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Evren H Gokce,1 Emrah Korkmaz,1 Sakine Tuncay-Tanriverdi,1 Eleonora Dellera,2 Giuseppina Sandri,2 M Cristina Bonferoni,2 Ozgen Ozer11Department of Pharmaceutical Technology, Faculty of Pharmacy, University of Ege, Izmir, Turkey; 2Department of Drug Sciences, University of Pavia, Pavia, ItalyBackground: The effective delivery of coenzyme Q10 (Q10) to the skin has several benefits in therapy for different skin pathologies. However, the delivery of Q10 to deeper layers of skin is challenging due to low aqueous solubility of Q10. Liposomes and solid lipid nanoparticles (SLN) have many advantages to accomplish the requirements in topical drug delivery. This study aims to evaluate the influence of these nanosystems on the effective delivery of Q10 into the skin.Methods: Q10-loaded liposomes (LIPO-Q10) and SLNs (SLN-Q10) were prepared by thin film hydration and high shear homogenization methods, respectively. Particle size (PS), polydispersity index (PI), zeta potential (ZP), and drug entrapment efficiency were determined. Differential scanning calorimetry analysis and morphological transmission electron microscopy (TEM) examination were conducted. Biocompatibility/cytotoxicity studies of Q10-loaded nanosystems were performed by means of cell culture (human fibroblasts) under oxidative conditions. The protective effect of formulations against production of reactive oxygen species were comparatively evaluated by cytofluorometry studies.Results: PS of uniform SLN-Q10 and LIPO-Q10 were determined as 152.4 ± 7.9 nm and 301.1 ± 8.2 nm, respectively. ZPs were −13.67 ± 1.32 mV and −36.6 ± 0.85 mV in the same order. The drug entrapment efficiency was 15% higher in SLN systems. TEM studies confirmed the colloidal size. SLN-Q10 and LIPO-Q10 showed biocompatibility towards fibroblasts up to 50 µM of Q10, which was determined as suitable for cell proliferation. The mean fluorescence intensity % depending on ROS production determined in cytofluorometric studies could be listed as Q10 ≥ SLN-Q10 > LIPO-Q10.Conclusion: The LIPO-Q10 system was able to enhance cell proliferation. On the contrary, SLN-Q10 did not show protective effects against ROS accumulation. As a conclusion, liposomes seem to have advantages over SLN in terms of effective delivery of Q10 to skin for antioxidant purposes.Keywords: solid lipid nanoparticles, liposomes, coenzyme Q10, antioxidant, cytotoxicity

Evren H Gokce1, Emrah Korkmaz1, Eleonora Dellera2, Giuseppina Sandri2, M Cristina Bonferoni2, Ozgen Ozer11Department of Pharmaceutical Technology, Faculty of Pharmacy, University of Ege, Izmir, Turkey; 2Department of Drug Sciences, University of Pavia, Pavia, ItalyBackground: Excessive generation of radical oxygen species (ROS) is a contributor to skin pathologies. Resveratrol (RSV) is a potent antioxidant. Solid lipid nanoparticles (SLN) and nanostructured lipid carriers (NLC) can ensure close contact and increase the amount of drug absorbed into the skin. In this study, RSV was loaded into SLN and NLC for dermal applications.Methods: Nanoparticles were prepared by high shear homogenization using Compritol 888ATO, Myglyol, Poloxamer188, and Tween80. Particle size (PS), polydispersity index (PI), zeta potential (ZP), drug entrapment efficiency (EE), and production yield were determined. Differential scanning calorimetry (DSC) analysis and morphological transmission electron microscopy (TEM) examination were conducted. RSV concentration was optimized with cytotoxicity studies, and net intracellular accumulation of ROS was monitored with cytofluorimetry. The amount of RSV was determined from different layers of rat abdominal skin.Results: PS of uniform RSV-SLN and RSV-NLC were determined as 287.2 nm ± 5.1 and 110.5 nm ± 1.3, respectively. ZP was –15.3 mV ± 0.4 and –13.8 mV ± 0.1 in the same order. The drug EE was 18% higher in NLC systems. TEM studies showed that the drug in the shell model was relevant for SLN, and that the melting point of the lipid in NLC was slightly lower. Concentrations below 50 µM were determined as suitable RSV concentrations for both SLN and NLC in cell culture studies. RSV-NLC showed less fluorescence, indicating less ROS production in cytofluorometric studies. Ex vivo skin studies revealed that NLC are more efficient in carrying RSV to the epidermis.Conclusion: This study suggests that both of the lipid nanoparticles had antioxidant properties at a concentration of 50 µM. When the two systems were compared, NLC penetrated deeper into the skin. RSV-loaded NLC with smaller PS and higher drug loading appears to be superior to SLN for dermal applications.Keywords: solid lipid nanoparticles, nanostructured lipid carriers, resveratrol

