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This review refers to biocompatible microemulsions, which in recent decades have attracted the interest of formulators as nanosystems useful for the skin drug delivery. Microemulsions are homogeneous pseudoternary colloidal dispersions, thermodynamically stable, fluid, transparent, isotropic, consisting of an oil phase and an aqueous phase, stabilized by a mixture of surfactant and cosurfactant and with the droplet diameter of the dispersed phase usually within the range 10-100 nm. To support the potential of biocompatible microemulsions as an innovative topical pharmaceutical form, this paper provides an overview of their type, formulation, structure, composition and characterization, as well as their advantages and disadvantages. Currently, the main purpose of the dermal microemulsion formulation is to obtain optimal drug bioavailability under conditions of minimal skin irritability. Numerous studies carried out in the last two decades have shown the potential of microemulsions to increase the percutaneous penetration of drugs, acting as penetration enhancers due to the following advantageous characteristics: high solubilization capacity of natural and synthetic lipophilic and hydrophilic compounds; the release of a large amount of active ingredient in the skin, followed by an increased dermal distribution and permeation. Ensuring skin tolerance in the presence of large amounts of surfactant and co-surfactant in the formulation of microemulsions can be achieved by selecting clinically accepted excipients for topical preparations and generally recognized as safe (Food and Drug Administration). Therefore, biocompatible dermal microemulsions can be prepared using natural excipients (vegetable oils, non-ionic surfactants, volatile oils), which are biodegradable and have lower skin toxicity and irritant potential than synthetic ones.

A series of novel hybrid chalcone N-ethyl-piperazinyl amide derivatives of oleanonic and ursonic acids were synthesized, and their cytotoxic potential was evaluated in vitro against the NCI-60 cancer cell line panel. Compounds 4 and 6 exhibited the highest overall anticancer activity, with GI50 values in some cases reaching nanomolar values. Thus, the two compounds were further assessed in detail in order to identify a possible apoptosis- and antiangiogenic-based mechanism of action induced by the assessed compounds. DAPI staining revealed that both compounds induced nuclei condensation and overall cell morphological changes consistent with apoptotic cell death. rtPCR analysis showed that up-regulation of pro-apoptotic Bak gene combined with the down-regulation of the pro-survival Bcl-XL and Bcl-2 genes caused altered ratios between the pro-apoptotic and anti-apoptotic proteins’ levels, leading to overall induced apoptosis. Molecular docking analysis revealed that both compounds exhibited high scores for Bcl-XL inhibition, suggesting that compounds may induce apoptotic cell death through targeted anti-apoptotic protein inhibition, as well. Ex vivo determinations showed that both compounds did not significantly alter the angiogenesis process on the tested cell lines.

The skin integrity is essential due to its pivotal role as a biological barrier against external noxious factors. Pentacyclic triterpenes stand as valuable plant-derived natural compounds in the treatment of skin injuries due to their anti-inflammatory, antioxidant, antimicrobial, and healing properties. Consequently, the primary aim of the current investigation was the development as well as the physicochemical and pharmaco-toxicological characterization of betulin- and lupeol-based oleogels (Bet OG and Lup OG) for topical application in skin injuries. The results revealed suitable pH as well as organoleptic, rheological, and textural properties. The penetration and permeation of Bet and Lup oleogels through porcine ear skin as well as the retention of both oleogels in the skin were demonstrated through ex vivo studies. In vitro, Bet OG and Lup OG showed good biocompatibility on HaCaT human immortalized cells. Moreover, Bet OG exerted a potent wound-healing property by stimulating the migration of the HaCaT cells. The in ovo results demonstrated the non-irritative potential of the developed formulations. Additionally, the undertaken in vivo investigation indicated a positive effect of oleogels treatment on skin parameters by increasing skin hydration and decreasing erythema. In conclusion, oleogel formulations are ideal for the local delivery of betulin and lupeol in skin disorders.

To initiate our research into the development of biocompati&icirc, le gelled-microemulsions based on essential oils (EOs) and sucrose esters (SEs) for the topical delivery of fluconazole, this formulation study investigated the usefulness of two relatively harmless natural non-ionic surfactants from the group of SEs (sucrose laurate and stearate) to form, in the presence of antifungal EOs, stable, isotropic microemulsions effective on fluconazole solubilization. Fluconazole&rsquo, s solubility in EO significantly depended on their chemical composition, showing higher values for cinnamon, oregano and clove essential oils, further selected as oil phase components for microemulsion formulations. The phase behavior of several EO&ndash, isopropyl miristate/SE&ndash, isopropanol/water systems was assessed through pseudo-ternary phase diagrams constructed by microplate dilution technique. The hydrocarbon chain length of the SE and EO type strongly influenced the size of the microemulsion region in the pseudo-ternary phase diagrams. Ten microemulsion formulations containing 2% fluconazole, 6% or 10% oil mixture of EO&ndash, isopropyl myristate in 1:1 ratio, 45% SE-isopropanol mixture and water, were selected and evaluated for physicochemical properties (droplet size, polydispersity, viscosity, refractive index, zeta potential and pH). All formulations were physicochemically acceptable, but viscosity enhancement and further in vitro and in vivo tests are required for the development of biocompatible, clinically safe and effective fluconazole topical preparations.

