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Control drug delivery system an overview

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  • 1. 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
    • Regulatory implications
    • ***Design and fabrication of technology based controlled release drug delivery systems
    • Cases studies: oral, parenteral, implantable, transdermal, micro/nano particulate colloidal carriers
  • 2. Release : 1987-01-30 Publisher : Informa HealthCare Format : Hardcover 744 pages ISBN : 0824775880
  • 3. Reasons for Interest…
    • Drug re-positioning –patenting
    • Biotherapeutics
    • Better targeting
    • Better T.I. (therapeutic index, TD 50 /ED 50 )
      • Precise spatial and temporal placement within body
  • 4. An Ideal Drug Delivery System
    • Release rate dictated by the needs of the body over the period of treatment
      • Constant, 0-order (clear PK  PD)
      • Variable (rhythm)
    • Channel the drug to the active site, cell, tissue, organ (drug targeting)
    • “ No such DDS exists which combines 1 and 2…!!!”
  • 5. Terminology
    • Systems which can provide “some” control of drug release in the body
      • Temporal
      • Spatial
      • Both
      • Specify release rate and duration in vivo by simple in vitro tests
    • Prolonged or sustained release systems are not controlled release systems by this definition
  • 6. Controlled Delivery Attempts to:
    • 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
  • 7. Rationale of Controlled Drug Delivery
    • Alter PK/PD by:
      • Design of drug delivery system
      • Modify drug structure
      • Modify physiology
    • Duration of drug action is a design property of the rate controlled dosage form and not a property of the drug molecule’s inherent kinetic characteristics.
  • 8. Factors Influencing the Design and Performance of Controlled Release Dosage forms
    • Drug properties
    • Route of drug delivery
    • Target sites
    • Acute or chronic therapy
    • The disease
    • The patient
  • 9. Physicochemical Properties of a Drug Influencing Design and Performance
    • Solubility
    • Partition coefficient
    • Molecular weight
    • Chemical stability
    • Physical stability
    • Protein binding
  • 10. Biological Characteristics of a Drug Influencing Design and Performance
    • ADME(T)
      • Duration of action
      • Safety
        • Side effects
        • Margin of safety
    • Role of disease state
    • Role of Circadian Rhythm
  • 11. Selected routes of Drug Administration
    • Enteral – Intestinal
      • All other routes considered Parenteral
    Is this enteral or parenteral drug delivery ?                            What type of injection is this ?
  • 12. Routes: (par-enteral?)
    • Intravenous/intraarterial
    • Intramuscular/subcutaneous
    • Oral
    • Buccal / Sublingual
    • Rectal
    • Nasal
    • Pulmonary
    • Vaginal
    • Intrauterine
    • Transdermal
    • Ocular
    P E P P P P P P P P P
  • 13. Necessary to dose at intervals shorter than ½ life?
    • T.I.~2
    • No physiological constraints
    • Delivery limited
  • 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
  • 21. PK/PD basis of controlled drug delivery: dosing considerations and bioavailability assessment
    • Models of Drug Input and Elimination
      • 0-order absorption followed by 1 st -order elimination
      • 1 st -order absorption followed by 1 st -order elimination
      • Model independent PK analysis
    • Pharmacodynamic Models
      • Fixed-effect model [drug]  effect obs. or n/obs.
