Cucurbit[7]uril encapsulated cisplatin overcomes cisplatin resistance via a pharmacokinetic effect

The cucurbit[n]uril (CB[n]) family of macrocycles has been shown to have potential in drug delivery where they are able to provide physical and chemical stability to drugs, improve drug solubility, control drug release and mask the taste of drugs. Cisplatin is a small molecule platinum-based anticancer drug that has severe dose-limiting side-effects. Cisplatin forms a host-guest complex with cucurbit[7]uril (cisplatin@CB[7]) with the platinum atom and both chlorido ligands located inside the macrocycle, with binding stabilised by four hydrogen bonds (2.15-2.44 ?). Whilst CB[7] has no effect on the in vitro cytotoxicity of cisplatin in the human ovarian carcinoma cell line A2780 and its cisplatin-resistant sub-lines A2780/cp70 and MCP1, there is a significant effect on in vivo cytotoxicity using human tumour xenografts. Cisplatin@CB[7] is just as effective on A2780 tumours compared with free cisplatin, and in the cisplatin-resistant A2780/cp70 tumours cisplatin@CB[7] markedly slows tumour growth. The ability of cisplatin@CB[7] to overcome resistance in vivo appears to be a pharmacokinetic effect. Whilst the peak plasma level and tissue distribution are the same for cisplatin@CB[7] and free cisplatin, the total concentration of circulating cisplatin@CB[7] over a period of 24 hours is significantly higher than for free cisplatin when administered at the equivalent dose. The results provide the first example of overcoming drug resistance via a purely pharmacokinetic effect rather than drug design or better tumour targeting, and demonstrate that in vitro assays are no longer as important in screening advanced systems of drug delivery.     

A Preformulation Strategy for the Selection of Penetration Enhancers for a Transungual Formulation

Onychomycosis is associated with the cutaneous fungal infection of the nail and the nail folds (skin surrounding the nail). It is therefore important to target drug delivery into the nail folds along with nail plate and the nail bed. Systematic and strategic selection of the penetration enhancers specific for the skin and the nail is discussed. Twelve penetration enhancers were screened for their ability to improve solubility, in vitro nail penetration, in vitro skin permeation, and in vitro skin penetration of the antifungal drug ciclopirox olamine. In contrast to transdermal drug delivery, the main selection criteria for skin penetration enhancer in topical drug delivery were increased drug accumulation in the epidermis and minimal permeation across the skin. Thiourea improved the solubility and nail penetration of ciclopirox olamine. It also showed enhancement in the transungual diffusion of the drug. Propylene glycol showed a 12-fold increase in solubility and 3-fold increase in epidermal accumulation of ciclopirox olamine, while minimizing the transdermal movement of the drug. Thiourea was the selected nail permeation enhancer and propylene glycol was the selected skin penetration enhancer of ciclopirox olamine. A combination of the selected enhancers was also explored for its effect on drug delivery to the nail and nail folds. The enhancer combination reduced the penetration of ciclopirox in the skin and also the permeation through the nail. The proposed preformulation strategy helps to select appropriate enhancers for optimum topical delivery and paves way towards an efficient topical formulation for passive transungual drug delivery.     

经皮给药载体载MD-CPT透明质酸纳米乳的细胞吞噬与体内药代动力学研究

本文在研究制备了包载10,11-亚甲二氧基喜树碱(MD-CPT)的透明质酸纳米乳(HANs)经皮给药系统的基础上,进一步研究了载MD-CPT透明质酸纳米乳的细胞吞噬,并进行了体内药代动力学分析.通过优化制备条件,得到了皮肤渗透性良好的缓释剂型.从CLSM观察到药物被细胞摄入并传递入细胞核,同时,载药纳米乳的细胞吞噬效率呈时间依赖性,不同细胞株HSF、HUVES、MCF-7、KF的细胞吞噬率略有不同.用Rhodanmine B标记HANs,通过荧光显微镜观察到载药纳米乳透过角质层到达真皮层的拟动态过程.利用HPLC检测MD-CPT血药浓度,测得经皮给药半衰期T1/2是静脉注射的3.6倍,肌肉注射的1.6倍,体内药物滞留时间显著增加;血药浓度峰谷值差异小,曲线平缓,说明经皮给药能保证血药浓度呈现可控的持续性.最终通过活体成像系统和组织切片荧光显微镜,直观地反映出经皮给药后药物在大鼠体内的分布情况和各组织器官药物含量,确定载药纳米乳主要采取胞间渗透的扩散方式,在局部给药的区域滞留时间较长,有利于对浅表性的病灶区持续给药,延长药效,而剩余的MD-CPT和解离的HANs都进入了血液循环,最终通过新陈代谢被排出体外.为无创型HANs经皮给药系统应用于浅表性肿瘤治疗提供了理论基础.     

