Transcript Clinical Relevance of Drug Releases Testing

Clinical Relevance of
Drug Release Testing
James E. Polli
[email protected]
October 3, 2016
Outline
• In vitro dissolution in development
• Experimental findings
– Volume
– Food effect
– Surfactant effect
Two of the Most Common Complaints
about In Vitro Dissolution
• Too sensitive (i.e. over discrimination)
• Not sensitive enough (i.e. not
discriminating enough)
• Opportunities
– Regulatory relief
– Methods development/standardization of
more challenging dissolution problems (e.g.
BCS class 2)
Comments of Dr. M. Pernarowski
• “Dissolution methodology exists. It is an
exercise in futility. It is a necessity. It is all
things to some; very little to others. Why
then do we determine the dissolution
characteristics of tablets and capsules …?
Comments of Dr. M. Pernarowski
• “… First, we determine dissolution times to insure
biological availability. The state of the art is far
from perfect and it is for this reason that we must
hedge and state that dissolution per se is no
guarantee of therapeutic efficacy. At the same
time, I do not think it wise to continually argue
that dissolution has no in vivo significance. This is
simply a mis-statement of facts and tends to
downgrade the importance of the technique.
Comments of Dr. M. Pernarowski
• “…[Secondly] A discriminating method for the
determination of dissolution characteristics is
an excellent research tool. … Products with
poor dissolution characteristics are obviously
poor candidates for the market place or for
clinical trials. … Unfortunately, the converse is
not always true. … Laboratory tricks whose
sole purpose is to increase the rate of solution
are … not always a guarantee that the
formulated product will be biologically
available.
Comments of Dr. M. Pernarowski
• “[Thirdly] Lastly, … various methods
are now being used to control
manufactured products. Such a
control method is more capable of
detecting difference between products
… and different lots of the same
product than is the traditional
disintegration test.”
Use of Surfactant:
What do we want?
Complications
• Attaining complete dissolution and sink conditions
– Enhanced drug solubility (e.g. via additional
surfactant) tends to reduce dissolution test
sensitivity.
• Same EVERYTHING across dose strengths
– Historical tendency to prefer the same test
methods and same specs, even though different
doses can result in a fundamental change in the
dissolution problem.
• A higher dose may dissolve slower or to a lesser
extent, than lower dose.
Effect of Dosage Form Size on
Dissolution
T Higuchi (1961). Rate of release of medicaments from ointment bases
containing drugs in suspension. J Pharm Sci 50:874-874.
Dissolution in Formulation Design
re-assess
initial effort
in vivo dissolution
in vivo performance
prediction
Roles of In Vitro Dissolution
• Product development tool
• QC test
• Clinically relevant assessment tool [a/k/a
in vivo performance test]
– Meaning?
• A measure of in vivo dissolution
– As assessed by deconvolution of PK
profile when absorption is dissolutionlimited?
Need for a Second
In Vitro Dissolution Method
• QC test
– Use: current application in batch-to-batch
consistency
• Clinically relevant assessment tool
[a/k/a in vivo performance test]
– Meaning?
– Use: Product development tool; SUPAC-type
situations
Biopharmaceutic Risk
from 2009-2012
32 NDAs vs 4 INDs
n=25 oral solid dosage forms
From: Dr Sandra Suarez Sharp, “FDA’s Experience on IVIVC-New Drug Products”,
PQRI Workshop on Application of IVIVC in Formulation Development, September 5-6, 2012.
Meaning of “In Vivo Performance”
•
•
•
•
In vivo dissolution (profile)
In vivo absorption (profile)
In vivo pharmacokinetic profile
Sensitive to efficacy or safety
• All above are related, but lack of clarity is a barrier.
• Do we want in vitro dissolution to predict first-pass
metabolism?
• We have to be careful about what we expect of in vitro
dissolution. Lack of clarity detracts from reliable utility of
in vitro dissolution.
