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Stabilizing excipients for engineered clopidogrel bisulfate procubosome derived in situ cubosomes for enhanced intestinal dissolution: Stability and bioavailability considerations.
Eur J Pharm Sci 2019; 136:104954EJ

Abstract

Clopidogrel bisulfate (CB) is a golden antiplatelet treatment, yet its benefits are limited by its low bioavailability (<50%) caused by poor intestinal solubility and absorption. The present study aims to improve CB intestinal solubility and absorption through developing a novel stable dry CB procubosomes tablets ready to disintegrate and re-disperse upon dilution in the GIT forming in situ CB cubosome nanoparticles while simultaneously overcome the poor stability of conventional cubosome dispersion at room temperature. Glyceryl monooleate based CB cubosome dispersion was prepared using Poloxamer 407 as surfactant, freeze dried using different stabilizing excipients (dextrose, mannitol and avicel) then compressed into procubosome tablets. The effect of excipient's physicochemical properties on the flowability, in vitro dissolution and stability at accelerated conditions (40 ± 2 °C/75 ± 5% RH) were evaluated. The prepared procubosomes exhibited an excipient type dependent dissolution profile where Avicel based procubosome tablet CF2 showed the highest in vitro dissolution profile among other excipients used during the freeze drying process. Upon transition to intestinal pH of 6.8 to mimic the drug absorption site, CF2 procubosome Avicel tablet, was able to preserve the enhanced CB release profile (99.6 ± 6.92%) compared to commercial Plavix® where, CB dissolved % dropped dramatically to 79.1 ± 2.45%. After storage for six months, CF2 retained the fresh tablet drug content of 98.5 ± 5.82% and dissolution properties. Moreover, following oral administration in rabbits, CF2 showed higher relative bioavailability (153%) compared to commercial Plavix® with significant higher Cmax,shorter tmax, as well as enhanced antiplatelet activity.

Authors+Show Affiliations

Department of Pharmaceutics and Industrial Pharmacy, Faculty of Pharmacy, Cairo University, Egypt; Department of Pharmaceutics and Industrial Pharmacy, Faculty of Pharmacy, October University for Modern Sciences and Arts (MSA University), Egypt. Electronic address: hellaithy@msa.eun.eg.Department of Pharmaceutics and Industrial Pharmacy, Faculty of Pharmacy, Cairo University, Egypt.Department of Pharmaceutics and Industrial Pharmacy, Faculty of Pharmacy, Cairo University, Egypt. Electronic address: nevine.abdelmalak@pharma.cu.edu.eg.Department of Pharmaceutics and Industrial Pharmacy, Faculty of Pharmacy, October University for Modern Sciences and Arts (MSA University), Egypt. Electronic address: nihal_elmahdy@hotmail.com.

Pub Type(s)

Journal Article

Language

eng

PubMed ID

31189083

Citation

El-Laithy, Hanan M., et al. "Stabilizing Excipients for Engineered Clopidogrel Bisulfate Procubosome Derived in Situ Cubosomes for Enhanced Intestinal Dissolution: Stability and Bioavailability Considerations." European Journal of Pharmaceutical Sciences : Official Journal of the European Federation for Pharmaceutical Sciences, vol. 136, 2019, p. 104954.
El-Laithy HM, Badawi A, Abdelmalak NS, et al. Stabilizing excipients for engineered clopidogrel bisulfate procubosome derived in situ cubosomes for enhanced intestinal dissolution: Stability and bioavailability considerations. Eur J Pharm Sci. 2019;136:104954.
El-Laithy, H. M., Badawi, A., Abdelmalak, N. S., & Elsayyad, N. M. E. (2019). Stabilizing excipients for engineered clopidogrel bisulfate procubosome derived in situ cubosomes for enhanced intestinal dissolution: Stability and bioavailability considerations. European Journal of Pharmaceutical Sciences : Official Journal of the European Federation for Pharmaceutical Sciences, 136, p. 104954. doi:10.1016/j.ejps.2019.06.008.
El-Laithy HM, et al. Stabilizing Excipients for Engineered Clopidogrel Bisulfate Procubosome Derived in Situ Cubosomes for Enhanced Intestinal Dissolution: Stability and Bioavailability Considerations. Eur J Pharm Sci. 2019 Aug 1;136:104954. PubMed PMID: 31189083.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Stabilizing excipients for engineered clopidogrel bisulfate procubosome derived in situ cubosomes for enhanced intestinal dissolution: Stability and bioavailability considerations. AU - El-Laithy,Hanan M, AU - Badawi,Alia, AU - Abdelmalak,Nevine Shawky, AU - Elsayyad,Nihal Mohamed Elmahdy, Y1 - 2019/06/09/ PY - 2019/04/04/received PY - 2019/06/04/revised PY - 2019/06/05/accepted PY - 2019/6/13/pubmed PY - 2019/6/13/medline PY - 2019/6/13/entrez KW - Bioavailability KW - Clopidogrel bisulfate KW - Cubosomes KW - Freeze drying KW - Procubosomes KW - Stability KW - Stabilizing excipients SP - 104954 EP - 104954 JF - European journal of pharmaceutical sciences : official journal of the European Federation for Pharmaceutical Sciences JO - Eur J Pharm Sci VL - 136 N2 - Clopidogrel bisulfate (CB) is a golden antiplatelet treatment, yet its benefits are limited by its low bioavailability (<50%) caused by poor intestinal solubility and absorption. The present study aims to improve CB intestinal solubility and absorption through developing a novel stable dry CB procubosomes tablets ready to disintegrate and re-disperse upon dilution in the GIT forming in situ CB cubosome nanoparticles while simultaneously overcome the poor stability of conventional cubosome dispersion at room temperature. Glyceryl monooleate based CB cubosome dispersion was prepared using Poloxamer 407 as surfactant, freeze dried using different stabilizing excipients (dextrose, mannitol and avicel) then compressed into procubosome tablets. The effect of excipient's physicochemical properties on the flowability, in vitro dissolution and stability at accelerated conditions (40 ± 2 °C/75 ± 5% RH) were evaluated. The prepared procubosomes exhibited an excipient type dependent dissolution profile where Avicel based procubosome tablet CF2 showed the highest in vitro dissolution profile among other excipients used during the freeze drying process. Upon transition to intestinal pH of 6.8 to mimic the drug absorption site, CF2 procubosome Avicel tablet, was able to preserve the enhanced CB release profile (99.6 ± 6.92%) compared to commercial Plavix® where, CB dissolved % dropped dramatically to 79.1 ± 2.45%. After storage for six months, CF2 retained the fresh tablet drug content of 98.5 ± 5.82% and dissolution properties. Moreover, following oral administration in rabbits, CF2 showed higher relative bioavailability (153%) compared to commercial Plavix® with significant higher Cmax,shorter tmax, as well as enhanced antiplatelet activity. SN - 1879-0720 UR - https://www.unboundmedicine.com/medline/citation/31189083/Stabilizing_excipients_for_engineered_clopidogrel_bisulfate_procubosome_derived_in_situ_cubosomes_for_enhanced_intestinal_dissolution:_Stability_and_bioavailability_considerations L2 - https://linkinghub.elsevier.com/retrieve/pii/S0928-0987(19)30217-9 DB - PRIME DP - Unbound Medicine ER -