Control drug delivery system an overview

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

1. ***Fundamentals and Practical Applications of Controlled Release Drug Delivery

2. Influence of drug properties and routes of drug administration on the design of sustained and controlled release technology

3. Theory of mass transfer4. Fundamental considerations in polymer science for

pharmaceutical application5. PK/PD basis of controlled drug delivery: dosing considerations

and bioavailability assessment6. Regulatory implications7. ***Design and fabrication of technology based controlled

release drug delivery systems8. Cases studies: oral, parenteral, implantable, transdermal,

micro/nano particulate colloidal carriers

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

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

1. Release rate dictated by the needs of the body over the period of treatment

– Constant, 0-order (clear PKPD)– Variable (rhythm)

2. Channel the drug to the active site, cell, tissue, organ (drug targeting)

3.3. ““No such DDS exists which combines 1 No such DDS exists which combines 1 and 2…!!!”and 2…!!!”

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:

1. 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

2. Localize drug action by spatial placement of a controlled release system (usually rate controlled) adjacent to or in the diseased tissue or organ

3. Target drug action by using carriers or chemical derivatization to deliver drugs to a particular “target” cell type

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

1. Drug properties

2. Route of drug delivery

3. Target sites

4. Acute or chronic therapy

5. The disease

6. The patient

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

• ADME(T)– Duration of action– Safety

• Side effects

• Margin of safety

• Role of disease state

• Role of Circadian Rhythm

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?)

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

P

EP

PP

P

PP

P

PP

Necessary to dose at intervals shorter than ½ life?

1.T.I.~22.No physiological

constraints3.Delivery limited

Can these drugs benefit from sustained release formulations?

Duration of Action

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

Making/Fabricating Polymers…

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• 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: slow elimination

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

Increase and Reduce…

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

Hovik Gukasyan, PhD

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

•TD sol = 15 g/mL (pH 7.4)•0.2 g/day•1000 day duration ~ 3 yr•Phase III – 3 yr study

OF

HOH

H

OOH

OO

200 g drug90% drug/10% PVA

FA = fluocinolone acetonidePD-0076535

25 gaugePVAPVA or Silicone seal

PolyimideTube

3.5 mm

OD=0.37 mm

Solubility is a main driver for release rate- most legacy VEGFRcompounds ( free bases)were not soluble enough

10% PVA solution

OH

nO

O

n m

Polyvinyl alcohol

Ethyl vinyl acetate

Ethyl cellulose

Tube assembly and parts,prior to filling

“wet granulation of FA” and filling the tubes…

Filled tubes, cutting them to right dimensionsprior to applying seals

Sealing

Examples of what seals “should” look like visually

Delivery device, “introducer”

Impact of solubility in PBS/Vitreous

• Preferred solubility range 40-400g/mL

• Below 40g, explore formulation options to increase the rate of dissolution (implication on timelines)

• Above 400g, explore increasing PVA crystallinity

20

40

60

80

100

120

140

PF-003

7140

4x

PF-005

2570

5a

PF-004

4685

9a

PF-003

3721

0

AG-028

588x

PF-002

3275

8a

PF-034

3130

5x

PF-000

8729

8x

PF-005

4730

9-14

x

PF-001

3864

7x

AG-028

613x

PF-001

3864

8x

PF-003

7375

8a

PF-004

4839

3ND

PF-006

0005

1-51

ND

PF-003

5758

2ND

g/m

L s

olu

bil

ity

buffer solubilityvitreous 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

Change entire medium every 24hrsAnalyze by HPLC method8 day studyPlot cumulative drug released over time

cu

mu

lati

ve

dru

g r

ele

ase

d

time

“lag time”Linear p

ortion of c

urve = steady s

tate release ra

te

“Release” studies

90% Active in 10% PVA “paste”

Ctot = Cs

Dire

ctio

n of

m

ass

tran

spor

t

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

Specific Example: Part 2

Hovik Gukasyan, PhD

Q = amount of drug permeatedD = diffusion coefficientA = surface areaC = solubility of drugh = thickness of membranet = time

Assumptions:1. 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

Dev

ice

Pro

per

ties

Compound Properties

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

• 1000l 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 isPapp * diffusion path length = cm2/sec

