Pluronic® F-127 and Pluronic Lecithin Organogel (PLO): main features and their applications in topical and transdermal administration of drugs.

Topical drug treatment aims at providing high concentrations of drugs at the site of application so as to avoid adverse systemic effects associated with oral administration. Smart polymers, or stimuli-responsive polymers, are able to respond to a stimulus by showing physical or chemical changes in their behaviour as, for example, the delivery of the drug carried by them. The thermo-responsive nature of Pluronic® F-127 (Basf, Ludwigshafen, Germany) makes it an excellent candidate for the delivery of drugs at various application sites. In recent years, PF-127, and later, Pluronic lecithin organogels (PLO), have attracted particular interest in the design of dermal and transdermal delivery systems with a view to promoting, improving or retarding drug permeation through the skin, bearing in mind that for topical delivery systems, accumulation in the skin with minimal permeation is desired, while for systemic delivery, the opposite behaviour is preferred. In this review, we discuss the properties and characteristics of PF-127 and Pluronic lecithin organogels (PLO), and present many examples and advantages of the application of these polymeric systems in topical and transdermal administration of drugs. This article is open to POST-PUBLICATION REVIEW. Registered readers (see "For Readers") may comment by clicking on ABSTRACT on the issue's contents page.

Editorial-Current Insights on Lipid-Based Nanosystems.

Lipid-based nanosystems, including solid lipid nanoparticles (SLN) and nanostructured lipid carriers (NLC), cationic lipid nanoparticles, nanoemulsions and liposomes, have been extensively studied to improve drug delivery through different administration routes [...].

Overcoming Challenges in Pediatric Formulation with a Patient-Centric Design Approach: A Proof-of-Concept Study on the Design of an Oral Solution of a Bitter Drug.

Designing oral formulations for children is very challenging, especially considering their peculiarities and preferences. The choice of excipients, dosing volume and palatability are key issues of pediatric oral liquid medicines. The purpose of the present study is to develop an oral pediatric solution of a model bitter drug (ranitidine) following a patient centric design process which includes the definition of a target product profile (TPP). To conclude on the matching of the developed solution to TPP, its chemical and microbiological stability was analyzed over 30 days (stored at 4 °C and room temperature). Simulation of use was accomplished by removing a sample with a syringe every day. Taste masking was assessed by an electronic tongue. The developed formulation relied on a simple taste masking strategy consisting in a mixture of sweeteners (sodium saccharine and aspartame) and 0.1% sodium chloride, which allowed a higher bitterness masking effectiveness in comparison with simple syrup. The ranitidine solution was stable for 30 days stored at 4 °C. However, differences were noted between the stability protocols (unopened recipient and in-use stability) showing the contribution of the simulation of use to the formation of degradation products. Stock solution was subjected to acid and alkali hydrolysis, chemical oxidation, heat degradation and a photo degradation stability assessment. The developed pediatric solution matched the TPP in all dimensions, namely composition suitable for children, preparation and handling adapted to hospital pharmaceutical compounding and adequate stability and quality. According to the results, in-use stability protocols should be preferred in the stability evaluation of pediatric formulations.

Influence of psoriasis lesions' location and severity on psychosocial disability and psychopathology. Observational study and psychometric validation of the SAPASI Portuguese version.

