Presence Of Permeation Enhancers Research Articles

Transdermal Delivery of Lercanidipine Hydrochloride: Effect of Chemical Enhancers and Ultrasound

The effects of permeation enhancers and sonophoresis on the transdermal permeation of lercanidipine hydrochloride (LRDP) across mouse skin were investigated. Parameters including drug solubility, partition coefficient, drug degradation and drug permeation in skin were determined. Tween-20, dimethyl formamide, propylene glycol, poly ethylene glycol (5% v/v) and different concentration of ethanol were used for permeation enhancement. Low frequency ultrasound was also applied in the presence and absence of permeation enhancers to assess its effect on augmenting the permeation of drug. All the permeation enhancers, except propylene glycol, increased the transdermal permeation of LRDP. Sonophoresis significantly increased the cumulative amount of LRDP permeating through the skin in comparison to passive diffusion. A synergistic effect was noted when sonophoresis was applied in presence of permeation enhancers. The results suggest that the formulation of LRDP with an appropriate penetration enhancer may be useful in the development of a therapeutic system to deliver LRDP across the skin for a prolonged period (i.e., 24 h). The application of ultrasound in association with permeation enhancers could further serve as non-oral and non-invasive drug delivery modality for the immediate therapeutic effect.

Hydroxypropylmethylcellulose films for prolonged delivery of the antipsychotic drug chlorpromazine

The aim of this study was to develop transdermal films based on hydroxypropylmethylcellulose with the purpose of improving transdermal permeation of chlorpromazine hydrochloride, an antipsychotic drug used to alleviate the symptoms and signs of psychosis. Hydroxypropylmethylcellulose films were prepared and evaluated for their drug content, film thickness, residual water content and bioadhesive properties. In-vitro permeation experiments were performed in the absence and in the presence of permeation enhancers (oleic acid, polysorbate 80, or both) with the purpose of improving drug availability. Other formulative parameters, such as drug and plasticizer concentration and hydroxypropylmethylcellulose type, were investigated. Both oleic acid and polysorbate 80 had significant effect on drug permeation with respect to the control formulation. In particular films containing a mixture of oleic acid and polysorbate 80 provided the best enhancement activity for chlorpromazine. Moreover, a decrease in propylene glycol or chlorpromazine content or an increase of hydroxypropylmethylcellulose viscosity provided lower cumulative amounts of drug permeated. The results obtained confirm that chlorpromazine permeation can be easily modulated by varying the composition of hydroxypropylmethylcellulose-based films. These formulations could serve as candidates for transdermal delivery of antipsychotic drugs.

Paracellular and transcellular pathways facilitate insulin permeability in rat gut

The aim of this study was to conduct a systematic investigation of the absorption of insulin in the rat intestine in the presence of permeation enhancers and protease inhibitors. An in-situ perfused rat gut model was used for the co-perfusion of insulin and PEG 4000 in the presence or absence of bile salts, bile salt:fatty acid surfactant systems and protease inhibitors. Perfusion experiments were conducted for 180 min with perfusate and blood collection at regular intervals. Permeability coefficients for insulin were calculated from plasma insulin and PEG 4000 permeability coefficients were calculated from lumenal disappearance data. In the absence of enzyme inhibitors, insulin permeability was consistently lower than PEG 4000, but increased in proportion to PEG 4000 permeability. Large increases in insulin permeability were obtained for mixed micellar systems and protease inhibitors. In the presence of protease inhibitors and simple micelle systems, PEG 4000 permeability was three-fold greater than insulin permeability. In the presence of absorption enhancers, PEG 4000 permeability increased up to a maximum value of 3.63 x 10(-6)cm s(-1), a value five-fold less than that of the estimated aqueous boundary layer permeability for PEG 4000. This suggests that PEG 4000 permeability is primarily membrane controlled. Insulin permeability is enhanced to a maximum value of 9.17 x 10(-6)cm s(-1), suggesting that paracellular transport routes do not account exclusively for insulin permeation across the intestinal epithelium. The results add support to suggestions that routes other than the paracellular route may contribute to insulin absorption in rat gut.

