leuprolide and glycolic-acid

Leuprorelin (leuprolide, D-Leu6-(des-Gly10-NH2)-LH-RH ethylamide) acetate is a super-active agonist of luteinizing hormone-releasing hormone (LH-RH). We developed once-a-month injectable microcapsules of this agonist by our novel in-water drying method. This depot formulation can release the drug at an apparent zero-order rate over one month with bioerosion of copoly (lactic/glycolic acid) utilized as a wall material of the polycore microcapsules. A dramatic prolonged depression of pituitary-gonadal axis, chemical castration, was achieved by the once-a-month injection in experimental animals; it expects a reliable efficacy for treating hormone-dependent prostatic, breast cancers and endometriosis. Studies on the dosage design of this new delivery system of leuprorelin are summarized.

Topics: Amino Acid Sequence; Animals; Breast Neoplasms; Capsules; Delayed-Action Preparations; Drug Delivery Systems; Endometriosis; Glycolates; Humans; Injections; Lactates; Lactic Acid; Leuprolide; Male; Molecular Sequence Data; Polymers; Prostatic Neoplasms

The purpose of this research was to assess the acylation reactions of peptides, salmon calcitonin (sCT), human parathyroid hormone 1-34 (hPTH1-34) and leuprolide, in poly(lactic-co-glycolic acid) (PLGA) microspheres. Capillary electrophoresis (CE) and matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF MS) were used for determining and monitoring peptide acylation and quantitating acylation products in the degrading PLGA microspheres. In the degrading PLGA microspheres of sCT and hPTH1-34, the acylation products were observed and determined to be adducts with glycolic acid units from degradable PLGA polymer by MALDI-TOF MS. In the microsphere of leuprolide, however, the acylation product was not observed even after 28 days of incubation at the release medium, which represents the different stabilities among peptides according to the primary structure. As the leuprolide contains tyrosine and serine having hydroxyl group of nucleophilic amino acids, the acylation reaction of peptide is shown to be mainly due to the primary amino groups of N-terminus or lysine residue. The complementary use of CE and MALDI-TOF MS will be useful for searching the counter measures as well as determining the peptide acylation in the manufactured formulations on the market.

Topics: Acylation; Amino Acid Sequence; Animals; Calcitonin; Drug Carriers; Electrophoresis, Capillary; Glycolates; Humans; Lactic Acid; Leuprolide; Lysine; Microspheres; Molecular Sequence Data; Parathyroid Hormone; Peptide Hormones; Polyglycolic Acid; Polylactic Acid-Polyglycolic Acid Copolymer; Polymers; Salmon; Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization

Topics: Capsules; Chemistry, Pharmaceutical; Glycolates; Gonadotropin-Releasing Hormone; Lactates; Lactic Acid; Leuprolide; Polyesters; Polymers