Cutaneous/Mucocutaneous Leishmaniasis Treatment for Wound Healing: Classical versus New Treatment Approaches

Cutaneous leishmaniasis (CL) and mucocutaneous leishmaniasis (ML) show clinical spectra that can range from a localized lesion (with a spontaneous healing process) to cases that progress to a generalized systemic disease with a risk of death. The treatment of leishmaniasis is complex since most of the available drugs show high toxicity. The development of an effective topical drug formulation for CL and ML treatment offers advantages as it will improve patient’s compliance to the therapy given the possibility for self-administration, as well as overcoming the first pass metabolism and the high costs of currently available alternatives. The most common dosage forms include solid formulations, such as membranes and semi-solid formulations (e.g., ointments, creams, gels, and pastes). Topical treatment has been used as a new route of administration for conventional drugs against leishmaniasis and its combinations, as well as to exploit new substances. In this review, we discuss the advantages and limitations of using topical drug delivery for the treatment of these two forms of leishmaniasis and the relevance of combining this approach with other pharmaceutical dosage forms. Emphasis will also be given to the use of nanomaterials for site-specific delivery.Coordenacao de Aperfeicoamento de Pessoal de Nivel Superior (CAPES)Fundacao de Amparo a Pesquisa do Estado do Sergipe (FAPITEC) 88887.159533/2017-00Conselho Nacional de Desenvolvimento Cientifico e Tecnologico (CNPQ) CNPq 301964/2019-0 01/2019 06/2019Fundacao Carolin

Baricitinib Liposomes as a New Approach for the Treatment of Sjögren’s Syndrome

Sjogren's syndrome is a chronic systemic autoimmune disease affecting from 0.2 to 3% of the general population. The current treatment for Sjogren'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 Sjogren'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-alpha-phosphatidylcholine (L alpha-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. L alpha-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

Formulation Strategies to Improve Nose-to-Brain Delivery of Donepezil

Donepezil (DPZ) is widely used in the treatment of Alzheimer’s disease in tablet form for oral administration. The pharmacological efficacy of this drug can be enhanced by the use of intranasal administration because this route makes bypassing the blood–brain barrier (BBB) possible. The aim of this study was to develop a nanoemulsion (NE) as well as a nanoemulsion with a combination of bioadhesion and penetration enhancing properties (PNE) in order to facilitate the transport of DPZ from nose-to-brain. Composition of NE was established using three pseudo-ternary diagrams and PNE was developed by incorporating Pluronic F-127 to the aqueous phase. Parameters such as physical properties, stability, in vitro release profile, and ex vivo permeation were determined for both formulations. The tolerability was evaluated by in vitro and in vivo models. DPZ-NE and DPZ-PNE were transparent, monophasic, homogeneous, and physically stable with droplets of nanometric size and spherical shape. DPZ-NE showed Newtonian behavior whereas a shear thinning (pseudoplastic) behavior was observed for DPZ-PNE. The release profile of both formulations followed a hyperbolic kinetic. The permeation and prediction parameters were significantly higher for DPZ-PNE, suggesting the use of polymers to be an effective strategy to improve the bioadhesion and penetration of the drug through nasal mucosa, which consequently increase its bioavailability.This research was funded by the Secretaría de Educación Superior, Ciencia, Tecnología e Innovación (SENESCYT—Ecuador)

Caspofungin-Loaded Formulations for Treating Ocular Infections Caused by Candida spp

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.Spanish National Research Council (CSIC), project no. 202080E231University of Barcelona and the University of Granada (Official State Gazette 311, on 27 November 2020

Gel Formulations with an Echinocandin for Cutaneous Candidiasis: The Influence of Azone and Transcutol on Biopharmaceutical Features

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

Liposomal Triamcinolone acetonide: influence of composition in performance and stability

