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Quercetin (Que) is a flavonoid associated with high oxygen radical scavenging activity and potential neuroprotective activity against Alzheimer's disease. Que's oral bioavailability is limited by its low water solubility and extended peripheral metabolism; thus, nasal administration may be a promising alternative to achieve effective Que concentrations in the brain. The formation of Que-2-hydroxypropylated-β-cyclodextrin (Que/HP-β-CD) complexes was previously found to increase the molecule's solubility and stability in aqueous media. Que-methyl-β-cyclodextrin (Que/Me-β-CD) inclusion complexes were prepared, characterized, and compared with the Que/HP-β-CD complex using biophysical and computational methods (phase solubility, fluorescence and NMR spectroscopy, differential scanning calorimetry (DSC), and molecular dynamics simulations (MDS)) as candidates for the preparation of nose-to-brain Que's delivery systems. DSC thermograms, NMR, fluorescence spectroscopy, and MDS confirmed the inclusion complex formation of Que with both CDs. Differences between the two preparations were observed regarding their thermodynamic stability and inclusion mode governing the details of molecular interactions. Que's solubility in aqueous media at pH 1.2 and 4.5 was similar and linearly increased with both CD concentrations. At pH 6.8, Que's solubility was higher and positively deviated from linearity in the presence of HP-β-CD more than with Me-β-CD, possibly revealing the presence of more than one HP-β-CD molecule involved in the complex. Overall, water solubility of lyophilized Que/Me-β-CD and Que/HP-β-CD products was approximately 7-40 times and 14-50 times as high as for pure Que at pH 1.2-6.8. In addition, the proof of concept experiment on ex vivo permeation across rabbit nasal mucosa revealed measurable and similar Que permeability profiles with both CDs and negligible permeation of pure Que. These results are quite encouraging for further ex vivo and in vivo evaluation toward nasal administration and nose-to-brain delivery of Que.

Chronic wounds unresponsive to existing treatments constitute a serious disease burden. Factors that contribute to the pathogenesis of chronic ulcers include oxidative stress, comorbid microbial infections, and the type of immune system response. Preclinically, and in a case study, a formulation containing a Ceratothoa oestroides olive oil extract promoted wound healing. Patients with chronic venous and pressure ulcers, clinically assessed as being unresponsive to healing agents, were treated for 3 months with an ointment containing the C oestroides extract combined with antibiotic and/or antiseptic agents chosen according to the type of bacterial infection. Treatment evaluation was performed using the Bates-Jensen criteria with +WoundDesk and MOWA cell phone applications. After 3 months of treatment, C oestroides resulted in an average decrease of 36% in the Bates-Jensen score of ulcers ( P < .000), with the decrease being significant from the first month ( P < .007). The combined use of topically applied antibiotics and antiseptics efficiently controlled microbial ulcer infection and facilitated wound healing. In relation to other factors such as initial wound size, chronicity appeared to be an important prognostic factor regarding the extent of wound healing. Future clinical investigations assessing the wound healing efficacy of the C oestroides olive oil extract are warranted.

Acute radiodermatitis is the most common side effect in non-melanoma skin cancer patients undergoing radiotherapy. Nonetheless, despite the ongoing progress of clinical trials, no effective regimen has been found yet. In this study, a non-woven patch, comprised of electrospun polymeric micro/nanofibers loaded with an aqueous extract of Pinus halepensis bark (PHBE), was fabricated and clinically tested for its efficacy to prevent radiodermatitis. The bioactivity of the PHBE patch was evaluated in comparison with a medical cream indicated for acute radiodermatitis. Twelve volunteer patients were selected and randomly assigned to two groups, applying either the PHBE patch or the reference cream daily. Evaluation of radiation-induced skin reactions was performed during the radiotherapy period and 1 month afterwards according to the Radiation Therapy Oncology Group (RTOG) grading scale, photo-documentation, patient-reported outcomes (Visual Analog Scale, questionnaire), biophysical measurements (hydration, transepidermal water loss, erythema, melanin), and image analysis. In contrast with the reference product, the PHBE patch showed significant anti-inflammatory activity and restored most skin parameters to normal levels 1 month after completion of radiation therapy. No adverse event was reported, indicating that the application of the PHBE patch can be considered as a safe medical device for prophylactic radiodermatitis treatment.

