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Investigation of utilization of nanosuspension formulation to enhance exposure of 1,3-dicyclohexylurea in rats: Preparation for PK/PD study via subcutaneous route of nanosuspension drug delivery.

Chiang PC, Ran Y, Chou KJ, Cui Y, Wong H - Nanoscale Res Lett (2011)

Bottom Line: Furthermore, the oral pharmacokinetics of DCU in rodent are such that the use of DCU to understand PK/PD relationships of sEH inhibitors in preclinical efficacy model is less than ideal.In this study, the limitation of orally delivered DCU nanosuspension was assessed by a surface area sensitive absorption model and pharmacokinetic modeling.It was found that dosing DCU nanosuspension did not provide the desired plasma profile needed for PK/PD investigation.

View Article: PubMed Central - HTML - PubMed

Affiliation: Small Molecule Research, Genentech, 1 DNA Way, South San Francisco, CA 94080, USA. Chiang.pochang@gene.com.

ABSTRACT
1,3-Dicyclohexylurea (DCU), a potent soluble epoxide hydrolase (sEH) inhibitor has been reported to lower systemic blood pressure in spontaneously hypertensive rats. One limitation of continual administration of DCU for in vivo studies is the compound's poor oral bioavailability. This phenomenon is mainly attributed to its poor dissolution rate and low aqueous solubility. Previously, wet-milled DCU nanosuspension has been reported to enhance the bioavailability of DCU. However, the prosperities and limitations of wet-milled nanosuspension have not been fully evaluated. Furthermore, the oral pharmacokinetics of DCU in rodent are such that the use of DCU to understand PK/PD relationships of sEH inhibitors in preclinical efficacy model is less than ideal. In this study, the limitation of orally delivered DCU nanosuspension was assessed by a surface area sensitive absorption model and pharmacokinetic modeling. It was found that dosing DCU nanosuspension did not provide the desired plasma profile needed for PK/PD investigation. Based on the model and in vivo data, a subcutaneous route of delivery of nanosuspension of DCU was evaluated and demonstrated to be appropriate for future PK/PD studies.

No MeSH data available.


PXRD DCU before milling (bottom) and post milling (top).
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Figure 2: PXRD DCU before milling (bottom) and post milling (top).

Mentions: The stability of the DCU formulations (both regular suspension and nanosuspension) was assessed, and no issue was found. No particle size, potency, and form change was observed in a period of 7 days. All samples were found to be consistent with the previously reported data [13-15]. In general, an analysis of unmilled and milled DCU particles revealed a mean particle size of 20.2 μm (regular suspension) and 0.8 μm (nanosuspension), respectively (Figure 1). No form change was detected by PXRD when compare pre and post milling sample (Figure 2). The rate of dissolution of the DCU nanosuspension versus regular suspension is expected to increase at least 20-folds. To estimate the impact of dissolution, the Noyes and Whitney equation was used:


Investigation of utilization of nanosuspension formulation to enhance exposure of 1,3-dicyclohexylurea in rats: Preparation for PK/PD study via subcutaneous route of nanosuspension drug delivery.

Chiang PC, Ran Y, Chou KJ, Cui Y, Wong H - Nanoscale Res Lett (2011)

PXRD DCU before milling (bottom) and post milling (top).
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3211509&req=5

Figure 2: PXRD DCU before milling (bottom) and post milling (top).
Mentions: The stability of the DCU formulations (both regular suspension and nanosuspension) was assessed, and no issue was found. No particle size, potency, and form change was observed in a period of 7 days. All samples were found to be consistent with the previously reported data [13-15]. In general, an analysis of unmilled and milled DCU particles revealed a mean particle size of 20.2 μm (regular suspension) and 0.8 μm (nanosuspension), respectively (Figure 1). No form change was detected by PXRD when compare pre and post milling sample (Figure 2). The rate of dissolution of the DCU nanosuspension versus regular suspension is expected to increase at least 20-folds. To estimate the impact of dissolution, the Noyes and Whitney equation was used:

Bottom Line: Furthermore, the oral pharmacokinetics of DCU in rodent are such that the use of DCU to understand PK/PD relationships of sEH inhibitors in preclinical efficacy model is less than ideal.In this study, the limitation of orally delivered DCU nanosuspension was assessed by a surface area sensitive absorption model and pharmacokinetic modeling.It was found that dosing DCU nanosuspension did not provide the desired plasma profile needed for PK/PD investigation.

View Article: PubMed Central - HTML - PubMed

Affiliation: Small Molecule Research, Genentech, 1 DNA Way, South San Francisco, CA 94080, USA. Chiang.pochang@gene.com.

ABSTRACT
1,3-Dicyclohexylurea (DCU), a potent soluble epoxide hydrolase (sEH) inhibitor has been reported to lower systemic blood pressure in spontaneously hypertensive rats. One limitation of continual administration of DCU for in vivo studies is the compound's poor oral bioavailability. This phenomenon is mainly attributed to its poor dissolution rate and low aqueous solubility. Previously, wet-milled DCU nanosuspension has been reported to enhance the bioavailability of DCU. However, the prosperities and limitations of wet-milled nanosuspension have not been fully evaluated. Furthermore, the oral pharmacokinetics of DCU in rodent are such that the use of DCU to understand PK/PD relationships of sEH inhibitors in preclinical efficacy model is less than ideal. In this study, the limitation of orally delivered DCU nanosuspension was assessed by a surface area sensitive absorption model and pharmacokinetic modeling. It was found that dosing DCU nanosuspension did not provide the desired plasma profile needed for PK/PD investigation. Based on the model and in vivo data, a subcutaneous route of delivery of nanosuspension of DCU was evaluated and demonstrated to be appropriate for future PK/PD studies.

No MeSH data available.