Local drug delivery system using biodegradable polymers

For last five years, we are developing the novel local drug delivery devices using biodegradable polymers, especially polylactide (PLA) and poly(D,L-lactide-co-glycolide) (PLGA) due to its relatively good biocompatibility, easily controlled biodegradability, good processability and only FDA approved synthetic degradable polymers. The relationship between various kinds of drug [water soluble small molecule drugs : gentamicin sulfate (GS), fentanyl citrate (FC), BCNU, azidothymidine (AZT), pamidronate (ADP), 1,25(OH)2 vitamin D3, water insoluble small molecule drugs : fentanyl, ipriflavone (IP) and nifedipine, and water soluble large peptide molecule drug : nerve growth factor (NGF), and Japanese encephalitis virus (JEV)], different types of geometrical devices [microspheres (MSs), microcapsule, nanoparticle, wafers, pellet, beads, multiple-layered beads, implants, fiber, scaffolds, and films], and pharmacological activity are proposed and discussed for the application of pharmaceutics and tissue engineering. Also, local drug delivery devices proposed in this work are introduced in view of preparation method, drug release behavior, biocompatibility, pharmacological effect, and animal studies. In conclusion, we can control the drug release profiles varying with the preparation, formulation and geometrical parameters. Moreover, any types of drug were successfully applicable to achieve linear sustained release from short period (1∼3 days) to long period (over 2 months). It is very important to design a suitable formulation for the wanting period of bioactive molecules loaded in biodegradable polymers for the local delivery of drug. The drug release is affected by many factors such as hydrophilicity of drug, electric charge of drug, drug loading amount, polymer molecular weight, the monomer composition, the size of implants, the applied fabrication techniques, and so on. It is well known that the commercialization of new drug needs a lot of cost of money (average: over 10 million US dollar per one drug) and time (average: above 9 years) whereas the development of DDS and high effective generic drug might be need relatively low investment with a short time period. Also, one core technology of DDS can be applicable to many drugs for the market needs. From these reasons, the DDS research on potent generic drugs might be suitable for less risk and high return.

[1]  G. Khang,et al.  Preparation and characterization of Japanese encephalitis virus vaccine loaded poly(L-lactide-co-glycolide) microspheres for oral immunization. , 1999, Bio-medical materials and engineering.

[2]  M. Iwamoto,et al.  Culture of stromal cells derived from medullary cavity of human long bone in the presence of 1,25-dihydroxyvitamin D3, recombinant human bone morphogenetic protein-2, or ipriflavone. , 1998, Bone.

[3]  H. Lee,et al.  Preparation and characterization of poly(3-hydroxybutyrate-co-3-hydroxyvalerate) microspheres for the sustained release of 5-fluorouracil. , 2001, Bio-medical materials and engineering.

[4]  G. Henderson,et al.  Analyzing normetabolites of the fentanyls by gas chromatography/electron capture detection. , 1988, Journal of analytical toxicology.

[5]  H. Okada,et al.  Biodegradable microspheres in drug delivery. , 1995, Critical reviews in therapeutic drug carrier systems.

[6]  D. Rickard,et al.  Importance of 1,25-dihydroxyvitamin D3 and the nonadherent cells of marrow for osteoblast differentiation from rat marrow stromal cells. , 1995, Bone.

[7]  Y. Caplan,et al.  A fentanyl fatality involving midazolam. , 1990, Forensic science international.

[8]  J. Thompson,et al.  Gentamicin beads in vascular surgery: long-term results of implantation. , 1999, Cardiovascular surgery.

[9]  H. Lee,et al.  BCNU-loaded poly(D, L-lactide-co-glycolide) wafer and antitumor activity against XF-498 human CNS tumor cells in vitro. , 2003, International journal of pharmaceutics.

[10]  H. Lee,et al.  A local delivery system for fentanyl based on biodegradable poly(L-lactide-co-glycolide) oligomer. , 2002, International journal of pharmaceutics.

[11]  D. O'hagan,et al.  Intestinal translocation of particulates — implications for drug and antigen delivery , 1990 .

[12]  Bong Lee,et al.  Preparation and characterization of small intestine submucosa powder impregnated poly(L-lactide) scaffolds: the application for tissue engineered bone and cartilage , 2002 .

[13]  M. Nimni Polypeptide growth factors: targeted delivery systems. , 1997, Biomaterials.

[14]  H. Brem,et al.  Effects of GLIADEL® wafer initial molecular weight on the erosion of wafer and release of BCNU , 1996 .

[15]  R. Chole,et al.  Inhibition of Osteoclast Recruitment at a Local Site by 1-Hydroxyethylidene-1,1-Bisphosphonate (HEBP) , 1990, The Annals of otology, rhinology, and laryngology.

[16]  G. Khang,et al.  Cell-Synthetic Surface Interactions , 2002 .

[17]  G. Khang,et al.  Study on in vitro release patterns of fentanyl-loaded PLGA microspheres. , 2003, Journal of microencapsulation.

[18]  W. Saltzman Growth-Factor Delivery in Tissue Engineering , 1996 .

[19]  M. H. Fernandes,et al.  Long-term effects of parathyroid hormone, 1,25-dihydroxyvitamin d3, and dexamethasone on the cell growth and functional activity of human osteogenic alveolar bone cell cultures , 2000 .

[20]  H. Lee,et al.  Preparation and characterization of fentanyl-loaded PLGA microspheres: in vitro release profiles. , 2002, International journal of pharmaceutics.

[21]  M. Schimpf,et al.  Bioerodible polymers for delivery of macromolecules , 1990 .

[22]  J. Heller Polymers for controlled parenteral delivery of peptides and proteins , 1993 .

[23]  Toguchi Hajime,et al.  Drug delivery using biodegradable microspheres , 1994 .

[24]  R. Chole,et al.  First Place — Resident Basic Science Award 1993: Risedronate Activity in the Fetal and Neonatal Mouse , 1993, Otolaryngology--head and neck surgery : official journal of American Academy of Otolaryngology-Head and Neck Surgery.

[25]  G. Khang,et al.  Quantitative analysis of fentanyl in rat plasma by gas chromatography with nitrogen-phosphorus detection. , 2001, Journal of chromatography. B, Biomedical sciences and applications.

[26]  G. Khang,et al.  Nifedipine controlled delivery by sandwiched osmotic tablet system. , 2000, Journal of controlled release : official journal of the Controlled Release Society.

[27]  H. Lee,et al.  Evaluation ofin vitro release profiles of fentanyl-loaded PLGA oligomer microspheres , 2002 .

[28]  R Langer,et al.  New methods of drug delivery. , 1990, Science.

[29]  S. Cho,et al.  Preparation of 5-fluorouracil-loaded poly(L-lactide-co-glycolide) wafer and evaluation ofin vitro release behavior , 2003 .

[30]  Mark Saltzman W,et al.  Materials for protein delivery in tissue engineering. , 1998, Advanced drug delivery reviews.

[31]  R. J. Matejczyk Fentanyl related overdose. , 1988, Journal of analytical toxicology.

[32]  I H Kalfas,et al.  Principles of bone healing. , 2001, Neurosurgical focus.