Enhanced transdermal delivery of indomethacin-loaded PLGA nanoparticles by iontophoresis

Nanoparticles effectively deliver therapeutic agent by penetrating into the skin. Indomethacin (IM) and coumarin-6 were loaded in PLGA nanoparticles with an average diameter of 100 nm. IM and coumarin-6 were chosen as a model drug and as a fluorescent marker, respectively. The surfaces of the nanoparticles were negatively charged. Permeability of IM-loaded PLGA nanoparticles through rat skin was studied. Higher amount of IM was delivered through skin when IM was loaded in nanoparticles than IM was free molecules. Also, iontophoresis was applied to enhance the permeability of nanoparticles. When iontophoresis with 3 V/cm was applied, permeability of IM was much higher than that obtained by simple diffusion of nanoparticles through skin. The combination of charged nanoparticle system with iontophoresis is useful for effective transdermal delivery of therapeutic agents.     

Enhanced transdermal delivery by using electrostatically interactive chitosan nanocapsules

This paper describes a useful means of noninvasively enhancing transdermal delivery efficiency. For this, chitosan nanocapsules with positive surface charges were fabricated by using the in situ precipitation method. These nanocapsules cannot only have an ability to encapsulate the drug molecule (this study used riboflavin 5′-monophosphate), but also electrotatically interact with the stratum corneum layer. To demonstrate this, fluorescence-labeled polymer nanoparticles with different particle sizes as well as surface charges were topically applied onto the skin and their distribution was directly imaged. This demonstration experiment allowed us to figure out that once the nanocapsules were provided with positive surface charges, they readily deposited into the stratum corneum layer due to the electrostatic interaction. Further quantitative characterization of the penetrating amount of riboflavin 5′-monophosphate by using the Frantz diffusion cell method showed that our chitosan nanocapsule system effectively improved transdermal delivery efficiency.     

Enhanced delivery of retinoic acid to skin by cationic liposomes

We studied the delivery of retinoic acid to skin by using cationic liposomes consisting of double-chained cationic surfactant, phosphatidylcholine (PC) and retinoic acid in excised guinea pig dorsal skin. Egg yolk PC liposomes contaning retinoic acid at a molar ratio of 4 : 1 increased the delivery of retinoic acid about two-fold, compared with its addition as an isopropyl myristate solution. Cationic liposomes containing 1,2-dioleoyl-3-trimethylammonium propane (DOTAP) further enhanced the incorporation dependent on the DOTAP content. Liposomes consisting of DOTAP, egg yolk PC, and retinoic acid at a molar ratio of 2 : 2 : 1 induced a 3.7-fold increase in the skin incorporation compared with the egg yolk PC liposomes without DOTAP. Significant difference was not observed when either dimyristoylphosphatidylcholine (DMPC) or dipalmitoylphosphatidylcholine (DPPC) was used instead of egg yolk PC as well as when dimethyldipalmitylammonium was used instead of DOTAP. These results suggest the potential of the use of the cationic liposomes for the intradermal delivery of lipophilic drugs like retinoic acid.     

Quantitation of transdermal tadalafil in human skin by reversed-phase high-performance liquid chromatography

A reliable and sensitive HPLC method was developed for the quantitation of tadalafil transdermal permeation through human skin. An RP column with UV detection at 290 nm was used for chromatographic separation at ambient temperature. The mobile phase was acetonitrile-water containing 20 mM pH 7 phosphate buffer (35/65, v/v) with a flow rate of 1.0 mL/min. The LOQ achieved was 1 ng/mL, and the calibration curve showed good linearity over the concentration range of 5-2000 ng/mL for tadalafil, with a determination coefficient (R2) of 0.998. The RSD values of intraday and interday analyses were all within 7%. Parameters of validation proved the precision of the method; this validated method was applied for the determination of tadalafil in transdermal permeation and drug deposition in human skin studies.     

