Biomedical Engineering Reference
In-Depth Information
4.5.4
Preclinical Toxicology
Two types of studies were carried out. In one study, the polymer was hydrolyzed
and the hydrolysate tested and the other study utilized the actual formulation [33].
4.5.4.1
Polymer Hydrolysate
Hydrolyzing the polymer into its hydrolysis products simulates the instantaneous
erosion of an implant and thus represents a worst case scenario.
The hydrolysate was prepared by hydrolyzing the polymer in phosphate-buffered
saline (PBS) at 80 °C for 24 h, adjusting the pH to 7.4 with NaOH, adding the
methoxy polyethylene glycol, mixing thoroughly, adding deionized water to adjust
osmolarity and fi nally fi ltering through a 0.45-
m fi lter. The solution was then
injected subcutaneously into male and female Sprague-Dawley rats and into male
and female beagle dogs. In the rat study, the doses used were 0, 1, 3, and 10 mL/
kg and in beagle dogs, the dose was 0, 0.05, 0.1, and 0.2 mL/kg. Both animal
species were observed for 14 days, and no adverse effects by clinical observation
and gross necropsies were found. In addition, no histological evidence of systemic
toxicity was observed in all organs evaluated.
μ
4.5.4.2
Wound Instillation
The following incisional wound instillation study was carried out in rats. A 1- cm
full-thickness incision was made, a subcutaneous pocket thus created by blunt
dissection, the APF 112 formulation administered into the subcutaneous pocket,
the skin closed with 4-0 nylon sutures, which were removed after 7 days.
The study was carried out using Sprague-Dawley male and female rats using 500
and 1000
L in a single dose and the rats sacrifi ced at day 8. Both doses were well
tolerated, but the 1000
μ
μ
L dose resulted in some leakage and wound distension.
4.5.5
Phase II Clinical Trial
The objectives of this trial was to evaluate the safety and tolerability of APF 112
when administered into the surgical incision during inguinal hernia repair, a mod-
erately to severely painful procedure. Results indicated excellent safety and tolerabil-
ity, and pharmacokinetics showed sustained release of mepivacaine over 72 h [34].
However, due to an unexpectedly low level of pain displayed by the control group
in the study, it was not possible to demonstrate that APF 112 is effective in con-
trolling postsurgical pain.
4.5.6
Development of APF 530 Granisetron Delivery System
4.5.6.1
Preclinical Toxicology
Since APF 530 uses the same polymer as that used in APF 112, no polymer hydro-
lysate studies were needed.
