Biomedical Engineering Reference
In-Depth Information
O
O
+
HO-R-OH
O
O
O
O
O
O
O
O
O
(R)
n
O
O
O
R(OH)
3
Crosslinked polymer
Scheme 4.7
Synthesis of crosslinked POE II.
4.2.2
Drug Delivery
4.2.2.1
Development of Ivermectin Containing Strands to Prevent Heartworm
Infestation in Dogs
The most extensive investigation of POE II for drug delivery was carried out at the
former Interx Laboratories of Merck (Kansas City, MO). In this application, a
crosslinked polymer was used.
A crosslinked POE II can be prepared as shown in Scheme 4.7 [13]. Briefl y, a
prepolymer of DETOSU and a diol is prepared so that the prepolymer has ketene
acetal end-groups. This prepolymer is then reacted with a triol, or polyols having
a functionality greater than 2 to form a crosslinked network.
In this particular instance, the objective was to develop an ivermectin device
capable of preventing heartworm infestation in dogs for at least 6 months [14].
Since ivermectin is not stable at 140-155 °C, extrusion of strands was not a viable
method so that a device based on a crosslinked POE II was developed. Ivermectin
has three hydroxyl groups and can thus compete with the crosslinker,
1,2,6-hexanetriol, for the ketene acetal end-groups. Consequently, in the fi nal
device, ivermectin is chemically bound to the matrix.
4.2.2.2
Experimental Procedure
The poly(ortho ester) matrix was prepared by a two-step procedure involving the
preparation of a low molecular weight prepolymer followed by a crosslinking reac-
tion. HD (3.72 g, 31.5 mmol) was dissolved in 20 mL of freshly distilled (from
sodium) THF. DETOSU (10.03 g, 47.3 mmol) in a 50 mol% excess over HD was
added via an oven-dried syringe. The mixture was refl uxed 1 h under nitrogen to
form a ketene acetal end-capped prepolymer. The THF was removed at room
temperature under reduced pressure (ca. 4 mmHg). An aliquot (3.122 g) of the
prepolymer was triturated with 0.151 g of magnesium hydroxide (hydrolytic
