
  • the biodegradable polymer is poly(D,L-lactide- co-glycolide) (PLG), poly(D,L-lactide) (PLA), or poly(D,L-lactide-co- ⁇ -caprolactone) (PLC).
  • the biodegradable polymer is poly(D,L-lactide-co- ⁇ -caprolactone) (PLC).
  • the PLC comprises at least one carboxylic acid end group.
  • the PLC is a carboxylic acid-initiated PLC.
  • the carboxylic acid is glycolic acid or lactic acid.
  • the biodegradable polymer is acid-initiated 75:25 PLC.
  • the biodegradable polymer is PLG.
  • the PLG comprises at least one hydroxyl end group.
  • the PLG is a core- diol-initiated PLG.
  • the core diol is 1,6-hexane-diol.
  • the PLG is a mono functional alcohol-initiated PLG.
  • the alcohol is dodecanol.
  • the biodegradable polymer is acid-initiated 50:50 PLG.
  • the biodegradable polymer is 1,6-hexane-diol-initiated 75:25 PLG. In another aspect, the biodegradable polymer is 1,6-hexane-diol-initiated 85:15 PLG. [0016] In one aspect of the composition, the biodegradable polymer is dodecanol- initiated PLA. [0017] In one aspect of the composition, the biocompatible polymer has a weight average molecular weight of from about 5 kDa to about 60 kDa. [0018] In one aspect of the composition, the biocompatible polymer has a weight average molecular weight of from about 5 kDa to about 35 kDa.
  • the biocompatible polymer comprises less than about 0.5 wt%, or less than about 0.4 wt%, or less than about 0.3 wt%, or less than about 0.2 wt% or less than about 0.1 wt% unreacted lactide monomer.
  • the amount of biodegradable polymer in the composition is from about 10% to about 60% by weight of the composition.
  • the amount of biocompatible solvent in the composition is from about 10% to about 85% by weight of the composition.
  • the therapeutically effective amount of degarelix or pharmaceutically acceptable salt in the composition is from about 10% to about 40% by weight of the composition.
  • the therapeutically effective amount of degarelix or pharmaceutically acceptable salt thereof is from about 40 mg – 500 mg.
  • the therapeutically effective amount of degarelix or pharmaceutically acceptable salt thereof is from about 80 mg – 500 mg.
  • the therapeutically effective amount of degarelix or pharmaceutically acceptable salt thereof is from about 120 mg – 500 mg.
  • the biocompatible organic solvent is selected from the group consisting of N-methyl-2-pyrrolidone (NMP), dimethyl sulfoxide (DMSO), dimethylacetamide (DMA), benzyl benzoate (BnBzO), polyethylene glycol 15 hydroxystearate, methyl ethyl ketone, methyl lactate, benzyl alcohol, propylene carbonate (PC), triacetin, tributyl citrate, acetyl tributyl citrate, acetyl triethyl citrate, triethyl citrate, diethylene glycol monomethyl ether, ethyl acetate, N-ethyl-2-pyrrolidone, glycofurol, and combinations thereof.
  • NMP N-methyl-2-pyrrolidone
  • DMSO dimethyl sulfoxide
  • DMA dimethylacetamide
  • BnBzO benzyl benzoate
  • PC propylene carbonate
  • triacetin
  • the biocompatible organic solvent is NMP or DMSO.
  • a single dose of the composition is about 2.5 mL or less, about 2.4 mL or less, about 2.3 mL or less, about 2.2 mL or less, about 2.1 mL or less, about 2.0 mL or less, about 1.9 mL or less, about 1.8 mL or less, about 1.7 mL or less, about 1.6 mL or less, about 1.5 mL or less, about 1.4 mL or less, about 1.3 mL or less, about 1.2 mL or less, about 1.1 mL or less, about 1 mL or less, about 0.75 mL or less, about 0.5 mL or less, or about 0.375 mL or less.
  • the composition has been terminally sterilized or sterile filtered. In one aspect, wherein the composition has been terminally sterilized by e-beam. [0029] In one aspect of the composition, the composition further comprises one or more additives.
  • the additive is selected from the group consisting of polysorbate 20, polysorbate 80, poloxamer 188, sorbitan trioleate, lecithin (e.g., soya or egg), polyethylene glycol (PEG), PEG 300, 2-pyrrolidone, alpha-tocopherol, Vitamin E TPGS, sucrose cocoate, sucrose stearate, sucrose laurate, proline, arginine, sodium metabisulfite butylated hydroxyanisole, butylated hydroxyquinone, butylhydroxyanisol, hydroxycoumarin, butylated hydroxytoluene, cephalm, ethyl gallate, propyl gallate, octyl gallate, lauryl gallate, propyl-hydroxybenzoate, trihydroxybutylrophenone, vitamin E, lecithin, ethanolamine, ZnCl 2 , MgCl 2 , CaCl 2 , DL-methioninecitric
  • the degarelix is lyophilized, and the biodegradable polymer is dissolved in the biocompatible solvent.
  • the degarelix is dissolved in a first biocompatible solvent, and the biodegradable polymer is dissolved in a second biocompatible solvent.
  • the first and second biocompatible solvent are the same.
  • a pharmaceutical composition comprising about 10-30 wt% of degarelix acetate; about 20-80 wt% of N-methyl-2-pyrrolidone (NMP); and about 10-50 wt% of 75:25 poly(lactide-co- ⁇ -caprolactone) (PLC) copolymer having at least one carboxylic acid end group and having a weight average molecular weight of about 5-30 kDa is disclosed.
  • NMP N-methyl-2-pyrrolidone
  • PLC poly(lactide-co- ⁇ -caprolactone) copolymer having at least one carboxylic acid end group and having a weight average molecular weight of about 5-30 kDa
  • the composition comprises about 16 wt% of degarelix acetate; about 57 wt% of N-methyl-2-pyrrolidone (NMP); and about 27 wt% of 75:25 poly(lactide-co- ⁇ -caprolactone) (PLC) copolymer having at least one carboxylic acid end group and having a weight average molecular weight of about 17 kDa.
  • the composition comprises about 16 wt% of degarelix acetate; about 57 wt% of NMP; and about 27 wt% of 75:25 PLC copolymer having at least one carboxylic acid end group and having a weight average molecular weight of about 8 kDa.
  • unreacted lactide and caprolactone monomers in the PLC copolymer are less than about 1.0 wt%. In yet another aspect, unreacted lactide and caprolactone monomers in the PLC copolymer are less than about 0.5 wt%, than about 0.4 wt %, less than about 0.3 wt %, less than about 0.2 wt% and less than about 0.1 wt%.
  • a pharmaceutical composition comprising a first container comprising 30-70 wt% of 75:25 PLC copolymer having at least one carboxylic acid end group and having a weight average molecular weight of 5-30 kDa, and 30-70 wt% of N- methyl-2-pyrrolidone (NMP); and a second container comprising 20-40 wt% of degarelix acetate and 60-80 wt% NMP is disclosed.
  • NMP N- methyl-2-pyrrolidone
  • the first container comprises 50 wt% of 75:25 PLC copolymer having at least one carboxylic acid end group and having a weight average molecular weight of 17 kDa, and 50 wt% of N- methyl-2-pyrrolidone (NMP); and the second container comprises 35 wt% of degarelix acetate and 65 wt% NMP.
  • the first container comprises 70 wt% of 75:25 PLC copolymer having at least one carboxylic acid end group and having a weight average molecular weight of 8 kDa, and 30 wt% of NMP; and the second container comprising 35 wt% of degarelix acetate and 65 wt% NMP.
  • unreacted lactide and caprolactone monomers in the PLC copolymer are less than about 1.0 wt%.
  • unreacted lactide and caprolactone monomers in the PLC copolymer are less than about 0.5 wt%, than about 0.4 wt %, less than about 0.3 wt %, less than about 0.2 wt% and less than about 0.1 wt%.
  • a pharmaceutical composition comprising about 10-30 wt% of degarelix acetate; about 20-80 wt% of NMP; and about 10-50 wt% of poly(D,L-lactide) (PLA) polymer having at least one carboxylic acid end group and having a weight average molecular weight of about 5-30 kDa is disclosed.
  • the composition comprises about 16 wt% of degarelix acetate; about 57 wt% of NMP; and about 27 wt% of poly(D,L-lactide) (PLA) polymer having at least one carboxylic acid end group and having a weight average molecular weight of about 23 kDa.
  • unreacted lactide monomers in the PLA polymer are less than about 1.0 wt%.
  • unreacted lactide monomers in the PLA polymer are less than about 0.5 wt%, than about 0.4 wt %, less than about 0.3 wt %, less than about 0.2 wt% and less than about 0.1 wt%.
  • a pharmaceutical composition comprising a first container comprising 30-70 wt% of PLA polymer having at least one carboxylic acid end group and having a weight average molecular weight of 5-30 kDa, and 30-70 wt% of NMP; and a second container comprising 20-40 wt% of degarelix acetate and 60-80 wt% NMP is disclosed.
  • the first container comprising 50 wt% of PLA polymer having at least one carboxylic acid end group and having a weight average molecular weight of 23 kDa, and 50 wt% of NMP; and the second container comprising 35 wt% of degarelix acetate and 65 wt% NMP.
  • unreacted lactide monomers in the PLA polymer are less than about 1.0 wt%. In still another aspect, unreacted lactide monomers in the PLA polymer are less than about 0.5 wt%, than about 0.4 wt %, less than about 0.3 wt %, less than about 0.2 wt% and less than about 0.1 wt%.
  • a pharmaceutical composition comprising about 10-30 wt% of degarelix acetate; about 20-80 wt% of NMP; and about 10-50 wt% of 75:25 poly(D,L- lactide-co-glycolide) (PLG) copolymer having at least one carboxylic acid end group and having a weight average molecular weight of about 5-30 kDa is disclosed.
  • PLG poly(D,L- lactide-co-glycolide)
  • the composition comprises about 16 wt% of degarelix acetate; about 57 wt% of NMP; and about 27 wt% of 75:25 poly(D,L-lactide-co-glycolide) (PLG) copolymer having at least one carboxylic acid end group and having a weight average molecular weight of about 17 kDa.
  • PLG poly(D,L-lactide-co-glycolide) copolymer having at least one carboxylic acid end group and having a weight average molecular weight of about 17 kDa.
  • unreacted lactide and glycolide monomers in the PLG copolymer are less than about 1.0 wt%.
  • unreacted lactide and glycolide monomers in the PLG copolymer are less than about 0.5 wt%, than about 0.4 wt %, less than about 0.3 wt %, less than about 0.2 wt% and less than about 0.1 wt%.
  • a pharmaceutical composition comprising a first container comprising 30-70 wt% of 75:25 PLG copolymer having at least one carboxylic acid end group and having a weight average molecular weight of 5-30 kDa, and 30-70 wt% of NMP; and a second container comprising 20-40 wt% of degarelix acetate and 60-80 wt% NMP is disclosed.
  • the first container comprises 50 wt% of 75:25 PLG copolymer having at least one carboxylic acid end group and having a weight average molecular weight of 17 kDa, and 50 wt% of NMP; and the second container comprises 35 wt% of degarelix acetate and 65 wt% NMP.
  • unreacted lactide and glycolide monomers in the PLG copolymer are less than about 1.0 wt%.
  • unreacted lactide and glycolide monomers in the PLG copolymer are less than about 0.5 wt%, than about 0.4 wt %, less than about 0.3 wt %, less than about 0.2 wt% and less than about 0.1 wt%.
  • a pharmaceutical composition comprising about 10-30 wt% of degarelix acetate; about 20-80 wt% of NMP; and about 10-50 wt% of 75:25 PLG copolymer having at least one hydroxyl end group and having a weight average molecular weight of about 5-30 kDa is disclosed.
  • the composition comprises about 16 wt% of degarelix acetate; about 57 wt% of NMP; and about 27 wt% of 75:25 PLG copolymer having at least one hydroxyl end group and having a weight average molecular weight of about 19 kDa.
  • a pharmaceutical composition comprising a first container comprising 30-70 wt% of 75:25 PLG copolymer having at least one hydroxyl end group and having a weight average molecular weight of 5-30 kDa, and 30-70 wt% of NMP; and a second container comprising 20-40 wt% of degarelix acetate and 60-80 wt% NMP.
  • the first container comprises 50 wt% of 75:25 PLG copolymer having at least one hydroxyl end group and having a weight average molecular weight of 19 kDa, and 50 wt% of NMP; and the second container comprises 35 wt% of degarelix acetate and 65 wt% NMP.
