Proultraflexible lipid vesicles for effective transdermal delivery of levonorgestrel: Development,characterization, and performance evaluation

The present investigation aimed at formulation, performance evaluation, and stability studies of new vesicular drug carrier system protransfersomes for transdermal delivery of the contraceptive agent, levonorgestrel. Protransfersome gel (PTG) formulations of levonorgestrel were prepared and characterized for vesicle shape, size, entrapment efficiency, turbidity, and drug permeation across rat skin and were evaluated for their stability. The system was evaluated in vivo for biological assay of progestational activity including endometrial assay, inhibition of the formation of corpora lutea, and weight gain of uterus. The effects of different formulation variables (type of alcohol, type and concentration of surfactant) on transdermal permeability profile were assessed. The optimized PTG formulation showed enhanced in vitro skin permeation flux of 15.82±0.37 μg/cm²/hr as compared to 0.032±0.01 μg/cm²/hr for plain drug solution. PTG also showed good stability and after 2 months of storage there was no change in liquid crystalline nature, drug content, and other characteristic parameters. The peak plasma concentration of levonorgestrel (0.139±0.05 μg/mL) was achieved within 4 hours and maintained until 48 hours by a single topical application of optimized PTG formulation. In vivo performance of the PTG formulation showed increase in the therapeutic efficacy of drug. Results indicated that the optimized protransfersomal formulation of levonorgestrel had better skin permeation potential, sustained release characteristic, and better stability than proliposomal formulation.     

Formulation development and in vitro and in vivo evaluation of membrane-moderated transdermal systems of ampicillin sodium in ethanol: pH 4.7 buffer solvent system

The objective of the present study was to develop membrane-moderated transdermal systems of ampicillin sodium and to evaluate them with respect to various in vitro and in vivo parameters. The membrane-type transdermal systems were prepared using a drug with various antinucleant polymers— hydroxypropyl methylcellulose (HPMC), methylcellulose (MC), cellulose acetate phthalate, chitosan, sodium alginate (SA), and sodium carboxymethylcellulose—in an ethanol: pH 4.7 buffer volatile system by the solvent evaporation technique with HPMC as the rate-controlling membrane for all the systems. The swelling properties of the polymers were studied, and drug-polymer interaction studies were performed. The patches were subjected to various physicochemical studies, in vitro release studies, permeation studies, and skin irritation studies. The best patch among the formulations was selected for further in vivo studies. Compared to the other patches, SA exhibited the highest moisture content at 16%; a 21% moisture uptake was found with MC. The release and permeation of the drug from the SA patch was found to be the maximum. The in vivo study of the SA patch exhibited a peak plasma concentration C_max of 126 μg/mL at T_max 4 hours. Hence, it can be concluded that hydrophilic ampicillin sodium can be developed as a transdermal delivery system with SA that is an alternative to intravenous administration and has minimal adverse effects. Published: January 26, 2007     

Microemulsions Containing Medium-Chain Glycerides as Transdermal Delivery Systems for Hydrophilic and Hydrophobic Drugs

We evaluated the ability of microemulsions containing medium-chain glycerides as penetration enhancers to increase the transdermal delivery of lipophilic (progesterone) and hydrophilic (adenosine) model drugs as well as the effects of an increase in surfactant blend concentration on drug transdermal delivery. Microemulsions composed of polysorbate 80, medium-chain glycerides, and propylene glycol (1:1:1, w/w/w) as surfactant blend, myvacet oil as the oily phase, and water were developed. Two microemulsions containing different concentrations of surfactant blend but similar water/oil ratios were chosen; ME-lo contained a smaller concentration of surfactant than ME-hi (47:20:33 and 63:14:23 surfactant/oil/water, w/w/w). Although in vitro progesterone and adenosine release from ME-lo and ME-hi was similar, their transdermal delivery was differently affected. ME-lo significantly increased the flux of progesterone and adenosine delivered across porcine ear skin (4-fold or higher, p < 0.05) compared to progesterone solution in oil (0.05 ± 0.01 μg/cm²/h) or adenosine in water (no drug was detected in the receptor phase). The transdermal flux of adenosine, but not of progesterone, was further increased (2-fold) by ME-hi, suggesting that increases in surfactant concentration represent an interesting strategy to enhance transdermal delivery of hydrophilic, but not of lipophilic, compounds. The relative safety of the microemulsions was assessed in cultured fibroblasts. The cytotoxicity of ME-lo and ME-hi was significantly smaller than sodium lauryl sulfate (considered moderate-to-severe irritant) at same concentrations (up to 50 μg/mL), but similar to propylene glycol (regarded as safe), suggesting the safety of these formulations.     