Background/aim Cigarette smoke (CS) is a major environmental health threat. The oxidative stress induced by CS on keratinocytes and the possible protective effect of nicotine, its receptor inhibitors, and Pinus halepensis bark extract in relation to known antioxidants were investigated. Materials and methods Primary mouse keratinocytes were exposed to cigarette smoke in the presence and absence of Pinus halepensis bark extract (1 μg/ml), rutin (50 μM) and ascorbic acid (250 μM), nicotine (1 μM) with or without mecamylamine (5 μM) and α-bungarotoxin (0.1 μM). Keratinocyte viability and oxidative stress were evaluated by MTT and fluorescence assays. Results Pinus halepensis bark extract decreased the oxidative stress and increased the viability of keratinocytes, and moreover, these effects were more pronounced compared to the mixture of rutin and L-ascorbic acid. Nicotine significantly enhanced the viability potentiation of the beneficial effect induced by Pinus halepensis bark extract. Mecamylamine and α-bungarotoxin showed no specific effect. Conclusion Pinus halepensis bark extract in combination with nicotine may successfully reverse skin damage induced by cigarette smoke.

The aim of this work was to develop a transdermal gel formulation for enhanced delivery of candesartan. The in vitro skin permeation of the drug was examined using modified Franz type diffusion cells and epidermal membrane, taken from full thickness hairless mouse skin. Initially, a full 24 factorial design was employed, in order to estimate the effects and interactions of the following factors: the chemical form of the Active Pharmaceutical Ingredient (API), the concentration of triethanolamine (TEtA), the concentration of 1,8-cineole and the type of the vehicle's co-solvent, on the in vitro skin permeation. The experimental design revealed the optimum formulation consisting of candesartan, 5% TEtA, 10% 1,8-cineole and glycerol formal, which provided an increased flux, approximately two hundred times higher than the control formulation. Furthermore, NMR and mass spectrometry demonstrated the ion pair formation between TEtA and candesartan as an effective strategy for significantly improving its in vitro skin permeation.

The in vitro skin permeation of furosemide, a commonly used loop diuretic, through human epidermis, as a preliminary step towards the development of a transdermal therapeutic system, was examined. A screening study was carried out, in order to estimate the effects of the type, the concentration of enhancer and the concentration of gelling agent on the cumulative amount of furosemide permeated through human epidermis, using a 3(3) factorial design. The type and the concentration of enhancer were further evaluated as they were found to affect significantly furosemide permeation. In order to further increase the amount of the drug permeated, the combination of two enhancers, Azone and oleyl alcohol, at three concentration levels was employed, using an optimization technique. The results indicated that higher amounts of furosemide permeated were observed when Azone was used at 5.0-6.5% (v/v) and oleyl alcohol at 7.5-9% (v/v), in the gels used. These formulations seem to be suitable for possible transdermal delivery of furosemide for pediatric use.

The in vitro permeation of ondansetron through human cadaver epidermis, as a preliminary step toward the development of a transdermal therapeutic system, was investigated. In vitro release studies were carried out using modified Franz diffusion cells and human epidermis, taken from cadaver skin by heat separation technique. To estimate the effect of the type and concentration of the penetration enhancers and the skin from different donors, an 8(1)3(2) asymmetrical factorial design was used. Formulations containing lauric acid and oleic acid as penetration enhancers, showed the largest Q values [amounts of ondansetron permeated per unit area of epidermal membrane (microg/cm2)] at 24, 48, and 72 hr, as well as steady-state flux values, among all formulations tested. The other enhancers increased the flux in the following order: lauryl alcohol>glycerol monooleate>Azone >cineole>oleyl alcohol>1-methyl-2-pyrrolidinone. Moreover, the concentration of the penetration enhancer and the type of the skin were proved to significantly affect the permeation rate of ondansetron through human epidermis. From the results obtained, it was shown that the formulations containing lauric acid or oleic acid at 5% or 10% could increase sufficiently the permeation of ondansetron. Therefore, the transdermal administration of ondansetron seems feasible.

