Feasibility study for transdermal delivery of meperidine

The present study examines the feasibility of meperidine for transdermal delivery. Meperidine possesses characteristics favorable for percutaneous absorption, i.e., a high lipid/water partition coefficient of 25 at pH 7.4, a low molecular weight of 247, and water solubility. Following solubility and apparent partition coefficient experiments, meperidine base rather than salt, was chosen for permeation experiments. The release of meperidine from a drug delivery device (disc) was studied in vitro. Ex vivo permeation of meperidine through excised rat skin was studied using the Thomas diffusion cell, and the fluxes from different solvents were compared. From the in vitro and ex vivo studies, a disc was chosen for final in vivo evaluation in rats, and compared to I.V. and P.O. administration of meperidine.     

Iontophoretic transdermal delivery of buspirone hydrochloride in hairless mouse skin

The transdermal delivery of buspirone hydrochloride across hairless mouse skin and the combined effect of iontophoresis and terpene enhancers were evaluated in vitro using Franz diffusion cells. Iontophoretic delivery was optimized by evaluating the effect of drug concentration, current density, and pH of the vehicle solution. Increasing the current density from 0.05 to 0.1 mA/cm² resulted in doubling of the iontophoretic flux of buspirone hydrochloride, while increasing drug concentration from 1% to 2% had no effect on flux. Using phosphate buffer to adjust the pH of the drug solution decreased the buspirone hydrochloride iontophoretic flux relative to water solutions. Incorporating buspirone hydrochloride into ethanol:water (50:50 vol/vol) based gel formulations using carboxymethylcellulose and hydroxypropylmethylcellulose had no effect on iontophoretic delivery. Incorporation of three terpene enhancers (menthol, cineole, and terpineol) into the gel and when combined with iontophoresis it was possible to deliver 10 mg/cm²/day of buspirone hydrochloride.     

Structural characterization of prazosin hydrochloride and prazosin free base

The three-dimensional solid-state structures of prazosin hydrochloride, C19H22N5O4+.Cl- (A), and prazosin free base, C19H21N5O4 (B), have been determined by synchrotron X-ray powder diffraction. A and B crystallize in triclinic P-1 and monoclinic Cc space groups, respectively, with one structural unit per asymmetric part. In A and B, the prazosin molecule adopts different conformations, which do not correspond to those obtained by DFT optimizations of protonated and free prazosin.     

Effects of cinnamene enhancers on transdermal delivery of ligustrazine hydrochloride.

Cinnamene compounds, cinnamic acid, cinnamaldehyde and cinnamic alcohol, were employed as enhancers. The effects and mechanisms of penetration promoters on the in vitro percutaneous absorption of ligustrazine hydrochloride across hairless porcine dorsal skin were investigated. Transdermal fluxes of ligustrazine hydrochloride through porcine skin were determined in vitro by Franz-type diffusion cells. The results indicated that the penetration flux of ligustrazine hydrochloride by cinnamic acid was the greatest. Significant statistical differences (P<0.05) were found between cinnamic acid and other promoters. Fourier transform-infrared (FT-IR) were carried out to analyze the effects of enhancers on the biophysical properties of the stratum corneum and the permeation enhancement mechanisms. FT-IR results revealed that the changes of peak shift and peak area due to C-H stretching vibrations in the stratum corneum lipids were associated with the selected enhancers. All of them could perturb and extract the stratum corneum lipids to different extent. Morphological changes of the skin treated with enhancers were monitored by a scanning electron microscope. It was demonstrated that the extraction of the stratum corneum lipids by the enhancers led to the disruption of stratum corneum and the desquamation of stratum corneum flake. Apparent density was newly proposed to estimate the desquamated extent of stratum corneum flake. Correlation analysis revealed that there was a linear relationship between apparent density and decrease in peak area. The results showed that the permeation enhancement mechanisms of cinnamene were pleiotropic ones, including disordering the lipids, extracting the lipids and competitive hydrogen bonding between cinnamene enhancers and amides of ceramide head groups in stratum corneum.     

Effect of egg yolk lecithin on transdermal delivery of bunazosin hydrochloride

Transdermal delivery of bunazosin HCl and the enhancing effect of egg yolk lecithin were examined using an in-vitro hairless mouse skin preparation and rabbits for in-vivo systemic absorption. The delivery of bunazosin in-vitro was small, but it was significantly enhanced when lecithin was incorporated into the same vehicle. This enhancing effect was confirmed with other drugs in-vitro. The enhancing ability was also seen in-vivo. Very little bunazosin was delivered from a propylene glycol suspension, but levels of 100-200 ng mL-1 were achieved by the incorporation of the lechithin.     

