Nanopartículas de PCL com acetato de hidrocortisona como uma terapia dermatológica inovadora para a dermatite atópica

A dermatite atópica é uma patologia cutânea crónica que requer cuidados intensivos da pele e tratamento farmacológico; contudo, os tratamentos disponíveis necessitam urgentemente de ser melhorados, especialmente quando utilizados por períodos longos ou em grupos específicos (ex: crianças). A nanotecnologia tem contribuído com sistemas de veiculação inovadores e pode oferecer terapias efectivas e direcionadas. Os objectivos deste estudo centraram-se na preparação caracterização das nanopartículas de policaprolactona carregadas com acetato de hidrocortisona em termos das propriedades físico-químicas, eficiência de encapsulação, ensaios de libertação in vitro e ensaios de segurança dos excipientes utilizados em voluntários humanos. As nanopartículas produzidas apresentaram um tamanho médio de 258,4 24,5 nm e um índice de polidispersão de 0,084. O potencial zeta foi -4,39 0,62 mV e a eficiência de encapsulação foi 36,32 0,03 %. A libertação in vitro do fármaco foi controlada ao longo do tempo. Além disso, os testes de segurança indicaram que os excipientes foram bem tolerados. Este estudo demonstra que as nanopartículas de policaprolactona são sistemas estáveis para veiculação de acetato de hidrocortisona que poderão conduzir a uma libertação prolongada do fármaco, com resultados promissores ao nível da sua segurança quando aplicados na pele humana.

Endocrine disrupters and human health: Could oestrogenic chemicals in body care cosmetics adversely affect breast cancer incidence in women? A review of evidence and call for further research

In the decade that has elapsed since the suggestion that exposure of the foetal/developing male to environmental oestrogens could be the cause of subsequent reproductive and developmental effects in men, there has been little definitive research to provide conclusions to the hypothesis. Issues of exposure and low potency of environmental oestrogens may have reduced concerns. However, the hypothesis that chemicals applied in body care cosmetics (including moisturizers, creams, sprays or lotions applied to axilla or chest or breast areas) may be affecting breast cancer incidence in women presents a different case scenario, not least in the consideration of the exposure issues. The specific cosmetic type is not relevant but the chemical ingredients in the formulations and the application to the skin is important. The most common group of body care cosmetic formulation excipients, namely p-hydroxybenzoic acid esters or parabens, have been shown recently to be oestrogenic in vitro and in vivo and now have been detected in human breast tumour tissue, indicating absorption (route and causal associations have yet to be confirmed). The hypothesis for a link between oestrogenic ingredients in underarm and body care cosmetics and breast cancer is forwarded and reviewed here in terms of. data on exposure to body care cosmetics and parabens, including dermal absorption; paraben oestrogenicity; the role of oestrogen in breast cancer; detection of parabens in breast tumours; recent epidemiology studies of underarm cosmetics use and breast cancer; the toxicology database; the current regulatory status of parabens and regulatory toxicology data uncertainties. Notwithstanding the major public health issue of the causes of the rising incidence of breast cancer in women, this call for further research may provide the first evidence that environmental factors may be adversely affecting human health by endocrine disruption, because exposure to oestrogenic chemicals through application of body care products (unlike diffuse environmental chemical exposures) should be amenable to evaluation, quantification and control. The exposure issues are clear and the exposed population is large, and these factors should provide the necessary impetus to investigate this potential issue of public health. Copyright (C) 2004 John Wiley Sons, Ltd.

Chitosan-based mucoadhesive tablets for oral delivery of ibuprofen

Chitosan and its half-acetylated derivative have been compared as excipients in mucoadhesive tablets containing ibuprofen. Initially the powder formulations containing the polymers and the drug were prepared by either co-spray drying or physical co-grinding. Polymer–drug interactions and the degree of drug crystallinity in these formulations were assessed by infrared spectroscopy and differential scanning calorimetry. Tablets were prepared and their swelling and dissolution properties were studied in media of various pHs. Mucoadhesive properties of ibuprofen-loaded and drug-free tablets were evaluated by analysing their detachment from pig gastric mucosa over a range of pHs. Greater polymer–drug interactions were seen for spray-dried particles compared to co-ground samples and drug loading into chitosan-based microparticles (41%) was greater than the corresponding half-acetylated samples (32%). Swelling and drug release was greater with the half-acetylated chitosan tablets than tablets containing the parent polymer and both tablets were mucoadhesive, the extent of which was dependent on substrate pH. The results illustrate the potential sustained drug delivery benefits of both chitosan and its half-acetylated derivative as mucoadhesive tablet excipients.

