Pharmaceutical Manufacturing Handbook: Production and

NASAL DELIVERY OF PEPTIDE AND HIGH-MOLECULAR-WEIGHT DRUGS 615
Remaining radioactivity %
100
80
60
40
20
0
Native sCT
Mono-PEG-sCT
Di- PEG-sCT
0 10 20 30
Time (min)
40 50
FIGURE 13 Blood clearance of PEGylated salmon calcitonins in rat. ( Reproduced from
ref. 79 with permission of Taylor & Francis. )
The same group — Shin et al. [81] — did nasal absorption studies of a low -
molecular - weight PEG (2000) instead of the 5000 and 12,000 they tried previously.
They also used commercially available succinimidyl - propionated monomethoxy -
poly(ethylene glycol) - 2000 (SP - mPEG) for the chemical modifi cation instead of
synthesizing it, as in their previous studies. The PEGylation of sCT was done by
mixing SC - mPEG and sCT, and this mixture was shaken at 25 o C. The reaction
mixture was stopped by using an excess of 1.0 M glycine solution. This conjugated
mixture was then subjected to size exclusion chromatography. Radioiodination of
the sCT and the PEG - sCT were carried out and the radiolabeled 125 I - sCT and
125 I - mono - PEG2000 - sCT were then used for the nasal absorption studies.
Tissue distribution studies were also done in rats after nasal administration. As
seen in Figure 14 and Table 2 , it was found that the elimination half - life of the
unmodifi ed sCT was 199 min, whereas the SP - mPEG2000 - modifi ed sCT showed an
increased terminal elimination with a half - life of 923 min. It was also found that the
SP - mPEG2000 - modifi ed sCT took a signifi cantly longer time to reach its maximum
concentration, 520 min, as compared with the 77 min for the unmodifi ed sCT, and
the AUC was found to be 20,638 μ g/min/mL, which is much higher than the 3650 μ g/
min/mL for the unmodifi ed sCT. The authors reported that the increase in the terminal
half - life observed could be due to a fl ip - fl op phenomenon. Also, when the
tissue distribution of the formulation was examined 12 h after administration, the
highest radioactivity was found in the liver. The details of the biodistribution studies
are as shown in Table 3 .
The same group [82] further studied the stability of these mono - PEG2000 - sCT
and the unmodifi ed sCT in the rat nasal mucosa. It was found that PEGylated sCT
exhibited signifi cant resistance against trypticlike and nonspecifi c enzymatic degradation.
Ahsan et al. [49] showed that when sCT was formulated with alkylglycosides,
bioavailability was enhanced following both nasal and ocular administration. Miacalcin
(Novartis Pharma AS, Huningue, France) was used to prepare the formulation
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