RESUMO
This study evaluated the ability of different sweeteners to improve dissolution and to form and stabilize supersaturated solutions of griseofulvin (GSF), comparing a eutectic mixture and amorphous formulations. Among the sweeteners tested, only saccharin (SAC) was able to delay drug precipitation in buffer (area under the curve (AUC) increase of 40%) and in fasted state simulated intestinal Fluid (FaSSIF, AUC increase of 20%) compared to pure media. GSF solubility was not affected by the presence of isomalt (ISO), maltitol (MALT) and SAC in buffer pH 6.5 but was reduced in FaSSIF. The quenched cooled amorphous formulation GSF-SAC QC -with the carrier that forms a eutectic mixture with GSF -provided higher drug release in buffer than amorphous formulations with ISO and MALT. In FaSSIF, SAC slightly changed the microenvironment's hydrophobicity (observed in fluorescence studies) and both its amorphous formulation (GSF-SAC QC) and its eutectic mixture (GSF-SAC EM) dissolved at concentrations above drug solubility, achieving supersaturation ratio (SR, Eq. (1)) of 4.14 and 3.15, respectively. The main finding of this study was that for the first time a eutectic mixture acted as a supersaturating drug delivery system, emphasizing the importance of investigating EMs during preformulation studies of fast-crystallizing poorly water-soluble drugs.
Assuntos
Griseofulvina , Sacarina , Sistemas de Liberação de Medicamentos , Liberação Controlada de Fármacos , SolubilidadeRESUMO
The purpose of this study was to associate the poorly water-soluble antihypertensive drugs candesartan cilexetil (CC) and hydrochlorothiazide (HCTZ) as fixed-dose combination, in the form of ternary Amorphous Solid Dispersions (ASD), using hydroxypropylmethylcellulose acetate succinate (HPMCAS) type M as polymeric carrier. The potential of the system to generate and to maintain supersaturation of both drugs was also evaluated. The ASDs were prepared by ball milling technique and solid-state characterization was performed by differential scanning calorimetry (DSC), Fourier transformed infrared spectroscopy (FTIR) and X-ray powder diffraction (XRPD). Interaction between drugs and polymer in solid-state was evaluated by molecular metadynamics simulations. In vitro supersaturation profiles were determined in biorelevant medium. Physicochemical stability of ASDs was also evaluated under different storage conditions. Amorphization of both drugs was confirmed by solid-state characterization techniques. Molecular metadynamics simulations indicated that CC has stronger interaction with HMPCAS than HCTZ. In vitro supersaturation studies have shown that ternary ASDs could generate and maintain supersaturation of both drugs in biorelevant medium. The polymer reduced the desupersaturation of both drugs. Ternary ASDs also showed physicochemical stability over a period of 90 days, demonstrating the potential of the polymer in reducing the drugs recrystallization over the time. Ternary ASDs of CC, HCTZ and HPMCAS can be considered a promising system to associate the drugs as fixed-dose combinations. Also, these systems generate and maintain supersaturation of both drugs in biorelevant medium, with great storage stability. HPMCAS M was a good carrier for reducing the desupersaturation of associated HCTZ and CC.
Assuntos
Anti-Hipertensivos , Portadores de Fármacos , Composição de Medicamentos , Polímeros , Solubilidade , Difração de Raios XRESUMO
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.
Assuntos
Genfibrozila , Comprimidos , Composição de Medicamentos , Liberação Controlada de Fármacos , Genfibrozila/química , SolubilidadeRESUMO
Eutectic mixtures have been known for a long time in the pharmaceutical field. However, its potential as a system to improve the solubility and dissolution of poorly water-soluble drugs remains little explored. Studies involving the microstructural characterization and the preparation of solid dosage forms containing eutectic mixtures are also an issue to be developed. Recently, the number of studies involving the preparation of eutectic mixtures to improve the solubility and oral bioavailability of poorly soluble drugs has increased considerably, including drug-carrier and drug-drug mixtures. In this review is discussed the potential of eutectic mixtures as an alternative pharmaceutical solid system to enhance drugs solubility, dissolution rate or oral bioavailability. Different aspects like history, physico-chemical, microstructural properties, preparation methods, mechanisms involved in solubility/dissolution enhancement, techniques for solid state characterization, in vivo studies, advantages, limitations and formulation perspective are also discussed.
Assuntos
Disponibilidade Biológica , Química Farmacêutica , Água , Portadores de Fármacos , SolubilidadeRESUMO
The emergence of new materials with improved antibacterial, anti-inflammatory and healing properties compared to conventional wound dressings has both social and economic appeal. In this study, novel chitosan-based (CTS) membranes containing curcumin (CUR) incorporated in Pluronic (PLU) copolymers were developed and characterized to obtain suitable properties for applications as a wound healing dressing. The mechanical, thermal, swelling, wettability, release and permeation properties were evaluated by DSC, TGA, water contact angle measurements, FTIR, fluorescence and microscopic techniques. Membranes containing PLU and CUR presented wettability close to the ideal range for interaction with cellular components (contact angle ~40-70°), improved mechanical properties, higher thermal stability, high swelling degree (>800%) and CUR release (~60%) compared to samples without PLU addition. A higher retention of CUR in the epidermis than in the dermis layer was observed, which also was confirmed by confocal microscopy. Furthermore, the CTS-PLU membranes loaded with CUR showed to be active against Staphylococcus aureus and Pseudomonas aeruginosa (MIC = 25 and 100 mg mL-1, respectively), the microbial species most present in chronic wounds. Overall, the CTS-PLU-CUR membranes presented suitable properties to act as a new wound healing dressing formulation and in vivo studies should be performed to confirm these benefits.
