RESUMEN
PURPOSE: Therapeutic peptides generally exhibit poor oral bioavailability and require alternative methods of delivery. Implanted microelectromechanical systems-based multi-reservoir devices enable programmable, chronic, pulsatile peptide delivery. This report describes parathyroid hormone fragment (hPTH (1-34)) formulations suitable for delivery from a multi-reservoir array. METHODS: The stability of hPTH(1-34) lyophilizates obtained from aqueous acidic solutions was assessed by reverse phase high pressure liquid chromatography. An in vitro test device measured in vitro release kinetics. RESULTS: Novel, highly concentrated (>50 mg/mL) hPTH(1-34) solutions were dispensed as bulk samples (1-3 mg peptide) in vials and as individual doses (13-21 microg peptide) in reservoir arrays. Bulk and array samples were lyophilized and stored at 37 degrees C. Bulk lyophilizate hPTH(1-34) purity after lyophilization, after 8 weeks, and after 26 weeks exceeded 96%, 90%, and 80%, respectively. The hPTH(1-34) stored in multi-reservoir arrays exhibited similar purity over 29 weeks at 37 degrees C. Initially and over 29 weeks, over half of the peptide was consistently released from arrays into neutral, isotonic solution in less than 30 min with quantitative recoveries (>95%) within 3 h. CONCLUSIONS: Clinically relevant formulations of hPTH(1-34) for use with implantable multi-reservoir devices are achievable.
Asunto(s)
Hormona Paratiroidea/química , Cromatografía Líquida de Alta Presión , Estabilidad de Medicamentos , Liofilización , Humanos , Espectrometría de Masas , Hormona Paratiroidea/administración & dosificación , SolubilidadRESUMEN
PURPOSE: Implanted multi-reservoir arrays improve dosing control relative to osmotic pumps or polymer depots. The limited reservoir volume requires concentrated formulations. This report describes the development of a stable solid phase formulation of leuprolide acetate for chronic in vivo delivery from a multi-reservoir microchip and examines the correlation between in vitro release kinetics and serum pharmacokinetics. MATERIALS AND METHODS: Concentrated formulations (>10% w/v) were prepared using small volume processing methods. Drug yield, release kinetics, and formulation stability were evaluated in vitro by HPLC. The correlation between in vitro and in vivo kinetic data was determined for a solid formulation by direct comparison of data sets and using absorption kinetics calculated from the Wagner-Nelson equation. RESULTS: High yield and the control of release kinetics by altering peptide formulation or reservoir geometry were demonstrated. Lyophilized leuprolide in a soluble solid matrix exhibited reproducible release kinetics and was stable (>95% leuprolide monomer) after 6 months at 37 degrees C. A strong correlation was found between in vitro release kinetics and in vivo absorption by direct comparison of data sets and using the Wagner-Nelson absorption (slopes of 1.01 and 0.91; R(2) 0.99). CONCLUSIONS: Reproducible releases of a stable solid leuprolide formulation from a multi-reservoir microchip were achieved in vitro. Chronic pulsatile release was subsequently performed in vivo. Comparison of in vitro and in vivo data reveals that pharmacokinetics were controlled by the rate of release from the device.
Asunto(s)
Antineoplásicos Hormonales/química , Leuprolida/química , Animales , Antineoplásicos Hormonales/sangre , Antineoplásicos Hormonales/farmacocinética , Química Farmacéutica , Cromatografía Líquida de Alta Presión , Perros , Composición de Medicamentos , Implantes de Medicamentos , Estabilidad de Medicamentos , Almacenaje de Medicamentos , Cinética , Leuprolida/sangre , Leuprolida/farmacocinética , Masculino , Modelos Biológicos , Modelos Químicos , Polietilenglicoles/química , Reproducibilidad de los Resultados , Solubilidad , Tecnología Farmacéutica/instrumentación , TemperaturaRESUMEN
Implanted drug delivery systems are being increasingly used to realize the therapeutic potential of peptides and proteins. Here we describe the controlled pulsatile release of the polypeptide leuprolide from microchip implants over 6 months in dogs. Each microchip contains an array of discrete reservoirs from which dose delivery can be controlled by telemetry.