OBJECTIVES: The psychosocial impact of psoriasis is well documented. However, the contributing role of clinical disease characteristics is not satisfactorily explored. This study aimed to validate the Self-administered Psoriasis Area and Severity Index (SAPASI) to a Portuguese population (SAPASI-PT) and to perform its cross-validation, assessing how the results will generalize to an independent data set, with the Psoriasis Area and Severity Index (PASI), in order to assess the influence of psoriasis' severity on psychosocial disability and psychopathology. METHODS: A cross-sectional study with 228 patients with psoriasis was carried out. Data was collected through a sociodemographic and clinical questionnaire, SAPASI-PT, the Psoriasis Disability Index (PDI) and the Brief Symptoms Inventory (BSI). The cultural and linguistic adaptation of SAPASI to a Portuguese version and the cross validation with PASI was carried out. Multiple associations between psychosocial disability, psychopathology and severity, discomfort and location of lesions were investigated through logistic regression models. RESULTS: A good adjustment model for SAPASI-PT is found. Also, associations between psychosocial disability, psychopathology and the psoriasis severity and discomfort are found. The existence of lesions is positively associated with the severity of the disease. Patients with lesions in hands or genitals are those reporting a greater discomfort. The presence of lesions in hands is positively associated with PDI, i.e., with leisure and with treatment, marginally. Additionally, patients scoring higher in the personal dimension are found to have a significantly greater percentage of lesions in the genitals. CONCLUSIONS: The psoriasis severity and location of lesions are important determinants of patients´ quality of life. Lesions on face, hands and genitals are associated with a higher impact on psychosocial wellbeing of patients. Psychological counselling should be considered within psoriasis treatment context in patients with the described disease manifestations.

Design and characterization of Nanostructured lipid carriers (NLC) and Nanostructured lipid carrier-based hydrogels containing Passiflora edulis seeds oil.

This study aims to design and characterize Nanostructured lipid carriers (NLC) and Nanostructured lipid carrier-based hydrogels with Passiflora edulis seeds oil, a by-product from Madeira Island food industry. NLC were prepared by the ultrasonication technique, using passion fruit seeds oil as a liquid lipid and glyceryl distearate as a solid lipid. These NLC were then gelled with Poly (acrylic acid). Long-term stability studies were conducted with NLC and NLC-based hydrogels stored for 12 months. The following tests were performed: morphology, encapsulation efficiency, particle size analysis, polydispersity index analysis, zeta potential, pH measurement, color analysis, viscosity studies, texture analysis, in vitro occlusion test, ex vivo skin penetration study, tyrosinase inhibition activity, in vitro skin permeation experiments and in vitro cytotoxicity studies. The developed NLC had spherical shape and narrow particle sizes distribution with mean sizes in the range of 150 nm and PDI below 0.3, Zeta potential values around -30 mV and high Encapsulation efficiency. The tyrosinase inhibitory activity and skin retention of the nanoparticles was superior to that of the non-encapsulated oil. The developed formulations did not show cytotoxicity towards HaCat cells and presented suitable viscosity and texture properties for skin application, proving to be good candidates as depigmenting agent.

Development of a Platform to Align Education and Practice: Bridging Academia and the Profession in Portugal.

Limited fitness for practice may result from a mismatch between education and practice. Aiming to meet the common interests of academics and practitioners, the Portuguese Pharmaceutical Society (PPS) developed the Education and Practice Platform (EPP). The EPP includes one representative from each pharmacy faculty, and all Councils of Speciality Boards of Practice. Brainstorming with involved parties enabled sharing of interests, concerns and identifying a common path. Aims, mission, vision and values were set. The EPP's mission is to: act as an enabler to foster the quality and adequacy of education through sharing best practices, ultimately leading to facilitate professional integration, and to foster quality development in teaching practices with recognition for autonomy in freedom to teach and to learn. Its vision is an alignment of education and practice with the PPS' statutes to ensure validation of the competences defined for each practice area, and compliance with international guidance. Key performance indicators (KPIs) were set. Activities developed include the creation of a national forum to discuss education and practice, development of workshops on teaching methods and pharmacy internships, enhanced representation in international events and response to global and national requests. Ongoing work focuses on the creation of a common training framework in hospital and community pharmacy practice adapted to Portugal. The EPP is a worldwide case study, encouraging the development of discussion contributing to an open climate of sharing best practices, indirectly leading to foster a better alignment between education and practice. Many of these results are so far intangible in scientific terms but worth describing.

Cyclodextrins as Drug Carriers in Pharmaceutical Technology: The State of the Art.