Management of overactive bladder with transdermal oxybutynin

In clinical trials, transdermal oxybutynin (OXY-TDS) has shown comparable efficacy and improved tolerability when compared with conventional pharmacotherapy. Systemic anticholinergic adverse effects are comparable to those with placebo, most likely owing to avoidance of first-pass hepatic metabolism and conversion of oxybutynin to N-desethyloxybutynin. OXY-TDS has predictable pharmacokinetic absorption and elimination parameters, as shown in both in vitro and in vivo studies. Consistent plasma concentrations of oxybutynin avoid labile peak and trough concentrations seen with immediate-release formulations, paralleling extended-release drug delivery. This novel drug delivery system has unique dermatologic skin application site reactions, including erythema and pruritus. Skin reactions are usually mild and can be minimized by varying the site of patch application. Most eczematous dermatologic reactions can be appropriately treated with a moderately potent topical corticosteroid cream. A small percentage of patients will discontinue therapy as a result of bothersome application site skin reactions.     

Distribution and metabolism of topically applied progesterone in a rat model

This study investigated the transdermal uptake and subsequent tissue distribution of [³H]progesterone applied in a commercially available progesterone cream in a rat model. Concentrations of lipid- and water-soluble metabolites of [³H]progesterone were also measured in plasma, urine and selected tissues (uterus, liver, kidney, salivary gland) 3 h after its topical application. Female rats were ovariectomized and adrenalectomized to remove all endogenous progesterone, and 4 weeks later were anaesthetized and 150 mg Pro-Feme® cream (containing progesterone 3.2% w/w and 200 μCi [³H]progesterone) was applied to the abdominal skin. Six arterial blood samples were then obtained from a carotid cannula over the following 3 h, and urine and selected tissue samples were collected after the final blood sample. Plasma progesterone increased progressively until 90 min, then remained relatively stable. Plasma levels of [³H]progesterone were high by the 15-min sample and increased only slightly thereafter. Water-soluble metabolites were detectable in plasma at 15 min, whereas lipid-soluble metabolites became apparent only by 60 min then increased progressively to 180 min. The tissue:plasma concentration ratio for [³H]progesterone exceeded 1 in all tissues, most notably in uterus (8.4) and lung (9.6), whereas urinary [³H]progesterone levels were only half those in plasma. Concentrations of lipid- and water-soluble progesterone metabolites were most prevalent in liver and kidney, and both reached very high concentrations in urine. These results demonstrate that topically applied progesterone is rapidly absorbed transdermally and that its patterns of distribution and metabolism are comparable to those previously reported for intravascularly administered progesterone.     

Cream Formulation Impact on Topical Administration of Engineered Colloidal Nanoparticles

In order to minimize the impact of systemic toxicity of drugs in the treatment of local acute and chronic inflammatory reactions, the achievement of reliable and efficient delivery of therapeutics in/through the skin is highly recommended. While the use of nanoparticles is now an established practice for drug intravenous targeted delivery, their transdermal penetration is still poorly understood and this important administration route remains almost unexplored. In the present study, we have synthesized magnetic (iron oxide) nanoparticles (MNP) coated with an amphiphilic polymer, developed a water-in-oil emulsion formulation for their topical administration and compared the skin penetration routes with the same nanoparticles deposited as a colloidal suspension. Transmission and scanning electron microscopies provided ultrastructural evidence that the amphiphilic nanoparticles (PMNP) cream formulation allowed the efficient penetration through all the skin layers with a controllable kinetics compared to suspension formulation. In addition to the preferential follicular pathway, also the intracellular and intercellular routes were involved. PMNP that crossed all skin layers were quantified by inductively coupled plasma mass spectrometry. The obtained data suggests that combining PMNP amphiphilic character with cream formulation improves the intradermal penetration of nanoparticles. While PMNP administration in living mice via aqueous suspension resulted in preferential nanoparticle capture by phagocytes and migration to draining lymph nodes, cream formulation favored uptake by all the analyzed dermis cell types, including hematopoietic and non-hematopoietic. Unlike aqueous suspension, cream formulation also favored the maintenance of nanoparticles in the dermal architecture avoiding their dispersion and migration to draining lymph nodes via afferent lymphatics.     