  • a pharmaceutical composition comprising about 10-30 wt% of degarelix acetate; about 10-40 wt% of NMP; about 10-40 wt% of DMSO; and (d) about 10-50 wt% of 75:25 PLG copolymer having at least one hydroxyl end group and having a weight average molecular weight of about 5-30 kDa is disclosed.
  • the composition comprises about 16 wt% of degarelix acetate; about 30 wt% of NMP; about 27 wt% of DMSO; and (d) about 27 wt% of 75:25 PLG copolymer having at least one hydroxyl end group and having a weight average molecular weight of about 19 kDa.
  • a pharmaceutical composition comprising a first container comprising 30-70 wt% of 75:25 PLG copolymer having at least one hydroxyl end group and having a weight average molecular weight of 5-30 kDa, and 30-70 wt% of NMP; and a second container comprising 20-40 wt% of degarelix acetate and 60-80 wt% DMSO is disclosed.
  • the first container comprises 50 wt% of 75:25 PLG copolymer having at least one hydroxyl end group and having a weight average molecular weight of 19 kDa, and 50 wt% of NMP; and the second container comprises 35 wt% of degarelix acetate and 65 wt% DMSO.
  • a pharmaceutical composition comprising about 10-30wt% of degarelix citrate; about 20-80 wt% of NMP; and about 10-50 wt% of 75:25 PLG copolymer having at least one hydroxyl end group and having a weight average molecular weight of about 5-30 kDa is disclosed.
  • the composition comprises about 16 wt% of degarelix citrate; about 57 wt% of NMP; and about 27 wt% of 75:25 PLG copolymer having at least one hydroxyl end group and having a weight average molecular weight of about 19 kDa.
  • a pharmaceutical composition comprising a first container comprising 30-70 wt% of 75:25 PLG copolymer having at least one hydroxyl end group and having a weight average molecular weight of 19 kDa, and 50 wt% of NMP; and a second container comprising 20-40 wt% of degarelix citrate and 60-80 wt% NMP is disclosed.
  • the first container comprises 50 wt% of 75:25 PLG copolymer having at least one hydroxyl end group and having a weight average molecular weight of 19 kDa, and 50 wt% of NMP; and the second container comprises 35 wt% of degarelix citrate and 65 wt% NMP.
  • the amount of degarelix or the pharmaceutically acceptable salt thereof in the pharmaceutical composition is from about 8 wt% to about 39 wt% degarelix free base equivalent. In one aspect, the amount of degarelix or the pharmaceutically acceptable salt thereof in the pharmaceutical composition is from about 17 wt% to about 39 wt% degarelix free base equivalent.
  • the amount of degarelix or the pharmaceutically acceptable salt thereof in the pharmaceutical composition is from about 8 wt% to about 29 wt% degarelix free base equivalent. In one aspect, the amount of degarelix or the pharmaceutically acceptable salt thereof in the pharmaceutical composition is from about 8 wt% to about 20 wt% degarelix free base equivalent. In one aspect, the amount of degarelix or the pharmaceutically acceptable salt thereof in the pharmaceutical composition is from about 10 wt% to about 16 wt% degarelix free base equivalent. In one aspect, the amount of degarelix or the pharmaceutically acceptable salt thereof in the pharmaceutical composition is from about 14 wt% to about 15.5 wt% degarelix free base equivalent.
  • the amount of degarelix or a pharmaceutically acceptable salt thereof (degarelix API) in a composition of the invention is from about 30 wt% to about 35 wt% degarelix free base equivalent. In one aspect, the amount of degarelix API in the pharmaceutical composition is from about 31 wt% to about 34 wt% degarelix free base equivalent. In one aspect, the amount of degarelix API in the pharmaceutical composition is from about 31 wt% to about 33 wt% degarelix free base equivalent. In one aspect, the amount of degarelix API in the pharmaceutical composition is from about 31 wt% to about 32 wt% degarelix free base equivalent.
  • a target dose to be administered to a subject when a target dose to be administered to a subject is calculated based on degarelix free base equivalent in the composition, the percent by weight of solvent, and the percent by weight of additive if included, may be modified accordingly.
  • methods of treating prostate cancer and central precocious puberty (CPP) as well as methods of reducing serum testosterone levels and suppressing ovarian function by subcutaneously administering the compositions disclosed herein to subjects in need thereof is also contemplated.
  • a method of treating prostate cancer in a subject comprising subcutaneously administering the compositions disclosed herein to the subject is disclosed.
  • the prostate cancer is advanced prostate cancer.
  • the dose amount of degarelix or pharmaceutically acceptable salt in the composition is administered in a dose amount of about 40 mg to about 500 mg.
  • a method of reducing serum testosterone levels in a subject to 50 ng/dL or less, comprising subcutaneously administering the compositions disclosed herein to the subject is disclosed.
  • the serum testosterone level is below 20 ng/dL.
  • the serum testosterone level is below 10 ng/dL.
  • a method of suppressing ovarian function in a subject with hormone-receptor positive breast cancer comprising subcutaneously administering the compositions disclosed herein to the subject is disclosed.
  • the hormone receptor positive breast cancer is estrogen receptor (ER) positive breast cancer.
  • estradiol (E2) production level is suppressed to a level less than about 20 pg/mL to about less than about 2 pg/mL.
  • the subject’s follicle stimulating hormone (FSH) level is suppressed to a level less than about 40 IU/L.
  • the subject’s luteinizing hormone (LH) level is suppressed to a level less than about 4 IU/L.
  • CPP central precocious puberty
  • the subject’s CPP blood serum LH concentration level is reduced to a pre-pubertal concentration level of less than about 4 IU/L.
  • the composition is administered about once every 1 month, about once every 2 months, about once every 3 months, about once every 4 months, about once every 5 months, or about once every six months.
  • the composition is administered to the subject about once every three months.
  • the composition is administered as a loading dose followed by a maintenance dose of the composition about 1 month, 2 months or 3 months after the loading dose has been administered.
  • a loading dose when a loading dose is administered, the maintenance dose is administered every 1 month, every 2 months or every 3 months thereafter. In one embodiment, no loading dose is administered, and the composition is administered about once every 1 month, about once every 2 months, about once every 3 months, about once every 4 months, about once every 5 months, or about once every six months.
  • a delivery system comprising a syringe or syringes prefilled with a composition disclosed herein, in some embodiments together with instructions suitable for using the delivery system to administer the composition to a subject.
  • a prefilled syringe system for administration of the compositions disclosed herein, comprising a single syringe containing the composition disclosed herein, is described.
  • the syringe is a mixing syringe. In one aspect, the syringe is an autoinjector syringe. In still another aspect, the syringe is a dual-chambered syringe, and the composition disclosed herein is contained within one chamber of the syringe. In yet another aspect, the syringe is a dual-chambered syringe, and the biodegradable polymer and biocompatible solvent are contained in one chamber of the syringe and the degarelix or pharmaceutically acceptable salt thereofis contained in the second chamber of the syringe. In one aspect, the degarelix is lyophilized.
  • the degarelix or or pharmaceutically acceptable salt thereof is dissolved or suspended in the biocompatible solvent.
  • a prefilled syringe system for administration of the compositions disclosed herein, comprising a first syringe containing the biodegradable polymer and the biocompatible solvent, and a second syringe containing the degarelix is described.
  • the first syringe and the second syringe are coupled together.
  • the degarelix or pharmaceutically acceptable salt thereof is lyophilized.
  • the degarelix or pharmaceutically acceptable salt thereof is dissolved or suspended in the biocompatible solvent.
  • kits comprising the prefilled syringe system disclosed herein and instructions for use of the prefilled syringe system to administer a composition contained therein are disclosed.
  • a product comprising the compositions disclosed herein for use in a method of treating prostate cancer or CPP is disclosed.
  • a product comprising the compositions disclosed herein for use in a method of reducing serum testosterone levels below to 50 ng/dL is disclosed.
  • a product comprising the compositions disclosed herein for use in a method of suppressing ovarian function in a subject with hormone-receptor positive breast cancer is disclosed.
  • Fig. 1 shows the percentage recovery of degarelix from the degarelix/organic solvent formulation samples (formulas 1, 2 and 5 (F1, F2 and F5) )(prefilled syringes) stored at 25°C for 0 months, 1 month, 3 months and 6 months.
  • F1 Degarelix acetate drug substance (DgA-DS)/N-methyl-2-pyrrolidone (NMP) (65%/35%);
  • F2 DgA-DS/dimethyl sulfoxide (DMSO) (65%/35%);
  • F5 DgA-DS/DMSO (60%/35%).
  • FIG. 2 shows the in vivo degarelix levels in plasma over the first 3 days post- injection using a rat model as described in section 19 of the Example section.
  • Fig.3 shows the in vivo degarelix levels in plasma over 28 days post-injection using a rat model as described in section 19 of the Example section.
  • Fig.4 shows the in vivo degarelix levels in plasma over 63 days post-injection using a rat model as described in section 19 of the Example section.
  • Fig.5 shows a magnified view of the in vivo degarelix levels in plasma over 63 days post-injection using a rat model as described in section 19 of the Example section.
  • Fig.6 shows the in vivo degarelix levels in plasma over 119 days post-injection using a rat model as described in section 19 of the Example section.
  • Fig.7 shows a magnified view of the in vivo degarelix levels in plasma over 119 days post-injection using a rat model as described in section 19 of the Example section.
  • Fig. 8 shows a semi-log view of the in vivo testosterone levels in plasma over 105 days post-injection using a rat model as described in section 19 of the Example section.
  • active pharmaceutical ingredient As used herein, the terms “active pharmaceutical ingredient”, abbreviated as “API”, and “drug” can be used interchangeably and generally refer to a biologically active compound that has therapeutic effects on the body.
  • the “active pharmaceutical ingredient” may refer to an active drug, or a pharmaceutically acceptable salt of an active drug. As used herein, these terms may be used to refer to degarelix or a pharmaceutically acceptable salt thereof.
  • Decorated drug As used herein, these terms may be used to refer to degarelix or a pharmaceutically acceptable salt thereof.
  • “Degarelix API” (whether capitalized or not) as used herein refers to degarelix or any pharmaceutically acceptable salt thereof.
  • esteer refers to a chemical functional group, C(O)OR’ where R’ represents an alkyl as defined herein.
  • antioxidant refers to compounds which are used to extend the shelf-life of products by preventing or inhibiting the oxidation of active substances and excipients.
  • An antioxidant may react with free radicals thereby blocking or inhibiting free radical chain reactions, or the antioxidant may have a lower redox potential than the active substances and excipients in the formulation. Additionally, or alternatively, a synergist antioxidant may enhance the effects of other antioxidants.
  • biocompatible means “not harmful to living tissue” or “safe for injection within a human body”.
  • biodegradable refers to any material that is converted, breaks down, or degrades, under physiological conditions into innocuous or natural byproducts, such as (but not limited to) water, gas, biomass, and/or organic salts, without regard to any specific degradation mechanism or process.
  • GPC gel permeation chromatography
  • the terms “patient” and “subject” are interchangeable and generally refer to an animal or a human to which a composition disclosed herein is administered or is to be administered.
  • the term “pharmaceutically acceptable salt” refers to a salt of a compound, which possesses the desired pharmacological activity of the parent compound.
  • Such salts include, but are not limited to: (1) acid addition salts, formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like; or formed with organic acids such as acetic acid, propionic acid, hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, lauric acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, 3-(4-hydroxybenzoyl)benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, 1,2-ethane-disulfonic acid, 2-hydroxyethan
  • solvent refers to a liquid that dissolves a solid or liquid solute, or to a liquid external phase of a suspension throughout which solid or liquid substances may be suspended or dispersed.
  • biocompatible solvent may be used interchangeably with the term “solvent”.
  • co-solvent refers to a substance added to a solvent to increase or modify the solubility of a solute in the solvent.
  • a co-solvent may increase or decrease solubility of a solute in a primary solvent and/or may impart other desirable characteristics onto a formulation (e.g., the extent of water insolubility of the solvents and co-solvents in a solvent system can impact the desired rate of diffusion into bodily fluids for controlling the rate and scope of degarelix API gelation; or solvent/co- solvents can control the viscosity of the compositions of the invention, which aids in preparing and administering the extended release composition to a subject).
  • solvent/co- solvents can control the viscosity of the compositions of the invention, which aids in preparing and administering the extended release composition to a subject.
  • the term “solubilizer” refers to a compound that increases the solubility of another substance.
  • the term “surfactant” refers to a compound that lowers the surface tension between two liquids, between a gas and a liquid, or between a liquid and a solid.
  • a surfactant can act as a wetting agent, which aids in dispersing an active pharmaceutical ingredient in a liquid vehicle, or as a solubilizer under some circumstances.
