Reaction #1483115

ord-db28e5164fd348f89acafb4f6c2c26ae

Reaction equation

CC(=O)O.CCNC(=O)[C@@H]1CCCN1C(=O)[C@H](CCCNC(=N)N)NC(=O)[C@H](CC(C)C)NC(=O)[C@@H](CC(C)C)NC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)[C@H](CO)NC(=O)[C@H](Cc1c[nH]c2ccccc12)NC(=O)[C@H](Cc1c[nH]cn1)NC(=O)[C@@H]1CCC(=O)N1
Leuprolide acetate
O=C(O)c1cc2ccccc2c(Cc2c(O)c(C(=O)O)cc3ccccc23)c1O.[Na+]
disodium pamoate
→
CCNC(=O)[C@@H]1CCCN1C(=O)[C@H](CCCNC(=N)N)NC(=O)[C@H](CC(C)C)NC(=O)[C@@H](CC(C)C)NC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)[C@H](CO)NC(=O)[C@H](Cc1c[nH]c2ccccc12)NC(=O)[C@H](Cc1c[nH]cn1)NC(=O)[C@@H]1CCC(=O)N1
Leuprolide
Yield 60.0%

Reactants

—
PLGA
CC(=O)O.CCNC(=O)[C@@H]1CCCN1C(=O)[C@H](CCCNC(=N)N)NC(=O)[C@H](CC(C)C)NC(=O)[C@@H](CC(C)C)NC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)[C@H](CO)NC(=O)[C@H](Cc1c[nH]c2ccccc12)NC(=O)[C@H](Cc1c[nH]cn1)NC(=O)[C@@H]1CCC(=O)N1
Leuprolide acetate
O=C(O)c1cc2ccccc2c(Cc2c(O)c(C(=O)O)cc3ccccc23)c1O.[Na+]
disodium pamoate

Reagents

None

Solvents

—
in-water
ClCCl
CH2Cl2
OCc1ccccc1
BnOH

Conditions

Detailed conditions
See reaction.notes.procedure_details.

Workup

  1. 1
    workup.ADDITIONadded to the polymer solution
  2. 2
    Otheryielding a homogeneous organic phase
  3. 3
    Otherto provide an emulsion
  4. 4
    OtherThe emulsion was collected directly into a 0.3% PVA solvent extraction solution (100 mL)
  5. 5
    workup.ADDITIONwas added
  6. 6
    workup.STIRRINGstirred for an additional four hours
  7. 7
    FiltrationHardened microparticles were collected by filtration
  8. 8
    Washwashed with water, air
  9. 9
    Otherdried
  10. 10
    Otherstored at 4° C

Procedure

A microparticle formulation was prepared by an oil-in-water emulsion/solvent extraction method. PLGA polymer (MW 24,000, 160 mg) was dissolved in CH2Cl2 (1000 μL). Leuprolide acetate (40 mg) was dissolved in BnOH (1000 μL) and added to the polymer solution yielding a homogeneous organic phase. The resulting organic phase was combined with a 1% PVA aqueous phase containing 50 mM disodium pamoate to provide an emulsion. The emulsion was collected directly into a 0.3% PVA solvent extraction solution (100 mL) and stirred for 10 minutes. A secondary extraction solution consisting of 2% isopropanol (200 mL) was added and stirred for an additional four hours. Hardened microparticles were collected by filtration, washed with water, air dried and stored at 4° C. This provided formulation BK (120 mg, 60.0% yield) with a median particle size 43.1 μm. The core load (10.6%), encapsulation efficiency (53.0%) and in vitro burst (21.1%) were determined by RP-HPLC assay.

Source

DOI: 10.6084/m9.figshare.5104873.v1Patent: US08900636B2uspto-grants-2014_12