Origanum vulgare L. is a widely used aromatic plant, especially due to its content in essential oil, mainly rich in carvacrol and thymol. The ethnopharmacological uses of Origanum vulgare L. essential oil (OEO) comprise digestive, respiratory, or dermatological disorders. The review focuses on the increasing number of recent studies investigating several biological activities of OEO. The bioactivities are in tight relation to the phytochemical profile of the essential oil, and also depend on taxonomic, climatic, and geographical characteristics of the plant material. The antibacterial, antifungal, antiparasitic, antioxidant, anti-inflammatory, antitumor, skin disorders beneficial effects, next to antihyperglycemic and anti-Alzheimer activities were reported and confirmed in multiple studies. Moreover, recent studies indicate a positive impact on skin disorders of OEO formulated as nanocarrier systems in order to improve its bioavailability and, thus, enhancing its therapeutic benefits. The review brings an up to date regarding the phytochemistry and bioactivity of Origanum vulgare L. essential oil, underlining also the most successful pharmaceutical formulation used for skin disorders.

Cancer persists as a global challenge due to the extent to which conventional anticancer therapies pose high risks counterbalanced with their therapeutic benefit. Naturally occurring substances stand as an important safer alternative source for anticancer drug development. In the current study, a series of modified lupane and ursane derivatives was subjected to in vitro screening on the NCI-60 cancer cell line panel. Compounds 6 and 7 have been identified as highly active with GI50 values ranging from 0.03 µM to 5.9 µM (compound 6) and 0.18–1.53 µM (compound 7). Thus, these two compounds were further assessed in detail in order to identify a possible antiproliferative mechanism of action. DAPI (4′,6-diamidino-2-phenylindole) staining revealed that both compounds induced nuclei condensation and overall cell morphological changes consistent with apoptotic cell death. rtPCR analysis showed that both compounds induced upregulation of proapoptotic Bak and Bad genes while downregulating Bcl-XL and Bcl-2 antiapoptotic genes. Molecular docking analysis revealed that both compounds exhibited high scores for Bcl-XL inhibition, while compound 7 showed higher in silico Bcl-XL inhibition potential as compared to the native inhibitor ATB-737, suggesting that compounds may induce apoptotic cell death through targeted antiapoptotic protein inhibition, as well.

Rutin (Rut) is a natural flavonol, well-known for its broad-spectrum of therapeutic effects, including antioxidant and antitumoral activities, still, it has a reduced clinical outcome due to its limited solubility in aqueous solutions. To overcome this drawback, this study proposes a novel formulation for rutin as a proniosomal gel for cutaneous applications. The gel was prepared by coacervation phase-separation method and complies with the standard requirements in terms of particle size (140.5 &plusmn, 2.56 nm), zeta potential (&minus, 27.33 &plusmn, 0.09 mV), encapsulation capacity (&gt, 50%), pH (7.002 &plusmn, 0.18) and rheological properties. The results showed high biocompatibility of the gel on the 3D reconstructed human epidermis model characterized by increased viability of the cells and a lack of irritant and phototoxic potential. The evaluations on 2D cells confirm the preferential cytotoxic effect of Rut on melanoma cells (IC50 value = 8.601 &micro, M, nuclear fragmentation) compared to normal keratinocytes. Our data suggest that the proniosomal gel is a promising drug carrier for Rut in the management and prevention of skin disorders.

The aim of the present investigation was to develop and evaluate microemulsion-loaded hydrogels (MEHs) for the topical delivery of fluconazole (FZ). The solubility of FZ in oils, surfactants and cosurfactants was evaluated to identify the components of the microemulsion. The pseudo-ternary phase diagrams were constructed using the novel phase diagram by micro-plate dilution method. Carbopol EDT 2020 was used to convert FZ-loaded microemulsions into gel form without affecting their structure. The selected microemulsions were assessed for globule size, zeta potential and polidispersity index. Besides this, the microemulsion-loaded hydrogel (MEH) formulations were evaluated for drug content, pH, rheological properties and in vitro drug release through synthetic membrane and excised pig ear skin in comparison with a conventional hydrogel. The optimised MEH FZ formulations consisting of FZ 2%, Transcutol P 11.5% and 11%, respectively, as oil phase, Lansurf SML 20-propyleneglycol 52% and 50%, respectively, as surfactant–cosurfactant (2:1), Carbopol EDT 2020 1.5% as gelling agent and water 34.5% and 37%, respectively, showed highest flux values and high release rate values, and furthermore, they had low surfactant content. The in vitro FZ permeation through synthetic membrane and excised pig ear skin from the studied MEHs was best described by the zero-order and first-order models. Finally, the optimised MEH FZ formulations showed similar or slightly higher antifungal activity as compared to that of conventional hydrogel and Nizoral® cream, respectively. The results suggest the potential use of developed MEHs as vehicles for topical delivery of FZ, encouraging further in vitro and in vivo evaluation.

