Microemulsions as drug delivery systems for topical ocular administration

The conventional ophthalmic dosage forms are relatively simple: usually, water-soluble drugs are delivered in aqueous solution and water-insoluble drugs are prepared as suspensions or ointments. However, these delivery systems currently used present very low corneal bioavailability, systemic exposure because of nasolacrimal drainage and lack of efficiency in the posterior segment of ocular tissue. Recent research efforts have focused on the development of new ophthalmic drug delivery systems. As a result of these efforts, microemulsions are promising dosage forms for ocular use. These delivery systems are dispersions of water and oil that require surfactant and co-surfactant agents in order to stabilize the interfacial area. The microemulsions have a transparent appearance, thermodynamic stability and small droplet size of the dispersed fase (<1,0 mm), providing them with the capacity of being sterilized by filtration. Furthermore, these systems offer additional advantages that include: low viscosity, great ability as drug delivery vehicles, widened properties as absorption promoters and easiness of preparation, which do not require much energy and the use of special equipments. In this review, we present the technology and some preliminary studies of microemulsions in relation to ocular drug delivery systems.As formas farmacêuticas oftálmicas convencionais são relativamente simples: drogas solúveis em água são formuladas em solução aquosa e drogas pouco solúveis em suspensão ou pomada. Entretanto, essas formulações apresentam como inconvenientes baixa biodisponibilidade corneal, absorção sistêmica devida à drenagem nasolacrimal e reduzida eficácia no segmento posterior do olho. Assim, o desenvolvimento de novos sistemas de liberação de drogas de administração oftálmica tem sido um dos principais temas de pesquisa em tecnologia farmacêutica nos últimos anos. Entre as alternativas avaliadas, destacam-se principalmente as microemulsões. Estas formas farmacêuticas que são dispersões de água e óleo, estabilizadas por um emulsionante e por um co-emulsionante, transparentes, termodinamicamente estáveis, apresentam partículas de tamanho menor que 1,0 mm e, portanto, passíveis de serem esterilizadas por filtração. Além disso, as microemulsões apresentam baixa viscosidade, possuem grande capacidade para o transporte de drogas, demonstram comprovada propriedade promotora de absorção para as drogas veiculadas e são facilmente obtidas, sem a necessidade de utilização de equipamentos sofisticados e de componentes de custo proibitivo. O presente artigo objetiva revisão de literatura abordando o tema e os principais estudos relacionados com a utilização de microemulsões como sistemas de liberação de drogas oftálmicas.Universidade Federal de Minas Gerais Faculdade de FarmáciaUniversidade Federal de São Paulo (UNIFESP)Universidade Federal de Minas Gerais Hospital das Clínicas Serviço de UveítesUniversidade Federal de Minas GeraisUNIFESPSciEL

DEVELOPMENT AND VALIDATION OF A HIGH PERFORMANCE LIQUID CHROMATOGRAPHIC METHOD DETERMINATION OF ZIDOVUDINE ENCAPSULATED IN PCL NANOPARTICLES

A reversed-phase high-performance liquid chromatographic (HPLC) method was developed and validated for the determination of encapsulation efficiency of zidovudine in nanoparticules. The method was carried out in isocratic mode using 0.040M sodium acetate: methanol: acetonitrile: glacial acetic acid (880:100:20:2) as mobile phase, a C8 column at 25ºC and UV detection at 240 nm. The method was linear (r2 ˃ 0.99) over the range of 25.0-150.0 μg/mL, precise (RSD ˂ 5%), accurate (recovery = 100.5%), robust and selective. The validated HPLC-UV method can be successfully applied to determine the rate of zidovudine in nanoparticules.A reversed-phase high-performance liquid chromatographic (HPLC) method was developed and validated for the determination of encapsulation efficiency of zidovudine in nanoparticules. The method was carried out in isocratic mode using 0.040M sodium acetate: methanol: acetonitrile: glacial acetic acid (880:100:20:2) as mobile phase, a C8 column at 25ºC and UV detection at 240 nm. The method was linear (r2 ˃ 0.99) over the range of 25.0-150.0 μg/mL, precise (RSD ˂ 5%), accurate (recovery = 100.5%), robust and selective. The validated HPLC-UV method can be successfully applied to determine the rate of zidovudine in nanoparticules

Delay of neuropathic pain sensitization after application of dexamethasone-loaded implant in sciatic nerve-injured rats

