Download Development and validation of an in vitro–in vivo correlation for

Development and validation of an in
vitro–in vivo correlation for extended
buspirone HCl release tablets
Sevgi Takka, Adel Sakr and Arthur Goldberg
Journal of Controlled Release
February 2003, Pages 147-157 14 ,Volume 88, Issue 1
Objective
• According to the Biopharmaceutics classification system,
buspirone hydrochloride can be classified as a “Class 1”
drug, i.e., high solubility and permeability.
• In addition, it is a highly variable drug, exhibiting a very
high first pass metabolism and only about 4% of an
orally administered dose will reach the systemic
circulation unchanged after oral administration.
• Therefore, the purpose of this study was to develop an
IVIVC for a novel hydrophilic matrix extended release
buspirone hydrochloride tablets.
Formulation
• Extended release formulations of buspirone
hydrochloride were developed using hydroxypropyl
methylcellulose (HPMC) as one of the release rate
controlling excipients, and Eudragit L100-55 as the other
controlled release polymer, and included silicified
microcrystalline cellulose as filler, and magnesium
stearate as lubricant.
• The formulations were designed to release buspirone
hydrochloride at two different rates referred to as “Slow”
and “Fast”. The high-viscosity HPMC (Methocel K100M)
and the low-viscosity HPMC (Methocel K100LV) are
used for slow and fast release, respectively
Dissolution Testing
• The release characteristics of the formulations were
determined using USP Apparatus II, at 50 and 100 rpm,
in 0.1 M HCl or pH 6.8 phosphate buffer maintained at
37 °C.
• Dissolution tests were performed on six tablets and the
amount of drug released was analyzed
spectrophotometrically at a wavelength of 238 nm.
• Dissolution samples were collected at the following
times: 0, 0.5, 1.0, 1.5, 2.0, 3.0, 4.0, 6.0, 8.0, 10, 12 and
24 h.
Dissolution Testing
•
Cumulative buspirone hydrochloride release versus time profile for “Slow”
and “Fast” extended release tablets using (a) pH 6.8, 50 rpm, (b) 0.1 M HCl,
50 rpm, (c) pH 6.8, 100 rpm, (d) 0.1 M HCl, 100 rpm.
Dissolution Testing
•
Cumulative buspirone hydrochloride release versus square root of time profile for
“Slow” and “Fast” extended release tablets using (a) pH 6.8, 50 rpm, (b) 0.1 M HCl,
50 rpm, (c) pH 6.8, 100 rpm, (d) 0.1 M HCl, 100 rpm.
Dissolution Testing
• It is observed that the high-molecular-weight (high
viscosity) polymer has a slower dissolution rate than the
dosage form with the lower-molecular-weight (lower
viscosity) polymer in both pH media.
• The release of buspirone hydrochloride from the slow
and fast formulations were expected to be almost
indistinguishable from each other when the dissolution is
measured in 0.1 M HCl based on high solubility of drug
in acidic media, but f2 values were 42.2 and 47.7 at 50
and 100 rpm, respectively.
• However, at pH 6.8, the differences between the
formulations were more evident. Weakly basic buspirone
hydrochloride has a lower solubility in pH 6.8 phosphate
buffer than in 0.1 M HCl. The calculated similarity factors
(f2) confirmed the conclusion
Dissolution Testing
Dissolution Testing
• pH 6.8 phosphate buffer at both 50 and 100 rpm were
found to be the more discriminating dissolution media in
our study and 50 rpm in phosphate buffer was then used
in the IVIVC model development.
• Release profiles were compared using the similarity
factor f2.
• f2 is a logarithmic reciprocal square root transformation
of the sum of squared error and is a measurement of the
similarity in the percent of dissolution between the two
curves.
• The similarity factor is 100 when the test and reference
profiles are identical and approaches zero as the
dissimilarity increases.
0.5