Novel polyvinylpyrrolidones to improve delivery of poorly-water soluble drugs; from design to synthesis and evaluation

Polyvinylpyrrolidone is a widely used in tablet formulations with the linear form acting as a wetting agent and disintegrant whereas the cross-linked form is a super-disintegrant. We have previously reported that simply mixing the commercial cross-linked polymer with ibuprofen disrupted drug crystallinity with consequent improvements in drug dissolution behavior. In this study, we have designed and synthesized novel cross-linking agents containing a range of oligoether moieties which have then be polymerized with vinylpyrrolidone to generate a suite of novel excipients with enhanced hydrogen-bonding capabilities. The polymers have a porous surface and swell in most common solvents and in water; properties which suggest their value as disintegrants. The polymers were evaluated in simple physical mixtures with ibuprofen as a model poorly-water soluble drug. The results show that the novel PVPs induce the drug to become “X-ray amorphous”, which increased dissolution to a greater extent than that seen with commercial cross-linked PVP. The polymers stabilize the amorphous drug with no evidence for recrystallization seen after 20 weeks storage.

In situ gelling systems based on Pluronic F127/Pluronic F68 formulations for ocular drug delivery

This study evaluated the use of Pluronic F127 and Pluronic F68 as excipients for formulating in situ gelling systems for ocular drug delivery. Thermal transitions have been studied in aqueous solutions of Pluronic F127, Pluronic F68 as well as their binary mixtures using differential scanning calorimetry, rheological measurements, and dynamic light scattering. It was established that the formation of transparent gels at physiologically relevant temperatures is observed only in the case of 20 wt % of Pluronic F127. The addition of Pluronic F68 to Pluronic F127 solutions increases the gelation temperature of binary formulation to above physiological range of temperatures. The biocompatibility evaluation of these formulations using slug mucosa irritation assay and bovine corneal erosion studies revealed that these polymers and their combinations do not cause significant irritation. In vitro drug retention study on glass surfaces and freshly excised bovine cornea showed superior performance of 20 wt % Pluronic F127 compared to other formulations. In addition, in vivo studies in rabbits demonstrated better retention performance of 20 wt % Pluronic F127 compared to Pluronic F68. These results confirmed that 20 wt % Pluronic F127 offers an attractive ocular formulation that can form a transparent gel in situ under physiological conditions with minimal irritation.

Drug Excipient Interaction Study with Polymorphic Forms of Tibolone

Powder mixtures (1:1) of tibolone polymorphic forms I (monoclinic) and II (triclinic) and excipients have been prepared and compacted. The samples were stored at 50 degrees C and 90% RH for one month and subsequently were evaluated using differential scanning calorimetry (DSC) and high-performance liquid chromatography (HPLC). The results indicate that during the compaction, the applied pressure reduced the chemical stability of tibolone in both polymorph forms. The triclinic form was more chemically unstable, both pure and in contact with excipients, than the monoclinic form. Lactose monohydrate was shown to reduce chemical degradation for both forms. Ascorbyl palmitate was shown to affect the tibolone stability differently depending on the polymorphic form used.

THERMAL BEHAVIOR STUDY AND DECOMPOSITION KINETICS OF SALBUTAMOL UNDER ISOTHERMAL AND NON-ISOTHERMAL CONDITIONS

The thermal decomposition of salbutamol (beta(2) - selective adrenoreceptor) was studied using differential scanning calorimetry (DSC) and thermogravimetry/derivative thermogravimetry (TG/DTG). It was observed that the commercial sample showed a different thermal profile than the standard sample caused by the presence of excipients. These compounds increase the thermal stability of the drug. Moreover, higher activation energy was calculated for the pharmaceutical sample, which was estimated by isothermal and non-isothermal methods for the first stage of the thermal decomposition process. For isothermal experiments the average values were E(act) = 130 kJ mol(-1) (for standard sample) and E(act) = 252 kJ mol(-1) (for pharmaceutical sample) in a dynamic nitrogen atmosphere (50 mL min(-1)). For non-isothermal method, activation energy was obtained from the plot of log heating rates vs. 1/T in dynamic air atmosphere (50 mL min(-1)). The calculated values were E(act) = 134 kJ mol(-1) (for standard sample) and E(act) (=) 139 kJ mol(-1) (for pharmaceutical sample).

