Pharmaceutical Manufacturing Handbook: Production and

NASAL DELIVERY OF PEPTIDE AND HIGH-MOLECULAR-WEIGHT DRUGS 619
Anti–factor Xa activity (U/mL)
Anti–Factor Xa activity (U/mL)
0.6
0.5
0.4
0.3
0.2
0.1
0.5% Octanoylsucrose
0.25% Octanoylsucrose
0.125% Octanoylsucrose
Saline
0.0
0 100 200
Time (min)
(a)
300 400
0.6
0.5
0.4
0.3
0.2
0.1
0.5% Dodecanoylsucrose
0.25% Dodecanoylsucrose
0.125% Dodecanoylsucrose
Saline
0.0
0 100 200 300 400
Time (min)
(c)
0.0
0 100 200
Time (min)
(b)
300 400
Time (min)
(d)
FIGURE 16 Changes in anti – factor Xa activity after nasal administration of enoxaparin
formulated in saline or in presence of different concentrations of the following: ( a ) octanoylsucrose;
( b ) decanoylsucrose; ( c ) dodecanoylsucrose; ( d ) sodium glycocholate and dodecanoylsucrose
to anesthetized rats (enoxaparin dose, 330 U/kg). Data represent mean ± SEM,
n = 3, 5. ( Reproduced from ref. 84 with permission of Pharmaceutical Press. )
Anti–Factor Xa activity (U/mL)
Anti–Factor Xa activity (U/mL)
0.6
0.5
0.4
0.3
0.2
0.1
0.6
0.5
0.4
0.3
0.2
0.1
0.5% Decanoylsucrose
0.25% Decanoylsucrose
0.125% Decanoylsucrose
Saline
1% Sodium glycocholate
0.5% Dodecanoylsucrose
Saline
0.0
0 100 200 300 400
The authors also studied the infl uence of the chain length of alkylmaltosides on
the nasal absorption of enoxaparin. The results indicated that increases in the concentration
of alkylmaltosides increased the AUC for plasma anti – factor Xa; it was
found that the absolute and relative bioavailabilities of enoxaparin increased by
twofold with an increase in alkyl chain length from 8 to 14 carbons. Of all the alkylmaltosides,
TDM was found to be the most potent absorption enhancer [85] .
Furthermore, we have also shown the effi cacy of cyclodextrins in enhancing
absorption following the nasal delivery of LMWHs. Three different cyclodextrins
were employed: β - cyclodextrins ( β - CD), hydroxypropyl β - CD (HP β - CD), and
dimethyl β - CD (DM β - CD). β - CD showed therapeutic levels of anti – factor Xa only
at 2.5 and 5% β - CD, but there was no signifi cant difference between the two concentrations,
which was attributed to their solubility limit. In the case of HP β - CD,
neither 1.25 nor 2.5% produced an appreciable increase in anti – factor Xa levels;