Biomedical Engineering Reference
In-Depth Information
Ability of these materials to enhance the intestinal permeability was demonstrated using mono-
layers of caco-2 cells. Caco-2 cell models are widely used in vitro cell culture model for intestinal
epithelium. Having originated from human colon adenocarcinoma cells, these cells can differen-
tiate into polarized cells with distinct mucosal (apical) and serosal (basolateral) cell membrane
domain. Although they have originated from colon cells, caco-2 cells have many properties of small
intestine absorptive cells including microvilli, intercellular junctions, and many of the enzymes
nutrient transporters and effl ux transporters present in the small intestine. The tightness of the
intercellular junctional complex can be characterized by measuring the transepithelial electrical
resistance (TER) [91,92].
Numerous investigations using caco-2 cells demonstrated the ability of PAA-based systems to
enhance the intestinal permeability. Luessen et al. demonstrated that carbopol and polycarbophil
can reduce the TER of caco-2 cells at neutral pH and can improve the transport of hydrophilic
markers across the epithelial barrier [89]. Kriwet et al. showed that PAA microparticles could
widen the intercellular spaces in the monolayers of the caco-2 cells [93]. Microparticles of
poly(methacrylic- g -ethylene glycol) hydrogels loaded with insulin and salmon calcitonin demon-
strated that the polymer microparticles cause a signifi cant increase in the permeability of these
proteins across the cell monolayers [94,95]. This material was also found noncytotoxic and capable
of opening the tight junctions in a reversible manner [96].
Another advantage of using PAA-based systems is their pH-dependent release profi le because
of the protonation or deprotonation of carboxylic acid groups [80]. In acidic media, acid groups
remain unionized and remain collapsed, protecting encapsulated drugs from the hostile gastric
environment. In the small intestine region, where pH is above the p K a of PAA, the acid groups get
deprotonated and exist in the form of ionized acid groups. Repulsion caused by the adjacent ionized
acid group causes the hydrogel network to swell, which in turn leads to the release of the encapsu-
lated material from the system. So protein encapsulated in the particles is protected from the gastric
environment and is released in the favorable regions of the intestinal tract [97].
Peppas and his group have made numerous attempts to utilize poly(methacrylic- g -ethylene
glycol) nano- and microspheres as oral protein-delivery system. Insulin-loaded pH-responsive poly
(methacrylic- g -ethylene glycol) microspheres were administered orally to both healthy and diabetic
Wistar rats. Within 2 h of administration of the insulin-containing polymers, strong dose-dependent
hypoglycemic effects were observed in both healthy and diabetic rats up to 8 h [98,99]. Further
studies carried out on particles composed of a 1:1 molar ratio of methacrylic acid or ethylene glycol
units showed the pronounced hypoglycemic effects following oral administration to healthy rats and
achieving a 9.5% pharmacological availability compared with subcutaneous insulin injection [100].
Enteric polymers based on PMAA esters such Eudragit were also studied for developing oral
protein-delivery systems. The effectiveness of Eudragit L100 microspheres containing a protease
inhibitor was evaluated in normal and diabetic rats [101]. The dosage form based on insulin with
protease inhibitor was administered orally with a 20 IU/kg insulin dose by force-feeding. Micro-
spheres without protease inhibitor and with trypsin inhibitor (TI) or chymostatin (CS) produced
no marked hypoglycemic response in both groups of rats. A signifi cant continuous hypoglycemic
effect was found after oral administration of microspheres containing aprotinin (AP) or Bowman-
Birk inhibitor (BBI) in both normal and diabetic rats when compared with controls. The hypoglyce-
mic effect of Eudragit S100 enteric-coated capsules containing sodium salicylate as an absorption
promoter was studied in hyperglycemic beagle dogs [102]. This system demonstrated 25-30%
reduction in plasma glucose levels and about 12.5% relative to subcutaneous injection of regular
soluble insulin.
Eudragit S100 microspheres were prepared using water-in-oil-in-water emulsion solvent-
evaporation technique, and their application toward oral insulin delivery was evaluated [103].
Oral administration of PVA-stabilized microspheres in normal albino rabbits (equivalent to 6.6 IU
insulin/kg of animal weight) demonstrated a 24% reduction in blood glucose level, with maximum
plasma glucose reduction of 76%
±
3.0% in 2 h, and the effect continued up to 6 h.
 
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