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Development of a Clinically Relevant Dissolution Method for Metaxalone Immediate Release Formulations Based on an IVIVC Model

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Abstract

Purpose

The aim of the present work was to classify metaxalone according to the Biopharmaceutics Classification System (BCS), to develop a clinically relevant dissolution method that can be used to predict the oral absorption of metaxalone and to establish an in vitro-in vivo correlation (IVIVC).

Methods

Solubility of the drug was studied in different pH media and permeability studies were performed using a Caco-2 cell model. The in vitro dissolution and in vivo disposition of metaxalone from 3 different immediate release (IR) tablet formulations were investigated using USP 2 apparatus and a single dose, four-way, crossover bioequivalence study in healthy humans along with an oral solution of the drug, respectively. An IVIVC was established by using a direct, differential based method.

Results

Metaxalone has been confirmed as a Class II drug according to BCS. Bioavailability studies performed in humans demonstrated that dissolution was the rate limiting step for bioavailability of the drug and one of the test products had significantly improved bioavailability compared to the marketed product Skelaxin®. An IVIVC model was developed that demonstrated an acceptable internal predictability.

Conclusion

The IVIVC demonstrated that formulation factors play a significant role in dissolution and absorption of metaxalone. A pH 4.5 dissolution medium containing 0.5% NaCl with 0.2% SLS (USP apparatus 2 at 50 rpm) is clinically relevant to predict bioavailability of the drug and is superior to the USP method in terms of the Quality by Design (QbD) concept.

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Abbreviations

AB:

Apical to basolateral

ANOVA:

Analysis of variance

AUCt :

Area under the curve from time zero to time of last non-zero concentration

BA:

Basolateral to apical

BCS:

Biopharmaceutics classification system

Caco-2:

Human colonic adenocarcinoma cells

Cmax :

Maximum observed concentration

DDE:

Direct, differential equation

DMEM:

Dulbecco’s modified Eagle's medium

EMA:

European medicines agency

FDA:

Food and drug administration

HEPES:

Hank’s balanced salt solution

HPLC:

High pressure liquid chromatographic

HPMC:

Hydroxypropylmethyl cellulose 6cp

ICH:

International conference on harmonization

IR:

Immediate release

IVIVC:

In vitro-in vivo correlation

K2EDTA:

Dipotassium ethylenediaminetetraacetic (edetic) acid

LC MSD:

Liquid chromatography with mass spectrometry detection

LLOQ:

Lower limit of quantification

NEAA:

Nonessential amino acids solution

PE:

Prediction errors

PK:

Pharmacokinetic

PVP:

Povidone K30

QbD:

Quality by design

QC:

Quality control

SLS:

Sodium lauryl sulfate

TEER:

Transepithelial electrical resistance

USP:

United States Pharmacopeia

UV:

Ultraviolet

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ACKNOWLEDGMENTS AND DISCLOSURES

We would like to thank Ms. Teresa Wloch of PLIVA Krakow Research and Development and Ms. Zdravka Tadić for their technical assistance in preparing Test formulations (A, B and oral solution). This work has been supported by Pliva Croatia Ltd. and in part by Croatian Science Foundation under the project 3526.

Author information

Author notes

  1. M. Zahirul I. Khan

    Present address: PharmaVision Australia, 28 Bourneville Ave, Brighton East, Melbourne, Vic., 3187, Australia

Authors and Affiliations

  1. Research and Development, PLIVA Croatia Ltd, Prilaz baruna Filipovića 25, 10000, Zagreb, Croatia

    Lucija Vuletić, Maja Radić & Biserka Cetina-Čižmek

  2. Faculty of Pharmacy and Biochemistry, University of Zagreb, Zagreb, Croatia

    Lucija Vuletić & Jelena Filipović-Grčić

  3. Research and Development, PLIVA Krakow, 80 Mogilska Str., 31-546, Krakow, Poland

    M. Zahirul I. Khan

  4. Intellomics d.o.o., Trg Ivana Kukuljevića 4, Zagreb, Croatia

    Drago Špoljarić

Authors
  1. Lucija Vuletić
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  2. M. Zahirul I. Khan
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  3. Drago Špoljarić
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Corresponding authors

Correspondence to Lucija Vuletić or Biserka Cetina-Čižmek.

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Ethical Approval

All procedures performed in this study involving human participants were in accordance with the ethical standards of the institution and/or national research committee and with the 1946 Helsinki declaration and its later amendments or comparable ethical standards.

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Guest Editors: Kin Yip Tam, Zoran Mandic, and Tonglei Li

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Vuletić, L., Khan, M.Z.I., Špoljarić, D. et al. Development of a Clinically Relevant Dissolution Method for Metaxalone Immediate Release Formulations Based on an IVIVC Model. Pharm Res 35, 163 (2018). https://doi.org/10.1007/s11095-018-2434-1

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  • DOI: https://doi.org/10.1007/s11095-018-2434-1

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