The use of water-soluble polymers of natural, semisynthetic, and synthetic origin for dermal and transdermal drug delivery systems is manifold. Among the most used biopolymers in the formulation of skin preparations, the cellulose ether derivatives as representatives of semisynthetic polymers distinguish through their specific physico‐ chemical properties, by which the pharmacist can select the appropriate cellulose derivative for a particular purpose. The hydrogels containing cellulose derivatives as gelling agents are widely used as water-soluble ointment bases, because they usually associate the characteristics of both conventional and innovative hydrogels, including especially safety, biocompatibility, biodegradability, and a relatively easy way of preparation and low price. The present chapter describes the following issues: the physicochemical properties of water-soluble cellulose derivatives in relationship with their type and grade; physical and chemical properties of cellulose-derivatives-based hydrogels and their compatibility with other auxiliary substances commonly used in the formulation of pharmaceutical hydrogels; the development and manufacturing of these hydrogels on both small and large scales; the characterization of cellulose derivatives hydrogels as pharmaceutical dosage forms through different compendial and noncompendial methods; and well-recognized and novel applications of cellulosederivatives-based hydrogels for dermal and transdermal drug delivery.

BACKGROUND: Curcuma longa Linnaeus and Zingiber officinale Roscoe are two main representatives ofZingiberaceae family studied for a wide range of therapeutic properties, including: antioxidant, anti-inflammatory, anti-angiogenic, antibacterial, analgesic, immunomodulatory, proapoptotic, anti-human immunodeficiency virus properties and anticancer effects. This study was aimed to analyse the ethanolic extracts of Curcuma rhizome (Curcuma longa Linnaeus) and Zingiber rhizome (Zingiber officinale Roscoe) in terms of polyphenols, antioxidant activity and anti-melanoma potential employing the B164A5 murine melanoma cell line. RESULTS: In order to evaluate the total content of polyphenols we used Folin-Ciocâlteu method. The antioxidant activity of the two ethanolic extracts was determined by DPPH assay, and for the control of antiproliferative effect it was used MTT proliferation assay, DAPI staining and Annexin-FITC-7AAD double staining test. Results showed increased polyphenols amount and antioxidant activity forCurcuma rhizome ethanolic extract. Moreover, 100 μg/ml of ethanolic plant extract from both vegetal products presented in a different manner an antiproliferative, respectively a proapoptotic effect on the selected cell line. CONCLUSIONS: The study concludes that Curcuma rhizome may be a promising natural source for active compounds against malignant melanoma.

There are a great variety of processing the analytical spectroscopy data, especially useful in multicomponent systems [Ewing et al., 1953; Garrido et al., 2004; Lykkesfeld, 2001; Oka et al., 1991; Sanchez & Kowalski, 1986]. These methods essentially are based on different strategies of mathematical strategies including specific formalism of mathematical statistics and of matrix algebra [Garrido et al., 2004; Szabadai, 2005]. The matrix-based methods reffer to quantitative analysis [Bosch-Reigh et al., 1991; Garrido et al., 2008; Li et al., 2011; Lozano et al., 2009; Ruckenbusch et al., 2006; Szabadai, 2005], to determination of the number of independent chemical equilibria in multicomponent systems [Szabadai, 2005] and for correction the action of various perturbing factors such as stray light or backgroud absorption [Burnius, 1959; Fox & Mueller, 1950; Melnick, 1952; Morton & Stubbs, 1946, 1947, 1948; Owen, 1995; Page & Berkovitz, 1943; Szabadai, 2005].

The aim of this work was to evaluate thermal stability of some W/O/W concentrated double emulsions (with 80% dispersed phase) containing 1% piroxicam following their theological behaviour at various temperatures. W/O/W double emulsions containing 1% piroxicam were prepared using the two-step procedure.The variable parameter of formulations was the hydrophilic macromolecule compound dispersed in the internal and external aqueous phases (hydroxyethylcellulose and Carbopol 940). Rheological behaviour and viscosity of the obtained W/O/W double emulsions was measured at 15 degrees C, 20 degrees C, 25 degrees C, 30 degrees C and 35 degrees C respectively, after preparation. The obtained results demonstrated that the studied W1/O/W2 double emulsions containing 1% piroxicam were stable under applied thermal stress, although they exhibited some differences in rheological properties caused by formulation variable.

Aim: The aim of this study was to investigate the correlation between biochemical, functional and structural markers of endothelium damage. Material and methods: 68 patients with essential hypertension were included in a prospective study. We studied biochemical markers respectively functional and structural evaluation. Results: A higher mean values of sICAM-1 (380 respectively 334) and hs-CRP (4, 31 respectively 3, 32) was observed in the first two groups with endothelial dysfunction as compared with the control group (227 respectively 1, 91). The mean values of sP-selectin was higher for the first group (134) compared also with the second and the third groups (88 respectively 68, p < 0,001) with normal values. Conclusions: High ICAM-1, P-selectin and hs-CRP plasma levels was observed and a significant correlation with structural changes and with functional changes in endothelium dependent FMD and could be used as a biochemical marker of endothelial dysfunction.