Solubility (g/mL)25mM PB pH7.4 in saline, maintained at 37°C, crystalline material equilibrated for 72hrs

Es

tim

ate

d

g/d

ay

rel

eas

e f

rom

Me

did

ur®

5

10

15

20

25

30

35

40

45

0 5000 10000 15000 20000 25000 30000

CAI, PF4246518

NH

O

F

NH

O5FU

0.5

1

1.5

2

0 100 200 300 400 500

PF

19

04

40

PF

54

73

09P

F3

37

210

FA

PF

36

68

01

PF

52

04

61PF484286

Nevirapine

Linear fity=0.0026x+0.086R2=0.994includes 5FUexcludes CAI

Correlation of solubility to functional performance

N

NH

NN

O PF520461

OCH3

O

O

CH3

CH3

OH

OH

F

CH3

F

O

HH

H

H

-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

Lo

g P

app

NH

O

F

NH

O

PF190440

PF547309

PF366801

PF337210

PF484286

Nevirapine

PF4246518

5FU

FA

NH

O

F

NH

O

Solubility 26mg/mLMW 130g/mol6.8g/min flux, obtained from steady state portion of curveusing 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 250Time (min)

Cu

mu

lati

ve m

g o

f 5F

U t

ran

sfer

red

ac

ross

PV

A m

emb

ran

e

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)

Pre

dic

ted

In V

itro

R

ele

as

e (g

/da

y)

0

0.5

1

1.5

2

2.5

Du

rati

on

(y

ea

rs)

*Release (g/day)

**Duration (years; f(x)=1/x type of functionwhere payload is 200g)

Release Rate/Diffusion

Dev

ice

Pro

per

ties

Compound Properties

Membrane thickness¶

Curing temperature¶

Partition coefficient

Need to update equation?

D = Q/A¶”Ck”t h¶

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=6hr (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

Solmax

Vitreous SpacePolyimid capillary tube shell

Collagen fibrils

Hyaluronan matrix

Po

lyv

iny

l alc

oh

ol

(PV

A) m

em

bra

ne

pH7.4, 37°C, H2O

Water filled pores, tortuous path

25 g

auge

Anomalous Release of Drugs from Polymeric Matrices

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

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

Hig

h release

Lo

w

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 coating2 layers

3 layers

2 layers

3 layers

2 layers

3 layers

2 layers

3 layers

EVA coats

Polymeric Drug Delivery SystemsPolymeric Drug Delivery Systems

Hovik Gukasyan, Ph.D.

I.Polymer TypesII.Factors Influencing Drug

ReleaseIII.Systems

1.Matrix2.Reservoir

IV.Degradable Polymers

TypeType

Rel

ease

Rat

e

Time

Polymer-Based Approaches to Control Drug ReleasePolymer-Based Approaches to Control Drug Release

Polymer Type Examples Drug TypeHydrophilic

Biodegradable

Swellable

Bioadhesive

Ion-exchange

Hydrophobic

Poly(2-hydroxyethyl methacrylate)

Poly(vinyl pyrrolidone)Poly(lactic acid)Poly(glycolic acid)Collagen

Ethylene/Vinyl Alcohol

PolycarbophilFibronectin segment

Polystyrene sulfonic acid

PolydimethylsiloxanePolyethyleneEthylene/Vinyl acetatePolyurethane

Lipophilic and Hydrophilic

Lipophilic

3

HydrogelsHydrogels

Natural -- Collagen Cellulose Cross-linked dextrans

Synthetic -- Poly(alkyl methacrylates)

4

Sp

Mesh size, Sp of macrmolecular network. Crosslinks (o) may bephysical entanglements or chemical, permanent junctions. Spheresrepresent the available space for drug diffusion between chains.

