Abstract: Drug flux across microneedle (MN)-treated skin is influenced by the characteristics of the MN array, formed microconduits and physicochemical properties of the drug molecules in addition to the overall diffusional resistance of microconduits and viable tissue. Relative implication of these factors has not been fully explored. In the present study, the in vitro permeation of a series of six structurally related ionic xanthene dyes with different molecular weights (MW) and chemical substituents, across polymer MN-pretreated porcine skin was investigated in relation of their molecular characteristics. Dyes equilibrium solubility, partition coefficient in both n-octanol or porcine skin/aqueous system, and dissociation constants were determined. Results indicated that for rhodamine dyes, skin permeation of the zwitterionic form which predominates at physiological pH, was significantly reduced by an increase in MW, the skin thickness and by the presence of the chemically reactive isothiocyanate substituent. These factors were generally shown to override the aqueous solubility, an important determinant of drug diffusion in an aqueous milieu. The data obtained provided more insight into the mechanism of drug permeation across MN-treated skin, which is of importance to both the design of MN-based transdermal drug delivery systems and of relevance to skin permeation research.
Abstract: Propylene glycol (PG)-phospholipid vesicles have been advocated as flexible lipid vesicles for enhanced skin delivery of drugs. To further characterize the performance of these vesicles and to address some relevant pharmaceutical issues, miconazole nitrate(MN)-loaded PG nanoliposomes were prepared and characterized for vesicle size, entrapment efficiency, in vitro release, and vesicle stability. An issue of pharmaceutical importance is the time-dependent, dilution-driven diffusion of propylene glycol out of the vesicles. This was addressed by assessing propylene glycol using gas chromatography in the separated vesicles and monitoring its buildup in the medium after repeated dispersion of separated vesicles in fresh medium. Further, the antifungal activity of liposomal formulations under study was assessed using Candida albicans, and their in vitro skin permeation and retention were studied using human skin. At all instances, blank and drug-loaded conventional liposomes were included for comparison. The results provided evidence of controlled MN delivery, constant percent PG uptake in the vesicles (â45.5%) in the PG concentration range 2.5 to 10%, improved vesicle stability, and enhanced skin deposition of MN with minimum skin permeation. These are key issues for different formulation and performance aspects of propylene glycol-phospholipid vesicles.
Abstract: Despite innovation in the design and functionalization of polymer nanofiber wound healing materials, information on their interaction with the biochemical wound environment is lacking. In an earlier study, we have reported the interaction of fusidic acid-loaded PLGA ultrafine fibers (UFs) with wound bacteria. Massive bacterial colonization and the formation of a dense biofilm throughout the mat were demonstrated. This was associated with a marked enhancement of initial drug release at concentrations allowing eradication of planktonic bacteria and considerable suppression of biofilm. The present study aimed at extending earlier findings to gain more mechanistic insights into the potential response of the fusidic acid-laden UFs under study to controlled microbial bioburden. Initial drug release enhancement was shown to involve surface erosion of the ultrafibrous mats likely mediated by microbial esterase activity determined in the study. Release data could be correlated with microbial bioburden over the inoculum size range 10³-10ⷠCFU/ml, suggesting a bioburden-triggered drug release enhancement mechanism. Moreover, the effectiveness of fusidic acid-laden UFs in the healing of either lightly contaminated or Staphylococcus aureus heavily infected wounds in a rat model suggested in-use relevant antimicrobial release patterns. Findings indicated active participation of polymer ultrafine wound dressings in a dynamic interaction with the wound milieu, which affects their structure-function relationship. Understanding such an interaction is fundamental to the characterization and performance assessment of wound materials under biorelevant conditions and the design of polymer-based infection-responsive biomaterials.
Abstract: Investigations on chemical enhancement of skin penetration of gold nanoparticles are considered crucial to have a deeper insight into the main barrier of particle penetration.
Abstract: There is an urgent need to replace the injection currently used for low molecular weight heparin (LMWH) multidose therapy with a non- or minimally invasive delivery approach. In this study, laser-engineered dissolving microneedle (DMN) arrays fabricated from aqueous blends of 15% w/w poly(methylvinylether-co-maleic anhydride) were used for the first time in active transdermal delivery of the LMWH nadroparin calcium (NC). Importantly, an array loading of 630IU of NC was achieved without compromising the array mechanical strength or drug bioactivity. Application of NC-DMNs to dermatomed human skin (DHS) using the single-step 'poke and release' approach allowed permeation of approximately 10.6% of the total NC load over a 48-h study period. The cumulative amount of NC that permeated DHS at 24h and 48h attained 12.28±4.23IU/cm(2) and 164.84±8.47IU/cm(2), respectively. Skin permeation of NC could be modulated by controlling the DMN array variables, such as MN length and array density as well as application force to meet various clinical requirements including adjustment for body mass and renal function. NC-loaded DMN offers great potential as a relatively low-cost functional delivery system for enhanced transdermal delivery of LMWH and other macromolecules.