Drug-Cyclodextrin-Vesicles Dual Carrier Approach for Skin Targeting of Anti-acne Agent

In the present study attempt was made for preparation of isotretinoin-hydroxypropyl β cyclodextrin (HP-β-CD) inclusion complex and encapsulate this complex in elastic liposomes to study the effect of dual carrier approach on skin targeting of isotretinoin. The isotretinoin HP-β-CD complex was prepared by freeze-drying method and characterized by IR spectroscopy. The drug and drug-CD complex loaded elastic liposomal formulation were prepared and characterized in vitro, ex-vivo and in vivo for shape, size, entrapment efficiency, no. of vesicles per cubic mm, in vitro skin permeation and deposition study, photodegradation and skin toxicity assay. The transdermal flux for different vesicular formulations was observed between 10.5 ± 0.5 to 13.9 ± 1.6 μg/cm²/h. This is about 15-21 folds higher than that obtained from drug solution (0.7 ± 0.1 μg/cm²/h) and 4-5 folds higher than obtained with drug-CD complex solution (2.7 ± 0.1 μg/cm²/h). The amount of drug deposit was found to increase significantly (p < 0.05) by cyclodextrin complexation (30.1 ± 0.1 μg). The encapsulation of this complex in elastic liposomal formulation further increases its skin deposition (262.2 ± 21 μg). The results of skin irritation study using Draize test also showed the significant reduction in skin irritation potential of isotretinoin elastic liposomal formulation in comparison to free drug. The results of the present study demonstrated that isotretinoin elastic liposomal formulation possesses great potential for skin targeting, prolonging drug release, reduction of photodegradation, reducing skin irritation and improving topical delivery of isotretinoin.     

In Vitro Percutaneous Permeation and Skin Accumulation of Finasteride Using Vesicular Ethosomal Carriers

In order to develop a novel transdermal drug delivery system that facilitates the skin permeation of finasteride encapsulated in novel lipid-based vesicular carriers (ethosomes)finasteride ethosomes were constructed and the morphological characteristics were studied by transmission electron microscopy. The particle size, zeta potential and the entrapment capacity of ethosome were also determined. In contrast to liposomes ethosomes were of more condensed vesicular structure and they were found to be oppositely charged. Ethosomes were found to be more efficient delivery carriers with high encapsulation capacities. In vitro percutaneous permeation experiments demonstrated that the permeation of finasteride through human cadaver skin was significantly increased when ethosomes were used. The finasteride transdermal fluxes from ethosomes containing formulation (1.34 ± 0.11 μg/cm²/h) were 7.4, 3.2 and 2.6 times higher than that of finasteride from aqueous solution, conventional liposomes and hydroethanolic solution respectively (P < 0.01).Furthermore, ethosomes produced a significant (P < 0.01) finasteride accumulation in the skin, especially in deeper layers, for instance in dermis it reached to 18.2 ± 1.8 μg/cm². In contrast, the accumulation of finasteride in the dermis was only 2.8 ± 1.3 μg/cm² with liposome formulation. The study demonstrated that ethosomes are promising vesicular carriers for enhancing percutaneous absorption of finasteride.     

Design and development of multivesicular liposomal depot delivery system for controlled systemic delivery of acyclovir sodium

The aim of the present study was to design a depot delivery system of acyclovir sodium using multivesicular liposomes (MVLs) to overcome the limitations of conventional therapies and to investigate its in vivo effectiveness for sustained delivery. MVLs of acyclovir were prepared by the reverse phase evaporation method. The loading efficiency of the MVLs (45%–82%) was found to be 3 to 6 times higher than conventional multilamellar vesicles (MLVs). The in vitro release of acyclovir from MVL formulations was found to be in a sustained manner and only 70% of drug was released in 96 hours, whereas conventional MLVs released 80% of drug in 16 hours. Following intradermal administration to Wistar rats, the MVL formulations showed effective plasma concentration for 48 hours compared with MLVs and free drug solution (12–16 hours). C_max values of MVL formulations were significantly less (8.6–11.4 μg/mL) than MLV and free drug solution (12.5 μg/mL). The AUC_0–48 of the MVL formulations was 1.5- and 3-fold higher compared with conventional liposomes and free drug solution, respectively. Overall, formulations containing phosphatidyl glycerol as negatively charged lipid showed better results. The MVL delivery system as an intradermal depot offers the advantage of a very high loading and controlled release of acyclovir for an extended period of time. The increase in AUC and decrease in C_max reflects that the MVL formulations could reduce the toxic complications and limitations of conventional IV and oral therapies. Published: September 20, 2005     

