Outline and Recommended Reading Controlled Drug Delivery: Fundamentals and Applications, Drugs and t

1
Outline and Recommended ReadingControlled 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

2
Release 1987-01-30Publisher Informa
HealthCareFormat Hardcover 744 pagesISBN
0824775880
3
Reasons for Interest

• Drug re-positioning patenting
• Biotherapeutics
• Better targeting
• Better T.I. (therapeutic index, TD50/ED50)
• 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 molecules 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?)
P

• Intravenous/intraarterial
• Intramuscular/subcutaneous
• Oral
• Buccal / Sublingual
• Rectal
• Nasal
• Pulmonary
• Vaginal
• Intrauterine
• Transdermal
• Ocular

P
E
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 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.

22
0-order release with a fast release component
rapid elimination
23
0-order release with a fast release component
slow elimination
24
1st-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 products controlled release
  nature
• Biopharmaceutics/dissolution
• Proper choice of apparatus
• Sink conditions
• Most discriminating variable knows, process
  critical
• Complete release (gt75-80)
• In vivo bioavailability data

27
Specific Example Part 1

• Hovik Gukasyan, PhD

28
Drug Delivery to the Back of the Eye
Intravitreal device delivery

• 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)

29
Medidur Device with FA for DME

200 mg drug 90 drug/10 PVA
PVA or Silicone seal
Polyimide Tube
PVA
2
5

g
a
u
g
e
3.5 mm
OD0.37 mm

FA fluocinolone acetonide PD-0076535
Solubility is a main driver for release rate-
most legacy VEGFR compounds ( free bases) were
not soluble enough

• TD sol 15 mg/mL (pH 7.4)
• 0.2 mg/day
• 1000 day duration 3 yr
• Phase III 3 yr study

30
10 PVA solution
31
Ethyl vinyl acetate
Polyvinyl alcohol
Ethyl cellulose
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 40-400mg/mL
• Below 40mg, explore formulation options to
  increase the rate of dissolution (implication on
  timelines)
• Above 400mg, explore increasing PVA crystallinity

39
buffer solubility
140
vitreous solubility

• Experimental conditions
• 2-3mgs compound
• 2mL solvent
• 72hr incubation at 37C
• 25 rotations/min
• n1-3, x crystalline,
• a amorphous,
• ND solid state not determined

120
100
DEX
80
mg/mL solubility
60
40
TA
20
FA
PF-00337210
AG-028588x
AG-028613x
PF-00371404x
PF-00525705a
PF-00446859a
PF-00232758a
PF-03431305x
PF-00087298x
PF-00138647x
PF-00138648x
PF-00373758a
PF-00448393ND
PF-00357582ND
PF-00547309-14x
PF-00600051-51ND
40
(No Transcript)
41
Release studies
42
Blood flow, systemic circulation clearance
CL (or sampling)
Vitreous Humor (or sampling compartment)
Direction of mass transport
90 Active in 10 PVA paste
Ctot Cs
10PVA coat
Silicone adhesive seal (low dose configuration)
43
PVA Endcap
PF337210
PF337210
PF337210
SU14813
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).
44
PVA Endcap
Polarized light to enhance the contrast for
visualizing the end cap.
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
D Q/ACt ? h

• Assumptions
• Diffusion via H2O-filled pores
• h XYZ mm
• A XYZ cm2

Device Properties
Compound Properties
Release Rate/Diffusion
47
Diffusion Chamber PVA Membrane
Papp dC/dt 1/CA cm/sec
Diffusion coefficient is Papp diffusion path
length cm2/sec

• PVA membrane fabrication
• 10w/v (aq). 78kDa 98 hydrolyzed
• SOP 3 layers, air dried, cure at 135C for 5
  hours
• other formulation variables
• of layers can be 2
• curing temp. range 100-180C
• 1000ml sample from 4mL chamber (25mM PB pH7.4 in
  saline, maintained at 37C)
• CORRECT FOR AREA!!!
• Cr Cn (1 mL / 4 mL) x Cn-1

48
Correlation of solubility to functional
performance
45
CAI, PF4246518
40
35
5FU
30
2
Nevirapine
25
1.5
Estimated mg/day release from Medidur
20
PF547309
PF190440
PF337210
PF520461
PF366801
Linear fit y0.0026x0.086 R20.994 includes
5FU excludes CAI
1
FA
15
0.5
10
PF484286
0
100
200
300
400
500
5
0
5000
10000
15000
20000
25000
30000
Solubility (mg/mL) 25mM PB pH7.4 in saline,
maintained at 37C, crystalline material
equilibrated for 72hrs
49
clogP or clogD at pH7.4 if ionizable
-2
-1
0
1
2
3
4
5
PF4246518
-4.5
FA
PF547309
-5.5
PF484286
5FU
PF337210
-6.5
Nevirapine
PF520461
Log Papp
PF366801
-7.5
-8.5
PF190440
-9.5
50
Example and validation compound, AVERAGE n3
membranes
Solubility 26mg/mL MW 130g/mol 6.8mg/min flux,
obtained from steady state portion of
curve using a linear fit described by ymxb,
R20.99
2.0
1.8
1.6
1.4
1.2
Cumulative mg of 5FU transferred
1.0
across PVA membrane
0.8
0.6
0.4
0.2
0
50
100
150
200
250
Time (min)
51
Model
1.4
2.5
1.2
2
1
Predicted In Vitro Release (mg/day)
Duration (years)
0.8
1.5
0.6
1
0.4
0.5
0.2
0
0
50
100
150
200
250
300
350
400
450
500
Solubility (mg/mL)
52
Need to update equation? D Q/AC?kt ? h
Membrane thickness
Partition coefficient
Curing temperature
Device Properties
Compound Properties
Release Rate/Diffusion
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 f6phr (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
Polyimid capillary tube shell
Vitreous Space
Collagen fibrils
Polyvinyl alcohol (PVA) membrane
pH7.4, 37C, H2O
25 gauge
Water filled pores, tortuous path
Hyaluronan matrix
55
Anomalous Release of Drugs from Polymeric Matrices
56

