Search

EP-4739354-A2 - GLUTATHIONE-RESPONSIVE METHOTREXATE POLYMERSOMES FOR MANAGEMENT OF ECTOPIC PREGNANCY

EP4739354A2EP 4739354 A2EP4739354 A2EP 4739354A2EP-4739354-A2

Abstract

Methotrexate-containing polymersomes and a method for treating an ectopic pregnancy using the methotrexate-containing polymersome.

Inventors

  • TARATULA, Olena
  • TARATULA, OLEH
  • BALDWIN, Maureen
  • MYATT, Leslie
  • MAMNOON, Babak

Assignees

  • Oregon State University
  • Oregon Health & Science University

Dates

Publication Date
20260513
Application Date
20240703

Claims (20)

  1. 1. A method for treating an ectopic pregnancy, comprising administering a therapeutically effective amount of a methotrexate-containing polymersome to a subject in need thereof, wherein the methotrexate-containing polymersome comprises methotrexate and an amphiphilic block polyethylene glycol-disulfide-polycaprolactone (PEG-SS-PCL) copolymer having a hydrophilic PEG block and a hydrophobic PCL block with a disulfide moiety covalently coupling the PEG block to the PCL block, wherein the polymersome has a bilayer structure, with a hydrophilic interior core, hydrophobic layer and a hydrophilic outer shell formed by the hydrophilic PEG block, wherein methotrexate, or a pharmaceutically acceptable salt thereof, is encapsulated in the hydrophilic interior core.
  2. 2. The method of Claim 1, wherein the methotrexate-containing polymersome contains from about 20 to about 50 mg methotrexate per 10 mg polymersome.
  3. 3. The method of Claim 1, wherein the methotrexate-containing polymersome contains from about 35 mg methotrexate per 12 mg polymersome.
  4. 4. The method of Claim 1, wherein the ectopic pregnancy is successfully treated by administration of a single dose of the methotrexate-containing polymersome.
  5. 5. The method of Claim 1, wherein the ectopic pregnancy is successfully treated by administration of two doses of the methotrexate-containing polymersome.
  6. 6. The method of Claim 5, wherein the two doses are systemically administered from about 1 to about 4 days apart.
  7. 7. The method of Claim 1, wherein the amount of methotrexate administered is from about 1 mg/m 2 to about 50 mg/m 2 (methotrexate/subject surface area).
  8. 8. The method of Claim 1, wherein the amount of methotrexate administered is from about 0.1 mg/kg to about 2.0 mg/kg (methotrexate/subject body weight).
  9. 9. The method of any one of Claims 1-8, wherein the methotrexate-containing polymersome is administered by intravenous injection.
  10. 10. A methotrexate-containing polymersome, comprising: (a) methotrexate, or a pharmaceutically acceptable salt thereof, and (b) an amphiphilic block polyethylene glycol-disulfide-polycaprolactone (PEG- SS -PCL) copolymer having a hydrophilic PEG block and a hydrophobic PCL block with a disulfide moiety covalently coupling the PEG block to the PCL block, wherein the polymersome has a bilayer structure, with a hydrophilic interior core, hydrophobic layer and a hydrophilic outer shell formed by the hydrophilic PEG block, and wherein methotrexate, or a pharmaceutically acceptable salt thereof, is encapsulated in the hydrophilic interior core.
  11. 11. The polymersome of Claim 10, wherein hydrophilic PEG block has a molecule weight from about 2 kDa to about 10 kDa.
  12. 12. The polymersome of Claim 10, wherein hydrophilic PEG block has a molecule weight of about 2 kDa.
  13. 13. The polymersome of Claim 10, wherein hydrophobic PCL block has a molecule weight from about 5 kDa to about 20 kDa.
  14. 14. The polymersome of Claim 10, wherein hydrophobic PCL block has a molecule weight of about 5 kDa.
  15. 15. The polymersome of Claim 10, wherein hydrophilic PEG block has a molecule weight of about 2 kDa and the hydrophobic PCL block has a molecule weight of about 5 kDa.
  16. 16. The polymersome of Claim 10, wherein methotrexate is present in the polymersome in an amount from about 3 mg per 47 mg polymersome.
  17. 17. The polymersome of Claim 10, wherein the methotrexate-containing polymersome contains from about 35 mg methotrexate per 12 mg polymersome.
  18. 18. The polymersome of Claim 10, wherein methotrexate is present in the polymersome in an amount of about 0.75 mg per 1.0 mg polymersome.
  19. 19. The polymersome of any one of Claims 10-18 having a hydrodynamic size of about 25 to about 90 nm.
  20. 20. The polymersome of any one of Claims 10-19 having a poly dispersity index of about 0.01 to about 0.2.