Isolation of the trans-I and trans-II isomers of Cu(cyclam) via complexation with the macrocyclic host cucurbit[8]uril

The macrocyclic ligand cyclam occurs as a 70:30 mixture of its trans-I and trans-II configurations, respectively, when included as its Cu^II complex inside the cavity of the macrocyclic host compound cucurbit[8]uril. This is the first report of an unsubstituted cyclam occurring in either of these two relatively high-energy configurations in the solid state. By comparison, Ni^II(cyclam) included in CB[8] in the solid state has been shown in the literature to exist in the more stable and much more common trans-III configuration. The existence of the Cu^II(cyclam) guest in the high-energy trans-I configuration as the major isomer is postulated to be the result of the supportive nature of the CB[8] cavity, resulting from specific hydrogen bonding between the cyclam amine hydrogens and the carbonyl groups of the CB[8] host. This solid Cu^II(cyclam)@CB[8] host-guest inclusion structure also exhibits other interesting features, again distinguished from the previously reported Ni^II analog. The CB[8] hosts are only partially occupied in this solid structure, with one-third of the host cavities remaining empty. Those that are occupied show significant distortion of one of the two cavity portals, to accommodate hydrogen bonding. In addition, the Cu^II(cyclam) guest is found to reside off-centre, and to partially extend outside of the CB[8] cavity, in order to optimize hydrogen bonding interactions.     

Microparticulate Based Topical Delivery System of Clobetasol Propionate

Psoriasis is a chronic, autoimmune skin disease affecting approximately 2% of the world's population. Clobetasol propionate which is a superpotent topical corticosteroid is widely used for topical treatment of psoriasis. Conventional dosage forms like creams and ointments are commonly prefered for the therapy. The purpose of this study was to develop a new topical delivery system in order to provide the prolonged release of clobetasol propionate and to reduce systemic absorption and side effects of the drug. Clobetasol propionate loaded-poly(D,L-lactic-co-glycolic acid) (PLGA) microspheres were prepared by oil-in-water emulsion–solvent evaporation technique. Particle size analysis, morphological characterization, DSC and XRD analyses and in vitro drug release studies were performed on the microparticle formulations. Emulgel formulations were prepared as an alternative for topical delivery of clobetasol propionate. In vitro drug release studies were carried out from the emulgel formulations containing pure drug and drug-loaded microspheres. In addition, the same studies were performed to determine the drug release from the commercial cream product of clobetasol propionate. The release of clobetasol propionate from the emulgel formulations was significantly higher than the commercial product. In addition, the encapsulation of clobetasol propionate in the PLGA microspheres significantly delayed the drug release from the emulgel formulation. As a result, the decrease in the side effects of clobetasol propionate by the formulation containing PLGA microspheres is expected.     

Potential of Cyclodextrin Complexation and Liposomes in Topical Delivery of Ketorolac: In Vitro and In Vivo Evaluation

The objective of this investigation was to evaluate the effect of delivery strategies such as cyclodextrin complexation and liposomes on the topical delivery of ketorolac acid (KTRA) and ketorolac tromethamine. Ketorolac acid–hydroxypropyl-β-cyclodextrin solid dispersions (KTRA-CD) were prepared by kneading method. The liposomes containing ketorolac tromethamine (KTRM) and KTRA-CD were prepared. The in vitro permeation of KTRM solution, KTRA solution, KTRA-CD, and liposomes containing KTRM or KTRA-CD through guinea pig skin was evaluated. The anti-inflammatory activity of the topically applied KTRA-CD gel (containing 1% w/w KTRA) was compared to that of orally delivered KTRM solution. The KTRA-CD demonstrated significantly higher transdermal transport of ketorolac as compared to all other systems whereas liposomes significantly reduced the transport of ketorolac. The anti-inflammatory activity of the topically applied KTRA-CD gel was similar to that of the orally administered KTRM. Thus, cyclodextrin complexation enabled effective transdermal delivery of the ketorolac.     

