It is Possible to Achieve Tablets With Good Tabletability From Solid Dispersions - The Case of the High Dose Drug Gemfibrozil.

BACKGROUND: Solid Dispersions (SDs) have been extensively used to increase the dissolution of poorly water-soluble drugs. However, there are few studies exploring SDs properties that must be considered during tablet development, like tabletability. Poorly water-soluble drugs with poor compression properties and high therapeutic doses, like gemfibrozil, are an additional challenge in the production of SDs-based tablets. OBJECTIVE: This study evaluates the applicability of SDs to improve both tabletability and dissolution rate of gemfibrozil. A SD-based tablet formulation was also proposed. METHODS: SDs were prepared by ball milling, using hydroxypropyl methylcellulose (HPMC) as a carrier, according to a 23 factorial design. The formulation variables were gemfibrozil:HPMC ratio, milling speed, and milling time. The response in the factorial analysis was the tensile strength of the compacted SDs. Dissolution rate and solid-state characterization of SDs were also performed. RESULTS: SDs showed simultaneous drug dissolution enhancement and improved tabletability when compared to corresponding physical mixtures and gemfibrozil. The main variable influencing drug dissolution and tabletability was the gemfibrozil:HPMC ratio. Tablets containing gemfibrozil- HPMC-SD (1:0.250 w/w) and croscarmellose sodium showed fast and complete drug release, while those containing the same SD and sodium starch glycolate exhibited poor drug release due to their prolonged disintegration time. CONCLUSION: SDs proved to be effective for simultaneously improving tabletability and dissolution profile of gemfibrozil. Tablets containing gemfibrozil-HPMC-SD and croscarmellose sodium as disintegrating agent showed improved drug release and good mechanical strength, demonstrating the potential of HPMC-based SDs to simultaneously overcome the poor dissolution and tabletability properties of this drug.

Avaliação do aumento da solubilidade aquosa do praziquantel incorporado em microesferas de poli(3-hidroxibutirato) e Eudragit® E / Evaluation of enhanced aqueous solubility of praziquantel incorporated in poly (3-hydroxybutyrate) and Eudragit® E microspheres

O praziquantel é o fármaco de escolha no tratamento da esquistossomose, porém, sua baixa solubilidade aquosa pode comprometer sua biodisponibilidade por via oral. Neste trabalho o praziquantel foi incorporado em microesferas de poli(3-hidroxibutirato) (PHB) e Eudragit® E pela técnica de emulsão-evaporação do solvente, com o intuito de melhorar sua solubilidade aquosa. As micropartículas preparadas com PHB apresentaram forma esférica e eficiência de encapsulação do fármaco de 78%. Quando preparadas com Eudragit® E/PHB na proporção de 50/50, apresentaram-se porosas e com eficiência de encapsulação de 42%. As microesferas preparadas com os polímeros na proporção de 75/25 apresentaram-se mais porosas que as anteriores e com 52% de praziquantel encapsulado. Ensaios de dissolução in vitro demonstraram melhora significativa na solubilidade aquosa do praziquantel incorporado às microesferas de Eudragit® E/PHB 75/25. O aumento da solubilidade está associado à elevada porosidade das microesferas e ao emprego do Eudragit® E como carreador hidrofílico.

Praziquantel is the drug of choice for the treatment of schistosomiasis, however, its low water solubility may undermine the oral bioavailability. In this study, praziquantel was incorporated into microspheres prepared with poly(3-hydroxybutyrate) (PHB) and a polymethacrylate (Eudragit® E), using an emulsion-solvent evaporation method, in order to improve its aqueous solubility. Microparticles prepared with PHB had spherical shape and encapsulation efficiency of 78%. When prepared with Eudragit® E/PHB at a ratio of 50/50 the microspheres were porous and encapsulated 42% of the drug, and for a ratio of 75/25 the microspheres were more porous than those of the previous formulations, with an encapsulation efficiency of 52%. Dissolution in vitro led to a significant improvement in the aqueous solubility of praziquantel incorporated into Eudragit® E/PHB 75/25 microspheres. This increased solubility is linked to the high porosity of the microspheres and the use of Eudragit® E as a hydrophilic carrier.

