Outline and Recommended Reading “Controlled Drug Delivery: Fundamentals and Applications”, (Drugs and the Pharmaceutical Sciences; v. 29). 2 nd ed. Revised and Expanded, edited by J.R. Robinson and V.H.L. Lee 1987
***Fundamentals and Practical Applications of Controlled Release Drug Delivery
Influence of drug properties and routes of drug administration on the design of sustained and controlled release technology
Theory of mass transfer
Fundamental considerations in polymer science for pharmaceutical application
PK/PD basis of controlled drug delivery: dosing considerations and bioavailability assessment
***Design and fabrication of technology based controlled release drug delivery systems
Sustain drug action at a predetermined rate by maintaining a relatively constant, effective drug level in the body with concomitant minimization of undesirable side effects associated with a sawtooth kinetic pattern
Localize drug action by spatial placement of a controlled release system (usually rate controlled) adjacent to or in the diseased tissue or organ
Target drug action by using carriers or chemical derivatization to deliver drugs to a particular “target” cell type
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.
Diffusion is an Effective Transport Mechanism over Small Distances
Passive Diffusion Through a Membrane: The Partition Coefficient
200 g drug 90% drug/10% PVA FA = fluocinolone acetonide PD-0076535 2 5 g a u g e PVA PVA or Silicone seal Polyimide Tube 3.5 mm OD=0.37 mm Solubility is a main driver for release rate - most legacy VEGFR compounds ( free bases) were not soluble enough
20 40 60 80 100 120 140 PF-00371404 x PF-00525705 a PF-00446859 a PF-00337210 AG-028588 x PF-00232758 a PF-03431305 x PF-00087298 x PF-00547309-14 x PF-00138647 x AG-028613 x PF-00138648 x PF-00373758 a PF-00448393 ND PF-00600051-51 ND PF-00357582 ND g/mL solubility buffer solubility vitreous solubility
90% Active in 10% PVA “paste” C tot = C s Direction of mass transport 10%PVA coat Vitreous Humor (or sampling compartment) CL (or sampling) Silicone adhesive seal (“low dose” configuration) Blood flow, systemic circulation clearance
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
Polarized light to enhance the contrast for visualizing the end cap. PVA Endcap
“ SOP”: 3 layers, air dried, cure at 135 ° C for 5 hours
other formulation variables
# of layers can be 2
curing temp. range 100-180 ° C
1000 l sample from 4mL chamber (25mM PB pH7.4 in saline, maintained at 37 ° C)
CORRECT FOR AREA!!!
C r = C n + (1 mL / 4 mL) x C n-1
P app = dC/dt * 1/CA = cm/sec Diffusion coefficient is P app * diffusion path length = cm 2 /sec
Solubility ( g/mL) 25mM PB pH7.4 in saline, maintained at 37°C, crystalline material equilibrated for 72hrs Estimated g/day release from Medidur® 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
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
Solubility 26mg/mL MW 130g/mol 6.8 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?
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 ( g/mL) Predicted In Vitro Release ( g/day) 0 0.5 1 1.5 2 2.5 Duration (years) *Release ( g/day) **Duration (years; f(x)=1/x type of function where payload is 200 g)
Release Rate/Diffusion Device Properties Compound Properties Membrane thickness¶ Curing temperature¶ Partition coefficient Need to update equation? D = Q/ A ¶ ”C k” t h ¶
Mapping Tunable Implant Parameters Per Compound i.e. curing temperature, #of PVA/EVA coat layers, surface area of end caps
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 100°C (or lowest acceptable temp. must be determined using clear physical cutoff limits, i.e. %weight loss-polymer over time in release) vs. 135°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
Polymeric Drug Delivery Systems Hovik Gukasyan, Ph.D.
Factors Influencing Drug Release
Type Release Rate Time Polymer-Based Approaches to Control Drug Release
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
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
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
Factors Influencing Drug Release from Polymers Diffusing molecule polymer chains polymer chains (a) Symmetrical model (b) Unsymmetrical model 8
NCE ( physicochemical properties, SAR, in vitro assays ) or a new formulation containing new excipients or vehicles.
FDA provides most current and thorough look at (non)clinical development of a nonbiodegradable ocular implants. Toxicologic Pathology, 36:49-62, 2008
Technology utilizes polyimid and polyvinyl alcohol polymers, both of which have ocular clinical use precedence.
In ~1000 patients (some with multiple implants), PHIII clinical trial.
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 “dose” 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 – “eye reacts as it should” Incidental or spontaneous changes that can result in histopathological observations Placebo design & formulation
Silicone seal Silicone seal XYZ layers XYZ layers 1 2 3
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
2. Progestasert 27 Platform Progesterone in reservoir with BaSO 4 and silicone oil Rate-controlling polymeric membrane and entry portal Therapeutic program: 65µg/day progesterone for one year
Comparison of in vitro and in vivo release rates from the Progesterate ® system 28 100 80 60 40 20 0 50 100 150 200 250 300 350 400 450 Time (day) Release Rate (µg/day)
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
H 2 O soluble Swelling Dimensional stability H 2 O insoluble Chemical change No backbone cleavage H 2 O insoluble Chemical cleavage MW↓
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
32 Erosion + Diffusion Diffusion 0 1 2 3 4 5 15 10 5 Time Drug released