Fabrication,Physicochemical Characterization,and Performance Evaluation of Biodegradable Polymeric Microneedle Patch System for Enhanced Transcutaneous Flux of High Molecular Weight Therapeutics

A revolutionary paradigm shift is being observed currently, towards the use of therapeutic biologics for disease management. The present research was focused on designing an efficient dosage form for transdermal delivery of α-choriogonadotropin (high molecular weight biologic), through biodegradable polymeric microneedles. Polyvinylpyrrolidone-based biodegradable microneedle arrays loaded with high molecular weight polypeptide, α-choriogonadotropin, were fabricated for its systemic delivery via transdermal route. Varied process and formulation parameters were optimized for fabricating microneedle array, which in turn was expected to temporally rupture the stratum corneum layer of the skin, acting as a major barrier to drug delivery through transdermal route. The developed polymeric microneedles were optimized on the basis of quality attributes like mechanical strength, axial strength, insertion ratio, and insertion force analysis. The optimized polymeric microneedle arrays were characterized for in vitro drug release studies, ex vivo drug permeation studies, skin resealing studies, and in vivo pharmacokinetic studies. Results depicted that fabricated polymeric microneedle arrays with mechanical strength of above 5 N and good insertion ratio exhibited similar systemic bioavailability of α-choriogonadotropin in comparison to marketed subcutaneous injection formulation of α-choriogonadotropin. Thus, it was ultimately concluded that the designed drug delivery system can serve as an efficient tool for systemic delivery of therapeutic biologics, with an added benefit of overcoming the limitations of parenteral delivery, achieving better patient acceptability and compliance.     

Evaluation of Paeonol Skin-Target Delivery from Its Microsponge Formulation: In Vitro Skin Permeation and In Vivo Microdialysis

The aim of the present study was to design a novel topical skin-target drug-delivery system, the paeonol microsponge, and to investigate its drug-release patterns in dosage form, both in vitro and in vivo. Paeonol microsponges were prepared using the quasi-emulsion solvent-diffusion method. In vitro release studies were carried out using Franz diffusion cells, while in vivo studies were investigated by microdialysis after the paeonol microsponges were incorporated into a cream base. In vitro release studies showed that the drug delivered via microsponges increased the paeonol permeation rate. Ex vivo drug-deposition studies showed that the microsponge formulation improved drug residence in skin. In addition, in vivo microdialysis showed that the values for the area under the concentration versus time curve (AUC) for the paeonol microsponge cream was much higher than that of paeonol cream without microsponges. Maximum time (T_max) was 220 min for paeonol microsponge cream and 480 min for paeonol cream, while the half-life (t_1/2) of paeonol microsponge cream (935.1 min) was almost twice that of paeonol cream (548.6 min) in the skin (n = 3). Meanwhile, in the plasma, the AUC value for paeonol microsponge cream was half that of the paeonol cream. Based on these results, paeonol-loaded microsponge formulations could be a better alternative for treating skin disease, as the formulation increases drug bioavailability by lengthening the time of drug residence in the skin and should reduce side-effects because of the lower levels of paeonol moving into the circulation.     