Definitions and Epidemiology of Candida Species not Susceptible to Echinocandins

Antifungal susceptibility testing of Candida against the echinocandin antifungal agents (anidulafungin [ANF], caspofungin [CSF], micafungin [MCF]) has been standardized by the Clinical and Laboratory Standards Institute (CLSI) Subcommittee on Antifungal Testing. The CLSI proposed a single set of clinical breakpoints (CBPs) for all three echinocandins and all species of Candida: susceptible, minimum inhibitory concentration (MIC) ≤ 2 μg/mL; nonsusceptible, MIC > 2 μg/mL. Subsequently, these CBPs have been shown to lack sensitivity in detecting strains of Candida with acquired resistance mechanisms associated with treatment failure. Studies using the CLSI method have defined wild-type (WT) MIC distributions and epidemiologic cutoff values (ECVs) for each echinocandin and the common species of Candida. The ECVs serve as a sensitive means of discriminating WT strains from those with acquired resistance mechanisms. WT MIC distributions revealed ECV ranges of 0.03 to 0.25 μg/mL for all major species except C. parapsilosis (1–4 μg/mL) and C. guilliermondii (4–16 μg/mL). These ECVs reliably differentiate WT strains of each species from non-WT strains containing fks mutations. These data, coupled with additional biochemical, clinical, pharmacokinetic, and pharmacodynamic considerations, have resulted in new CBPs of ≤0.25 μg/mL (susceptible), 0.5 μg/mL (intermediate), and ≥1 μg/mL (resistant) for ANF, CSF, and MCF for C. albicans, C. tropicalis, and C. krusei. For these agents and C. parapsilosis, the new CBPs are ≤2 μg/mL (susceptible), 4 μg/mL (intermediate), and ≥8 μg/mL (resistant). For C. glabrata, the CBPs for ANF and CSF are ≤0.12 μg/mL (susceptible), 0.25 μg/mL (intermediate), and ≥0.5 μg/mL (resistant), whereas those for MCF are ≤0.06 μg/mL, 0.12 μg/mL, and ≥0.25 μg/mL, respectively. Application of both ECVs and the lower species-specific CBPs for the echinocandins has proven useful in both resistance surveillance and clinical care and will serve as an important step in international harmonization of in vitro susceptibility testing of this important antifungal class.     

Transdermal Delivery of an Anti-Cancer Drug via W/O Emulsions Based on Alkyl Polyglycosides and Lecithin: Design,Characterization, and <Emphasis Type="Italic">In Vivo</Emphasis> Evaluation of the Possible Irritation Potential in Rats

The purpose of this work was to develop w/o emulsions that could be safely used to promote transdermal delivery of 5-fluorouracil (5-FU). Two pseudo-ternary phase diagrams comprising oleoyl-macrogol glycerides, water, and a surfactant/co-surfactant (S/CoS) mixture of lecithin, ethanol, and either coco glucoside or decyl glucoside were investigated for their potential to develop promising 5-FU emulsions. Six systems were selected and subjected to thermodynamic stability tests; heat–cool cycles, centrifugation, and finally freeze–thaw cycles. All systems passed the challenges and were characterized for transmission electron microscopy, droplet size, rheological behavior, pH, and transdermal permeation through newly born mice skin in Franz diffusion cells. The systems had spherical droplets ranging in diameter from 1.81 to 2.97 μm, pH values ranging from 7.50 to 8.49 and possessed Newtonian flow. A significant (P < 0.05) increase in 5-FU permeability parameters as steady-state flux, permeability coefficient was achieved with formula B5 comprising water (5% w/w), S/CoS mixture of lecithin/ethanol/decyl glucoside (14.67:12.15:18.18% w/w, respectively) and oleoyl-macrogol glycerides (50% w/w). When applied to shaved rat skin, this system was well tolerated with only moderate skin irritation that was recovered within 12 h. Indeed, minor histopathologic changes were observed after 5-day treatment. Further studies should be carried out, in the future, to investigate the potentiality of this promising system to promote transdermal delivery of 5-FU through human skin.     

