Insulin penetration enhancers

When diabetic rabbits (24) were treated with 50 IU of bovine insulin imbibed at 50 mg/g poly (acrylic acid) (Figure 14) no reduction in serum glucose over that achieved by the dry blend control could be detected. Pretreatment of the animals with oral doses of either a penetration enhancer, sodium taurocholate, or a protease inhibitor, aproteinin, failed to improve the insulin activity. One possible explanation for this unexpected lack of activity might be that the diseased animals exhibit impaired ileal absorption of fluids (25). 

Other fatty acids as absorption enhancers have been reported. Ogiso et al. [112] demonstrated that lauric acid (C12) produced the largest increase in permeation rate, penetration coefficient, and partition coefficient of propranolol. Onuki et al. [113] reported that docosa-hexaenoic acid (DHA) has a strong insulin permeability enhancement effect and little toxicity, compared to oleic acid and eicosapentaenoic acid (EPA) using a water-in-oil-in-water (W/O/W) multiple emulsion with no or little mucosal damage. 

Richardson, J.L., L. Ilium, and N.W. Thomas. 1992. Vaginal absorption of insulin in the rat Effect of penetration enhancers on insulin uptake and mucosal histology. Pharm Res 9 878. 

Oral dosage forms may contain various other additives to increase the solubility and hence oral bioavailability of the drag, such as co-solvents, buffers and surfactants. Newer technologies may also incorporate additives such as enzyme inhibitors, to prevent premature degradation of enzymatically labile drags. For example, the inclusion of trypsin inhibitors, such as soyabean trypsin inhibitor and aprotinin, have been shown to be effective in enhancing the effect of insulin in rats. Penetration enhancers may also be included to facilitate the uptake of poorly absorbed moieies. These are discussed below in Section 6.7.4. 

Interestingly, compounds which have been investigated for their penetration-enhancing effect at the absorbing membrane have also been shown to decrease the metabolism of certain peptides. By denaturing leucine aminopeptidase and preventing enzyme-substrate complex formation, the bile salt sodium glycocholate has been shown to protect insulin from proteolysis in the rat nasal mucosa. 

Biodegradable starch microspheres, 40 pm in diameter, were shown to be capable of enhancing the vaginal absorption of insulin. The effect was further enhanced when the penetration enhancer lysophosphatidylcholine was used. 

Rastogi, S. K., and Singh, J. (2005), Effect of chemical penetration enhancer and iontophoresis on the in vitro percutaneous absorption enhancement of insulin through porcine epidermis, Pharm. Dev. Technol., 10(1), 97-104. 

Finally, it should be noted that during the last decade both weakly crosslinked poly(acrylic acid) derivatives and chitosan derivatives were described as safe penetration enhancers for hydrophilic compounds especially as they can trigger mechanisms of tight junction opening of mucosal tissues and did not show acute toxicity. Poly(acrylic acid) derivatives were shown to have excellent mucoadhesive properties and can inhibit the activity of gut enzymes, such as trypsin, chymo-trypsin, and carboxypepsidases. Chitosan salts and Ni-trimethylchitosan chloride revealed to be potential absorption enhancers for nasal absorption of calcitonin and insulin and for the intestinal absorption of buserilin.f ... 

The combined effect of (3-CyD with absorption enhancers such as sodium glycocholate or Azone on the nasal absorption of human fibroblast interferon- 3 in powder form in rabbits has been described. HP- 3-CyD was useful as a biocompatible solubilizer for lipophilic absorption enhancers involved in the nasal preparations of peptides.When insuUn was admiifistered nasally to rats, simultaneous use of an oily penetration enhancer, HPE-101, (l-[2-(decylthio)-ethyl]azacyclopentane-2-one) or oleic acid solubilized in HP-(3-CyD showed a marked increase in serum immuno-reactive insulin levels and marked hypoglycemic (Figure 40.11). The potentiation of the enhancing effect of HPE-101 by HP-(3-CyD can be explained by the facilitated transfer of HPE-101 into the nasal mucosa. Studies on the release of membrane proteins and scanifing electron microscopic observations of rat nasal mucosa indicated that the local mucosal damage due to the combination with HP- 3-CyD may not be serious obstacles to their safe use. 

Priborsky, J., Takayama, K., Nagai, T., Waitzova, D., and Elis, J. (1987). Combination effect of penetration enhancers and propylene glycol on in vitro transdermal absorption of insulin. Drug. Des. Deliv., 2 91-97. 

The subcutaneous route for administration of insulin has many serious drawbacks, and alternative routes continue to attract considerable research interest. Nearly all available orifices of the human body seem to have gained attention as presenting possible noninvasive sites for insulin absorption. However, even by using modem enhancer techniques, only a small or minor fraction of the hormone becomes bioavailable when provided by most of these routes, except perhaps the pulmonary route. Key barriers to insulin absorption via the alternative routes are the resistance of those membranes to insulin penetration, the tendency of insulin to exist in associated form, and insulin proteolysis. Protection from proteolysis through some sort of encapsulation, the use of complex emulsion systems, and/or the use of protease inhibitors—association of the hormone with polymeric particles, and addition of permeation enhancers have been utilized to overcome those barriers. The absorption and enzymatic barriers to nonparenterally administered protein dmgs and the use of enhancers to modify absorption have been discussed in recent reviews (Lee, 1986 Lee e/a/., 1991a Zhou, 1994). The present review of alternative administration of insulin mainly covers investigations published since 1970. 

The major obstacles for transmucosal delivery of insulin are the barrier properties of mucosa, rapid degradation, and limited absorption area [89,90]. Hence, strategies studied to overcome these obstacles include the use of materials that combine mucoadhesive, enzyme inhibitory and penetration-enhancing properties, which can improve patient compliance and prolong the contact time of drugs to mucosal membrane. However, further efforts are needed to design standardized in vitro and ex vivo biological... 

Combinations of penetration enhancers have given limited success in the delivery of insulin through the vagina. However, the subject of insulin delivery across the vaginal membrane is still a challenge for future researchers and scientists in the field of vaginal delivery. 

Surface-active substances, which are known to enhance penetration through the skin barrier, also needs to be added. These should, of course, not cause any irritation in the nose and other air pathways. Insulin is currently being marketed commercially for IDD. 

Since its discovery, isolation, and purification in the early twentieth century, insulin has been administered to diabetic patients exclusively by injection until the recent introduction of inhaled insulin. Insulin possesses certain physiochemical properties that contribute to its limited absorption from the gastrointestinal tract, and requires subcutaneous injection to achieve clinically relevant bioavailability. With a molecular size of 5.7 kDa, insulin is a moderately sized polypeptide composed of two distinct peptide chains designated the A chain (21 amino acid residues) and the B chain (30 amino acid residues) and joined by two disulfide bonds. Like all polypeptides, insulin is a charged molecule that cannot easily penetrate the phospholipid membrane of the epithelial cells that line the nasal cavity. Furthermore, insulin monomers self-associate into hexameric units with a molecular mass greater than 30 kDa, which can further limit its passive absorption. Despite these constraints, successful delivery of insulin via the nasal route has been reported in humans and animals when an absorption enhancer was added to the formulation. 

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