Sinem Yaprak Karavana,1 Evren Homan Gökçe,1 Seda Rençber,1 Seda Özbal,2 Çetin Pekçetin,2 Pelin Güneri,3 Gökhan Ertan11Department of Pharmaceutical Technology, Faculty of Pharmacy, Ege University, Bornova-Izmir, 2Department of Histology and Embryology, School of Medicine, Dokuz Eylul University, Inciralti, Izmir, 3Department of Oral Diagnosis and Radiology, Faculty of Dentistry, Ege University, Bornova-Izmir, TurkeyAim: To develop a suitable buccal bioadhesive gel formulation containing cyclosporine A solid lipid nanoparticles (CsA SLNs) for the treatment of recurrent aphthous stomatitis.Methods: The suitability of the prepared formulations for buccal application was assessed by means of rheological studies, textural profile analysis, and ex vivo drug-release studies. Plastic flows, typical gel-like spectra, and suitable mechanical properties were obtained from prepared formulations. The retention time was explored in in vivo distribution studies and the effect of the gel containing CsA SLNs on the healing of oral mucosal ulceration was investigated in an animal model. In vivo distribution studies are a very important indicator of the retention time of formulations at the application site.Results: Distribution studies showed that 64.76% ± 8.35% of the formulation coded "F8+SLN" remained on the buccal mucosa 6 hours after application. For the second part of the in vivo experiments, 36 rabbits were separated into three groups: the first group was treated with the gel formulation without the active agent; the second group with the gel formulation containing CsA SLNs; and the third group, used as the control group, received no treatment. Wound healing was established by scoring of the rate of wound healing on Days 3, 6, 9, and 12. Histological observations were made on the same days as the scoring studies. The bioadhesive gel formulation that included CsA SLNs increased the rate of mucosal repair significantly.Conclusion: This study has shown that the bioadhesive gel formulation containing CsA SLNs reported here is a promising candidate for the topical treatment of recurrent aphthous stomatitis.Keywords: SLNs, buccal application, wound healing, oral mucosal disease

Background: Prednisolone-derived corticosteroid (PDC) has anti-inflammatory activity in ocular administration. However, drug administration to the eye is extremely difficult due to the complex structure of the eye. Because of the ability of the eye to retain the drug and its physiology, the bioavailability of drugs applied to the eye is very low., Objective: One of the methods to overcome bioavailability problem is to formulate the drug as a nanoemulsion (NE). NEs are thermodynamically stable, colloidal drug delivery systems. They have small globule size and high surface area. These properties give them the ability to cross the biological membrane and increase the therapeutic efficacy of the drug molecule., Methodology: The high energy method was used to create an NE eye drop formulation containing PDC, and the effects of changing homogenization processes on NE formation were investigated. After deciding on the optimum formulation; characterization, assay, and in vitro release studies were performed, and the stability of the formulation was followed for 12 months., Results: The optimum formulation selected initially had 126.6 ± 40.12 nm and 99.9 ± 1.2% PDC, it had 125.4 ± 41.20 nm and 99.29 ± 1.3% PDC after 12 months in 25 °C 40% RH conditions. Cytotoxicity studies have shown no significant cytotoxic effects in NE-containing PDC., Conclusion: The preparation and optimization of topical NE formulations containing PDC for ocular inflammation treatment were achieved. The developed formulation was stable for 12 months and no toxic effect was found in cell culture studies. This formulation could be useful as an alternative to PDC for ocular applications.

