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Camila Folle,1 Ana M Marqués,2 Natalia Díaz-Garrido,3– 5 Paulina Carvajal-Vidal,1 Elena Sánchez López,1,6 Joaquim Suñer-Carbó,1,6 Lyda Halbaut,1,6 Mireia Mallandrich,1,6 Marta Espina,1,6 Josefa Badia,3– 5 Laura Baldoma,3– 5 Maria Luisa García,1,6 Ana Cristina Calpena1,6 1Department of Pharmacy and Pharmaceutical Technology and Physical Chemistry, Faculty of Pharmacy and Food Sciences, University of Barcelona, Barcelona, Spain; 2Department of Biology, Healthcare and Environment, Faculty of Pharmacy and Food Sciences, University of Barcelona, Barcelona, Spain; 3Department of Biochemistry and Physiology, Faculty of Pharmacy and Food Sciences, University of Barcelona, Barcelona, Spain; 4Institute of Biomedicine of the University of Barcelona (IBUB), Barcelona, Spain; 5Research Institute Sant Joan De Déu (IR‑SJD), Barcelona, Spain; 6Institute of Nanoscience and Nanotechnology (IN2UB), University of Barcelona, Barcelona, SpainCorrespondence: Camila Folle; Elena Sánchez López, Department of Pharmacy and Pharmaceutical Technology and Physical Chemistry, Faculty of Pharmacy and Food Sciences, University of Barcelona, Barcelona, 08028, Spain, Email camilafolle@ub.edu; esanchezlopez@ub.eduPurpose: Acne vulgaris is one of the most prevalent dermal disorders affecting skin health and appearance. To date, there is no effective cure for this pathology, and the majority of marketed formulations eliminate both healthy and pathological microbiota. Therefore, hereby we propose the encapsulation of an antimicrobial natural compound (thymol) loaded into lipid nanostructured systems to be topically used against acne.Methods: To address this issue, nanostructured lipid carriers (NLC) capable of encapsulating thymol, a natural compound used for the treatment of acne vulgaris, were developed either using ultrasonication probe or high-pressure homogenization and optimized using 22-star factorial design by analyzing the effect of NLC composition on their physicochemical parameters. These NLC were optimized using a design of experiments approach and were characterized using different physicochemical techniques. Moreover, short-term stability and cell viability using HaCat cells were assessed. Antimicrobial efficacy of the developed NLC was assessed in vitro and ex vivo.Results: NLC encapsulating thymol were developed and optimized and demonstrated a prolonged thymol release. The formulation was dispersed in gels and a screening of several gels was carried out by studying their rheological properties and their skin retention abilities. From them, carbomer demonstrated the capacity to be highly retained in skin tissues, specifically in the epidermis and dermis layers. Moreover, antimicrobial assays against healthy and pathological skin pathogens demonstrated the therapeutic efficacy of thymol-loaded NLC gelling systems since NLC are more efficient in slowly reducing C. acnes viability, but they possess lower antimicrobial activity against S. epidermidis, compared to free thymol.Conclusion: Thymol was successfully loaded into NLC and dispersed in gelling systems, demonstrating that it is a suitable candidate for topical administration against acne vulgaris by eradicating pathogenic bacteria while preserving the healthy skin microbiome. Keywords: lipid nanoparticles, thymol, acne vulgaris, NLC, gels, antimicrobial

Three-dimensional (3D) bioprinting is considered one of the most advanced tools to build up materials for tissue engineering. The aim of this work was the design, development and characterization of a bioink composed of human mesenchymal stromal cells (hMSC) for extrusion through nozzles to create these 3D structures that might potentially be apply to replace the function of damaged natural tissue. In this study, we focused on the advantages and the wide potential of biocompatible biomaterials, such as hyaluronic acid and alginate for the inclusion of hMSC. The bioink was characterized for its physical (pH, osmolality, degradation, swelling, porosity, surface electrical properties, conductivity, and surface structure), mechanical (rheology and printability) and biological (viability and proliferation) properties. The developed bioink showed high porosity and high swelling capacity, while the degradation rate was dependent on the temperature. The bioink also showed negative electrical surface and appropriate rheological properties required for bioprinting. Moreover, stress-stability studies did not show any sign of physical instability. The developed bioink provided an excellent environment for the promotion of the viability and growth of hMSC cells. Our work reports the first-time study of the effect of storage temperature on the cell viability of bioinks, besides showing that our bioink promoted a high cell viability after being extruded by the bioprinter. These results support the suggestion that the developed hMSC-composed bioink fulfills all the requirements for tissue engineering and can be proposed as a biological tool with potential applications in regenerative medicine and tissue engineering., Competing Interests: Declarations. Ethics approval: Subcutaneous adipose tissue was obtained from patients undergoing liposuction procedure after informed consent. This study was approved by the Ethics Committee of Clinical University Hospital of Málaga (Spain) (number: 02/022010). Consent to participate: Not applicable. Consent to publish: All authors agreed with the final version of this manuscript and with the current submission. Competing interests: The authors have no relevant financial or non-financial interests to disclose. The authors alone are responsible for the content and writing of the paper., (© 2024. The Author(s).)

Aim: Oral candidiasis is often challenging due to limited effectiveness of topical treatments. This study aimed to develop novel caspofungin formulations for administration onto the oral mucosa to enhance drug retention and efficacy., Method: Five caspofungin (2%, w/v) formulations were developed to assess their permeability, retention and mucoadhesiveness. Ex vivo permeability assays were performed on buccal and sublingual mucosae, and histological analyses conducted to evaluate tissue tolerance., Results: Formulation composed of chitosan demonstrated the highest retention in both buccal (5183.24 ± 587.32 µg/cm 2 ) and sublingual (1090.72 ± 110.26 µg/cm 2 ) mucosae. Other formulations exhibited significantly lower retention, ranging from 7.53 ± 0.81 to 1852.10 ± 193.24 µg/cm 2 in buccal mucosa and 1.64 ± 0.14 to 317.74 ± 31.78 µg/cm 2 in sublingual mucosa. Chitosan-based formulation exhibited the highest mucoadhesive strength, with values of 5179.05 ± 31.99 mN/cm 2 for buccal and 7026.10 ± 123.41 mN/cm 2 for sublingual mucosae, and also superior extensibility, which facilitates application in the oral cavity. All formulations showed antifungal activity against Candida spp., and histological analyses revealed minor epithelial alterations., Conclusion: The developed formulations offer distinct advantages for treating oral candidiasis, with chitosan formulation emerging as the most promising due to its superior retention, mucoadhesion force, and spreadability, making it a potential candidate for further clinical investigation.

Background: Baricitinib, commonly used for autoimmune diseases, is typically administered orally, which can lead to systemic adverse effects. A topical formulation could potentially offer localized therapeutic effects while minimizing these side effects., Objectives: This study focuses on developing a lipid-based topical formulation of baricitinib (BCT-OS) for treating psoriasis., Methods: The optimized formulation was then assessed for physical, chemical, and biopharmaceutical characterization. Furthermore, the anti-inflammatory efficacy of the formulation was tested in a model of psoriasis induced by imiquimod in mice, and its tolerance was determined by the evaluation of biomechanical skin properties and an inflammation test model induced by xylol in mice., Results: BCT-OS presented appropriate characteristics for skin administration in terms of pH, rheology, extensibility, and stability. The formulation also demonstrated a notable reduction in skin inflammation in the mouse model, and high tolerability without affecting the skin integrity., Conclusions: BCT-OS shows promise as an alternative treatment for psoriasis, offering localized therapeutic benefits with a potentially improved safety profile compared to systemic administration.

