In vitro and in vivo evaluations of biodegradable implants for hormone replacement therapy: Effect of system design and PK-PD relationship

This investigation evaluated the feasibility of using subdermally implantable devices fabricated by nonconventional 3-dimensional printing technology for controlled delivery of ethinyl estradiol (EE2). In vitro release kinetics of EE2 and in vivo pharmacokinetics pharmacodynamics in ovariectomized New Zealand White rabbits were carried out to study 3 implant prototypes: implant I (single-channel EE2 distribution in polycaprolactone polymer core), implant II (homogeneous EE2 distribution in polycaprolactone polymer matrix), and implant III (concentration-gradient EE2 distribution in polycaprolactone and poly(dl-lactide-co-glycolide) (50∶50 matrix). EE2 was found to be released from all the implants in a nonlinear pattern with an order of implant III>implant II>implant I. The noncompartmental pharmacokinetic analysis of plasma EE2 profiles in rabbits indicated a significant difference (p>.05) in Cmax, tmax, and mean residence time between implant I and implants II and III, but no difference in the area under the plasma concentration time curves calculated by trapezoidal rule (AUC) among the implants. For pharmacodynamic studies, endogenous follicle-stimulating hormone (FSH) and luteinizing hormone (LH) levels were observed to be suppressed following implantation of all implants, which demonstrated that a therapeutically effective dose of EE2 had been delivered. Furthermore, the noncompartmental analysis of plasma FSH and LH profiles in rabbits showed a significant difference (p<.05) in AUC and the mean residence time between implant III and implants I and II. A good in vivo/in vitro relationship was observed between daily amounts of EE2 released and plasma profiles of EE2 for all implants. This relationship suggests that plasma profiles of EE2 could be predicted from in vitro measurement of daily amount of EE2 released Therefore, performing in vitro drug release studies may aid in the development of an EE2 implant with the desired in vivo release rate.

[1]  D. Mishell,et al.  First week drug concentrations in women with levonorgestrel rod or Norplant capsule implants. , 1997, Contraception.

[2]  C. Inturrisi,et al.  Pharmacokinetics and pharmacodynamics of subcutaneous naltrexone pellets in the rat. , 1986, The Journal of pharmacology and experimental therapeutics.

[3]  D. Hess,et al.  Pulsatile patterns of gonadotropins and ovarian steroids during estrus and pseudopregnancy in the rabbit. , 1988, Biology of reproduction.

[4]  E. Scholl,et al.  Comparative investigation of drug delivery of collagen implants saturated in antibiotic solutions and a sponge containing gentamicin. , 1996, Biomaterials.

[5]  J. Shah,et al.  Efficacy and Pharmacokinetics of Site-Specific Cefazolin Delivery Using Biodegradable Implants in the Prevention of Post-operative Wound Infections , 1998, Pharmaceutical Research.

[6]  C. Inturrisi,et al.  Pharmacokinetics and pharmacodynamics of subcutaneous morphine pellets in the rat. , 1985, The Journal of pharmacology and experimental therapeutics.

[7]  H. C. Coelingh Bennink,et al.  Ovarian function during the use of a single contraceptive implant: Implanon compared with Norplant. , 1998, Fertility and sterility.

[8]  Emanuel M. Sachs,et al.  Solid free-form fabrication of drug delivery devices , 1996 .

[9]  I. Sivin,et al.  Levonorgestrel Subdermal Implants A Review of Contraceptive Efficacy and Acceptability , 1998 .

[10]  P. Gangadharam,et al.  Maintenance of therapeutically active levels of isoniazid for prolonged periods in rabbits after a single implant of biodegradable polymer. , 1994, Tubercle and lung disease : the official journal of the International Union against Tuberculosis and Lung Disease.

[11]  Yie W. Chien,et al.  Novel Drug Delivery Systems , 1991 .

[12]  K. Pau,et al.  Feedback effects of ovarian steroids on the hypothalamic-hypophyseal axis in the rabbit. , 1986, Biology of reproduction.

[13]  J. Brouwers.  Advanced and controlled drug delivery systems in clinical disease management , 1996, Pharmacy World and Science.

[14]  M. Ramchandani,et al.  In vitro and in vivo release of ciprofloxacin from PLGA 50:50 implants. , 1998, Journal of controlled release : official journal of the Controlled Release Society.

[15]  H. Brem,et al.  Morphological Characterization of Polyanhydride Biodegradable Implant Gliadel® During in Vitro and in Vivo Erosion Using Scanning Electron Microscopy , 1996, Pharmaceutical Research.

[16]  B. Krauss,et al.  The relation between pharmacokinetics and endocrine effects of buserelin implants in patients with mastalgia , 1991, Clinical endocrinology.

[17]  Yie W. Chien,et al.  Polymer-Controlled Drug Delivery Systems: Science and Engineering , 1985 .

[18]  S. Schwendeman,et al.  Development of a multiple-drug delivery implant for intraocular management of proliferative vitreoretinopathy. , 1998, Journal of controlled release : official journal of the Controlled Release Society.

[19]  カニユージヤ，サトビー,et al.  Three-dimensional printing techniques , 1993 .

[20]  J. C. Shah,et al.  Kinetics and mechanism of release from glyceryl monostearate-based implants: evaluation of release in a gel simulating in vivo implantation. , 1998, Journal of pharmaceutical sciences.