  1  n

2
f 2  50 log 1    Rt  Tt    100



  n  t 1

Dissolution Testing
• DTZ release from different formulations was also fitted to
the Higuchi:
Mt
 kt 0.5
M
• Where Mt/M∞ is the fraction of drug released at time t
and k is the apparent release rate constant.
Bioavailability study
• An open-label, fasting, single dose, three-treatment
crossover study using normal healthy volunteers.
• Eighteen male, non-smoking volunteers were enrolled in
the study and received two extended release, once-perday, formulations (slow and fast) of buspirone
hydrochloride (30 mg) in a randomized fashion.
• In addition to the extended release formulations, an
immediate release (2×15 mg) of buspirone hydrochloride
(BUSPAR®) was also administered.
Bioavailability study
• The order of treatment administration was randomized in
three sequences (ABC, BCA, CAB) in blocks of three.
• Blood samples were obtained at 22 time points from predose (0 h) until 36 h post-dose. A washout period of 1
week was allowed between dose administrations.
• Subjects fasted for 12 h prior to the morning drug
administration when the extended and immediate
release products were administered, and for 4 h prior to
the evening drug administration of the immediate release
product.
Bioavailability study
Bioavailability study
• There are discernible differences in the plasma level
concentrations between the three dosage forms (“Slow”,
“Fast” and IR tablets).
• It was also found that the rank order of release observed
in the dissolution testing was also apparent in the
plasma buspirone hydrochloride concentration profiles
with a mean Cmax of 1.37 and 1.76 ng/l for the slow and
fast releasing formulations.
• However, the same rank order was not observed in the
AUC∞
Bioavailability study
Bioavailability study
• There is no significant or noticeable difference in the
AUC from the slowest releasing dosage form compared
to the fast releasing dosage form, showing that the
extent of absorption of buspirone was the same despite
the differences in release rates between the two dosage
forms.
• The AUC of buspirone was much higher from the
extended release forms than from the IR tablets.
In vivo data analysis
• The measured plasma concentrations were used to
calculate the area under the plasma concentration–time
profile from time zero to the last concentration time point
(AUC(0–t)).
• The AUC(0–t) was determined by the trapezoidal method.
AUC(0–∞) was determined by the following equation:
• ke was estimated by fitting the logarithm of the
concentrations versus time to a straight line over the
observed exponential decline.
In vivo data analysis
• The Wagner–Nelson method was used to calculate the
percentage of the buspirone hydrochloride dose
absorbed:
• where F(t) is the amount absorbed. The percent
absorbed is determined by dividing the amount absorbed
at any time by the plateau value, keAUC(0–∞) and
multiplying this ratio by 100:
In-vitro–in-vivo correlation
• The data generated in the bioavailability study were used
to develop the IVIVC.
• The percent of drug dissolved was determined using the
aforementioned dissolution testing method and the
fraction of drug absorbed was determined using the
method of Wagner–Nelson.
In-vitro–in-vivo correlation
• The dissolution rate constants were determined from %
released vs. the square root of time.
• Linear regression analysis was applied to the in-vitro–invivo correlation plots and coefficient of determination (r2),
slope and intercept values were calculated.
In-vitro–in-vivo correlation
• Level A in-vitro–in-vivo correlation was investigated
using the percent dissolved vs. the percent absorbed
data for both the slow and fast formulations, using both
0.1 M HCl and pH 6.8 phosphate buffer dissolution
media at both 50 and 100 rpm.
• A good linear regression relationship was observed
between the dissolution testing using pH 6.8 phosphate
buffer at 50 rpm and the percents absorbed for the
combined data of the two dosage forms
• Another good linear regression relationship was
observed between the dissolution testing using 0.1 M
HCl as the dissolution media at 50 rpm, and the percents
absorbed for the combined data of the two dosage forms
In-vitro–in-vivo correlation
In-vitro–in-vivo correlation
• It is also observed that the in-vivo absorption rate
constant (ka) correlates well with the pH 6.8 phosphate
buffer in-vitro dissolution rate constant (kdiss), exhibiting
a correlation coefficient of 0.9353.
• This was a better correlation than was obtained using
the dissolution rates in 0.1 M HCl, and therefore, pH 6.8
phosphate buffer was selected as the dissolution media
of choice.
In-vitro–in-vivo correlation
Plot of in vitro dissolution rate (kdiss) versus in vivo absorption rate (ka) constants
(The zero–zero point is theoretical).
Internal validation of the IVIVC
• The internal predictability of the IVIVC was examined by
using the mean in-vitro dissolution data and mean in-vivo
pharmacokinetics of the extended matrix tablets.
Internal validation of the IVIVC
• The prediction of the plasma buspirone hydrochloride
concentration was accomplished using the following
curve fitting equation:
• where, y=predicted plasma concentration (ng/ml);
Const.=the constant representing F/Vd, where F is the
fraction absorbed, and Vd is the volume of distribution;
ka: absorption rate constant; ke: overall elimination rate
constant.
• The de-convolution was accomplished on a spreadsheet in Excel®.
Internal validation of the IVIVC
• To further assess the predictability and the validity of the
correlations, we determined the observed and IVIVC
model-predicted Cmax and AUC values for each
formulation. The percent prediction errors for Cmax and
AUC were calculated as follows:
• where Cmax(obs) and Cmax(pred) are the observed and
IVIVC model-predicted maximum plasma concentrations,
respectively; and AUC(obs) and AUC(pred) are the
observed and IVIVC model-predicted AUC for the
plasma concentration profiles, respectively.
Internal validation of the IVIVC
• Observed and predicted buspirone hydrochloride plasma
concentration for the (A) “Fast” and (B) “Slow” releasing
formulation using the IVIVC model.
Internal validation of the IVIVC
External validation of the IVIVC
• The external validation was accomplished by reformulating the extended release dosage form to a
release rate between the “Fast” and the “Slow” rates,
selected to provide a Cmax of the re-formulated product
equivalent to the Cmax obtained from the IR tablets, and
to re-test the re-formulated product against the IR tablets
in another bioequivalence test in human subjects.