BACKGROUND: Cyclodextrins (CDs) are versatile excipients with an essential role in drug delivery, as they can form non-covalently bonded inclusion complexes (host-guest complexes) with several drugs either in solution or in the solid state. METHODS: The main purpose of this publication was to carry out a state of the art of CDs as complexing agents in drug carrier systems. In this way, the history, properties and pharmaceutical applications of the CDs were highlighted with typical examples. The methods to enhance the Complexation Efficiency (CE) and the CDs applications in solid dosage forms were emphasized in more detail. RESULTS: The main advantages of using these cyclic oligosaccharides are as follows: (1) to enhance solubility/ dissolution/ bioavailability of poorly soluble drugs; (2) to enhance drug stability; (3) to modify the drug release site and/or time profile; and (4) to reduce drug side effects (for example, gastric or ocular irritation). These compounds present favorable toxicological profile for human use and therefore there are various medicines containing CDs approved by regulatory authorities worldwide. On the other hand, the major drawback of CDs is the increase in formulation bulk, once the CE is, in general, very low. This aspect is particularly relevant in solid dosage forms and limits the use of CDs to potent drugs. CONCLUSION: CDs have great potential as drug carriers in Pharmaceutical Technology and can be used by the formulator in order to improve the drug properties such as solubility, bioavailability and stability. Additionally, recent studies have shown that these compounds can be applied as active pharmaceutical ingredients.

Cyclodextrins as excipients in tablet formulations.

This paper aims to provide a critical review of cyclodextrins as excipients in tablet formulations, highlighting: (i) the principal pharmaceutical applications of cyclodextrins; (ii) the most relevant technological aspects in pharmaceutical formulation development; and (iii) the actual regulatory status of cyclodextrins. Moreover, several illustrative examples are presented. Cyclodextrins can be used as complexing excipients in tablet formulations for low-dose drugs. By contrast, for medium-dose drugs and/or when the complexation efficiency is low, the methods to enhance the complexation efficiency play a key part in reducing the cyclodextrin quantity. In addition, these compounds are used as fillers, disintegrants, binders and multifunctional direct compression excipients of the tablets.

Semisolid formulations based on solid-in-oil-in-water systems containing proteins

Abstract In recent years, improvements have been made, through biotechnological processes, in the production and development of peptides capable of increasing collagen and elastin synthesis for anti-aging skin care. However, proteins have many limitations due to their structural, chemical and physical fragility to external aggressions, which may cause conformational changes, leading to loss of biological activity. Therefore, it is important to create delivery systems that protect these biomolecules from damage, allowing them to reach their target. This work aimed to develop a system able to carry bovine serum albumin (BSA), used as a model of a protein, and to incorporate this system in a semisolid formulation suitable for skin application. A microemulgel based on a solid-in-oil-in-water (S/O/W) microemulsion was prepared. Firstly, the association efficiency (AE) of lyophilized BSA-sucrose ester complex and the size of S/O nanodispersion were assessed; then, the characterization and stability evaluation of the final semisolid formulation through evaluation of pH, texture and rheological behavior were performed. The average value of AE was 54.74% ± 2.17. It was possible to develop an S/O/W microemulsion, which allowed the subsequent development of an S/O/W microemulgel that assured suitable pH, texture and rheological characteristics for skin application.

Development and characterization of mucoadhesive buccal gels containing lipid nanoparticles of ibuprofen.

The lipid nanoparticles, namely Nanostructured Lipid Carriers (NLC), as drug delivery systems have been investigated for several years. One of the delivery routes for which these carriers can be applied is buccal administration. However, the liquid dispersions of lipid nanoparticles can be rapidly removed from oral cavity by saliva. Thus, the development of a system that allows increased retention time on the mucosa is necessary. For this reason, the development of mucoadhesive preparations for buccal administration of lipid nanoparticles becomes important. Hydrogels prepared with mucoadhesive polymers (Carbopol® 980 and polycarbophil) constitute a promising option. The aim of this work was to develop mucoadhesive buccal hydrogels with NLC, using ibuprofen as a model drug. The obtained results showed that the developed NLC dispersions presented particles in the nanometric size range, with low polydispersity index values and efficient ability for the entrapment of the model drug. Moreover, the incorporation of NLC in hydrogels of mucoadhesive polymers resulted in preparations with desirable rheological features as well as texture (firmness and adhesiveness) and mucoadhesive properties, which could benefit the therapeutic efficacy, by increasing the residence time and easiness for topical application in the buccal mucosa. Additionally, the developed preparations exhibited sustained drug release as intended for these systems.