• IVIVR – in vitro dissolution – in vivo absorption relationship
– Absorption = dissolution + permeation
Status Quo
• Organizations will often not pursue
approaches that lack utility in drug
development or lack high regulatory
certainty.
• Status quo
– Stakeholders know current strength/limitations of in
vitro dissolution
– Budget
• No requirement for “biostudies with several formulations”
• Uncertain elements
– Budget
– Acceptable role of modeling and simulation
Dissolution in Development
• “Our boss, who is not a dissolution
person, thinks our lab is problematic.
Our results from using well-known
‘biorelevent media’ do not agree with
in vivo PK.”
Novel In Vitro Dissolution Methods
• Two major elements
– Apparatus and operating conditions
– Media
• Apparati
– Compendial
– Two or more “lumen” compartments (e.g.
stomach and duodenum per ASD model)
– Systems with “absorption compartment” (e.g.
biphasic systems to mimic absorption during
dissolution for low solubility drugs to avoid “too
much” surfactant)
Outline
• In vitro dissolution in development
• Experimental findings
– Volume
– Food effect
– Surfactant effect
Recent FDA Guidance
2015 Dissolution Guidance
2015 BCS Biowaiver Guidance
In Vivo Dissolution Volume
• Low solubility drugs : in
vitro dissolution volume
will impact in vitro
performance of dosage
form
• Volume of water available
for dissolution in vivo is <<
900mL
Mudie, D.M.; Murray,K.; Hoad, C.L.; Pritchard, S.E.; Garnett, M.C.; Amidon, G.L.; Gowland, P.A.; Spiller, R.C.; Amidon,G.E.; Marciani, L.
Quantification of Gastrointestinal Liquid Volumes and Distribution Following a 240 mL Dose of Water in the Fasted State. 2014, 11, 3039−3047.
Lamotrigine
•
•
•
•
•
Lamotrigine: BCS Class 2b drug
Dose: 100mg
At pH 4.5: exhibited both 3-fold and 10fold sink conditions in each 500 mL and
900 mL dissolution volumes
At pH 1.2: exhibited 3-fold sink conditions,
but not 10-fold sink conditions
At pH 6.8: did not exhibit either 3-fold or
10-fold sink conditions
pH
Solubility
(mg/mL)
Volume to
dissolve label
amount (mL)
Volume for 10fold sink
conditions (mL)
Volume for 3fold sink
conditions (mL)
1.2
1.09
91.7
917
275
4.5
2.53
39.5
395
119
6.8
0.210
476
4760
1430
Volume
% Dissolved
in 15 min
% Dissolved
in 30 min
500 ml
900 ml
500ml
900ml
500ml
900ml
92.2
101.2
93.5
99.7
54.0
68.7
94.9
101.0
95.5
101.6
69.1
85.5
f2
(5-15min)
f2
(5-30min)
47.2
56.4
58.0
59.2
47.0
42.0
Outline
• In vitro dissolution in development
• Experimental findings
– Volume
– Food effect
– Surfactant effect
In vitro Lipolysis Model
Fe-Lipolysis/Fa-Lipolysis
Danazol
Amiodarone
Ivermectin
+ve food effect is >
30% AUC
enhancement in the
presence of food
Bioavailability Enhancement
Fe-Lipolysis/Fa-Lipolysis
Drug
AUC0-15 min ratio AUC0-30 min ratio
(SEM)
(SEM)
in vivo AUC
ratio
(SEM)
Danazol
2.28 (0.10)
2.46 (0.07)
≈ 3.00
Amiodarone
13.0 (0.2)
10.5 (0.3)
≈ 2.30
Ivermectin
8.35 (0.10)
8.13 (0.03)
≈ 3.00
Raman S and Polli JE (2016): Prediction of Positive Food Effect: Bioavailability
Enhancement of BCS Class II Drugs. DOI: 10.1016/j.ijpharm.2016.04.013. Int. J. Pharm.
506:110-115.
