Transdermal delivery of piroxicam using microemulsions

To improve the skin permeability of piroxicam, a new oil-in-water microemulsion containing 0.5% piroxicam was developed. Among various oils investigated for their suitability as an oil phase for the microemulsion system, oleic acid showed both excellent solubility and skin permeation enhancing effect for piroxicam. Microemulsion existence ranges were identified through the construction of the pseudo-ternary phase diagram. The effect of the content of oleic acid and the ratio of the surfactant/cosurfactant on skin permeation of piroxicam were evaluated with excised rat skins. The optimum formulation with the highest skin permeation rate (47.14 microg/cm2/h) consisted of 0.5% piroxicam, 10% oleic acid, 60% Labrasol/ethanol (1:5) and water.     

Controlled penetration of ceramides into and across the stratum corneum using various types of microemulsions and formulation associated toxicity studies

Several skin diseases such as psoriasis and atopic dermatitis are associated with the depletion or disturbance of stratum corneum (SC) lipids such as ceramides (CERs), free fatty acids and cholesterol. Studies suggested that replenishment of these lipids might help to treat diseased, affected or aged skin. With this premises in mind, there are some formulations in the market that contain SC lipids and currently, to facilitate permeation of the lipids deep into the SC, various CERs, and other SC lipid microemulsions (MEs) were developed and characterised using lecithin or TEGO® CARE PL 4 (TCPL4) as base surfactants. However, to date, there are no reports that involve the permeability of SC lipids into and across the SC, and therefore, the penetration of CER [NP] as a model ceramide from various formulations was investigated ex vivo using Franz diffusion cell. Besides, the toxicity of the MEs was assessed using hen’s egg test chorioallantoic membrane (HET-CAM). The results of the study showed that CER [NP] could not permeate into deeper layers of the SC from a conventional hydrophilic cream. Unlike the cream, CER [NP] permeated into the deeper layers of the SC from both type of MEs, where permeation of the CER was more and into deeper layers from droplet type and lecithin-based MEs than bicontinuous (BC) type and TCPL4 based MEs, respectively. The CER also permeated into deeper layers from ME gels which was, however, shallow and to a lesser extent when compared with the MEs. The results of HET-CAM showed that both MEs are safe to be used topically, with lecithin-based MEs exhibiting better safety profiles than TCPL4 based MEs. Concluding, the study showed that the MEs are safe to be used on the skin for the controlled penetration of CER [NP] deep into the SC.     

Formulation,optimization and evaluation of transferosomal gel for transdermal insulin delivery

The present study deals with the development of transferosomal gel containing insulin by reverse phase evaporation method for painless insulin delivery for use in the treatment of insulin dependent diabetes mellitus. The effect of independent process variables like ratio of lipids (soya lecithin:cholesterol), ratio of lipids and surfactants, and ratio of surfactants (Tween 80:sodium deoxycholate) on the in vitro permeation flux (μg/cm²/h) of formulated transferosomal gels containing insulin through porcine ear skin was optimized using 2³ factorial design. The optimal permeation flux was achieved as 13.50 ± 0.22 μg/cm²/h with drug entrapment efficiency of 56.55 ± 0.37% and average vesicle diameter range, 625–815 nm. The in vitro insulin permeation through porcine ear skin from these transferosomal gel followed zero-order kinetics (R² = 0.9232–0.9989) over a period of 24 h with case-II transport mechanism. The in vitro skin permeation of insulin from optimized transferosomal gel by iontophoretic influence (with 0.5 mA/cm² current supply) also provided further enhancement of permeation flux to 17.60 ± 0.03 μg/cm²/h. The in vivo study of optimized transferosomal gel in alloxan-induced diabetic rat has demonstrated prolonged hypoglycemic effect in diabetic rats over 24 h after transdermal administration.     

Development of udenafil-loaded microemulsions for intranasal delivery: in vitro and in vivo evaluations

