betadex and deslorelin

To compare the systemic delivery of deslorelin following intratracheal administration of different deslorelin formulations. The formulations included dry powders of deslorelin, large-porous deslorelin-poly(lactide-co-glycolide) (PLGA) particles, and small conventional deslorelin-PLGA particles. Also, solution formulations of deslorelin and deslorelin-hydroxy-propyl-beta-cyclodextrin (HPbetaCD) complexes were tested.. Dry powders of deslorelin, large-porous (mean diameter, 13.8 microm; density, 0.082 g/cc), and small conventional (mean diameter, 2.2 microm; density, 0.7 g/cc) deslorelin-PLGA particles and solutions of deslorelin with or without HPbetaCD were administered intratracheally to Sprague-Dawley rats. Blood samples were collected at 3 h, 1, 3, and 7 days postdosing, and plasma deslorelin concentrations were determined using enzyme immunoassay. At the end of 7 days, lungs were isolated, and bronchoalveolar lavage fluid was collected and analyzed for deslorelin.. At the end of 7 days, deslorelin plasma concentrations in the large-porous deslorelin-PLGA particle group were 120-fold and 2.5-fold higher compared to deslorelin powder and small conventional deslorelin-PLGA particles, respectively. Co-administration of HPbetaCD resulted in 2-, 3-, and 3-fold higher plasma deslorelin concentrations at 3 h, 1 and 3 days, respectively, compared to deslorelin solution. On day 7, deslorelin concentrations in bronchoalveolar lavage fluid as well as plasma were in the order: large porous particles > small conventional particles > deslorelin-HPbetaCD solution > deslorelin powder > deslorelin solution.. Large-porous deslorelin PLGA particles can sustain deslorelin delivery via the deep lungs. Co-administration of HPbetaCD enhances the systemic delivery of deslorelin. The pulmonary route is useful as a noninvasive alternative for the systemic delivery of deslorelin.

Topics: 2-Hydroxypropyl-beta-cyclodextrin; Administration, Inhalation; Animals; beta-Cyclodextrins; Bronchoalveolar Lavage Fluid; Drug Carriers; Lactic Acid; Lung; Male; Particle Size; Pharmaceutical Solutions; Polyglycolic Acid; Polylactic Acid-Polyglycolic Acid Copolymer; Polymers; Porosity; Powders; Rats; Rats, Sprague-Dawley; Trachea; Triptorelin Pamoate

The purpose of this study is to investigate the mechanisms and thermodynamics of the interaction between hydroxypropyl beta-cyclodextrin (HPdetaCD) and [D-Trp6, des-Gly10] LHRH ethylamide (deslorelin), a peptide drug.. We used UV and fluorescence spectroscopy to study the interaction of HPbetaCD and deslorelin. Circular dichroism was used to study the conformational changes induced in deslorelin upon interaction with HP beta CD. The thermodynamics of the interaction of deslorelin and HPbetaCD was studied using isothermal titration calorimetry (ITC). We also determined the effect of HPbetaCD on the degradation of deslorelin by alpha-chymotrypsin.. UV and fluorescence spectroscopy indicated that HPbetaD induced a change in polarity of the environment surrounding the chromophores of deslorelin. Wavelength selective fluorescence indicated an increase in the fluorescence polarization of deslorelin with an increase in excitation wavelength in the presence of HPbetaCD suggesting that tryptophan is present in a media of reduced mobility. Circular dichroism studies indicated that HPbetaCD stabilizes the conformation of deslorelin. In addition, ITC indicated an exothermic reaction between deslorelin and HPbetaCD with a low enthalpy of binding of approximately -600 cal/mol and a binding affinity of approximately -1.25 x 10(2) M-1. Finally, the rate of degradation of deslorelin by alpha-chymotrypsin was decreased by 33% in the presence of HPbetaCD.. These results indicate that there is an interaction between HPbetaCD and deslorelin, which involves the inclusion of aromatic amino acids of deslorelin into the hydrophobic cavity of the cyclodextrin. This inclusion, providing steric hindrance, may be one of the mechanisms by which HPbetaCD reduces enzymatic hydrolysis of deslorelin.

Topics: 2-Hydroxypropyl-beta-cyclodextrin; alpha-Cyclodextrins; Amino Acids, Aromatic; beta-Cyclodextrins; Chymotrypsin; Cyclodextrins; Drug Interactions; Drug Stability; Excipients; Gonadotropin-Releasing Hormone; Protein Conformation; Spectrometry, Fluorescence; Thermodynamics; Triptorelin Pamoate