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Outline and Recommended Reading“Controlled Drug Delivery: Fundamentals and Applications”, (Drugs and the Pharmaceutical Sciences; v. 29). 2nd ed. Revised and Expanded, edited by J.R. Robinson and V.H.L. Lee 1987 : 

Outline and Recommended Reading“Controlled Drug Delivery: Fundamentals and Applications”, (Drugs and the Pharmaceutical Sciences; v. 29). 2nd 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

Slide 2: 

Release: 1987-01-30Publisher: Informa HealthCareFormat: Hardcover 744 pagesISBN: 0824775880

Reasons for Interest… : 

Reasons for Interest… Drug re-positioning –patenting Biotherapeutics Better targeting Better T.I. (therapeutic index, TD50/ED50) Precise spatial and temporal placement within body

An Ideal Drug Delivery System : 

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…!!!”

Terminology : 

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

Controlled Delivery Attempts to: : 

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

Rationale of Controlled Drug Delivery : 

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.

Factors Influencing the Design and Performance of Controlled Release Dosage forms : 

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

Physicochemical Properties of a Drug Influencing Design and Performance : 

Physicochemical Properties of a Drug Influencing Design and Performance Solubility Partition coefficient Molecular weight Chemical stability Physical stability Protein binding

Biological Characteristics of a Drug Influencing Design and Performance : 

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

Selected routes of Drug Administration : 

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 ?

Routes: (par-enteral?) : 

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

Necessary to dose at intervals shorter than ½ life? : 

Necessary to dose at intervals shorter than ½ life? T.I.~2 No physiological constraints Delivery limited

Can these drugs benefit from sustained release formulations? : 

Can these drugs benefit from sustained release formulations?

Duration of Action : 

Duration of Action

Theory of Mass Transfer : 

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 : 

Diffusion is an Effective Transport Mechanism over Small Distances

Passive Diffusion Through a Membrane: The Partition Coefficient : 

Passive Diffusion Through a Membrane: The Partition Coefficient

Making/Fabricating Polymers… : 

Making/Fabricating Polymers…

Chemical structures of polymers and copolymers used in product preparation : 

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

PK/PD basis of controlled drug delivery: dosing considerations and bioavailability assessment : 

PK/PD basis of controlled drug delivery: dosing considerations and bioavailability assessment Models of Drug Input and Elimination 0-order absorption followed by 1st-order elimination 1st-order absorption followed by 1st-order elimination Model independent PK analysis Pharmacodynamic Models Fixed-effect model [drug]  effect obs. or n/obs.

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

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

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

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

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

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

Increase and Reduce… : 

Increase and Reduce…

Regulatory implications : 

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

Specific Example: Part 1 : 

Specific Example: Part 1 Hovik Gukasyan, PhD

Drug Delivery to the Back of the Eye : 

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

Medidur Device with FA for DME : 

Medidur Device with FA for DME TD sol = 15 mg/mL (pH 7.4) 0.2 mg/day 1000 day duration ~ 3 yr Phase III – 3 yr study 200 mg 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

10% PVA solution : 

10% PVA solution

Slide 31: 

Polyvinyl alcohol Ethyl vinyl acetate Ethyl cellulose

Slide 32: 

Tube assembly and parts, prior to filling

Slide 33: 

“wet granulation of FA” and filling the tubes…

Slide 34: 

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

Slide 35: 

Sealing

Slide 36: 

Examples of what seals “should” look like visually

Slide 37: 

Delivery device, “introducer”

Impact of solubility in PBS/Vitreous : 

Impact of solubility in PBS/Vitreous Preferred solubility range 40-400mg/mL Below 40mg, explore formulation options to increase the rate of dissolution (implication on timelines) Above 400mg, explore increasing PVA crystallinity

Slide 39: 

20 40 60 80 100 120 140 PF-00371404x PF-00525705a PF-00446859a PF-00337210 AG-028588x PF-00232758a PF-03431305x PF-00087298x PF-00547309-14x PF-00138647x AG-028613x PF-00138648x PF-00373758a PF-00448393ND PF-00600051-51ND PF-00357582ND mg/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

“Release” studies : 

“Release” studies

Slide 42: 

