Bruce J. Aungst

Intestinal permeation enhancers.

This review addresses the field of improving oral bioavailability through the use of excipients that increase intestinal membrane permeability. The critical issues to consider in evaluating these approaches are 1) the extent of bioavailability enhancement achieved, 2) the influence of formulation and physiological variables, 3) toxicity associated with permeation enhancement, and 4) the mechanism of permeation enhancement. The categories of permeation enhancers discussed are surfactants, fatty acids, medium chain glycerides, steroidal detergents, acyl carnitine and alkanoylcholines, N-acetylated alpha-amino acids and N-acetylated non-alpha-amino acids, and chitosans and other mucoadhesive polymers. Some of these approaches have been developed to the stage of initial clinical trials. Several seem to have potential to improve oral bioavailabilities of poorly absorbed compounds without causing significant intestinal damage. In addition, the possible use of excipients that inhibit secretory transport is reviewed.

Enhancement of naloxone penetration through human skin in vitro using fatty acids, fatty alcohols, surfactants, sulfoxides and amides

Abstract Human skin permeation of naloxone was examined in vitro using various vehicles and penetration enhancers. To screen various chemicals as penetration enhancers propylene glycol containing 10% adjuvant was used. Fatty acids and fatty alcohols were very effective promoters of naloxone flux. In both the acid and alcohol series, maximum flux was with C 12 adjuvants, and for C 18 acids and alcohols unsaturated adjuvants were more effective than saturated ones. Other effective skin penetration enhancers included some non-ionic and cationic surfactants, decylmethylsulfoxide, Azone, and N-alkylpyrrolidones. Lauric acid and lauryl alcohol in isopropanol, polyethylene glycol 400, and mineral oil vehicles were not as effective in promoting naloxone skin penetration as when dissolved in propylene glycol. Sodium lauryl sulfate in propylene glycol slightly increased flux, but a much greater effect was observed using a mineral oil vehicle. Concentration/enhancement profiles were determined for lauric acid and lauryl alcohol. Skin penetration enhancing effects are, to some extent, specific and dependent on the drug, vehicle, enhancer concentration and probably other factors. Possible mechanisms of altering skin permeability are discussed.

Contributions of Drug Solubilization, Partitioning, Barrier Disruption, and Solvent Permeation to the Enhancement of Skin Permeation of Various Compounds with Fatty Acids and Amines

The contributions of several proposed mechanisms by which fatty acids and amines might increase skin permeation rates were assessed. Permeation rates of model diffusants with diverse physicochemical properties (naloxone, testosterone, benzoic acid, indomethacin, fluorouracil, and methotrexate) through human skin were measured in vitro. The enhancers evaluated were capric acid, lauric acid, neodecanoic acid, and dodecylamine. Increased drug solubility in the vehicle, propylene glycol (PG), in some cases accounted for the increases in flux in the presence of adjuvants, since permeability coefficients were unchanged. Partition coefficients of some drugs into isopropyl myristate or toluene were increased by the adjuvants, but this did not occur for combinations of an acid with a base (adjuvant-drug or drug-adjuvant). Increases in flux not accounted for by increases in drug solubility or partitioning were assumed to involve disruption of the barrier function of skin (increased skin diffusivity). All fatty acids increased skin diffusivity of naloxone, testosterone, indomethacin, and fluorouracil but not of methotrexate or benzoic acid. Dodecylamine increased skin diffusivity only for fluorouracil. Capric acid and dodecylamine, but not lauric acid or neodecanoic acid, increased the skin permeation rate of PG, suggesting that enhanced solvent penetration could also be involved as a mechanism for increased skin permeation of the drug. However, the increase in PG flux due to dodecylamine was nullified when methotrexate was added to the vehicle, possibly because of a dodecylamine/methotrexate interaction. These studies demonstrate that drug solubilization in the vehicle, increased partitioning, increased solvent penetration, and barrier disruption each can contribute to increased skin permeation rates in the presence of fatty acids and amines. The relative contributions of the mechanisms vary with the drug, the adjuvant, and the vehicle.

