Development and validation of an in vitro

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Development and validation of an in vitroin vivo
correlation for extended buspirone HCl release
tablets

• Sevgi Takka, Adel Sakr and Arthur Goldberg
• Journal of Controlled Release
• Volume 88, Issue 1, 14 February 2003, Pages
  147-157

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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.
  

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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

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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.

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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.

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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.

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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

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Dissolution Testing
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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.

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Dissolution Testing

• DTZ release from different formulations was also
  fitted to the Higuchi
• Where Mt/M8 is the fraction of drug released at
  time t and k is the apparent release rate
  constant.

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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-per-day, formulations (slow and
  fast) of buspirone hydrochloride (30 mg) in a
  randomized fashion.
• In addition to the extended release formulations,
  an immediate release (215 mg) of buspirone
  hydrochloride (BUSPAR) was also administered.

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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 pre-dose (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.

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Bioavailability study
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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 AUC8

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Bioavailability study
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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.

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In vivo data analysis

• The measured plasma concentrations were used to
  calculate the area under the plasma
  concentrationtime profile from time zero to the
  last concentration time point (AUC(0t)).
• The AUC(0t) was determined by the trapezoidal
  method. AUC(08) 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.

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In vivo data analysis

• The WagnerNelson 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(08) and multiplying this ratio by 100

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In-vitroin-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 WagnerNelson.

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In-vitroin-vivo correlation

• The dissolution rate constants were determined
  from released vs. the square root of time.
• Linear regression analysis was applied to the
  in-vitroin-vivo correlation plots and
  coefficient of determination (r2), slope and
  intercept values were calculated.

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In-vitroin-vivo correlation

• Level A in-vitroin-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

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In-vitroin-vivo correlation
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In-vitroin-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.

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In-vitroin-vivo correlation

• Plot of in vitro dissolution rate (kdiss) versus
  in vivo absorption rate (ka) constants (The
  zerozero point is theoretical).

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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.

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Internal validation of the IVIVC

• The prediction of the plasma buspirone
  hydrochloride concentration was accomplished
  using the following curve fitting equation
• where, ypredicted 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
  spread-sheet in Excel.

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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.

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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.

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Internal validation of the IVIVC
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External validation of the IVIVC

• The external validation was accomplished by
  re-formulating 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.

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