FeSSIF-V2L/FaSSIF-V2L
Danazol
Amiodarone
Ivermectin
+ve food effect is > 30%
AUC enhancement in
the presence of food
Lipolysis Imaging Using AFM
Lipolysis Time Course Analysis on AFM
t = 0 min
t = 5 min
t = 15 min
t = 30 min
Electron Source
Lipolysis Imaging Using cryo-TEM
e-
ee-
e-
ee2-D Image
Colloids embedded
in vitreous ice
Magnetic Lens
Fe-Lipolysis Analysis on cryo-TEM
t = 0 min
Colloidal structures
observed:
(a) unilamellar and
multilamellar vesicles
(b) lipid droplets
Fe-Lipolysis Analysis on cryo-TEM
t = 5 min
Colloidal structures
observed:
(a) & (c) unilamellar and
multilamellar vesicles
(b) lipid droplets
(d) micelles
Fe-Lipolysis Analysis on cryo-TEM
t = 10 min
Colloidal structures
observed:
(a) unilamellar and
multilamellar vesicles
(b) lipid droplets
(c) micelles
Fe-Lipolysis Analysis on cryo-TEM
Time
(min)
Danazol
Colloidal particles observed
0
Lipid droplets, vesicles,
micelles
5
Lipid droplets, vesicles,
micelles, protein aggregates
10
Lipid droplets, vesicles,
micelles, protein aggregates
15
Lipid droplets, vesicles,
micelles
30
Lipid droplets, vesicles,
micelles
• Vesicles and micelles are primarily
responsible for solubilization.
• Highest amount solubilized is 10 min
onwards
Outline
• In vitro dissolution in development
• Experimental findings
– Volume
– Food effect
– Surfactant effect
Wood’s Apparatus
G.D. Lehmkuhl and J.L. Hudson. Flow and mass transfer near
enclosed rotating disc: experiment. Chem Engin Sci 26:1601-1613, 1971.

Levich Equation
J D  0.62 DD2 3 1 6w1 2 D 
• JD is the flux of the dissolving drug
• DD is the diffusivity of free drug in the stagnant
diffusion layer
• v is the kinematic viscosity of the stagnant diffusion
layer
• w is the rotational speed of the Wood apparatus disk
• [D] is the concentration of the drug at the surface of
the tablet, which is assumed to be the aqueous drug
solubility
Objective
• To assess the contributions of surfactant-mediated
solubility and micellar diffusivity on the ability of
surfactant to enhance drug dissolution.
• Balakrishnan, A., Rege, B.D., Amidon, G.L., and Polli,
J.E. (2004): Surfactant-mediated dissolution:
contributions of solubility enhancement and
relatively low micelle diffusivity. J. Pharm. Sci.
93:2064-2075.
Model Development
Model
f m DD2 3M
f  1  2 3
f f DD
• f is the degree of surfactant-mediated dissolution
enhancement
• fm is the fraction of drug in micelle and ff is the
fraction of free drug
• DD and DD-M are the diffusivities of free drug and
drug-loaded micelles, respectively.
Influence of micelle diffusivity
• If
• If
DD  M
DD  M
23
DM
= 0.1, D
DD
DD= 0.05,
23
D
D
DD2 3M
= 0.215
23
D
D
= 0.136
Enhancement of griseofulvin solubility and
dissolution by SDS and CTAB
Fold Enhancement
120
Solubility
Enhancement
105
90
Dissolution
Enhancement
75
60
45
30
15
0
10mM
SDS
20mM
SDS
40mM
SDS
60mM
SDS
Surfactant
6.67mM
CTAB
13.32mM
CTAB
20mM
CTAB
Observed versus predicted dissolution enhancement of
griseofulvin by SDS and CTAB
Observed Fold Enhancement
31
26
21
16
f m DD2 3M
f  1
 23
f f DD
11
6
1
1
6
11
16
21
Predicted Fold Enhancem ent
SDS (closed circles) and CTAB (open circles)
26
31
Outline
• In vitro dissolution in development
• Experimental findings
– Volume
– Food effect
– Surfactant effect