Development and characterization of transdermal drug delivery systems for diltiazem hydrochloride

Transdermal drug delivery system of diltiazem hydrochloride was developed to obtain a prolonged controlled drug delivery. Both the matrix diffusion controlled (MDC) and membrane permeation controlled (MPC) systems were developed. The matrix diffusion controlled systems used various combinations of hydrophilic and lipophillic polymers, whereas membrane permeation controlled systems were developed using the natural polymer chitosan. The MDC systems were prepared using the cast film method and the MPC systems by an adhesive sealing technique. Both the systems were characterized for in vitro and in vivo performance. The MDC systems were characterized for physicochemical properties such as tensile strength, moisture content, and water vapor transmission. The in vitro release studies showed that the release from the matrix diffusion controlled transdermal drug delivery systems follows a nonfickian pattern and that from the membrane permeation controlled transdermal drug delivery systems follow zero-order kinetics. The release from the matrix systems increased on increasing the hydrophilic polymer concentration, but the release from the membrane systems decrease on cross-linking of the rate controlling membrane and also on addition of citric acid to the chitosan drug reservoir gel. The in vivo studies of the selected systems showed that both systems are capable of achieving the effective plasma concentration for a prolonged period of time. The MPC system achieved effective plasma concentration a little more slowly than the MDC system, but it exhibited a more steady state plasma level for 24 hr.     

The effect of component of microemulsions on transdermal delivery of buspirone hydrochloride

The aim of this study was to evaluate the influence of components such as type, level, and hydrophilic-lipophilic balance (HLB) value of surfactant, type and amount of cosurfactant, and drug concentration on the permeability of buspirone hydrochloride microemulsions through rat skin. The cumulative amount at 24 h ranged from 502.2 ± 57.8 to 1754.3 ± 616.6 μg/cm(2), flux ranged from 23.03 ± 1.84 to 83.36 ± 25.08 μg/(cm(2)/h), and lag time ranged from 3.0 to 4.7 h, indicating that the permeation parameters of buspirone from microemulsions were markedly influenced by the composition of microemulsions. In comparison with the effect of composition of microemulsions on the buspirone permeation capacity, it was found that microemulsions containing surfactant with HLB value of 11.16 possessed higher flux. The viscosity of microemulsions increased, flux decreased, and lag time was prolonged when amount of surfactant in microemulsions increased. The various cosurfactants can also influence the microemulsion formation and drug permeability. The microemulsion with ethanol as cosurfactant had higher permeation rate. However, the buspirone microemulsion with higher flux can provide the therapeutic minimum effective concentration, at workable administrated area about 3.3-5.8 cm(2), demonstrating microemulsions could be a promising drug carrier for transdermal delivery systems.     

盐酸丁卡因凝胶剂经皮渗透作用

目的：制备盐酸丁卡因凝胶剂，并考察不同透皮促进剂对其透皮吸收的影响。方法：配制含不同透皮促进剂的盐酸丁卡因凝胶剂，采用简单扩散小室和紫外分光光度法测定药物透皮吸收量。结果：加1%月桂氮Zhuo酮，加1%，3%，5%薄荷脑或加两者混合透皮促进剂，将药物碱化均可显著增加盐酸丁卡因凝胶剂的透皮吸收量，其累积释药量与时间呈线性关系。结论：单独使用1%月桂氮Zhuo酮对盐酸丁卡因凝胶透皮吸收作用不明显，3%，5%薄荷脑或加1%月桂氮Zhuo酮两者混合透皮保进剂对盐酸丁卡因凝胶透皮吸收作用明显，1%月桂氮Zhuo酮 3%薄荷脑对盐酸丁卡因凝胶透皮吸收作用最明显。     

Elastic liposomes mediated transdermal delivery of an anti-hypertensive agent: propranolol hydrochloride

One major problem encountered in transdermal drug delivery is the low permeability of drugs through the skin barrier. In the present investigation ultradeformable lipid vesicles, that is, elastic liposomes were prepared incorporating propranolol hydrochloride for enhanced transdermal delivery. Elastic liposomes bearing propranolol hydrochloride were prepared by conventional rotary evaporation method and characterized for various parameters including vesicles shape and surface morphology, size and size distribution, entrapment efficiency, elasticity, turbidity, and in vitro drug release. In vitro flux, enhancement ratio (ER), and release pattern of propranolol hydrochloride were calculated for transdermal delivery. In vivo study conducted on male albino rats (Sprague Dawley) was also taken as a measure of performance of elastic liposomal, liposomal, and plain drug solution. The better permeation through the skin was confirmed by confocal laser scanning microscopy (CLSM). Results indicate that the elastic liposomal formulation for transdermal delivery of propranolol hydrochloride provides better transdermal flux, higher entrapment efficiency, ability as a self-penetration enhancer and effectiveness for transdermal delivery as compared to liposomes.     

