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Novel formulations of dipyridamole with microenvironmental pH-modifiers for improved dissolution and bioavailability under hypochlorhydria

DOI: 10.1016/j.ijpharm.2012.05.040
Title: Novel formulations of dipyridamole with microenvironmental pH-modifiers for improved dissolution and bioavailability under hypochlorhydria
Journal Title: International Journal of Pharmaceutics
Volume: 434
Publication Date: 15 September 2012
Start Page: 148
End Page: 154
Published online: online 26 May 2012
ISSN: 0378-5173

  • a Department of Pharmacokinetics and Pharmacodynamics, School of Pharmaceutical Sciences, University of Shizuoka, 52-1 Yada, Suruga-ku, Shizuoka 422-8526, Japan

  • b Department of Chemistry, Manufacturing and Control, Kobe Pharma Research Institute, Nippon Boehringer Ingelheim Co., Ltd., 6-7-5, Minatojima-minamimachi, Chuo-ku, Kobe, Hyogo 650-0047, Japan

  • c Department of Pharmaceutical Physical Chemistry, College of Pharmaceutical Sciences, Matsuyama University, 4-2, Bunkyo, Matsuyama, Ehime 790-8578, Japan
  • Abstract: dy was undertaken to develop new dipyridamole (DP) formulations with acidic microenvironmental pH-modifiers for improving dissolution and absorption under hypochlorhydric conditions. Dipyridamole granules (DPG) with ten acidic pH-modifiers were prepared with conventional wet granulation, and their manufacturability, stability and dissolution behavior were characterized. Pharmacokinetic profiling of the optimized DPG with acid was carried out in omeprazole-treated rats as a hypochlorhydric model. On the basis of the manufacturability, stability and dissolution behavior of new DPG formulations, p-toluenesulfonic acid (TS) was found to be a suitable acidic pH-modifier for DPG formulation. Although DPG showed pH-dependent dissolution behavior, DPG with TS exhibited a high rate and extent of dissolution in both acidic and neutral media. After oral administration of DPG (10 mg DP/kg) in omeprazole-treated hypochlorhydric rats, there was ca. 40% reduction of the area under the curve of plasma concentration vs. time from zero to 3 h (AUC0–3) for DPG compared with that in normal rats. However, AUC0–3 for DPG/TS under hypochlorhydria was almost identical to that of DPG in normal rats. From these findings, the addition of TS as a microenvironmental pH-modifier in DP formulation might be beneficial in expanding the therapeutic potential of DP in hypochlorhydric patients.
    Accepted: 19 May 2012
    Received: 5 March 2012
    Revised: 18 April 2012
    Keywords: Dipyridamole; pH-modifier; Dissolution; Bioavailability; Hypochlorhydric
    Abbreviations: ANOVA, analysis of variance; API, active pharmaceutical ingredient; AA, adipic acid; D, l-aspartic acid; AUC, area under the curve of plasma concentration vs. time; BCS, biopharmaceutics classification system; CA, citric acid monohydrate; Cmax, maximum concentration; CV, coefficient of variation; DP, dipyridamole; DPG, dipyridamole granule; E, l-glutamic acid; HCl, hydrochloric acid; HPC, hydroxypropyl cellulose; HPLC, high-performance liquid chromatography; IDR, intrinsic dissolution rate; MLE, maleic acid; MLI, dl-malic acid; PK, pharmacokinetic; TS, p-toluenesulfonic acid monohydrate; RH, relative humidity; SA, succinic acid; SEM, scanning electron microscopy; SIR, selected ion recording; T1/2, half-life; TA, l-tartaric acid; Tmax, time to maximum concentration; UPLC/ESI-MS, ultra performance liquid chromatography equipped with electrospray ionization mass spectrometry; UV, ultraviolet; PXRD, powder X-ray diffraction
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