John J. Arnold

Enhanced Bioavailability of Calcitonin Formulated with Alkylglycosides Following Nasal and Ocular Administration in Rats

AbstractPurpose. The purpose of this study was to characterize the effects of alkylglycosides on the bioavailability of calcitonin following nasal and ocular administration. Methods. A salmon calcitonin specific radioimmunoassay kit was used to measure calcitonin levels in anesthetized rats at various times after nasal or ocular administration of calcitonin formulated with saline or with octylmaltoside, a medium chain length alkylglycoside or tetradecylmaltoside, a long chain alkylglycoside. The extent of calcitonin absorption was determined directly from the plasma calcitonin level-time curve and the bioavailability of calcitonin was determined from the area under the plasma calcium level-time curve. The calcium level was determined using a colorimetric method. Results. When the nasal formulation contained calcitonin plus saline or 0.125% octylmaltoside, little or no calcitonin was absorbed. However, plasma calcitonin levels were increased and plasma calcium levels were decreased when the nasal formulation contained calcitonin plus 0.125% or 0.25% tetradecylmaltoside. Maximal calcitonin levels were observed 7.5-10 min after nasal administration of the formulation. Ocular administration of calcitonin formulated with tetradecylmaltoside also resulted in calcitonin absorption, but less calcitonin absorption was found after ocular administration than after nasal administration. Conclusion. The experimental data indicate that tetradecylmaltoside, but not octylmaltoside, can be effectively used to enhance the bioavailability of nasally and ocularly administered calcitonin.

Effects of the permeability enhancers, tetradecylmaltoside and dimethyl-β-cyclodextrin, on insulin movement across human bronchial epithelial cells (16HBE14o−)

The permeability of human bronchial epithelial cells (16HBE14o(-)) to radiolabelled insulin ([125I]insulin) formulated in the absence or presence of two different saccharide-containing permeability enhancers was investigated. In the absence of either enhancer, mannitol permeability and transepithelial electrical resistance (R(TE)) remained essentially unaffected for the duration of a 2-h experiment. Addition of either 0.125% tetradecylmaltoside (TDM) or 1% dimethyl-beta-cyclodextrin (DMBCD) to the apical surface of cells resulted in increased mannitol permeability and decreased R(TE), suggesting a loosening of cellular tight junctions and a concomitant increase in paracellular movement. Addition of [125I]insulin to the apical side of 16HBE14o(-) cells in the absence or presence of 1% DMBCD resulted in little or no [125I]insulin movement to the basolateral chamber or degradation in the apical chamber. However, in the presence of 0.125% TDM, the amount of intact [125I]insulin remaining in the apical chamber was substantially decreased, while [125I]insulin and 125I-labeled fragments were recovered on the basolateral side of the cells after 2 h. These findings provide evidence that the loosening of the tight junctions between cells achieved with DMBCD is not sufficient to stimulate transepithelial insulin movement, whereas exposure to 0.125% TDM causes an increase in [125I]insulin permeation and degradation.

Sucrose cocoate, a component of cosmetic preparations, enhances nasal and ocular peptide absorption.

Sucrose cocoate (SL-40), an emulsifier employed in emollient, skin-moisturizing cosmetic formulations, contains a mixture of sucrose esters of coconut fatty acids in aqueous ethanol solution. In order to determine its potential utility in enhancing nasal and ocular drug delivery, absorption studies were performed in anesthetized Sprague-Dawley male rats with calcitonin and insulin, two distinct therapeutic peptides. Administration of a nasal insulin formulation containing 0.5% sucrose cocoate caused a rapid and significant increase in plasma insulin levels, with a concomitant decrease in blood glucose levels. When insulin was administered ocularly in the presence of 0.5% sucrose cocoate, a smaller increase in plasma insulin levels, and a decrease in blood glucose levels, were observed. Administration of a nasal calcitonin formulation containing 0.5% sucrose cocoate caused a rapid increase in plasma calcitonin levels and a concomitant decrease in plasma calcium levels. Mass spectrometric analyses were used to characterize the nature of the sucrose fatty acid esters in the mixture. The most abundant sucrose ester in sucrose cocoate was sucrose monododecanoate, with smaller amounts of sucrose monodecanoate and sucrose monotetradecanoate. In vivo experiments confirmed that this ester was an effective enhancer of nasal peptide drug absorption.

Tetradecylmaltoside (TDM) enhances in vitro and in vivo intestinal absorption of enoxaparin, a low molecular weight heparin.

Tetradecylmaltoside (TDM) was evaluated as a potential gastrointestinal absorption enhancer for low molecular weight heparin (LMWH), enoxaparin. The in vitro efficacy of TDM (0.0625, 0.125 and 0.25% w/v) in enhancing transport of 3H-enoxaparin or 14C-mannitol was investigated in human colonic epithelial cells (C2BBel). Metabolic stability of the drug was determined in C2BBel cell extracts. Transepithelial electrical resistance (TEER) was measured before and after exposure of the cells to TDM. Enoxaparin was further administered to anesthetized Sprague–Dawley rats in oral formulations in the absence or presence of increasing concentrations of TDM and drug absorption was monitored by measuring anti-factor Xa activity in rat blood. In vitro permeability study shows that apparent permeability (Papp) of 3H-enoxaparin across C2BBe1 cells was increased by 8-fold in the presence of 0.0625% TDM compared to untreated cells. The movement of 14C-mannitol across the cell monolayer followed a similar pattern in the presence of increasing concentrations of TDM. No degradation or depolymerization of enoxaparin was observed when the drug was incubated in C2BBel cell extract. TEER was reversible after 60 min exposure of the cells to 0.0625% (w/v) TDM. Oral formulations of enoxaparin containing TDM administered to anesthetized rats significantly and rapidly increased gastrointestinal absorption as compared to those animals which received enoxaparin plus saline (p<0.05). In the presence of 0.125% TDM in the formulation, enoxaparin oral bioavailability was increased by 2.5-fold compared to the saline control group. Overall, the data on the effect of TDM on the in vitro and in vivo intestinal permeation of enoxaparin suggest that TDM may represent a promising excipient for use in oral LMWH formulations.

Mutual Inhibition of the Insulin Absorption-Enhancing Properties of Dodecylmaltoside and Dimethyl-β-cyclodextrin Following Nasal Administration

AbstractPurpose. To determine if a nasal insulin formulation containing two distinct absorption–enhancing agents exhibits an additive or synergistic increase in the rate of systemic insulin absorption. Methods. The pharmacokinetics and pharmacodynamics of insulin absorption were measured in hyperglycemic anesthetized rats following nasal insulin administration with formulations containing two different types of absorption–promoting agents, dimethyl–β–cyclodextrin (DMBCD) and dodecylmaltoside (DDM). Results. When either DDM (0.1–0.5%) or DMBCD (1.0–5.0%) was added to the nasal insulin formulation, a significant and rapid increase in plasma insulin levels was observed, with a concomitant decrease in blood glucose concentration. A combined preparation containing 0.25% DDM (0.005 M) and 2.5% DMBCD (0.019M), however, failed to cause an increase in plasma insulin levels or a decrease in blood glucose concentration. Increasing concentrations of DDM added to an insulin formulation with a fixed DMBCD concentration caused a decrease, rather than an increase, in systemic absorption of insulin. Conclusions. Mixing DMBCD and DDM resulted in mutual inhibition of their ability to enhance systemic absorption of insulin following nasal delivery. The results are consistent with the formation of an inclusion complex between DDM and DMBCD which lacks the ability to enhance nasal insulin absorption.