Description

GLUTATHIONE-RESPONSIVE METHOTREXATE POLYMERSOMES FOR MANAGEMENT OF ECTOPIC PREGNANCY CROSS-REFERENCE TO RELATED APPLICATION [0001] This application claims the benefit of U.S. Patent Application No. 63/512003, filed July 5, 2023, expressly incorporated herein by reference in its entirety. STATEMENT OF GOVERNMENT LICENSE RIGHTS [0002] This invention was made with government support under R01CA237569, R01HD101450, R03TR004020, and R37CA234006, each awarded by the National Institutes of Health. The government has certain rights in the invention. BACKGROUND [0003] The first-line treatment for ectopic pregnancy (EP), the chemotherapeutic methotrexate (MTX), has a failure rate of more than 10%, which can lead to severe complications or death. Inadequate accumulation of administered MTX at the ectopic implantation site significantly contributes to therapeutic failure. [0004] Ectopic pregnancy (EP) is defined as the abnormal implantation of an embryo, most often outside of the uterus, and accounts for about 1-2% of pregnancies in the USA. Hemorrhage caused by ruptured EP continues to be the primary cause of first- trimester maternal death, accounting for 16% of first-trimester emergency room visits annually. EP is presumed when serum human chorionic gonadotropin (hCG) levels surpass 3,000 mIU mL-1 and there is no intrauterine gestational sac visible by ultrasound, and if hCG levels do not decline after uterine evacuation. The most common treatment of confirmed or presumed early unruptured EP is systemic administration of the chemotherapy agent methotrexate (MTX), an inhibitor of folate-dependent steps in nucleic acid synthesis, which effectively destroys the rapidly dividing ectopic trophoblast and thus prevents the placenta from developing and invading adjacent tissues. The recommended clinical dosing regimen for MTX is a single intramuscular injection of 1 mg kg-1 or 50 mg m-2. Unfortunately, the failure rate of MTX treatment can exceed 10%; the risk factors for which are poorly understood but may include high body mass index, rapid clearance, or inaccurate diagnosis. Rapid clearance of MTX most likely leads to insufficient accumulation of the drug at the ectopic implantation site, which ultimately results in therapeutic failure. In this scenario, repeated or higher doses are required, which can result in various side effects ranging from nausea and vomiting to interstitial pneumonitis and bone marrow suppression. As MTX remains the first-line treatment for EP, there is a pressing need to improve MTX efficacy. MTX treatment is also associated with substantial side effects. [0005] Despite the advances in treating EP with MTX noted above, a need exists for MTX formulations that improve the delivery and retention of an effective dose of MTX in the developing placenta, the site of ectopic implantation and, consequently, increase its safety and efficacy to provide enhanced therapeutic outcomes. The present disclosure seeks to fulfill this need and provides further related advantages. SUMMARY [0006] In one aspect, the present disclosure provides a methotrexate-containing polymersome. In certain embodiments, methotrexate-containing polymersome comprises: [0007] (a) methotrexate, or a pharmaceutically acceptable salt thereof, and [0008] (b) an amphiphilic block polyethylene glycol-disulfide- polycaprolactone (PEG-SS-PCL) copolymer having a hydrophilic PEG block and a hydrophobic PCL block with a disulfide moiety covalently coupling the PEG block to the PCL block, [0009] wherein the polymersome has a bilayer structure, with a hydrophilic interior core, hydrophobic layer and a hydrophilic outer shell formed by the hydrophilic PEG block, and [0010] wherein methotrexate, or a pharmaceutically acceptable salt thereof, is encapsulated in the hydrophilic interior core. [0011] In certain embodiments, the polymersome’ s hydrophilic PEG block has a molecule weight of about 2 kDa and the hydrophobic PCL block has a molecule weight of about 5 kDa. [0012] In one related aspect, the disclosure provides a pharmaceutical composition comprising the polymersome described herein and a pharmaceutically acceptable carrier. [0013] In another related aspect, the disclosure provides the polymersome described herein in lyophilized form. [0014] In further aspect, the present disclosure provides a method for treating an ectopic pregnancy. In certain embodiments, the methods comprise administering a therapeutically effective amount of a methotrexate-containing polymersome to a subject in need thereof. In the method, the amount of methotrexate, or a pharmaceutically acceptable salt thereof, is sufficient to result in resolution of serum human chorionic gonadotropin. In certain embodiments, the methotrexate-containing polymersome is administered in a single dose. In other embodiments, the methotrexate-containing polymersome is administered in two doses. DESCRIPTION OF THE DRAWINGS [0015] The foregoing aspects and many of the attendant advantages o