Possible involvement of multiple P-glycoprotein-mediated efflux systems in the transport of verapamil and other organic cations across rat intestine

AbstractPurpose. We investigated the intestinal transport of verapamil, chlorpromazine, and propantheline, particularly their P-glycoprotein-mediated secretion. Methods. Permeation of rat intestinal segments in vitro was determined using diffusion cells. Results. Verapamil permeation in the serosal-to-mucosal direction was much greater than in the mucosal-to-serosal direction using duodenal, jejunal, and colonic membranes. The concentration dependence of jejunal permeation in the absorptive and secretory directions was consistent with saturability of a secretory transport system. Using a monoclonal antibody to inhibit P-glycoprotein-mediated secretion caused a significant enhancement of verapamil absorption through the jejunum. In contrast, the rat ileum did not preferentially transport verapamil in the secretory direction, and the P-glycoprotein antibody had no effect on ileal absorption. Chlorpromazine and propantheline enhanced the mucosal-to-serosal permeation of verapamil through the jejunum, most likely due to competitive inhibition of the P-glycoprotein-mediated secretory process. Vinblastine, tetraethylammonium, and guanidine did not affect verapamil permeation. Propantheline was also a substrate for P-glycoprotein-mediated secretory transport, but in contrast to verapamil, propantheline secretory transport was expressed in rat ileum. Conclusions. These results suggest that these cationic compounds are transported by plural P-glycoprotein-mediated efflux systems with different substrate specificities depending on the intestinal site.

Comparison of the effects of various transmucosal absorption promoters on buccal insulin delivery

Abstract We have evaluated the effects of various classes of transmucosal and transdermal absorption promoters on buccal insulin absorption in rats. Insulin absorption was estimated from the cumulative response of plasma glucose concentrations and by comparison to an i.m. dose/response curve. In the absence of an absorption promoter, buccal insulin was less than 4% as effective as i.m. insulin. All steroidal detergents examined as absorption promoters markedly improved buccal insulin absorption, using aqueous vehicles containing 5% adjuvant. Concentrations greater than 1% were required. The non-ionic surfactant, laureth-9, was also an effective absorption promoter and was effective at lower concentrations. Ester non-ionic surfactants had no effects. The effect of pH was evaluated for sodium fusidate and laureth-9 vehicles, and with both adjuvants buccal insulin absorption was lower at pH 5.4 than at pH 3.4 or pH 7.4. Other effective absorption promoters included sodium lauryl sulfate, sodium laurate (at pH 8.9), palmitoyl carnitine, and a lauric acid/propylene glycol vehicle. With the most effective absorption-promoting vehicles, buccal insulin was one-fourth to one-third as effective as i.m. insulin.

Site Dependence of Absorption-Promoting Actions of Laureth-9, Na Salicylate, Na2EDTA, and Aprotinin on Rectal, Nasal, and Buccal Insulin Delivery

The site dependence of the absorption-promoting actions of laureth-9, Na salicylate, Na2EDTA, and aprotinin was studied in rats. Insulin absorption was estimated on the basis of the cumulative hypo-glycemic response from 0 to 4 hr postdose, relative to that after intramuscular insulin. Insulin was administered with or without adjuvants to isolated rectal, nasal, and buccal absorption sites. Laureth-9, a nonionic surfactant which irreversibly removes membrane proteins or lipids, promoted insulin absorption from each site. The rectal, nasal, and buccal routes were 30% as effective as the i.m. route. The enhancing effects of Na salicylate and Na2EDTA, which have reversible mechanisms of permeability enhancement, were specific for rectal absorption. With these adjuvants, rectal insulin was 30–40% as effective as i.m. insulin, but nasal and buccal doses were less than 5% as effective as i.m. doses. This specificity can be at least partly explained by considering the site-to-site differences in membrane histology, although differences in pore size and membrane biochemistry might also contribute. The protease inhibitor aprotinin was ineffective in increasing insulin efficacy via each route, either alone or in combination with laureth-9.

Structure/Effect Studies of Fatty Acid Isomers as Skin Penetration Enhancers and Skin Irritants

Comparisons were made of branched vs unbranched saturated fatty acids and cis vs trans unsaturated fatty acids as skin penetration enhancers and primary skin irritants. Skin penetration studies used naloxone base as the diffusant, propylene glycol as the vehicle, and human skin. Maximum naloxone flux was with C9–12-branched and unbranched fatty acids. For C5–14 fatty acids, branched and unbranched isomers had similar effects. One branched C18 fatty acid isomer (C16-branched isostearic acid) was more effective in enhancing skin penetration than a differently branched (C2-branched isostearic acid) or unbranched C18 isomer (stearic acid). There was no significant difference between cis and trans unsaturated C16–18 fatty acid isomers in their effects on naloxone flux, and all unsaturated fatty acids were more effective enhancers than the corresponding saturated isomers. Several of these fatty acid/propylene glycol vehicles were evaluated in a rabbit primary skin irritation test. Irritation indices were poorly correlated with the effectiveness of the vehicles in enhancing naloxone flux. It was possible to enhance naloxone skin penetration greatly with a vehicle with only minimal skin irritation potential.