This study encompasses the validation of a simple, rapid, and sensitive HPLC/UV method developed in accordance with the guidelines set by ICH Q2(R2) for obtaining the active pharmaceutical ingredient from the glycosaminoglycan family in topical formulations. Previous methods reported for analyzing glycosaminoglycans in semisolid formulations are relatively complex and time-consuming, involving extraction, purification, and derivatization. This developed analytical method allows for straightforward extraction of the active pharmaceutical ingredient from the matrix, enabling the direct injection of samples. This method was performed and validated for the assay of the pharmaceutical gel and cream formulations to investigate the parameters of linearity ( r = 0.9997 for the gel formulation and r = 0.9993 for the cream formulation), precision, accuracy, specificity, and robustness by HPLC/UV. Additionally, this method was used to determine the active ingredient in in vitro release studies. In vitro similarity correlation against commercial products was performed according to the Mann-Whitney U statistical test. The similarity results were 96.5-102.7% for the gel formulation and 98.0-106.0% for the cream formulation, which remained within the limits (75-133.33%) according to USP 1724. This proved that in vitro release profiles for both formulations were like those of the commercial product. In light of the research findings, we believe that the HPLC/UV analysis presented can be further enhanced in the future for determining the levels of active ingredients in various pharmaceutical formulations or for monitoring the levels of glycosaminoglycans in biological matrixes., Competing Interests: The authors declare no competing financial interest., (© 2024 The Authors. Published by American Chemical Society.)

Xylometazoline is a well-established nasal decongestant that has been used alone and in combination with dexpanthenol as an over the counter (OTC) medicine. Considering the possibility of further improvement of xylometazoline nasal formulations, hyaluronic acid (HA) was evaluated as an additional ingredient. The aim of this study was to investigate the permeation, mucosal retention, and mucoadhesion properties of a new xylometazoline-HA [Xylo-HA] formulation ex vivo and to explore the potential benefits of incorporating HA in the formulation in vitro. Sheep nasal mucosa was used in the ex vivo study, where Xylo-HA was compared with xylometazoline alone [Xylo-Mono], and in combination with dexpanthenol [Xylo-Dex] to understand the impact of formulation changes. The permeation of xylometazoline was generally low (Xylo-Mono 11.14 ± 4.75 %, Xylo-HA 14.57 ± 5.72 % and Xylo-Dex 11.00 ± 3.05 % of the applied dose). The steady state fluxes of xylometazoline were determined as 12.64 ± 3.52 μg/cm 2 h, 14.94 ± 3.38 μg/cm 2 h and 12.19 ± 2.05 μg/cm 2 h for Xylo-Mono, Xylo-HA and Xylo-Dex, respectively. No significant differences were observed between the formulations in the permeation nor mucosal retention studies (p > 0.05 for all), while Xylo-HA exhibited superior mucoadhesive proprieties (p < 0.05 for all). The effects on wound healing and barrier integrity of the three xylometazoline formulations were tested in vitro on HaCaT cells. To better elucidate the role of HA, an additional HA formulation without xylometazoline was prepared (HA-Mono). A scratch test was performed to evaluate wound healing, revealing that the test formulations did not achieve complete wound closure within 72 h and demonstrated a similar effect at the end of the testing period. To assess the effect on barrier integrity, cells were treated for 5 days with daily measurements of transepithelial electrical resistance (TEER). At the end of the experiment, Xylo-Dex showed a moderate 14 % increase in TEER, while Xylo-Mono did not significantly affect this parameter. TEER rose by 951 % in the Xylo-HA, and by 10497 % in the HA group, suggesting that incorporating HA led to enhanced barrier function. Further clinical studies are recommended to better understand the clinical implications and efficacy of the Xylo-HA formulation, with particular focus on the role of HA., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Background: Pomegranate peel extract is known as a powerful antioxidant and due to preventing oxidation, it can reduce color change of dyed hair after washing. Liposomes are vesicular systems that include lipids and can form a film on hair fibers. Delivery system and active agent have a synergistic effect on protecting hair color and reducing dyeing frequency., Aims: This study aimed to prepare liposomes suspension as an innovative formulation of pomegranate peel extract to reduce hair color changing., Methods: Pomegranate peel extract-loaded liposomes were prepared with lipidic film hydration method. The characterizations of formulations (F1 and F2) were defined by several parameters. The pH, particle size, polydispersity index, zeta potential, microscopical image, loading capacity (LC), and encapsulation efficiency (EE) of formulations were determined. The antioxidant capacity of formulations and actives were tested. The effect of formulations on hair color change was shown with ex-vivo studies., Results: The results showed that cholesterol influenced particle size, zeta potential, and antioxidant capacity. The particle sizes of formulations were 217.71 ± 6.74 nm and 577.5 ± 1.41 nm for F1 and F2, respectively. F2 formulation had better results for zeta potential (33.8 mV) while F1 was neutral. Morphologic images confirmed vesicular structure or liposomes. The EE was found higher for F2 than F1 (F1: 57.14 and F2: 78.69). Antioxidant studies confirmed that active substance and the vesicular system had a synergistic effect on protection from oxidation. Selected formulation reduced hair color change as shown in ex-vivo tests., Conclusion: Pomegranate peel extract-loaded liposomes were designed for hair color protection. It was shown with this study that prepared formulations have a good color protection on hair fibers due to antioxidant properties of pomegranate peel extract and film forming effect of liposomal formulations. According to results, prepared liposomal formulations may serve as a good alternative for reducing dyeing frequency and protecting hair fibers., (© 2022 Wiley Periodicals LLC.)