Development and Validation of a Novel Questionnaire for Adherence with Topical Treatments in Psoriasis (QATOP).

BACKGROUND: Self-report measures are the most used methodologies for the evaluation of adherence to psoriasis topical treatment, although currently there is no standard questionnaire for this purpose. OBJECTIVE: The present study aimed at developing a novel questionnaire (Questionnaire for Adherence to TOPical treatment [QATOP]) for the assessment of adherence to topical treatment in psoriasis. METHODS: A questionnaire containing nine items organized into two parts (part 1: current patient treatment; part 2: adherence to treatment, amount used, and treatment-associated variables) was developed, supported by a systematic literature review, qualitative patient focus interviews, and expert-group input. Its content validity was determined by a pilot study of six patients. Adherence to topical treatment was then assessed in 35 patients with psoriasis, after 45 days of treatment, using the QATOP and a medication log. Associations between different items of the QATOP and the log were investigated. RESULTS: Adherence results were 63.5 ± 29.2% for the log and 60.9 ± 24.4% for the QATOP, and were strongly correlated (R = 0.819, p < 0.001). Distinct posologic regimens were reported by patients, which, in some cases, were not the usual doses. Patients also reported using doses of medicine on each application that were markedly lower than required. CONCLUSION: The QATOP is a valid and reliable self-report measure of adherence to topical treatment in patients with psoriasis. The use of this standard questionnaire could improve the methodological quality of adherence studies. Improvement of the clarity of posologic instructions is clearly urgently needed.

Compressed mini-tablets as a biphasic delivery system.

Compressed mini-tablets systems are presented as a biphasic delivery system designed for zero-order sustained drug release. The outer layer that fills the void spaces between the mini-tablets was formulated to release the drug in a very short time (fast release), while the mini-tablets provided a prolonged release. Different composition (HPMC or EC) and number (10 or 21) of mini-tablets were used to obtain different drug release rates. The in vitro performance of these systems showed the desired biphasic behaviour: the drug contained in the fast releasing phase (powder enrobing the mini-tablets) dissolved within the first 2 min, whereas the drug contained in the mini-tablets was released at different rates, depending up on formulation. Based on the release kinetic parameters calculated, it can be concluded that mini-tablets containing HPMC were particularly suitable approaching to zero-order (constant) release over 8h time periods.

New Thermoresponsive Eyedrop Formulation Containing Ibuprofen Loaded-Nanostructured Lipid Carriers (NLC): Development, Characterization and Biocompatibility Studies.

The low bioavailability and consequently the poor therapeutic response of traditional ophthalmic formulations is caused by reduced pre-corneal residence time of the formulation in contact with the ocular surface. The use of colloidal carrier systems, namely lipid nanoparticles in combination with in situ gelling polymers, is an excellent strategy which results in the exponential increase of the bioavailability of ophthalmic drugs. In the present study, we have developed thermoresponsive eyedrops prepared with nanostructured lipid carriers (NLC) dispersions for the controlled delivery of ibuprofen. Lipid solubility studies and DSC measurements have proved that the lipids solubilise ibuprofen and present a good compatibility. NLC were prepared based on the melt-emulsification and ultrasonication technique and lipid nanoparticles with a Z-average of 120-150 nm, polydispersity index below 0.3, highly positive zeta potential and an efficacy of encapsulation of ~87% were obtained. The cytotoxicity of NLC was evaluated by the Alamar Blue reduction assay using the Y-79 human retinoblastoma cell line, and no relevant toxicity was observed after exposure to 0-100 µg/mL NLC for up to 72 hours. The HET-CAM assay was used to assess the product eye compatibility, confirming that the developed product does not exhibit irritant potential. The in vitro release studies showed ibuprofen release over several hours.

In situ gelling systems: a strategy to improve the bioavailability of ophthalmic pharmaceutical formulations.

