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Design and development of combination tablets of lansoprazole and pH modifier for enhanced stability and pH modulation

  • 홍일기 (Il-Ki Hong, 아주대학교 일반대학원)

초록/요약

We investigated the microenvironmental pH （pHM）-modulating mechanism and intermolecular interaction of alkalizers and their impact on the aqueous stability, release profiles of drugs and alkalizers, pharmacokinetics, and intragastric pH variability in 46 healthy human subjects of lansoprazole （LAN）, an acid-labile model drug. Preliminary screening of five alkalizers （CaCO3, MgO, NaHCO3, meglumine, and L-arginine） in LAN-loaded wet granules under simulated gastric fluid demonstrated that calcium carbonate （CaCO3） appeared to be the best stabilizing agent for LAN in a dose-dependent manner according to solution pH changes and drug contents. Immediate-release fixed-dose combination tablets （IFT） containing LAN and CaCO3 were prepared via a dual granulation process using a fluidized bed dryer （FBD） and/or a high shear mixer （HSM）. Unlike the commercial enteric-coated granule-loaded Lanston® capsule, IFT released LAN and CaCO3 simultaneously, achieving over 90% drug release within 30 min while maintaining its aqueous stability in pH 1.2 gastric fluid via the acid-neutralizing capacity of simultaneously released CaCO3. The increased modulation of pHM and the intermolecular complex of LAN with calcium ions are crucial for stabilizing LAN under low pH conditions. The optimal IFT formulation demonstrated long-term stability for 3 years, maintaining drug content and dissolution rates while liberating impurities （〈0.2%） within regulatory guidelines. IFT demonstrated bioequivalence with the commercial enteric-coated Lanston® capsule with decreased “time to reach the maximum plasma concentration” and displayed superior intragastric pH control, maintaining pH above 4 for a longer duration over 24 h in a cross-over design in 46 healthy human subjects. The current novel IFT containing acid-labile LAN and CaCO3 can be used to substitute current enteric-coated LAN tablets for the immediate release and rapid onset of LAN without chemical degradation in the gastric fluid.

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목차

1. Introduction 1
2. Materials and Methods 6
2.1. Materials 6
2.2. Preliminary screening of alkalizers for LAN stability 6
2.2.1. Preparation of wet granules containing LAN and alkalizer 6
2.2.2. Effect of alkalizers on gastric stability 9
2.2.3. Effect of CaCO3 contents 9
2.3. Field emission scanning electron microscopy (FE-SEM) 12
2.4. pHM measurement of LAN-alkalizer tablet 12
2.5. Solid-state characterization of LAN–alkalizer formulations 14
2.5.1. Differential scanning calorimetry (DSC) 14
2.5.2. Powder X-ray diffraction (PXRD) 14
2.5.3. Fourier transform infrared spectroscopy (FT-IR) 15
2.6. Manufacturing process of IFTs 15
2.7. In vitro dissolution studies 20
2.7.1. Dissolution profile of LAN from matrix formulations 20
2.7.2. Comparative release kinetics of LAN and CaCO3 20
2.8. Quantitative analysis of LAN and calcium content 21
2.9. Comparative pharmacokinetics and intragastric pH variability 22
2.9.1. Study design 22
2.9.2. Study protocol 23
2.9.3. Pharmacokinetic assessment 23
2.9.4. Pharmacodynamic assessment 24
2.10. Statistical analysis 24
3. Results and Discussion 26
3.1. Effect of alkalizers on gastric stability 26
3.2. FE-SEM of LAN-alkalizer granules 28
3.3. pHM measurement 30
3.4. Solid-state characterization of LAN–alkalizer formulations 34
3.4.1. Thermal characterization of LAN–alkalizer by DSC 34
3.4.2. PXRD 36
3.4.3. Molecular characterization by FT-IR spectroscopy 38
3.5. In vitro dissolution studies 40
3.5.1. Enhanced gastric stability of LAN pHM-modulation 40
3.5.2. Synergistic release mechanism of IFT 42
3.6. Long-term stability studies 45
3.7. In vivo pharmacokinetic and pharmacodynamic analyses 49
3.8. Safety rationale of CaCO3 as a formulation excipient in a PPI-combination immediate-release tablet 55
4. Conclusions 58
5. References 59

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