This study explores the incorporation of 10% 3-O-ethyl L-ascorbic acid (ETVC), a derivative of vitamin C, into two lipid gel systems: a hydrogel (HG) consisting exclusively of lipids and water and a bigel (BG) combining the hydrogel with an oleogel made from olive oil and beeswax. We investigated the ETVC release profiles from both materials using synthetic membranes and measured their permeation through porcine skin in vitro. Additionally, the interaction of these lipid gel systems with the stratum corneum (SC) was determined. Results from the release study indicate that the BG exhibited slower ETVC release compared to the HG. The permeation experiments showed that the presence of lipids in the formulations enhanced ETVC retention in the skin. The HG delivered a higher amount to the SC, while the BG achieved greater retention in the epidermis. This difference is attributed to the different lipophilic nature of each material. The structural analysis of SC lipids revealed that the organization of surface lipids remained unaltered by the application of the gels. Finally, an in vitro efficacy test in porcine skin using methylene blue indicated that our ETVC gels exhibited antioxidant activity. These findings provide valuable insights into the potential of lipid-based gels for topical applications.

Topical ocular drug delivery faces several challenges due to the eye's unique anatomy and physiology. Physiological barriers, tear turnover, and blinking hinder the penetration of drugs through the ocular mucosa. In this context, nanoparticles offer several advantages over traditional eye drops. Notably, they can improve drug solubility and bioavailability, allow for controlled and sustained drug release, and can be designed to specifically target ocular tissues, thus minimizing systemic exposure. This study successfully designed and optimized PLGA and PCL nanoparticles for delivering baricitinib (BTB) to the eye using a factorial design, specifically a three-factor at five-levels central rotatable composite 2 3+ star design. The nanoparticles were small in size so that they would not cause discomfort when applied to the eye. They exhibited low polydispersity, had a negative surface charge, and showed high entrapment efficiency in most of the optimized formulations. The Challenge Test assessed the microbiological safety of the nanoparticle formulations. An ex vivo permeation study through porcine cornea demonstrated that the nanoparticles enhanced the permeability coefficient of the drug more than 15-fold compared to a plain solution, resulting in drug retention in the tissue and providing a depot effect. Finally, the in vitro ocular tolerance studies showed no signs of irritancy, which was further confirmed by HET-CAM testing.

Metallic nanoparticles (MNPs) have garnered significant attention due to their ability to improve the therapeutic index of medications by reducing multidrug resistance and effectively delivering therapeutic agents through active targeting. In addition to drug delivery, MNPs have several medical applications, including in vitro and in vivo diagnostics, and they improve the biocompatibility of materials and nutraceuticals. MNPs have several advantages in drug delivery systems and genetic manipulation, such as improved stability and half-life in circulation, passive or active targeting into the desired target selective tissue, and gene manipulation by delivering genetic materials. The main goal of this review is to provide current information on the present issues and prospects of MNPs in drug and gene delivery systems. The current study focused on MNP preparation methods and their characterization by different techniques, their applications to targeted delivery, non-viral vectors in genetic manipulation, and challenges in clinical trial translation., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Shahalaei, Azad, Sulaiman, Derakhshani, Mofakham, Mallandrich, Kumarasamy and Subramaniyan.)

Nanocomposite gels consist of nanoparticles dispersed in a gel matrix. The main aim of this work was to develop nanocomposite gels for topical delivery of Flurbiprofen (FB) for humans and farm animals. Nanocomposite gels were prepared stemming from nanoparticles (NPs) freeze-dried with two different cryoprotectants, D-(+)-trehalose (NPs-TRE) and polyethylene glycol 3350 (NPs-PEG), sterilized by gamma (γ) irradiation, and gelled with Sepigel ® 305. Nanocomposite gels with FB-NPs-TRE and FB-NPs-PEG were physiochemically characterized in terms of appearance, pH, morphological studies, porosity, swelling, degradation, extensibility, and rheological behavior. The drug release profile and kinetics were assessed, as well as, the ex vivo permeation of FB was assessed in human, porcine and bovine skin. In vivo studies in healthy human volunteers were tested without FB to assess the tolerance of the gels with nanoparticles. Physicochemical studies demonstrated the suitability of the gel formulations. The ex vivo skin permeation capacity of FB-NPs nanocomposite gels with different cryoprotectants allowed us to conclude that these formulations are suitable topical delivery systems for human and veterinary medicine. However, there were statistically significant differences in the permeation of each formulation depending on the skin. Results suggested that FB-NPs-PEG nanocomposite gel was most suitable for human and porcine skin, and the FB-NPs-TRE nanocomposite gel was most suitable for bovine skin.

Recently, the number of people acquiring tattoos has increased, with tattoos gaining significant popularity in people between 20 and 40 years old. Inflammation is a common reaction associated with tattooing. The purpose of this study was to evaluate a nanostructured lipid carrier loading pranoprofen (PRA-NLC) as a tattoo aftercare formulation to reduce the inflammation associated with tattooing. In this context, the in vitro drug release and the ex vivo permeation-through-human-skin tests using Franz cells were appraised. The tolerance of our formulation on the skin was evaluated by studying the skin's biomechanical properties. In addition, an in vivo anti-inflammatory study was conducted on mice skin to evaluate the efficacy of the formulation applied topically after tattooing the animals. PRA-NLC showed a sustained release up to 72 h, and the amount of pranoprofen retained in the skin was found to be 33.48 µg/g/cm 2 . The formulation proved to be well tolerated; it increased stratum corneum hydration, and no signs of skin irritation were observed. Furthermore, it was demonstrated to be non-cytotoxic since the cell viability was greater than 80%. Based on these results, we concluded that PRA-NLC represents a suitable drug delivery carrier for the transdermal delivery of pranoprofen to alleviate the local skin inflammation associated with tattooing.

Thyme oil (THO) possesses excellent antibacterial and antioxidant properties which are suitable for skin inflammatory disorders such as acne vulgaris. However, THO is insoluble in water and its components are highly volatile. Therefore, these drawbacks may be overcome by its encapsulation in biodegradable PLGA nanoparticles (THO-NPs) that had been functionalized using several strategies. Moreover, cell viability was studied in HaCat cells, confirming their safety. In order to assess therapeutic efficacy against acne, bacterial reduction capacity and antioxidant properties were assessed. Moreover, the anti-inflammatory and wound-healing abilities of THO-NPs were also confirmed. Additionally, ex vivo antioxidant assessment was carried out using pig skin, demonstrating the suitable antioxidant properties of THO-NPs. Moreover, THO and THO-NPs were dispersed in a gelling system, and stability, rheological properties, and extensibility were assessed. Finally, the biomechanical properties of THO-hydrogel and THO-NP-hydrogel were studied in human volunteers, confirming the suitable activity for the treatment of acne. As a conclusion, THO has been encapsulated into PLGA NPs, and in vitro, ex vivo, and in vivo assessments had been carried out, demonstrating excellent properties for the treatment of inflammatory skin disorders.