Assuntos
Antibacterianos/química , Antibacterianos/farmacocinética , Quitosana/análogos & derivados , Curcumina/química , Curcumina/farmacocinética , Membranas/química , Antibacterianos/farmacologia , Bandagens/microbiologia , Varredura Diferencial de Calorimetria , Quitosana/química , Quitosana/farmacocinética , Curcumina/farmacologia , Liberação Controlada de Fármacos , Humanos , Testes de Sensibilidade Microbiana , Microscopia Confocal , Pseudomonas aeruginosa/efeitos dos fármacos , Pele/diagnóstico por imagem , Pele/efeitos dos fármacos , Pele/patologia , Espectroscopia de Infravermelho com Transformada de Fourier , Staphylococcus aureus/efeitos dos fármacos , Propriedades de Superfície , Termogravimetria , Água/química , Cicatrização/efeitos dos fármacosRESUMO
Efavirenz (EFZ) and tenofovir disoproxil fumarate (TDF) can be used simultaneously in the treatment of human immunodeficiency virus type1 infection. In this work the impact of TDF, a hydrophilic drug, on the solubility and dissolution rate of EFZ, a poorly water-soluble drug, was evaluated. EFZ/TDF binary mixtures in different molar ratios were prepared. Differential scanning calorimetry (DSC) results indicate the formation of a eutectic mixture, the molar ratio of 65/35 being the eutectic point. It was observed an increase in the EFZ solubility in water and acidic conditions (0.1â¯N HCl and biorelevant medium), in the presence of TDF. On the other hand, there was a decreasing on EFZ solubility in phosphate buffer pH 6.8, probably influenced by the lower solubility of TDF in this medium. The high solubility of TDF in water and acidic medium may have contributed to improve the solubility of EFZ, as well as the formation of a eutectic mixture, supported by X-ray powder diffraction (XRPD) and Fourier Transform infrared spectroscopy (FTIR) analyses. However, TDF solubility and dissolution rate was not significantly influenced by the presence of EFZ.
Assuntos
Benzoxazinas/química , Solubilidade/efeitos dos fármacos , Tenofovir/química , Alcinos , Varredura Diferencial de Calorimetria/métodos , Ciclopropanos , Pós/química , Espectroscopia de Infravermelho com Transformada de Fourier , Difração de Raios X/métodosRESUMO
Solid dispersions (SDs) of chlorthalidone (CTD) are promising systems to enhance drug dissolution rate, generate and maintain drug supersaturation levels in gastrointestinal fluids. In this work, SDs of CTD were prepared by spray drying using sodium alginate (SA) as carrier. Six formulations were prepared, varying the drug loading and composition, through the combination of SA with surfactants (sodium lauryl sulfate (SLS) or polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer (SOL)). In all SDs, except when SA was used alone at low drug loading, CTD was in the amorphous form. At sink conditions, all SDs showed a faster dissolution rate than the crystalline drug. At non-sink conditions, the SDs prepared with SA and SLS at low drug loading exhibited the best performance to maintain supersaturating drug levels. All SDs, except those prepared with SA alone or SA-SLS at high drug loading, presented no drug recrystallization after 34 months of storage.
Assuntos
Alginatos/química , Clortalidona/química , Portadores de Fármacos/química , Liberação Controlada de Fármacos , Tamanho da Partícula , Polimerização , Solubilidade , Tensoativos/químicaRESUMO
Suspensions of poly ε-caprolactone (PCL) nanoparticles loaded with thyme essential oil were prepared as a natural antioxidant in mayonnaise. Mean particle size was 204.9 ± 2.7 and 240.0 ± 5.5 nm respectively for nanoparticles prepared with PCL alone (NP-C) and for those loaded with thyme essential oil (NP-T). The polydispersity index indicated a homogeneous distribution of all particles, with no significant difference between NP-C and NP-T samples. The nanoparticles showed a large negative charge evidenced by zeta potential rates, indicating high physical stability. The use of PCL as a polymer provided high encapsulation efficiency for thyme essential oil (91.15 ± 2.12 %). DPPH (2,2-diphenyl-1-picrylhydrazyl) method determined IC50 rates were 476.4 ± 33.6 and 483.5 ± 20.4 µg mL-1respectively for unencapsulated oil and for NP-T, evidencing pronounced antioxidant activity. NP-C, NP-T and synthetic antioxidant butylhydroxytoluene (BHT) were applied to samples of mayonnaise and their oxidative stability evaluated for eight days in an oven at 63 ± 3ºC. Results of hydroperoxide value (HP) and thiobarbituric acid reactive substances (TBARS) showed that NP-T had a similar performance as synthetic antioxidant BHT in the prevention of mayonnaise lipid oxidation
Assuntos
Óleos Voláteis/administração & dosagem , Thymus (Planta)/classificação , Oxidação/prevenção & controle , