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Case Studies Drug Release Measurements on Ophthalmic Dosage Forms

AAPS Workshop: Special Dosage Forms Whats New with In Vitro Drug Release November 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 cation ion-exchange resin with bound drug)

Gels & Emulsions


Pluronic-g-poly(acrylic acid) copolymer gel

Implants
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Retisert (fluocinolone acetonide intravitreal implant) 0.59 mg

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

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)

Background: Formulation Landscape


Inserts & Implants ~3% Suspensions ~20% Solutions ~55% Ointments ~20% Gels & Emulsions ~2%

Background

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

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

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
105 95 85 % Released 75 65 55 45 35 0 5 10 15 20 25 30 35

Lot 1 Lot 2 Unmilled

Lot 2

Lot 1

Un-milled

Tim e (m in)

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Case 1: Summary
Dissolution test designed for maximum discrimination for 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


Extended release dosage form

Na+ (tears)
Resin Resin

drug+

drug+

Na+

+
Na+

+
drug+

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Case 2: Measurement of Drug Release


Peristaltic Pump ~15 ml / min Spectrophotometer with 0.1 mm flow cell 2 measurements/min

stir bar 15 ml Suspension

Scaled to mimic the eye dose = 50 l X 300 = 15 ml


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low flow syringe pump delivers tear fluid @ 300 ul/min

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

Case 2: Data Analysis


mg free drug = (V A) (Vi [ Ai Ad ,i ]) m
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])
0.6
Active

40
Active

35 30

0.5

Placebo

Placebo

0.4
Absorbance
Free Drug (mg)

25 20 15 10 5 0

0.3

0.2

0.1

0 0 20 40 60 80
Time (min)

20

40

60

80
Time (min)

100

120

140

160

100

120

140

160

-5

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Case 2: Effect of Tear Addition Rate


35 30 25
Free Drug (mg)

Faster addition of ions, faster release of drug


500 ul/min 300 ul/min 150 ul/min

20 15 10 5 0 0 50 100
Time (min)

Ion exchange equilibrium is fast Release is not kinetically limited

150

200

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Case 2: Effect of Tear Strength


35

30

Faster addition of ions, faster release of drug Drug release is independent of volume (on experimental scale)
300ul/min 80 mM 300ul/min 40 mM 300ul/min 160 mM

25 Free Drug (mg)

20 15

10

0 0 20 40 60 80 Time (min) 100 120 140 160

Release is dependent only on the number of ions added

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Case 2: Drug Release Conclusions


35

30

25 Free Drug (mg) 300ul/min 80 mM 300ul/min 40 mM 15 300ul/min 160 mM 150ul/min 80 mM 500ul/min 80 mM 10

All curves overlap when plotted vs. moles of ions added Tear production is the rate limiting step for drug release

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0 0 1000 2000 3000 4000 5000 6000 Positive Ions Added (umols)

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Case 2: Effect of Resin Particle Size


35 30
10 Particle Volume (%) 8 6 4 2 0 0.01 0.1 1 10 100 1000 10000

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Free Drug (mg)

20 15 10
AAQ-074, VMD 10 um Lot 1

Lot 2 AAQ-073, VMD 25 um

Particle Size (microns) AAQ-073 Lot 1 AAQ-074 Lot 2

5 0 0 20 40 60 80
Time (min)

100

120

140

160

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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 of copolymer mixtures of Pluronic-g and poly acrylic acid result in liquids which form gels when administered to the eye. Formation of a gel and mucoadhesive properties act to 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 for Ophthalmic 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)

50 mm

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
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Case 3: In Vitro Drug Release Results


100 90 Gel 80 70 % Dissolved 60 50 40 30 20 10 0 0 120 240 360 Time (min) 480 600 720 Drug

Zero order release observed


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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 a steady 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 for 9 days in phosphate buffer @ 37C Individual implants placed in 1 ml buffer and extracted for 24 hrs Extraction solution analyzed by High Performance Liquid Chromatography (HPLC) Acceptance criteria on the average of 12 implants and individual implants Study may be continued under wet storage conditions for up to 3 years (research test)
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Case 4: Retisert Drug Release Results Dry Storage


Stability Linear Trend Analysis Datafile: Retisert ReleaseRate Stability Watfrd 3yr.txt

Release rate (mcg/day)

0.7

0.8

Lot 1 5R0304003A Lot 2 5R0307002A Lot 3 5R0308002A

0.4 0

0.5

0.6

12

18

24 time ( Months )

30

36

42

48

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

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Case 4: Retisert Drug Release Results Wet Storage


0.80

0.70

0.60

Lot 3 Lot 2 Lot 1 Log. (Lot 2) Log. (Lot 1) Log. (Lot 3)

0.50

uG/Day

0.40

0.30

0.20

0.10

0.00 0 100 200 300 400 500 600 700 800

Days of Hydration

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Case 4: Retisert In Vivo Results - Explants


100 90 80
% FA Remaining

95% Confidence Intervals Linear Regression

70 60 50 40 30 20 10 0 0 200 400 600 800 y = -0.0644x + 86.595 2 R = 0.9176

1000

1200

1400

Days in Use

Slope = 0.38 g/day


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Case 4: Retisert In-Vivo In-Vitro Relationship

120 In-Vivo % Released 100 80 60 40 20 0 0 10 20 30 40 50 60 70 80 In-Vitro % Released y = 1.2421x + 8.3482 R2 = 0.9211

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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 relationship with 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 in developing 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 forming solution on the US market

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