Neuroimmune interactions underlying the development of pain sensitization in models of neuropathic pain have been widely studied. In this study, we evaluated the development of allodynia and its reduction associated with peripheral antineuroinflammatory effects induced by a dexamethasone-loaded biodegradable implant. Chronic constriction injury (CCI) of the sciatic nerve was performed in Wistar rats. The electronic von Frey test was applied to assess mechanical allodynia. The dexamethasone-loaded implant was placed perineurally at the moment of CCI or 12 days after surgery. Dorsal root ganglia (DRG; L4-L5) were harvested and nuclear extracts were assayed by Western blot for detection of nuclear factor (NF)-κB p65/RelA translocation. Dexamethasone delivered from the implant delayed the development of allodynia for approximately three weeks in CCI rats when the implantation was performed at day 0, but allodynia was not reversed when the implantation was performed at day 12. NF-κB was activated in CCI rat DRG compared with naïve or sham animals (day 15), and dexamethasone implant inhibited p65/ RelA translocation in CCI rats compared with control. This study demonstrated that the dexamethasoneloaded implant suppresses allodynia development and peripheral neuroinflammation. This device can reduce the potential side effects associated with oral anti-inflammatory drugs

Sistemas de transporte de drogas para o segmento posterior do olho: bases fundamentais e aplicações Drug delivery systems for the posterior segment of the eye: fundamental basis and applications

As doenças do segmento posterior do olho são responsáveis pela maioria dos casos de cegueira irreversível no mundo inteiro. Este cenário estimula o desenvolvimento de novas modalidades de tratamento para estas doenças. O sucesso no tratamento visa, essencialmente, o transporte de doses efetivas de drogas diretamente para os locais a serem tratados. Devido às dificuldades encontradas no transporte de drogas para o segmento posterior do olho, pesquisas têm sido realizadas no sentido de desenvolver sistemas de administração intra-oculares que permitam liberar concentrações terapêuticas das drogas por período prolongado. Tais sistemas podem proporcionar inúmeras vantagens, como: aumentar a biodisponibilidade e a concentração local da droga, atingir especificamente um tipo de tecido ou célula, reduzir a freqüência de injeções intra-oculares. Tais vantagens podem aumentar o conforto do paciente e reduzir as complicações observadas com a utilização das injeções intra-oculares. Diferentes sistemas de transporte de drogas têm sido desenvolvidos com as finalidades acima descritas. Estes sistemas podem ser compostos por polímeros biodegradáveis ou não-biodegradáveis ou serem formulações lipídicas. Os sistemas de transporte de drogas são representados, principalmente, pelas micro e nanopartículas e pelos implantes, sendo eles compostos por diferentes polímeros; pelos lipossomos, que são compostos por lípides e emulsionantes; e pela iontoforese, que se baseia na aplicação de corrente elétrica. Nesta revisão, as principais características dos diferentes sistemas de transporte de drogas serão descritas, expondo suas potencialidades de aplicação clínica.<br>The diseases of the posterior segment of the eye are responsible for most cases of irreversible blindness worldwide. These conditions stimulate the development of new modalities of treatment for vitreoretinal diseases. The success in the treatment aims, mainly, the delivery of effective doses of pharmacological agents directly to the target sites. Because of the difficulties in delivering drugs to the posterior segment of the eye, the development of intraocular delivery systems that allow the delivery of therapeutic concentrations of drugs for long periods are being studied. These systems offer many advantages, such as increase in drug bioavailability, obtaining constant and sustained drug release, to achievement of elevated local concentrations of drugs without systemic side effects, targeting one specific tissue or cell type, reducing the frequency of intraocular injections. These advantages can increase the comfort of the patient and reduce the complications observed with intraocular injections. Several drug delivery systems are being developed with the above described purposes. These systems may be prepared with biodegradable or non-biodegradable polymers or they may be lipid formulations. The drug delivery systems are represented, mainly, by micro- e nanoparticles and implants, composed of different polymers; by liposomes, which are made of lipids and surfactants; and by iontophoresis, that is based on the application of an electric current. In this review, the main characteristics of the different drug delivery systems will be shown, with their potentialities of clinical application

Design, optimization and evaluation of clozapine tablets by response surface analysis

