Penetration enhancers

Penetration enhancers can enhance oral absorption by their action on the transcellular or paracellular pathway. For effects on the transcellular pathway, surfactants and fatty acids may alter membrane lipid organization and may thus increase oral transport. Surfactants can be incorporated into lipid bilayers, thus changing the physical properties of the cell membranes. For effects on the paracellular pathway, chelating agents can disrupt the integrity of occluding junctional complexes by chelating calcium or magnesium around tight junctions.76 Exposure of Caco-2 cell monolayers to SDS has been

Figure 7.2 Decrease in plasma calcium level as a biological response for the salmon calcitonin availability in rats after oral administration of three dosage forms, all containing 50 mg of the peptide. Strongest response was obtained with dosage form described in the text. (Reproduced from Guggi, D., Krauland, A. H., and Bernkop-Schnurch, A., J. Controlled Release, 92: 125-135, 2003, with permission from Elsevier.)

Figure 7.2 Decrease in plasma calcium level as a biological response for the salmon calcitonin availability in rats after oral administration of three dosage forms, all containing 50 mg of the peptide. Strongest response was obtained with dosage form described in the text. (Reproduced from Guggi, D., Krauland, A. H., and Bernkop-Schnurch, A., J. Controlled Release, 92: 125-135, 2003, with permission from Elsevier.)

reported to increase the absorption of mannitol, vasopressin, and polyethylene glycol. Transepithelial electrical resistance (TEER) measurements, together with fluorescence and transmission electron microscopy, suggest that exposure of Caco-2 cell culture to SDS resulted in apical membrane wounds, shortening of the microvilli of the cells, and structural separation of the tight junctions. It was suggested that SDS enhances peptide absorption across the intestinal epithelium by the paracellular pathway.77

Bile salts such as sodium deoxycholate and sodium cholate can also be used in the formulation to promote the absorption of insulin from the colon.78 The penetration enhancement of insulin by surfactants and bile salts may also be related to their ability to dissociate insulin aggregates. SDS, at 5 mM concentration, has been reported to completely dissociate porcine-zinc-insulin hexamers into monomers. When insulin was injected into the distal jejunum/proximal ileum segment of the rat, 5 mM SDS increased its absorption from a negligible value to 2.8%. Similarly, a 30-mM concentration of sodium glycocholate also increased insulin absorption to 2.3%.79

Mixed micellar systems have also been used to enhance the oral absorption of polypeptides.80 Such systems are also known to form naturally in the GI tract to aid the absorption of lipids. The dietary fats are first emulsified by bile salts in the intestine and then acted on by pancreatic lipase to produce monoglycerides and free fatty acids. The monoglycerides, free fatty acids, and bile salts then all combine to form mixed micelles from which the digested lipids are then absorbed. Mixed micelles have been used to enhance the oral absorption of human calcitonin (hCT) across the rat colon. In both the rat and humans, the bioavailability of intracolonically administered hCT is normally less than 1%. By using 40 mM monoolein:40 mM sodium tauro-cholate, the absorption of hCT was increased ninefold. This absorption enhancer was shown to increase the intestinal absorption of molecules over the molecular weight range of 4000 to 40,000 without causing acute tissue damage.81 Lipoidal dispersions of insulin in fatty acids using sodium glyco-cholate as an emulsifier and absorption promoter have been investigated. The hypoglycemic effects after oral administration to rabbits were found to be dependent on the fatty acid used. A palmitic acid system reduced blood glucose from 105 to 75 mg/dl in 30 min. This effect was significantly higher than that obtained with unsaturated fatty acids or with non-fatty acid sys-

tems.82

Penetration enhancers may enhance the absorption of drugs preferentially in some specific region of the GI tract.83 Cyclodextrins have also been used to enhance the absorption of insulin from the lower jejunal/upper ileal segments of the rat by an in situ closed-loop method. By using 10% w/v dimethyl-cyclodextrin (DMCD) with 0.5 mg/ml of porcine-zinc insulin, the bioavailability was increased from a negligible value (~0.06%) to 5.63%. The mechanism probably involves dissociation of insulin oligomers by DMCD because DMCD increases the rate constant for degradation of insulin hex-amers by a-chymotrypsin.84

In reported studies, a polyoxyethylated castor oil derivative (HCO-6O®) and organic acids (e.g., citric acid) have been reported to markedly increase the pharmacological activity of recombinant human granulocyte colony-stimulating factor (rhG-CSF) in rats. The solution or tablets were administered into the rat's intestine, and the blood total leukocyte counts were measured as a pharmacological index of rhG-CSF.85 86

When penetration enhancers are used to enhance oral absorption, it should be realized that they have limitations that may prevent their general acceptance for usage. Also, the potential lack of specificity of penetration enhancers may have long-term toxicity implications that can only be evaluated in chronic studies. The potential lytic nature of surfactants raises safety concerns because the intestinal epithelium provides a barrier to the entry of toxins, bacteria, and viruses. Similarly, chelators that cause Ca2+ depletion do not act specifically on tight junctions but rather may induce global changes in cells such as disruption of actin filaments or adherent junctions. Thus, it will be difficult to induce opening of tight junctions in a rapid, reversible, and reproducible manner.8O

Supplements For Diabetics

Supplements For Diabetics

All you need is a proper diet of fresh fruits and vegetables and get plenty of exercise and you'll be fine. Ever heard those words from your doctor? If that's all heshe recommends then you're missing out an important ingredient for health that he's not telling you. Fact is that you can adhere to the strictest diet, watch everything you eat and get the exercise of amarathon runner and still come down with diabetic complications. Diet, exercise and standard drug treatments simply aren't enough to help keep your diabetes under control.

Get My Free Ebook


Post a comment