  • 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…
  • 26. Regulatory implications
    • Demonstration of safety and efficacy
      • Already approved drugs
    • Submitted data
      • Specifications meet claims made
      • No dose dumping
      • Steady state performance equivalent
      • Daily dose equivalent
      • Tight specifications (low variability)
    • Recommended reference standard for comparative studies
    • Demonstration of product’s controlled release nature
      • Biopharmaceutics/dissolution
        • Proper choice of apparatus
        • Sink conditions
        • Most discriminating variable knows, process critical
        • Complete release (>75-80%)
    • In vivo bioavailability data
  • 27. Specific Example: Part 1 Hovik Gukasyan, PhD
  • 28. Drug Delivery to the Back of the Eye
    • Subtenon
      • Injection behind the eye in the subtenon space
    • Intravitreal ( IVT)
      • Injection of a suspension or device into the vitreous
    • Topical
      • Solution/Suspension dispensed to front of the eye ( exploratory)
    Intravitreal device delivery
  • 29. Medidur Device with FA for DME
    • TD sol = 15  g/mL (pH 7.4)
    • 0.2  g/day
    • 1000 day duration ~ 3 yr
    • Phase III – 3 yr study
    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
  • 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”
  • 38. Impact of solubility in PBS/Vitreous
    • Preferred solubility range 40-400  g/mL
    • Below 40  g, explore formulation options to increase the rate of dissolution (implication on timelines)
    • Above 400  g, explore increasing PVA crystallinity
  • 39. 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
    • Experimental conditions
    • 2-3mgs compound
    • 2mL “solvent”
    • 72hr incubation at 37 ° C
    • 25 rotations/min
    • n=1-3, x : crystalline,
    • a : amorphous,
    • ND : solid state not determined
    FA TA DEX
  • 40.  
  • 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
  • 46. Functional Principles of Medidur® Technology Q = amount of drug permeated D = diffusion coefficient A = surface area C = solubility of drug h = thickness of membrane t = time
    • Assumptions:
    • Diffusion via H 2 O-filled pores
    • h = XYZ mm
    • A = XYZ cm 2
    D = Q/ A ”C” t  h Release Rate/Diffusion Device Properties Compound Properties
  • 47. Diffusion Chamber & PVA Membrane
    • PVA membrane fabrication
    • 10%w/v (aq). 78kDa 98% hydrolyzed
    • “ 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
  • 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 ¶
  • 53. Assumptions
    • Daily dose required for sufficient target tissue exposure and efficacy
    • Well behaved release e.g. D = Q/ACt  h
    • Diffusion coefficient theoretical:
      • (1/f)*kT where f=6  hr (calculated for a sphere is minimal value, asymmetry and nonelastic interaction with solvent)
      • Dependent on size and shape of drug, interaction of drug with solvent and viscosity of solvent
    • Diffusion coefficient calculated:
      • Q vs. t plot
      • Release rate study
  • 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
  • 56. 2 layers vs. 3 layers?
    • Total 40 configurations
    • n=3 per config
    • 2 cure sets
    • 100 ° C (or lowest
    • acceptable temp.) vs. 135 ° C
    • 120 cores  2 curing temp.= 240 cores needed
    Mapping Tunable Implant Parameters Per Compound i.e. curing temperature, #of PVA/EVA coat layers, surface area of end caps
  • 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
  • 58. Polymeric Drug Delivery Systems Hovik Gukasyan, Ph.D.
    • Polymer Types
    • Factors Influencing Drug Release
    • Systems
      • Matrix
      • Reservoir
    • Degradable Polymers
  • 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
  • 62.  
  • 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
  • 66.  
  • 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
  • 68.  
  • 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
  • 71.  
  • 72. 5. Biocompatibility Acute Chronic Healing PMN’s Fibroblasts Fibrosis Mononuclear Leukocytes 15 TIME INTENSITY
  • 73. Placebo considerations…
    • NCE ( physicochemical properties, SAR, in vitro assays ) or a new formulation containing new excipients or vehicles.
    • Medidur®/Retisert®/Vitrasert®
      • 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.
  • 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
  • 75. Placebo Proposals
    • MATCH
    • Size
    • Material
    • Number
    • Delivery Configuration
    Silicone seal Silicone seal XYZ layers XYZ layers 1 2 3
  • 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
  • 77.  
  • 78.  
  • 79. Geometry - Sector and Hemisphere 19
  • 80.  
  • 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
  • 84.  
  • 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)

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