Cindy Buhse, Ph.D. Director

Office of Testing and Research

Center for Drug Evaluation and Research US Food and Drug Administration

FDA Research in Dissolution

Outline • Research on current dissolution

methodologies • Alternative approaches

– Modeling – Apparatus – Medium

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Research on current dissolution methodologies

• Enhanced mechanical calibration • Gauge R&R Studies • Understand vibration • Modeling of USP Apparatus 3 and 4

Goals: understand and reduce variability

3

4

X

• Disintegration

• Solids transfer

• Dissolution

• Changing pH

• Food and drink

• Absorption

• Clearance

X

X

Does Current Dissolution Method Have Any Biological Relevance?

Picture copied from website, www.protechcro.com/images/01Dissolution.pdf, accessed July 2, 2012

Picture copied from website, www.google.com/images?q=digest+system&hl=en&gbv=2&tbm=isch&ei=uZQZUIT4O-ju0gHx8oCYAg&start=20&sa=N, accessed July 30, 2012

We are asking end product testing to serve as both QC and surrogate for clinical studies!

1) Use of mechanistic modeling to obtain IVIVC. 2) Can existing apparatus be used to better mimic the GI tract? 3) New dissolution technology systems 4) “Biorelevant” media

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Exploring New Approaches

Absorption/IVIVC Modeling

Examining the strengths/weaknesses of various absorption modeling approaches in IVIVC modeling for compounds with diverse BCS and formulation characteristics.

IVIVC modeling of BCS class 1 ER formulation using two-stage, numerical deconvolution. Comparison of

observed and IVIVC-predicted cp-time profiles. Source: M. Kakhi, P. Marroum, J. Chittenden. Analysis of level A in vitro–in vivo correlations for an extended-release formulation with limited bioavailability. Biopharm. Drug Dispos. 34: 262–277 (2013)

Absorption modeling of simulated data for 1-compartment PK with enterohepatic circulation using a combination of nonlinear mixed effects and stochastic

deconvolution. Comparison of observed (simulated) and NLME/stoch. Decon-predicted cp-time profiles.

Source: M. Kakhi and J. Chittenden. Modeling of Pharmacokinetic Systems Using Stochastic Deconvolution. J. Pharm. Sci.

102:4433–4443 (2013)

Work in progress: mechanistic absorption modeling/IVIVC of BCS class 3 compounds using Gastro Plus. 6

V1

V2

V3

V3

V1 V2

V3

Schematic Diagram

Analyzer

V2 V3V1

New Technology: FloVitro™

System characteristics: • Cell Volume range: V1 (40-60 mL), V2 (60- 400 mL), V3 (400-9700 mL) • Paddle speed (300 rpm in V1, V2 and V3) • SGF Flow rate (1 – 4 mL/min), SIF Flow rate (1 - 8 mL/min), Run times (10 – 24 hrs)

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• Concentration in Cell 3 at time(t) = A(– k1*t) + B(–k

2*t)

k1: input rate constant k2: removal rate constant A and B: constant coefficients

Ref.: Lyn Hughes, Amie Gehris (Dow Chemicals), FDA RSR Group, presented at the 2009 and 2011 AAPS Annual Meeting

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Dissolution Test Method Set-up and Data Collection

0

5

10

15

20

25

0 500 1000 1500 2000 2500 3000

Time (mins)

Con

cent

ratio

n (m

g/L)

Predicted Conc

adjusted in v ivo

1) Literature data for setting up system conditions (cell volumes, flow rates, and residence times).

2) Algorithm-predicted concentrations (solid line) and normalized in vivo data

3) Scaled Cell 2 data, normalized in vivo literature data (symbols) and measured Cell 3 data

Doxycycline in vivo vs in vitro Cell2 and Cell3

-10

0

10

20

30

40

0 200 400 600 800 1000 1200 1400 1600

Time, minutes

Con

cent

ratio

n, m

g/L in vivo (normalized)

Cell3

Cell2 x 0.1

Doxycycline Formulation in vivo Data

0.00

0.50

1.00

1.50

2.00

2.50

0 500 1000 1500 2000

Time (h)

Con

cent

ratio

n (u

g/m

l)

Time (min)

Flovitro Technology: Furosemide (BCS Class IV) Dissolution Media Mimicking Fed and Fasted State

Ref: Lyn Hughes, Amie Gehris (Dow Chemicals), FDA RSR Group, presented at the 2011 AAPS Meeting 9

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USP monograph (USP35-NF30 Page 3294) for Furosemide Tablets (BCS class IV) .

Dissolution performed in a USP dissolution apparatus occurs in an environment that is very different from the human gastrointestinal (GI) tract.

supersaturation

Danazol (BCS class II): Fed vs Fasted

Ref: Lyn Hughes, Amie Gehris (Dow Chemicals), FDA RSR Group, presented at the 2011 AAPS Annual Meeting 11

Gastric pH records at: A )4 hourly feeds B) 3 hourly feeds C) 2 hourly feeds

Adapted from reference: D.J. Mitchell, B.G. McClure, T.T.J. Tubman, “Simultaneous monitoring of gastric and oesophageal pH reveals limitations of conventional oesophageal pH monitoring in milk fed infants”, Arch. Dis. Child,2001, 84: 273-276

For neonates and young children---Do we know the effect of milk in the media with a pH of 4 – 5.5?

12 0------Time(hours)----------------------6

In Vitro Dissolution of Furosemide 20-mg tablets using FloVitro™ Technology in Simulated Media

AAPS 2011 Poster Presentation: Application of FloVitro™ Technology to Evaluate Dissolution

of Furosemide and Danazol in Simulated Media at Fed and Fasted Conditions A. Selen, W.J. Rodriguez,

W. H. Doub, L. F. Buhse, E. G. Chikhale, S. K. De, Z. Gao, A. S. Gehris, L. Hughes, R. Lu, H. Mahayni,

P.K. Maturu, T. D. Mehta

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Dissolution Medium

Cell 1

Waste

UV/vis UV/vis

Cell 2

Z Gao, AAPS PharmSciTech, 10(4), 2009, 1401-1405.

Adapting current apparatus USP 4 with second vessel

Modified USP 4 Method One pass for medium

(water)

10 mg Prednisone tablets

Cell 2 Concentration

15 Z Gao, AAPS PharmSciTech, submitted, 2012.

BCS I, propranolol HCl

BCS II, phenazopyridine HCl

Closed loop with flow rate at 4mL/min 150 mL SGF for 1 hour then, 500 SIF for 23 hours

Adapting current apparatus USP 4 with diffusion cell and artificial membrane

Adding mechanical force during dissolution testing

16 Reference: Z Gao, In-Vitro Dissolution Testing of Gelatin Capsules with Applied Mechanical Compression, AAPS, Orlando, FL, 10, 2015.

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Advantage and Disadvantage of New Methods

• Disintegration

• Solids transfer

• Dissolution

• Changing pH

• Food and drink

• Absorption

• Clearance

• Standardized Method

New Dissolution

Methods

Current USP

Dissolution Methods

X

X

X

?

Mechanical forces?

Potential advantages of new approaches

• When can an in vitro test predict in vivo performance – When can “biorelevant apparatus and media” assist in the development of in vitro

and in vivo correlations for more routine testing? – Do we need a simulated absorption phase in the in vitro test?

• What is the solubility profile of the drug in the GI tract? – Effect of food contents and digestion products – Is the dosage form releasing the drug at the site optimal for

therapeutic benefit? • Predicting formulation changes

– Including reducing or eliminating food effect

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New approaches are needed for development of clinically relevant dissolution methods

Results from New

Dissolution Methods

Results from USP

Dissolution Methods

Data from Clinical Trial

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The Future of Dissolution Research

• Continue to explore new in vitro approaches (modeling, apparatus, media);

• Work with academia and other stake holders to obtain in vivo results needed for testing of sensitivity and predictive ability of in vitro methods;

• Generate the data to support guidance and review activities related to moving toward clinically relevant in vitro drug release testing.

Thank You • Maziar Kakhi • Arzu Selen • Zongming Gao • Paul Seo • Rik Lostritto • Lawrence Yu

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