Design and evaluation of a bioadhesive film for transdermal delivery of propranolol hydrochloride

The objective of the study was to develop a suitable trans-dermal delivery system for propranolol hydrochloride (PPL) via employing chitosan as a film former. Drug concentration uniformity, thickness, moisture uptake capacity and skin bioadhesion of the films were characterized. The effects of chitosan and PPL concentration and different penetration enhancers on the release and permeation profiles from the films were investigated. Skin irritation of the candidate film was evaluated. Chitosan film (PPL 2 mg cm(-2), chitosan 2%, m/m, cineol 10%, m/m) was found nonirritant and achieved 88.2% release after 8 hours in phosphate buffer. Significant high (p < 0.001) permeation of PPL through rat skin was obtained using this film compared to the film without enhancer (about 8 times enhancement factor), making it a promising trans-dermal delivery system for PPL.     

Identification and assessment of permeability enhancing vehicles for transdermal delivery of glucosamine hydrochloride

As an initial step to develop the transdermal delivery system of glucosamine hydrochloride (GL-HCl), the permeation study across the rat skin in vitro was performed to identify the most efficient vehicle with regard to the ability to deliver GL-HCl transdermally. The GL-HCl formulations such as o/w cream, liposome suspension, liposomal gel, and liquid crystalline vehicles were prepared and compared for transdermal flux of GL-HCl. The liquid crystalline vehicles were more effective in increasing the skin permeation of GL-HCl than o/w cream and liposomal vehicles. Of the liquid crystalline vehicles tested, the permeation enhancing ability of the cubic phase was greater than that of the hexagonal phase when the nanoparticle dispersion was used. The skin permeation enhancing ability of the cubic nanoparticles for GL-HCl was further increased by employing both oleic acid and polyethylene glycol 200. Therefore, the cubic liquid crystalline nanodispersion containing oleic acid and PEG 200 can provide a possibility of clinical application of transdermal GL-HCl.     

Effects of enantiomer and isomer permeation enhancers on transdermal delivery of ligustrazine hydrochloride

Enantiomers and isomers, such as D-limonene, L-limonene, and alpha-terpinene, were selected as enhancers. The effects and mechanisms of penetration enhancers on in vitro transdermal delivery of ligustrazine hydrochloride (LH) across hairless porcine dorsal skin were investigated. Transdermal fluxes of LH through porcine skin were determined in vitro by Franz-type diffusion cells. D-limonene, L-limonene, and alpha-terpinene could significantly promote the transdermal fluxes of LH, but no statistical difference (p > 0.05) between them was found. The lag time of L-limonene and alpha-terpinene were 2.55 and 2.20 times compared with that of D-limonene. Fourier transform-infrared (FTIR) was carried out to analyze the effects of enhancers on the biophysical natures of the stratum corneum (SC) and the permeation enhancement mechanism. FTIR spectra revealed that the changes of peak shift and peak area due to C-H stretching vibrations in the SC lipids were associated with the selected enhancers. All of them could perturb and extract the SC lipids to different extent and L-limonene showed obvious changes. Morphological changes of the skin treated with enhancers were monitored by a scanning electron microscope (SEM). The extraction of the SC lipids by the enhancers led to the disruption of SC and the desquamated SC flake. Apparent density (AD) was newly proposed to estimate the desquamated extent of SC flake. The results showed that the enantiomers and isomers enhanced the permeation of LH by pleiotropic mechanisms.     

Feasibility of proniosomes-based transdermal delivery of frusemide: formulation optimization and pharmacotechnical evaluation

The aim of the present study was to formulate non-ionic surfactant vesicles of frusemide to enhance its skin permeation and to develop a transdermal therapeutic system using provesicular approach. The effect of various formulation variables on the transdermal flux, amount of drug deposited in skin, and plasma level of drug were studied. The skin permeation studies were conducted on rat skin and human skin for quantification of permeation parameters. With PGS3 formulation [Span 40:soyalecithin:cholesterol (4.5:4.5:1)], the plasma level in the rats had reached to a level of 0.42 +/- 0.13 microg/mL at the sampling interval of 4 hr and remained within the therapeutic concentration range (1.66-0.3 microg/mL) for the next 12 hr. Results showed that proniosomal formulation was able to sustain the drug level in the blood and offer a promising means for non-invasive delivery of frusemide.     