• Total 40 configurations
• n3 per config
• 2 cure sets
• 100C (or lowest
• acceptable temp.) vs. 135C
• 120 cores ?2 curing temp. 240 cores needed

2 layers vs. 3 layers?
Mapping Tunable Implant Parameters Per
Compound i.e. curing temperature, of PVA/EVA
coat layers, surface area of end caps
57
100C (or lowest acceptable temp. must be
determined using clear physical cutoff limits,
i.e. weight loss-polymer over time in release)
vs. 135C
18 gauge
25 gauge
No end cap
Silicone seal
Silicone seal
No end cap
No end cap
No end cap
No end cap
No end cap
5 PVA coating
5 EVA coating
2 layers
2 layers
2 layers
5 PVA coating
2 layers
5 EVA coating
2 layers
Silicone seal
2 layers
Silicone seal
2 layers
2 layers
2 layers
2 layers
2 layers
2 layers
3 layers
3 layers
2 layers
2 layers
Silicone seal
Silicone seal
3 layers
3 layers
3 layers
3 layers
3 layers
3 layers
3 layers
3 layers
3 layers
Silicone seal
3 layers
Silicone seal
3 layers
Silicone seal
3 layers
Silicone seal
10 PVA coating
10 EVA coating
10 PVA coating
10 EVA coating
2 layers
2 layers
2 layers
2 layers
2 layers
2 layers
Silicone seal
Silicone seal
2 layers
2 layers
2 layers
2 layers
2 layers
2 layers
2 layers
2 layers
Silicone seal
3 layers
Silicone seal
3 layers
3 layers
3 layers
3 layers
3 layers
3 layers
3 layers
3 layers
3 layers
3 layers
3 layers
Silicone seal
3 layers
Silicone seal
3 layers
Silicone seal
Silicone seal
Possible tox doses
Possible efficacious doses
EVA coats
58
Polymeric Drug Delivery Systems
Hovik Gukasyan, Ph.D.

• Polymer Types
• Factors Influencing Drug Release
• Systems
• Matrix
• Reservoir
• Degradable Polymers

59
Polymer-Based Approaches to Control Drug Release
Type
Release Rate
Time
60
Polymer Type
Examples
Drug Type
Lipophilic and Hydrophilic
Poly(2-hydroxyethyl methacrylate) Poly(vinyl
pyrrolidone) Poly(lactic acid) Poly(glycolic
acid) Collagen Ethylene/Vinyl Alcohol Polycarbophi
l Fibronectin segment Polystyrene sulfonic
acid Polydimethylsiloxane Polyethylene Ethylene/Vi
nyl acetate Polyurethane
Hydrophilic Biodegradable Swellable
Bioadhesive Ion-exchange Hydrophobic
Lipophilic
3
61
Hydrogels
Natural -- Collagen
Cellulose Cross-linked
dextrans Synthetic -- Poly(alkyl methacrylates)
4
62
(No Transcript)
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
64
7
65
Factors Influencing Drug Release from Polymers
(a) Symmetrical model
polymer chains
Diffusing molecule
(b) Unsymmetrical model
polymer chains
8
66
(No Transcript)
67
Factors Influencing Drug Release
1. Molecular Weight
10
68
(No Transcript)
69
12
70
3. Glass Transition Temperature
13
71
(No Transcript)
72
5. Biocompatibility
Healing
Acute
Chronic
PMNs
Fibroblasts
Fibrosis
Mononuclear Leukocytes
15
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, 3649-62,
  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, 3649-62, 2008
75
Placebo Proposals
1

• MATCH
• Size
• Material
• Number
• Delivery Configuration

2
Silicone seal
Silicone seal
3
XYZ layers
XYZ layers
76
Species differences in the development of the
fibrous capsule surrounding poly(2-hydroxyethyl
methylcrylate) implants
16
77
(No Transcript)
78
(No Transcript)
79
(No Transcript)
80
(No Transcript)
81
Release of stearic acid into methanol from a
cylindrical sector
21
82
Cummulative Release
Time (days)
Schematic diagram of an inwardly-releasing
hemisphere
22
83
Reservoir System
.
.
.
.
.
.
.
.
.
.
.
.
.
.
23
84
(No Transcript)
85
s
tem
s
86
PILO-40
PILO-20
26
87
2. Progestasert
27
88
Comparison of in vitro and in vivo release rates
from the Progesterate system
28
89
3. Transdermal System
29
90
H2O soluble Swelling Dimensional stability
H2O insoluble Chemical change No backbone cleavage
H2O 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
92
32
93
33
94
Osmotic Pumps
34
95
Attributes
35
96
36
97
Indocid
37