Microdialysis sampling coupled to HPLC for transdermal delivery study of ondansetron hydrochloride in rats

The transdermal delivery of ondansetron hydrochloride (ON) solution in propylene glycol (PG) with a widely used penetration enhancer, oleic acid (OA), was studied in rats by a microdialysis sampling technique. Dialysate samples collected from the probe were directly injected into the HPLC system without any pre-treatment and no interference occurred in the blank sample. A good linearity between the standard concentrations and peak areas within the calibration range was achieved. In vivo recovery (32.52 +/- 1.8%) of the probe was assessed with the retrodialysis method, which was used to calculate the ON concentration in the dermis. Oleic acid at the concentrations of 2% and 5% (w/v) increased the steady-state delivery rate from 0.001 to 0.030 and 0.058 microg/h, respectively. OA proved to be an effective enhancer for transdermal delivery of ON in rats.     

Quantitative determination of octadecenedioic acid in human skin and transdermal perfusates by gas chromatography-mass spectrometry

A gas chromatographic (GC) method with mass spectrometric (MS) detection is developed and validated for the accurate and precise determination of octadecenedioic acid (C18:1 DIOIC) in human skin samples and transdermal perfusates. C18:1 DIOIC is extracted using methanol. The saturated analogue 1,18-octadecanedioic acid (C18:0 DIOIC) is added as internal standard. Prior to analysis, both compounds are converted to their trimethylsilylated derivatives using N,O-bis(trimethylsilyl)trifluoroacetamide with 15% trimethylchlorosilane. Quantitation is performed in selected ion monitoring mode with a limit of quantitation of 250 ng/mL. Linearity with a correlation coefficient of 0.998 is obtained over a concentration range of 250-2000 ng/mL. Values for within-day accuracy range from 94.5% to 102.4%, and from 97.5% to 105.8% for between-day accuracy. Within- and between-day precision values are better than 5% and 7%, respectively. The recovery values from the various matrices vary from 92.6% to 104.0%. The GC-MS method is employed for the determination of C18:1 DIOIC after application of an emulsion containing the active ingredient onto human skin in vitro. The results demonstrate that the method is suitable for the determination of C18:1 DIOIC in human skin samples and transdermal perfusates.     

Membrane permeation-controlled transdermal delivery system design. Influence of controlling membrane and adhesive on skin permeation of isosorbide dinitrate

A membrane permeation-controlled transdermal delivery system (MC-TDS) of isosorbide dinitrate (ISDN), a model drug, was prepared from polyvinyl alcohol aqueous gel containing the drug, a membrane consisting of ethylene-vinyl acetate copolymer membrane and acrylic adhesive (EV-a). The permeability of ISDN through the EV-a membrane was 2.5 times higher than that through excised hairless rat skin. The ratio of plasma concentration of ISDN after application of MC-TDS on stripped (damaged) skin relative to intact skin was lower than that after application of Frandol tape-S, a marketed ISDN TDS, which suggests that the EV-a membrane might work as a control membrane for overall delivery rate of ISDN to the body. When MC-TDS stored at 30 degrees C for 13.5-48h was applied to the damaged skin, however, the initial plasma concentration of ISDN was very much higher than the expected therapeutic level and was not controlled by the EV-a membrane. The initial high plasma concentration of ISDN after application of the stored MC-TDS on the damaged skin was due to migration of ISDN from the reservoir to the adhesive during storage at 30 degrees C. The migration of drugs into the adhesive might be an important problem in developing efficient MC-TDS.     

Colloidochemical aspects of transdermal drug delivery (review)

This review generalizes scientific information on factors that determine the efficacy of transdermal drug delivery, including the barrier functions of skin, the properties of drugs and enhancers of skin permeability, and the type of a transdermal therapeutic system, i.e., plaster. Colloidochemical aspects of transdermal drug delivery are considered in relation to the amphiphilic structure of drugs and action mechanisms of enhancers, among which nonionic surfactants prevail. Advantages of microreservoir-type transdermal therapeutic systems are shown, information on which is very scarce; the prospects of their development on the basis of oil-in-water and water-in-oil emulsions containing nonionic surfactants and polymer adhesives are outlined.     

