Matrix-type Transdermal Delivery System Research Articles

In vitro skin permeation of buprenorphine transdermal patch

This study was aimed to develop the new transdermal formulation to improve the permeability of buprenorphine. The apparent partition coefficients of buprenorphine were measured using the buffers at pH 1.2 to 10.0 as aqueous phase. The solubility of buprenorphine was 12.97 μg/mL in the 0.1 M phosphate buffer at pH 6.8. The influences of vehicles at different pH, adhesives, and permeation enhancers on the penetration of buprenorphine through nude mouse skin were investigated using the static Franz diffusion cells. The permeation parameter J(subscript ss) of buprenorphine increased along with the reduction of the pH of receptor fluid, and the vehicle at pH 6.8 was used in the following skin permeation studies. The pressure sensitive adhesives (PSA) including polyisobutylene (PIB), polystyrene-block-polyisoprene-block-polystyrene (SIS), and acrylic adhesives were evaluated. The permeability of buprenorphine was higher in the PIB or SIS adhesives than that in the acrylic adhesives under the condition without enhancer. When combined the enhancers with propylene glycol (PG) to improve the penetration of buprenorphine, the permeation-enhancing effects of enhancers were in the following order: lauric acid ＞ linolenic acid ＞ menthol ＞ oleic acid ＞ N-methyl-2-pyrrolidone (NMP) ＞ laurocapram ＞ glabridin. Finally, a matrix-type transdermal delivery system for buprenorphine was formulated using acrylic adhesive, PG, and lauric acid. The Jss parameter was 2.68±0.20 μg/cm^2/h and buprenorphine permeated across the nude mouse skin was 31.68%.

Transdermal Delivery of the Free Base of 3-Fluoroamphetamine: In Vitro Skin Permeation and Irritation Potential.

This work aimed to continue our effort in establishing the feasibility of 3-fluoroamphetamine (also known as PAL-353) to be a transdermal drug candidate by studying the delivery of the base form through the human cadaver skin in lieu of the previously investigated salt form, and for the first time using an EPIDERM™-reconstructed human epidermal model to predict the skin irritation potential of PAL-353, in support of development for a matrix-type transdermal delivery system. Passive and enhanced (with chemical permeation enhancers) transdermal delivery were investigated via in vitro permeation studies that were performed on Franz diffusion cells with dermatomed human cadaver skin. After 24h, PAL-353 free base revealed high passive permeation of 417.49 ± 30.12, 1577.68 ± 165.41, and 4295.16 ± 264.36μg/cm2, with applied formulation concentrations of 5.5 (F1), 20 (F2), and 40 (F3) mg/mL, respectively. Oleyl alcohol produced an approximately threefold steady-state flux enhancement at 5% or 10% w/w but may not be needed as the free base alone provided therapeutically relevant permeation. Further, it was predicted that therapeutically relevant delivery would be unlikely to cause skin irritation using the EPIDERM™-reconstructed human epidermal model. In conclusion, the present study further supported the development of PAL-353 transdermal delivery systems.

Effect of Different Pressure-Sensitive Adhesives on Performance Parameters of Matrix-Type Transdermal Delivery Systems.

Matrix-type transdermal delivery systems (TDS) are comprised of the drug dissolved or dispersed in a pressure-sensitive adhesive (PSA) matrix and are designed to provide a controlled delivery through the skin and into systemic circulation. PSAs can directly affect the permeation, release, and performance characteristics of the system. In this study we aimed to design and characterize transdermal delivery systems formulated with lidocaine—as the model drug—loaded in different PSAs, including silicone, polyisobutylene (PIB), and acrylate. TDS containing lidocaine at its saturation points were prepared by the solvent casting method. In vitro permeation studies across dermatomed porcine ear skin were performed using Franz diffusion cells. In vitro release studies were carried out using USP apparatus 5 (paddle over disk). The cumulative amount permeated from the acrylate was significantly higher than silicone and PIB. The acrylate TDS contained a ten times higher drug amount than silicone TDS, but the permeation flux was only two folds higher. Results also showed the release of drug does not linearly correlate to saturation, as the silicone TDS comprising of the lowest amount of drug loading, showed the highest percentage release indicating the choice of PSA affected the drug release and permeation profile.