Acne constitutes one of the most prevalent skin disorder affecting both skin and mental health of patients. However, no cure has been developed so far. In this area, Thymol constitutes a potential candidate since it is able to restore the healthy microbiota of the skin. However, its permeation properties cause its fast elimination and, to avoid this problem, thymol has been loaded into nanostructured lipid carriers (TH-NLCs). Moreover, to increase the suitability of these systems for skin applications, several surface functionalization strategies of TH-NLCs had been assessed. Among the different molecules, phosphatidylcholine-TH-NLCs demonstrated to be safe as well as to provide high antioxidant activity in cellular studies. Therefore, to administer these systems to the skin, functionalized TH-NLCs were dispersed into a carbomer gel developing semi-solid formulations. Rheological properties, porosity and extensibility of TH dispersed in carbomer as well as phosphatidylcholine-TH-NLCs were assessed demonstrating suitable properties for dermal applications. Moreover, both formulations were applied in healthy volunteers demonstrating that gel-phosphatidylcholine-TH-NLCs were able to increase in skin hydration, decrease water loss and reduce skin sebum. Therefore, gel-phosphatidylcholine-TH-NLCs proved to be a suitable system for skin pathologies linked with high sebum generation, loss of hydration and high oxidation, such as acne vulgaris., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 The Authors. Published by Elsevier B.V. All rights reserved.)

Thymol-loaded PLGA nanoparticles (TH-NPs) were incorporated into different semi-solid formulations using variable gelling agents (carbomer, polysaccharide and poloxamer). The formulations were physicochemically characterized in terms of size, polydispersity index and zeta potential. Moreover, stability studies were performed by analyzing the backscattering profile showing that the gels were able to increase the nanoparticles stability at 4 °C. Moreover, rheological properties showed that all gels were able to increase the viscosity of TH-NPs with the carbomer gels showing the highest values. Moreover, the observation of carbomer dispersed TH-NPs under electron microscopical techniques showed 3D nanometric cross-linked filaments with the NPs found embedded in the threads. In addition, cytotoxicity studies showed that keratinocyte cells in contact with the formulations obtained cell viability values higher than 70 %. Furthermore, antimicrobial efficacy was assessed against C. acnes and S. epidermidis showing that the formulations eliminated the pathogenic C. acnes but preserved the resident S. epidermidis which contributes towards a healthy skin microbiota. Finally, biomechanical properties of TH-NPs dispersed in carbomer gels in contact with healthy human skin were studied showing that they did not alter skin properties and were able to reduce sebum which is increased in acne vulgaris. As a conclusion, TH-NPs dispersed in semi-solid formulations and, especially in carbomer gels, may constitute a suitable solution for the treatment of acne vulgaris., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 The Authors. Published by Elsevier B.V. All rights reserved.)

Flavanones are natural compounds that display anti-inflammatory activity. The aim of this work was to prepare PLGA nanoparticles (NPs) containing natural flavanones I ((2 S )-5,7-dihydroxy-6-methyl-8-(3-methyl-2-buten-1-il)-2-phenyl-2,3-dihydro-4 H -1-Benzopyran-4-one) and II (2 S )-5,7-dihydroxy-2-(4'-methoxyphenyl)-6-methyl-8-(3-methyl-2-buten-1-yl)-2,3-dihydro-4 H -1-Benzopyran-4-one) (NP I and NP II, respectively) so as to evaluate their potential for topical anti-inflammatory ocular therapy. An in silico study was carried out using the Molinspiration ® and PASS Online web platforms before evaluating the in vitro release study and the ex vivo porcine cornea and sclera permeation. The HPLC analytical method was also established and validated. Finally, the in vitro anti-inflammatory efficacy of NPs was studied in the HCE-2 model. The flavanones I and II could be released following a kinetic hyperbolic model. Neither of the two NPs was able to permeate through the tissues. NP I and NP II were found to be respectful of any changes in the tissues' morphology, as evidenced by histological studies. In HCE-2 cells, NP I and NP II were not cytotoxic at concentrations up to 25 µM. NP I showed higher anti-inflammatory activity than NP II, being able to significantly reduce IL-8 production in LPS-treated HCE-2 cells. In summary, ocular treatment with NP I and NP II could be used as a promising therapy for the inhibition of ocular inflammation.

Wound healing is a natural physiological reaction to tissue injury. Hydrogels show attractive advantages in wound healing not only due to their biodegradability, biocompatibility and permeability but also because provide an excellent environment for cell migration and proliferation. The main objective of the present study was the design and characterization of a hydrogel loaded with human mesenchymal stromal cells (hMSCs) for use in would healing of superficial skin injures. Poloxamer 407® was used as biocompatible biomaterial to embed hMSCs. The developed hydrogel containing 20 % (w/w) of polymer resulted in the best formulation with respect to physical, mechanical, morphological and biological properties. Its high swelling capacity confirmed the hydrogel's capacity to absorb wounds' exudate. LIVE/DEAD® assay confirm that hMSCs remained viable for at least 48 h when loaded into the hydrogels. Adding increasing concentrations of hMSCs-loaded hydrogel to the epithelium did not affect keratinocytes' viability and healing capacity and all wound area was closed in less than one day. Our study opens opportunities to exploit poloxamer hydrogels as cell carriers for the treatment of skin superficial wound., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 The Author(s). Published by Elsevier B.V. All rights reserved.)

Apremilast (APM) is a novel drug for the treatment of psoriasis and psoriatic arthritis. APM is a phosphodiesterase 4 (PDE4) inhibitor, raising intracellular cAMP levels and thereby decreasing the inflammatory response by modulating the expression of TNF-α, IL-17, IL-23, and other inflammatory cytokines. The goal of this study is to develop APM gels as a new pharmaceutical formulation for the treatment of topical psoriasis. APM was solubilized in Transcutol-P and incorporated into Pluronic F127, Sepigel, and carbomer bases at different proportions. All formulations were characterized physiochemically. A biopharmaceutical study (release profile) was performed, and ex vivo permeation was evaluated using a human skin model. A toxicity assay was carried out on the HaCaT cell line. A mouse model of imiquimod-induced psoriasis skin inflammation was carried out to determine its efficacy by histological analysis, RNA extraction, and RT-qPCR assays. APM gel formulations showed good physicochemical characteristics and a sustained release profile. There was no permeation of any gel measured through human skin, indicating a high retained amount of APM on the skin. Cell viability was greater than 80% at most dilution concentrations. APM gels treated the psoriasis mouse model, and it shows a reduction in the proinflammatory cytokines (IL-8, IL-17A, IL-17F, and IL-23). APM gels could be a new approach for the treatment of topical psoriasis.

Essential oils are a complex mixture of aromatic substances whose pharmacological actions, including antimicrobial, antioxidant, anticancer, and anti-inflammatory activities, have been widely reported. This study aimed to evaluate the anti- Candida and dermal anti-inflammatory activity of essential oils from native and cultivated Ecuadorian plants. Essential oils from Bursera graveolens , Dacryodes peruviana , Mespilodaphne quixos , and Melaleuca armillaris were isolated by hydrodistillation and were characterized physically and chemically. Its tolerance was analyzed by in vitro and in vivo studies. The antifungal activity was studied against Candida albicans , Candida glabrata , and Candida parapsilosis , whereas the anti-inflammatory effect was evaluated by a mouse ear edema model. The main compounds were limonene, α-phellandrene, ( E )-methyl cinnamate, and 1,8-cineole, respectively. All essential oils showed high tolerability for skin application, antifungal activity against the three Candida strains, and anti-inflammatory efficacy by decreasing edema and overexpression of pro-inflammatory cytokines. Dacryodes peruviana essential oil showed the highest antifungal activity. On the other hand, Dacryodes peruviana and Melaleuca armillaris showed the greatest anti-inflammatory potential, decreasing edema by 53.3% and 65.25%, respectively, and inhibiting the overexpression of TNF-α, IL-8, IL-17A, and IL-23. The results suggest that these essential oils could be used as alternative therapies in the treatment of both cutaneous candidiasis and dermal inflammation.

