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.

2. Release : 1987-01-30 Publisher : Informa HealthCare Format : Hardcover 744 pages ISBN : 0824775880

14. Can these drugs benefit from sustained release formulations?

15. Duration of Action

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

18. Passive Diffusion Through a Membrane: The Partition Coefficient

19. Making/Fabricating Polymers…

20. Chemical structures of polymers and copolymers used in product preparation Current Drug Metabolism, 2007, 8, 91-107

22. 0-order release with a fast release component: rapid elimination

23. 0-order release with a fast release component: slow elimination

24. 1 st -order release with a fast release component: slow elimination

25. Increase and Reduce…

27. Specific Example: Part 1 Hovik Gukasyan, PhD

30. 10% PVA solution

31. Polyvinyl alcohol Ethyl vinyl acetate Ethyl cellulose OH n O O n m

32. Tube assembly and parts, prior to filling

33. “wet granulation of FA” and filling the tubes…

34. Filled tubes, cutting them to right dimensions prior to applying seals

35. Sealing

36. Examples of what seals “should” look like visually

37. Delivery device, “introducer”

41. “Release” studies

42. 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

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

45. Specific Example: Part 2 Hovik Gukasyan, PhD

48. 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

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  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 (  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)

52. Release Rate/Diffusion Device Properties Compound Properties Membrane thickness¶ Curing temperature¶ Partition coefficient Need to update equation? D = Q/ A ¶ ”C  k” t  h ¶

54. Vitreous Space Polyimid capillary tube shell Collagen fibrils Hyaluronan matrix Polyvinyl alcohol (PVA) membrane pH7.4, 37 ° C, H 2 O Water filled pores, tortuous path 25 gauge Sol max

55. Anomalous Release of Drugs from Polymeric Matrices

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 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

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

61. Hydrogels Natural -- Collagen Cellulose Cross-linked dextrans Synthetic -- Poly(alkyl methacrylates) 4

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

67. Factors Influencing Drug Release 1. Molecular Weight 10 20 40 60 80 100 Avg. cumulative %age WR-7557 release in vitro 0 10 30 40 50 60 70 80 90 20 Time (days) 150 000 Molecualr Weight 210 000 Molecular Weight 450 000 Molecular Weight

69. 12 %Crystallinity Polymer Poly(L-lactic acid) Poly(DL-lactic acid) Poly(Glycolic acid) 37% 0% 50%

70. 3. Glass Transition Temperature 13 0.83 0.84 0.85 V/(10 -3 m 3 kg -1 ) -25 0 25 50 T/°C T g (0.02) T g (100) 0.02h 100h Polymer T g (°C) SS Flux (10 11 g/cm/s) Poly(  -caprolactone) Poly(DL-lactic acid) 1:1 copolymer -65 57 27 6.1 0.00033 5.8

72. 5. Biocompatibility Acute Chronic Healing PMN’s Fibroblasts Fibrosis Mononuclear Leukocytes 15 TIME INTENSITY

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 “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

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

79. Geometry - Sector and Hemisphere 19

81. Release of stearic acid into methanol from a cylindrical sector 21 24 16 8 0 40 80 120 160 200 240 Amount Released (mg) Time (hour)

82. Cummulative % Release Time (days) Schematic diagram of an inwardly-releasing hemisphere 22 10 20 30 40 50 60 0 20 40 60 80

83. Reservoir System 23 . . . . . . . . . . . . . . M t Time t L = l 2 6D t B = l 2 3D

85. tem s s

86. PILO-40 PILO-20 26 Time (days) Pilocarpine Release Rate (µg/hr) 100 80 60 40 20 0 1 2 3 4 5 6 7

87. 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

88. 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)

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 MW↓

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

93. 33 0 10 20 30 40 50 60 70 80 90 10 20 30 40 50 45 46 47 48 49 50 51 Days Drug release rate, µg/day/cm Crystallinity, % polymer crytsallinity drug release rate

94. Osmotic Pumps 34 Osmotic delivery orifice Semi-permeable membrane Osmotic core containing drug

95. Attributes 35 0 1 2 3 4 5 6 7 10 20 30 40 Stirring Stirring No Stirring Hours Delivery rate, mg/hr

96. 36 0 1 2 3 4 5 6 10 20 30 40 Hours Delivery rate, mg/hr Time in gastric fluid Time in intestinal fluid 15 percent of total delivered

97. 37 Indocid 0 2 4 6 8 10 12 0 5 10 15 20 25 GITS-A GITS-B Indomethacin caps (25mg at 0, 4, 8, 12 hours) Indomethacin caps 3 x 25 mg Time (hours) Amount of indomethacin present in the body (mg)