Development and In vitro Evaluation of Self-Adhesive Matrix-Type Transdermal Delivery System of Ondansetron Hydrochloride

Purpose: To develop and evaluate self-adhesive matrix-type ondansetron hydrochloride (OND) transdermal formulation.Methods: OND transdermal patches were prepared using solvent casting method. The matrix polymer composition was Eudragit E 100, polyvinyl pyrrolidone and either propylene glycol or dibutyl sebacate as plasticizer. Mean patch thickness, tensile strength, moisture content, water absorption capacity and drug content of the patches were studied. In vitro release and permeation of the patches were determined using Franz diffusion cell.Results: Mean patch thickness, moisture content, and water uptake increased with increased contents of polyvinyl pyrrolidone (PVP) and plasticiser. Higher levels of PVP and plasticiser increased drug release. Addition of release modifier such as succinic acid (SA) and myristic acid (MA) to the patch formulations produced a significant increase in drug release from the patch. Higuchi plots for patches containing propylene glycol (PG) were non-linear (r2 = 0.9564), indicating that they did not follow Higuchi release model whereas the plots for most of the patches containing dibutyl sebacate (DBS) followed Higuchi release model (r2 = 0.9974).Conclusion: DBS is a superior plasticiser to PG for OND matrix patches while succinic acid (SA) is a more effective release modifier than myristic acid (MA) for PG patches.Keywords: Ondansetron hydrochloride, Drug release, Release modifier, Transdermal, Dibutyl sebacate, Succinic acid, Higuchi model, Plasticizer

Long-term safety, efficacy, and patient acceptability of the tulobuterol patch

Correspondence: Hisatoshi Sugiura Department of Respiratory Medicine, Tohoku University Graduate School of Medicine, 1-1 Seiryo-machi, Aoba-ku, Sendai 980-8574, Japan Tel +81 22 717 8539 Fax +81 22 717 8549 Email sugiura@rm.med.tohoku.ac.jp Abstract: The tulobuterol patch contains a β 2 -adrenergic agonist, is the first transdermal bronchodilator, and was developed in Japan. It relies on a matrix-type transdermal delivery system that contains both crystallized and molecular forms of tulobuterol. This delivery system enables the drug content to be released steadily over 24 hours. When the tulobuterol patch is applied to the skin at bedtime, the serum concentration of tulobuterol peaks in the early morning, suppressing the morning dip in pulmonary function. This pharmacological property also prevents steep increases in plasma drug levels, which reduces the risk of adverse events. Because the tulobuterol patch is easy to use and requires only once-daily application, treatment adherence in patients using the patch is superior to that of other therapies. The clinical efficacy of the patch in patients with asthma and chronic obstructive pulmonary disease at any age has been established in many clinical studies since launch in 1998, and the product has a good safety profile. Therefore, the tulobuterol patch is currently used for the long-term treatment of patients with asthma and chronic obstructive pulmonary disease. Here we review the characteristics of the tulobuterol patch and the results of clinical trials that have investigated the effects of the patch on pulmonary function, quality of life, and adherence. We also discuss the usefulness of the tulobuterol patch in clinical practice.

Synergic enhancing-effect of DEET and dodecylamine on the skin permeation of testosterone from a matrix-type transdermal delivery system

The synergic in vitro skin permeation enhancing-effect of N,N-diethyl-m-toluamide (DEET) and dodecylamine was investigated in order to develop a novel non-scrotal matrix-type transdermal delivery system of testosterone (TS). When DEET was loaded in DuroTak® 87-2510 together with 2% TS and 3% dodecylamine, the in vitro rat skin permeation rate of TS synergistically increased as DEET concentration increased up to 0.5%. No further increase in permeation was observed thereafter and a plateau was observed up to 3.8% DEET. Moreover, compared to 0.5% DEET concentration, the addition of 3.8% of DEET in combination with 3% dodecylamine and 6% TS further increased the permeation rate of TS, and the maximum permeation rate of 11.21 μg/cm2/h was achieved. The in vitro skin permeation rates of TS from a transdermal delivery system of DuroTak® 87-2510 containing 6% TS, 3% dodecyamine, and 3.8% DEET were in the following order: hairless mouse skin > rat skin > human cadaver skin. Assuming that a system with a surface area of 60 cm2 is applied, the human cadaver skin permeation rate of 5.74 μg/cm2/h achieved in this study can be interpreted as being equivalent to delivering ∼ 8. 27 mg of TS per day. Considering that the commercially available product (Testoderm®TTS) for non-scrotal skin of the same surface area is designed to administer 5 mg of TS per day, the new formulation could maintain therapeutic plasma concentration of TS at a smaller surface area of 40 cm2.

In Vitro and In Vivo Evaluation of a Novel Nonscrotal Matrix-Type Transdermal Delivery System of Testosterone

A matrix-type testosterone (TS) transdermal delivery system for nonscrotal skin was developed with DuroTak® 87-2510 as an adhesive polymer. When 3% dodecylamine was used in combination with 10% span 80, the in vitro rat permeation rate increased from 2.29 µg/cm2/hr to 6.51 µg/cm2/hr as the TS loading dose increased from 2% to 6%. The maximum flux of experimental patch was about 14-fold higher than that of Testoderm®. Release kinetics of TS from the patches was proportional to t1/2 following the Higuchi equation, and the release rate of TS increased as TS loading dose increased. Also, a good linear relationship between the skin permeation rate and the release rate was observed, which implies that the release rate is the rate-limiting process of the skin permeation. In vivo study showed that the plasma concentration of TS promptly increased and reached the peak level within 3–6 hours of application of the experimental patch. Area under the curve (AUC0 ~ 48) and Cmax also linearly increased in a dose-dependent manner up to 6% of TS. These results demonstrate the feasibility of developing a nonscrotal matrix-type transdermal delivery system of TS.