Atopic dermatitis (AD) is a chronic autoimmune inflammatory skin disorder which causes a significant clinical problem due to its prevalence. The ongoing treatment for AD is aimed at improving the patient's quality of life. Additionally, glucocorticoids or immunosuppressants are being used in systemic therapy. Baricitinib (BNB) is a reversible Janus-associated kinase (JAK)-inhibitor; JAK is an important kinase involved in different immune responses. We aimed at developing and evaluating new topical liposomal formulations loaded with BNB for the treatment of flare ups. Three liposomal formulations were elaborated using POPC (1-palmitoyl-2-oleoyl-glycero-3-phosphocholine), CHOL (Cholesterol) and CER (Ceramide) in different proportions: (i) POPC, (ii) POPC:CHOL (8:2, mol/mol) and (iii) POPC:CHOL:CER (3.6:2.4:4.0 mol/mol/mol). They were physiochemically characterized over time. In addition, an in vitro release study, ex vivo permeation and retention studies in altered human skin (AHS) were also performed. Histological analysis was used to study the tolerance of the formulations on the skin. Lastly, the HET-CAM test was also performed to evaluate the irritancy capacity of the formulations, and the modified Draize test was performed to evaluate the erythema and edema capacity of the formulations on the altered skin. All liposomes showed good physicochemical properties and were stable for at least one month. POPC:CHOL:CER had the highest flux and permeation, and the retention in the skin was equal to that of POPC:CHOL. The formulations exhibited no harmful or irritating effects, and the histological examination revealed no changes in structure. The three liposomes have shown promising results for the aim of the study.

The increasing number of skin cancer cases worldwide and the adverse side effects of current treatments have led to the search for new anticancer agents. In this present work, the anticancer potential of the natural flavanone 1, extracted from Eysenhardtia platycarpa , and four flavanone derivatives 1a-d obtained by different reactions from 1 was investigated by an in silico study and through cytotoxicity assays in melanoma (M21), cervical cancer (HeLa) cell lines and in a non-tumor cell line (HEK-293). The free compounds and compounds loaded in biopolymeric nanoparticles (PLGA NPs 1, 1a-d) were assayed. A structure-activity study (SAR) was performed to establish the main physicochemical characteristics that most contribute to cytotoxicity. Finally, ex vivo permeation studies were performed to assess the suitability of the flavanones for topical administration. Results revealed that most of the studied flavanones and their respective PLGA NPs inhibited cell growth depending on the concentration; 1b should be highlighted. The descriptors of the energetic factor were those that played a more important role in cellular activity. PLGA NPs demonstrated their ability to penetrate ( Q p of 17.84-118.29 µg) and be retained ( Q r of 0.01-1.44 g/g skin /cm 2 ) in the skin and to exert their action for longer. The results of the study suggest that flavanones could offer many opportunities as a future anticancer topical adjuvant treatment.

Pranoprofen (PRA)-loaded nanostructured lipid carriers (NLC) have been dispersed into blank gels composed of 1% of Carbomer 940 (PRA-NLC-Car) and 3% of Sepigel ® 305 (PRA-NLC-Sep) as a novel strategy to refine the biopharmaceutical profile of PRA, for dermal administration in the treatment of skin inflammation that may be caused by possible skin abrasion. This stratagem intends to improve the joining of PRA with the skin, improving its retention and anti-inflammatory effect. Gels were evaluated for various parameters such as pH, morphology, rheology, and swelling. In vitro drug release research and ex vivo permeation through the skin were carried out on Franz diffusion cells. Additionally, in vivo assays were carried out to evaluate the anti-inflammatory effect, and tolerance studies were performed in humans by evaluating the biomechanical properties. Results showed a rheological profile common of semi-solid pharmaceutical forms for dermal application, with sustained release up to 24 h. In vivo studies using PRA-NLC-Car and PRA-NLC-Sep in Mus musculus mice and hairless rats histologically demonstrated their efficacy in an inflammatory animal model study. No signs of skin irritation or modifications of the skin's biophysical properties were identified and the gels were well tolerated. The results obtained from this investigation concluded that the developed semi-solid formulations represent a fitting drug delivery carrier for PRA's transdermal delivery, enhancing its dermal retention and suggesting that they can be utilized as an interesting and effective topical treatment for local skin inflammation caused by a possible abrasion.

Sialolithiasis mainly affects the oral salivary glands due to the presence of small stones that obstruct the secretion of saliva. The treatment and control of pain and inflammation during the course of this pathology is essential to guarantee the patient's comfort. For this reason, a ketorolac calcium cross-linked alginate hydrogel was developed, and it was then applied in the area of the buccal cavity. The formulation was characterized (swelling and degradation profile, extrusion, extensibility, surface morphology, viscosity, and drug release). The drug release was studied ex vivo in static Franz cells and with a dynamic ex vivo method under artificial saliva continuous flow. The product exhibits adequate physicochemical properties considering the intended purpose, and the drug concentrations retained in the mucosa were high enough to deliver a therapeutic local concentration able to reduce the pain associated with the patient's conditions. The results confirmed the suitability of the formulation for application in the mouth.

Alternative formulations need to be developed to improve the efficacy of treatments administered via the vaginal route. Mucoadhesive gels with disulfiram, a molecule that was originally approved as an antialcoholism drug, offer an attractive alternative to treat vaginal candidiasis. The aim of the current study was to develop and optimize a mucoadhesive drug delivery system for the local administration of disulfiram. Such formulations were composed of polyethylene glycol and carrageenan to improve the mucoadhesive and mechanical properties and to prolong the residence time in the vaginal cavity. Microdilution susceptibility testing showed that these gels had antifungal activity against Candida albicans , Candida parapsilosis , and Nakaseomyces glabratus . The physicochemical properties of the gels were characterized, and the in vitro release and permeation profiles were investigated with vertical diffusion Franz cells. After quantification, it was determined that the amount of the drug retained in the pig vaginal epithelium was sufficient to treat candidiasis infection. Together, our findings suggest that mucoadhesive disulfiram gels have the potential to be an effective alternative treatment for vaginal candidiasis.

Fungal keratitis causes corneal blindness worldwide. The treatment includes antibiotics, with Natamycin being the most commonly used; however, fungal keratitis is difficult to treat, so alternative therapies are needed. In situ gelling formulations are a promising alternative; this type of formulation has the advantages of eye drops combined with the advantages of ointments. This study was designed to develop and characterize three formulations containing 0.5% CSP: CSP-O1, CSP-O2, and CSP-O3. CSP is an antifungal drug that acts against a diverse variety of fungi, and Poloxamer 407 (P407) is a polymer of synthetic origin that is able to produce biocompatible, biodegradable, highly permeable gels and is known to be thermoreversible. Short-term stability showed that formulations are best stored at 4 °C, and rheological analysis showed that the only formulation able to gel in situ was CSP-O3. In vitro release studies indicated that CSP-O1 releases CSP most rapidly, while in vitro permeation studies showed that CSP-O3 permeated the most. The ocular tolerance study showed that none of the formulations caused eye irritation. However, CSP-O1 decreased the cornea's transparency. Histological results indicate that the formulations are suitable for use, with the exception of CSP-O3, which induced slight structural changes in the scleral structure. All formulations were shown to have antifungal activity. In view of the results obtained, these formulations could be promising candidates for use in the treatment of fungal keratitis.