Lecithin organogels as a potential phospholipid-structured system for topical drug delivery: A review

The purpose of this review is to give an insight into the considerable potential of lecithin organogels (LOs) in the applications meant for topical drug delivery. LOs are clear, thermodynamically stable, viscoelastic, and biocompatible jelly-like phases, chiefly composed of hydrated phospholipids and appropriate organic liquid. These systems are currently of interest to the pharmaceutical scientist because of their structural and functional benefits. Several therapeutic agents have been formulated as LOs for their facilitated transport through topical route (for dermal or transdermal effect), with some very encouraging results. The improved topical drug delivery has mainly been attributed to the biphasic drug solubility, the desired drug partitioning, and the modification of skin barrier function by the organogel components. Being thermodynamically stable, LOs are prepared by spontaneous emulsification and therefore posses prolonged shelf life. The utility of this novel matrix as a topical vehicle has further increased owing to its very low skin irritancy potential. Varied aspects of LOs viz formation, composition, phase behavior, and characterization have been elaborated, including a general discussion on the developmental background. Besides a comprehensive update on the topical applications of lecithin organogels, the review also includes a detailed account on the mechanistics of organogelling. Published: October 6, 2005     

Microemulsion-Based Topical Hydrogels of Tenoxicam for Treatment of Arthritis

Tenoxicam (TNX) is a non-steroidal anti-inflammatory drug (NSAID) used for the treatment of rheumatoid arthritis, osteoarthritis, ankylosing spondylitis, backache and pain. However, prolonged oral use of this drug is associated with gastrointestinal adverse events like peptic ulceration, thus necessitating its development as topical formulation that could obviate the adverse effects and improve patient compliance. The present study was aimed at development of microemulsion-based formulations of TNX for topical delivery at the affected site. The pseudoternary phase diagrams were developed and microemulsion formulations were prepared using Captex 300/oleic acid as oil, Tween 80 as surfactant and n-butanol/ethanol as co-surfactant. Optimized microemulsions were characterized for drug content, droplet size, viscosity, pH and zeta potential. The ex vivo permeation studies through Laca mice skin were performed using Franz diffusion cell assembly, and the permeation profile of the microemulsion formulation was compared with aqueous suspension of drug and drug incorporated in conventional cream. Microemulsion formulations of TNX showed significantly higher (p?<?0.001) mean cumulative percent permeation values in comparison to conventional cream and suspension of drug. In vivo anti-arthritic and anti-inflammatory activity of the developed TNX formulations was evaluated using various inflammatory models such as air pouch model, xylene-induced ear edema, cotton pellet granuloma and carrageenan-induced inflammation. Microemulsion formulations were found to be superior in controlling inflammation as compared to conventional topical dosage forms and showed efficacy equivalent to oral formulation. Results suggest that the developed microemulsion formulations may be used for effective topical delivery of TNX to treat various inflammatory conditions.     

Nanoethosomal formulation for skin targeting of amphotericin B: an in vitro and in vivo assessment

Abstract

The present study is envisaged to develop nanoethosomal formulation for enhanced topical delivery of amphotericin B (AmB) for the treatment of cutaneous fungal infections. AmB encapsulated nanoethosomes were prepared using mechanical dispersion method in a strength of 0.1% w/w similar to the strength of marketed topical formulation. Vesicle size of nanoethosomal formulations was found to be in the range of 186?±?2 to 298?±?4?nm. The optimized nanoethosomal formulation was further incorporated in gel base to form AmB nanoethogel formulation. Rheological characterization study of nanoethogel demonstrated its viscoelastic nature with high elasticity and resistance to deformation at 37?°C. The yield stress value was found to be 108.05?±?2.4 and 52.15?±?0.9?Pa for nanoethogel and marketed gel formulation, respectively. The nanoethogel formulation exhibited 2.7- and 3.5-fold higher steady state transdermal flux and skin deposition of AmB, respectively, in comparison to marketed formulation. Confocal laser scanning microscopy (CLSM) study also revealed enhanced skin permeation and deposition with nanoethogel formulation. In vivo study showed that topical application of nanoethogel does not exhibit any skin irritation as tested by Draize test. The developed formulation, in comparison to the marketed gel, demonstrated a remarkable increase in the antifungal activity against Candida albicans. It is thus corroborated from the above results that nanoethosomal formulation represents an efficacious carrier for effective topical delivery of AmB.     

