BEH.462/3. 962J Molecular Principles of Biomaterials Spring 2003 Lecture 5: Controlled release devices ast time: Using enzyme substrate and cytokine peptides to engineer biological recognition of synthetic polymer Tod controlled release devices and applications principles of controlled release devices based on degradable polymers Synthesis of controlled release devices Theory of polymer-based controlled release adin Materials for protein delivery in tissue engineering, S.P. Baldwin and W.M. Saltzman, Adv Drug Deliv. Rev., 33, 71-86(1998) Controlled Release Applications in Biological Engineering and Medicine Overview Controlled release: Cargo molecules( small molecule drug, protein, DNA, etc. )released to physiological environment at a designed rate why develop controlled release systems? o Recent estimates from FDA: -10 years and $150 to develop a single new drug product- looking for added alue o Many drugs have a narrow therapeutic index(difference between toxic level and therapeutic level Requires multiple injection Poor patient compliance ncreased incidence of infection and hemmorhages o Danger of systemic toxicity with more potent drugs; some drugs simply cannot be used IL-2 promotes lymphocyte proliferation, useful as an anti-cancer drug but toxic at systemic level (induces fever, pulmonary edema, and vascular shock) o Targeted delivery possible o Improves availability of drugs with short half lives in vivo Some peptides have half-lives of a few minutes or even seconds o Release systems can double as adjuvants for vaccines Show Figure 1 p 347 Ratner Where applicable Application Examples Active concentration of cargo Provide missing soluble factors Replace deficient human growth 1-10 pM; Hormones promoting cell differentiation, hormone in children 5-10nM growth, survival, or other functions Sustained or modulated delivery of Release of anti-cancer drugs at varies a therapeutic dru site of tumors to induce cancer Lecture 5- Controlled Release Devices 1 of 14
BEH.462/3.962J Molecular Principles of Biomaterials Spring 2003 Lecture 5: Controlled Release Devices Last time: Using enzyme substrate and cytokine peptides to engineer biological recognition of synthetic polymers Today: controlled release devices and applications principles of controlled release devices based on degradable polymers Synthesis of controlled release devices Theory of polymer-based controlled release Reading: ‘Materials for protein delivery in tissue engineering,’ S.P. Baldwin and W.M. Saltzman, Adv. Drug Deliv. Rev., 33, 71-86 (1998) Controlled Release Applications in Biological Engineering and Medicine Overview • Controlled release: Cargo molecules (small molecule drug, protein, DNA, etc.) released to physiological environment at a designed rate • why develop controlled release systems? o Recent estimates from FDA: ~10 years and $150 to develop a single new drug product- looking for added value o Many drugs have a narrow therapeutic index (difference between toxic level and therapeutic level) Requires multiple injections Poor patient compliance Increased incidence of infection and hemmorhages o Danger of systemic toxicity with more potent drugs; some drugs simply cannot be used IL-2 promotes lymphocyte proliferation, useful as an anti-cancer drug but toxic at systemic level (induces fever, pulmonary edema, and vascular shock) o Targeted delivery possible o Improves availability of drugs with short half lives in vivo Some peptides have half-lives of a few minutes or even seconds o Release systems can double as adjuvants for vaccines • Show Figure 1 p. 347 Ratner Where applicable: Application Examples Active concentration of cargo Provide missing soluble factors promoting cell differentiation, growth, survival, or other functions Replace deficient human growth hormone in children 1-10 pM; Hormones 5-10 nM Sustained or modulated delivery of a therapeutic drug Release of anti-cancer drugs at site of tumors to induce cancer varies Lecture 5 – Controlled Release Devices 1 of 14
