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Development, Internal and External Validation of Naproxen Sodium Sustained Release Formulation: an Level A In Vitro-In Vivo Correlation/Naproksen Sodyum Sureli Serbest Formulasyonun Gelistirilmesi, Ic ve Dis Olarak Dogrulamasi: Bir Duzey A In Vitro-In Vivo Korelasyon.

INTRODUCTION

In vitro-in vivo correction is a predictive mathematical model relating the relationship between an in vitro property of a dosage form and an in vivo response. (5) In vitro-in vivo correlation (IVIVC) is most widely established by using formulations with different release rates i.e. slow, medium and fast, data on the in vitro release rates and in vivo plasma concentration-time profiles of developed formulations, and by using deconvolution techniques to confirm the link between dissolution rate and fraction absorbed. The Food Drug Administration (FDA) guidelines has discussed the three categories of IVIVC models: namely, level A, B, and C models. Level A is a linear is most widely used as it is developed point to point correlation and stands for in vitro and in vivo absorption rate of the drug. Level A can be developed on both deconvolution and convolution-based methods. Level B compares the mean in vitro dissolution time to the mean in vivo residence time or the mean in vivo dissolution time. Level C is a single point comparison of dissolution time point to one pharmacokinetic parameter [e.g. [C.sub.max], area under the curve (AUC), and [T.sub.max] time of the maximum plasma concentration]. Level D is a rank order analysis. (5) The development and validation of IVIVC is vital for optimization of sustained release dosage form as it predicts the in vivo release profile of the sustained release (SR) dosage form based on in vitro data. (9)

Various IVIVC studies have been published for a number of formulations, including Busprion, propranolol, nevirapine, metoprolol and other drugs. (6-17) The concepts and methods used in establishing the IVIVC are reviewed elsewhere. (4,5) According to BCS classification naproxen sodium comes under class 2 drug and in addition naproxen is relatively having a short life suggest suitable applicant for modified release formulation. (1,2) The present work is intended to formulate naproxen sodium sustained release tablet, develop and validate the internal and external predictability of level A IVIVC models. In vitro dissolution study was performed to check the release profile and bioavailability study conducted to check the rate and extent of absorption of developed naproxen sodium sustained release and marketed immediate release tablet. Further established and validated IVIVC models can be used as a surrogate for the bioequivalence study, minimize the time and cost for manufacturers, a quality control tool to measure the product performance, a waiver for human studies when the minor changes are done as specified in the scale-up and post-approval changes (SUPAC)- immediate release and SUPAC-modified release guidance.

MATERIALS AND METHODS

Chemicals and reagents

Naproxen sodium, HPMC K100M supplied as a gift sample by Strides Arcolab Limited, Bangalore and Colorcon Asia Pvt. Limited, Goa, India. All other materials like talc, magnesium stearate, ethyl cellulose were procured from local dealer.

In vitro dissolution study and data analysis

The drug release profiles were examined by using by using the United States Pharmacopeia (USP) dissolution apparatus (type 2, paddle) pH 1.2, 4.5, 5.5, 6.8 and 7.4 at 50 & 75 rpm (rotation per min). The dissolution studies were performed on six tablet of naproxen sodium 375 mg SR tablets (i.e. slow, medium and fast) and naproxen sodium 500 mg tablet (marketed immediate release). Samples were drawn at 0.0, 0.5, 1.0, 1.5, 2.0, 3.0, 4.0, 6.0, 8.0, 12.0, 18.0 and 24.0 hours and analyzed by using UV spectroscopy at a wavelength of 332 nm. The percentage fraction dissolved and percentage release at various time points were determined. The similarity of dissolution profiles were evaluated for fast versus slow, slow versus medium and medium versus fast by using the similarity factor (f2).