  • the term “therapeutically effective amount” means the amount of a compound or drug product that, when administered to a patient for treating a disease and/or treating or preventing one or more symptoms of a disease, is sufficient to affect such treatment or prevention for the disease.
  • the “therapeutically effective amount” can vary depending on, for example, the compound or drug product, disease progression, the disease or condition to be treated, whether the therapy is an adjuvant therapy or a primary or curative therapy, and/or the age, weight, etc., of the patient to be treated.
  • a therapeutically effective amount of degarelix can include an amount effective to: (1) treat a disease including, but not limited to, advanced prostate cancer; (2) decrease plasma levels of luteinizing hormone (LH), reduce plasma level of follicle stimulating hormone (FSH), and/or reduce and maintain serum testosterone levels below castration level of 50 ng/dL; and/or (3) provide a plasma level of degarelix in a subject that is sufficient to achieve any of the results in (2).
  • Therapeutically effective amounts of degarelix or a pharmaceutically acceptable salt thereof in a variety of diseases and conditions are described in more detail below.
  • area under the curve is the area under a plot of the concentration of a drug in the blood plasma as a function of time, and reflects the actual body exposure to a drug after administration of a dose of the drug. AUC is dependent on the rate of elimination of the drug from the body and the dose administered.
  • the terms "at least one”, “one or more”, and “and/or” are open- ended expressions that are both conjunctive and disjunctive in operation.
  • each of the expressions "at least one of A, B and C", “at least one of A, B, or C", “one or more of A, B, and C", “one or more of A, B, or C", “A, B, and/or C", and "A, B, or C” means A alone, B alone, C alone, A and B together, A and C together, B and C together, or A, B and C together.
  • each one of A, B, and C in the above expressions refers to an element, such as X, Y, and Z, or class of elements, such as X1-Xn, Y1-Ym, and Z1-Zo
  • the phrase is intended to refer to a single element selected from X, Y, and Z, a combination of elements selected from the same class (e.g., X1 and X2) as well as a combination of elements selected from two or more classes (e.g., Y1 and Zo).
  • the term “depot” refers to the degarelix and/or biodegradable polymer in a composition/formulation disclosed herein once exposed to an aqueous environment (e.g., including a physiological environment in a body of an animal) in which, upon dissipation of the solvent in situ, a solid, semi-solid, or liquid depot is formed comprising the biodegradable polymer and the degarelix API which self-aggregates (e.g., as fibrils or a gel). Together, the biodegradable polymer and the degarelix API create a drug reservoir from which the degarelix is released over an extended period of time.
  • an aqueous environment e.g., including a physiological environment in a body of an animal
  • Every numerical range given throughout this disclosure is deemed to include both terminal values as well as each and every narrower numerical range that falls within such broader numerical range, as if such narrower numerical ranges were all expressly written herein.
  • the phrase from about 2 to about 4 includes the whole number and/or integer ranges from about 2 to about 3, from about 3 to about 4 and each possible range based on real (e.g., irrational and/or rational) numbers, such as from about 2.1 to about 4.9, from about 2.1 to about 3.4, and so on.
  • Degarelix is a decapeptide, selective gonadotropin-releasing hormone (GnRH) receptor antagonist (blocker) that competitively and reversibly binds to GnRH receptors in the pituitary. This results in a significant reduction of follicle-stimulating hormone (FSH) and luteinizing hormone (LH), thus reducing testosterone levels in males, or estrogen levels in females.
  • GnRH selective gonadotropin-releasing hormone
  • FSH follicle-stimulating hormone
  • LH luteinizing hormone
  • degarelix compositions of the invention are indicated for LH suppression or testosterone suppression in adult male patients with advanced hormone-dependent prostate cancer in whom androgen deprivation is warranted.
  • Degarelix compositions of the invention are also useful for LH suppression or estrogen (e.g., estradiol) suppression in adult female patients with pre-menopausal or perimenopausal breast cancer, and are also useful for conditions including, but not limited to, endometriosis or uterine fibroids.
  • Degarelix compositions are also useful for LH suppression or sex hormone suppression (testosterone or estrogen, depending on whether the patient is male or female) in children with central precocious puberty (CPP).
  • CPP central precocious puberty
  • a long-acting injectable formulation of degarelix that (1) is easy to prepare and administer (e.g., by a health care provider); (2) provides sustained or extended release of degarelix for more than a month after a single dose, and in one embodiment, for at least three months or longer; and (3) is administered in a total injection volume of about 2.5 mL or less, or about 2 mL or less.
  • a long acting, injectable composition or formulation (used interchangeably and which may also be referred to as a “drug product” “pharmaceutical product” “product” or “finished drug product”) that comprises degarelix or a pharmaceutically acceptable salt thereof, in polymer-based drug delivery system.
  • the formulation comprises a biodegradable polymer and a biocompatible, water-miscible solvent, and can optionally further include an additive as disclosed herein.
  • the degarelix polymeric composition/formulation is a flowable solution/suspension where, upon delivery (i.e., injection) into an aqueous environment (e.g., the body of a human), the water-miscible solvent exchanges with surrounding aqueous body fluids, which results in the formation of a polymer-drug depot, that acts as a drug reservoir for extended release of the drug (i.e. release of the drug over an extended period of time).
  • composition/formulations disclosed herein provide sustained or extended release of degarelix or a pharmaceutically acceptable salt thereof for more than a month when injected at low volumes (e.g., ⁇ 2.5 mL or ⁇ 2 mL) via subcutaneous injection.
  • the long-acting injectable compositions suitable for use in the methods of this disclosure which may also be referred to as pharmaceutical compositions or formulations, extended-release compositions or formulations, or controlled release compositions or formulations, provide a biodegradable or bioerodible microporous in situ formed depot of biodegradable polymer and self-aggregated degarelix in a subject, from which the degarelix or a pharmaceutically acceptable salt thereof, is released over a period of one month or longer, and preferably at least three months or longer.
  • the composition/formulation can be supplied in a prefilled single or dual chamber syringe, or in a two-syringe mixing system.
  • the composition is administered from the syringe system in injection volumes of less than or equal to 2.5 mL, less than or equal to 2.4 mL, less than or equal to 2.3 mL, less than or equal to 2.2 mL, less than or equal to 2.1 mL, less than or equal to 2.0 mL, less than or equal to 1.9 mL, less than or equal to 1.8 mL, less than or equal to 1.7 mL, less than or equal to 1.6 mL, or less than equal to 1.5 mL and is suitable for subcutaneous injection.
  • This composition solves the problem of the multiple, high-volume injections provided by the current degarelix product on the market.
  • degarelix or a pharmaceutically acceptable salt thereof is released from the polymer depot over a period of at least about 1 month or longer, at least about 1.5 months or longer, at least about 2 months or longer, at least about 2.5 months or longer, at least about 3 months or longer, at least about 3.5 months or longer, at least about 4 months or longer, at least about 4.5 months or longer, at least about 5 months or longer, or at least about 6 months or longer.
  • compositions/formulations disclosed herein comprise degarelix or a pharmaceutically acceptable salt thereof in polymer-based drug delivery system.
  • the pharmaceutically acceptable salts of the degarelix include, but are not limited to, degarelix acetate, degarelix citrate, degarelix pamoate, and degarelix mesylate.
  • “Degarelix API” refers to degarelix or any pharmaceutically acceptable salt thereof.
  • the disclosed compositions comprise a biodegradable polymer, a biocompatible solvent, and degarelix or a pharmaceutically acceptable salt thereof.
  • the biodegradable polymer or copolymers are: substantially insoluble in water and body fluid, biocompatible, and biodegradable and/or bioerodible within the body of a subject.
  • the pharmaceutical compositions are administered to a patient by subcutaneous injection as a liquid or gel wherein a solid, semi-solid, or liquid depot is formed in situ upon dissipation of the solvent.
  • the depot so formed releases degarelix or a pharmaceutically acceptable salt thereof, in a controlled, or extended, release manner.
  • concentration of the degarelix or a pharmaceutically acceptable salt thereof, in the disclosed compositions can vary and may range from about 1% to about 40% by weight of the final formulation or composition (i.e., the formulation or composition in its ready-to-inject state), including any whole number percent to any other whole number percent within the range of from about 1 percent to about 40 percent by weight.
  • the total weight percent of each of the components in the final formulation/composition equals 100% (e.g., if the amount of degarelix salt in the formulation is 20 wt%, then the total amount of polymer and solvent in the formulation, absent any additives, is 80 wt%).
  • the concentration of the degarelix or pharmaceutically acceptable salt thereof in the composition may be about 5% by weight of the composition, or about 10% by weight of the composition, or about 15% by weight of the composition, or about 20% by weight of the composition, or about 25% by weight of the composition, or about 30% by weight of the composition, or about 35% by weight of the composition, or about 40% by weight of the composition.
  • the concentration of degarelix or pharmaceutically acceptable salt thereof is no more than about 25% by weight of the composition.
  • the amount of degarelix API in compositions of the invention may range from any tenth of a percent to any other tenth of a percent within the range of from about 1% to about 40% by weight.
  • the amount of degarelix API in a composition of the invention is referenced with respect to the amount of a pharmaceutically acceptable salt of degarelix, such as degarelix acetate or other salt, in the composition.
  • the amount of degarelix API in a composition of the invention is referenced with respect to the amount of degarelix free base equivalent in the composition (which may also simply be referred to as the amount of degarelix in the composition).
  • determination of the dose amount of degarelix API to be administered to a subject may be calculated based on the amount of degarelix free base equivalent in the composition rather than the amount of degarelix salt in order to account for differences in purity, water, or acetic acid content (e.g., in the case of degarelix acetate), among various API lots. Calculation of the free base equivalent of degarelix in a composition is well understood within the art.
  • the percentage (by weight) of degarelix as free base in a composition where the degarelix API is degarelix acetate can be calculated in a simple formula such as: 100 – (wt% drug substance water content – wt% drug substance acetic acid content) * degarelix purity by assay (anhydrous/acid free base) * wt% degarelix acetate in the composition.
  • the free base equivalent may also be provided from the USP Monograph for a drug substance.
  • the amount of degarelix or the pharmaceutically acceptable salt thereof in the pharmaceutical composition is from about 8 wt% to about 39 wt% degarelix free base equivalent.
  • the amount of degarelix or the pharmaceutically acceptable salt thereof in the pharmaceutical composition is from about 17 wt% to about 39 wt% degarelix free base equivalent. In one aspect, the amount of degarelix or the pharmaceutically acceptable salt thereof in the pharmaceutical composition is from about 8 wt% to about 29 wt% degarelix free base equivalent. In one aspect, the amount of degarelix or the pharmaceutically acceptable salt thereof in the pharmaceutical composition is from about 8 wt% to about 20 wt% degarelix free base equivalent. In one aspect, the amount of degarelix or the pharmaceutically acceptable salt thereof in the pharmaceutical composition is from about 10 wt% to about 16 wt% degarelix free base equivalent.
  • the amount of degarelix or the pharmaceutically acceptable salt thereof in the pharmaceutical composition is from about 14 wt% to about 15.5 wt% degarelix free base equivalent. In one aspect, the amount of degarelix or a pharmaceutically acceptable salt thereof (degarelix API) in a composition of the invention is from about 30 wt% to about 35 wt% degarelix free base equivalent. In one aspect, the amount of degarelix API in the pharmaceutical composition is from about 31 wt% to about 34 wt% degarelix free base equivalent. In one aspect, the amount of degarelix API in the pharmaceutical composition is from about 31 wt% to about 33 wt% degarelix free base equivalent.
  • the amount of degarelix API in the pharmaceutical composition is from about 31 wt% to about 32 wt% degarelix free base equivalent.
  • the percent by weight of solvent, and the percent by weight of additive if included may be modified accordingly.
  • Biocompatible/biodegradable Polymers include polymers, copolymers and/or terpolymers formed of repeating units, which can be linear, branched, grafted and/or star-shaped.
  • the polymers can comprise monomer residues, such as lactide, glycolide, caprolactone, p-dioxanone, trimethylene carbonate, 1,5-dioxepan-2-one, 1,4-dioxepan-2-one, ethylene oxide, propylene oxide, sebacic anhydride, diketene acetals/diols, lactic acid, and combinations thereof.
  • monomer residues such as lactide, glycolide, caprolactone, p-dioxanone, trimethylene carbonate, 1,5-dioxepan-2-one, 1,4-dioxepan-2-one, ethylene oxide, propylene oxide, sebacic anhydride, diketene acetals/diols, lactic acid, and combinations thereof.