In vitro evaluation of patch formulations for topical delivery of gentisic acid in rats

Gentisic acid (GA) is used in cosmetics as a skin-whitening agent for the treatment of skin pigmentary disorders by influencing the synthesis of melanin through inhibition of melanosomal tyrosinase activity. In order to achieve effective topical delivery of GA to the active site in the skin, a matrix-type transdermal delivery system was developed. The in vitro skin permeation as well as skin deposition of GA was studied in rats. Among the five pressure-sensitive adhesives tested, DuroTak 87-2510 was the most effective to achieve the highest permeation rate of GA. Dodecylamine showed the most potent enhancement among the enhancers tested, and significantly increased the permeation rate of GA up to 112.99 (±30.12) μg/cm 2 per h at the concentration of 1%, when 6% GA was incorporated in DuroTak 87-2510. Moreover, a linear relationship was observed between the skin permeation rate of GA and the amount of the skin deposition after 12 h of permeation ( r 2=0.95). Thus, the in vitro skin permeation data may be useful to determine the amount of GA actually deposited in the skin.

The Effects of Pressure-Sensitive Adhesives and Solubilizers on the Skin Permeation of Testosterone from a Matrix-Type Transdermal Delivery System

ABSTRACTMatrix-type transdermal delivery systems of testosterone (TS) were formulated with three different pressure-sensitive adhesives (PSA). The effects of PSA, skin permeation enhancers, and solubilizers on the rat skin permeation rate of TS were systematically investigated. Without a solubilizer, the skin permeation rate of TS reached its maximum value when only 2% of TS was loaded in the matrix and the crystal formation in the matrix was very rapid and severe. Two surfactants differing in their hydrophile–lipophile balance (HLB) number were, therefore, considered. Span 80, which was of the lower HLB number, was more effective than Tween 80 in increasing the solubility, and thereby increasing the permeation rate of TS. Moreover, the concentrations of both the solubilizer and the skin permeation enhancer affected the skin permeation rate. Thus, the highest skin permeation rate (4.14 µg/cm2/hr) was achieved when 2% TS was loaded in DuroTak® 87-2516 together with 10% Span 80 and 3% dodecylamine, the permeation enhancer. In vivo study showed that the application of an experimental patch on rat abdominal skin resulted in a prompt and significantly higher plasma concentration of TS than that of a commercial product (Testoderm®) designed to apply on the scrotal skin. The area under the curve (AUC) increased linearly as the loading dose of TS increased up to 6%. Thus, based on these results, a non-scrotal matrix-type transdermal delivery system of TS could be developed.

Prodrugs of gestodene for matrix-type transdermal drug delivery systems.

The aim of this study was to enhance the transdermal absorption of the highly active progestin gestodene from matrix type transdermal delivery systems (TDDS) by formation of prodrugs with improved matrix solubility. Gestodene esters were synthesized via acylation of the drug with the respective carboxylic anhydrides. Subsequently TDDS were produced using the solvent cast method. Selected formulations were examined with in vitro diffusion experiments using skin of nude mice. One prodrug, gestodene caproate proved to be an oil at ambient temperature and showed a very high solubilty of over 10.5% in the TDDS matrix. Within in vitro penetration studies using those systems the prodrug exhibited a significantly higher transdermal penetration rate than gestodene from reference systems. Furthermore, the prodrug was hydrolyzed to the parent drug to a high extent during the passage of the skin. Designing prodrugs to the requirements of matrix TDDS is an efficient way of enhancing the transdermal drug flux rate.

Release and permeation kinetics of matrix-type transdermal delivery systems for verapamil.

Release and permeation kinetics of matrix-type transdermal delivery systems for verapamil.

Drug permeation through skin from matrix-type drug delivery systems

Nitroglycerin permeation through hairless mouse skin from various matrix-type transdermal delivery systems has been explained fairly well on the basis of a two-layer skin model. The diffusivity and solubility of the drug in the stratum corneum and in the viable skin have been calculated. The diffusivity in the stratum corneum was found to be affected by the type of delivery system, while that in the viable skin was hardly influenced by the delivery system. The loading dose, diffusivity and solubility of the drug in the delivery system were found to be the important design parameters for skin-control transdermal drug delivery and, therefore, the transdermal delivery system has to be optimized by controlling these three parameters to achieve a maximum rate of skin permeation with minimum drug loading dose.