Pharmacokinetics of aconitine in rat skin after oral and transdermal gel administrations

The purpose of this study was to evaluate percutaneous penetration and arrhythmogenic effects of aconitine after transdermal administration, compared with the oral route. Skin penetration of aconitine was tested by a microdialysis technique in rats and in vivo recovery was determined by retrodialysis. After oral and transdermal administration of aconitine, dialysate was sampled at 20 min intervals until the end of the experiment for the determination of concentration of aconitine in skin. Blood samples were collected and analyzed using a validated HPLC‐MS/MS method. In addition, we concurrently recorded the electrocardiogram (ECG). The in vivo recovery of aconitine in the skin was calculated to be 39.59%. The C_max values for aconitine absorbed into the skin after oral and transdermal administration were 1.51 ± 0.53 and 2723.8 ± 848.8 ng/mL, respectively, and within the plasma, 215.86 ± 79.29 and 20.92 ± 3.15 ng/mL. The C_max value for the plasma concentration of aconitine after oral administration was approximately 10 times higher than with the transdermal route. For oral administration, the ECG revealed various types of arrhythmias at a period of T_max, which is normal in transdermal gel administration. These results indicate that transdermal aconitine gel is a safe formulation that can deliver the drug in sufficient amounts and safe concentrations to produce therapeutic action in rats. Copyright © 2011 John Wiley & Sons, Ltd.     

Synthesis and preliminary in vivo evaluations of polyurethane microstructures for transdermal drug delivery

ABSTRACT: BACKGROUND: Polymers have been considered as important materials in fabrication of microstructures for various medical purposes including drug delivery. This study evaluates polyurethane as material for hollow microstructures preparation. RESULTS: Polyurethane microstructures were obtained by interfacial polyaddition combined with spontaneous emulsification and present slightly acid pH values. Scanning electron microscopy revealed the existence of irregular shapes and agglomerated microstructures. The material is heat resistant up to 280 [DEGREE SIGN]C. Good results were recorded on murine skin tests in case of polyurethane microstructures based on isophorone diisocyanate. Mesenchymal stem cells viability presents good results for the same sample after 48 hours based on the Alamar Blue test. CONCLUSIONS: The research revealed the reduced noxiousness of this type of microstructures and consequently the possibility of their use for therapeutic purposes.     

Progress in natural polymer engineered biomaterials for transdermal drug delivery systems

The route of a specific drug carrier system is always a significant platform of development that combines the principles of biomedical technology, nanotechnology, and pharmaceutical drug design. Transdermal (TD) drug delivery involves the release of the drug via the stratum corneum of the tissue membrane into the sustained release by diffusion across the epidermal layer. This method (often known as topical drug delivery) has increased noteworthy research enthusiasm in the course of recent decades due to its relatively simpler and non-invasive administration. Over the past few decades, considerable advancement was achieved in TD delivery and a number of drugs are now successfully reported. In this review, we focus on the progress regarding applications of important biopolymers described for the TD drug release applications and related aspects. Three mostly reported plant and animal-derived polymers (such as natural rubber, chitosan, and cellulose for the development of TD carrier system) were extensively analyzed. The general principle of TD drug delivery, advantages, and limitations of the works reported were also discussed.     

Ionic liquids in transdermal drug delivery system: Current applications and future perspectives

The transdermal drug delivery(TDD) shows considerable advantages over other administration pathways.However, conventional enhancing permeation methods face a series of challenges owing to barrier function provided by the skin, of which enhancing abilities either are so strong that it results in toxicity and irritation, or too weak to achieve desirable therapeutical effects. To address these issues, it is an urgent need to develop a novel method to overcome the limitations of current measures. Fo...     