Abstract: The structure and functions of polymer nanofibers as wound dressing materials have been well investigated over the last few years. However, during the healing process, nanofibrous mats are inevitably involved in dynamic interactions with the wound environment, an aspect not explored yet. Potential active participation of ultrafine fibers as wound dressing material in a dynamic interaction with wound bacteria has been examined using three wound bacterial strains and antimicrobial fusidic acid (FA)-loaded electrospun PLGA ultrafine fibers (UFs). These were developed and characterized for morphology and in-use pharmaceutical attributes. In vitro microbiological studies showed fast bacterial colonization of UFs and formation of a dense biofilm. Interestingly, bacterial stacks on UFs resulted in a remarkable enhancement of drug release, which was associated with detrimental changes in morphology of UFs in addition to a decrease in pH of their aqueous incubation medium. In turn, UFs by allowing progressively faster release of bioactive FA eradicated planktonic bacteria and considerably suppressed biofilm. Findings point out the risk of wound reinfection and microbial resistance upon using non-medicated or inadequately medicated bioresorbable fibrous wound dressings. Equally important, data strongly draw attention to the importance of characterizing drug delivery systems and establishing material-function relationships for biomedical applications under biorelevant conditions.
Abstract: Interaction of nanoparticles with the skin barrier is a recent area of research that draws a lot of attention from the researchers. However, monitoring nanoparticles in or through the skin is mainly based on qualitative microscopical techniques. Yet, a quantitative approach is required for a better basic understanding. In response, a combined "multiphoton-pixel analysis" method was developed in this study for semiquantitation of gold nanoparticles penetration into different skin layers. The developed approach provides a useful tool for future studies focusing on skin penetration of nanoparticles for the aim of health risk assessment or for the design of topical and transdermal drug delivery systems.
Abstract: The ability of nanoparticles to penetrate the stratum corneum was the focus of several studies. Yet, there are controversial issues available for particle penetration due to different experimental setups. Meanwhile, there is little known about the mechanism and determinants of their penetration. In this paper the penetration of four model gold nanoparticles of diameter 6 and 15 nm, differing in surface polarity and the nature of the vehicle, through human skin was studied using multiphoton microscopy. This is in an attempt to profoundly investigate the parameters governing particle penetration through human skin. Our results imply that nanoparticles at this size range permeate the stratum corneum in a similar manner to drug molecules, mainly through the intercellular pathways. However, due to their particulate nature, permeation is also dependent on the complex microstructure of the stratum corneum with its tortuous aqueous and lipidic channels, as shown from our experiments performed using skin of different grades of barrier integrity. The vehicle (toluene-versus-water) had a minimal effect on skin penetration of gold nanoparticles. Other considerations in setting up a penetration experiment for nanoparticles were also studied. The results obtained are important for designing a new transdermal carrier and for a basic understanding of skin-nanoparticle interaction.
Abstract: To measure penetration and metabolic effects of ion-stabilized, polar, 15Â nm gold nanoparticles in aqueous solution (AuNP-Aq) and sterically stabilized, non-polar, 6Â nm gold nanoparticles in toluene (AuNP-TOL) on excised human skin.
Abstract: Microneedle (MN) arrays have attracted considerable attention in recent years due to their ability to facilitate effective transdermal drug delivery. Despite appreciable research, there is still debate about how different MN dimensions or application modes influence permeabilization. This study aimed to investigate this issue by taking transepidermal water-loss measurements of dermatomed human skin samples following the insertion of solid polymeric MNs. Insertions caused an initial sharp drop in barrier function followed by a slower incomplete recovery - a paradigm consistent with MN-generation of microchannels that subsequently contract due to skin elasticity. While 600 μm-long MNs were more skin-perturbing than 400 μm MNs, insertion of 1000 μm-long MNs caused a smaller initial drop in integrity followed by a degree of long term permeabilization. This is explainable by the longest needles compacting the tissue, which then decompresses over subsequent hours. Multiple insertions had a similar effect as increasing MN length. There was some evidence that increasing MN density suppressed the partial barrier recovery caused by tissue contraction. Leaving MNs embedded in skin seemed to reduce the initial post-insertion drop in barrier function. Our results suggest that this in vitro TEWL approach can be used to rapidly screen MN-effects on skin.