6

Incr

emen

t of

Wat

er U

pta

ke

(%)

60

40

20

Hours

5 10 15 20

Fraction

of Dru

g Released

(F)

0.4

0.2

2:1 MEEMA-HEMA(9.1% w/w)

water uptakefraction released

7

Factors Influencing Drug Release from Factors Influencing Drug Release from PolymersPolymers

Diffusingmolecule

polymerchains

polymerchains

(a) Symmetrical model

(b) Unsymmetrical model

8

Factors Influencing Drug ReleaseFactors Influencing Drug Release1. Molecular Weight

20

40

60

80

100

Avg

. cum

ulat

ive

%ag

e W

R-7

557

rele

ase

in v

itro

0 10 30 40 50 60 70 80 9020

Time (days)

150 000 Molecualr Weight

210 000 Molecular Weight

450 000 Molecular Weight

10

2. 2. CrystallinityCrystallinity

Change in the Crystallinity of Poly(-Caprolactone) as a

Function of Molecular Weight

MolecularWeight (Mw)

59,30053,00046,40037,10030,60026,80023,40021,700

Crystallinity(%)

47.550.650.552.557.058.658.459.5

11

2. 2. CrystallinityCrystallinity

Change in the Crystallinity of Poly(-Caprolactone) as a

Function of Molecular Weight

MolecularWeight (Mw)

59,30053,00046,40037,10030,60026,80023,40021,700

Crystallinity(%)

47.550.650.552.557.058.658.459.5

11

%CrystallinityPolymer

Poly(L-lactic acid)Poly(DL-lactic acid)Poly(Glycolic acid)

37%0%

50%

12

0.83

0.84

0.85V

/(10

-3 m

3 k

g-1)

-25 0 25 50T/°C

Tg(0.02)

Tg(100)

0.02h

100h

Polymer Tg (°C) SS Flux(1011 g/cm/s)

Poly(-caprolactone)Poly(DL-lactic acid)1:1 copolymer

-655727

6.10.00033

5.8

3. Glass Transition Temperature3. Glass Transition Temperature

13

4. Cross4. Cross--Links DensityLinks Density

Dependence of in vitro and in vivo Release Profiles of Norgestomet and Polymer Diffusivities on Extent of Cross-Linkage (XL) in Hydrogel Implants

XL(%)

1.24.89.6

12.014.416.819.2

Dp x 103

(cm2/day

97.224.212.19.78.16.96.1

Q/t1/2 (mg cm-2 day -1/2)In vitro In vivoa

0.6050.3960.1850.1330.1010.0740.058

0.6400.504--------------------

0.129

aResults from the subcutaneous implantation of Norgestomet-releasing Hydrogen implants in 39 cows for 16 days

14

4. Cross4. Cross--Links DensityLinks Density

Dependence of in vitro and in vivo Release Profiles of Norgestomet and Polymer Diffusivities on Extent of Cross-Linkage (XL) in Hydrogel Implants

XL(%)

1.24.89.6

12.014.416.819.2

Dp x 103

(cm2/day

97.224.212.19.78.16.96.1

Q/t1/2 (mg cm-2 day -1/2)In vitro In vivoa

Q/t1/2 (mg cm-2 day -1/2)In vitro In vivoa

0.6050.3960.1850.1330.1010.0740.058

0.6400.504--------------------

0.129

aResults from the subcutaneous implantation of Norgestomet-releasing Hydrogen implants in 39 cows for 16 days

14

TIME

INT

EN

SIT

Y5. Biocompatibility5. Biocompatibility

Acute ChronicHealing

PMN’s Fibroblasts

FibrosisMononuclear Leukocytes

15

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, 2008Toxicologic 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.

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

Toxicologic Pathology, 36:49-62, 2008Toxicologic Pathology, 36:49-62, 2008

Placebo Proposals

MATCH• Size• Material• Number• Delivery

Configuration Silicone sealSilicone seal

XYZ layersXYZ layers

1

2

3

Animal Species

RatHamsterGuinea Pig

Capsule

ThickThinThin

Thickness, mm

0.16 - 0.250.05 - 0.050.03 - 0.06

Species differences in the development of the fibrouscapsule surrounding poly(2-hydroxyethyl methylcrylate)implants

