Development of Bioequivalent Extended Release Dosage Forms Using Biorelevant Dissolution Media: In-Vitro Screening for Selected BCS I, II, and III Model Compounds
Refereed conference paper presented and published in conference proceedings

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Traditionally, for developing a bioequivalent generic drug corresponding to its innovator drug, in-vitro dissolution tests in compendial dissolution media (CDM) would be selected to guide the screening of formulations. Due to CDM’s composition not considering the physiological environment of the gastrointestinal (GI) tract, a biased estimation of the dissolution rate/solubility would be obtained for some poorly soluble drugs. Biorelevant dissolution media (BDM) are designed to mimic the human GI environment in the lipid/enzyme composition, pH, buffer capacity and osmolality. The aim of our project is to verify if BDM guided formulation screening could increase the probability of getting a bioequivalent extended-release (ER) product for the selected BCS I, II and III compounds. As the pilot investigation, we are reporting the formulation screening results under a BDM guided optimization process.

Potassium chloride, diclofenac sodium and metformin hydrochloride were selected as the representatives for BCS I, II, and III model compounds, respectively. Their corresponding reference products of SLOW-K® prolonged-release tablet (600mg), Voltaren®-XR (100mg) and GLUCOPHAGE® XR (500mg) were also chosen for the current study. To obtain extended-release effect for the three model compounds, preparation technologies, such as membrane-coating, hydroxypropyl methylcellulose (HPMC) matrix, and insoluble matrix, were tried and the resulting ER tablets were tested against their reference product for dissolution profiles using both CDM and BDM. CDM included purified water, 0.1N HCl, pH4.5 acetate buffer, pH6.8 phosphate buffer, and pH7.5 phosphate buffer as those included by USP, CP or EP. BDM are FaSSGF (Fasted State Simulated Gastric Fluid), FaSSIF-V2 (Fasted State Simulated Intestinal Fluid Version-2) and FeSSIF-V2 (Fed State Simulated Intestinal Fluid Version-2). The dissolution profiles of the ER tablets were examined using USP Apparatus II with a rotation speed of 100 rpm in 900/1000 mL dissolution media at 37oC. Comparison between dissolution profiles are analyzed by estimation of a similarity factor (f2) and dissolution profiles are considered similar if these values were between 50 and 100.

Similar dissolution profiles were observed for BCS I and III compounds in BDM and CDM at the same pH, whereas the BCS II compound showed a higher dissolution rate in BDM than that in CDM which may be due to the additives in BDM. Compositions of ER tablets were adjusted if the dissolution profiles’ similarity factor between a ER tablet and its corresponding reference in any kind of CDM or DBM was less than 50. The process repeated until a ER tablet formulation could meet all requirements. Thus, a membrane-coated tablet for potassium chloride, a wax-matrix tablet for diclofenac sodium, and a HPMC matrix tablet for metformin were developed.

Based on similar in-vitro dissolution profiles under both CDM and BDM with that from reference products, pharmaceutical equivalent tablets for the selected BCS I, II, and III model compounds were developed, which will be verified on health human subjects. (Financial Support from ITS/165/16FX)
All Author(s) ListYufeng Zhang, Hua Liu, Johnson Tang, Zhong Zuo
Name of Conference2017 American Association of Pharmaceutical Scientists (AAPS) Annual Meeting and Exposition
Start Date of Conference11/11/2017
End Date of Conference15/11/2017
Place of ConferenceSan Diego, CA
Country/Region of ConferenceUnited States of America
LanguagesEnglish-United States

Last updated on 2018-02-10 at 09:42