Stability and compatibility study on enalapril maleate using thermoanalytical techniques

This paper demonstrates the application of thermal analysis in compatibility and stability studies between it ACE inhibitor (enalapril maleate) and excipients. The results have helped to elucidate the reason of a stability problem observed (luring the storage of enalapril maleate tablets. Incompatibility between enalapril maleate and colloidal silicon dioxide was detected. Besides, it was confirmed that the reaction between enalapril maleate and NaHCO3 increases the thermal stability of the drug. This Study Supports the importance of using thermoanalytical methods in the development of pharmaceuticals.

Thermoanalytical Characterization and Dissolution Profiles Studies of Metronidazole Tablets

In the present study dissolution tests and thermoanalytical (TA) techniques were applied to metronidazole tablets from five laboratories (R, G, SA, SB, SC) available on the Brazilian market. The TA profiles indicated that in some formulations interactions between components led to eutectic products with lower melting points than metronidazole. The formulations SB and SC showed dissolution profiles that did not agree with published standards, confirming the TA results. All dissolution data were mathematically compared with kinetic models of release, demonstrating the main release mechanism was first order in all the tablets. The formulations were statistically compared by ANOVA and post-hoc tests (Tukey and Newman-Keuls), reveling significant differences in dissolution efficiency (DE).

Compatibility and decomposition kinetics studies of prednicarbate alone and associated with glyceryl stearate

In this work, TG/DTG and DSC techniques were used to the determination of thermal behavior of prednicarbate alone and associated with glyceryl stearate excipient ( 1: 1 physical mixture). TG/DTG curves obtained for the binary mixture showed a reduction of approximately 37 degrees C to the thermal stability of drug (T(dm/dt-0) (Max)(DTG)). The disappearance of stretching band at 1280 cm(-1) (nu(as) C-O, carbonate group) and the presence of streching band with less intensity at 1750 cm(-1) (nu(s) C-O, ester group) in IR spectrum obtained to the binary mixture submitted at 220 degrees C, when compared with IR spectrum of drug submitted to the same temperature, confirmed the chemical interaction between these substances due to heating. Kinetics parameters of decomposition reaction of prednicarbate were obtained using isothermal (Arrhenius equation) and non-isothermal (Ozawa) methods. The reduction of approximately 45% of activation energy value (E(a)) to the first step of thermal decomposition reaction of drug in the 1:1 (mass/mass) physical mixture was observed by both kinetics methods.

Obtenção de sistemas multiparticulados de isoniazida revestidos com polímero de liberação entérica

Known for thousands of years, tuberculosis (TB) is the leading cause of mortality by a single infectious disease due to lack of patient adherence to available treatment regimens, the rising of multidrug resistant strains of TB (MDR-TB) and co-infection with HIV virus. Isoniazid and rifampicin are the most powerful bactericidal agents against M. tuberculosis. Because of that, this couple of drugs becomes unanimity in anti-TB treatment around the world. However, the rifampicin in acidic conditions in the stomach can be degraded rapidly, especially in the presence of isoniazid, which reduces the amount of available drug for absorption, as well as its bioavailability, contributing to the growing resistance to tuberculostatic drugs. Rifampicin is well absorbed in the stomach because of its high solubility between pH 1 and 2 and the gastric absorption of isoniazid is considered poor, therefore it is mostly intestinal. This work has as objective the development of gastro-resistant multiple-systems (granules and pellets) of isoniazid aiming to prevent the contact with rifampicin, with consequent degradation in acid stomach and modulate the release of isoniazid in the intestine. Granules of isoniazid were obtained by wet method using both alcoholic and aqueous solutions of PVP K-30 as aggregating and binder agent, at proportions of 5, 8 and 10%. The influence of the excipients (starch, cellulose or filler default) on the physical and technological properties of the granules was investigated. The pellets were produced by extrusionesferonization technique using isoniazid and microcrystalline cellulose MC 101 (at the proportion of 85:15) and aqueous solution of 1% Methocel as platelet. The pellets presented advantages over granular, such as: higher apparent density, smaller difference between apparent and compaction densities, smoother surface and, especially, smaller friability, and then were coated with an organic solution of Acrycoat L 100 ® in a fluidized bed. Different percentages of coating (15, 25 and 50%) were applied to the pellets which had their behavior evaluated in vitro by dissolution in acidic and basic medium. Rifampicin dissolution in the presence of uncoated and coated isoniazid pellets was evaluated too. The results indicate that the gastro resistance was only achieved with the greatest amount of coating and isoniazid is released successfully in basic step. The amount of rifampicin in the dissolution medium when the isoniazid pellets were not coated was lower than in the presence of enteric release pellets. Therefore, the polymer Acrycoat L 100 ® was efficient for coating with gastro-resistant function and can solve the problem of low bioavailability of rifampicin and help to reduce its dosage