Comprimidos contendo microesferas de cetoprofeno como sistema de liberação bifásica / Tablets containing ketoprofen microspheres as abiphasic delivery system

Sistema de liberação bifásica é aquele que promove a liberação do fármaco em dois estágios: um de liberação imediata e o outro de liberação prolongada. No presente trabalho o cetoprofeno foi incorporado em microesferas de Kollidon® SR e acetobutirato de celulose e, posteriormente, as microesferas foram comprimidas com o intuito de obter comprimidos de liberação bifásica. As microesferas foram obtidas através do método de emulsão e evaporação do solvente óleo em água (O/A), originando partículas esféricas e eficiência de encapsulação de 81,9%, indicando que o processo de obtenção permitiu uma incorporação bastante eficiente do fármaco nas microesferas. Três formulações (F) de comprimidos foram obtidas por compressão direta utilizando-se uma prensa hidráulica: F1 - contendo as microesferas de cetoprofeno; F2 - contendo microesferas de cetoprofeno, crospovidona e celulose microcristalina; e F3 - contendo as microesferas de cetoprofeno, o cetoprofeno não encapsulado, além dos excipientes citados anteriormente (comprimidos bifásicos). Análises por microscopia eletrônica de varredura evidenciaram que o processo de compressão não afetou a morfologia das microesferas, as quais mantiveram sua integridade. A liberação do fármaco a partir dos comprimidos bifásicos inicialmente foi rápida, com 75% do fármaco dissolvido em uma hora, seguida de uma liberação prolongada, atingindo 88% de fármaco dissolvido em doze horas. Os resultados obtidos sugerem que o sistema proposto pode ser otimizado para a liberação do cetoprofeno em dois estágios, para administração por via oral.

A biphasic delivery system is one from which a drug is released in two stages, consisting of an immediate release and a prolonged release. In this study, ketoprofen was incorporated into Kollidon SR® and cellulose acetate butyrate microspheres, which were then compressed in order to obtain biphasic release tablets. The microspheres were produced by an oil-in-water (O/W) emulsion and solvent evaporation method, resulting in spherical particles and an encapsulation efficiency of 81.9%, indicating that the process allowed a very efficient incorporation of the drug into the microspheres. Three tablet formulations were compounded by direct compression in a hydraulic press: F1, containing only the ketoprofen microspheres; F2, containing ketoprofen microspheres, crospovidone and microcrystalline cellulose, and F3, containing the ketoprofen microspheres plus non-encapsulated ketoprofen, together with the aforementioned excipients (biphasic tablets). Examination by scanning electron microscopy showed that the compression process did not affect the morphology of the microspheres, which remained whole and undamaged. The drug release from the biphasic tablets was initially rapid, 75% of the drug being dissolved in one hour, followed by a sustained slow release, 88% of the drug being dissolved in twelve hours. These results suggest that the proposed delivery system can be optimized for two-stage ketoprofen release via oral administration.

Enhancement of felodipine dissolution rate through its incorporation into Eudragit® E-PHB polymeric microparticles: in vitro characterization and investigation of absorption in rats.

In this study, felodipine was incorporated into microparticles prepared with Eudragit® E and it blended with poly(3-hydroxybutyrate) (PHB) using the emulsion-solvent evaporation technique, with the aim of improving the dissolution rate of the drug. The formulation prepared with Eudragit® E showed irregular and fragmented microparticles, with a loading efficiency (LE) of 82.6%. When the microparticles were prepared with a blend of Eudragit® E and PHB, they had a spherical form with a LE of 103.9%. X-ray diffraction and differential thermal analysis indicated a reduction in the crystallinity of felodipine after its incorporation into the microparticles, which caused a significant increase in the felodipine dissolution rate. An investigation into the absorption in rats was carried out using high-performance liquid chromatography analysis of the blood collected 20 and 60 min after the animals were administered felodipine [30 mg/Kg, orally (p.o.)] or felodipine microparticles (30 mg/Kg, p.o.). Animals that were given felodipine showed mean plasmatic levels of 0.0125 (±0.00156) and 0.0240 (±0.0069) µg mL(-1) after 20 and 60 min, respectively, whereas animals that received microparticles containing felodipine showed respective mean plasmatic levels of 0.0651 (±0.0120) and 0.0369 (±0.0145) µg mL(-1) . Our data suggest that the incorporation into microparticles significantly enhanced the release of felodipine, improving its absorption in rats.