Microemulsion for topical delivery of fenoprofen calcium: in vitro and in vivo evaluation

The aim of this study was to investigate microemulsion (ME) based topical delivery system for fenoprofen calcium (FPCa) to eliminate its oral gastrointestinal adverse effects. ME was prepared by the water titration method using oleic acid as oil phase, tween 80 as a surfactant and propylene glycol as a cosurfactant. Oleic acid was selected as oil phase due to its good solubilizing capacity. ME existence region was determined using pseudo-ternary phase diagrams for preparing different formulations. Six different formulations were selected with various values of oil (25–68%), water (2–3%), and the mixture of surfactant and cosurfactant (1:1) (24–67%). The selected ME formulae were characterized for optical birefringence, transmission electron microscopy (TEM), pH, % transmittance, electronic conductivity, drug content, droplet size, rheological properties and stability evaluation. In vitro release study of FPCa from ME s through the synthetic membrane and hairless rat skin were evaluated. The optimized formula ME5 consisting of 5% w/w FPCa, 60% w/w oleic acid as oil phase, 3% w/w aqueous phase, and 32% w/w of surfactant phase containing Tween 80 and propylene glycol (1:?1) showed the highest transdermal flux and highest skin permeation rate. Finally, the % inhibition of carrageenan-induced rat paw edema of the optimized formula ME5 was highly significant (p?0.001) as compared to plain gel of FPCa. In conclusion, ME is a promising technique for topical delivery of FPCa.     

Formulation,Characterization, and Clinical Evaluation of Microemulsion Containing Clotrimazole for Topical Delivery

The objective of the present study was to formulate and evaluate microemulsion systems for topical delivery of clotrimazole (CTM). The solubility of CTM in various oils was determined to select the oil phase of the microemulsion systems. Pseudoternary phase diagrams were constructed to identify the area of microemulsion existence. Five CTM microemulsion formulations (M1–M5) were prepared and evaluated for their thermodynamic stability, pH, refractive index, droplet size, viscosity, and in vitro release across cellulose membrane. Among the prepared microemulsion formulations, M3 (lemon oil/Tween 80/n-butanol/water) and M4 (isopropyl myristate/Tween 80/n-butanol/water) microemulsion systems were found to be promising according to their physical properties and CTM cumulative percentage release. Gel form of M3 and M4 were prepared using 1% Carbopol 940 as the hydrogel matrix. Both formulations were evaluated in the liquid and gel forms for drug retention in the skin in comparison to the marketed CTM topical cream and their stability examined after storage at 40°C for 6 months. Microemulsion formulations achieved significantly higher skin retention for CTM over the CTM cream. Stability studies showed that M4 preparations were more stable than M3. The in vitro anti-fungal activity of M4 against Candida albicans was higher than that of the conventional cream. Moreover, clinical evaluation proved the efficacy and tolerability of this preparation in the treatment of various topical fungal infections.     

Whey Protein/Polysaccharide-Stabilized Emulsions: Effect of Polymer Type and pH on Release and Topical Delivery of Salicylic Acid

Emulsions are widely used as topical formulations in the pharmaceutical and cosmetic industries. They are thermodynamically unstable and require emulsifiers for stabilization. Studies have indicated that emulsifiers could affect topical delivery of actives, and this study was therefore designed to investigate the effects of different polymers, applied as emulsifiers, as well as the effects of pH on the release and topical delivery of the active. O/w emulsions were prepared by the layer-by-layer technique, with whey protein forming the first layer around the oil droplets, while either chitosan or carrageenan was subsequently adsorbed to the protein at the interface. Additionally, the emulsions were prepared at three different pH values to introduce different charges to the polymers. The active ingredient, salicylic acid, was incorporated into the oil phase of the emulsions. Physical characterization of the resulting formulations, i.e., droplet size, zeta potential, stability, and turbidity in the water phase, was performed. Release studies were conducted, after which skin absorption studies were performed on the five most stable emulsions, by using Franz type diffusion cells and utilizing human, abdominal skin membranes. It was found that an increase in emulsion droplet charge could negatively affect the release of salicylic acid from these formulations. Contrary, positively charged emulsion droplets were found to enhance dermal and transdermal delivery of salicylic acid from emulsions. It was hypothesized that electrostatic complex formation between the emulsifier and salicylic acid could affect its release, whereas electrostatic interaction between the emulsion droplets and skin could influence dermal/transdermal delivery of the active.     