The effect of submicron emulsion systems on transdermal delivery of kaempferol

In this study, submicron emulsions have been employed as a carrier for the topical application of kaempferol. The effect of components of submicron emulsions on the physicochemical properties and permeation capability of drug were evaluated. In case of drug-loaded submicron emulsions, the cumulative amount over 12?h (Q(12?h)), lag time and deposition in skin amount ranged from 13.0±3.4 to 236.1±21.2?μg/cm(2), 1.7 to 5.3?h, and 1.10 to 7.76?μg/cm(2), respectively, which indicated that the permeation parameters of kaempferol were markedly influenced by the component ratio. Kaempferol dispensed in isopropyl myristate was used as the control. The Q(12?h), lag time and deposition amount in skin were 4.2±1.8?μg/cm(2), 6.0?h and 2.25±0.60?μg/cm(2), respectively. The data showed that used appropriate submicron emulsions as vehicle could significantly increase the Q(12?h) and deposition amount in skin and shorten the lag time, demonstrating that submicron emulsions have a potent enhancement effect for kaempferol transdermal delivery.     

Acute toxicity and skin irritation of pyrrolidone derivatives as transdermal penetration enhancer

We investigated preliminary acute toxicity and primary skin irritation of nine pyrrolidone derivatives which had been previously developed as transdermal penetration enhancers. The acute toxicity was observed at a dose of 500 mg/kg after intraperitoneal administration in mice. Their primary skin irritations were examined with rabbit dorsal skin. 1-Lauryl-2-pyrrolidone induced the most severe irritation among the derivatives. Pyrrolidone derivatives having methyl group and methyloxycarbonyl group caused little irritation. The primary irritation indices of pyrrolidone derivatives were not relative to their accumulations in the skin but to their enhancing effects. In conclusion, 1-hexyl-4-methyloxycarbonyl- and 1-lauryl-4-methyloxycarbonyl-2-pyrrolidone are suggested to be adequate enhancers, judging from the balance of their enhancing activity and irritation.     

Preparation of organic nanoparticles using microemulsions: their potential use in transdermal delivery

Organic nanoparticles of cholesterol and retinol have been synthesized in various AOT (Aerosol OT; sodium bis(2-ethylhexyl) sulfosuccinate)/heptane/water microemulsions by direct precipitation of the active principle in the aqueous cores. The nanoparticles are observed by transmission electron microscopy (TEM) using the adsorption of a contrasting agent, such as iodine vapor. The size of the nanoparticles can be influenced, in principle, by the concentration of the organic molecules and the diameter of the water cores, which is related to the ratio R=[H2O]/[surfactant]. The particles remain stable for several months. The average diameter of the cholesterol nanoparticles varies between 3.0 and 7.0 nm, while that of retinol varies between 4.0 and 10 nm. The average size of the cholesterol nanoparticles does not change much either as a function of the ratio R or as a function of the concentration of cholesterol. The constant size of the nanoparticles can be explained by the thermodynamic stabilization of a preferential size of the particles. Chloroform is used to carry the active principle into the aqueous cores. Retinol molecules form J-complexes composed of two or three molecules, as detected by UV-visible spectroscopy.     

Synthesis and characterization of an acrylate pressure sensitive adhesive for transdermal drug delivery

The present investigation was directed towards the synthesis of a copolymer of 2‐ethylhexyl acrylate and acrylic acid to be exploited as a pressure sensitive adhesive (PSA) matrix in transdermal drug delivery systems. The polymer synthesis involved free radical solution polymerization using 2, 2′‐azobisisobutyronitrile as the free radical initiator. The experimental methodology involved the optimization of reaction conditions for the polymer synthesis. The optimized copolymer was then characterized by IR, ¹H‐NMR, DSC, GPC and XRD. The PSA was also evaluated for percent free monomer content, intrinsic viscosity, refractive index, moisture uptake potential and film forming properties. To assess it suitability in the development of transdermal systems, peel strength values with respect to release liner as well as human skin and skin irritation potential were also determined. In addition, wear performance test was conducted to evaluate adhesion and adhesive transfer. The synthesized adhesive was found to have good peel strength; exhibited excellent adhesion and adhesive transfer on removal. It was found suitable for use in transdermals and could be further exploited either as an adhesive matrix or as a system component in the area of transdermal drug delivery. Copyright © 2002 John Wiley & Sons, Ltd.     