In vivo bioavailability study and data analysis

This was an single center, randomized, single-dose, open-label, 4-way crossover, bioavailability study to compare the rate and extent of absorption of a naproxen sodium 375 mg SR tablets (i.e. slow, medium and fast) and naproxen sodium 500 mg tablet (marketed immediate release), in six healthy male subjects under fasting conditions. Samples were collected at 0.0, 0.5, 1.0, 1.5, 2.0, 2.5, 3.0, 3.5, 4.0, 4.5, 5.0, 5.5, 6.0, 8.0, 10.0, 12.0, 16.0 and 24.0 hours post dose sample. A washout period of 7 days between the dosing of four periods. The study was approved by ethics committee and informed consent were provided by subjects prior enrolled into the study and. Validation of the method was carried out after the development of the liquid chromatography mass spectrometry (LCMS) methods. Validation performed as per the USFDA guidelines i.e. specificity/selectivity, carry over, linearity, precision and accuracy, recovery, dilution integrity, ruggedness, stabilities like freeze thaw stability, bench top stability, long term stability, stock solution stability. A simple and sensitive validated LCMS/MS method used for estimation of plasma sample by using protein precipitate extraction. The calibration curves were linear in the range of 1.167 [micro]g/mL to 163.729 [micro]g/mL for naproxen sodium. Bioavailability study evaluated through plasma concentration data by using pharmacokinetic parameters like [C.sub.max], AUC, [T.sub.max], half lifeand estimation performed by using Phoenix 6.4.0 version software.

IVIVC model development

Linear regression analysis was used to study the relationship between the drug dissolved and the drug absorbed in percentage. A correlation was established for naproxen sodium 375 mg SR tablets (i.e. slow, medium and fast) formulations (M/F, S/F, and S/M). A linear regression done by using a least squares method to estimate the regression parameters. Determination coefficient ([r.sup.2]) was evaluated. The deconvolution procedure was used to obtain in vivo input profiles of naproxen sodium from the sustained release dosage forms. The percent of dissolved is plotted against the dissolution sampling points of target formulation to check whether developed IVIVC model is valid.

IVIVC validation

The objective is to predict the outcome of in vivo profile with a given model and target formulation of in vitro profile. Internal validation provides basis for the acceptability of the model and external validation is superior and gives the self-confidence in the model. As per the FDA guidance on IVIVC for level A criteria as follows: for internal validation the mean absolute percent prediction error i.e. for [C.sub.max] and AUC should not exceed 10%, and for individual formulation should not exceed 15%. For external validation the prediction errors i.e. [C.sub.max] and AUC, for the formulation should not exceed 10%, 10% to 20% indicates in conclusive predictability and demonstrate the requirement for further study. The percent prediction errors (PE) for [C.sub.max] and AUC were calculated as follows:

[formula not reproducible] (1)

%P[E.sub.AUC] = (AUC (observed) - AUC (prediction)/AUC (observed)) X 100 (2)

RESULT AND DISCUSSION

In vitro dissolution study

The in vitro dissolution studies were performed at different pH conditions (namely pH 1.2, 4.5, 5.5, 6.8, 7.4) to select appropriate pH condition. The results of dissolution studies at different pH conditions with 50 rpm, at pH 1.2 and 50 rpm, drug release was partial and utmost 11% released from the formulations (F1-F6; SR tablets composition are mentioned in Table 1) within 3 hours as shown in the Figure 1. At pH 4.5, the drug release was very slow till 24 hours. The release was incomplete for all the formulations (F1-F6; SR tablets) as shown in the Figure 2. At pH 5.5 homogeneous and slow release of drug from all the 6 formulations (F1-F6; SR tablets) over the period of 24 h, 80.59-99.86% of drug was released as shown in the Figure 3. At pH 6.8 and 7.4 about 86.79-97.32% as shown in the Figure 4 and 86.95-95.81% release of drug was observed as shown in the Figure 5. Hence pH 5.5 selected for in vitro dissolution studies for naproxen sodium. There is no significant changes observed in drug release when performed with 75 rpm. The in vitro drug release studies performed as per the USP method i.e. pH 7.4 pH condition at 50 rpm for naproxen sodium SR tablets (i.e. F2 slow, F5 medium and F4 fast). The in vitro release characteristics of the fast, medium, and slow sustained release tablet of naproxen sodium were determined and presented in Figure 6. The similarity factor ([r.sup.2]) was calculated fast versus slow 52.52, fast versus medium 69.87 and medium versus slow 64.08 respectively. (4)

The percentage fraction dissolved for naproxen sodium are in the rank order of marketed immediate release, fast, medium and slow sustained release tablets and are presented in the Figure 6.