  • Biodegradable polymers suitable for use with the disclosed compositions include, but are not limited to, polylactic acid, polyglycolic acid, polylactide (D-lactide, L- lactide), poly(D,L-lactide) (PLA), polyglycolide, polycaprolactones, poly(D,L-lactide-co- glycolide) (PLG), poly(D,L-lactide-co- ⁇ -caprolactone) (PLC), polyanhydrides, polyamides, polyurethanes, polyesteramides, polyorthoesters, polydioxanones, polyacetals, polyketals, polycarbonates, polyphosphazenes, polyhydroxybutyrates, polyhydroxyvalerates, polyalkylene oxalates, polyalkylene succinates, poly(malic acid), polyglutamic acids, poly(alkyl cyanoacrylates) polyethylene glycol, hyaluronic acid, alginate, collagen, chi
  • the biodegradable polymer may be a copolymer of two monomers having a molar ratio of any two whole numbers X to Y, such that the sum of X and Y is 100.
  • the biodegradable polymer may be a copolymer of two monomers having a molar ratio of any two whole numbers X to Y, where X and Y are each at least about 10 and no more than about 90, such that the sum of X and Y is 100, e.g., a copolymer comprising a 10:90 to 90:10 molar ratio of X:Y.
  • X and Y may be at least about 15 to no more than about 85 such that the sum of X and Y is 100, e.g., a copolymer comprising a 15:85 to 85:15 molar ratio of X:Y.
  • X and Y may be at least about 25 to no more than about 75 such that the sum of X and Y is 100, e.g., a copolymer comprising a 25:75 to 75:25 molar ratio of X:Y.
  • both X and Y may be about 50, e.g., a copolymer comprising a 50:50 molar ratio of X:Y.
  • the biodegradable polymer is a copolymer comprising (a) D,L-lactide, D-lactide, L-lactide or glycolide monomer residues and (b) caprolactone monomer residues.
  • the biodegradable polymer is a copolymer comprising lactide, preferably D,L-lactide, and caprolactone monomer residues.
  • the biodegradable polymer is poly(D,L-lactide-co- ⁇ -caprolactone) (PLC).
  • PLC comprises at least one carboxylic acid end group.
  • the PLC is a carboxylic acid-initiated PLC.
  • the carboxylic acid is glycolic acid or lactic acid.
  • the polymer is a copolymer comprising a molar ratio of lactide (or glycolide) to ⁇ -caprolactone ranging from about 10:90 to about 90:10, from about 20:80 to about 80:20, from about 25:75 to about 75:25, or from about 30:70 to about 70:30.
  • the ratio of lactide (or glycolide) to ⁇ -caprolactone is from about 25:75 to about 75:25.
  • the ratio of lactide (or glycolide) to ⁇ -caprolactone is from about 50:50 to about 75:25.
  • the ratio of lactide (or glycolide) to ⁇ - caprolactone is about 50:50. In still another aspect, the ratio of lactide (or glycolide) to ⁇ - caprolactone is about 75:25. In one aspect, the biodegradable polymer is acid-initiated 75:25 poly(D,L-lactide-co- ⁇ -caprolactone). [00100] In some embodiments, the biodegradable polymer is a copolymer comprising (a) D,L-lactide, D-lactide, L-lactide or glycolide monomer residues and (b) trimethylene carbonate (TMC) monomer residues.
  • TMC trimethylene carbonate
  • the biodegradable polymer is a copolymer comprising lactide, preferably D,L-lactide, and TMC monomer residues.
  • the biodegradable polymer is a copolymer comprising a molar ratio of lactide (or glycolide) to TMC ranging from about 10:90 to about 90:10, from about 20:80 to about 80:20, from about 25:75 to about 75:25, or from about 30:70 to about 70:30.
  • the ratio of lactide (or glycolide) to TMC is from about 25:75 to about 75:25.
  • the ratio of lactide (or glycolide) to TMC is about 50:50.
  • the ratio of lactide (or glycolide) to TMC is about 75:25.
  • the biodegradable polymer is a copolymer comprising (a) D,L-lactide, D-lactide, or L-lactide monomer residues and (b) glycolide monomer residues.
  • the biodegradable polymer is poly(DL-lactide-co-glycolide) (PLG).
  • PLG comprises at least one carboxylic acid end group.
  • the PLG is a core-diol-initiated PLG.
  • the core diol is 1,6-hexane diol.
  • the PLG was initiated with an uncapped polyethylene glycol (PEG).
  • the PLG is a mono functional alcohol-initiated PLG.
  • the mono functional alcohol is dodecanol.
  • the PLG was initiated with a mono- capped PEG (mPEG).
  • the PLG has a molar ratio of lactide monomers to glycolide monomers from about 50:50 to about 90:10.
  • the PLG has a molar ratio of lactide to glycolide monomers from about 45:55 to about 99:1.
  • the PLG copolymer may comprise a lactide to glycolide monomer molar ratio from about 50:50 to about 90:10, from about 50:50 to about 80:20, from about 50:50 to about 70:30, or from about 50:50 to about 75:25. In one aspect the molar ratio of lactide monomers to glycolide monomers is 50:50, 75:25 or 85:15. In one aspect, the biodegradable polymer is acid-initiated 50:50 poly(D,L-lactide-co-glycolide). In another aspect, the biodegradable polymer is 1,6-hexane diol initiated 75:25 poly(D,L-lactide-co-glycolide).
  • the biodegradable polymer is 1,6-hexane diol initiated 85:15 poly(D,L- lactide-co-glycolide). In yet a further aspect, the biodegradable polymer is dodecanol- initiated poly(D,L-lactide). [00102] In some embodiments, the biodegradable polymer is poly(D,L-lactide) (PLA). In one aspect, the (PLA) comprises at least one carboxylic acid end group.
  • suitable polymers include biodegradable polymers comprising a copolymer with lactide (including D,L-lactide, D-lactide, and/or L- lactide) and/or glycolide residues, wherein the molar percentage of the lactide and/or glycolide residues make up greater than about 5% and less than about 95% of the polymer.
  • lactide including D,L-lactide, D-lactide, and/or L- lactide
  • glycolide residues wherein the molar percentage of the lactide and/or glycolide residues make up greater than about 5% and less than about 95% of the polymer.
  • the lactide and/or glycolide monomer residues make up at least about 5%, at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, or at least about 95% of total monomer residues of the copolymer.
  • suitable polymers of the invention include biodegradable polymers comprising a copolymer with caprolactone and/or TMC residues, wherein the caprolactone and/or trimethylene carbonate residues make up in an amount greater than about 5% and less than about 95% of the polymer.
  • the caprolactone and/or TMC monomer residues make up at least about 5%, at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, or at least about 95% of total monomers of the copolymer.
  • the biodegradable polymer may be formed using an initiator selected to provide a desired structure or functionality to the polymer in the form of a particular polymer block structure or end group structure which is introduced and/or incorporated into/onto the biodegradable polymer.
  • the polymer may be formed using an organic acid (e.g., a hydroxy acid such as, for instance, glycolic acid) as the initiator which may result in the formation of a polymer comprising at least one carboxylic acid end group.
  • the polymer may be formed using a monofunctional alcohol (e.g., dodecanol, or monomethoxy endcapped monofunctional polyethylene glycols (PEGs)) as the initiator which may result in the formation of a polymer comprising at least one hydroxy end group.
  • a monofunctional alcohol e.g., dodecanol, or monomethoxy endcapped monofunctional polyethylene glycols (PEGs)
  • PEGs monomethoxy endcapped monofunctional polyethylene glycols
  • the polymer may be formed using a diol (e.g., hexanediol, PEG300, PEG400, PEG600) as the initiator which may result in the formation of a polymer comprising at least one hydroxy end group and that is also substantially free of terminal carboxy end groups.
  • the biodegradable polymer may be formed using an initiator selected to provide a desired structure, and in particular a desired polymer block structure or end group structure, to the biodegradable polymer.
  • the polymer may be formed using a low-molecular weight PEG (e.g., the above-mentioned PEG300, PEG400 or PEG600) as an initiator, which may result in the formation of a block copolymer comprising a low-molecular weight PEG block.
  • block A may comprise first monomer residues selected from D,L- lactide, D-lactide, or L-lactide, and second monomer residues selected from glycolide, ⁇ - caprolactone, or trimethylene carbonate.
  • Block B comprises a low-molecular weight polyethylene glycol (PEG).
  • the blocks may be arranged in any number or order (e.g. as a di-block copolymer A-B, or a tri-block copolymer A-B-A or B-A-B). Such polymers are formed by initiation of the first and second monomer residues with a low-molecular weight PEG initiator.
  • biodegradable polymers suitable for use in formulations according to the present invention may, generally, comprise a weight average molecular weight ranging from about 1 kDa and about 100 kDa.
  • the biodegradable polymer may comprise a weight average molecular weight ranging from about 1 kDa to about 5 kDa, from about 1 kDa to about 10 kDa, from about 1 kDa to about 15 kDa, from about 1 kDa to about 20 kDa, from about 1 kDa to about 25 kDa, from about 1 kDa to about 30 kDa, from about 1 kDa to about 40 kDa, from about 1 kDa to about 50 kDa, from about 1 kDa to about 60 kDa, from about 1 kDa to about 70 kDa, from about 1 kDa to about 80 kDa, from about 1 kDa to about 90
  • the weight average molecular weight is from about 5 kDa to about 60 kDa. In one aspect, the weight average molecular weight is from about 5 kDa to about 55 kDa. In one aspect, the weight average molecular weight is from about 5 kDa to about 50 kDa. In one aspect, the weight average molecular weight is from about 5 kDa to about 45 kDa. In one aspect, the weight average molecular weight is from about 5 kDa to about 40 kDa. In still another aspect, the weight average molecular weight is from about 5 kDa to 35 kDa.
  • the biodegradable polymer may make up about 10 wt%, about 15 wt%, about 20 wt%, about 25 wt%, about 30 wt%, about 35 wt%, about 40 wt%, about 45 wt%, about 50 wt%, about 55 wt%, or about 60 wt% of the composition.
  • the biodegradable polymer may make up about 20 wt%, about 25 wt%, or about 30 wt% of the composition.
  • the biodegradable polymer may make up any whole-number weight percentage of the composition from about 10 wt% to about 60 wt%.
  • the biodegradable polymer may make up any tenth of a whole number percent of the composition from about 10 wt% to about 60 wt%.
  • the biodegradable polymers may optionally be purified prior to use in the long-acting formulation to remove low-molecular weight oligomers and/or unreacted monomers, and/or catalyst.
  • purifying polymers include the methods described in U.S. Pat. No. 4,810,775, U.S. Patent No. 7,019,106, and U.S. Patent No. 9,187,593, among others.
  • the biocompatible polymer comprises less than about 0.5%, or less than about 0.4%, or less than about 0.3%, or less than about 0.2% or less than about 0.1% unreacted monomers. In some embodiments of the composition, the biocompatible polymer comprises less than about 0.5%, or less than about 0.4%, or less than about 0.3%, or less than about 0.2% or less than about 0.1% unreacted lactide monomer.
  • Biocompatible Solvents Any suitable water-miscible solvent can be employed, provided the solvent is biocompatible, and miscible to dispersible in aqueous medium or body fluid. Examples of suitable solvents are disclosed, e.g., in Aldrich Handbook of Fine Chemicals and Laboratory Equipment, Milwaukee, Wis.
  • the solvent is able to diffuse into body fluid so that the flowable polymer-based composition coagulates, gels or solidifies.
  • the solvent may or may not dissolve the polymer, although it is preferred that the solvent dissolves the polymer.
  • Solvents and co-solvents that may be used in the disclosed compositions are preferably biocompatible, non-toxic, solvents, which may be either hydrophilic or hydrophobic solvents, or may be a combination of hydrophilic solvents, hydrophobic solvents or hydrophilic and hydrophobic solvents, depending upon the desired release profile and the solubility of the polymer and/or the degarelix API in the polymer/solvent composition.
  • the solvent and/or co-solvent is an organic solvent.
  • the solvent and/or co-solvents is a polar aprotic solvent.
  • Suitable solvents and co-solvents may comprise one or more solvents selected from the group consisting of amides, acids, alcohols, esters of monobasic acids, ether alcohols, sulfoxides, lactones, polyhydroxy alcohols, esters of polyhydroxy alcohols, ketones, and ethers.
  • the solvents or cosolvents may comprise at least one of N-methyl-2-pyrrolidone (NMP), dimethyl sulfoxide (DMSO), dimethylacetamide (DMA), acetone, benzyl benzoate (BnBzO), polyethylene glycol 15 hydroxystearate, ethyl acetate, glycofurol, N-hydroxyethyl-2-pyrrolidone, polyethylene glycol (PEG), benzyl alcohol, propylene carbonate (PC), propylene glycol, 2-pyrrolidone, ⁇ -tocopherol, triacetin, tributyl citrate, acetyl tributyl citrate, acetyl triethyl citrate, triethyl citrate, and combinations thereof.
