Biomedical Engineering Reference
In-Depth Information
greater protection against proteolytic enzymes compared with their amorphous counterparts. The
most common and easy form of protein crystals are naked crystals, which have shown controlled
release and desirable pharmaceutical properties such as good resuspendability. The major barrier
for using naked crystals is the limited release profi le, usually within a day [147]. Encapsulation
of these crystals in biocompatible and biodegradable polymer systems may not only extend the
release to a much longer time, but also increase the protein stability to a higher degree. Unfor-
tunately, the manufacturing methods used for encapsulating protein in polymeric systems often
adversely affect protein stability because of exposure to organic solvent, hydrophobic surfaces,
and vigorous agitation [148].
Direct LbL self-assembly of polyelectrolytes onto protein crystals serves as a simple and easy
method for encapsulation. Similar to encapsulation of small-molecule drug crystals, this self-
assembly process has advantages including no exposure to organic solvent, less agitation, wide
selection of coating materials, precise release rate control, and high-loading density. It has been
found that either electrostatic or hydrophobic interactions can facilitate the fi rst layer growth on
protein crystals [149]. Further layers can be assembled following standard LbL self-assembly coat-
ing process on colloidal particles. Interestingly, the effi ciency of protein (α-chymotrypsin) encap-
sulation (the ratio of loaded protein amount over the protein content in solution before the coating
process) was reduced with more layers of coating. The estimated effi ciency was 73%, 50%, 40%,
and 33% for 3-, 5-, 7-, and 11-layer PSS/PAH-paired microcapsules (with PSS as the fi rst layer),
respectively. It was suggested that partial protein aggregates dissolution and loss of microcapsules
during washing steps may be the major reasons [149]. The encapsulation also provides a good pro-
tection of loaded materials. For example, small molecule enzyme inhibitor phenylmethane sulfonyl
fl uoride (MW: 174) can penetrate into the (PAH/PSS)
n
shells and reduce the enzymatic activity
by about 69%, while high-molecular weight inhibitor BPTI (MW: 6500) can only suppress 13%
activity [149].
10.3.5 E
NCAPSULATION
OF
S
MALL
-M
OLECULE
D
RUG
M
ICRO
/N
ANOPARTICLES
It is well-recognized that poor aqueous solubility is the major obstacle in small-molecule drug dis-
covery and development. Many drug candidates cannot be further developed mainly because of the
very low water solubility [150]. Even some drugs in clinical use are barely soluble in water. The most
direct method to increase the solubility is through salt generation but this can not be applied to non-
ionizable compounds. Instead, preparing drug crystals in nano or microsizes provides a promising
future for delivery of poorly soluble drugs. There are various methodologies including milling,
emulsifi cation solvent evaporation, pH-controlled precipitation, and supercritical fl uid-processing
for generating drug nanoparticle formulations [151,152]. Next, to prevent drug micro/nanocrystal
agglomeration or aggregation when dispersed in water, stabilizers are used to promote particle size
reduction process and generate physically stable formulations [151]. But excess amount of stabilizer
can induce Ostwald ripening. How to stabilize drug crystals in a simple and an effi cient way is of
great interest. Direct LbL self-assembly of polyelectrolyte on drug crystals may serve as an alterna-
tive with two functions: (1) stabilize drug crystal dispersion in aqueous environment and (2) control
drug release rate.
Some preliminary work has demonstrated the feasibility of direct self-assembly of polyelectro-
lyte layer on drug microcrystals and controlled of release [108,153-155]. A few conditions must be
satisfi ed before elaboration of coating: (1) a favorable pH environment for stabilizing drug crystals
and maintaining polyelectrolytes charged. For example, ibuprofen is 16 times less soluble in pH 5
than pH 7.4 [156]. In this case, we would prefer to use pH 5 to stabilize drug crystals as this gives
a much better loading effi ciency. Appropriate pairs of polyelectrolytes should be chosen so that at
such a pH both polycation and polyanion be well charged and (2) enabling surface charge of drug
crystals at that pH value. Some drugs are weakly charged in aqueous environment, but others are
neutral without charges. To impart charge on particle surface, ionic surfactants, phospholipids, or