Caspofungin is a drug that is used for fungal infections that are difficult to treat, including invasive aspergillosis and candidemia, as well as other forms of invasive candidiasis. The aim of this study was to incorporate Azone in a caspofungin gel (CPF-AZ-gel) and compare it with a promoter-free caspofungin gel (CPF-gel). An in vitro release study using a polytetrafluoroethylene membrane and ex vivo permeation into human skin was adopted. The tolerability properties were confirmed by histological analysis, and an evaluation of the biomechanical properties of the skin was undertaken. Antimicrobial efficacy was determined against Candida albicans , Candida glabrata , Candida parapsilosis , and Candida tropicalis . CPF-AZ-gel and CPF-gel, which had a homogeneous appearance, pseudoplastic behavior, and high spreadability, were obtained. The biopharmaceutical studies confirmed that caspofungin was released following a one-phase exponential association model and the CPF-AZ gel showed a higher release. The CPF-AZ gel showed higher retention of caspofungin in the skin while limiting the diffusion of the drug to the receptor fluid. Both formulations were well-tolerated in the histological sections, as well as after their topical application in the skin. These formulations inhibited the growth of C. glabrata , C. parapsilosis , and C. tropicalis , while C. albicans showed resistance. In summary, dermal treatment with caspofungin could be used as a promising therapy for cutaneous candidiasis in patients that are refractory or intolerant to conventional antifungal agents.

Curcumin shows anti-inflammatory activity, and it has been widely investigated for neurodegenerative diseases, adjuvant treatment in AIDS and antitumor activity against different tumors, among other activities. The goal of this work was to evaluate the capacity of curcumin and its derivatives (bisdemethoxycurcumin and bisdemethylcurcumin) in preventing the irritant effects of topically applied xylol and to assess the intrinsic capacity of curcuminoids in permeating human skin by ex vivo permeation tests. Its secondary goal was to validate an HPLC method to simultaneously determine the curcuminoids in the samples from the ex vivo permeation studies and drug extraction from the skin. Curcuminoid quantification was performed using an RP-C18 column, at isocratic conditions of elution and a detection wavelength of 265 nm. The method was specific with a suitable peak resolution, as well as linear, precise, and accurate in the range of 0.195-3.125 μg/mL for the three curcuminoids. Bisdemethylcurcumin showed the greatest permeation through the human skin, and it was the curcuminoid that was most retained within the human skin. The anti-inflammatory activity of the curcuminoids was evaluated in vivo using a xylol-induced inflammation model in rats. Histological studies were performed to observe any changes in morphology at the microscopic level, and these three curcuminoids were found to be respectful within the skin structure. These results show that these three curcuminoids are suitable for anti-inflammatory formulations for dermal applications, and they can be properly quantified using HPLC-UV.

The low water solubility of baricitinib (BCT) limits the development of new formulations for the topical delivery of the drug. The aims of this study were to assess the solubility of BCT in different solvents, including Transcutol, a biocompatible permeation enhancer that is miscible in water, to evaluate the drug uptake in human skin and porcine tissues (sclera, cornea, oral, sublingual, and vaginal), and to subsequently extract the drug from the tissues so as to determine the drug recovery using in vitro techniques. Analytical methods were developed and validated for the quantification of BCT in Transcutol using absorption and fluorescence spectroscopies, which are complementary to each other and permit the detection of the drug across a broad range of concentrations. Results show that Transcutol permits an increased drug solubility, and that BCT is able to penetrate the tissues studied. The solutions of BCT in Transcutol were stable for at least one week. Hence, Transcutol may be a suitable solvent for further development of topical formulations.

Essential oils are natural aromatic substances that contain complex mixtures of many volatile compounds frequently used in pharmaceutical and cosmetic industries. Dacryodes peruviana (Loes.) H.J. Lam is a native species from Ecuador whose anti-inflammatory activity has not been previously reported, thus the aim of this study was to evaluate the anti-inflammatory activity of D. peruviana essential oil. To that end, essential oil from D. peruviana fruits was isolated by hydrodistillation and characterized physically and chemically. The tolerance of the essential oil was analyzed by cytotoxicity studies using human keratinocytes. The anti-inflammatory activity was evaluated by an arachidonic acid-induced edema model in mouse ear. The predominant compounds in D. peruviana essential oil were α-phellandrene, limonene, and α-pinene, with the three compounds reaching approximately 83% of the total composition. Tolerance studies showed high biocompatibility of this essential oil with human keratinocytes. In vivo studies demonstrated a moisturizing effect and an alleviation of several events occurred during the inflammatory process after topical treatment with D. peruviana essential oil such as decline in skin edema; reduction in leukocytic infiltrate; and decrease in inflammatory cytokines TNFα, IL-8, IL-17A, and IL-23. Therefore, this essential oil could be an attractive treatment for skin inflammation.

Alzheimer's disease is characterized by a progressive deterioration of neurons resulting in a steady loss of cognitive functions and memory. Many treatments encounter the challenge of overcoming the blood-brain barrier, thus the intranasal route is a non-invasive effective alternative that enhances the drug delivery in the target organ-the brain-and reduces the side effects associated with systemic administration. This study aimed at developing intranasal gels of donepezil as an approach to Alzheimer's disease. Three different gels were elaborated and characterized in terms of pH, morphology, gelation temperature, rheology, and swelling. An in vitro release study and an ex vivo permeation in porcine nasal mucosa were conducted on Franz diffusion cells. The tolerability of the formulations was determined by the cytotoxicity in human nasal cells RPMI 2650. Results showed that pluronic gels exhibit the higher release rate and enhanced permeation compared to chitosan gel. Moreover, the combination of Pluronic F-127 and Transcutol ® P exerted a synergic effect on the permeation of donepezil through the nasal mucosa. The resulting gels showed suitable tolerance in the RPMI 2650 cell line and physicochemical characteristics for intranasal delivery, and thus gel formulations administered by nasal mucosa could be an alternative strategy to improve the bioavailability of donepezil.

Transmucosal delivery is commonly used to prevent or treat local diseases. Pranoprofen is an anti-inflammatory drug prescribed in postoperative cataract surgery, intraocular lens implantation, chorioretinopathy, uveitis, age-related macular degeneration or cystoid macular edema. Pranoprofen can also be used for acute and chronic management of osteoarthritis and rheumatoid arthritis. Quality by Design (QbD) provides a systematic approach to drug development and maps the influence of the formulation components. The aim of this work was to develop and optimize a nanostructured lipid carrier by means of the QbD and factorial design suitable for the topical management of inflammatory processes on mucosal tissues. To this end, the nanoparticles loading pranoprofen were prepared by a high-pressure homogenization technique with Tween 80 as stabilizer and Lanette ® 18 as the solid lipid. From, the factorial design results, the PF-NLCs-N6 formulation showed the most suitable characteristics, which was selected for further studies. The permeability capacity of pranoprofen loaded in the lipid-based nanoparticles was evaluated by ex vivo transmucosal permeation tests, including buccal, sublingual, nasal, vaginal, corneal and scleral mucosae. The results revealed high permeation and retention of pranoprofen in all the tissues tested. According to the predicted plasma concentration at the steady-state, no systemic effects would be expected, any neither were any signs of ocular irritancy observed from the optimized formulation when tested by the HET-CAM technique. Hence, the optimized formulation (PF-NLCs-N6) may offer a safe and attractive nanotechnological tool in topical treatment of local inflammation on mucosal diseases.