Estudo de pré-formulação para dose fixa combinada dos tuberculostáticos rifampicina, isoniazida, pirazinamida e etambutol (4 em 1)

According to the global framework regarding new cases of tuberculosis, Brazil appears at the 18th place. Thus, the Ministry of Health has defined this disease as a priority in the governmental policies. As a consequence, studies concerning treatment and prevention have increased. Fixed-dose combination formulations (FDC) are recognized as beneficial and are recommended by WHO, but they present instability and loss on rifampicin bioavailability. The main purpose of this work was to carry out a pre-formulation study with the schedule 1 tuberculosis treatment drugs: rifampicin, isoniazid, pyrazinamide and ethambutol and pharmaceutical excipients (lactose, cellulose, magnesium stearate and talc), in order to develop an FDC product (150 mg of rifampicin + 75 mg of isoniazid + 400 mg of pyrazinamide + 250 mg of ethambutol). The studies consisted of the determination of particle size and distribution (Ferret s diameter) and shape through optical microscopy, as well as rheological and technological properties (bulk and tapped densities, Hausner Factor, Carr s Index, repose angle and flux rate) and interactions among drugs and drug excipient through thermal analysis (DSC, DTA, TG and your derivate). The results showed that, except isoniazid, the other drugs presented poor rheological properties, determined by the physical characteristics of the particles: small size and rod like particles shape for rifampicin; rectangular shape for pyrazinamide and ethambutol, beyond its low density. The 4 drug mixture also not presented flowability, particularly that one containing drug quantity indicated for the formulation of FDC products. In this mixture, isoniazid, that has the best flowability, was added in a lower concentration. The addition of microcrystalline cellulose, magnesium stearate and talc to the drug mixtures improved flowability properties. In DSC analysis probable interactions among drugs were found, supporting the hypothesis of ethambutol and pyrazinamide catalysis of the rifampicin-isoniazid reaction resulting in 3- formylrifamycin isonicotinyl hydrazone (HYD) as a degradation product. In the mixtures containing lactose Supertab® DSC curves evidenced incompatibility among drugs and excipient. In the DSC curves of mixtures containing cellulose MC101®, magnesium stearate and talc, no alterations were observed comparing to the drug profiles. The TG/DTG of the binary and ternary mixtures curves showed different thermogravimetrics profiles relating that observed to the drug isolated, with the thermal decomposition early supporting the evidences of incompatibilities showed in the DSC and DTA curves

Avaliação da argila atapulgita para potencial uso como excipiente farmacêutico em formas sólidas

Clays are natural materials that have great potential for use as excipients for solid dosage forms. Palygorskite is a type of clay that has hydrophilic properties as well as a large surface area, which could contribute to the dissolution of drugs. Thus, the present study aims to evaluate the use of palygorskite clay, from Piaui (Northeast region of Brazil), as a pharmaceutical excipient for solid dosage forms, using rifampicin and isoniazid as the model drugs. The former is a poorly soluble drug often associated with isoniazid for tuberculosis treatment. Palygorskite was characterized by X-ray diffraction (XRD), X-ray fluorescence (XRF), particle size, transmission electron microscopy (TEM), scanning electron microscopy (SEM) and specific surface area (BET). The rheological and technological properties of palygorskite were determined and compared to those of talc, magnesium stearate and Aersosil 200. Mixtures between drugs and palygorskite were analyzed by differential scanning calorimetry (DSC), thermogravimetric analysis (TG) combined with thermal analysis (DTA) and Fourier Transform Infrared Spectroscopy (FT-IR), where the results were compared with those of the individual compounds. In addition, dissolution studies of solid dispersions and capsules containing the drugs, mixed with either palygorskite or a mixture of talc and magnesium stearate, were performed. The results showed that palygorskite has small particles with a high surface area. Its rheological characteristics were better than those of others commonly used glidants and lubricants. There was no interaction between palygorskite and the drugs (rifampicin and isoniazid). Among the dispersions studied, the mixture with palygorskite (5%) showed the highest drug dissolution when compared to other excipients. The dissolution of the rifampicin capsules containing palygosrkite was faster in higher concentrations. However, these differences were statistically different only in the first minutes of the dissolution experiment. The dissolution profile of isoniazid was also statistically different on the initial part of the experiment. The formulations prepared with isoniazid and palygorskite showed higher drug dissolution, but it was in descending order of concentration. According to these results, the palygorskite clay used in this study has great potential for application as an excipient for solid dosage forms