To achieve rapid onset of action and improved bioavailability of udenafil, a microemulsion system was developed for its intranasal delivery. Phase behavior, particle size, transmission electron microscope (TEM) images, and the drug solubilization capacity of the microemulsion were investigated. A single isotropic region was found in pseudo-ternary phase diagrams developed at various ratios with CapMul MCM L8 as an oil, Labrasol as a surfactant, and Transcutol or its mixture with ethanol (1:0.25, v/v) as a cosurfactant. Optimized microemulsion formulations with a mean diameter of 120-154 nm achieved enhanced solubility of udenafil (>10 mg/ml) compared with its aqueous solubility (0.02 mg/ml). An in vitro permeation study was performed in human nasal epithelial (HNE) cell monolayers cultured by the air-liquid interface (ALI) method, and the permeated amounts of udenafil increased up to 3.41-fold versus that of pure udenafil. According to the results of an in vivo pharmacokinetic study in rats, intranasal administration of udenafil-loaded microemulsion had a shorter T_max value (1 min) compared with oral administration and improved bioavailability (85.71%) compared with oral and intranasal (solution) administration. The microemulsion system developed for intranasal administration may be a promising delivery system of udenafil, with a rapid onset of action and improved bioavailability.     

Investigation of microemulsion microstructures and their relationship to transdermal permeation of model drugs: ketoprofen, lidocaine, and caffeine

In this study, microemulsion microstructures, key formulation variables, and their relationship to drug transdermal permeation enhancement were investigated. A microemulsion system with high water soluble capacity was developed, using isopropyl myristate, Labrasol, and Cremophor EL as oil, surfactant, and co-surfactant, respectively. The microstructures of the microemulsions were characterized by a combination of techniques including electrical conductivity measurement (EC), differential scanning calorimetry (DSC), electro-analytical cyclic voltammetry (CV), dynamic light scattering (DLS). Three microemulsion formulations with the model drugs at water contents of 20%, 40%, and 70% representing the microstructures of W/O, Bi-continuous, and O/W were prepared along the water dilution line of oil to surfactant ratio of 1/9. Skin permeation of hydrophobic and hydrophilic model drugs, ketoprofen, lidocaine, and caffeine in the microemulsion formulations was studied using Franz-cells and dermatomed porcine skin. Permeation of all drugs from microemulsions was enhanced significantly compared with the control propylene glycol formulation. The drug permeation flux and the cumulative permeation amount after 24 h increased with water content in the microemulsions, thus correlated to the formulation microstructures of W/O, Bi-continuous, and O/W. The permeation of lipophilic drugs ketoprofen and lidocaine increased with water content in a more pronounced manner, which seemed to follow an exponential growth trend, while the permeation of hydrophilic drug caffeine appeared to increase linearly. Additionally, at the same water content, increasing oil content led to higher ketoprofen permeation.     

Oleodendrimers: A novel class of multicephalous heterolipids as chemical penetration enhancers for transdermal drug delivery

This paper reports synthesis and evaluation of Janus type generation G-1 and G-2 dendrimers. The dendrimers have been constructed by linking two building blocks, dendrons and oleic acid, through ester and amide bonds and were well characterized by Fourier-transform infrared (FT-IR), ¹H NMR, ¹³C NMR and electrospray ionization mass spectrometry (ESI-MS). The dendrimers have been evaluated for in vitro cytotoxicity using sulforhodamine B assay (SRB assay) and in vivo skin irritation potential. The ester linked dendrimers did not exhibit any cytotoxicity even up to 80 μg/ml while G-1 and G-2 generations dendrimers with amide linkage exhibited toxicity above 70 μg/ml and 21 μg/ml, respectively, none of the dendrimers showed any skin irritation. All the dendrimers, tested for their skin permeation enhancement potential using diclofenac sodium (DS) as a model drug at a concentration of 1% in gels, showed significant increase in steady-state flux (ER_flux) of the drug as compared to control (without enhancer), and oleic acid. Amongst the dendrimers, the ester linked G-1 and G-2 dendrimers showed highest ER_flux, 3.33 ± 0.31 and 3.39 ± 0.21, respectively.     

Effect of permeation enhancers on transdermal delivery of fluoxetine: In vitro and in vivo evaluation

The aim of this study was to investigate the feasibility of transdermal fluoxetine (FX) delivery. The effects of chemical forms (base or salt) and permeation enhancers on in vitro skin permeation of FX were assessed using hairless mouse, rat and human cadaver skin. The optimized formulations from the in vitro studies were then evaluated in an in vivo pharmacokinetic study in rats. The in vitro skin permeation studies suggested that the FX base (FXB) and isopropyl myristate (IPM)–limonene mixture could be suitable for transdermal delivery of FX. The permeation parameters of FX through human cadaver skin were well correlated with that through hairless mouse and rat skin, suggesting that these animal models can be used for predicting the permeability of FX through human skin. After transdermal administration of FX with IPM or the IPM–limonene mixture to rats, the mean steady-state plasma concentration (C_ss) was 66.20 or 77.55 ng/mL, respectively, which was maintained over 36 h and had a good correlation with the predicted C_ss from the in vitro data. These in vitro and in vivo data demonstrated that permeation enhancers could be a potential strategy for transdermal delivery of FX.     

