alleman - drug release measurements

8/6/2019 Alleman - Drug Release Measurements

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Case Studies Drug Release Measurements onOphthalmic Dosage Forms

AAPS Workshop:

Special Dosage Forms Whats New

with In Vitro Drug ReleaseNovember 2009

Kent Alleman, PhD.

Bausch & Lomb, Inc.

Analytical & Materials Sciences


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Outline Case Studies

Background Solutions

Ointments

Suspensions

Ophthalmic Suspension (suspension of API)

Ophthalmic Suspension (suspension of a cationion-exchange resin with bound drug)

Gels & EmulsionsPluronic-g-poly(acrylic acid) copolymer gel

Implants

Retisert (fluocinolone acetonide intravitrealimplant) 0.59 mg


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Background

Drug delivery to the eye is generally difficult

Baseline and reflex tear production Blinking

Drainage

Drug delivery to the anterior is very difficult

Corneal barrier

Nearly impossible to measure directly


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Background

Drug delivery options

Implants (by pass the cornia) Inserts (residence time)

Mucoadhesives (residence time)

Gels & emulsions (residence time)

Cyclodextrins (solubility & transport)

Iontophoresis (EMF driving force)


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Background: Formulation Landscape

Solutions~55%

Ointments~20%

Suspensions

~20%

Inserts & Implants

~3%

Gels & Emulsions~2%


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Background


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Background

Standard dissolution tests and equipment are

designed to simulate the GI tract Generally involve large volumes

Human eye ~ 7-30 l

USP 4 (flow cell)

Development of unique tests, equipment, and

specifications often required


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Solutions

By definition, drug is already dissolved

Identification

Assay

Related substances (impurities)

pH Osmolality

Preservative assay

Particulate matter

Sterility

Preservative Efficacy


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Ophthalmic Ointments / Semi-Solids

Treated like other ointment products

In vitro release is often not tested

Franz cell / membrane diffusion

Diffusion across animal corneas

Direct contact with media


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Case 1: Ophthalmic Suspension

Traditional suspension of drug particles

Drug release measured via USP 2 (paddle, 50 RPM)

in 900 ml simulated tear fluid at pH 5.0 and 7.7, 37C

Effect of drug particle size probed


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Case 1: Ophthalmic Suspension

Dissolution of Supsension in Tear Solution at pH 5.0

35

45

55

65

75

85

95

105

0 5 10 15 20 25 30 35

Time (min)

%Re

leased

Lot 1

Lot 2

Unmilled

Lot 2 Lot 1 Un-milled


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Case 1: Summary

Dissolution test designed for maximum discriminationfor particle size differences

Lot 1 & 2 very similar

Smaller drug particles = faster dissolution Particle size measurements are the appropriate

Quality Control test (not dissolution)


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Case 2: Ion Exchange Resin Suspension

drug+

Resin

Na+ (tears)

drug+

Na+

Resin

Na+ drug+

+ +

Extended release dosage form


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Case 2: Measurement of Drug Release

Spectrophotometerwith 0.1 mm flow cell

2 measurements/min

Peristaltic Pump

~15 ml / min

15 ml Suspension

low flow

syringe pump

deliverstear fluid@ 300 ul/min

stir bar

Scaled to mimic the eye

dose = 50 l X 300 = 15 ml

tear rate ~ 1 l/min X 300 = 300 l/min


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Case 2: Data Analysis

m

AAVAVdrugfreemg

idii ])[()( ,=

V = volume at time t (ml)

A = absorbance at time t (AU)

Vi = initial volume (ml)

Ai = absorbance at t = 0 (AU)

A d,I = absorbance at t = 0 due to free drug (AU)

m = slope from calibration curve (AU/[mg/ml])

-5

0

5

10

15

20

25

30

35

40

0 20 40 60 80 100 120 140 160

Time (min)

FreeDrug(m

g)

Active

Placebo

0

0.1

0.2

0.3

0.4

0.5

0.6

0 20 40 60 80 100 120 140 160

Time (min)

Absorban

ce

Active

Placebo


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Case 2: Effect of Tear Addition Rate

Faster addition of ions,

faster release of drug

Ion exchange equilibrium

is fast

Release is not kinetically

limited0

5

10

15

20

25

30

35

0 50 100 150 200

Time (min)

Fre

eDrug(mg)

500 ul/min

300 ul/min

150 ul/min


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Case 2: Effect of Tear Strength

0

5

10

15

20

25

30

35

0 20 40 60 80 100 120 140 160

Time (min)

FreeDrug(mg)

300ul/min 80 mM

300ul/min 40 mM

300ul/min 160 mM

Faster addition of ions,

faster release of drug

Drug release is

independent of volume (on

experimental scale)

Release is dependent only

on the number of ionsadded


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Case 2: Drug Release Conclusions

All curves overlap whenplotted vs. moles of ions

added

Tear production is the ratelimiting step for drug

release

0

5

10

15

20

25

30

35

0 1000 2000 3000 4000 5000 6000

Positive Ions Added (umols)

Free

Drug(mg)

300ul/min 80 mM

300ul/min 40 mM

300ul/min 160 mM

150ul/min 80 mM

500ul/min 80 mM


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Case 2: Effect of Resin Particle Size

0

2

4

6

8

10

0.01 0.1 1 10 100 1000 10000

Particle Size (microns)

ParticleVolume(%)

AAQ-073 AAQ-074

0

5

10

15

20

25

30

35

0 20 40 60 80 100 120 140 160

Time (min)

FreeDrug(mg)

AAQ-074, VMD 10 um

AAQ-073, VMD 25 um

Lot 1 Lot 2

Lot 1

Lot 2


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Case 2: Summary

Novel drug release test developed

Not intended for routine QC use (research only)

Variation in test parameters indicate a robust and

stable formulation and release mechanism QC test to control resin particle distribution (for

comfort and quality)


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Case 3: Erodible Gels /

Gel Forming Solutions

The unique thermo-rheological properties ofcopolymer mixtures of Pluronic-g and poly acrylicacid result in liquids which form gels whenadministered to the eye.