The aim of this study was to determine the effect of the rotor speed, the amount of water sprayed and the atomizing air pressure on the size, size distribution and shape of the pellets produced in a fluid bed rotor granulator, using microcrystalline cellulose and α-lactose monohydrate as starting materials. It is a follow up study based on the conclusions of a 3 3 full factorial design performed previously. Initially, a new 2 3 full factorial design with center points was set up. However, the results of the analysis of variance, revealed the lack of fit of the linear model for the size and shape factors. Therefore, the original 2 3 factorial design was expanded to a central composite design in order to fit a second order polynomial that was then found to describe the data adequately. An increase of the amount of water added, resulted in larger pellets with increased sphericity, while an increase of the rotor speed decreased the size of the pellets and increased their sphericity. All the above-mentioned effects were found to be statistically significant (p

UV radiation is related to oxidative stress and skin aging. UV induced reactive oxygen species lead to progressive degradation of dermal collagen and elastin. Four of the most known anti-aging agents were examined in the photoaged skin of hairless SKH-hr2 mice. 50 mice were irradiated with increasing UVR doses (0.5–2 MED) 3 times per week for 4 weeks. After the end of the irradiations, 5 formulations containing retinoic acid 0.05%, lactic acid 10%, salicylic acid 3%, epidermal growth factor 3.3% and the vehicle were applied on the back of the mice for 3 weeks. Hydration, transepidermal water loss (TEWL), elasticity and skin thickness, were frequently measured. After the end of applications, oxidative stress was evaluated in skin biopsies and strippings of stratum corneum using fluorescence spectroscopy, as well endogenous antioxidants using HPLC–EC detection. Epidermal thickening was evident in all mice after UV exposure. After treatment with lactic acid the thickness decreased significantly. Highest TEWL was observed in the retinoic acid group. The skin treated with salicylic acid demonstrated the lowest levels of ascorbic and uric acid. In strippings, lactic acid icreased the levels of antioxidants. Highest elasticity was measured in the retinoic acid group. In conclusion, retinoic and lactic acids seem to be the most effective treatments for the photodamaged skin.

In this study a complex of flurbiprofen and 2-hydroxypropyl-β-cyclodextrin (2-HPβCD), was prepared employing a freeze-drying method. The production parameters and the final specifications of this product were optimised by using response surface methodology. The results show that the freeze-dried complex meets the requirements for solubility to be considered as a possible injectable form.

The in vitro permeation of nimodipine through human cadaver skin, as a preliminary step toward the development of a transdermal therapeutic system, was investigated. In vitro release studies were carried out using modified Franz diffusion cells and human epidermal membrane, taken from full-thickness cadaver skin by heat separation technique. To estimate the effect of the type of enhancer, the concentration of enhancer and the concentration of the gelling agent on the permeation of nimodipine, a 2(3) factorial design was involved. The type of enhancer was further evaluated, because it was found to be important for the permeation of nimodipine; the concentration of enhancer and the concentration of the gelling agent were kept at their optimum levels in all experiments. Six groups of enhancers (alkanols, alkanoic acids, alkanoic acids ethyl esters, caprylic acid alkyl esters, essential oils and some other enhancers) were examined for their ability to increase the permeation of nimodipine. It was found that myristyl alcohol, caprylic acid, L-menthol, and oleic acid gave better permeation rates at 24 hr, with oleic acid being the better enhancer, and higher permeation rates at 48 and 72 hr were achieved only when cineol was used.