  • NMP N-methyl-2-pyrrolidone
  • DMSO dimethyl sulfoxide
  • DMA dimethylacetamide
  • acetone benzyl benzoate
  • a suitable solvent is selected from N-methyl-2- pyrrolidone (NMP) and/or dimethyl sulfoxide (DMSO).
  • NMP N-methyl-2- pyrrolidone
  • DMSO dimethyl sulfoxide
  • the biodegradable polymer is dissolved in the biocompatible solvent or combination or mixture of solvents and/or co-solvents.
  • the degarelix or pharmaceutically acceptable salt thereof may be dissolved in a first biocompatible solvent and the biodegradable polymer may be dissolved in a second biocompatible solvent.
  • the first and second biocompatible solvents are the same.
  • the biodegradable polymer is dissolved in the biocompatible solvent, and the degarelix or pharmaceutically acceptable salt thereof is not dissolved in the solvent, but is provided in lyophilized or other dry form.
  • the biocompatible solvent, or combination or mixture of solvents and/or co- solvents used in a composition of the invention will generally comprise between about 20 wt% and about 80 wt% of the final formulation, or between about 30 wt% and about 70 wt% of the final formulation, or between about 40 wt% and about 60 wt% of the final formulation, or alternatively the solvent or combination or mixture of solvents and/or co- solvents can range from any whole number percentage by weight of the formulation to any other whole number percentage by weight of the final formulation between about 20 wt% and about 80 wt%.
  • the pharmaceutical compositions disclosed herein may comprise various additives (which may also be referred to as “excipients”) to improve the stability, the injectability, or/and other properties of the composition.
  • the pharmaceutical compositions may comprise one or more of antioxidants, chelating agents, surfactants, co-solvents (also discussed above), stabilizers, complexing agents, antioxidants, and solubilizers.
  • the pharmaceutical compositions may comprise one or more solubilizers to increases the solubility of one or more other component of the composition.
  • Solubilizers useful in the disclosed compositions include any solubilizer useful for parenteral injection, and include, but are not limited to, surfactants which lower the surface tension between two liquids, between a gas and a liquid, or between a liquid and a solid and other solubilizers.
  • solubilizers and/or surfactants for use in the invention include, but are not limited to, polysorbate 20, polysorbate 80, poloxamer 188, sorbitan trioleate, lecithin (e.g., soya or egg), Vitamin E TPGS, sugar based esters or ethers (e.g., sugar acid esters of fatty alcohols or sugar alcohol esters of fatty acids, including, but not limited to, sucrose cocoate, sucrose stearate, sucrose laurate, etc.), amino acid-based solubility enhancers (e.g., proline, arginine, DL-methionine), protein-based solubility enhancers (e.g., hydrophobins), and others.
  • sugar based esters or ethers e.g., sugar acid esters of fatty alcohols or sugar alcohol esters of fatty acids, including, but not limited to, sucrose cocoate, sucrose stearate, sucrose laurate, etc.
  • the pharmaceutical compositions may comprise one or more antioxidants to inhibit oxidation of the API and improve the stability of the formulation.
  • suitable antioxidants for use in the invention include, but are not limited to, citric acid, methanesulfonic acid, ascorbic acid, ethylenediaminotetraacetic acid (EDTA), mercaptoethanol, sodium metabisulfite butylated hydroxyanisole, butylated hydroxyquinone, butylhydroxyanisol, hydroxycoumarin, butylated hydroxytoluene, cephalm, ethyl gallate, propyl gallate, octyl gallate, lauryl gallate, propyl-hydroxybenzoate, trihydroxybutylrophenone, dimethylphenol, dibutylphenol, vitamin E, lecithin and ethanolamine.
  • the pharmaceutical compositions may comprise one or more complexing agents to inhibit oxidation and/or degradation of the API and improve the stability of the formulation.
  • suitable complexing agents for use in the invention include, but are not limited to, ethylenediaminotetraacetic acid (EDTA), divalent metal salts (ZnCl 2 , MgCl 2 , CaCl 2 ), nitrilotriacetic acid, n-hydroxyethylethylenediaminetriacetic acid (HEDTA), ethylene glycol-bis( ⁇ -aminoethyl ether)-N,N,N′,N′-tetraacetic acid (EGTA) as well as several simple organic acids, such as, polycarboxylic acid (citric acid), hydrochloric acid, sulfuric acid, pamoic acid, and palmitic acid.
  • EDTA ethylenediaminotetraacetic acid
  • ZnCl 2 , MgCl 2 , CaCl 2 divalent metal salts
  • HEDTA n
  • the pharmaceutical compositions may comprise one or more stabilizing agents to prevent drug and/or polymer degradation (physical or chemical) and improve the stability of the formulation and increase shelf life.
  • stabilizing agents include, but are not limited to: surfactants (e.g., polysorbate 20, polysorbate 80, poloxamer 188), complexing agents (e.g., divalent metal salts), acid additives (e.g., acetic acid, citric acid, succinic acid, methane sulfonic acid, sulfuric acid, hydrochloric acid, pamoic acid, palmitic acid, hydrobromic acid, nitric acid, chromic acid, trifluoroethanes sulfonic acid, trichloroacetic acid, dichloroacetic acid, bromoacetic acid, chloroacetic acid, cyanoacetic acid, 2-chloropropanoic acid, 4-cyanobutanoic acid, perchloric acid, phosphoric acid, hydrogen iodide, and combinations
  • compositions comprising degarelix or a pharmaceutically acceptable salt thereof, a biocompatible and biodegradable polymer, a biocompatible solvent, and optionally one or more additives. All such compositions are contemplated for administration to a subject to treat a disease or condition for which administration of a GnRH agonist or GnRH antagonist may be useful.
  • compositions of the invention are contemplated for use to treat prostate cancer, including advanced prostate cancer; to treat central precocious puberty (CPP); to treat pre-menopausal or peri-menopausal breast cancer; or to treat other conditions, including, but not limited to endometriosis or uterine fibroids.
  • compositions are contemplated for administration to a subject to reduce luteinizing hormone (LH) levels in a subject, to reduce follicle stimulating hormone (FSH) levels in a subject, and in males, to reduce serum testosterone levels, and in females, to reduce serum estrogen levels.
  • LH luteinizing hormone
  • FSH follicle stimulating hormone
  • the degarelix or a pharmaceutically acceptable salt thereof in the disclosed compositions may form a monophasic mixture (e.g., a solution) or a biphasic mixture (e.g., a suspension or a dispersion) within the composition.
  • the extended release compositions comprising the degarelix or pharmaceutically acceptable salt thereof, according to the present invention may appropriately be either a “solution”, or a “dispersion”, or a “suspension” of the degarelix or pharmaceutically acceptable salt thereof, in the solvent or in the combination of the biodegradable polymer and the solvent.
  • the degarelix or pharmaceutically acceptable salt thereof may in some embodiments be dissolved in solvent (as in a solution), or in the combination of polymer and solvent (as in a solution), or form solid particles sufficiently large for suspension and sedimentation as part of a heterogeneous mixture (as in a suspension or dispersion).
  • the degarelix or pharmaceutically acceptable salt thereof is dissolved in the solvent when in the absence of the biocompatible polymer, and, when mixed in combination with the solvent(s) and the biocompatible polymer, may be in suspension or dispersion, or partial suspension, where some of the degarelix or pharmaceutically acceptable salt remains in solution and some is in suspension or dispersion.
  • the polymer- solvent system composition may be a liquid-liquid dispersion.
  • types of dispersions may include liquid-in oil, oil-in liquid, or oil-in-oil dispersions.
  • the polymer-solvent system composition may be an emulsion.
  • the degarelix API is a stable solution and stays in solution in the biocompatible solvent and thus little or no reconstitution or mixing is needed to maintain the stable solution.
  • the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising in the final formulation: (a) between about 10 wt% and about 30 wt% of a pharmaceutically acceptable salt of degarelix; (b) between about 20 wt% and about 80 wt% of N-methyl-2-pyrrolidone (NMP); and (c) between about 10 wt% and about 50 wt% of 75:25 poly(lactide-co- ⁇ -caprolactone) (PLC) copolymer, where the total weight percent of each of the components in the formulation equals 100% (e.g., if the amount of degarelix salt in the formulation is 20 wt%, then the total amount of polymer and solvent in the formulation, absent any additives, is 80 wt%).
  • PLC poly(lactide-co- ⁇ -caprolactone)
  • the PLC copolymer has at least one carboxylic acid end group. In one aspect, the PLC copolymer has a weight average molecular weight of between about 5 kDa and about 30 kDa. In one aspect, the pharmaceutically acceptable salt of degarelix is selected from degarelix acetate and degarelix citrate.
  • the present disclosure provides a pharmaceutical composition
  • a pharmaceutical composition comprising about 16 wt% of degarelix acetate; about 57 wt% of N-methyl-2- pyrrolidone (NMP); and about 27 wt% of 75:25 poly(lactide-co- ⁇ -caprolactone) (PLC) copolymer having at least one carboxylic acid end group and having a weight average molecular weight of about 17 kDa.
  • the present disclosure provides a pharmaceutical composition
  • a pharmaceutical composition comprising about 16 wt% of degarelix acetate; about 57 wt% of NMP; and about 27 wt% of 75:25 PLC copolymer having at least one carboxylic acid end group and having a weight average molecular weight of about 8 kDa.
  • the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising a first container comprising 30-70 wt% of 75:25 PLC copolymer having at least one carboxylic acid end group and having a weight average molecular weight of 5-30 kDa, and 30-70 wt% of N-methyl-2-pyrrolidone (NMP); and a second container comprising 20-40 wt% of a pharmaceutically acceptable salt of degarelix and 60-80 wt% NMP.
  • the pharmaceutically acceptable salt of degarelix is selected from degarelix acetate and degarelix citrate.
  • the first and second containers are a first and second syringe, respectively.
  • the first and second containers are a first and second chamber of a dual-chambered syringe, respectively.
  • the present disclosure provides a pharmaceutical composition comprising a first container comprising 50 wt% of 75:25 PLC copolymer having at least one carboxylic acid end group and having a weight average molecular weight of 17 kDa, and 50 wt% of N-methyl-2-pyrrolidone (NMP); and a second container comprising 35 wt% of degarelix acetate and 65 wt% NMP.
  • the first and second containers are a first and second syringe, respectively.
  • the first and second containers are a first and second chamber of a dual-chambered syringe, respectively.
  • the present disclosure provides a pharmaceutical composition comprising: a first container comprising 70 wt% of 75:25 PLC copolymer having at least one carboxylic acid end group and having a weight average molecular weight of 8 kDa, and 30 wt% of NMP; and a second container comprising 35 wt% of degarelix acetate and 65 wt% NMP.
  • the first and second containers are a first and second syringe, respectively.
  • the first and second containers are a first and second chamber of a dual-chambered syringe, respectively.
  • the present invention provides a pharmaceutical composition comprising in the final formulation between about 10 wt% and about 30 wt% of a pharmaceutically acceptable salt of degarelix; between about 20 wt% and about 80 wt% of N-methyl-2-pyrrolidone (NMP); and between about 10 wt% and about 50 wt% of 75:25 poly(D,L-lactide) (PLA) polymer, where the total weight percent of each of the components in the formulation equals 100% (e.g., if the amount of degarelix salt in the formulation is 20 wt%, then the total amount of polymer and solvent in the formulation, absent any additives, is 80 wt%).
  • NMP N-methyl-2-pyrrolidone
  • PLA poly(D,L-lactide)
  • the PLA polymer has at least one carboxylic acid end group. In one aspect, the PLA polymer has a weight average molecular weight of between about 5 kDa and about 30 kDa. In one aspect, the pharmaceutically acceptable salt of degarelix is selected from degarelix acetate and degarelix citrate. [00127] In some embodiments, the present disclosure provides a pharmaceutical composition comprising about 16 wt% of degarelix acetate; about 57 wt% of NMP; and about 27 wt% of poly(D,L-lactide) (PLA) polymer having at least one carboxylic acid end group and having a weight average molecular weight of about 23 kDa.
  • PLA poly(D,L-lactide)
  • the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising a first container comprising 30-70 wt% of 75:25 PLA polymer having at least one carboxylic acid end group and having a weight average molecular weight of 5-30 kDa, and 30-70 wt% of N-methyl-2-pyrrolidone (NMP); and a second container comprising 20-40 wt% of a pharmaceutically acceptable salt of degarelix and 60-80 wt% NMP.