Nigella sativa L. is shown wide spread over the world and contains many useful phytochemicals. Much of the biological activity of the seeds has been shown due to the presence of thymoquinone (TQ). Its poor aqueous solubility of TQ hinders its delivery to target site. The aim of this work was to prepare TQ bigels composed of Carbopol 974 P NF (C974) in PEG 400 (organogel) or C974 in water (hydrogel) with microwave heating method. A novel technique, high speed homogenization followed by microwave heating, was used to prepare organogels. The pH, electrical conductivity, differential scanning calorimetry, rheological properties, and morphological structure of the formulations have been evaluated, and the effect of microwave on drug content and TQ antioxidant activity has been investigated. The bigels of TQ were successfully produced via high-speed homogenization followed by microwave-assisted heating for the first time in this study. Highly lipophilic TQ was successfully dissolved in organogel, and it was not affected from the microwaves. It can be stated that microwave heating is a promising method to obtain C974 organogels and thus bigels with appropriate above indicated investigated physicochemical characteristics. The time and energy consumption could be decreased with microwave-assisted heating, especially for gel preparation in the field of pharmaceuticals.

Background: The eyes are among the most readily accessible organs in terms of location in the body, yet drug delivery to eye tissues is particularly problematic. The anatomy, physiology and biochemistry of the eye limit the ophthalmic delivery of drugs. Numerous strategies in ophthalmic drug delivery have been made to expand the bioavailability and to prolong the remaining time of drugs treated topically to eye., Methods: Designing a novel delivery vehicles that can proficiently target the diseased eye tissue, generate high drug levels, and keep sustained and effective concentrations with no or minimum side effects is the main concentration of present examination. One of the encouraging approaches currently is the use of lipidic nanoparticle vehicles categorized by a submicron-meter dimension. Due to their properties and numerous advantages, solid lipid nanoparticles and nanostructure lipid carriers are promising systems for ocular drug delivery., Conclusion: The focus of this review is on the recent developments in ophthalmic lipid nanoparticles, the rationale for their use, drug loaded SLNs and NLCs, and the characteristic advantages, limitations of this system and recent studies., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.)

