This document outlines the key concepts and fundamentals of controlled drug delivery, including:
- The influence of drug properties and routes of administration on controlled release technology design.
- The theory of mass transfer and fundamental polymer science considerations for pharmaceutical applications.
- Pharmacokinetic/pharmacodynamic bases for controlled delivery, dosing, and bioavailability assessment.
- Regulatory implications and case studies of various controlled release drug delivery systems for oral, parenteral, implantable, transdermal, and other applications.
16. Theory of Mass Transfer Fick's first law relates the diffusive flux to the concentration field, by postulating that the flux goes from regions of high concentration to regions of low concentration, with a magnitude that is proportional to the concentration gradient (spatial derivative). Fick's second law predicts how diffusion causes the concentration field to change with time.
17. Diffusion is an Effective Transport Mechanism over Small Distances
42. 90% Active in 10% PVA āpasteā C tot = C s Direction of mass transport 10%PVA coat Vitreous Humor (or sampling compartment) CL (or sampling) Silicone adhesive seal (ālow doseā configuration) Blood flow, systemic circulation clearance
43. Photomicrographs of implants prepared by 'potting and slicing' of the tube to show drug matrix and the end caps. Process used involves an Al-mount which resulted in the sample becoming contaminated with aluminium particles ( the black bits in the photo). PVA Endcap PF337210 PF337210 PF337210 SU14813
44. Polarized light to enhance the contrast for visualizing the end cap. PVA Endcap
48. Solubility ( ļ g/mL) 25mM PB pH7.4 in saline, maintained at 37Ā°C, crystalline material equilibrated for 72hrs Estimated ļ g/day release from MedidurĀ® 5 10 15 20 25 30 35 40 45 0 5000 10000 15000 20000 25000 30000 CAI, PF4246518 5FU 0.5 1 1.5 2 0 100 200 300 400 500 PF190440 PF547309 PF337210 FA PF366801 PF520461 PF484286 Nevirapine Linear fit y=0.0026x+0.086 R 2 =0.994 includes 5FU excludes CAI Correlation of solubility to functional performance
49. PF520461 -9.5 -8.5 -7.5 -6.5 -5.5 -4.5 -2 -1 0 1 2 3 4 5 clogP or clogD at pH7.4 if ionizable Log P app PF190440 PF547309 PF366801 PF337210 PF484286 Nevirapine PF4246518 5FU FA
50. Solubility 26mg/mL MW 130g/mol 6.8 ļ g/min flux, obtained from steady state portion of curve using a linear fit described by y=mx+b, R 2 =0.99 Example and validation compound, AVERAGE n=3 membranes 0 0.2 0.4 0.6 0.8 1.0 1.2 1.4 1.6 1.8 2.0 50 100 150 200 250 Time (min) Cumulative mg of 5FU transferred across PVA membrane Why ethyl vinyl acetate, EVA, membranes do not work?
51. Model 0 0.2 0.4 0.6 0.8 1 1.2 1.4 50 100 150 200 250 300 350 400 450 500 Solubility ( ļ g/mL) Predicted In Vitro Release ( ļ g/day) 0 0.5 1 1.5 2 2.5 Duration (years) *Release ( ļ g/day) **Duration (years; f(x)=1/x type of function where payload is 200 ļ g)
52. Release Rate/Diffusion Device Properties Compound Properties Membrane thicknessĀ¶ Curing temperatureĀ¶ Partition coefficient Need to update equation? D = Q/ A Ā¶ āC ļµ kā t ļ“ h Ā¶
53.
54. Vitreous Space Polyimid capillary tube shell Collagen fibrils Hyaluronan matrix Polyvinyl alcohol (PVA) membrane pH7.4, 37 Ā° C, H 2 O Water filled pores, tortuous path 25 gauge Sol max
57. No end cap Silicone seal No end cap No end cap Silicone seal No end cap No end cap No end cap 25 gauge 18 gauge 100Ā°C (or lowest acceptable temp. must be determined using clear physical cutoff limits, i.e. %weight loss-polymer over time in release) vs. 135Ā°C Possible tox doses Possible efficacious doses 2 layers 2 layers 2 layers Silicone seal 3 layers 3 layers 3 layers Silicone seal 2 layers 2 layers 2 layers Silicone seal 3 layers 3 layers 3 layers Silicone seal 2 layers 2 layers 2 layers Silicone seal 3 layers 3 layers 3 layers Silicone seal 2 layers 2 layers 2 layers Silicone seal 3 layers 3 layers 3 layers Silicone seal 10% PVA coating 10% EVA coating 5% PVA coating 5% EVA coating 2 layers 2 layers 2 layers Silicone seal 3 layers 3 layers 3 layers Silicone seal 2 layers 2 layers 2 layers Silicone seal 3 layers 3 layers 3 layers Silicone seal 2 layers 2 layers 2 layers Silicone seal 3 layers 3 layers 3 layers Silicone seal 2 layers 2 layers 2 layers Silicone seal 3 layers 3 layers 3 layers Silicone seal 10% PVA coating 10% EVA coating 5% PVA coating 5% EVA coating 2 layers 3 layers 2 layers 3 layers 2 layers 3 layers 2 layers 3 layers EVA coats High release Low
58.