  • the pharmaceutically acceptable salt of degarelix is selected from degarelix acetate and degarelix citrate.
  • the first and second containers are a first and second syringe, respectively.
  • the first and second containers are a first and second chamber of a dual-chambered syringe, respectively.
  • the present disclosure provides a pharmaceutical composition comprising a first container comprising 50 wt% of PLA polymer having at least one carboxylic acid end group and having a weight average molecular weight of 23 kDa, and 50 wt% of NMP; and a second container comprising 35 wt% of degarelix acetate and 65 wt% NMP.
  • the first and second containers are a first and second syringe, respectively.
  • the first and second containers are a first and second chamber of a dual-chambered syringe, respectively.
  • the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising in the final formulation between about 10 wt% and about 30 wt% of a pharmaceutically acceptable salt of degarelix; between about 20 wt% and about 80 wt% of N-methyl-2-pyrrolidone (NMP); and between about 10 wt% and about 50 wt% of 75:25 poly(D,L-lactide-co-glycolide) (PLG) copolymer, where the total weight percent of each of the components in the formulation equals 100% (e.g., if the amount of degarelix salt in the formulation is 20 wt%, then the total amount of polymer and solvent in the formulation, absent any additives, is 80 wt%).
  • NMP N-methyl-2-pyrrolidone
  • PLG poly(D,L-lactide-co-glycolide) copolymer
  • the PLG copolymer has at least one carboxylic acid end group. In one aspect, the PLG copolymer has a weight average molecular weight of between about 5 kDa and about 30 kDa. In one aspect, the pharmaceutically acceptable salt of degarelix is selected from degarelix acetate and degarelix citrate.
  • the present disclosure provides a pharmaceutical composition
  • a pharmaceutical composition comprising about 16 wt% of degarelix acetate; about 57 wt% of NMP; and about 27 wt% of 75:25 poly(D,L-lactide-co-glycolide) (PLG) copolymer having at least one carboxylic acid end group and having a weight average molecular weight of about 17 kDa.
  • PLG poly(D,L-lactide-co-glycolide)
  • the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising a first container comprising 30-70 wt% of 75:25 PLG polymer having at least one carboxylic acid end group and having a weight average molecular weight of 5-30 kDa, and 30-70 wt% of N-methyl-2-pyrrolidone (NMP); and a second container comprising 20-40 wt% of a pharmaceutically acceptable salt of degarelix and 60-80 wt% NMP.
  • the pharmaceutically acceptable salt of degarelix is selected from degarelix acetate and degarelix citrate.
  • the first and second containers are a first and second syringe, respectively.
  • the first and second containers are a first and second chamber of a dual-chambered syringe, respectively.
  • the present disclosure provides a pharmaceutical composition comprising: a first container comprising 50 wt% of 75:25 PLG copolymer having at least one carboxylic acid end group and having a weight average molecular weight of 17 kDa, and 50 wt% of NMP; and a second container comprising 35 wt% of degarelix acetate and 65 wt% NMP.
  • the first and second containers are a first and second syringe, respectively.
  • the first and second containers are a first and second chamber of a dual-chambered syringe, respectively.
  • the present invention provides a pharmaceutical composition comprising in the final formulation between about 10 wt% and about 30 wt% of a pharmaceutically acceptable salt of degarelix; between about 20 wt% and about 80 wt% of N-methyl-2-pyrrolidone (NMP); and between about 10 wt% and about 50 wt% of 75:25 poly(D,L-lactide-co-glycolide) (PLG) copolymer, where the total weight percent of each of the components in the formulation equals 100% (e.g., if the amount of degarelix salt in the formulation is 20 wt%, then the total amount of polymer and solvent in the formulation, absent any additives, is 80 wt%).
  • NMP N-methyl-2-pyrrolidone
  • PLG poly(D,L-lactide-co-glycolide) copolymer
  • the PLG copolymer has at least one hydroxyl end group. In one aspect, the PLG copolymer has a weight average molecular weight of between about 5 kDa and about 30 kDa. In one aspect, the pharmaceutically acceptable salt of degarelix is selected from degarelix acetate and degarelix citrate. [00135] In some embodiments, the present disclosure provides a pharmaceutical composition comprising about 16 wt% of degarelix acetate; about 57 wt% of NMP; and about 27 wt% of 75:25 PLG copolymer having at least one hydroxyl end group and having a weight average molecular weight of about 19 kDa.
  • the present disclosure provides a pharmaceutical composition
  • a pharmaceutical composition comprising about 16 wt% of degarelix citrate; about 57 wt% of NMP; and about 27 wt% of 75:25 PLG copolymer having at least one hydroxyl end group and having a weight average molecular weight of about 19 kDa.
  • the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising a first container comprising 30-70 wt% of 75:25 PLG polymer having at least one hydroxyl end group and having a weight average molecular weight of 5- 30 kDa, and 30-70 wt% of N-methyl-2-pyrrolidone (NMP); and a second container comprising 20-40 wt% of a pharmaceutically acceptable salt of degarelix and 60-80 wt% NMP.
  • the pharmaceutically acceptable salt of degarelix is selected from degarelix acetate and degarelix citrate.
  • the first and second containers are a first and second syringe, respectively.
  • the first and second containers are a first and second chamber of a dual-chambered syringe, respectively.
  • the present disclosure provides a pharmaceutical composition comprising a first container comprising 50 wt% of 75:25 PLG copolymer having at least one hydroxyl end group and having a weight average molecular weight of 19 kDa, and 50 wt% of NMP; and a second container comprising 35 wt% of degarelix acetate and 65 wt% NMP.
  • the present disclosure provides a pharmaceutical composition
  • a pharmaceutical composition comprising a first container comprising 50 wt% of 75:25 PLG copolymer having at least one hydroxyl end group and having a weight average molecular weight of 19 kDa, and 50 wt% of NMP; and a second container comprising 35 wt% of degarelix citrate and 65 wt% NMP.
  • the first and second containers are a first and second syringe, respectively.
  • the first and second containers are a first and second chamber of a dual-chambered syringe, respectively.
  • the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising in the final formulation between about 10 wt% and about 30 wt% of a pharmaceutically acceptable salt of degarelix; between about 20 wt% and about 80 wt% of N-methyl-2-pyrrolidone (NMP); between about 10 wt% and 40 wt% of DMSO, and between about 10 wt% and about 50 wt% of 75:25 poly(D,L-lactide-co-glycolide) (PLG) copolymer, where the total weight percent of each of the components in the formulation equals 100% (e.g., if the amount of degarelix salt in the formulation is 20 wt%, then the total amount of polymer and solvents in the formulation, absent any additives, is 80 wt%).
  • NMP N-methyl-2-pyrrolidone
  • PLG poly(D,L-lactide-co-glycolide) copolymer
  • the PLG copolymer has at least one hydroxyl end group. In one aspect, the PLG copolymer has a weight average molecular weight of between about 5 kDa and about 30 kDa. In one aspect, the pharmaceutically acceptable salt of degarelix is selected from degarelix acetate and degarelix citrate. [00141] In some embodiments, the present disclosure provides a pharmaceutical composition comprising about 16 wt% of degarelix acetate; about 30 wt% of NMP; about 27 wt% of DMSO; and about 27 wt% of 75:25 PLG copolymer having at least one hydroxyl end group and having a weight average molecular weight of about 19 kDa.
  • the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising a first container comprising 30-70 wt% of 75:25 PLG polymer having at least one hydroxyl end group and having a weight average molecular weight of 5- 30 kDa, and 30-70 wt% of N-methyl-2-pyrrolidone (NMP); and a second container comprising 20-40 wt% of a pharmaceutically acceptable salt of degarelix and 60-80 wt% DMSO.
  • the pharmaceutically acceptable salt of degarelix is selected from degarelix acetate and degarelix citrate.
  • the first and second containers are a first and second syringe, respectively.
  • the first and second containers are a first and second chamber of a dual-chambered syringe, respectively.
  • the present disclosure provides a pharmaceutical composition comprising a first container comprising 50 wt% of 75:25 PLG copolymer having at least one hydroxyl end group and having a weight average molecular weight of 19 kDa, and 50 wt% of NMP; and a second container comprising 35 wt% of degarelix acetate and 65 wt% DMSO.
  • the first and second containers are a first and second syringe, respectively.
  • the first and second containers are a first and second chamber of a dual-chambered syringe, respectively.
  • the amount of degarelix or the pharmaceutically acceptable salt thereof in the pharmaceutical composition is from about 8 wt% to about 39 wt% degarelix free base equivalent. In one aspect, the amount of degarelix or the pharmaceutically acceptable salt thereof in the pharmaceutical composition is from about 17 wt% to about 39 wt% degarelix free base equivalent. In one aspect, the amount of degarelix or the pharmaceutically acceptable salt thereof in the pharmaceutical composition is from about 8 wt% to about 29 wt% degarelix free base equivalent.
  • the amount of degarelix or the pharmaceutically acceptable salt thereof in the pharmaceutical composition is from about 8 wt% to about 20 wt% degarelix free base equivalent. In one aspect, the amount of degarelix or the pharmaceutically acceptable salt thereof in the pharmaceutical composition is from about 10 wt% to about 16 wt% degarelix free base equivalent. In one aspect, the amount of degarelix or the pharmaceutically acceptable salt thereof in the pharmaceutical composition is from about 14 wt% to about 15.5 wt% degarelix free base equivalent. In one aspect, the amount of degarelix or a pharmaceutically acceptable salt thereof (degarelix API) in a composition of the invention is from about 30 wt% to about 35 wt% degarelix free base equivalent.
  • the amount of degarelix API in the pharmaceutical composition is from about 31 wt% to about 34 wt% degarelix free base equivalent. In one aspect, the amount of degarelix API in the pharmaceutical composition is from about 31 wt% to about 33 wt% degarelix free base equivalent. In one aspect, the amount of degarelix API in the pharmaceutical composition is from about 31 wt% to about 32 wt% degarelix free base equivalent.
  • unreacted lactide, caprolactone, and/or glycolide monomers in the polymers or copolymers are less than about 1.0 wt%, less than about 0.5 wt%, than about 0.4 wt %, less than about 0.3 wt %, less than about 0.2 wt% and less than about 0.1 wt%.
  • the first and/or second container may be a syringe as disclosed herein.
  • the first and second containers are a first and second syringe, respectively.
  • the first and second containers are a first and second chamber of a dual-chambered syringe, respectively.
  • the methods of this disclosure are used in the treatment of diseases or conditions including prostate cancer, including advanced prostate cancer.
  • the methods of this disclosure are used in reducing serum testosterone levels in a subject to a level below a castrate level of at least 50 ng/dL, or below 20 ng/dL or below 10 ng/dL.
  • the compositions disclosed herein suppresses the subject’s luteinizing hormone (LH), which in one aspect, is reduced to a level less than about 4 IU/L.
  • the methods of this disclosure are used in suppressing ovarian function in a subject with hormone-receptor positive breast cancer.
  • the hormone receptor positive breast cancer is pre-menopausal breast cancer. In one aspect, the hormone receptor positive breast cancer is peri-menopausal breast cancer. In one aspect, the hormone receptor positive breast cancer is estrogen receptor (ER) positive breast cancer. In one aspect, the compositions disclosed herein suppress a subject’s estradiol (E2) production to a level less than about 20 pg/mL, less than about 15 pg/mL, less than about 10 pg/mL, less than about 5 pg/mL, less than about 4 pg/ml, less than about 3 pg/mL, or less than about 2 pg/mL.
  • E2 estradiol
  • the E2 production level is reduced to about 2.7 pg/mL.
  • the compositions disclosed herein suppresses the breast cancer subject’s follicle stimulating hormone (FSH) to a level less than about 40 IU/L.
  • the compositions disclosed herein suppresses the breast cancer subject’s luteinizing hormone (LH) to a level less than about 4 IU/L.
  • the methods of this disclosure are used in treating endometriosis or uterine fibroids.
  • the methods of this disclosure are used in the treatment of central precocious puberty (CPP).
  • CPP is defined by early sexual development prompted by production and release of gonadotropins and/or sex steroids from normal endogenous sources including the hypothalamus or pituitary. Aberrations in gonadotropin and/or sex hormone concentration levels in children with CPP can result from various sources, including, but not limited to, physical injury, infection, genetic disease, or associated tumors. CPP caused by a genetic or undetermined pathology is classified to be idiopathic in nature, while CPP caused by a central nervous system (CNS) tumor and/or lesion is classified as organic in nature. CPP is accompanied by advanced bone age, accelerated growth velocity, and Hypothalamic- Pituitary-Gonadal-axis activation.