In vivo bioavailability study and data analysis

The mean pharmacokinetic profile for all formulations are presented in Table 2. The rank order release in the dissolution testing was obvious in the plasma concentration profile of naproxen sodium as in the Figure 7. AUC of naproxen slow release and medium release tablet was significantly higher compare to immediate release and fast release tablet. There is significant difference observed in naproxen slow and medium sustained release tablet compare to marketed immediate release and fast sustained tablet. AUC of naproxen sustained release tablets was much higher than immediate release tablet, may due to change in location of naproxen sodium absorption in gastrointestinal tract.

In vitro-in vivo correlation development

Level A in vitro and in vivo correlation was developed by comparing percent dissolved versus the percent absorbed of naproxen sodium fast, medium and slow sustained release and marketed immediate release tablets. The IVIVC plot was constructed using percentage of drug dissolved at pH 7.4 buffer dissolution media at 50 rpm versus the percentage of drug absorbed. The slope of the best-fit line was examined using linear regression analysis and coefficient of correlation ([r.sup.2]). IVIVC model linear regression of percentage dissolved and percentage absorbed for naproxen sodium sustained release tablet presented in the Figure 8-10. The correlation coefficient ([r.sup.2]) for naproxen sodium SR tablets medium versus slow was 0.987, fast versus medium was 0.948, and naproxen sodium SR tablets fast versus medium was 0.96 respectively. Good linear regression relationship observed between all the three test formulation. Edington et al. (9) described the dissolution methodology which discriminates between the formulation and mimics the in vivo release profile in development of IVIVC.

IVIVC validation

The internal validation of the IVIVC was examined by using the mean in vitro dissolution data and mean in vivo pharmacokinetics of the naproxen sodium sustained release tablets (i.e. slow, medium fast) corresponds to fast/medium/slow SR tablets. Each of IVIVC model predicted naproxen sodium plasma concentration versus time profiles were compared to the experimental data using prediction error metrics. The observed plasma concentration of naproxen sodium sustained release tablets (i.e. slow, medium and fast) are presented in the Figure 11-13, good correlation found between the observed and predicted plasma concentration.

Internal validation

The validity of correlation assessed by determining how well the IVIVC model predict the rate and extent of naproxen sodium as characterized by [C.sub.max] (maximum plasma concentration) and AUC (area under the plasma concentration-time curve from time zero to the time of the last quantifiable concentration). The prediction error estimated by using naproxen sodium slow SR tablets as a target formulation refer the Table 3. [C.sub.max] and AUC were found close to the mean values. The prediction error estimated by using naproxen sodium fast sustained release tablets as a target formulation refer the Table 4. [C.sub.max] and AUC were found close to the mean values. The prediction error estimated by using naproxen sodium medium sustained release tablets as a target formulation refer the Table 5. [C.sub.max] and AUC were found close to the mean values. As per the FDA for IVIVC the average absolute prediction error should be 10% and in addition individual formulation should not exceed 15%. In the present study relatively low prediction error for [C.sub.max] and AUC observed strongly suggest that the naproxen sodium IVIVC models are valid. Cross validation between the naproxen sodium sustained release tablets showed well within the acceptance limits and provides the self confidence to next stage of validation.

External validation

IVIVC for naproxen sodium immediate release tablet was used as a target formulation to predict the plasma concentration of naproxen sodium sustained release tablets (i.e. slow, medium and fast). Figure 14-16 shows the plasma concentration versus time of predicted formulation (immediate release tablet) with naproxen sodium fast, medium and slow SR tablet. The predicted curve for the naproxen sodium SR tablets (i.e. slow, medium and fast) are identical to immediate release tablet and considered model is valid.

CONCLUSION

This study established and validated the internal and external predictability of an IVIVC relationship for naproxen sodium formulation. Meaningful relationship was observed between the in vitro and in vivo parameters, thus indicates an exceptional IVIVC model for naproxen sodium SR tablets (i.e. slow, medium and fast). The resulted prediction errors are within the acceptance limit as per the USFDA guidelines for both [C.sub.max] and AUC. It can support dissolution data to predict the in vivo absorption, act as a biowaiver for bioequivalence and bioavailability studies and serve as a model for evaluating the naproxen sodium sustained release formulation. It can supports and validates the use of dissolution methods and specification settings, assisting in quality control which will be supportive for SUPAC.