16

Matrix Matrix SytstemsSytstems (Monolithic(MonolithicSystems)Systems)

t=t1 t=t2

Cs

t=t3

Cylindrical DevicesCylindrical Devices

Drug release is described by Fick’s Law

Cs

t=t1

Cs

t=t2

Cs

t=t3

}

l}

l

}

l

17

Matrix Matrix SytstemsSytstems (Monolithic(MonolithicSystems)Systems)

t=t1 t=t2

Cs

t=t3t=t1t=t1 t=t2t=t2

Cs

t=t3

CsCsCs

t=t3

Cylindrical DevicesCylindrical Devices

Drug release is described by Fick’s LawDrug release is described by Fick’s Law

Cs

t=t1

Cs

t=t2

Cs

t=t3

}

l}

l

}

l

Cs

t=t1

Cs

t=t2

Cs

t=t3

Cs

t=t1

CsCsCs

t=t1

Cs

t=t2

CsCs

t=t2

Cs

t=t3

CsCsCs

t=t3

}

l}

l

}

l

}

l}

l

}

l

17

Constraint

CO > CS

CO >> CS

Mt

A[DCS(2CO-CS)t)]1/2

A(2DCSCOt)1/2

dMt/dt

(A/2)[(DCS/t)(2CO-CS)]

(A/2)[2DCSCO/t]1/2

Drug Loading

Dru

g re

leas

ed (m

g/cm

2 )

0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0

2018161412108642

(Hours)1/2

18

Constraint

CO > CS

CO >> CS

Mt

A[DCS(2CO-CS)t)]1/2

A(2DCSCOt)1/2

dMt/dt

(A/2)[(DCS/t)(2CO-CS)]

(A/2)[2DCSCO/t]1/2

Constraint

CO > CS

CO >> CS

Mt

A[DCS(2CO-CS)t)]1/2

A(2DCSCOt)1/2

dMt/dt

(A/2)[(DCS/t)(2CO-CS)]

(A/2)[2DCSCO/t]1/2

Constraint

CO > CS

CO >> CS

Constraint

CO > CS

CO >> CS

Mt

A[DCS(2CO-CS)t)]1/2

A(2DCSCOt)1/2

Mt

A[DCS(2CO-CS)t)]1/2

A(2DCSCOt)1/2

dMt/dt

(A/2)[(DCS/t)(2CO-CS)]

(A/2)[2DCSCO/t]1/2

dMt/dt

(A/2)[(DCS/t)(2CO-CS)]

(A/2)[2DCSCO/t]1/2

Drug Loading

Dru

g re

leas

ed (m

g/cm

2 )

0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0

2018161412108642

(Hours)1/2

Drug LoadingDrug Loading

Dru

g re

leas

ed (m

g/cm

2 )

0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0D

rug

rele

ased

(mg/

cm2 )

0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0

0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0

2018161412108642

(Hours)1/2

2018161412108642 2018161412108642

(Hours)1/2

18

Geometry - Sector and HemisphereGeometry - Sector and Hemisphere

19

ai

ao

R

ai

Top Viewt=0

Side ViewCross Section

t=0

Slice, Side ViewCross Section

t=0

20

aiai

ao

R

ai

Top Viewt=0

Side ViewCross Section

t=0

Slice, Side ViewCross Section

t=0

20

24

16

8

0 40 80 120 160 200 240Am

ou

nt

Rele

ased

(m

g)

Time (hour)

Release of stearic acid into methanol from a cylindrical sector

21

10 20 30 40 50 600

20

40

60

80C

um

mu

lati

ve %

Rele

ase

Time (days)

Schematic diagram of an inwardly-releasing hemisphere

22

Mt

TimetL=l2

6DtB=

l2

3D

Mt DCo

l(t

l2

6D)

Mt DCo

l(t

l2

3D)

Reservoir SystemReservoir System

23

.. ..

.

.

...

....

.

Q (m

g/cm

2 )

0 5

Time (hours)

10 15 20 25

2

4

6

8

10

12

14A B

C

D

0.15mm

0.60

1.0

2.5

24

Q (m

g/cm

2 )

0 5

Time (hours)

10 15 20 25

2

4

6

8

10

12

14A B

C

D

0.15mm

0.60

1.0

2.5

24

Membrane

Core

Ring5.7

mm

13.4 mm

Transparent rate-controlling membranes

Pilocarpinereservoir

Annular ring(surroundsreservoir -

opaque whitefor visibility inhandling and

inserting system)

Schematic diagram of an ocular therapeutic systemSchematic diagram of an ocular therapeutic system

OcusertOcusert®® continuous drug delivery devicecontinuous drug delivery device

25

Membrane

Core

Ring5.7

mm

13.4 mm

Membrane

Core

Ring

Membrane

Core

Ring5.7

mm

13.4 mm

Transparent rate-controlling membranes

Pilocarpinereservoir

Annular ring(surroundsreservoir -

opaque whitefor visibility inhandling and

inserting system)

Schematic diagram of an ocular therapeutic systemSchematic diagram of an ocular therapeutic system

OcusertOcusert®® continuous drug delivery devicecontinuous drug delivery device

25

tems

s

Time (days)

Pilocarp

ine R

ele

ase R

ate

(µ

g/h

r)100

80

60

40

20

0 1 2 3 4 5 6 7

PILO-40

PILO-20

26

2. Progestasert2. Progestasert

Platform

Progesterone in reservoirwith BaSO4 and silicone oil

Rate-controlling polymericmembrane and entry portal

Therapeutic program: 65µg/dayprogesterone for one year 27

100

80

60

40

20

0 50 100 150 200 250 300 350 400 450

Time (day)

Rele

ase R

ate

(µ

g/d

ay)

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

28

Covering membrane

Drug reservoir

Micropore membranecontrolling drug release

Adhesive contact surface

Surface of skin

Drug moleculesCapillary

9.5 - 14.3 mm

0.1

7 m

m3. Transdermal System3. Transdermal System

29

xx x

x x

C

O OR

C

O OH

C

O OR

C

O O-

x

x x

x

x x

x

x x

x

Type I

Type II

Type III

Biodegradable PolymersBiodegradable Polymers

30

xx x

x x

C

O OR

C

O OH

C

O OR

C

O O-

x

x x

x

x x

x

x x

x

Type I

Type II

Type III

xx x

x x

xx x

x x

xx x

x x

C

O OR

C

O OH

C

O OR

C

O O-

C

O OR

C

O OH

C

O OR

C

O OR

C

O OH

C

O OH

C

O OR

C

O O-

C

O OR

C

O OR

C

O O-

C

O O-

x

x x

x

x x

x

x x

xx

x x

x

x x

x

x x

x

x x

x

x x

xx

x x

x

Type I

Type II

Type III

Biodegradable PolymersBiodegradable Polymers

30

H2O solubleSwellingDimensional stability

H2O insolubleChemical changeNo backbone cleavage

H2O insolubleChemical cleavageMW↓

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.

010 20 30 40 50 60

20

40

60

80

100

0

20

40

60

80

100

0Time (hours)

Dru

g r

ele

ased

(%

)P

oly

mer e

rod

ed

(%)C4 ester

Drug release

Polymer dissolution

31

Erosion + Diffusion

Diffusion

0 1 2 3 4 5

15

10

5

Time

Dru

g r

ele

ased

32

0 10 20 30 40 50 60 70 80 90

10

20

30

40

50

45

46

47

48

49

50

51

Days

Dru

g r

ele

ase r

ate

, µ

g/d

ay/c

mC

rysta

llinity

, %

polymer crytsallinity

drug release rate

33

Osmotic deliveryorifice

Semi-permeablemembrane

Osmotic corecontaining drug

Osmotic Osmotic PumpsPumps

34

0 1 2 3 4 5 6 7

10

20

30

40Stirring StirringNo Stirring

Hours

Delivery

rate

, m

g/h

r

AttributesAttributes

35

0 1 2 3 4 5 6

10

20

30

40

Hours

Delivery

rate

, m

g/h

rTime in gastric fluidTime in intestinal fluid

15 percent oftotal delivered

36

0 2 4 6 8 10 120

5

10

15

20

25GITS-AGITS-B

Indomethacin caps (25mg at 0, 4, 8, 12 hours)Indomethacin caps 3 x 25 mg

Time (hours)

Am

ou

nt

of

ind

om

eth

acin

pre

sen

t in

th

e b

od

y (

mg

)

37

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