Estudo de compatibilidade e estabilidade térmica do ácido retinóico e hidroquinona por termogravimetria

Retinoic acid (RA) and hydroquinone (HQ) assets are widely used in pharmaceutical and cosmetic formulations, for having depigmenting properties and are largely produced in drugstores. To assist in the development of formulations containing the active RA and HQ National Forms of Brazilian Pharmacopoeia (2005 and 2012 ) proposes formulations with different excipients such as cetyl alcohol (AC), cetostearyl alcohol (ACT), methylparaben (MTP), propyl paraben ( PPB), glycerin (GLY), dipropylene glycol (DPG), imidazolidinil urea ( IMD ), cyclomethicone (CCM ), butylated hydroxytoluene (BHT), octyl stearate (ETO), EDTA, decil oleate (ODC) and hydroxipropymethyl celullose (HPMC). One of the difficulties found in most cosmetic formulations is the large number of incompatibilities between the components of the formulations, so the aim this study was to evaluate thermal stability and interactions between these active pharmaceutical ingredients and excipients. The depigmenting agents were analyzed by DSC and TG and excipients were analyzed by TG. The dynamic thermogravimetric curves were obtained on a SHIMADZU thermobalance, model DTG-60, using an alumina crucible, at the heating rate of 10ºC min-1, in the temperature range of 25-900 ºC, under an atmosphere of nitrogen at 50 mL min-1. The DSC curves were obtained using Shimadzu calorimeter, model DSC-60, using aluminum crucible, at the heating rate of 10ºC min-1, in the temperature range of 25-400ºC. The thermogravimetric and calorimetric curves were analyzed using TASYS software SHIMADZU. In this study no were found interactions between AR and the following excipients: MTP, PPB, IMD, ODC, EDTA, CCM, ETO, HPMC. However, were found interactions with the following excipients: AC, ACT, BHT, GLI and DPG. For HQ were found interactions with IMD and DPG. Interactions remained even changing proportions of the mixtures and the ternary. Thus, the studies conducted with excipients of National Formulary from 2005 and 2012 showed that these new excipients do not interact by thermogravimetry with the active pharmaceutical ingredients of this study

Emprego de redes neurais artificiais supervisionadas e não supervisionadas no estudo de parâmetros reológicos de excipientes farmacêuticos sólidos

In this paper artificial neural network (ANN) based on supervised and unsupervised algorithms were investigated for use in the study of rheological parameters of solid pharmaceutical excipients, in order to develop computational tools for manufacturing solid dosage forms. Among four supervised neural networks investigated, the best learning performance was achieved by a feedfoward multilayer perceptron whose architectures was composed by eight neurons in the input layer, sixteen neurons in the hidden layer and one neuron in the output layer. Learning and predictive performance relative to repose angle was poor while to Carr index and Hausner ratio (CI and HR, respectively) showed very good fitting capacity and learning, therefore HR and CI were considered suitable descriptors for the next stage of development of supervised ANNs. Clustering capacity was evaluated for five unsupervised strategies. Network based on purely unsupervised competitive strategies, classic "Winner-Take-All", "Frequency-Sensitive Competitive Learning" and "Rival-Penalize Competitive Learning" (WTA, FSCL and RPCL, respectively) were able to perform clustering from database, however this classification was very poor, showing severe classification errors by grouping data with conflicting properties into the same cluster or even the same neuron. On the other hand it could not be established what was the criteria adopted by the neural network for those clustering. Self-Organizing Maps (SOM) and Neural Gas (NG) networks showed better clustering capacity. Both have recognized the two major groupings of data corresponding to lactose (LAC) and cellulose (CEL). However, SOM showed some errors in classify data from minority excipients, magnesium stearate (EMG) , talc (TLC) and attapulgite (ATP). NG network in turn performed a very consistent classification of data and solve the misclassification of SOM, being the most appropriate network for classifying data of the study. The use of NG network in pharmaceutical technology was still unpublished. NG therefore has great potential for use in the development of software for use in automated classification systems of pharmaceutical powders and as a new tool for mining and clustering data in drug development