Abstract: Oxybenzone wax microparticles (MPs) were prepared by the hydrophobic congealable disperse phase method. The formulation of oxybenzone-loaded MPs was optimized using a 2â´ experimental design. Factorial analysis indicated that the main MP characteristics were influenced by initial drug loading, emulsification speed, emulsifier concentration and hydrophilic-lipophilic balance. MPs were spherical with 50.5â88.1 μm size range, 17.8â38.9 drug content in mg/100 mg MPs and 33.1â87.2% oxybenzone release in 1 h. A wide range of sunscreen delivery systems suitable for different formulation purposes were generated which may contribute to the advanced formulation of sunscreen products with improved performance.
Abstract: Marketed topical gels of the antifungal drug naftifine hydrochloride contain 50% alcohol as cosolvent. Repeated exposure to alcohol could be detrimental to skin. The aim of this study is to develop an alcohol-free niosome gel containing 1% naftifine hydrochloride. Niosomes were prepared and formulation variables were optimized to achieve maximum entrapment coupled with stability. Maximum drug entrapment and niosome stability entailed imparting a negative charge to the vesicles where entrapment efficiency reached 50%. Niosomes were incorporated into a hydroxyethylcellulose gel. The final gel contained a total drug concentration of 1% (wt/wt) half of which was entrapped in the niosomes. The results suggest the potential usefulness of the niosome gel.
Abstract: In the formulation of polymer microspheres (MSs) loaded with verapamil hydrochloride (VRP), a low molecular weight ionizable drug, by W/O/W emulsification, the pH of the external aqueous phase proved to be a primary determinant of both IE and drug release behavior. Increasing the pH of the external aqueous phase enhanced IE (approximately 100% at pH 8.4). This was associated with a considerable increase in initial release rate at pH 1.2. Two multivariate methods, factorial analysis (FA) and artificial neural network (ANN), were used to investigate the impact of the combined effect of the external phase pH and other parameters (polymer concentration and initial drug load) on MS characteristics; IE, initial drug release, MS size and yield. FA indicated that the external aqueous phase pH affected all responses, with a particularly strong correlation with IE in addition to a combined synergistic effect with polymer concentration on MS size. ANN showed better internal and external predictive ability of responses compared to FA. The ANN model developed in the study can be successfully used for multivariate modeling of the encapsulation and release of VRP and similar drug salts from hydrophobic polymer MSs prepared by multiple emulsification in addition to other MS characteristics.
Abstract: The purpose of this study was the development of a microbiological method for the assessment of the ultraviolet (UV) screening effect of sunscreen preparations and determination of their sun protection factor. The method is based on the lethal effect of UV radiation on Escherichia coli (E. coli ) and the protective ability of sunscreens. The time of UV exposure required for the reduction of the E. coli viable count by 90% (decimal reduction time, DRT) was used as the photoprotection assessment parameter. The method was tested by assessing the effect of selected experimental variables on the DRT. The suitability of the method as a quality control tool for sunscreen preparations was then checked by assessing the influence of selected formulation variables on the photoprotective effect of a series of o/w emulsion formulations with different compositions. The method proved valid for detecting changes in the photoprotective effect of a market sunscreen product as a result of modifying experimental conditions. It also proved valid for ranking market sunscreen products according to their UV screening effect. Equally important, the method could successfully detect changes in the photoprotective effect of sunscreen test formulations as a function of the concentration and type of the sunscreen agents.
Abstract: Although the formulation of effective topical drug delivery system is one of the most sophisticated pharmaceutical preparations, it has attracted researchers due to many medical advantages associated with it. Topical drug delivery systems can act superficially on skin surface, locally in dermal layer of the skin or transdermally to provide successful delivery of drug molecules to the systemic circulation avoiding the traditional problems and limitations of conventional routes of drug delivery. Many novel formulations have been utilized topically to enhance either permeability or drug targeting to a specific layer of the skin such as Liposomes, ethosomes, transfersomes, niosomes and catezomes. The main problem with all of these formulations is that there is no distinct barrier between the targeting and localization action to a certain layer of the skin and the transdermal action to the circulation of these preparations. Any minimal change in the formulation could transform it from a local targeting preparation to a systemic one. This article deals with the innovations pertaining to the use of various types of liposomal preparations and liposomal like preparations for topical drug delivery and the patents associated with it.
Abstract: Alendronate sodium, used systemically as a bone protective agent, proved to also be effective locally in various dental bone applications. Development of alendronate-loaded microspheres with high loading efficiency for such applications would be greatly challenged by the hydrophilicity and low MW of the drug. The aim of this study was to incorporate alendronate sodium, into poly (lactide-co-glycolide) (PLGA) microspheres (MS) with high loading efficiency.
Abstract: The pharmaceutical quality of 7 local omeprazole capsule brands in Egypt was assessed relative to the proprietary product (Losec). Drug content, content uniformity, drug release (using USP test for enteric coated articles and a modified release test) were determined. Products were subjected to a 3-month stability study. Of the 7 brands, 6 had satisfactory drug content and content uniformity. All brands passed the USP drug release test. The modified release test proved to be more discriminative. After 3 months storage, drug content of 3 brands remained > 90% and 2 of these brands maintained drug release above 75%. Changes in pellet appearance during storage were indicative of omeprazole chemical degradation.