Intranasal delivery: Physicochemical and therapeutic aspects

Interest in intranasal (IN) administration as a non-invasive route for drug delivery continues to grow rapidly. The nasal mucosa offers numerous benefits as a target issue for drug delivery, such as a large surface area for delivery, rapid drug onset, potential for central nervous system delivery, and no first-pass metabolism. A wide variety of therapeutic compounds can be delivered IN, including relatively large molecules such as peptides and proteins, particularly in the presence of permeation enhancers. The current review provides an in-depth discussion of therapeutic aspects of IN delivery including consideration of the intended indication, regimen, and patient population, as well as physicochemical properties of the drug itself. Case examples are provided to illustrate the utility of IN dosing. It is anticipated that the present review will prove useful for formulation scientists considering IN delivery as a delivery route.

Electrically-assisted skin delivery of pergolide in vitro: effect of pH, donor concentration and surfactants

The aim of the current study was to identify the variables determining the flux of transdermal iontophoretic delivery of pergolide in vitro and to evaluate the potentials of the delivery design to reach therapeutic plasma concentrations. The effect of: i) pH of donor solution, ii) donor concentration, and iii) the presence of permeation enhancers on pergolide transport were investigated. By reducing the pH in the donor compartment from 5 to 4 no significant difference in the transport rate of pergolide across human stratum corneum was noticed. Furthermore pergolide delivery does not increase linearly with the donor concentration: a further increase in concentration above 100μg/mL in the donor formulation, did not result in increased transport rates. When the non-ionic surfactant, laureth-3-oxyethylene ether (C12EO3) and propylene glycol (PG) were used in the donor formulation, a significant enhancement by a factor of 2.4 was achieved compared to the control (citrate buffer pH5). This indicates that the surfactant efficiently enhances the iontophoretic transport of pergolide. In conclusion, these in vitro studies indicate that it could be feasible to reach therapeutic levels by transdermal iontophoresis of pergolide.

An in situ single-pass perfusion model for assessing absorption across the intestinal mucosa of the brushtail possum

AIM: To develop an in situ animal model for assessing absorption of molecules across the intestinal mucosa of possums. METHODS: A surgical preparation was used to perfuse known concentrations of reference compounds (fluorescein and luteinising hormone-releasing hormone; LHRH) through measured sections of selected regions (jejunum, caecum, proximal colon) of the intestinal tract of 19 possums, over a 2-h period. Plasma concentrations of the compounds, which were perfused either with or without co-administration of a permeation enhancer (sodium deoxycholic acid; SDA), were determined in the perfusion effluent, peripheral and in some instances in the pre-hepatic circulation by spectrofluorometry (fluorescein) or radio-immunoassay (LHRH). Pharmacokinetic parameters of both compounds in the possum were determined over a period of up to 4 h in a further 30 animals (fluorescein, n=6; LHRH n=24), from their plasma profiles following intravenous (I/V) administration of a bolus dose. RESULTS: In animals perfused with 25 mg/ml fluorescein (Perfusion Experiment (PE) 1), the mean plasma concentration was 2.8 (SE 0.12) µg/ml in post-hepatic blood samples. When possums were perfused with 2.5 mg/ml fluorescein and 7 µg/ml LHRH (PE 2), mean plasma concentrations were 0.3 (SE 0.01) and 7.8 (SE 1.64) µg/ml fluorescein and 0.1 (SE 0.02) and 6.3 (SE 0.45) ng/ml LHRH, in the absence and presence of permeation enhancer, respectively. There was a poor correlation between pre-hepatic and post-hepatic concentrations. CONCLUSIONS: The single-pass in situ perfusion technique provided a useful model for investigating basic information on the absorption of biocontrol agents across the intestinal tract of possums, but had limitations that must be recognised.

Alginate/poly-L-lysine microparticles for the intestinal delivery of antisense oligonucleotides.