Fluidity enhancement: a critical factor for performance of liposomal transdermal drug delivery system

Liposomes are well known lipid carriers for drug delivery of bioactive molecules encapsulated inside their membrane. Liposomes as skin drug delivery systems were initially promoted primarily for localized effects with minimal systemic delivery. Subsequently, a novel vesicular system, transferosomes was reported for transdermal delivery with efficiency similar to subcutaneous injection. The multiple bilayered organizations of lipids applied in these vesicles structure are somewhat similar to complex nature of stratum corneal intercellular lipids domains. The incorporation of novel agents into these lipid vesicles results in the loss of entrapped markers but it is similar to fluidization of stratum corneum lipids on treatment with a penetration enhancer. This approach generated the utility of penetration enhancers/fluidizing agents in lipids vesicular systems for skin delivery. For the transdermal and topical applications of liposomes, fluidity of bilayer lipid membrane is rate limiting which governs the permeation. This article critically reviews the relevance of using different types of vesicles as a model for skin in permeation enhancement studies. This study has also been designed to encompass all enhancement measurements and analytical tools for characterization of permeability in liposomal vesicular system.     

Encapsulation of platinum(II)-based DNA intercalators within cucurbit[6,7,8]urils

The partial encapsulation of platinum(II)-based DNA intercalators of the type [Pt(5-Cl-phen)(ancillary ligand)](2+), where 5-Cl-phen is 5-chloro-1,10-phenanthroline and the ancillary ligand is ethylenediamine, (1S,2S)-diaminocyclohexane (S,S-dach) or (1R,2R)-diaminocyclohexane, within cucurbit[n]uril (CB[n], where n is 6, 7 or 8) has been examined by (1)H and (195)Pt NMR and mass spectrometry. For CB[7], the molecule encapsulates over the ancillary ligand of all metal complexes, whether this is ethylenediamine or diaminocyclohexane. For CB[8], encapsulation occurs over the sides of the 5-Cl-phen ligand at low [Pt(5-Cl-phen)(S,S-dach)](2+) (5CLSS) to CB[8] ratios (i.e. 0.25:1) but over the ancillary ligand at higher ratios (i.e. 2:1). For CB[6] binding, 5CLSS exhibits both portal and cavity binding, with the ancillary ligand displaying chemical shifts consistent with fast exchange kinetics on the NMR timescale for portal binding and slow exchange kinetics for cavity binding. Binding constants could not be determined using UV-vis, circular dichroism or fluorescence spectrophotometry, but a binding constant for binding of 5CLSS to CB[6] of approximately 10(5) M(-1) was determined using (1)H NMR. Finally, the effect of CB[n] encapsulation on the cytotoxicity of the metal complexes was examined using L1210 murine leukaemia cells in vitro growth inhibition assays. The cytotoxicity is highly dependent on both the metal complex and the CB[n] size, and whilst CB[7] and CB[8] generally decreased cytotoxicity, it was found that CB[6] increased the cyotoxicity of 5CLSS up to 2.5-fold.     

Liposomes as carriers for verbascoside: stability and skin permeation studies

In this study the influence of liposomal incorporation on both the stability and the in vitro (trans) dermal delivery of verbascoside was evaluated. The effect of drug entrapment into vesicles on its radical scavenging activity was also studied. Liposomes were obtained from soy phosphatidylcholine and cholesterol according to the film hydration method. Stability of verbascoside-loaded vesicles was studied over 6 months. Results showed that verbascoside can be incorporated in liposomes (E% = 57-66%), preventing its degradation. Stability studies (dynamic lager light scattering [DLLS] measurements and transmission electron microscopy [TEM] visualization) pointed out that vesicles were stable for 90 days and neither verbascoside leakage nor vesicle size alteration occurred during this period. The effects of vesicular incorporation on verbascoside diffusion through skin were investigated in vitro using newborn pig skin. Results showed that liposomes promoted drug accumulation into the stratum corneum but they did not give rise to any significant transdermal verbascoside delivery. Finally, results obtained from a 1, 1-diphenyl-2-pierylhydrazyl (DPPH) radical assay demonstrated that liposomes did not interfere with the radical scavenging activity of verbascoside.