The steady-state blood levels of a reformulated Theophylline sustained release tablet formulation (Quibron-T/SR®) were compared with Theo-dur® tablets 300mg SR. Statistical analysis was performed, using the two one-sided tests procedure, on the In-transformed values of maximum Theophylline plasma concentrations, trough plasma concentrations and Area Under the plasma concentration - time Curve. Data regarding Time to reach maximum plasma concentration were analyzed by analysis of variance on rank transformed values. In every case, the reformulated test treatment was found within the limits required to demonstrate bioequivalence.

During the past few years, great interest was developed in the subject of floating. In the present study, the floating and swelling characteristics of several excipients used controlled release technology were examined. The floating behavior was evaluated with resultant weight measurements, while a gravimetric method was employed for studying their swelling. The experiments were carried out in two different media, i.e. deionized water and simulated meal in order to monitor possible differences. The results indicated that higher molecular weight polymers and slower rates of polymer hydration are usually followed by enhanced floating behavior. The floating characteristics of all evaluated excipients were improved when simulated meal medium was used. Finally, the combination of resultant weight measurements and swelling experiments can be used to determine in vitro the buoyancy, weight and volume changes of orally administered dosage forms and to predict floating behavior.

The strong antidermatophytic action of griseofulvin, following oral administration, results from its concentration in the stratum corneum. However, this route of administration is often associated with various side effects. The purpose of this work was the preparation and in vitro evaluation of several gel formulations of griseofulvin, in which the drug was dissolved, for further clinical studies as an alternative topical dosage form. The in vitro release profiles of these formulations through artificial membranes and excised human skin, determined using Franz diffusion cells, showed that griseofulvin is released from the topical gel formulations employed and diffuses through skin. Additionally, stability studies conducted under room conditions for 16 months indicated that these formulations were adequately stable. Finally, preliminary clinical studies in humans showed that griseofulvin gels were effective and also well tolerated.

Transdermal application can be an alternative drug delivery route for ondansetron, an antiemetic drug. Previous studies found that fatty acids, namely oleic and lauric, were the most effective penetration enhancers. The aim of this study was to investigate the formation of an ion pair between ondansetron and lauric acid as a possible mechanism of its enhancing action. Several techniques were used to reveal the formation of an ion pair complex. Partitioning experiments, where the n-octanol/water coefficient was measured, showed an increase in the distribution coefficient in the presence of the acid, possibly as a result of the formation of more lipophilic ion pairs between the charged molecules of ondansetron and lauric acid. Further evidence of complex formation between ondansetron and lauric acid, was gained from the 13C-nuclear magnetic resonance (13C-NMR) spectra of ondansetron, lauric acid, and their mixture (molar ratio 1:1). The NMR spectra revealed alterations to the magnetic environment of the carbon atoms adjacent to the ionized group, which are the carbonyl group of the acid and the nitrogen of the imidazole ring of ondansetron. This evidence substantiates the theory of ion pair formation. Finally, thermal analysis of the binary mixtures of ondansetron and lauric acid revealed the formation of an additional compound, with different melting point from pure ondansetron and lauric acid, which is thermodynamically favored.

The effects of coating thickness, type of adhesive, and type and concentration of enhancer on the mechanical properties of two acrylic pressure-sensitive adhesives (PSAs) were investigated using a 2(4) factorial design and an optimization technique. Sixteen formulations containing 0% or 10% of either caprylic acid or methyl laurate in two different PSAs, namely Duro-Tak 87-2196 and Duro-Tak 87-2097, were prepared. The adhesive properties of these laminates were evaluated by applying the 90 degrees Dynamic Adhesive Strength Peel Test (90 degrees DASPT) and 1800 Release Liner Peel Test (180 degrees RLPT). Coating thickness, concentration of enhancer, and type of adhesive did affect the 90 degrees DASPT. For the 180 degrees RLPT, the most significant factors were coating thickness and concentration of enhancer, with a strong interaction observed between the two. Coating thickness and concentration of enhancer were also used to create mathematical models that correlated these factors with the mechanical properties of the PSAs. For this purpose, the optimization technique 3(2) was applied. It was found that the correlation of the above factors can be adequately described with polynomial equations, which can be used for predicting the mechanical properties of the laminates containing the above PSAs and methyl laurate (0%-10%).

The purpose of this study was to evaluate the effect of the concentration as well as the vehicle's pH on in vitro skin permeation by lactic acid from gel formulations, using an optimization technique. Nine gels containing 3%, 6%, and 9% (w/w) lactic acid in three different phosphate buffers, with pH values of 2.8, 3.8, and 4.8, were prepared and were applied in modified Franz diffusion cells. The pH of the vehicles and the lactic acid concentrations were used to create a mathematical model that correlates these factors with the cumulative amount of lactic acid permeated through human cadaver epidermis. For this purpose, the optimization technique 3(2) was applied. It was found that the correlation of the above factors can be adequately described with a polynomial equation, which can be used for predicting the cumulative amounts of lactic acid permeated. The results indicated that as the lactic acid's concentration increased, the cumulative amount permeated also increased after 24 h at all pH values. Moreover, the amount of lactic acid permeated decreased as the pH of the gels was increased. The greater amount permeated at all time intervals (6 h, 9 h, 12 h, and 24 h) was obtained when the concentration of lactic acid was 9% and the pH of the gel formulation was 2.8.

A 3(3) full factorial design study has been employed in order to investigate the effect of three variables on size, size distribution and three shape parameters, namely roundness, elongation and e(R), of pellets prepared in a fluid bed rotor granulator with the wet granulation technique. The first variable was a formulation variable, the % w/w content of microcrystalline cellulose (MCC) and the other two variables were processing variables, the temperature of inlet air and the spray rate of the granulation liquid. The analysis of variance showed that the three variables had a significant effect (P0.05) on pellet size and the shape factors, while only the spray rate influenced the particle size distribution. Significant interactions between the factors, for the size and the shape, were also found. The multiple regression analysis of the results led to equations that adequately describe the influence of the independent variables on the selected responses. Furthermore, the desirability function was employed in order to optimize the process under study. It was found that the optimum values of the responses could be obtained at the low levels of the % w/w content of MCC and temperature of inlet air and at the high level of the spray rate.

This study examined the effect of rotor speed, amount of water sprayed, and atomizing air pressure on the geometric mean diameter and geometric standard deviation of pellets produced in a fluid-bed rotor granulator using a 23 factorial design and an optimization technique. Pellets were prepared by wet granulation. Equal amounts of microcrystalline cellulose, alpha-lactose monohydrate, and distilled water were used as the granulation liquid. The size and the size distribution of the pellets were determined by sieve analysis. The size of the pellets was found to be dependent on the amount of water added, while an increase in rotor speed decreased their size. Both factors were found to be statistically significant (P.05). The effect of atomizing air pressure on pellet size was not statistically significant. None of the 3 factors significantly affected the geometric standard deviation of the pellets. The rotor speed and the amount of water sprayed were further selected in order to construct a mathematical model that correlates these factors with the geometric mean diameter of the pellets. For this purpose, the optimization technique 3(2) was used. The derived equation described the relationship between the selected factors and the size of the pellets. As a result, the experimental design techniques applied were found to be suitable in optimizing the pelletization process carried out in a fluid-bed rotor granulator.

Betamethasone -17- Valereate release characteristics, from several commercial dermatological bases, were evaluated before and after dilution with several excipients.It was found that betamethasone releases faster from creams than from ointments. In addition the release of the corticosteroid is affected by the composition of the diluting excipient.