Abstract: A method for determining the rate of hydrophilic and hydrophobic drugs release from different types of liposomal dispersions and gels using a dialysis method is described. Dibucaine base and 5-fluorouracil were used as model drugs for a hydrophobic and a hydrophilic drug, respectively. A dialysis technique was employed. Release rates were affected by the rate of rotation of the paddles of the tablet dissolution tester, temperature, and the volume of release medium. The method was used to evaluate the in vitro drug release from hydrophilic and hydrophobic drugs from liposomal dispersions and gels. The in vitro release study of dibucaine base showed no burst effect, while the in vitro release study of 5-fluorouracil showed a clear burst effect with an initial fast release phase followed by a sustained release phase.
Abstract: Possible leakage of 5-fluorouracil from stable plurilamellar vesicles was monitored during storage of the liposomal concentrates, gels and lyophilized powders. Changes in release profile of dibucaine were taken as indicator of instability. Release profiles were obtained using the dialysis technique for a freshly prepared liposomal concentrate, gel or reconstituted lyophilized powder (zero time) and storage for one, two and four weeks in well closed tubes at 4 degrees C for the liposomal concentrate or gel and at 25 degrees C for liposomal lyophilized powder. Aiming at increasing stability of 5-fluorouracil liposomal dispersion, freshly prepared liposomal concentrates were directly incorporated in hydroxypropyl methylcellulose gel. Stability release profiles of liposomal gels and concentrates indicated a significant increase in stability of liposomal formulations. Also, lyophilization increases the shelf life of liposomes by preserving it in a dry form as a lyophilized cake to be reconstituted immediately prior to administration or direct incorporation into a final dosage form. Release and physico-chemical stability studies showed superior potentials of the lyophilized product after reconstitution in comparison to concentrate and gel forms. It could be concluded that lyophilization of liposomes loaded with a water-soluble drug such as 5-fluorouracil could significantly increase the stability of the liposomal vesicles and decrease leakage from it.
Abstract: Formulation of local anesthetics in liposomal topical drug delivery system could provide a sustained and localized anesthesia. The aim of this study was to develop a liposomal dibucaine base (DB) local anesthetic delivery system. DB-loaded multilamellar vesicles (MLVs) were prepared through varying lipid composition, induced charge and pH of the hydration medium. Liposomes were characterized for morphology, size, entrapment efficiency (EE), in vitro drug release and stability including leakage stability. The percentage of drug entrapped in liposomes was found to be hydration medium pH dependent and charge dependent and more pronounced for negatively charged liposomes prepared using hydration medium of pH 9. In vitro release studies of liposomes have shown a sustained release of entrapped dibucaine compared to control solution. Results revealed that adjusting the various formulation variables of dibucaine base MLVs could yield stable and effective topical liposomal local anesthetic formulations.
Abstract: A solvent-treatment technique aiming at manipulating the properties of powdered materials is reported. Potentials of the technique were assessed using sulphadiazine (SD). A suspension of the drug in a preselected solvent (5% aqueous ammonia solution) was stirred under controlled conditions. The solvent was subsequently removed and the material dried. The effect of experimental variables such as stirring speed and time, powder/solvent ratio and inclusion of additives (Tween 80, sodium chloride and PVP) on the properties of solvent treated SD was assessed. Data obtained were compared with those for SD recrystallized under identical conditions. Solvent treatment of SD in the absence of additives resulted in a limited change in crystal morphology as indicated by SEM. This was associated with improved flowability and a limited reduction in dissolution rate relative to untreated SD. On the other hand, recrystallized SD exhibited superior flowability but a considerably low dissolution rate. Solvent treatment of SD in the presence of 2% PVP produced a microgranular directly compressible material.
Abstract: The effect of two hydrotrophic solubilizers on the heat coagulation of bovine serum albumin (BSA) has been investigated. Photon correlation spectroscopy indicated possible unfolding of BSA molecules in solutions of sodium benzoate and sodium salicylate at 25 degrees C. The effect of these hydrotropes on the heat coagulation of BSA was concentration-dependent. Relatively low concentrations stabilized the protein structure as indicated by the increase in the transition temperature(Tm) and induced gelation at temperatures and BSA concentrations lower than those required in the absence of hydrotropes. Higher concentrations of the hydrotropes considerably reduced Tm and inhibited gelation of BSA, the effect of sodium salicylate being more pronounced, as was the lower aggregation rate of BSA. The behaviour of these hydrotropes as protein denaturants differs from that of neutral electrolytes but is similar to that of concentrated solutions of urea.