自溶性微针的制备及其对盐酸青藤碱凝胶透皮性能的影响

目的：优选出自溶性微针的处方工艺,并考察所制备的微针对盐酸青藤碱凝胶透皮性能的影响。方法采用浇注法制备自溶性微针,穿刺试验考察其机械性能,并采用改良Franz扩散池考察自溶性微针预处理皮肤,对盐酸青藤碱凝胶透皮性能的影响。结果采用浇注法制备自溶性微针,其最佳处方为：基质材料硫酸软骨素和聚乙烯吡咯烷酮（PVP）按照1∶1的比例混合,加入重量比60％的水;所制得的微针针形完整、机械强度良好,能够很好的穿刺铝箔和大鼠皮肤;体外透皮实验显示,自溶性微针使得盐酸青藤碱凝胶的累积渗透量增加了3．62倍。结论优选的自溶性微针的处方与制备工艺简单、可行,可显著提高盐酸青藤碱凝胶的透皮性能,为载药微针的进一步研究提供参考依据。     

Single and multiple dose pharmacokinetic evaluation of a transdermal delivery system of imipramine hydrochloride

The transdermal route provides an attractive alternative to the presently used peroral therapy with tricyclic antidepressants due to the avoidance of first-pass metabolism and the associated side effects. In this investigation an earlier developed transdermal delivery system (TDS) of imipramine hydrochloride (CAS 113-52-0; IMH) was evaluated with respect to dose proportionality at three different dose levels. Linearity was observed with the lower doses. For the prediction of in vivo plasma levels, various pharmacokinetic parameters such as alpha, beta, volume of distribution, and AUC0-infinity. were determined by single dose intravenous administration (2 mg/kg). The lowest dose was selected for the multiple dose study taking into consideration the issues of stability, safety, therapeutic range and linearity of pharmacokinetics. At all dose levels the experimental plasma values were significantly lower than predicted levels (p < 0.05) but 30-50 fold higher than the therapeutic range with no significant difference at different dose levels. The plasma levels obtained by repeated application were comparable to that obtained in the single dose study. In addition, IMH exhibited dose proportional pharmacokinetics at the higher doses (above 50 mg/day). The developed TDS was able to maintain steady-state plasma levels for the entire duration of the multiple dose study.     

In vitro and In vivo characterization of the transdermal delivery of sertraline hydrochloride Films

Background and the purpose of the study

Sertraline hydrochloride is a selective serotonin reuptake inhibitor principally used in the treatment of major depressive disorder. To maintain the therapeutic plasma drug concentration of the drug for prolonged period, the transdermal drug delivery has been chosen as an alternative route of drug delivery. The pharmacokinetic properties of sertraline hydrochloride make it suitable for transdermal delivery. The purpose of the study was to investigate the effect of polymers and penetration enhancers on the transdermal delivery of the drug in order to improve its therapeutic efficacy.

Methods

In the preparation of films, Eudragit RL 100, Eudragit RS 100, hydroxy propyl methyl cellulose (HPMC) and ethyl cellulose were used as polymers. The films were characterized for thickness, tensile strength, drug content, moisture uptake, moisture content, water vapor transmission rate and drug release. The films exhibiting higher rates of drug release were subjected to study the effect of oleic acid and propylene glycol as penetration enhancers on skin permeation of sertraline hydrochloride. In vivo and skin irritation studies were performed for the optimized film.

Results

Films containing Eudragit RL 100, Eudragit RL 100 and HPMC showed the highest drug release of 94.34% and 96.90% respectively in a period of 42 hrs. The release data fitted into kinetic equations, yielded zero-order and fickian mechanism of drug release. There was a two-fold increase in skin permeation of sertraline hydrochloride in the presence of penetration enhancers in the film. The physical evaluation indicated the formation of smooth, flexible and translucent films. No skin irritation occurred on rabbit skin and the infrared studies showed the compatibility of the drug with the formulation excipients. The in vivo study revealed a constant plasma concentration of drug for long periods and the films containing penetration enhancers had achieved adequate plasma levels of the drug.

Conclusions

The obtained results indicated the feasibility for transdermal delivery of sertraline hydrochloride using eudragit RL 100 and HPMC.     