The low therapeutic efficacy exhibited by conventional ophthalmic solutions owing to precorneal elimination of the drug, drainage by gravity, nasolacrimal drainage, conjunctival absorption, and the absence of controlled release and of bioadhesive properties, can be overcome by the use of in situ gelling systems. The combination in the same formulation of different in situ gelling polymers with different stimuli-responsiveness mechanisms exploiting the unique physicochemical characteristics of the ocular tissues is one such strategy that has produced improved results compared with conventional systems. As we discuss here, the recent use of biodegradable and biocompatible polymers in colloidal carrier systems has proved to be the most effective strategy, resulting in the exponential increase of the bioavailability of the ophthalmic drugs.

Influence of drug incorporation, temperature and storage time on the pH, textural and rheological properties of different poloxamer hydrogels.

In recent years, Poloxamers had attracted a particular interest in the design of dermal and transdermal delivery systems in order to improve or retard drug permeation through the skin. In the present study, the influence of different parameters, such as, temperature, storage time, type of polymer (Lutrol(®) F-127 and Lutrol(®) F-108) and the addition of two types of drugs (ibuprofen and hydrocortisone) in the pH, texture and rheological behavior of topical pharmaceutical formulations containing poloxamers was assessed. In fact, the type of polymer used in the preparation of the hydrogels, the type of drug incorporated, the temperature and the storage time caused changes in the pH, texture and rheological behavior of topical formulations containing Lutrol(®) F-127 and Lutrol(®) F-108. Lutrol(®) F-127 hydrogels showed higher values of pH, firmness, adhesiveness and viscosity than Lutrol(®) F-108 hydrogels. The chemical nature of the drugs incorporated in these poloxamer hydrogels influence the pH of the preparations. Low percentages of drug incorporated into both types of hydrogels didn't affect significantly their textural and rheological characteristics. The hydrogels prepared with Lutrol(®) F- 127 proved to be more resistant to temperature variations, maintaining their rheological behavior over time.

Use of solid dispersions to increase stability of dithranol in topical formulations

The present study was planned to improve the stability of dithranol using solid dispersions (SD). Two different SD at a 1:9 ratio of dithranol/excipient were prepared: one of them using glyceryl behenate as excipient and the other using a mixture of argan oil with stearic acid (1:8 ratio) as excipient. Pure dithranol and SD of dithranol were incorporated in an oil-in-water cream and in a hydrophobic ointment in a drug/dermatological base ratio of 1:10. The physical and mechanical properties of semisolid formulations incorporating the pure drug and the developed SD were evaluated through rheological and textural analysis. To evaluate the stability, L*a*b* color space parameters of SD and semisolid formulations, and pH of hydrophilic formulations were determined at defined times, during one month. Each sample was stored at different conditions namely, light exposure (room temperature), high temperature exposition (37 °C) (protected from light) and protected from light (room temperature). Despite higher values of firmness and adhesiveness, hydrophobic ointment exhibited the best rheological features compared to the oil-in-water cream, namely a shear-thinning behavior and high thixotropy. These formulations have also presented more stability, with minor changes in L*a*b* color space parameters. The results of this study indicate that is possible to conclude that the developed SD contributed to the increased stability of dithranol.

Este trabalho teve como objetivo aumentar a estabalidade do ditranol através da preparação de dispersões sólidas (DS). Prepararam-se duas DS diferentes em proporção de 1:9 de ditranol/excipiente: em uma das DS utilizou-se beenato de glicerila como excipiente e na outra se utilizou mistura de óleo de argan com ácido esteárico (razão 1:8). Posteriormente, efetuou-se a incorporação de ditranol puro e das DS contendo este fármaco num creme hidrófilo ou óleo-água (O/A) e em pomada hidrófoba, na proporção 1:10 (fármaco ou respetivas DS/base dermatológica). As propriedades físicas e mecânicas das formulações semissólidas incorporando fármaco ou as respetivas DS previamente desenvolvidas, foram avaliadas através da análise do comportamento reológico e das propriedades de textura. Para avaliar a estabilidade, os parâmetros do espaço de cor L*a*b* das DS e das formulações semissólidas e o pH das preparações hidrófilas foram determinados em períodos de tempo definidos, durante um mês para cada amostra armazenada sob diferentes condições, especificamente, exposição à luz (à temperatura ambiente), protegidas da luz à temperatura elevada (37 °C) e protegidas da luz (temperatura ambiente). Embora tenham apresentado valores de firmeza e de adesividade mais elevados, as pomadas hidrófobas apresentaram melhores características reológicas do que os cremes óleo-água. Além disso, as pomadas hidrófobas também apresentaram melhor estabilidade, com pequenas alterações nos parâmetros do espaço de cor L*a*b*. Os resultados deste trabalho permitiram concluir que as DS desenvolvidas contribuíram para o aumento da estabilidade do ditranol.