90% Active in 10% PVA “paste” Ctot = Cs 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

Slide 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

Slide 44: 

Polarized light to enhance the contrast for visualizing the end cap. PVA Endcap

Specific Example: Part 2 : 

Specific Example: Part 2 Hovik Gukasyan, PhD

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 H2O-filled pores h = XYZ mm A = XYZ cm2 Functional Principles of Medidur® Technology D = Q/A”C”t  h Release Rate/Diffusion Device Properties Compound Properties

Diffusion Chamber & PVA Membrane : 

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 1000ml sample from 4mL chamber (25mM PB pH7.4 in saline, maintained at 37°C) CORRECT FOR AREA!!! Cr = Cn + (1 mL / 4 mL) x Cn-1 Papp = dC/dt * 1/CA = cm/sec Diffusion coefficient is Papp * diffusion path length = cm2/sec

Slide 48: 

Solubility (mg/mL) 25mM PB pH7.4 in saline, maintained at 37°C, crystalline material equilibrated for 72hrs Estimated mg/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 R2=0.994 includes 5FU excludes CAI Correlation of solubility to functional performance

Slide 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 Papp PF190440 PF547309 PF366801 PF337210 PF484286 Nevirapine PF4246518 5FU FA

Slide 50: 

Solubility 26mg/mL MW 130g/mol 6.8mg/min flux, obtained from steady state portion of curve using a linear fit described by y=mx+b, R2=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

Slide 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 (mg/mL) Predicted In Vitro Release (mg/day) 0 0.5 1 1.5 2 2.5 Duration (years)

Slide 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¶

Assumptions : 

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=6phr (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

Slide 54: 

Vitreous Space Polyimid capillary tube shell Collagen fibrils Hyaluronan matrix Polyvinyl alcohol (PVA) membrane pH7.4, 37°C, H2O Water filled pores, tortuous path 25 gauge

Slide 55: 

Anomalous Release of Drugs from Polymeric Matrices

Slide 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

Slide 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

Slide 58: 

Polymeric Drug Delivery Systems Hovik Gukasyan, Ph.D. Polymer Types Factors Influencing Drug Release Systems Matrix Reservoir Degradable Polymers

Slide 59: 

Type Release Rate Time Polymer-Based Approaches to Control Drug Release

Slide 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

Slide 61: 

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

Slide 63: 

Mesh size, Sp of macrmolecular network. Crosslinks (o) may be physical entanglements or chemical, permanent junctions. Spheres represent the available space for drug diffusion between chains. 6

Slide 64: 

7

Slide 65: 

Factors Influencing Drug Release from Polymers Diffusing molecule polymer chains polymer chains (a) Symmetrical model (b) Unsymmetrical model 8

Slide 67: 

Factors Influencing Drug Release 1. Molecular Weight 10

Slide 69: 

12

Slide 70: 

3. Glass Transition Temperature 13

Slide 72: 

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

Placebo considerations… : 

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.

Slide 74: 

Toxicologic Pathology, 36:49-62, 2008

Placebo Proposals : 

Placebo Proposals MATCH Size Material Number Delivery Configuration Silicone seal Silicone seal XYZ layers XYZ layers 1 2 3

Slide 76: 

Species differences in the development of the fibrous capsule surrounding poly(2-hydroxyethyl methylcrylate) implants 16

Slide 81: 

Release of stearic acid into methanol from a cylindrical sector 21

Slide 82: 

Cummulative % Release Time (days) Schematic diagram of an inwardly-releasing hemisphere 22

Slide 83: 

Reservoir System 23 . . . . . . . . . . . . . .

Slide 85: 

tem s s

Slide 86: 

PILO-40 PILO-20 26

Slide 87: 

2. Progestasert 27

Slide 88: 

Comparison of in vitro and in vivo release rates from the Progesterate® system 28

Slide 89: 

3. Transdermal System 29

Slide 90: 

H2O soluble Swelling Dimensional stability H2O insoluble Chemical change No backbone cleavage H2O insoluble Chemical cleavage MW↓

Slide 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

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32

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33

Slide 94: 

Osmotic Pumps 34

Slide 95: 

Attributes 35

Slide 96: 

36

Slide 97: 

37 Indocid

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