The purpose of this work was, applying experimental design methodology on tablet formulation development by direct compression, to evaluate the influences of magnesium stearate and sodium croscarmelose quantities upon clozapine tablets, by a Central Composite Design. The results were fitted to non-linear regression and a second order equation was used to plot response surface graphics. The results showed that hardness and friability were influenced by magnesium stearate quantities, decreasing the mechanical resistance of tablets, and the sodium croscarmelose quantities caused a linear decreased on disintegration time and a increased on dissolution efficiency of tablets, on the studied experimental field

Design, optimization and evaluation of clozapine tablets by response surface analysis

The purpose of this work was, applying experimental design methodology on tablet formulation development by direct compression, to evaluate the influences of magnesium stearate and sodium croscarmelose quantities upon clozapine tablets, by a Central Composite Design. The results were fitted to non-linear regression and a second order equation was used to plot response surface graphics. The results showed that hardness and friability were influenced by magnesium stearate quantities, decreasing the mechanical resistance of tablets, and the sodium croscarmelose quantities caused a linear decreased on disintegration time and a increased on dissolution efficiency of tablets, on the studied experimental field

Formas farmacêuticas poliméricas para a administração de peptídeos e proteínas terapêuticos

A utilização terapêutica de peptídeos e proteínas é de grande importância para o tratamento de várias doenças. Entretanto, essas macromoléculas, devido às características intrínsecas, muitas vezes não alcançam o local de ação necessário para exercerem sua atividade. Neste contexto, este artigo de revisão apresenta os principais sistemas poliméricos de liberação em estudo atualmente, tais como micro e nanopartículas poliméricas e hidrogéis, que podem melhorar a efetividade do tratamento de doenças que requerem a administração de peptídeos e proteínas. O artigo, também, cita possíveis modificações químicas, tais como a peguilação, que também podem oferecer vantagens para o uso dessas macromoléculas como entidades terapêuticas

Poly-&#949;-caprolactone microspheres containing interferon alpha as alternative formulations for the treatment of chronic hepatitis C

Interferon-alpha (IFN-alpha) is one of the main drugs used in the treatment of hepatitis C. Use of IFN-alpha has some limitations that result in poor treatment efficacy and low patient compliance. Therefore, the aim of this study was to develop poly-&#949;-caprolactone (PCL) microspheres containing IFN-alpha as an alternative for the treatment of chronic hepatitis C. Microspheres were prepared using the multiple emulsion followed by solvent evaporation technique. Particle size, surface morphology, drug content and encapsulation efficiency of the microspheres produced were evaluated. The stability of the formulation was assessed after 90 days at -20ºC. An in vitro release study was performed in PBS. In vitro cytotoxicity of the formulation was studied using hepatic cell line. The freeze-dried microspheres had mean particle size, IFN-alpha content, and encapsulation efficiency of 38.52 ± 4.64 µm, 15.52 ± 3.28% and 83.93 ± 5.76%, respectively. There were no significant changes during storage and the structural integrity of the protein was not compromised by the preparation technique. A total of 82% of the IFN-alpha was released after 28 days and the developed microspheres did not present cytotoxicity to the hepatic cell line. In vivo studies are currently underway to evaluate the biological activity of IFN-alpha encapsulated into microspheres.O interferon alfa (IFN-alfa) é um dos principais fármacos utilizados no tratamento de hepatite C, mas o seu uso apresenta limitações que resultam em baixa eficácia do tratamento e não adesão do paciente. Diante disso, este estudo objetiva o desenvolvimento de microesferas de poli-&#949;-caprolactona (PCL) contendo IFN-alfa como alternativa ao tratamento de hepatite C crônica. As microesferas foram preparadas pelo método de emulsão múltipla seguido de evaporação do solvente e caracterizadas quanto ao diâmetro médio das partículas, morfologia da superfície, taxa e eficiência de encapsulamento. A estabilidade da formulação foi acompanhada durante 90 dias a -20 ºC. O estudo de liberação in vitro foi realizado em PBS. A citotoxicidade da formulação foi avaliada utilizando linhagem de células hepáticas. As microesferas liofilizadas apresentaram diâmetro médio, taxa de encapsulamento e eficiência de encapsulamento de 38,52 ± 4,64 µm, 15,52 ± 3,28% e 83,93 ± 5,76%, respectivamente. Não foram observadas alterações significativas durante o armazenamento e a integridade estrutural da proteína foi mantida após o preparo. Oitenta e dois por cento de IFN-alfa foram liberados em 28 dias e a formulação desenvolvida não apresentou toxicidade para as células testadas. Estudos in vivo estão em andamento para avaliar a atividade biológica do IFN-alfa encapsulado nas microesferas