Effects of nicotine administered via a transdermal delivery system on vigilance: a repeated measure study

Fifteen 18- to 25-year-old male smokers were tested in a within-subjects design to determine the influence of a transdermal patch of 21 mg nicotine on vigilance. Subjects were tested on the RVIP test (Rapid Visual Information Processing test) 1.30, 3.00 and 6.30 h after patch application, to verify the involvement of the dose of nicotine on the performance. This study confirms and extends the increasing effects of nicotine on vigilance previously found with orally and transdermally given nicotine. Moreover, it showed that such performance was independent of the time of nicotine absorption (1.30, 3.00 and 6.30 h after patch application), which suggests that a relatively low dose of nicotine suffices to activate vigilance processing. Regarding motor performance, no convincing effect of nicotine was observed on reaction time. Received: 20 October 1997/Final version: 2 September 1998     

A novel dextran hydrogel linking trans-ferulic acid for the stabilization and transdermal delivery of vitamin E

Long-term exposure of the skin to UV light causes degenerative effects, which can be minimized by using antioxidant formulations. The major challenge in this regard is that a significant amount of antioxidant should reach at the site for effective photoprotection. However, barrier properties of the skin limit their use. In the present study, vitamin E (α-tocopherol) was loaded into a dextran hydrogel containing ferulic moieties, covalently linked, to improve its topical delivery, and also to increase its relative poor stability, which is due to direct exposure to UV light. Methacrylic groups were first introduced onto the dextran polymer backbones, then the obtained methacrylated dextran was copolymerized with aminoethyl methacrylate, and subsequently esterificated with trans-ferulic acid. The new biopolymer was characterized by Fourier transform infrared spectroscopy. The values of content of phenolic groups were determined. Its ability in inhibiting lipid peroxidation in rat liver microsomal membranes induced in vitro by a source of free radicals, that is tert-butyl hydroperoxide, was studied. Hydrogel was also characterized for swelling behaviour, vitamin E loading efficiency, release, and deposition on the rabbit skin. Additionally, vitamin E deposition was compared through hydrogels, respectively, containing and not containing trans-ferulic acid. The results showed that ferulate hydrogel was a more effective carrier in protecting vitamin E from photodegradation than hydrogel without antioxidant moieties. Then antioxidant hydrogel could be of potential use for cosmetic and pharmaceutical purposes as carrier of vitamin E that is an antioxidant that reduces erythema, photoaging, photocarcinogenesis, edema, and skin hypersensitivity associated with exposure to ultraviolet B (UVB) radiation, because of its protective effects.     

Permeation enhancer dodecyl 6-(dimethylamino)hexanoate increases transdermal and topical delivery of adefovir: Influence of pH, ion-pairing and skin species

Adefovir (9-(2-phosphonomethoxyethyl)adenine) is an acyclic nucleoside phosphonate currently used for the treatment of hepatitis B. The aim of this study was to evaluate the effect of permeation enhancer DDAK (6-dimethylaminohexanoic acid dodecyl ester) on the transdermal and topical delivery of adefovir. In porcine skin, DDAK enhanced adefovir flux 42 times with maximum at pH 5.8 suggesting ion pair formation. DDAK increased thermodynamic activity and stratum corneum/vehicle distribution coefficient of adefovir, as well as it directly decreased the skin barrier resistance. Maximal flux was observed already at 2% adefovir + 1% DDAK. The results were confirmed in freshly excised human skin where DDAK enhanced adefovir flux 179 times to 8.9 μg/cm²/h. This rate of percutaneous absorption would allow for reaching effective plasma concentrations. After the topical application, adefovir concentrated in the stratum corneum with low penetration into the deeper skin layers from either aqueous or isopropyl myristate vehicle without the enhancer. With 1% DDAK, adefovir concentrations in the viable epidermis and dermis were 33–61 times higher. These results offer an attractive alternative to established routes of administration of adefovir and other acyclic nucleoside phosphonates.     