Scabies and hair lice are parasitic diseases that affect human skin and hair, respectively. The incidence and resistances of these infections are increasing. Tenutex ® (disulfiram and benzyl benzoate emulsion) is an alternative to standard insecticides to avoid resistances. The aim of the work is to evaluate the transdermal absorption and the in vitro efficacy against scabies and hair lice after different exposition times. Dermatomed human skin was used to assess the dermal absorption using a validated High Performance Liquid Chromatography (HPLC) method. HEK001 keratinocytes were used to evaluate the cytotoxicity of benzyl benzoate. Only benzyl benzoate was able to cross the skin, but it did not show cytotoxicity at any of the tested concentrations. The product efficacy was tested on Psoroptes ovis after direct contact and after administration on sheep skin explants at different contact times. Permethrin/malathion-resistant strains of Pediculus humanis capitis adults and eggs were directly exposed to Tenutex, and the vitality and hatchability, respectively, were evaluated. The anti-scabies study demonstrated that exposure for 6 or 24 h completely eradicated the parasite. The pediculicidal activity of Tenutex exhibited superior efficacy than standard treatment on resistant lice. The positive results obtained suggest that Tenutex ® is a good treatment option, especially in drug resistance situations.

Sjögren's syndrome is a chronic systemic autoimmune disease affecting from 0.2 to 3% of the general population. The current treatment for Sjögren's syndrome is aimed at controlling symptoms such as dry eyes and xerostomia. Systemic therapy with glucocorticoids or immunosuppressants is also used. Baricitinib is an immunosuppressant drug, specifically a Janus kinases 1 and 2 selective inhibitor. We propose ocular liposomal formulations loaded with baricitinib for the management of Sjögren's syndrome. The novelty of the work relies on the fact that, for the first time, baricitinib is intended to be used for topical delivery. Two liposomal formulations were prepared with different lipids: (i) L-α-phosphatidylcholine (Lα-PC) and (ii) a combination of lipids 1-palmitoyl-2-oleoyl-phosphatidylethanolamine: s1-Palmitoyl-2-oleoyl-sn-glycerol-3-phosphoglycerol (3:1, mol/mol) (POPE:POPG), and they were physicochemically characterized. The in vitro drug release and the ex vivo permeation through corneal and scleral tissues were also assessed. Finally, the tolerance of the formulations on the ocular tissues was evaluated by the HET-CAM technique, as well as through the histological analysis of the cornea and sclera and the cornea transparency. Both liposomes resulted in small, spherical shapes, with suitable physicochemical properties for the ocular administration. Lα-PC led to higher flux, permeation, and retention in the sclera, whereas POPE:POPG led to higher flux and permeation in the cornea. The formulations showed no irritant effects on the chorioallantoic membrane. Additionally, the liposomes did not affect the cornea transparency when they were applied, and the histological analysis did not reveal any structural alteration.

Carprofen (CP) is a non-steroidal anti-inflammatory drug (NSAID) frequently used to treat respiratory diseases in numerous small animals, but also in large species. CP is a formidable candidate for further therapeutic research of human inflammatory diseases using the pig as an animal model. However, CP administration in swine is very uncommon and respective pharmacokinetics/bioavailability studies are scarce. A simultaneous population pharmacokinetic analysis after CP intravenous and intramuscular administrations in pigs has shown high extent and rate of absorption and a similar distribution profile with respect to man and other mammals. However, clearance and half-life values found in swine suggest a slower elimination process than that observed in man and some other animal species. Although not reported in other species, liver and kidney concentrations achieved at 48 h post-intramuscular administration in pigs were ten times lower than those found in plasma. Simulations pointed to 4 mg/kg every 24 h as the best dosage regimen to achieve similar therapeutic levels to those observed in other animal species. All these findings support the use of pig as an animal model to study the anti-inflammatory effects of CP in humans.

This study describes the preparation and evaluation of two formulations, a hydrogel and a nanostructured system, containing ketorolac tromethamine as an anti-inflammatory agent for the local therapy against the inflammatory process derived from the surgical excision of Condyloma acuminata. Both formulations were physicochemically characterized. In vitro release profiles show that the nanoparticles release 92% ± 2.3 of the total ketorolac tromethamine encapsulated, while the chitosan gel releases 18.6% ± 0.2. The ex vivo permeation and distribution through human skin were also assayed and was observed how the main amount of ketorolac tromethamine is retained in the epidermis. In vivo studies were accomplished to evaluate the anti-inflammatory efficacy in mice which also involved the histological analysis to confirm the in vivo results. The nanoparticles present a significantly higher anti-inflammatory efficacy than chitosan gel. The tolerability of developed formulations was assessed by monitoring the biomechanical properties of the skin before and after application of both formulations. No statistical differences in trans-epidermal water loss and skin hydration with respect to the basal values were observed and the formulations exhibited higher anti-inflammatory activity compared to a reference ketotorlac tromethamine solution. Therefore, it can be concluded that both formulations can be proposed as outstanding candidates for offering a local anti-inflammatory therapeutical tool with potential clinical application.

Due to different oral and dental conditions, oral mucosa lesions such as those caused by the human papilloma virus and temporomandibular joint pathologies often have to be treated by surgical, ablative or extractive procedures. The treatment and control of pain and inflammation during these procedures is essential to guarantee the patient's well-being. For the foregoing reason, a hydrogel based on sodium alginate and hyaluronic acid containing 2% of ketorolac tromethamine has been developed. We characterized it physically, mechanically and morphologically. The rheological results suggest that the formulation can be easily and gently applied. Ex vivo permeation studies show that Ketorolac Tromethamine is able to penetrate through the buccal and sublingual mucosae, in addition to being retained in the mucosae's structure. Through an in vitro test, we were able to evaluate the role that saliva plays in the bioavailability of the drug, observing that more than half of the applied dose is eliminated in an hour. The histological and cytotoxic studies performed on pigs in vivo showed the excellent safety profile of the formulation, as well as its high tolerability. In parallel, a biomimetic artificial membrane (PermeaPad ® ) was evaluated, and it showed a high degree of correlation with the oral and sublingual mucosa.

Aim: The development and optimization of Ketorolac tromethamine-loaded polylactic-co-glycolic acid nanoparticles (KT-NPs) for the treatment of inflammatory processes of the eye. Materials & methods: KT-NPs were developed by factorial design and characterized by assessing their physicochemical properties. Biopharmaceutical behavior studies, ocular tolerance, anti-inflammatory efficacy and bioavailability tests were performed on pigs. Results: Optimized KT-NPs of 112 nm, narrow distribution with encapsulation efficiency near 100% were obtained. KT release followed the Weibull model and there was significantly greater retention in the cornea and sclera than in the commercial reference. KT-NPs showed no signs of ocular irritancy and similar anti-inflammatory efficacy to the commercial reference. Conclusion: KT-NPs were a suitable alternative for the treatment of inflammatory disorders of the anterior and posterior segments of the eye as an alternative to conventional topical formulations.