Transdermal delivery of zidovudine (AZT): The effects of vehicles,enhancers, and polymer membranes on permeation across cadaver pig skin

The purpose of this study was to investigate the effects of vehicles, enhancers, and polymer membranes on 3-azido-3-deoxythymidine (AZT) permeation across cadaver pig skin. Four binary vehicles (ethanol/water, isopropyl alcohol/water, polyethylene glycol 400/water, and ethanol/isopropyl myristate [IPM] were tested for AZT solubility and permeability across pig skin; ethanol/IPM (50/50, vol/vol) demonstrated the highest AZT flux (185.23 μ/cm²/h). Next, the addition of various concentrations of different enhancers (N-methyl-2-pyrrolidone [NMP], oleic acid, and lauric acid) to different volume ratios of ethanol/IPM was investigated for their effect on AZT solubility and permeability across pig skin. The use of 2 conbinations (ethanol/IPM [20/80] plus 10% NMP and ethanol/IPM [30/70] plus 10% NMP) resulted in increased AZT solubility (42.6 and 56.27 mg/mL, respectively) and also high AZT flux values (284.92 and 460.34 μg/cm²/h, respectively) without appreciable changes in lag times (6.25 and 7.49 hours, respectively) when compared with formulations using only ethanol/IPM at 20/80 and 30/70 volume ratios without addition of the enhancer NMP. Finally, AZT permeation across pig skin covered with a microporous polyethylene (PE) membrane was investigated. The addition of the PE membrane to the pig skin reduced AZT flux values to ∼50% of that seen with pig skin alone. However, the AZT flux value attained with ethanol/IPM (30/70) plus 10% NMP was 215.30 μg/cm²/h, which was greater than the target flux (208 μg/cm²/h) needed to maintain the steady-state plasma concentration in humans. The results obtained from this study will be helpful in the development of an AZT transdermal drug delivery system.     

Feasibility of transdermal delivery of fluoxetine

Feasibility of developing a transdermal drug delivery of fluoxetine has been investigated. Permeation studies of fluoxetine across human cadaver skin were carried out using Franz diffusion cells. The receptor phase consisted of pH 7.4 phosphate buffer maintained at 37°C. Permeation enhancement of fluoxetine, either in the salt or base form, was achieved using various enhancers like azone, SR-38, and ethanol. Various O/W microemulsion systems of fluoxetine were developed to study their effect on the skin permeation of fluoxetine. The results indicated that ethanol at 65% vol/vol was able to increase the permeation of fluoxetine the most, while microemulsion systems showed decrease in the permeation of fluoxetine. The permeation of fluoxetine obtained using a 65% vol/vol ethanolic solution was found to be sufficient to deliver the required dose (20–80 mg) from a patch of feasible size. The results seem promising for developing a transdermal drug delivery system of fluoxetine. Published: September 30, 2005     

Screening of Venlafaxine Hydrochloride for Transdermal Delivery: Passive Diffusion and Iontophoresis

The objective of the study was to investigate in vitro transdermal delivery of venlafaxine hydrochloride across the pigskin by passive diffusion and iontophoresis. For passive diffusion, experiments were carried out in Franz diffusion cell whereas for iontophoretic permeation, the diffusion cell was modified to contain both the donor and return electrode on the same side of skin. Anodal iontophoresis was carried out using a current density of 0.5 mA/cm². Donor concentrations used were 585.5 mg/ml (saturated solution) and 100 mg/ml. Experiments initially performed to determine the transport efficiency of venlafaxine ions showed promising results. Iontophoresis increased the permeation rate at both concentration levels over their passive counterparts (P < 0.01), but surprisingly higher steady-state flux was obtained from lower donor drug load (P < 0.01). The favorable pH of the unsaturated solutions is suggested to be the cause for this effect. Mild synergistic effect was observed when iontophoresis was carried out incorporating peppermint oil in the donor but the same was not found in passive diffusion. Highest steady-state flux obtained in the experiment was 3.279 μmol/cm²/h when peppermint oil (0.1%) was included in the donor. As the maintenance requirement of venlafaxine hydrochloride is approximately 9.956 μmol/h, the results suggested that the drug is a promising candidate for iontophoretic delivery.     

Pulmonary absorption of liposomal levonorgestrel

The purpose of these studies was to achieve desired bioavailability after pulmonary administration of Levonorgestrel (LN) and to provide prolonged effective concentration of the drug in plasma and to reduce reported side effects of orally administered drug. The plain drug suspension, physical mixture (plain drug with liposomal constituents), and drug-encapsulated liposomes containing 10 μg of drug were instilled intratracheally in rats. Similarly, 10-μg drug suspension (LO) was administered orally. The blood samples were withdrawn at specific time intervals and were subjected to LN analysis by spectrofluorimetric technique. The plasma drug concentration data of both the treatments were plotted, and pharmacokinetics data were calculated and compared with that of oral administration. Percentage relative bioavailability (F^*) of 97.6% 98.6%, and 109.9% were observed after pulmonary administration of plain drug formulation (LP1), physical mixture (plain drug along with constituents of liposomes [LP2], and liposomal (LP3) formulations of the drug, respectively. Following oral administration, C_max of 14.4±0.6 ng/mL was observed at 2.1±0.2 hours followed by subtherapeutic concentration beyond 30±0.2 hours, while after pulmonary administration of LP1, LP2, and LP3 formulations, C_max of 4.4±0.4 ng/mL, 4.2±0.5 ng/mL, and 4.4±0.6 ng/ML were observed at 6.0±0.2 hours, 7.0±0.2 hours, and 6.8±0.2 hours, respectively, followed by maintenance of effective plasma drug concentration up to 60±2 hours. These studies demonstrate superiority of pulmonary drug delivery with regards to maintenance of effective therapeutic concentration of the LN in the plasma over a period of 6 to 60 hours. Hence, the pulmonary delivery is expected to reduce frequency of dosing and systemic side effects associated with oral administration of LN.     

Effect of daptomycin on primary rat muscle cell cultures in vitro

Daptomycin is a lipopeptide antibiotic that has strong bactericidal activity against Gram-positive bacteria and that was previously reported to exhibit minor side effects on skeletal muscle. This study was designed to further characterize the effect of daptomycin on skeletal muscle through the use of primary cultures of muscles from rats. Our investigations demonstrated that daptomycin has a concentration-dependent and time-dependent effect on the plasma membrane of primary cultures of differentiated, spontaneously contracting rat myotubes. No effects were evident in non-differentiated myoblasts or other mononucleated cells present in cultures even at the highest daptomycin concentrations tested (6,000 μg/mL). In cultures treated with daptomycin at a concentration of 2,000 μg/mL, plasma membrane damage was observed in ∼20–30% of differentiated myotubes; no myotube damage was detected at concentrations of 1,000 μg/mL and below. A transient loss of spontaneous myotube contractions was evident at 750 μg/mL, while at 2,000 μg/mL and above, a permanent loss of spontaneous contractility was observed. These results suggest that the putative targets for daptomycin effects on skeletal muscle are structures on the plasma membrane of highly differentiated myotubes.     

A new atomic absorption spectral assay for the determination of trace IgG using immunonanogold

Nanogold in size of 10 nm was used to label goat anti-human IgG (GIgG) to obtain an immunonanogold probe (AuGIgG) for IgG. In pH 6.8 phosphate buffer solution and in the presence of immunoprecipitator polyethylene glycol 6000 (PEG 6000), IgG reacted with the probe (AuGIgG) to form AuGIgG–IgG–PEG immunocomplex. After the centrifugation to remove the immunocomplex, AuGIgG in the supernatant can be measured by atomic absorption spectrophotometry at gold absorption line 242.8 nm. The results showed that the absorption value decreased as the concentration of IgG increased, and the decreased absorption value was linear to IgG concentration in the range 0.025–0.375 μg/mL, with a detection limit of 0.008 μg/mL. On this base, a new nanogold-labeled atomic absorption spectral assay for IgG was established. The assay was applied to determine IgG in human serum sample with satisfactory results.     