An alternative formulation for the treatment of diabetic foot wounds that heal slowly is a requirement in pharmaceutical field. The aim of this study was to develop a dermal matrix consisting of skin proteins and lipids with an antioxidant that will enhance healing and balance the oxidative stress in the diabetic wound area due to the high levels of glucose. Thus a novel three dimensional collagen-laminin porous dermal matrix was developed by lyophilization. Resveratrol-loaded hyaluronic acid and dipalmitoylphosphatidylcholine microparticles were combined with this dermal matrix. Characterization, in vitro release, microbiological and in vivo studies were performed. Spherical microparticles were obtained with a high RSV encapsulation efficacy. The microparticles were well dispersed in the dermal matrix from the surface to deeper layers. Collagenase degraded dermal matrix, however the addition of RSV loaded microparticles delayed the degradation time. The release of RSV was sustained and reached 70% after 6h. Histological changes and antioxidant parameters in different treatment groups were investigated in full-thickness excision diabetic rat model. Collagen fibers were intense and improved by the presence of formulation without any signs of inflammation. The highest healing score was obtained with the dermal matrix impregnated with RSV-microparticles with an increased antioxidant activity. Collagen-laminin dermal matrix with RSV microparticles was synergistically effective due to presence of skin components in the formulation and controlled release achieved. This combination is a safe and promising option for the treatment of diabetic wounds requiring long recovery., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Coenzyme Q10 (Q10) loaded solid lipid nanoparticles (SLN) were prepared by the high speed homogenization method and incorporated into Carbopol 974P hydrogels. Compritol 888 ATO (C888) was employed as the lipid base; Poloxamer 188 (P188) and Tween 80 (Tw80) were used as surfactant and co-surfactant. Optimum particle size with narrow distribution was obtained as 152.2 nm for blank and 142.4 nm for Q10 loaded SLNs. The overall charge of loaded SLNs was -13.7 ± 1.3 mV. Q10 entrapment efficiency was 89 % and the production yield was 94 %. Transmission electron microscopy analysis provided evidence of colloidal size, spherical shape while differential scanning calorimetry analysis confirmed recrystallization of the lipid after the preparation of SLNs. Trolox equivalent antioxidant capacity (TEAC) analysis has shown that antioxidant potential of Q10 can be protected in SLNs. Rheological characteristics demonstrated that the SLN incorporating gels were shear thinning and the mechanical strength of the gels was suitable for topical application. Diffusion studies from rat abdominal skin revealed that the delivery of Q10 was doubled in SLN incorporating gels, approximately 40 μg cm-2, in comparison with gels prepared with only Q10 (not incorporated in SLNs). As a result, it can be stated that Q10-SLN loaded gels can be successful delivery systems for carrying Q10 efficiently into the skin without losing its antioxidant properties.

Background: Excessive generation of radical oxygen species (ROS) is a contributor to skin pathologies. Resveratrol (RSV) is a potent antioxidant. Solid lipid nanoparticles (SLN) and nanostructured lipid carriers (NLC) can ensure close contact and increase the amount of drug absorbed into the skin. In this study, RSV was loaded into SLN and NLC for dermal applications., Methods: Nanoparticles were prepared by high shear homogenization using Compritol 888ATO, Myglyol, Poloxamer188, and Tween80. Particle size (PS), polydispersity index (PI), zeta potential (ZP), drug entrapment efficiency (EE), and production yield were determined. Differential scanning calorimetry (DSC) analysis and morphological transmission electron microscopy (TEM) examination were conducted. RSV concentration was optimized with cytotoxicity studies, and net intracellular accumulation of ROS was monitored with cytofluorimetry. The amount of RSV was determined from different layers of rat abdominal skin., Results: PS of uniform RSV-SLN and RSV-NLC were determined as 287.2 nm ± 5.1 and 110.5 nm ± 1.3, respectively. ZP was -15.3 mV ± 0.4 and -13.8 mV ± 0.1 in the same order. The drug EE was 18% higher in NLC systems. TEM studies showed that the drug in the shell model was relevant for SLN, and that the melting point of the lipid in NLC was slightly lower. Concentrations below 50 μM were determined as suitable RSV concentrations for both SLN and NLC in cell culture studies. RSV-NLC showed less fluorescence, indicating less ROS production in cytofluorometric studies. Ex vivo skin studies revealed that NLC are more efficient in carrying RSV to the epidermis., Conclusion: This study suggests that both of the lipid nanoparticles had antioxidant properties at a concentration of 50 μM. When the two systems were compared, NLC penetrated deeper into the skin. RSV-loaded NLC with smaller PS and higher drug loading appears to be superior to SLN for dermal applications.

