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Oral Delivery of Ionic Complex of Ceftriaxone with Bile Acid Derivative in Non-human Primates

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ABSTRACT

Purpose

Since the absorption of ceftriaxone (CTO) in the intestine is restricted by its natural physiological characteristics, we developed a series of small synthetic compounds derived from bile acids to promote the absorption of CTO in the gastrointestinal tract.

Methods

Several bile acid derivatives were screened by measuring water solubility and partition coefficient of their complexes with CTO. The pharmacokinetic parameters of the selected CTO/HDCK ionic complex in monkeys were evaluated. The absorption pathway of CTO/HDCK complex was evaluated using Caco-2 cells and MDCK cells transfected with ASBT gene.

Results

HDCK enhanced the apparent membrane permeability of CTO 5.8-fold in the parallel artificial membrane permeability assay model. CTO/HDCK complex permeated Caco-2 cell via transcellular pathway, and interaction of the HDCK complex with ASBT was important to enhance uptake. When CTO/HDCK (equivalent to 50 mg/kg of ceftriaxone) formulated with lactose, poloxamer 407 and Labrasol was orally administered to monkeys, its maximum plasma concentration was 19.5 ± 1.8 μg/ml and oral bioavailability 28.5 ± 3.1%.

Conclusions

The CTO/HDCK formulation could enhance oral bioavailability of CTO in non-human primates. This oral formulation could be an alternative to injectable CTO with enhanced clinical effects.

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Abbreviations

ASBT:

apical sodium bile acid transporter

AUC:

area under the curve

Cmax :

the maximum plasma concentration

CTO:

sodium ceftriaxone

DAPI:

4,6-diamidino-2-phenylindole

DOCA:

deoxycholic acid

HDCK:

an oral drug carrier derived from deoxycholic acid

HPMCP:

hydroxypropyl methylcellulose phthalate

IVF:

in vitro fertilization

KRICT:

Korea Research Institute of Chemical Technology

MDCK:

Madin-Darby canine kidney

PAMPA:

parallel artificial membrane permeability assay

THF:

tetrahydrofuran

Tmax :

the time to reach the peak concentration

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ACKNOWLEDGMENTS AND DISCLOSURES

Ok-Cheol Jeon and Seung Rim Hwang contributed equally to this work. This study was supported by the Converging Research Center Program (grant no. 2012K001398) and the World Class University (WCU) program (grant no. R31-2008-000-10103-0) of the National Research Foundation of Korea (NRF), which is funded by the Ministry of Education, Science and Technology in Korea.

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Authors and Affiliations

  1. Department of Polymer Science and Engineering, Sungkyunkwan University, Suwon, 440-746, South Korea

    Ok-Cheol Jeon & Jae Hyung Park

  2. Mediplex Corp., , Seoul, 151-742, South Korea

    Ok-Cheol Jeon

  3. Research Institute of Pharmaceutical Sciences, College of Pharmacy, Seoul National University, Seoul, 151-742, South Korea

    Seung Rim Hwang, Taslim A. Al-Hilal, Hyun Tae Moon & Youngro Byun

  4. Amorepacific Corporation R&D Center, 314-1, Bora-dong, Giheung-gu, Yongin-si, Gyeonggi-do, 446-729, South Korea

    Jin Woo Park

  5. Russell H. Morgan Department of Radiology and Radiological Science School of Medicine, Johns Hopkins University, Baltimore, MD, 21205, USA

    Seulki Lee

  6. Department of Molecular Medicine and Biopharmaceutical Sciences Graduate School of Convergence Science and Technology College of Pharmacy, Seoul National University, Seoul, 151-742, South Korea

    Youngro Byun

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  1. Ok-Cheol Jeon
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  2. Seung Rim Hwang
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  3. Taslim A. Al-Hilal
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Correspondence to Jae Hyung Park or Youngro Byun.

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Jeon, OC., Hwang, S.R., Al-Hilal, T.A. et al. Oral Delivery of Ionic Complex of Ceftriaxone with Bile Acid Derivative in Non-human Primates. Pharm Res 30, 959–967 (2013). https://doi.org/10.1007/s11095-012-0932-0

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  • DOI: https://doi.org/10.1007/s11095-012-0932-0

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