Study of the Action of Se and Cu on the Growth Metabolism of <Emphasis Type="Italic">Escherichia coli</Emphasis> by Microcalorimetry

The biological effect of Se and Cu²⁺ on Escherichia coli (E. coli) growth was studied by using a 3114/3236 TAM Air Isothermal Calorimeter, ampoule method, at 37°C. From the thermogenesis curves, the thermokinetic equations were established under different conditions. The kinetics showed that a low concentration of Se (1–10 μg/mL) promoted the growth of E. coli, and a high concentration of Se (>10 μg/mL) inhibited the growth, but the Cu²⁺ was always inhibiting the growth of E. coli. Moreover, there was an antagonistic or positive synergistic effect of Se and Cu²⁺ on E. coli in the different culture medium when Se was 1–10 μg/ml and Cu²⁺ was 1–20 μg/ml. There was a negative synergistic effect of Se and Cu²⁺ on E. coli when Se was higher than 10 μg/ml and Cu²⁺ was higher than 20 μg/ml. The antagonistic or synergistic effect between Se and Cu²⁺ on E. coli was related to the formation of Cu–Se complexes under the different experimental conditions chosen.     

Cavamax W7 composite ethosomal gel of clotrimazole for improved topical delivery: development and comparison with ethosomal gel

The present research work was aimed to formulate clotrimazole encapsulated Cavamax W7 composite ethosomes by injection method for improved delivery across epidermis. 3² factorial design was used to design nine formulations (F1-F9) and compared with ethosomal formulations (F10-F12). F9 with vesicle size of 202.8 ± 4.8 nm, highest zeta potential (−83.6 ± 0.96 mV) and %EE of 98.42 ± 0.15 was selected as optimized composite ethosome and F12 as reference ethosomal formulation. As revealed by transmission electron microscopy F9 vesicles were more condensed, uniformly spherical in shape than F12 vesicles. Vesicular stability studies indicated F9 to be more stable as compared to F12. Both F9 and F12 were incorporated in carbopol 934 gel base to get G1–G8 gel formulations and evaluated for in vitro skin permeability. Cavamax W7 composite ethosomal optimized gel (G5) showed higher in vitro percent cumulative drug permeation (88.53 ± 2.10%) in 8 h and steady state flux (J _ss) of 3.39 ± 1.45 μg/cm²/min against the J _ss of 1.57 ± 0.23 μg/cm²/min for ethosomal gel (G1) and 1.13 ± 0.06 μg/cm²/min for marketed formulation. The J _ss flux of G5 was independent of amount of drug applied/unit area of skin. In vivo confocal laser scanning microscopic study of G5 depicted uniform and deeper penetration of rhodamine B (marker) in epidermis from Cavamax W7 composite ethosomal gel in comparison to G1. Finally, G5 demonstrated better (p < 0.05) antifungal activity against Candida albicans and Aspergillus niger than G1 thus, signifying that Cavamax W7 composite ethosomes present a superior stable and efficacious vesicular system than ethosomal formulation for topical delivery of clotrimazole.     

Enhanced Bioavailability of Buspirone From Reservoir-Based Transdermal Therapeutic System,Optimization of Formulation Employing Box–Behnken Statistical Design

The purpose of the present study was to develop and optimize reservoir-based transdermal therapeutic system (TTS) for buspirone (BUSP), a low bioavailable drug. A three-factor, three-level Box–Behnken design was employed to optimize the TTS. Hydroxypropyl methylcellulose, d-limonene and propylene glycol were varied as independent variables; cumulative amount permeated across rat abdominal skin in 24 h, flux and lag time were selected as dependent variables. Mathematical equations and response surface plots were used to relate the dependent and independent variables. The statistical validity of polynomials was established, and optimized formulation factors were selected by feasibility and grid search. Validation of the optimization study with seven confirmatory runs indicated high degree of prognostic ability of response surface methodology. BUSP-OPT (optimized formulation) showed a flux 104.6 μg cm⁻² h⁻¹, which could meet target flux. The bioavailability studies in rabbits showed that about 2.65 times improvement (p < 0.05) in bioavailability, after transdermal administration of BUSP-OPT compared to oral solution. The ex vivo–in vivo correlation was found to have biphasic pattern and followed type A correlation. Reservoir-based TTS for BUSP was developed and optimized using Box–Behnken statistical design and could provide an effective treatment in the management of anxiety.     