Transdermal and dermal delivery of adefovir: Effects of pH and permeation enhancers

The objective of this work was to investigate feasibility of transdermal and dermal delivery of adefovir (9-(2-phosphonomethoxyethyl)adenine), a broad-spectrum antiviral from the class of acyclic nucleoside phosphonates. Transport of 2% adefovir through and into porcine skin and effects of various solvents, pH, and permeation enhancers were studied in vitro using Franz diffusion cell. From aqueous donor samples, adefovir flux through the skin was 0.2-5.4 microg/cm2/h with greatest permeation rate at pH 7.8. The corresponding adefovir skin concentrations reached values of 120-350 microg/g of tissue. Increased solvent lipophilicity resulted in higher skin concentration but had only minor effect on adefovir flux. A significant influence of counter ions on both transdermal and dermal transport of adefovir zwitterion was observed at pH 3.4. Permeation enhancer dodecanol was ineffective, 1-dodecylazepan-2-one (Azone) and dodecyl 2-(dimethylamino)propionate (DDAIP) showed moderate activity. The highest adefovir flux (11.3+/-3.6 microg/cm2/h) and skin concentration (1549+/-416 microg/g) were achieved with 1% Transkarbam 12 (5-(dodecyloxycarbonyl)pentylammonium 5-(dodecyloxycarbonyl)pentylcarbamate) at pH 4. This study suggests that, despite its hydrophilic and ionizable nature, adefovir can be successfully delivered through the skin.     

Microemulsion and poloxamer microemulsion-based gel for sustained transdermal delivery of diclofenac epolamine using in-skin drug depot: In vitro/in vivo evaluation

Microemulsion (ME) and poloxamer microemulsion-based gel (PMBG) were developed and optimized to enhance transport of diclofenac epolamine (DE) into the skin forming in-skin drug depot for sustained transdermal delivery of drug. D-optimal mixture experimental design was applied to optimize ME that contains maximum amount of oil, minimum globule size and optimum drug solubility. Three formulation variables; the oil phase X₁ (Capryol^®), Smix X₂ (a mixture of Labrasol^®/Transcutol^®, 1:2 w/w) and water X₃ were included in the design. The systems were assessed for drug solubility, globule size and light absorbance. Following optimization, the values of formulation components (X₁, X₂, and X₃) were 30%, 50% and 20%, respectively. The optimized ME and PMBG were assessed for pH, drug content, skin irritation, stability studies and ex vivo transport in rat skin. Contrary to PMBG and Flector^® gel, the optimized ME showed the highest cumulative amount of DE permeated after 8 h and the in vivo anti-inflammatory efficacy in rat paw edema was sustained to 12 h after removal of ME applied to the skin confirming the formation of in-skin drug depot. Our results proposed that topical ME formulation, containing higher fraction of oil solubilized drug, could be promising for sustained transdermal delivery of drug.     

Enhanced transdermal delivery of luteolin via non-ionic surfactant-based vesicle: quality evaluation and anti-arthritic assessment

Luteolin (LUT) is a promising molecule with potential anti-arthritic activity. This investigation presents formulation and evaluation of niosomal transgel for enhanced transdermal delivery of LUT. Different non-ionic surfactants and vesicle compositions were employed for preparation of niosomes. The vesicle size analysis showed that all vesicles were in the range from 534.58 to 810.22?nm which favoured efficient transdermal delivery. The entrapment of LUT in vesicle was found to be higher in all surfactant. The developed formulation was proved significantly superior in terms of amount of drug permeation with an enhancement ratio of 2.66 when compared to a control formulation. The in vivo bioactivity studies revealed that the prepared niotransgel formulation of LUT was able to provide good anti-arthritic activity and the results were comparable to standard (diclofenac gel for anti-arthritic and analgesic). Finally, the results were confirmed through radiological analysis which proved that the prepared niotransgel was effectively able to treat arthritis and results were comparable with the standard formulation.     

Nanoparticle mediated brain targeted delivery of gallic acid: in vivo behavioral and biochemical studies for protection against scopolamine-induced amnesia

Abstract

Context: Gallic acid (GA) has well-documented antioxidant and CNS effects affecting glutathione, catalase and malonaldehyde levels in brain.

Objective: This study was designed to evaluate the anti-amnesic activity of pure GA in scopolamine (SC)-induced amnesic models and to enhance its effects using Tween 80®-coated nanoparticles.

Methods: GA-loaded chitosan nanoparticles (GANP) and corresponding Tween 80®-coated batch (cGANP) were formulated. Amnesia was induced by using SC (0.4?mg/kg, i.v.). GA, GANP, cGANP (dose equivalent to GA 10?mg/kg, i.p.) and positive control Piracetam (400?mg/kg, i.p.) were administered for successive 7 days to male Swiss albino mice. The in vivo pharmacodynamic study was performed using Morris water maze (MWM) and elevated plus maze (EPM) models; locomotor activity using photoactometer and brain acetyl cholinesterase (AChE) activity was also studied.