The pharmacological activity of a drug molecule depends on its ability to dissolve and interact with its biological target, either through dissolution and absorption, or through dissolution and receptor interaction. The low bioavailability that characterizes poorly water-soluble drugs is usually attributed to the dissolution kinetic profile. Novel strategies to effectively deliver these drugs include nanoparticulate approaches that either increase the surface area of the drug or improve the solubility characteristics of the drug. Nanosizing approaches are based on the production of drug nanocrytals dispersed in an aqueous surfactant solution, whereas other possibilities include drug loading in nanoparticles. Promising nanoparticulate approaches include the development of lipid-based nanocarriers to increase drug solubility followed by enhanced bioavailability. To select the best approach there are, however, some critical considerations to take into account, for example the physicochemical properties of the drug, the possibility to scale-up the production process, the toxicological considerations of the use of solvents and cosolvents, the selection of an environmentally sustainable methodology and the development of a more patient-friendly dosage form. This article addresses these relevant questions and provides feasible examples of novel strategies with respect to relevant administration routes.

Cyclosporine A (CsA) loaded solid lipid nanoparticles (SLNs) for topical ophthalmic applications were prepared by high shear homogenization and ultrasound method using Compritol 888 ATO, Poloxamer 188 and Tween 80, to investigate the cellular uptake of rabbit corneal epithelial cells (RCE) and to evaluate the cytotoxicity. The size of the optimized formulation was 225.9+/-5.5 nm with a polydispersity index of 0.253+/-0.05. The zeta potential and entrapment efficiency was detected as -16.9+/-0.7 mV and 95.6%, respectively. The CsA release was found to be enzyme (lipase/co-lipase complex) dependent. SLNs were sterilized at 110 and 121 degrees C. The cytotoxicity was evaluated in vitro by means of RCE cells and was higher at 121 degrees C sterilization temperature, probably due to a supposed leakage of Tween 80 following lipid re-crystallization. The permeation and penetration of CsA across/into the corneal cells were evaluated using in vitro and ex vivo experiments. The cellular uptake was investigated by replacing CsA with the fluorescent dye Rhodamine B. The penetration enhancement properties were supported by confocal laser scanning microscopy analysis. The internalization of SLNs in cornea and in RCE cell lines was confirmed, pointing out the possibility of CsA targeting to the cornea.

In some multidrug therapy programs, ketoconazole (KTZ) may be administered with some antacids that could modify its dissolution rate and reduce its absorption, thus leading to therapeutic failures. The primary aim of this study was to evaluate the influence of Compritol HD5 ATO and Compritol 888 ATO on this interaction in comparison with commercial KTZ tablets. The second aim was to prepare lipid granules of KTZ that could be an alternative to the commercial formulation. Therefore, six KTZ sustained-release granules were prepared with different lipid concentrations, because they were found to be more suitable than tablets that are dissolved only in gastric medium. The results confirmed that the dissolution rate of KTZ granules was significantly reduced in the presence of antacids. The ideal formulation was selected as granules including 5% of Compritol lipids in relation to the suitability of the target profile. Therapeutic effects of orally administered, ideal KTZ granule formulations, and commercial tablets were evaluated in vivo by the experimental model of murine vulvo-vaginal candidiasis (VVC) with and without antacids. It was found that formulations were very effective on VVC, and the therapeutic effect decreased significantly in the presence of antacids. Histopathological studies were carried out for vagina, stomach, and liver tissues and hepatoxicity was also examined. The levels of reduced glutathione (GSH) were measured to assess the oxidative stress induced by KTZ and function of the liver. It was observed that orally administered formulations of KTZ were successful in treating candidiasis in mice without irritancy in stomach. However, liver tissues were damaged. The decreased GSH levels indicated toxicity in our study. This study suggested that in vitro release and in vivo microbiological-toxicological properties of KTZ were affected by antacids and drug-excipient interactions. Lipid granules of KTZ prepared with Compritol 888 ATO could be proposed as a new KTZ solid dosage form with optimum dissolution and therapeutic characteristics.