HII mesophase and peptide cell-penetrating enhancers for improved transdermal delivery of sodium diclofenac

This study develops a novel transdermal delivery vehicle for the enhanced delivery of sodium diclofenac (Na-DFC). The system utilizes the advantages of reversed hexagonal lyotropic liquid crystals (H_IILC), combined with a peptide cell penetration enhancer (CPE), creating together an adaptable system that provides versatile options in the field of transdermal delivery.This enhancer peptide is based on a family of amphipatic peptides that exhibit improved membrane permeability. Franz permeation cell experiments revealed that the peptide enhancer (RALA) improved Na-DFC skin penetration of the liquid crystal 2.2-fold.We studied the structural effects of RALA solubilization on the H_II mesophase. RALA acts as a chaotropic agent, interfering in the structure of the water, and causes a measurable swelling of the aqueous cylinders by 5 Å.Small angle X-ray scattering (SAXS) and attenuated total reflectance–Fourier transform infrared (ATR–FTIR) measurements reveal enhanced hydration of the glycerol monooleate (GMO) headgroups and a 6.5% increase in the fraction of non-freezable water resulting from RALA incorporation. RALA caused a gradual increase in the GMO effective headgroup area due to the hydration, leading eventually to a transform of the hexagonal structure towards a lamellar one. Circular dichroism and ATR–FTIR measurements showed a conservation of the peptide structure when incorporated into the H_II mesophase.The combined H_IILC-CPE systems can serve as high potential vehicles for a variety of drugs, as they can easily be modified by varying the composition and temperature, according to the required dose and delivery features.     

Numerical study of a drug release profile in the transdermal drug delivery system

Drug release by diffusion from an unstressed thin polymer film with a dissolved crystallizable component was simulated using a kinetic Monte Carlo model. This model was used previously to study Ostwald ripening in a high crystallizable component regime and was shown to correctly simulate solvation, diffusion, and precipitation. In this study, the same model with modifications was applied to the drug transportation and release in the low concentration regime of interest to the transdermal drug delivery system (TDS) community. We demonstrate the model's utility by simulating diffusion, crystal precipitation, growth and shrinkage during storage, and drug release from the thin TDS to a surface under different conditions. The simulation results provide a first approximation for the drug release profile occurring from TDS to skin. It has been reported that growth of drug crystals in TDS occurs mainly in the middle third of the polymer layer at relatively higher temperatures. The results from the simulations showed that the release rate and concentration profile of a TDS depend on the dissolution process of the crystal. At low storage temperature, the drug precipitates to form small evenly distributed crystals throughout the thickness of the TDS patch. The release rate of these small, evenly distributed crystals most closely matched that of a completely dissolved drug.     

Film‐ and ointment‐based delivery systems for the transdermal delivery of TNP‐470

Pathological angiogenesis, the process of new blood vessel formation, is responsible for a broad range of neovascular‐related systemic diseases. One of the first antiangiogenic compounds tested in clinical trials against cancer was TNP‐470. Despite promising activity the injectable drug showed poor plasma stability and caused adverse side effects in high doses lead to termination of the trials. In our current work, we introduce the development of a transdermal delivery systems for controlled release of TNP‐470. Such formulation can potentially reduce toxicity due to controlled continuous dosing and improve stability by avoiding gastrointestinal first pass metabolism. Although transdermal delivery is a very challenging route for drug administration due to the low permeability of the skin, here we present a successful development of two different drug delivery systems, film and ointment for dermal application of TNP‐470. Chitosan film had high loading capacity of up to 50% w/w of TNP‐470 compared with 10% maximum loading in hydrocarbon ointment. A detailed step‐by‐step development of TNP‐470 films, from the initial solvent screening to final optimized formulation, is presented. Ex vivo skin permeation studies demonstrated a superior release of the drug from the film formulation compared with the ointment. Furthermore, histological test of the skin confirmed ointment safety showing no evidence of skin tissues damage. Our results present novel, promising, controlled release drug delivery systems with improved stability, efficacy, and safety profile of TNP‐470 via transdermal route.