BEH.462/3. 962J Molecular Principles of Biomaterials Spring 2003 cell apoptosis, ocular drugs for treatment of glat contraceptive drugs, antimalarial Create gradients of a molecule in Chemoattraction of immune cells 1-50 pM to antigen depot for vaccines One time procedure(e.g injection) Pulsatile release of antigen for 10-100 ug antigen with multiple dose delivery vaccines ene therapy orrection of cystic fibrosis gene 1-20 ug DNA efect. correction of adenosine deaminase deficiency (ADA SCID)in lymphocytes, replace defective gene in Duchenne muscular dystrophy, cancer immunothera Antimalarial drugs(Life Sciences 19, 867(1976)); contraceptive drugs;(Am. J Obstet. Gynec 135, 419(1979)) · Delivery Sites o Oral (delivery via intestinal tract) o Sublinguinal (under tongue) o Parenteral:(injection sites other than digestive system) Peritoneal (gut) · subcutaneous o Ocular o (Table 1 Edlund) Commercial Device Examples(weave this in list below) Drug delivery is one of the most clinically-commercialized areas of biomaterials Still only $30 billion/yr in 1998, modest share of world pharmaceuticals market · Alza ocusert o Depot for ocular delivery of pilocarpine for glaucoma PL o Luteinizing hormone releasing hormone(LHRH) treatment of prostate cancer(Drug Deliver Ind Pharm 16,2352(1990) Capronor o Polycaprolactone 1-year release of levonorgestrel (contraceptive)(CG. Pitt in Long Acting Contraceptive Delivery Systems, G L. Zatuchni ed (1984)p. 48-63) Advanced Polymer Systems o Ocular drug delivery · Gliadel o Polyanhydride wafers for release of carmustine(anti-brain tumor drug) Lecture 5- Controlled Release Devices 2 of 14
BEH.462/3.962J Molecular Principles of Biomaterials Spring 2003 cell apoptosis, ocular drugs for treatment of glaucoma, contraceptive drugs, antimalarial drugs Create gradients of a molecule in situ Chemoattraction of immune cells to antigen depot for vaccinesk1 1-50 pM One time procedure (e.g. injection) with multiple dose delivery Pulsatile release of antigen for vaccines 10-100 µg antigen Gene therapy Correction of cystic fibrosis gene defect, correction of adenosine deaminase deficiency (ADASCID) in lymphocytes, replace defective gene in Duchenne muscular dystrophy, cancer immunotherapy2 1-20 µg DNA Antimalarial drugs (Life Sciences 19, 867 (1976)); contraceptive drugs ; (Am. J. Obstet. Gynec. 135, 419 (1979)) • Delivery Sites o Oral (delivery via intestinal tract) o Sublinguinal (under tongue) o Rectal o Parenteral: (injection sites other than digestive system) • Intramuscular • Peritoneal (gut) • subcutaneous o Ocular o (Table 1 Edlund) Commercial Device Examples (weave this in list below) Drug delivery is one of the most clinically-commercialized areas of biomaterials Still only $30 billion/yr in 1998, modest share of world pharmaceuticals market • Alza ocusert o Depot for ocular delivery of pilocarpine for glaucoma • PLGA o Luteinizing hormone releasing hormone (LHRH) treatment of prostate cancer (Drug. Deliver. Ind. Pharm. 16, 2352 (1990) • Capronor o Polycaprolactone 1-year release of levonorgestrel (contraceptive) (C.G. Pitt in ‘Long Acting Contraceptive Delivery Systems,’ G.I. Zatuchni ed. (1984) p. 48-63) o • Advanced Polymer Systems o Ocular drug delivery • Gliadel o Polyanhydride wafers for release of carmustine (anti-brain tumor drug) Lecture 5 – Controlled Release Devices 2 of 14
BEH.462/3. 962J Molecular Principles of Biomaterials Spring 2003 Types of controlled release devices 3 1. Drug diffusion-controlled release a. Entrapped drug diffuses out of matrix at defined rate (SLIDE Drug diffusion-controlled release Solid matrix b. Can provide release by diffusion out of polymeric matrix or diffusion through a barrier C. Major disadvantages 1. Nondegradable implants i. Diffusion of large molecules such as proteins through the polymer is too slow to be effective Danger of ' dose dumping in barrier systems if membrane is ruptured d. Typically nondegradable polymer i. Poly(dimethylsiloxane)(Norplant contraceptive- 6 flexible tubes filled with levonorgestrel) e. We will see later that eroding polymer release devices can also have diffusion-controlled release over an early timeframe, before degradation has proceeded very far f. Release rates controlled by simple drug diffusion calculations 2. water diffusion-controlled release a. water influx controls release Lecture 5- Controlled Release Devices 3 of 14
