Effect of the Various Solvents on the In Vitro Permeability of Vitamin B12 through Excised Rat Skin

Purpose: To investigate the effect of different solvents on the in vitro skin permeability of vitamin B12.Method: Vitamin B12 (B12) permeability experiments through rat skin pretreated with various solvents namely, propylene glycol, oleoyl macrogol-6-glycerides, propylene glycol monocaprylate and oleic acid, were performed in Franz diffusion cells and compared with hydrated rat skin as control. The permeability parameters evaluated include steady-state flux (Jss), lag time (Tlag), permeability coefficient (Kp) and diffusion coefficient (D). The solvents’ permeability enhancement mechanisms were investigated by comparing of changes in peak position and their intensities of assymmetric (Asy) and symmetric (Sym) C-H stretching, and C=O stretching absorbance using Fourier transform infrared spectroscopy (FTIR), as well as by comparing mean transition temperature (Tm) and their enthalpies (ΔH) using differential scanning calorimetery (DSC).Results: All the solvents significantly decreased diffusion coefficient (p < 0.05), with capryol showing the greatest enhancement ratio (ERD) based on diffusion coefficient followed by labrafil, oleic acid and propylene glycol. Flux enhancement ratio (ERflux) for all the solvents was < ERD. The solubility of B12 in stratum corneum was the rate-limiting step in partitioning. All solvents with different lipophilic properties decreased drug solubility in the stratum corneum and hence lowered partitioning and flux. FTIR and DSC results showed lipid fluidization and extraction by labrafil and capryol, disruption of lipid structure and fluidization by oleic acid, and interaction with stratum corneum keratin by propylene glycol.Conclusion: Water is a suitable topical vehicle for B12 as it can increase partitioning and diffusion through rat skin.Keywords: Percutaneous absorption, Enhancer, Vitamin B12, Skin permeation, Diffusion coefficient, Flux, Enthalp

Pre-formulation and systematic evaluation of amino acid assisted permeability of insulin across in vitro buccal cell layers

The aim of this work was to investigate alternative safe and effective permeation enhancers for buccal peptide delivery. Basic amino acids improved insulin solubility in water while 200 and 400 µg/mL lysine significantly increased insulin solubility in HBSS. Permeability data showed a significant improvement in insulin permeation especially for 10 µg/mL of lysine (p < 0.05) and 10 µg/mL histidine (p < 0.001), 100 µg/mL of glutamic acid (p < 0.05) and 200 µg/mL of glutamic acid and aspartic acid (p < 0.001) without affecting cell integrity; in contrast to sodium deoxycholate which enhanced insulin permeability but was toxic to the cells. It was hypothesized that both amino acids and insulin were ionised at buccal cavity pH and able to form stable ion pairs which penetrated the cells as one entity; while possibly triggering amino acid nutrient transporters on cell surfaces. Evidence of these transport mechanisms was seen with reduction of insulin transport at suboptimal temperatures as well as with basal-to-apical vectoral transport, and confocal imaging of transcellular insulin transport. These results obtained for insulin is the first indication of a possible amino acid mediated transport of insulin via formation of insulin-amino acid neutral complexes by the ion pairing mechanism

Enhancing effect of bile salts on gastrointestinal absorption of insulin

Purpose: To investigate the effect of co-administration of two absorption enhancing bile  alts, sodium glycocholate (NaGc) and sodium salicylate (NaSal), on insulin absorption via intestinal targeted delivery system.Methods: Insulin (10 IU/kg), associated with and without absorption enhancers (5 % enhancer solution of NaGc or NaSal), was administered to the duodenum, jejunum, and ileum part of the diabetic rat's gastrointestinal (GI) tract by surgical technique. The insulin absorbed from the GI tract was evaluated by its hypoglycemic effect at 45 and 60 min post-administration.Results: The results showed that insulin formulations containing NaGc or NaSal administered into the duodenum and with little quantity in the jejunum decreased blood glucose levels, compared to the reference formulations (p &lt; 0.05). It was also observed that formulations containing cellulose acetate phthalate (CAP) protectors and enhancers may protect insulin during transit through the stomach for 180 min.Conclusion: Thus, the results of this study demonstrate that duodenum-specific delivery of insulin with NaGc and NaSal was achievable by oral administration compared to the other parts of small intestine. Furthermore, NaGc has a greater enhancing effect on duodenal, and to some extent, jejunal absorption of insulin.Keywords: Bile salts, Sodium glycocholate, Sodium salicylate, Insulin, Gastrointestinal administratio

Isolation, characterization and study of enhancing effects on nasal absorption of insulin in rat of the total saponin from Acanthophyllum squarrosum

Objective: Isolation of the total saponins from Acanthophyllum squarrosum   Boiss. and investigation of its surface activity, haemolytic effects on human erythrocytes, as well as enhancing potentials on intranasal insulin absorption in rat as compared to two other enhancers, i.e, Quillaja total saponin (QTS) and sodium cholate (SC). Materials and Methods: The decrease in blood glucose levels in five fasting rats following nasal administration of regular insulin solutions in the presence or absence of enhancers was determined by glucometric strips and used as an indication of insulin absorption. Results: The results showed that Acanthophyllum total saponin (ATS) decreased surface tension of water to about 50 dyne/cm and caused complete haemolysis of human RBCs at a concentration of 250 µg/ml. Following the instillation of solutions containing insulin and different absorption enhancers into the right nostril of rats, the percentage decrease in initial blood glucose was as follows: 72.46% (±2.39%) for ATS, 63.22% (±11.06%) for QTS and 60.06% (±14.93%) for SC. Percentage lowering of initial blood glucose concentrations against time showed that ATS exerts a stronger effect than the two other enhancers, although the difference was not statistically significant (P > 0.05). Conclusion: ATS has a considerable absorption enhancing effect and can possibly be used to increase insulin bioavailability via the nasal route. However, the potential toxic effects of this saponin on nasal mucosa should be further evaluated