Formation of a gel and mucoadhesive properties actto extend residence time in the eye

Drug is released slowly as the gel is eroded by tears In vitro and in vivo (rabbit) measurements performed

Temperature-Responsive, Pluronic-g-poly(acrylic acid) Copolymers In Situ Gels forOphthalmic Drug Delivery: Rheology, In Vitro Drug Release, and In Vivo Resident

Property W. Ma, H. Xu, S, Nie, W. Pan, Drug Development and Industrial Pharmacy,34:258-266, 2008.


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Case 3: Drug Release Measurements

Flow thru cell used (~1.25 mL)

Flow rate 1 mL/min (simulated tear fluid)

Collect effluent (10 mL), determine drug by UV

Freeze dry sample to determine dissolved copolymer(gravimetric)

Not attempting to mimic they eye

50 mm


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Case 3: In Vitro Drug Release Results

Zero order release observed

0

10

20

30

40

50

60

70

80

90

100

0 120 240 360 480 600 720

Time (min)

%

Dissolved

Gel

Drug


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Case 3: In Vitro Drug Release Results

Flow rate Polymer ratio (PAA / pluronic)

Copolymer conc. Drug conc.


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Case 3: In Vivo Drug Release Results

Compared Solution and Gel formulations

Collected tear fluid from rabbit conjunctival sac

Gel formulations increased exposure 1.2 4 X


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Case 3: Summary

Extended release formulation

Drug release test designed to show erosion rate

Useful for formulation comparisons In-vivo data shows an increase in exposure vs.

standard solution formulation

No attempt at IVIVC


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Case 4: Retisert Implants

Releases ~0.6 g/day decreasing over the first month to asteady state between 0.3-0.4 g/day for ~30 months


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Case 4: Retisert QC Drug Release Test

12 implants equilibrated at sink conditions for9 days in phosphate buffer @ 37C

Individual implants placed in 1 ml buffer andextracted for 24 hrs

Extraction solution analyzed by HighPerformance Liquid Chromatography (HPLC)

Acceptance criteria on the average of 12implants and individual implants

Study may be continued under wet storage

conditions for up to 3 years (research test)


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0 6 12 18 24 30 36 42 48

0.4

0.5

0.6

0.7

0.8

time ( Months )

Release

rate(mcg/day)

Stability Linear Trend AnalysisDatafile: Retisert ReleaseRate Stability Watfrd 3yr.txt

Dashed line = Conf Limit; Dotted line = Pred. limit

5R0304003A5R0307002A

5R0308002A

Case 4: Retisert Drug Release Results Dry Storage

Lot 1

Lot 2

Lot 3


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Case 4: Retisert Drug Release Results Wet Storage

0.00

0.10

0.20

0.30

0.40

0.50

0.60

0.70

0.80

0 100 200 300 400 500 600 700 800

Days of Hydration

u

G/Day

Lot 3

Lot 2

Lot 1

Log. (Lot 2)Log. (Lot 1)

Log. (Lot 3)


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Case 4: Retisert In Vivo Results - Explants

y = -0.0644x + 86.595

R2

= 0.9176

0

10

20

30

40

50

60

70

80

90

100

0 200 400 600 800 1000 1200 1400

Days in Use

%

FARemaining

95% ConfidenceIntervals

Linear Regression

Slope = 0.38 g/day


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Case 4: Retisert In-Vivo In-Vitro Relationship

y = 1.2421x + 8.3482R2 = 0.9211

0

20

40

60

80

100

120

0 10 20 30 40 50 60 70 80

In-Vitro % Released

In-Vivo

%R

eleased


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Case 4: Retisert - Summary

QC release rate test (10 days)

Specifications set on dry storage release rate

Specifications control average and individual implants

Wet storage release rates show a clear relationshipwith apparent in-vivo release


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Overall Summary

Solutions no release testing

Ointments not tested or treated similarly to trans-dermal Suspensions (of API) particle size test is most relevant

Suspensions (other) may require development of a

unique test Gels / Emulsions - ???

Inserts/Implants long term wet testing required, unique

test required

Residence time in the eye is an important factor indeveloping a correlation with in-vivo data


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Acknowledgements

Nadia Rusinovich

Tony LaRuffa

Brian Rohrs

Steve MacLeod Ted Huang

Harry King


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Backup Slides: Gels & Emulsions

Restasis (Allergan, 2003) and Durezol(Sirion Therapeutics, 2008) only two ophthalmic

emulsion products on the US market Akten and Pilopine HS only two ophthalmic gels

on the US market

Timoptic-XE (Merck, 1993) only gel formingsolution on the US market

alleman - drug release measurements

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