Characterization and stability studies of emulsion systems containing pumice

Emulsions are the most common form of skin care products. However, these systems may exhibit some instability. Therefore, when developing emulsions for topical application it is interesting to verify whether they have suitable physical and mechanical characteristics and further assess their stability. The aim of this work was to study the stability of emulsion systems, which varied in the proportion of the emulsifying agent cetearyl alcohol (and) sodium lauryl sulfate (and) sodium cetearyl sulfate (LSX), the nature of the oily phase (decyl oleate, cyclomethicone or dimethicone) and the presence or absence of pumice (5% w/w). While maintaining the samples at room temperature, rheology studies, texture analysis and microscopic observation of formulations with and without pumice were performed. Samples were also submitted to an accelerated stability study by centrifugation and to a thermal stress test. Through the testing, it was found that the amount of emulsifying agent affects the consistency and textural properties such as firmness and adhesiveness. So, formulations containing LSX (5% w/w) and decyl oleate or dimethicone as oily phase had a better consistency and remained stable with time, so exhibited the best features to be used for skin care products.

Emulsões são a forma de apresentação mais comum dos produtos para aplicação na pele. No entanto estes sistemas podem exibir alguma instabilidade. Por esta razão, quando do desenvolvimento de emulsões para aplicação tópica é importante verificar se estas apresentam propriedades físicas ou mecânicas adequadas e avaliar a sua estabilidade. O objetivo deste trabalho consistiu no estudo da estabilidade de emulsões, cujas variações entre elas foi a proporção de agente emulsificante álcool estearílico (mais) laurilsulfato de sódio (mais) estearilsulfato de sódio (LSX), a natureza da fase oleosa (decil oleato, ciclometicona ou dimeticona) e a presença ou ausência de pedra-pomes (5% m/m). Mantendo as amostras à mesma temperatura, realizaram-se o estudo da reologia, a análise de textura e observação microscópica das formulações com e sem pedra-pomes. Amostras foram, também, submetidas a estudo de estabilidade acelerada por centrifugação e a ensaio de estresse térmico. Através dos testes realizados, constatou-se que a quantidade de agente emulsificante influencia a consistência e as propriedades de textura, como a firmeza e a adesividade. As formulações contendo LSX (5% m/m) e decil oleato ou dimeticona como fase oleosa exibiram melhores caraterísticas como produtos para aplicação na pele, uma vez que estas formulações apresentaram menor firmeza e consistência e permaneceram estáveis com o tempo.

Formas farmacêuticas de liberação modificada: polímeros hidrifílicos / Modified release of drug delivery systems: hydrophilic polymers

Os sistemas de liberação de fármacos são parte integrante da investigaão farmacêutica. A maioria dos sistemas de liberação oral de fármacos é baseada em matrizes poliméricas. Nas duas décadas passadas, as matrizes hidrografílicas tornaram-se muito populares na formulação de formas farmacêuticas de liberação modificada. A escolha do polímero hidrofílico na formulação da matriz pode fornecer uma combinação apropriada dos mecanismos de intumescimento, de dissolução ou de erosão e determinam a cinética de liberação in vitro. As matrizes de intumescimento são sistemas monolíticos preparados pela compressão de mistura de um polímero hidrofílico e de um fármaco. Elas representam sistemas da liberação em que os vários mecanismos podem ser adaptados ao programa de liberação...