  • CNS central nervous system
  • the compositions disclosed herein reduce a subject having CPP blood serum LH concentration to a pre-pubertal concentration levels of ⁇ 4 IU/L.
  • the methods comprise subcutaneously or intramuscularly administering a disclosed long-acting injectable composition to a subject/patient suffering from prostate cancer, advanced prostate cancer, CPP, pre-menopausal breast cancer, post-menopausal breast cancer, as well as those subjects in need of reducing serum testosterone levels, estradiol levels, or LH levels.
  • an aqueous environment e.g.
  • the solvent dissipates in situ, and a solid, semi-solid, or liquid depot is formed comprising the biodegradable polymer and the degarelix API (self-aggregation or gelation of degarelix or pharmaceutically acceptable salt thereof occurs), together forming a drug reservoir or depot.
  • the resulting depot will release the degarelix or a pharmaceutically acceptable salt thereof, over a desired extended time period.
  • the degarelix or a pharmaceutically acceptable salt thereof is released into a subject/patient, for example, for a period of at least about 30 days or longer, at least about 60 days or longer, at least about 90 days or longer, at least about 120 days or longer, at least about 150 days or longer, or 180 days or longer.
  • the degarelix or a pharmaceutically acceptable salt thereof is released into a subject/patient, for example, for a period of at least about one month or longer, at least about two months or longer, at least about three months or longer, at least about four months or longer, at least about five months or longer, or six months or longer.
  • the degarelix or a pharmaceutically acceptable salt thereof is released into a subject/patient for a period of at least about four weeks or longer, at least about eight weeks or longer, at least about twelve weeks or longer, at least about sixteen weeks or longer, at least about 20 weeks or longer, or at least about 24 weeks or longer.
  • the long-acting composition may be administered to the patient/subject once about every 30 days, once about every 60 days, once about every 90 days, once about every 120 days, once about every 150 days, or once about every 180 days.
  • the long-acting composition may be administered to the patient/subject once about every 1 month, once about every 2 months, once about every 3 months, once about every 4 months, once about every 5 months, or once about every 6 months.
  • the composition is administered once about every 3 months.
  • the long-acting composition may be administered to the patient/subject once about every four weeks, once about every eight weeks, once about every twelve weeks, once about every sixteen weeks, once about every 20 weeks, or once about every 24 weeks.
  • a “month” can have between 28 and 31 days.
  • the amount of degarelix or a pharmaceutically acceptable salt thereof, that will be effective in the treatment or reduction of the above diseases or conditions, will depend on the nature/severity of the condition or symptom. In vitro or in vivo assays may optionally be employed to help identify optimal dosage ranges.
  • the amount of degarelix or a pharmaceutically acceptable salt thereof, administered will, of course, be dependent on, among other factors, the subject being treated, the age/weight of the subject, the severity of the affliction, the manner of administration and the judgment of the prescribing physician.
  • the dose amount of degarelix or a pharmaceutically acceptable salt thereof for treating prostate cancer and/or advanced prostate cancer, in the composition is administered in a dose amount of about 20 mg, about 25 mg, about 30 mg, about 35 mg, 40 mg, about 45 mg, about 50 mg, about 55 mg, about 60 mg, about 65 mg, about 70 mg, about 75 mg, about 80 mg, about 85 mg, about 90 mg, about 95 mg, about 100 mg, about 110 mg, about 120 mg, 125 mg, about 130 mg, about 135 mg, about 140 mg, about 145 mg, about 150 mg, about 155 mg, about 160 mg, about 165 mg, about 170 mg, about 175 mg, about 180 mg, about 185 mg, about 190 mg, about 195 mg, about 200 mg, about 210 mg, about 220 mg, about 225, about 230 mg, about 235 mg, about 240 mg, about 245 mg, about 250 mg, about 255 mg, about 260 mg, about 265 mg, about 270 mg, about 275 mg, about
  • a single dose may be administered in one injection. In still another aspect, a single dose may be administered in more than one injection.
  • the disclosed compositions are to be administered to a subject/patient once in a dosing period with varying durations between dosing (e.g., one month, 2 months, 3 months, 4 months, 5 months, or 6 months). In one aspect, the disclosed compositions are to be administered to a subject/patient in an initial loading dose followed by one or more maintenance doses of the disclosed compositions. Dosing may be provided alone or in combination with other drugs and may continue as long as required for effective treatment of the disease state or disorder. In some embodiments, the disclosed compositions are formulated to provide doses between about 20 mg – 500 mg.
  • the disclosed compositions are formulated to provide single doses of between about 40 mg – 500 mg. In some embodiments, the disclosed compositions are formulated to provide single doses of between about 80 mg – 500 mg. In some embodiments, the disclosed compositions are formulated to provide single doses of between about 120 mg – 500 mg. In some embodiments, the disclosed compositions are formulated to provide single doses between about 240 mg – 500 mg. In each of these embodiments, the composition is delivered in a total volume or per injection volume not to exceed 2.5 mL or not to exceed 2 mL.
  • the injection volume is about 2.5 mL or less, about 2.4 mL or less, about 2.3 mL or less, about 2.2 mL or less, about 2.1 mL or less, about 2.0 mL or less, about 1.9 mL or less, about 1.8 mL or less, about 1.75 mL or less, about 1.7 mL or less, about 1.6 mL or less, 1.5 mL or less, about 1.4 mL or less, about 1.3 mL or less, about 1.2 mL or less, about 1.1 mL or less, about 1 mL or less, about 0.75 mL or less, about 0.5 mL or less, or about 0.375 mL.
  • the injection volume is about 0.375 ml, about 0.5 ml, about 0.75 ml, about 1 ml, about 1.5 ml, or about 1.75 mL, or about 2 mL, or about 2.2 mL, or about 2.5 mL .
  • a single dose of the composition is administered to the patient in a single injection (i.e., multiple injections are not required in a single dosing period), where the injection volume is 2.5 mL or less, 2 mL or less, about 1.75 mL or less, 1.5 mL or less, about 1 mL or less, about 0.5 mL or less, or about 0.375 mL.
  • the composition is terminally sterilized such as by e-beam or Gamma irradiation or X-ray. In yet another aspect, the composition is sterile filtered. [00158] In some embodiments, the long-acting composition is administered as a monotherapy to patients. The therapeutic methods of this embodiment may reduce or eliminate one or more symptoms of the disease and/or condition disclosed herein.
  • the long-acting composition may be administered as a combination therapy, such as with chemotherapeutics, radiation therapy, surgery, endocrine therapies such as selective estrogen receptor modulators (SERMs; such as tamoxifen, toremifene, raloxifene, ospemifene, and apeledoxifene), selective estrogen receptor degraders (SERDs; such as fulvestrant), aromatase inhibitors (AIs; such as anastrozole, letrozole, exemestane, vorozole, formestane, and fadrozole); mammalian target of rapamycin (mTOR) inhibitors; such as temsirolimus, sirolimus, everolimus, and ridaforolimus); Phosphatidylinositol 3-kinases inhibitors (PI-3 kinase or PI3K; such as alpelisib, idelalisib, and buparlisib
  • the disclosed long-acting composition may be provided as a part of a delivery system comprising a syringe system, wherein the composition or formulation is contained within a syringe.
  • the syringe is a pre-filled syringe system containing the disclosed composition as a single dose or as multiple doses.
  • the syringe is a mixing syringe (e.g., a syringe that provides a mechanism for mixing the formulation contained therein, as needed).
  • the syringe is a dual-chambered syringe, and the disclosed composition is contained within one chamber of the syringe.
  • the syringe is a dual-chambered syringe, and the biodegradable polymer and biocompatible solvent are contained in one chamber of the syringe and the degarelix or pharmaceutically acceptable salt thereof is contained in the second chamber of the syringe.
  • the degarelix or a pharmaceutically acceptable salt thereof may be in a lyophilized form or may be dissolved or suspended in a biocompatible solvent, which may be the same as the biocompatible solvent that is used to dissolve the biodegradable polymer, or which may be different than the biocompatible solvent that is used to dissolve the biodegradable polymer.
  • a biocompatible solvent which may be the same as the biocompatible solvent that is used to dissolve the biodegradable polymer, or which may be different than the biocompatible solvent that is used to dissolve the biodegradable polymer.
  • Another pre-filled syringe delivery system, disclosed herein comprises a first syringe containing the biodegradable polymer and the biocompatible solvent, and a second syringe containing the degarelix or a pharmaceutically acceptable salt thereof.
  • the degarelix or a pharmaceutically acceptable salt thereof may be in a lyophilized form or may be dissolved or suspended in the biocompatible solvent, which may be the same as the biocompatible solvent that is used to dissolve the biodegradable polymer, or which may be different than the biocompatible solvent that is used to dissolve the biodegradable polymer.
  • the first syringe and the second syringe are coupled together to mix the contents of the first and second syringe.
  • the contents of the two syringes are mixed together to form a pharmaceutical composition for injection prior to administering the pharmaceutical composition to the subject.
  • the pharmaceutical composition may be administered to a patient by injection using a syringe system, including a syringe system as described herein.
  • the composition is injected by subcutaneous injection, although other parenteral routes, including intramuscular injection, are contemplated herein.
  • the composition may be administered by manual injection though a syringe with, for example, a 18 to 32 gauge needle, a 22 to 25 gauge needle, a 18 to 24 gauge needle, or an 18 to 22 gauge needle, or an 18 to 20 gauge needle, or may be administered by injection using an autoinjector.
  • a kit comprising a prefilled syringe system disclosed herein.
  • formulations may include solvent blends, other additives such as: co- solvents or stabilizer excipients such as poly-carboxylic acids or salts (e.g., citric acid), strong acid (methane sulfonic acid), hydrophobic acid or their salts (e.g., pamoic acid, palmitic acid), surfactants such as polysorbate 20, polysorbate 80, poloxamer 188, or any of these as release modifiers.
  • co- solvents or stabilizer excipients such as poly-carboxylic acids or salts (e.g., citric acid), strong acid (methane sulfonic acid), hydrophobic acid or their salts (e.g., pamoic acid, palmitic acid), surfactants such as polysorbate 20, polysorbate 80, poloxamer 188, or any of these as release modifiers.
  • co- solvents or stabilizer excipients such as poly-carboxylic acids or salts (e.g., citric acid), strong acid (
  • Non-aqueous water-miscible pharmaceutically acceptable organic solvents like N-methyl- 2-pyrrolidone (NMP), dimethyl sulfoxide (DMSO), and N, N-dimethylacetamide (DMA) have shown superior solubility capacity (at least 35-40% w/w) of degarelix than aqueous- based solvents.
  • NMP and DMSO can dissolve higher amounts of DgA without inducing self-aggregation, as seen in aqueous solvents.
  • Other solvents tested include— benzyl alcohol, PEG 300, propylene carbonate, triacetin, triethyl citrate, ethyl acetate, and benzyl benzoate.
  • Degarelix citrate (DgC)-DS preparation [00168] Degarelix citrate was formed by dissolving the degarelix as degarelix acetate (purchased from the vendor) in water ( ⁇ 40 mg/mL concentration) and then adding the aqueous solution of anhydrous citric acid (1M) drop by drop. The molar ratio of degarelix free-base to citric acid in the solution was varied as desired. The resulting solution was mixed for 10-15 mins and placed in the -80 °C freezer.
  • the contents were lyophilized to remove the water (and freeze-drying may remove some amount of acetic acid formed as a result of ion exchange).
  • the dried powder was re-dissolved in water and freeze-dried again.
  • the purity of the lyophilized degarelix citrate powder was tested using HPLC analysis. See descriptions of different degarelix citrate drug substance powders in Table 1.
  • Degarelix mesylate preparation [00169] Degarelix mesylate was formed by dissolving the degarelix as degarelix acetate (purchased from the vendor) in water ( ⁇ 40 mg/mL concentration) and then adding the aqueous solution of strong acid methane sulfonic acid (1M) drop by drop. The molar ratio of degarelix free-base to methane sulfonic acid in the solution was varied as desired. The resulting solution was mixed for 10-15 mins and placed in the -80 °C freezer. The contents were lyophilized to remove the water (and freeze-drying may remove some amount of acetic acid).
  • Polymers were either purchased from Sigma Aldrich (RESOMER® polymers) or synthesized in-house.
  • Poly(D.L-lactide-co-glycolide) (PLG) copolymers, poly-DL- lactide (PLA) polymers, or poly(D.L-lactide-co-caprolactone) (PDLCL or PLC) copolymers were produced using the following methods.