BEH.462/3.962J Molecular Principles of Biomaterials Spring 2003 Types of controlled release devices3 1. Drug diffusion-controlled release a. Entrapped drug diffuses out of matrix at defined rate (SLIDE) Solid matrix Drug diffusion-controlled release Barrier release Norplant¨ system b. Can provide release by diffusion out of polymeric matrix or diffusion through a barrier c. Major disadvantages i. Nondegradable implants ii. Diffusion of large molecules such as proteins through the polymer is too slow to be effective iii. Danger of ‘dose dumping’ in barrier systems if membrane is ruptured d. Typically nondegradable polymer i. Poly(dimethylsiloxane) (Norplant contraceptive- 6 flexible tubes filled with levonorgestrel) levonorgestrel e. We will see later that eroding polymer release devices can also have diffusion-controlled release over an early timeframe, before degradation has proceeded very far f. Release rates controlled by simple drug diffusion calculations 2. water diffusion-controlled release a. water influx controls release Lecture 5 – Controlled Release Devices 3 of 14
BEH.462/3. 962J Molecular Principles of Biomaterials Spring 2003 b. diffusivity in swollen polymer allows diffusion of drug out of matrix (SLIDE) i. poly(ethylene-Co-vinyl acetate) 3. erodible devices a. combination of polymer breakdown and drug diffusion through matrix releases cargo (SLIDE) eroding matrix Non-erodible capsule b. first example: Yolles Polym. News 1, 9(1971)or polym. Sci. Tecnol. 8, 245(1975): cyclazocine in PLA C. Advantage of being injectable(microspheres)and resorbable(no retrieval surgery) d. Disadvantage that therapy difficult to stop once injected due to difficult recovery of particles e. clinical product examples 1. Lupron depot a. One month injectable PLGA microspheres containing leuprolide acetate for treatment of endometriosis and prostatic cancer Lecture 5- Controlled release devices 4 of 14
BEH.462/3.962J Molecular Principles of Biomaterials Spring 2003 b. diffusivity in swollen polymer allows diffusion of drug out of matrix (SLIDE) c. also nondegradable polymers typically i. poly(ethylene-co-vinyl acetate) 3. erodible devices a. combination of polymer breakdown and drug diffusion through matrix releases cargo (SLIDE) eroding matrix Non-erodible capsule b. first example: Yolles Polym. News 1,9 (1971) or polym. Sci. Tecnol. 8, 245 (1975); cyclazocine in PLA sheets c. Advantage of being injectable (microspheres) and resorbable (no retrieval surgery) d. Disadvantage that therapy difficult to stop once injected due to difficult recovery of particles e. clinical product examples 1. Lupron depot a. One month injectable PLGA microspheres containing leuprolide acetate for treatment of endometriosis and prostatic cancer4 Lecture 5 – Controlled Release Devices 4 of 14
BEH.462/3. 962J Molecular Principles of Biomaterials Spring 2003 4. regulated release a. devices with externally-applied trigger to turn release on/off electrical (SLIDE) transdermal - Alza MacrofiuxB patch Osmotic pump·Aza Duros imilar Titanium microprojections t Osmotic engine Adhesive backing f Delivery orifice Titanium rod cas Osmotic engine: (one form Osmotic pump- Alza Duros implant Favorable Asmix Drug reservoir Titanium rod casing rug out other end b. benefit of complex control C. generally more bulky devices and require implantation Device types 1-4 generally pre-programmed *DISCUSSION OF #5 NEXT DAY IN COMPLEX RELEASE PROFILES Lecture- Controlled release devices 5 of 14
BEH.462/3.962J Molecular Principles of Biomaterials Spring 2003 4. regulated release a. devices with externally-applied trigger to turn release on/off i. electrical5 ii. mechanical (SLIDE) transdermal - Alza Macroflux® patch Osmotic pump - Alza Duros¨ implant Semipermeable membrane QuickTime™ and a Graphics decompressor are needed to see this picture. Osmotic engine piston Drug reservoir Delivery orifice Titanium rod casing Titanium microprojections Adhesive backing Drug matrix Osmotic engine: (one form) Osmotic pump - Alza Duros¨ implant needed to see this picture. Semipermeable membrane Osmotic engine piston Drug reservoir Delivery orifice b. benefit of complex control Favorable ∆Smix Titanium rod casing Water driven into ; swelling drives piston to push ÔengineÕ drug out other end c. generally more bulky devices and require implantation • Device types 1-4 generally ‘pre-programmed’ • *DISCUSSION OF #5 NEXT DAY IN COMPLEX RELEASE PROFILES Lecture 5 – Controlled Release Devices 5 of 14