Condyloma acuminata is an infectious disease caused by the human papilloma virus (HPV) and one of the most common sexually transmitted infections. It is manifested as warts that frequently cause pain, pruritus, burning, and occasional bleeding. Treatment (physical, chemical, or surgical) can result in erosion, scars, or ulcers, implying inflammatory processes causing pain. In this work, a biocompatible topical hydrogel containing 2% ketorolac tromethamine was developed to manage the painful inflammatory processes occurring upon the removal of anogenital condylomas. The hydrogel was physically, mechanically, and morphologically characterized: it showed adequate characteristics for a topical formulation. Up to 73% of ketorolac in the gel can be released following a one-phase exponential model. Upon application on human skin and vaginal mucosa, ketorolac can permeate through both of these and it can be retained within both tissues, particularly on vaginal mucosa. Another advantage is that no systemic side effects should be expected after application of the gel. The hydrogel showed itself to be well tolerated in vivo when applied on humans, and it did not cause any visible irritation. Finally, ketorolac hydrogel showed 53% anti-inflammatory activity, suggesting that it is a stable and suitable formulation for the treatment of inflammatory processes, such as those occurring upon chemical or surgical removal of anogenital warts.

The absorption study of drugs through different biological membranes constitutes an essential step in the development of new pharmaceutical dosage forms. Concerning orally administered forms, methods based on monolayer cell culture of Caco-2 (Caucasian colon adenocarcinoma) have been developed to emulate intestinal mucosa in permeability studies. Although it is widely accepted, it has disadvantages, such as high costs or high technical complexity, and limitations related to the simplified structure of the monolayer or the class of molecules that can be permeated according to the transport mechanisms. The aim of this work was to develop a new ex vivo methodology which allows the evaluation of the intestinal apparent permeability coefficient (P app ) while using fewer resources and to assess the correlation with Caco-2. To this end, pig ( Sus scrofa ) duodenum segments were mounted in Franz diffusion cells and used to permeate four different drugs: ketorolac tromethamine (Kt), melatonin (Mel), hydrochlorothiazide (Htz), and furosemide (Fur). No statistically significant differences ( p > 0.05) were observed corelating P app values from Franz diffusion cells and Caco-2 cell experiments for Kt, Htz, and Fur. However, there were statistically significant differences ( p < 0.05) correlating P app values and Mel. The difference is explained by the role of Mel in the duodenal epithelial paracellular permeability reduction. Ex vivo permeation may be an equivalent method to Caco-2 for drugs that do not produce intestinal membrane phenomena that could affect absorption., Competing Interests: The authors declare no conflict of interest.

The main purpose of this study was to develop a semisolid mucoadhesive formulation for the non-invasive vaginal administration of doxepin (DOX) for relief of pain derived from the scarring process after surgery. An orafix ® platform loading DOX was tested for adequate stability, rheology and vaginal mucoadhesion capacity. The formulation exhibited appropriate pH and was microbiologically stable. The rheological studies confirmed its pseudoplastic and thixotropic nature with prevalence of the elastic behavior component over the viscous one. Appropriate syringeability and spreadability results were also confirmed. Different experiments showed adequate mucoadhesion capacity even in the presence of simulated vaginal fluid. Finally, DOX release, permeation and retention in vaginal mucosa studies were also accomplished with promising results. DOX release kinetics followed the modified Higuchi model and the permeation studies did not render such high values as to suggest potential systemic absorption which could lead to undesirable systemic side effects. Therefore, we can hypostatize that the proposed formulation may assist to fill in the therapeutic gap regarding pure pain relief at local level in vagina., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Halobetasol propionate (HB) is a potent synthetic corticosteroid used against inflammatory skin diseases, such as dermatitis, eczema, and psoriasis, among others. The aim of this study is to define how the presence of different skin penetration enhancers (nonane, menthone, limonene, azone, carene, decanol, linoleic acid and cetiol) affects the penetration and retention in skin of HB. To determine drug penetration through skin, 5% of each promoter was used in an ex vivo system with human skin on Franz cells. The results showed that the highest permeation occurs in the presence of menthone, followed by nonane. Permeation parameters were determined. The in vivo test was assessed, and the formulation containing HB-menthone presented better anti-inflammatory efficacy. These results are useful to generate a specific treatment according to each patient's needs, and the inflammatory characteristics of the disease., Competing Interests: The authors declare no conflict of interest.

In the present investigation solvent displacement or nanoprecipitation, and emulsion/solvent evaporation methods were utilized to optimize poly(D,L-lactide-co-glycolide) nanoparticles for the vehiculization of the 5-fluorouracil. Formulation components from both the aqueous and organic phases, as well as, operating conditions were varied. Particles were characterized in terms of particle size and morphology, electrical properties, rheology, drug loading, stability, and drug release. Furthermore, in vitro cytotoxicity on human colon cells and different colon carcinoma cells was evaluated. Four types of nanoparticles were selected for drug loading, revealing differences between variables. Low viscosity values and their Newtonian behavior could assure the suitability of the nanoformulation for the intravenous route of administration. The greatest drug entrapment efficiency and best stability was achieved when the chemotherapeutic agent was incorporated into the internal aqueous phase of particles prepared by double emulsion/solvent evaporation. However, a more sustained drug release at pH 7.4 was possible when 5-fluorouracil was added to the external aqueous phase. These were the nanoformulations reporting the greatest antiproliferative efficacy compared with the free drug. The nanocarrier can optimize the antitumor activity of 5-fluorouracil, thus being a potential nanotool against colon cancer., (Copyright © 2017 Elsevier B.V. All rights reserved.)

The search for new alternatives for the prevention and treatment of cancer is extremely important to minimize human mortality. Natural products are an alternative to chemical drugs, since they are a source of many potential compounds with anticancer properties. In the present study, the (2 S )-5,7-dihydroxy-6-prenylflavanone (semi-systematic name), also called (2 S )-5,7-dihydroxy-6-(3-methyl-2-buten-1-yl)-2-phenyl-2,3-dihydro-4 H -1-Benzopyran-4-one (CAS Name registered) ( 1 ) was isolated from Eysenhardtia platycarpa leaves. This flavanone 1 was considered as the lead compound to generate new cytotoxic derivatives 1a , 1b , 1c and 1d . These compounds 1 , 1a , 1b , 1c , and 1d were then loaded in nanosized drug delivery systems such as polymeric nanoparticles (NPs). Small homogeneous spherical shaped NPs were obtained. Cytotoxic activity of free compounds 1 , 1a , 1b , 1c , and 1d and encapsulated in polymeric NPs (NPs 1 , NPs 1a , NPs 1b , NPs 1c and NPs 1d ) were evaluated against the pancreatic cancer cell line MiaPaCa-2. The obtained results demonstrated that NPs 1a and NPs 1b exhibited optimal cytotoxicity, and an even higher improvement of the cytotoxic efficacy was exhibited with the encapsulation of 1a . Based on these results, NPs 1a were proposed as promising anticancer agent candidates., Competing Interests: The authors declare no conflict of interest.

Purpose: In order to obtain dermal vehicles of ketorolac tromethamine (KT) for the local treatment of inflammation and restrict undesirable side effects of systemic levels hydrogels (HGs) of poloxamer and carbomer were developed., Methods: KT poloxamer based HG (KT-P407-HG) and KT carbomer based HG (KT-C940-HG) were elaborated and characterized in terms of swelling, degradation, porosity, rheology, stability, in vitro release, ex vivo permeation and distribution skin layers. Finally, in vivo anti-inflammatory efficacy and skin tolerance were also assessed., Results: HGs were transparent and kept stable after 3 months exhibiting biocompatible near neutral pH values. Rheological patterns fitted to Herschel-Bulkley for KT-C940-HG and Newton for KT-P407-HG due to its low viscosity at 25°C. Rapid release profiles were observed through first order kinetics. Following the surface the highest concentration of KT from C940-HG was found in the epidermis and the stratum corneum for P407-HG. Relevant anti-inflammatory efficacy of KT-P407-HG revealed enough ability to provide sufficient bioavailability KT to reach easily the site of action. The application of developed formulations in volunteers did not induce any visual skin irritation., Conclusions: KT-P407-HG was proposed as suitable formulation for anti-inflammatory local treatment without theoretical systemic side effect.