Microcapsules and Transdermal Patch: A Comparative Approach for Improved Delivery of Antidiabetic Drug

Glibenclamide (GL)-loaded microcapsules (MC) and transdermal patches (TDP) were formulated and in vitro and in vivo parameters compared to find out the best route of drug administration. The formulation TDP1 having a drug–polymer ratio 1:1 showed comparatively higher GL release and better permeation across mice skin (p < 0.05). From the comparative study, it was concluded that the transdermal system of GL produced better improvement compared to oral microcapsule administration (p < 0.05). The transdermal system exhibited comparatively slow and continuous supply of GL at a desired rate to systemic circulation avoiding metabolism, which improved day-to-day glycemic control in diabetic subjects. Transdermal system of GL exhibited better control of hyperglycemia and prolonged plasma half-life by transdermal systems (9.6 ± 1.2 h) in comparison with oral microcapsule (5.84 ± 2.1 h), indicating that the drug, when administered by transdermal systems, will remain in the body for a longer period. From the glucose tolerance test, transdermal route effectively maintained the normoglycemic levels in contrast to the oral group (MC1), which produced remarkable hypoglycemia ranging from −12.6 ± 2.1% to −18 ± 2.3%. The significantly high (p < 0.05) area under the curve values observed with transdermal system (1,346.2 ± 92.3 ng ml⁻¹ h⁻¹) also indicate increased bioavailability of the drug from these systems compared to the oral route (829.8 ± 76.4 ng ml⁻¹ h⁻¹).     

The Biodegradation of Zein <Emphasis Type="Italic">In Vitro</Emphasis> and <Emphasis Type="Italic">In Vivo</Emphasis> and its Application in Implants

A unique polymer-based sustained-release implant drug delivery system was prepared by using biocompatible and biodegradable Zein as the skeleton meterial. After preparing Zein colloids, the Zein-loaded implant rods were formulated by injection molding followed by evaporating the solvent, and being coated with poly(lactic-co-glycolic) acid (PLGA) solution. Drug release kinetics was examined by using Fluorouracil (5-FU) as model drug. Nearly zero-order release was achieved for the model drugs for a period of 0–25 days when the implants were incubated in distilled water at 37°C. And then the degradation kinetics of the rods in vivo and in vitro were evaluated, which indicated that Zein could be absorbed by body and has good degradation property. The effects of different ratios of Zein/5-FU and the rods’ diameter on drug release were studied, respectively. The plasma concentration of 5-FU in the implants were determined by HPLC after implanting a single dose of the implants in rats. All data were subsequently processed by using the computer program 3P97, and the values were showed as follows: the area under the plasma concentration–time curve (AUC) value was 321.88 (μg/ml) × day, and the mean residence time (MRT) value was 23.05 days. The sustained-release implants of Zein/5-FU were successfully formulated. The uniqueness of the article is that Zein has been used as a skeleton material in implant delivery system for the first time and zero-order release kinetics has been obtained successfully.     

A comparative analysis of deferoxamine treatment modalities for dermal radiation-induced fibrosis

The iron chelator, deferoxamine (DFO), has been shown to potentially improve dermal radiation-induced fibrosis (RIF) in mice through increased angiogenesis and reduced oxidative damage. This preclinical study evaluated the efficacy of two DFO administration modalities, transdermal delivery and direct injection, as well as temporal treatment strategies in relation to radiation therapy to address collateral soft tissue fibrosis. The dorsum of CD-1 nude mice received 30 Gy radiation, and DFO (3 mg) was administered daily via patch or injection. Treatment regimens were prophylactic, during acute recovery, post-recovery, or continuously throughout the experiment (n = 5 per condition). Measures included ROS-detection, histology, biomechanics and vascularity changes. Compared with irradiated control skin, DFO treatment decreased oxidative damage, dermal thickness and collagen content, and increased skin elasticity and vascularity. Metrics of improvement in irradiated skin were most pronounced with continuous transdermal delivery of DFO. In summary, DFO administration reduces dermal fibrosis induced by radiation. Although both treatment modalities were efficacious, the transdermal delivery showed greater effect than injection for each temporal treatment strategy. Interestingly, the continuous patch group was more similar to normal skin than to irradiated control skin by most measures, highlighting a promising approach to address detrimental collateral soft tissue injury following radiation therapy.