A combined approach of chemical enhancers and sonophoresis for the transdermal delivery of tizanidine hydrochloride

The effects of chemical enhancers and sonophoresis on the transdermal permeation of tizanidine hydrochloride (TIZ) across mouse skin were investigated. Parameters including drug solubility, apparent partition coefficient (APC), drug permeation, and degradation in skin were determined. Low frequency ultrasound was also applied in the presence and absence of chemical enhancers to assess whether drug permeation improved. APC values indicated that TIZ preferentially partitions into intercellular spaces and does not form a reservoir, with the drug also exhibiting good enzymatic stability in skin. Most of the enhancers studied significantly increased the permeation rate of TIZ through full thickness mouse skin in comparison with TIZ formulated in phosphate buffer. Maximum enhancement was observed for TIZ formulated as a suspension in 50% v/v aqueous ethanol containing 5% v/v citral. Sonophoresis significantly (p < 0.05) increased the cumulative amount of TIZ permeating through the skin at 15 and 30 min in comparison to passive diffusion. A synergistic effect was noted when sonophoresis was applied in the presence of chemical enhancers. The results suggest that the formulation of TIZ with an appropriate penetration enhancer may be useful in the development of a therapeutic system to deliver TIZ across the skin for a prolonged period, i.e. 24 hr. The application of ultrasound in association with chemical enhancers, such as the combination of 5% v/v citral in 50% v/v aqueous ethanol, could further serve as a non-oral and non-invasive drug delivery modality for the immediate therapeutic effect of muscle relaxants such as TIZ.     

Effect of nerodilol, carvone and anethole on the in vitro transdermal delivery of selegiline hydrochloride

The aim of the study was to investigate the effect of terpene enhancers (nerodilol, carvone or anethole) on the in vitro transdermal delivery of selegiline hydrochloride with a broad objective of developing a membrane-moderated transdermal therapeutic system (TTS). The in vitro permeation studies were carried across the rat epidermis from hydroxypropyl methylcellulose (HPMC) gel drug reservoir containing selected concentrations of nerodilol, carvone or anethole and selegiline hydrochloride. The amount of selegiline hydrochloride permeated during the 24 h of the study (Q24) from HPMC gel drug reservoir without terpene enhancer was 2169 +/- 50 microg/cm2 and the corresponding flux of the drug was 92 +/- 1 microg/cm2 x h. The amount of drug permeated and its flux increased with an increase in terpne concentration in HPMC gel drug reservoir. Nerodilol provided an approximately 3.2-fold increase in the flux of selegiline hydrochloride followed by carvone with a 2.8-fold increase, and anethole with a 2.6-fold increase. It is concluded that the terpene nerodilol, carvone and anethole produced a marked penetration enhancing effect on the in vitro transdermal delivery of selegiline hydrochloride that could possibly be used in the formulation of membrane-moderated TTS.     

Episodic transdermal delivery of testosterone

Film-forming lotions, precast films and adhesive patches containing testosterone (T) were prepared by compounding vinylic, acrylic and cellulosic polymers with a variety of excipients in order to achieve distribution of T in domains of heterogeneity within multicomponent matrices. The feasibility of this approach in achieving episodic transdermal delivery of testosterone (T) was investigated. Composition-dependent differences in extent of in vitro drug release and periodicity were observed. Representative formulations showing the most pronounced episodic T release in vitro were tested in female rats. Whereas intravenously administered T decayed exponentially, three maxima of T in serum were observed upon application of selected formulations. Thus, peak serum concentrations of 240, 36, and 29 ng/dL were observed at 0.2, 5, and 16.8 h after application of the preferred lotion formulation, and 89, 65, and 64 ng/dL at 1, 16.4, and 48.8 h after patches. Deconvolution, noncompartment pharmacokinetic analysis and multiple peak fitting also indicated episodicity. These results suggest the feasibility of using transdermal systems for pulsatile T delivery in a variety of clinical applications, including hormone supplementation and male contraception.     

Iontophoretic transdermal delivery of haloperidol

The in vitro iontophoretic transdermal delivery of haloperidol (HP) across pig skin was investigated. Anodal iontophoresis considerably increased HP skin penetration and accumulation as compared to the passive controls.The effect of NaCl and HP concentrations on the vehicle were also studied. As expected, HP iontophoretic transport decreased with NaCl content. On the other hand, HP concentration did not modify its electrotransport in the range of concentrations between 0.4 and 0.9 mg/mL, except at 24 hours. The influence of the current density (0.20-0.50 mA/cm2) was also investigated. The iontophoretic transport of HP tends to increase with current density. On the whole, this work shows that iontophoresis may be used to improve the topical application of HP for the treatment of chronic psychosis.