Microspheres prepared with biodegradable PHBV and PLA polymers as prolonged-release system for ibuprofen: in vitro drug release and in vivo evaluation

In this study, poly(hydroxybutyrate-co-hydroxyvalerate) (PHBV) and poly(l-lactide) (PLA) microspheres containing ibuprofen were prepared with the aim of prolonging the drug release. The oil-in-water (O/W) emulsion solvent evaporation technique was used, varying the polymer ratio. All formulations provided spherical particles with drug crystals on the surface and a porous and rough polymeric matrix when PHBV was used and smooth external surface when prepared with PLA. The in vitro dissolution profiles show that the formulation containing PHBV/PLA at the proportion of 30/70 presented the best results in terms of prolonging the ibuprofen release. The analysis of the concentration of ibuprofen in the blood of rats showed that maximum levels were achieved at between one and two hours after administration of the immediate-release form (pure drug), while the prolonged microspheres led to a small amount of the drug being released within the first two hours and reached the maximum level after six hours of administration. It was concluded that it is possible to prolong the release of ibuprofen through its incorporation into PHBV/PLA microspheres.

No presente estudo foram preparadas microesferas de poli(hidroxibutirato-co-hidroxivalerato) (PHBV) e poli(ácido láctico) (PLA) com o objetivo de prolongar a liberação do ibuprofeno, utilizado como fármaco modelo. Empregou-se o método de emulsificação e evaporação do solvente óleo em água (O/A), variando-se a proporção entre os polímeros. Todas as formulações originaram partículas esféricas com cristais de fármaco aderidos à superfície externa. As microesferas apresentaram superfície rugosa e porosa, quando o PHBV foi utilizado, e superfície externa lisa, quando preparadas com o PLA. Os perfis de dissolução in vitro evidenciaram que a formulação que continha PHBV/PLA na proporção de 30/70 apresentou melhores resultados para prolongar a liberação do ibuprofeno. Através da análise da concentração de ibuprofeno no plasma de ratos, após administração oral, verificou-se que os níveis máximos ocorreram entre 1 e 2 horas após a administração de ibuprofeno não encapsulado, enquanto o fármaco presente nas microesferas atingiu um pico máximo após 6 horas da administração. Conclui-se, portanto, que é possível prolongar a liberação do ibuprofeno após a sua incorporação às microesferas preparadas com os polímeros PHBV e PLA, especialmente na proporção de 30/70.

Preparo e caracterização de micropartículas de acetobutirato decelulose e poli(3-hidroxibutirato) contendo piroxicam / Preparation and characterization of cellulose acetate butyrate and poly(3-hydroxybutyrate) microparticles containing piroxicam

O objetivo deste trabalho foi avaliar a influência da massa molar do acetobutirato de celulose (ABC) e da adição de poli(3-hidroxibutirato) [PHB] sobre amorfologia das micropartículas, a eficiência de encapsulação e os perfis de liberação do piroxicam. As micropartículas foram preparadas por meio da técnica de emulsão/evaporação do solvente O/A e caracterizadas quanto à morfologia por microscopia eletrônica de varredura. O teor de fármaco nas micropartículas foi determinado utilizando o método de espectrofotometria de absorção na região do ultravioleta; os ensaios de liberação realizados, utilizando tampão fosfato pH 6,8. As micropartículas obtidas apresentaram formas irregulares, e aquelas preparadas a partir do ABC com maior massa molar apresentaram maior tamanho. Mediante planejamento fatorial, observou-se que as variáveis analisadas(massa molar do ABC e adição de PHB) não influenciaram a eficiência de encapsulação do piroxicam, mas exerceram influência sobre a quantidade inicial de piroxicam liberada a partir das micropartículas.

This work aims to evaluate the influence of the cellulose acetate butyrate (CAB) molar weight and the additionof poly(3-hydroxybutyrate) [PHB] on microparticle morphology, encapsulation efficiency and release profile of piroxicam. The microparticles were prepared using the O/Wemulsion/solvent evaporation technique and characterized according to the morphologyusing scanning electron microscopy. The drug content in the microparticles was determined through UV spectrophotometry and a dissolution assay was conducted usingphosphate buffer pH 6.8. The obtained microparticles presented irregular shape; the ones prepared with CAB with large molar weight presented a larger size. Through a factorial design, it was observed that the analyzed variables (CAB molar weight and PHB addition)did not influence the encapsulation efficiency, but did influence the initial release of piroxicam from the microparticles.