59. Type Release Rate Time Polymer-Based Approaches to Control Drug Release
60. Polymer Type Examples Drug Type Hydrophilic Biodegradable Swellable Bioadhesive Ion-exchange Hydrophobic Poly(2-hydroxyethyl methacrylate) Poly(vinyl pyrrolidone) Poly(lactic acid) Poly(glycolic acid) Collagen Ethylene/Vinyl Alcohol Polycarbophil Fibronectin segment Polystyrene sulfonic acid Polydimethylsiloxane Polyethylene Ethylene/Vinyl acetate Polyurethane Lipophilic and Hydrophilic Lipophilic 3
63. Mesh size, S p of macrmolecular network. Crosslinks (o) may be physical entanglements or chemical, permanent junctions. Spheres represent the available space for drug diffusion between chains. 6 S p
64. 7 Increment of Water Uptake (%) 60 40 20 Hours 5 10 15 20 Fraction of Drug Released (F) 0.4 0.2 2:1 MEEMA-HEMA (9.1% w/w) water uptake fraction released
65. Factors Influencing Drug Release from Polymers Diffusing molecule polymer chains polymer chains (a) Symmetrical model (b) Unsymmetrical model 8
74. Toxicologic Pathology, 36:49-62, 2008 Biocompatibility study of extracts from empty implants (available?) Procedure related trauma. Eye large enough to perform accurate injections. Offer delivery options; via other route-configurations. Volume displaced by core as a ratio of total volume of vitreous of species selected. Repeat injections: of similar or increasing ādoseā vs. insertion by incision more invasive Reliably detect and insert implants through narrow anatomy. Direct core at a more acute angle after penetration Core is not tethered can move around and/or settle Compound specific response: need an n-number of control compounds with characterized pharmacological profiles (on and off target) Immune response (sudden severe) and/or macrophage infiltration as a result of foreign body presence (i.e. core) not drug ā āeye reacts as it shouldā Incidental or spontaneous changes that can result in histopathological observations Placebo design & formulation
75.
76. Species differences in the development of the fibrous capsule surrounding poly(2-hydroxyethyl methylcrylate) implants 16 Animal Species Rat Hamster Guinea Pig Capsule Thick Thin Thin Thickness, mm 0.16 - 0.25 0.05 - 0.05 0.03 - 0.06
87. 2. Progestasert 27 Platform Progesterone in reservoir with BaSO 4 and silicone oil Rate-controlling polymeric membrane and entry portal Therapeutic program: 65Āµg/day progesterone for one year
88. Comparison of in vitro and in vivo release rates from the Progesterate Ā® system 28 100 80 60 40 20 0 50 100 150 200 250 300 350 400 450 Time (day) Release Rate (Āµg/day)
89. 3. Transdermal System 29 Covering membrane Drug reservoir Micropore membrane controlling drug release Adhesive contact surface Surface of skin Drug molecules Capillary 9.5 - 14.3 mm 0.17 mm
90. H 2 O soluble Swelling Dimensional stability H 2 O insoluble Chemical change No backbone cleavage H 2 O insoluble Chemical cleavage MWā
91. Rate of polymer dissolution and the rate of release of hydrocortisone for the n-butyl half-ester of methyl vinyl ether-maleic anhydride copolymer containing 10 wt% drug dispersion. 31 0 10 20 30 40 50 60 20 40 60 80 100 0 20 40 60 80 100 0 Time (hours) Drug released (%) Polymer eroded (%) C 4 ester Drug release Polymer dissolution
92. 32 Erosion + Diffusion Diffusion 0 1 2 3 4 5 15 10 5 Time Drug released