  • the amounts of monomers (DL- lactide or glycolide or caprolactone) and initiator (e.g., glycolic acid, 1,6-Hexanediol, polyethylene glycol (PEG)) were selected to obtain a targeted initiator, monomer molar ratio, and weight average molecular weight for each investigated polymer.
  • the monomer molar ratios and weight average molecular weights reported in individual examples are targeted values unless specified as actual or experimental.
  • the polymerization vessel was lowered into a temperature-controlled oil bath.
  • the vessel In the vessel, appropriate amounts of monomers (DL-lactide and/or glycolide and/or caprolactone, and initiator (glycolic acid or 1,6-Hexanediol) were added, the vessel contents were placed under a nitrogen atmosphere. The temperature of the vessel was increased until the reagents melted. A catalyst solution was made with appropriate amounts of stannous octoate and toluene and added to the vessel. The vessel was then heated to about 140-170°C under a nitrogen atmosphere for about 4-18 hours (depending on the polymer of interest) with constant stirring. Then, the vessel was evacuated to remove unreacted monomers, and the monomers were vacuum- distilled out of the polymerization mixture.
  • monomers DL-lactide and/or glycolide and/or caprolactone, and initiator (glycolic acid or 1,6-Hexanediol) were added, the vessel contents were placed under a nitrogen atmosphere. The temperature of the vessel was increased until the reagents
  • syringe A Prefilled syringes (Syringe A) containing polymer delivery system were prepared by weighing the required amounts of polymer solution into 1.2 mL female polypropylene syringe barrel with Luer lock and plunger tip and capped with male polypropylene syringe cap. Filled syringes were then packaged in labeled foil pouches with a desiccant pack and the pouches were sealed.
  • the filled syringes were stored under refrigerated conditions (e.g., 2-8 oC) or accelerated conditions ( ⁇ 25°C see individual experiments).
  • the syringes may be irradiated via e-beam irradiation (see individual experiment). 6.
  • DgA-DS or DgC-DS/organic-solvent bulk solution and prefilled syringes [00172]
  • the desired amount of the DgA-DS or DgC-DS was combined with the solvent NMP or DMSO or combination of solvents with or without a co-solvent or other additives, in the indicated amounts (see individual experiments below).
  • the API and solvent were combined in a glass vial or jar and blanketed with nitrogen. Jars were mixed using the jar mill, Turbula, or shaker at room temperature until homogeneous.
  • DgA or DgC are very soluble in NMP or DMSO and can load higher concentrations (at least 40% w/w).
  • the bulk solution was manually filled into syringes and capped with a tip cap.
  • the syringes used for filling were either 1.2 mL male polypropylene syringes or 1 mL male cyclic olefin copolymer syringes. Filled syringes were then packaged in labeled foil pouches with a desiccant pack and the pouches were sealed.
  • the filled syringes were stored under refrigerated conditions (e.g., 2- 8 oC) or accelerated conditions ( ⁇ 25°C see individual experiments).
  • the syringes may be irradiated via e-beam or gamma irradiation (see individual experiment) for terminal sterilization.
  • the stabilizer excipient can be selected from a list of acids which include polycarboxylic acids or their salts (Ex. citric acid), strong acids (Ex. methanesulfonic), hydrophobic acids or their salts (Ex.
  • DgA-DS desired amounts of DgA-DS, a stabilizer excipient(s) (e.g., anhydrous citric acid), and liquid polymer solution (see section 5 for bulk polymer solution preparation) were weighed into a scintillation vial, and the vial was put on a horizontal roller mixer to roll for 24-48 h for mixing. After mixing, the single- syringe formulations (solution/suspension) were considered ready for testing. 10.
  • XRD Characterization of the DgA-DS solutions Samples were prepared and analysis was performed at ambient temperature using the Rigaku MiniFlex XRD instrument according to standard protocols. After a sequence of samples was run, the data was processed using PDXL2 software.
  • Degarelix acetate did not show any crystallinity as an API powder, or at a concentration of 66 mg/mL in water. At higher concentrations, the peptide forms a gel. The gel was not crystalline. In theory, the gel exhibits peaks indicating a higher order structure attributed to the stacking of beta-sheets forming aggregates resulting in the gel formation. The addition of salts can aid the gelation to form at a lower concentration than without the salts. No gelation occurred in the presence of NMP solvent even when water was present. 11.
  • Degarelix/organic solvent solutions were prepared for HPLC analysis by dilution to volume with mobile phase A (0.1% trifluoroacetic acid water) and mixing thoroughly by vortex. Dilutions were performed as needed using volumetric glassware and mixed thoroughly by vortex mixing. A second dilution of 2 mL to 20 mL was performed with mobile phase A to obtain a working sample. [00180] For the HPLC test sample preparation of reconstituted/single-syringe formulations that contain polymer, syringe A and syringe B were coupled together and mixed for 45 cycles.
  • HPLC analysis for assay and related compounds was performed using an Agilent AdvanceBio Peptide 3.0 x 100 mm, 2.7 um column and an Agilent AdvanceBio Peptide Map Guard 3.0 x 5mm 2.7 um guard column at 30°C with a flow rate of 0.75 mL/min.
  • the runtime was 15 minutes with a 10- ⁇ L injection for assay and related compounds for the solution gel depot formulation, and a 20- ⁇ L injection for assay and related compounds for the polymer depot formulation.
  • the mobile phases were 0.1% trifluoroacetic acid water for mobile phase A and 0.1% trifluoroacetic acid acetonitrile for mobile phase B. Detection was performed with a diode array detector set at 220 nm. The method used a gradient. See Table 2 below for the gradient method for an example chromatogram. 12. Recovery of drug from different Degarelix/Organic solvent formulations [00182] Prefilled syringes of degarelix/organic solvent formulations were prepared as described in section 6. Recovery of drugs from different formulations was tested using the HPLC method (see section 11) and is listed in Table 3.
  • F6 sample was a control sample that does not contain any polymer or monomers and was included in the study as a control to understand if the solvent causes any degradation.
  • the F6 sample showed minimal signs of degradation (1% drop in assay after 24 h at 50°C), indicating that the drug is stable in NMP, and any degradation observed in other samples could be attributed to the presence of polymers/monomers.
  • Bold text in Table 7 for Samples F8, F10 and F15 indicates that these samples exhibited the most promising drug stability (e.g., less degradation of drug over the tested time period).
  • F16 and F17 are samples where DgA-DS was mixed with monomer solutions (Lactide/NMP or Glycolide/NMP), and it was observed that almost 90-100% of the drug was degraded by 7 days at room temperature, and 86-99% in 24 h at 50°C. These results indicated that the presence of monomers could induce significant degradation of the degarelix. These results indicate that purification of polymers to remove the residual or unreacted monomers will improve the stability of the API. [00196] Among F8-F14 samples that contain unpurified polymers, glycolic acid (GA) terminated PLC containing samples F8 and F10 have shown better compatibility with the drug compared to the PLG or PLC-PEG polymers.
  • monomer solutions Lactide/NMP or Glycolide/NMP
  • F8 and F10 samples showed ⁇ 5% (after 24 h at 50°C) and ⁇ 1.2% (after 7 days at room temperature) degradation, whereas other samples showed significantly higher degradation of the degarelix.
  • F15 sample that contains purified acid-terminated PLG polymer also showed promise, 7.2% (after 24 h at 50°C) and 4.5% (after 7 days at room temperature) degradation.
  • F9, F11, and F14 that contain similar polymers (acid-terminated PLGs) with a different monomer composition, the higher stability of degarelix in F15 could be related to the use of purified polymer in F15 compared to the unpurified versions in F9, F11, and F14.
  • Acid-terminated PLC polymer showed improved stability of degarelix compared to other polymers, even without purification. Based on these results, purified acid- terminated PLC polymer showed promising potential for use in formulating a single syringe formulation.
  • Table 8 Observations: Bold text in Table 8 for Samples F20, F24, F28 and F32 indicates that these samples exhibited the most promising drug stability (e.g., less degradation of drug over the tested time period).
  • DgA-DS containing formulations without citric acid F37 (15.0% impurities) and F41(15.2% impurities) generated significantly higher amount of impurities after only 14 days compared to the formulations that contained DgC- DS ( ⁇ 5% impurities after 21 days) or citric acid as an excipient ( ⁇ 8% after 18 days).
  • Lower levels of acylated impurities were observed for citric acid-based formulations than formulations that do not contain any citric acid.
  • citric acid as a stabilizer excipient to the drug-polymer formulation or using it as part of the alternate salt form that is prepared by co-lyophilization of DgA-DS with citric acid, both resulted in a similar improvement of drug stability on accelerated storage, and the lower impurity levels were observed. Further, this preliminary data suggested that stabilizers such as citric acid can be just added as an excipient to the formulation to improve the drug stability in presence of polymer, and the additional process of lyophilization to make DgC-DS form may be eliminated to simplify the manufacturing process.
  • Citric acid was added as an excipient to the formulation at four different molar levels [0.5 (F48), 1 (F45), 2 (F46), and 3 (F47) moles to 1 mole of degarelix).
  • F48 with 0.5 mol citric acid showed 7.8 % total impurities at day 18 vs.
  • F37 with no citric acid showed 15.0% total impurities at day 14.
  • F45 with 1 mol of citric acid showed 3.6% total impurities at day 18.
  • 0.5 moles of citric acid helped in improving the stability of DgA-DS compared to no additive version, higher levels of citric acid showed much better improvement in drug stability.
  • FIRMAGON ® 120 mg vial of FIRMAGON ® was reconstituted by adding 3 mL of sterile water for injection provided with the FIRMAGON ® kit, and the resulting reconstituted solution was at 40 mg/mL concentration of degarelix.
  • Table 12 Non-Clinical Study Dosing Details (“F#” denotes “Formulation Number”) [00211] In vivo degarelix release in rats for polymer-based formulations of degarelix at 28-days post injection is presented in Figure 2.
  • Figure 3 shows a magnified version of day- 0 to day-3 levels to show the Cmax levels.
  • FIG. 4 In vivo degarelix release in rats for polymer-based formulations of degarelix at 63-days post injection is presented in Figure 4.
  • Figure 5 shows a magnified version of the same data in Figure 4 to better illustrate the release of the different formulations.
  • Figures 6 and 7 show that all of the formulations released drug that resulted in measurable levels of degarelix in vivo for greater than 60 days.
  • Figure 6 In vivo degarelix release in rats for polymer-based formulations of degarelix at 119-days post injection is presented in Figure 6.
  • Figure 7 shows a magnified version of the same data in Figure 6 to better illustrate the release of the different formulations.
  • Figures 6 and 7 show that all of the formulations released drug that resulted in measurable levels of degarelix in vivo for greater than 90 days (at least 119 days). Also, the formulation L-TA11 (delarelix citrate) showed notably higher levels of drug in vivo compared to other formulations throughout the testing period.
  • In vivo testosterone concentration levels (ng/mL) in rats for the polymer-based formulations of degarelix API in this example at 105-days post injection is presented in Figure 8. Together, the results show that all of the formulations had plasma concentration of greater than 1 ng/mL which is the minimum drug concentration to induce chemical castration. In addition, the testosterone level remained below the “historical testosterone baseline” level and testosterone suppression occurred by day 4.

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Abstract

L'invention concerne des compositions injectables à action prolongée ainsi que des procédés d'utilisation de telles compositions injectables à action prolongée. Les compositions injectables à action prolongée comprennent du dégarelix (un antagoniste du récepteur de l'hormone de libération des gonadotrophines décapeptidiques (GnRH)) ou un sel pharmaceutiquement acceptable de celui-ci. Ces compositions peuvent également comprendre un polymère biodégradable, et un solvant organique biocompatible, éventuellement avec un ou plusieurs additifs.
EP24710302.1A 2023-02-10 2024-02-07 Formulations polymériques de dégarelix Pending EP4661840A2 (fr)

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US5702716A (en) 1988-10-03 1997-12-30 Atrix Laboratories, Inc. Polymeric compositions useful as controlled release implants
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EP1310517B2 (fr) 2000-08-07 2010-11-17 Wako Pure Chemical Industries, Ltd. Polymere d'acide lactique et son procede de preparation
HUE025842T2 (en) 2007-02-15 2016-04-28 Tolmar Therapeutics Inc Poly (lactide / glycolide) with reduced fracture properties and methods for producing polymers
WO2009148583A2 (fr) * 2008-06-03 2009-12-10 Qlt Usa, Inc. Procédé pour l'amélioration de la biodisponibilité de l'octréotide
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US10786515B2 (en) * 2015-08-03 2020-09-29 Tolmar International Limited Liquid polymer delivery system for extended administration of drugs
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