Enhancement of the intestinal absorption of peptides and nonpeptides

Abstract It is not uncommon for peptides and structurally-similar non-peptides to have poor intestinal permeability and low oral bioavailability. One possible way to solve a permeability problem is to formulate the compound with membrane permeation-enhancing excipients. Important criteria for success of this approach are: (1) achieving reproducible intestinal permeation, (2) doing so without causing toxicity, and (3) understanding the mechanisms of permeation enhancement. Some effective and potentially safe permeation enhancers are fatty acids, glycerides, surfactants, acyl carnitines, and bile salts. The literature on permeation enhancement with these agents is briefly reviewed. We evaluated permeation enhancement approaches to increase the oral bioavailability of a non-metabolized, cyclic peptide fibrinogen antagonist, DMP 728. Sodium caprate (15 mM) increased the in vitro intestinal permeation rate 3-fold. Oral absorption in dogs was also increased approximately 3-fold using a formulation containing 150 mg sodium caprate. Inter-animal variability in absorption was considerable, though. A diacidic, non-peptide angiotensin II antagonist, DuP 532, presented another case of a poorly membrane permeable lead compound. Sodium caprate did not affect DuP 532 oral bioavailability in rats. However, oral bioavailability of DuP 532 in rats and dogs was increased approximately 3-fold using glyceride vehicles. These excipients have the advantage of already being used in marketed products. As with DMP 728, there was substantial inter-animal variability of DuP 532 oral bioavailability, and optimization of the formulation would be required to improve reproducibility. These examples demonstrate the possibilities of significantly improving oral bioavailability of poorly permeable drugs using seemingly acceptable excipients.

The Influence of Donor and Reservoir Additives on Caco-2 Permeability and Secretory Transport of HIV Protease Inhibitors and Other Lipophilic Compounds

AbstractPurpose. To optimize the conditions for determining Caco-2 permeation of HIV protease inhibitors and other lipophilic compounds, and to compare cyclic urea HIV protease inhibitors with marketed compounds. Methods. Absorptive and secretory Caco-2 membrane permeation studies were performed with HIV protease inhibitors and various reference compounds, examining the effects of adding the solubilizing agents dimethylacetamide (DMAC) and albumin in donor and reservoir compartments, respectively. Results. DMAC was useful as an additive in the donor vehicles, increasing the dissolved concentrations of poorly water-soluble HIV protease inhibitors, and enabling more reliable determination of Papp values. Donor vehicles containing up to 5% DMAC could be used without altering Caco-2 barrier function, as indicated by the lack of effect on permeabilities of reference compounds with diverse absorption characteristics. The utilization of a reservoir containing albumin resulted in marked increases in absorptive Papp values for some HIV protease inhibitors as well as other lipophilic, highly protein bound compounds, consistent with albumin increasing the release of these compounds from the cell monolayer. Conclusions. Poorly soluble, lipophilic, highly bound compounds may require using solubilizing agents in the donor and reservoir compartments of Caco-2 permeation experiments for estimating in vivo absorption potential. If the reservoir does not provide adequate sink conditions, cellular retention could over-emphasize the contributions of secretory transport. The cyclic ureas, DMP 450, DMP 850, and DMP 851, have Caco-2 permeabilities suggestive of moderate-to-high oral absorption potential in humans.

P-glycoprotein, secretory transport, and other barriers to the oral delivery of anti-HIV drugs.

Orally administered anti-HIV drugs must be adequately and consistently absorbed for therapy to be successful. This review discusses the barriers to achieving oral bioavailability for the currently available anti-HIV drugs. Most reverse transcriptase inhibitors have good oral bioavailabilities. Didanosine bioavailability could be reduced by acid instability, first-pass hepatic metabolism, and possibly poor intestinal permeation. Bioavailability of zidovudine is also reduced by first-pass metabolism. The non-nucleoside reverse transcriptase inhibitors have oral bioavailabilities most probably limited by poor aqueous solubility. For each of the currently marketed HIV protease inhibitors, solubility, intestinal permeability, and first-pass metabolism could contribute to reducing oral bioavailability. The intestinal permeabilities of these agents is influenced by secretory transport. In vitro, secretory transport, which appears to be P-glycoprotein-mediated, is much greater than permeation in the absorptive direction for indinavir, nelfinavir, ritonavir, and saquinavir. The mechanisms of secretory intestinal transport are reviewed, and the factors that may influence the impact of secretory transport in vivo are considered.