Abstract
This study reports on the release of a novel natriuretic peptide, CD-NP, from an in situ polymer precipitation delivery system. Following extensive screening of in-vitro release profiles, an in-vivo evaluation of the efficacy of the delivery system was carried out in Wistar rats. Gel injection was performed subcutaneously on the back of the rats. A secondary messenger, cyclic Guanosine 3′5′ Monophosphate (cGMP), was tested for verification of CD-NP bioactivity, in addition to direct measurements of CD-NP levels in plasma and urine using a radio-immuno assay. Plasma evaluation showed an elevated level of CD-NP over 3 weeks' duration. Unexpectedly, plasma cGMP level followed a decreasing trend over the same duration despite high CD-NP level. Loss of drug bioactivity was ruled out as a high level of CD-NP and cGMP excretion was observed in the treatment group as compared to baseline readings. This unexpected low-plasma cGMP levels and high-urinary cGMP excretion suggest that there might be other compensatory responses to regulation of the CDNP bioactivity as a result of the high drug dosing. The results stress the importance of assessing the overall bioactivity of released drug (in-vivo) concurrently in addition to measuring its concentrations, to determine the correct release profile.
Highlights
Worldwide, cardiovascular diseases have emerged as the leading cause of death [1]
In-vitro buffer release The nature of CD-natriuretic peptides (NPs) peptide offers challenges for the gel formulation development
The release profile for the selected gel formulation, presented in figure 1A, demonstrated a sustained CD-NP release for more than 30 days. It has an initial burst of 1161% of the total CD-NP loading
Summary
Various forms of cardiovascular diseases result in the development of the syndrome of heart failure (HF). NP (uCD-NP) level, as shown, is measured at 260.10 pg/min and 461.65 pg/min for treatment and vehicle groups respectively. The uCD-NP was measured to be at 5506139.60 pg/min and 6006151.90 pg/min after the 1st and 2nd injection respectively. After the gel injections, there is a burst release of CD-NP from the gel Most of this un-used CD-NP will be excreted out of the system through urinary excretion. The amount of CD-NP excreted at 1/2/3 weeks reduced to 107612.70 pg/min, 34629.72 pg/min and 1768.19 pg/min respectively These are statistically significant when compared with the baseline level. There is no significant difference in uCD-NP output observed between the baseline and 3 weeks urinary output for the vehicle group
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