Key findings: GA-treated mice exhibited significant decrease in transfer latency in the EPM test; increase in time spent in target quadrant in MWM and reduced AChE activity. GA significantly reversed SC-induced amnesic activity. There was no significant change in locomotor activity of the mice by GA and its nanoparticle formulations. These effects were significantly increased by the administration of cGANP compared with pure GA administration but no significant change was observed for GANP.

Conclusion: GA possesses anti-amnesic activity by reversing the SC-induced amnesia which may be attributed to its anti-cholinesterase activity. Tween 80®-coated nanoparticle approach with improved brain targeting may serve as an effective approach to enhance its anti-amnesic effect.     

Preparation and phase behaviour of surface-active pharmaceuticals: self-assembly of DNA and surfactants with membranes. Differential adiabatic scanning microcalorimetric study

Some energetics issues relevant to preparation and surface characterization of zwitterionic phospholipid-DNA self-assemblies, as alternative models of the currently used problematic lipoplexes are presented. Nucleic acid compaction capacities of Mg(2+) and N-alkyl-N,N,N-trimetylammonium ions (C(n)TMA, n=12) were compared, with regard to surface interaction with unilamellar vesicles. Differential adiabatic scanning microcalorimetric measurements of synthetic phosphatidylcholine liposomes and calf thymus DNA and their ternary complexes with Mg(2+) and C(12)TMA, were employed for deduction of the thermodynamic model describing their structural transitions. Small monodisperce and highly stable complexes are established after precompaction of DNA with detergent, followed by addition of liposomes. In contrast, divalent metal cation-mediated aggregation of vesicles either leads to heterogeneous multilamellar DNA-lipid arrangements, or to DNA-induced bilayer destabilization and lipid fusion. Possible dependence of the cellular internalization and gene transfection efficiency on the structure and physicochemical properties of DNA-Mg(2+)-liposomes or DNA-cationic surfactant-liposome systems is emphasized by proposing the structure of their molecular self-organizations with further implications in gene transfer research.     

体外条件对不同类型灯盏花素缓控释制剂释放行为的影响

灯盏花素是从灯盏花中提取的黄酮类活性成分,包括灯盏乙素和灯盏甲素.灯盏乙素是其主要活性成分,在临床上被广泛用于治疗脑血管栓塞等症及心血管疾病等[1].随着中药现代化的兴起,将服用次数多、生物利用度低的灯盏花素普通制剂开发成新制剂已成为热点.以渗透泵和凝胶骨架技术为代表的缓控释制剂以其安全、顺应性好等优点发展快速.     

d-Amphetamine in squirrel monkeys of different social status: Effects on social and agonistic behavior,locomotion, and stereotypies

The influences of social status on amphetamine-induced behavioral effects in squirrel monkeys were investigated. Social status was determined by constructing a sociogram. d-Amphetamine (0.3–1.0 mg/kg orally, 0.3 and 0.6 mg/kg IM) increased stereotyped head movements and reduced the time spent in the sitting posture in all monkeys (N=25) regardless of sex, age, or social status. The high levels of locomotor activity in dominant and juvenile monkeys were decreased at higher amphetamine doses (0.6 mg/kg IM, 0.6 and 1.0 mg/kg orally), whereas the same doses increased locomotion in otherwise less active subdominant and submissive animals. Low doses of amphetamine (0.1, 0.3 mg/kg) decreased the incidence of agonistic behavior initiated by dominant monkeys, and higher doses (0.6, 1.0 mg/kg) caused these monkeys to change from predominant initiators of agonistic behavior into recipients. At 2 h after amphetamine administration (0.3 mg/kg IM), the high levels of locomotor behavior had returned to baseline, the social isolation began to disappear, and the disrupted agonistic behavior of dominant monkeys returned to control levels, yet the stereotyped head movements continued to occur with high frequency. In half of the monkeys, amphetamine produced a large increase in distress-like vocalizations. Amphetamine-mediated motor stereotypies may be mediated by mechanisms different than those responsible for agonistic behavior. The selective changes in agonistic behavior by dominant monkeys when challenged with amphetamine may reflect a status-related functional alteration of catecholaminergic processes upon which the drug acts.