A microparticle carrier based on alginate and poly-L-lysine was developed and evaluated for the delivery of antisense oligonucleotides at the intestinal site. Formulations of oligonucleotide-loaded microparticles having differences in the carrier molecular weight and composition were characterized in vitro and in vivo. Polymeric microparticles were prepared by ionotropic gelation and crosslinking of alginate with calcium ions and poly-L-lysine. The loading of the antisense oligonucleotide into the microparticles was achieved by absorption in aqueous medium. The association capacity, loading and particle size of the microparticles were characterized. The in vivo performances of various formulations after intrajejunal administration were studied in rat and in dog models. Microparticles had a sponge-like structure and an oligonucleotide loading of 27-35%. The composition of the medium affected the particle size and the in vitro release profiles. The oligonucleotide bioavailability after intrajejunal administration to rats in the presence of permeation enhancers was good for most of the tested systems. The application of microparticles in powder form compared to an equivalent suspension improved the intrajejunal bioavailability of the oligonucleotide (25% and 10% respectively) in rats. On the contrary, the intrajejunal administration to dogs resulted in poor oligonucleotide bioavailability (0.42%). The formulation of antisense oligonucleotides within alginate and poly-L-lysine microparticles is a promising strategy for the oral application.

Application of kinetic model to in vitro percutaneous permeation of drugs

Kinetic model using inter-compartmental rate constants, for permeation of drug across stratum corneum (k 1), for permeation across viable tissue layer of epidermis (k 2), and for back transfer of drug from viable tissue layer into the stratum corneum (k 3), was applied to in vitro percutaneous permeation process. Permeation data of four drugs, propranolol (PR), triamcinolone acetonide (TA), physostigmine (PHY), and tetrahydroaminoacridine (THA), previously studied across two skin membranes, hairless mouse skin (HMS) and human cadaver skin (HCS) were fitted to the permeation equation based on the kinetic model to obtain optimized values of the rate constants. The permeation profiles were also analyzed by the lag time method to estimate steady state flux (J ss), lag time (T lag), diffusion coefficient (D) and Skin/donor-phase partition coefficient (Km). The D and Km were used to regenerate the entire permeation profile (pre-steady and steady states) using equation based on Fick's laws of diffusion. The kinetic and diffusion models were compared by fits of the observed data to the model predicted values by linear regression, and obtaining R 2 and sum of squared deviations (SSD). Permeation data for all drugs across HMS or HCS, with or without the presence of permeation enhancer, were described very well by the kinetic model ( R 2 > 0.99), and the SSD's were smaller than that for the diffusion model except for THA. The rate of drug permeation across stratum corneum, k 0 (k 1 X Dose, amount of drug applied/cm 2 of skin in the donor phase) was similar to J ss as expected from the kinetic model. Diffusion coefficient of drug in the viable tissue (Dvt) ranged from 0.003–0.23 × 10 −7 cm 2/ s, similar to diffusion coefficient of similar sized molecules in protein gel as would be expected. Also, D vt was four orders of magnitude greater than D, the diffusion coefficient across stratum corneum, confirming stratum corneum to be the rate limiting barrier in the percutaneous permeation of the drugs studied. k 3 for all drugs were negligible indicating that no back diffusion of drug from viable tissue into the stratum corneum was occurring under the sink condition following infinite dose application. Also, except TA, none of the drug studied was lipophilic enough to be retained by the stratum corneum. Therefore, k 3 should not be used in the kinetic model for in vitro percutaneous permeation. For the PR 27-h, TA control and TA with 2% propylene glycol (PG) pretreatment experiments, the experiment duration was less than three T lag and steady state was not achieved, resulting in inaccurate estimates of D and Km and, hence, the regenerated profiles based on diffusion model did not describe the data well. However, kinetic model described these data also very well and SSD's were significantly smaller ( P = 0.05) than that for the diffusion model based regenerated profiles. The kinetic model is an alternative to diffusion model to describe the percutaneous permeation process, and the results presented here demonstrate the usefulness of the kinetic approach.