Biomedical Engineering Reference
In-Depth Information
emulsion process involves dissolving a polymer, such as poly(lactic-
co
-glycolic acid), in a water-
immiscible, volatile organic solvent, such as dichloromethane. The solution is then emulsifi ed (with
parameters of stirring rate and temperature optimized according to the polymer) in a large volume
of water containing an emulsifi er, such as poly(vinyl alcohol) (PVA), to yield an emulsion. To harden
the oil droplets, the solvent is either evaporated by maintaining the emulsion at reduced pressure or
at atmospheric pressure and the stir rate reduced, or extracted by transferring the emulsion to a large
volume of quenching medium (with or without surfactant) into which the solvent diffuses out of the
oil droplets [28-30]. The solid microspheres are then washed, collected by fi ltration, centrifugation,
or sieving, and dried or freeze-dried to produce free-fl owing microspheres.
A number of parameters can affect microsphere fabrication using the single emulsion pro-
cess. The initial emulsifi cation of the polymer is affected by the stirring rate and the temperature.
The rate of solvent removal depends on the temperature of the quenching medium, atmospheric
pressure, the ratio of emulsion volume to quench volume, and the solubility of the polymer and
the solvent. The rapid removal of solvent by the extraction method can lead to more porous
microspheres compared with those fabricated by the evaporation process. The oil-in-water single
emulsion technique is widely used to encapsulate lipid-soluble drugs, such as steroids, but poor
encapsulation effi ciencies of water-soluble drugs has been reported because the drugs diffuse out
or partition from the dispersed oil phase into the aqueous continuous phase. To increase the encap-
sulation effi ciency of water-soluble drugs, water-in-oil (or oil-in-oil) single emulsion processes
and double (multiple) emulsion processes (water-in-oil-in-water) processes have been developed
(Figure 20.3) [28]. Water-in-oil emulsifi cation involves dissolving the polymer and the drug in a
water-miscible organic solvent, such as acetonitrile. An emulsion is produced by dispersing the
polymer/drug solution into an oil, such as light mineral oil, in the presence of an oil-soluble sur-
factant such as Span. The organic solvent is evaporated or extracted and the oil removed from the
microspheres using a solvent such as
n
-hexane. The water-in-oil-in-water method is useful for
encapsulating water-soluble drugs, such as peptides and vaccines. An aqueous solution of drug is
added to a vigorously stirred organic phase, consisting of polymer dissolved in a water-immiscible,
volatile organic solvent, such as dichloromethane, to produce the fi rst microfi ne water-in-oil emul-
sion. The fi rst emulsion is then added to a larger volume of water containing an emulsifi er, such as
PVA, to form a water-in-oil-in-water emulsion. The solvent is subsequently removed by evapora-
tion or extraction processes.
Poly(lactic-
co
-glycolic acid) microspheres have recently been evaluated as a potential bulking
agent for the injection therapies, fabricated using a conventional oil/water emulsion and solvent
extraction/evaporation technique, as outlined above [31]. Furthermore, radiopaque polymer micro-
spheres that can be detected through x-ray fl uoroscopy after injection have been developed, enabling
direct monitoring of possible migration of the spheres
in vivo
or guidance for repeated treatment
[32,33]. A copolymer of methyl methacrylate and 2-[2
-triiodobenzoyl]oxoethyl methacrylate
was used to produce microspheres with intrinsic radiopacity due to the covalently bound iodine in
the side chain [32]. The copolymer was prepared via a free-radical polymerization. To fabricate
microspheres, the copolymer was dissolved in chloroform and added dropwise to a stirred solution
of detergent (Dubro, Proctor & Gamble). This resulted in the drops of copolymer solution being split
into smaller droplets by the turbulent aqueous medium. After continuous overnight stirring to allow
evaporation of the solvent, the microspheres were thoroughly washed and freeze-dried. Experi-
mental parameters found to infl uence the size and the distribution of the microspheres included
the concentration of copolymer dissolved in chloroform, the speed of stirring, and the height from
which the copolymer solution was dropped into the detergent solution, parameters that are generally
applicable to all emulsifi cation techniques used to produce microspheres. The authors of this study
suggested that because the density of the microspheres (approximately 1.35 g/cm
3
) closely matches
that of surrounding soft tissue, the migration of microspheres might be reduced [32]. Moreover,
if it was suspected that the microspheres were migrating to distant sites, they could be monitored
relatively easily using x-ray fl uoroscopy.
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