El acetónido de triamcinolona, antiinfl amatorio esteroideo, presenta por vía tópica los inconvenientes de la corticoterapia. No obstante, su incorporación a un sistema transportador, como los liposomas permitiría prolongar la dosis efectiva en el lugar de acción (dermis y epidermis), reduciendo los efectos secundarios. Así pues, se ha normalizado el método de elaboración de liposomas multilaminares portadores de acetónido de triamcinolona y evaluado el grado de captación del fármaco seleccionado, en función de la composición de los liposomas, determinando los componentes más idóneos para su obtención y los rendimientos proporcionados al variar las concentraciones de los mismos. La adición de colesterol para mejorar su estabilidad, provoca una reducción media en la captación; no obstante la encapsulación sigue siendo bastante elevada. La evaluación de la estabilidad muestra la infl uencia de la temperatura de conservación, de tal manera que los liposomas mantenidos a temperatura de refrigeración (4-6ºC)poseen una estabilidad mayor que las muestras a temperatura ambiente.In topical presentation, Triamcinolone acetonide, a steroidal anti-infl ammatory preparation, presents all the disadvantages of corticotherapy. However, on incorporation into a liposomal drug delivery system, the effectiveness of each dosage within the area of its activity (dermis and epidermis) is prolonged, serving to reduce secondary side effects. For this reason, an attempt has been made to standardize a method for the preparation of a multilaminar liposomal delivery system of triamcinolone acetonide and to assess how much of the drug could be encapsulated by the varying liposomal formulations tested and consequently, which of these would prove to be the most suitable. The addition of cholesterol to such formulations was found to improve stability. However, although such an addition was found to reduce levels of encapsulation of the drug, these still remained suffi ciently high. In the assessment of stability, storage temperature was found to bear an infl uence. Liposomes kept under cold storage (4-6ºC) presented higher stability than samples stored at room temperature

Principal Criteria for Evaluating the Quality, Safety and E cacy of hMSC-Based Products in Clinical Practice: Current Approaches and Challenges

Human Mesenchymal Stem Cells (hMSCs) play an important role as new therapeutic alternatives in advanced therapies and regenerative medicine thanks to their regenerative and immunomodulatory properties, and ability to migrate to the exact area of injury. These properties have made hMSCs one of the more promising cellular active substances at present, particularly in terms of the development of new and innovative hMSC-based products. Currently, numerous clinical trials are being conducted to evaluate the therapeutic activity of hMSC-based products on specific targets. Given the rapidly growing number of hMSC clinical trials in recent years and the complexity of these products due to their cellular component characteristics and medicinal product status, there is a greater need to define more stringent, specific, and harmonized requirements to characterize the quality of the hMSCs and enhance the analysis of their safety and efficacy in final products to be administered to patients. These requirements should be implemented throughout the manufacturing process to guarantee the function and integrity of hMSCs and to ensure that the hMSC-based final product consistently meets its specifications across batches. This paper describes the principal phases involved in the design of the manufacturing process and updates the specific technical requirements needed to address the appropriate clinical use of hMSC-based products. The challenges and limitations to evaluating the safety, efficacy, and quality of hMSCs have been also reviewed and discussed.This work was supported by Ministerio de Ciencia, Innovación y Universidades. Plan Estatal I+D+I, Grant Number: RTI2018-095410-B-100; Spanish Ministry of Economy (MINECO), Grant Number: RD16/0011/0030; Spanish Ministry of Science, Innovation and Universities (to JAG) and by the Ministerio de Economía, Industria y Competitividad (FEDER funds, project RTC-2016-5451-1) (to BC and PG-M). Additional it has been developed in the context of AdvanceCat with the support of ACCIÓ (Catalonia Trade & Investment; Generalitat de Catalunya) under the Catalonian European Regional Development Fund operational program, 2014-2020 (to PG-M)

Development of a cell-based medicinal product: Regulatory structures in the European Union