ACKNOWLEDGEMENTS

The authors gratefully acknowledge administration of Srinivas College of Pharmacy, SeQuent Research Limited & Strides Arcolab Ltd, Colorcon Asia Pvt Limited, India and Phoenix Winonlin Certara software Hyderabad, India for granting support to carry out the work.

Conflict of Interest: No conflict of interest was declared by the authors.

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Ramesh NARAYANASAMY (*), Ramakrishna SHABARAYA

Srinivas College of Pharmacy, Farengipete Post, Mangalore, Karnataka, India

(*)Correspondence: E-mail: ramesh7779@gmail.com, Phone: 91 824 223270C

Received: 12.12.2016, Accepted: 26.01.2017

DOI: 10.4274/tjps.87587
Table 1. Composition of naproxen sodium formulation (F1-F6)

Formulation  Naproxen sodium  HPMC K100M  Talc (1.5%)

F1           375               75 mg      -
F2           375              150 mg      -
F3           375              225 mg      -
F4           375               37.5 mg    6.75 mg
F5           375               37.5 mg    7.87 mg
F6           375               37.5 mg    9.00 mg

Formulation  Magnesium stearate (1.5%)  Talc (1%)

F1           -                           4.50 mg
F2           -                           5.25 mg
F3           -                           5.25 mg
F4           6.75 mg                     -
F5           7.87 mg                     -
F6           9.00 mg                     -

Formulation  Magnesium stearate (1%)  Ethyl cellulose

F1           4.50 mg                  -
F2           6.00 mg                  -
F3           6.00 mg                  -
F4           -                        37.5 mg
F5           -                        37.5 mg
F6           -                        37.5 mg

Table 2. Mean pharmacokinetic parameter of naproxen sodium for
marketed immediate release and sustained release tablet (fast, medium
and slow)

Formulation                    [T.sub.max] (hr)    [C.sub.max] (ug/mL)

Immediate release tablet       1.833[+ or -]0.258  54.209[+ or -]10.685
Fast sustained release tablet  2.167[+ or -]0.258  73.767[+ or -]4.889
Medium sustained release
tablet                         2.667[+ or -]0.258  68.879[+ or -]4.562
Slow sustained release tablet  3.583[+ or -]0.376  63.199[+ or -]3.141

Formulation                    AUC (hr*ug/mL)

Immediate release tablet       147.483[+ or -]36.265
Fast sustained release tablet  307.561[+ or -]7.775
Medium sustained release
tablet                         391.273[+ or -]82.259
Slow sustained release tablet  391.499[+ or -]69.217

AUC: Area under the curve

Table 3. Prediction errors (%) associated with [C.sub.max] and AUC for
naproxen sodium fast vs. slow sustained release tablets

Formulation  Parameter      PE%

Fast         AUC              4.852
Fast         [C.sub.max]    -21.187
Medium       AUC              0.794
Medium       [C.sub.max]    -26.879
Slow         AUC             -5.643
Slow         [C.sub.max]    -33.069

AUC: Area under the curve, PE: Prediction errors

Table 4. Prediction errors (%) associated with [C.sub.max] and AUC for
naproxen sodium fast vs. medium sustained release tablets

Formulation  Parameter    PE%

Fast         AUC          -18.760
Fast         [C.sub.max]  -35.896
Medium       AUC           14.180
Medium       [C.sub.max]  -40.250
Slow         AUC            6.8779
Slow         [C.sub.max]  -44.696

AUC: Area under the curve, PE: Prediction errors

Table 5. Prediction errors (%) associated with [C.sub.max] and AUC for
naproxen sodium medium vs. slow sustained release tablets

Formulation  Parameter    PE%

Fast         AUC           -5.852
Fast         [C.sub.max]  -31.281
Medium       AUC           -9.495
Medium       [C.sub.max]  -35.501
Slow         AUC          -15.271
Slow         [C.sub.max]  -39.791

AUC: Area under the curve, PE: Prediction errors
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Title Annotation:ORIGINAL ARTICLE
Author:Narayanasamy, Ramesh; Shabaraya, Ramakrishna
Publication:Turkish Journal of Pharmaceutical Sciences
Article Type:Report
Date:Aug 1, 2017
Words:3363
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