This study describes the development of semisolid formulations containing doxepin (DOX) for pain relief in oral mucositis, frequently related to chemotherapy and/or radiotherapy treatments in patients with head and neck cancer. Chemical permeation enhancers were evaluated and selected according to the results obtained from rheological studies, drug release, and drug permeation and retention through buccal mucosa. Finally, the selected formulation was compared in vivo, with a reference DOX mouthwash, whose clinical efficacy had been previously reported. The obtained findings showed that an orabase® platform loading transcutol® (10%) and menthol (5%) for the buccal vehiculization of DOX exhibited a decreased elastic and viscous behavior improving its application. The main drug release mechanism could be considered as diffusion according to Higuchi model. Obtained DOX permeation rates were considered optimal for an analgesic effect and far below to an antidepressant activity. Similar in vivo plasma concentrations were found for the semisolid formulation and the reference mouthwash. However, DOX amounts retained in the mucosa of animals for the semisolid formulation were higher than the reference, which let us hypostatize even stronger potential local therapeutic effect with additional advantages such as, mucoadhesive properties, absence of alcohol, some degree of freshness, as well as, drug palatability improvement., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Context: Elaboration of oral liquid formulations is the best alternative when no marketed forms are available for pediatrics., Objective: The development, characterization and stability evaluation of methadone (MI, MII, MIII) and phenobarbital (PI, PII) can be used for the treatment of neonatal abstinence syndrome (NAS)., Material and Methods: A standard operating procedure was established and parameters such as appearance, pH, rheological behavior and drug content were evaluated at three temperatures for 90 days., Results and Discussion: Changes in color of phenobarbital made necessary the storage below 25 °C. pH did not change in methadone solutions and was able to maintain phenobarbital solubilized. Degradation data at 4 °C fitted to Plateau equation followed by one phase decay. MI was stable for 60 days at the three temperatures; MII for 90 days at 4 and 25 °C and 60 days at 40 °C; MIII for 60 days at 4 °C, 15 days at 25 °C and 7 days at 4 °C. PI was stable for 60 days at 4 °C and 30 days at 25 °C. PII was stable for 7 days at 4 and 25 °C. All solutions met microbial specifications., Conclusion: A correct dosage for the treatment of NAS was guaranteed.

This work aimed the design and development of poly(lactic-co-glycolic) acid (PLGA) nanoparticles (NPs) for the ocular delivery of Carprofen (CP) by a central rotatable composite design 2(3)+ star. NPs showed adequate size for ocular administration (189.50 ± 1.67 nm), low polydispersity (0.01 ± 0.01), negative charge surface (-22.80 ± 0.66 mV) and optimal entrapment efficiency (74.70 ± 0.95%). Physicochemical analysis confirmed that CP was dispersed inside the NPs. The drug release followed a first order kinetic model providing greater sustained CP release after lyophilization. Ex vivo permeation analysis through isolated rabbit cornea revealed that a sufficient amount of CP was retained in the tissue avoiding excessive permeation and thus, potential systemic levels. Ex vivo ocular tolerance results showed no signs of ocular irritancy, which was also confirmed by in vivo Draize test. In vivo ocular anti-inflammatory efficacy test confirmed an optimal efficacy of NPs and its potential application in eye surgery., (Copyright © 2015 Elsevier B.V. All rights reserved.)

To develop more effective antifungal mucoadhesive systems for the treatment of oral candidiasis, three types of microspheres, alginate (AM1), chitosan coated (CCM) and hydrogel (AM2) containing nystatin (Nys) were successfully elaborated by emulsification/internal gelation method. Physicochemical properties of microspheres resulted in 85-135 μm mean sizes, spherical shaped with narrow distribution. Optimal encapsulation efficiency and negative zeta potentials were observed. AM2 showed a consistent decrease in viscosity with increasing shear rate (Herschel-Bulkley). Optimal mucoadhesive properties and swelling behaviour where evidenced. Nys release from AM1 and CCM followed a concentration gradient pattern, contrary AM2 followed a complex release mechanism. All systems exhibited a marked fungicidal activity against Candida albicans strains. In vivo studies demonstrated that Nys was not found in systemic circulation assuring the safety of the treatment. Nys amounts retained in the mucosa were more than enough to ensure an effective fungicidal action without tissue damage. Based on the obtained results, AM2 could be proposed as the vehicle with the best properties for the buccal vehiculization of Nys., (Copyright © 2014 Elsevier Ltd. All rights reserved.)

Topical administration is an appealing method for drug delivery due to its non-invasiveness, self-controlled application, avoidance of first-pass metabolism in the liver and reduction of systemic side effects compared to other conventional routes such as oral and parenteral. However, topical administration must overcome the permeable barriers that skin and mucosa represent for the drug to achieve its desired therapeutic effect. Penetration of drugs through human skin is mainly impaired by the stratum corneum- the uppermost keratinized skin layer. In contrast, the stratified squamous epithelium (a nonkeratinized tissue) represents the major physical barrier for transbuccal drug administration in humans. Different technologies have been studied to enhance the bioavailability or local effects of drugs administered through skin and buccal mucosa. Those technologies involve the use of physical or chemical enhancers and new dosage forms such as vesicles, cyclodextrins, nanoparticles and other complex systems. Combinations of these technologies may further increase drug delivery in some cases. As analgesia is one of the main therapeutic effects sought through topical administration, this paper focuses on the review of drug delivery systems to improve the topical and transdermal/transbuccal drug delivery of substances with known analgesic action. A discussion of their possibilities and limitations is also included.

According to previous studies reporting the anesthetic/analgesic action of oral topical doxepin administration, this study evaluated a model of buccal permeation to determine the depth of delivery of doxepin into excised porcine buccal mucosa following topical application of a saturated aqueous doxepin solution. Buccal mucosa permeation studies were performed using Franz diffusion cells. Cumulative amounts of doxepin permeated were plotted as a function of time. Kinetic permeation parameters as flux (Js), lag time (Tl) and permeability coefficient (Kp) were calculated. Theoretical human plasmatic steady-state doxepin concentration and drug retained in the tissue were also determined in order to evaluate its potential therapeutic use, central or peripheral. Finally, a histological evaluation of the buccal mucosa was performed to test potential damage due to the permeation phenomenon. Obtained results showed a poor aqueous doxepin permeation through buccal mucosa membrane (median parameters Js=34.79 μg/h, Kp=0.49×10(-3)cm/h and Tl=2.8h). Predicted doxepin plasma concentrations would reach 46 ng/mL, far from the required to have central nervous system activity as tricyclic agent. However, median doxepin amount remaining in the mucosa membrane was 0.24 μg/cm(2)/μg tissue, which evidenced a reservoir function of the buccal mucosa. Histologically, no structural damage was observed in the tissues. This study lays the foundation for further research within this area with a view to potentially adopting alternative strategies for enhanced buccal absorption of doxepin in clinical practice., (Copyright © 2014 Elsevier B.V. All rights reserved.)