IntroductionNew therapies with genes, tissues and cells have taken the emerging field for the treatment of many diseases. Advances on stem cell therapy research have led to international regulatory agencies to harmonize and regulate the development of new medicines with stem cells.Sources of dataEuropean Medicines Agency on September 15, 2012.Areas of agreementCell therapy medicinal products should be subjected to the same regulatory principles than any other medicine.Areas of controversyTheir technical requirements for quality, safety and efficacy must be more specific and stringent than other biologic products and medicines.Growing pointsCell therapy medicinal products are at the cutting edge of innovation and offer a major hope for various diseases for which there are limited or no therapeutic options.Areas timely for developing researchThe development of cell therapy medicinal products constitutes an alternative therapeutic strategy to conventional clinical therapy, for which no effective cure was previously available. © 2012 Published by Oxford University Press. All rights reserved.This work was supported by Fundación Progreso y Salud, Consejería de Salud, Junta de Andalucía (Grant PI-0022/2008); Consejería de Innovación Ciencia y Empresa, Junta de Andalucía (Grant CTS-6505; INP-2011-1615-900000); FEDER co-funded grants from Instituto de Salud Carlos III (Red TerCel-Grant RD06/0010/0025; PI10/00964) and the Ministry of Health and Consumer Affairs (Advanced Therapies Program Grant TRA-120). CIBERDEM is an initiative of the Instituto de Salud Carlos III.Peer Reviewe

Evaluation of the anti-wrinkle efficacy of cosmetic formulations with an anti-aging peptide (Argireline®).

The purpose of this research was to evaluate, by means of in vivo studies, the efficacy of new cosmetic active ingredients which effect of botox, called Argireline®), so that width and depth of wrinkles could be established. For this, it is prepared two formulations: an emulsion with an external aqueous phase for normal to dry skin, and a gel for oily skin. We likewise study the water content of the skin after the application of both formulas, as this must be one of the priority functions of facial treatments in general, as well as the level of satisfaction from the subjective point of view, fundamental for patients and their continuation of the treatment. After the designed tests, it is possible to verify that there is a remarkable diminution of the wrinkles size tested in each patient during the month of treatment. Besides, it is possible to review how the moisturizing capacity has been increased in all cases. At the end of the visual test, all the volunteers experienced a reduction in the depth of wrinkles, and from the subjective point of view, the appearance and elasticity of the skin were improved. Finally it is possible to conclude that Argireline® (acetyl hexapeptide-8 ) shows a great antiaging capacity in all the cases that have been studied and the tried compounds have increased moisturizing power

Study of the stability of packaging and storage conditions of human mesenchymal stem cell for intra-arterial clinical application in patient with critical limb ischemia

Critical limb ischemia (CLI) is associated with significant morbidity and mortality. In this study, we developed and characterized an intra-arterial cell suspension containing human mesenchymal stem cells (hMSCs) for the treatment of CLI. Equally, the stability of cells was studied in order to evaluate the optimal conditions of storage that guarantee the viability from cell processing to the administration phase. Effects of various factors, including excipients, storage temperature and time were evaluated to analyze the survival of hMSCs in the finished medicinal product. The viability of hMSCs in different packaging media was studied for 60 h at 4 °C. The best medium to maintain hMSCs viability was then selected to test storage conditions (4, 8, 25 and 37 °C; 60 h). The results showed that at 4 °C the viability was maintained above 80% for 48 h, at 8 °C decreased slightly, whereas at room temperature and 37 °C decreased drastically. Its biocompatibility was assessed by cell morphology and cell viability assays. During stability study, the stored cells did not show any change in their phenotypic or genotypic characteristics and physicochemical properties remained constant, the ability to differentiate into adipocytes and osteocytes and sterility requirements were also unaltered. Finally, our paper proposes a packing media composed of albumin 20%, glucose 5% and Ringer's lactate at a concentration of 1 × 106 cells/mL, which must be stored at 4 °C as the most suitable to maintain cell viability (>80%) and without altering their characteristics for more than 48 h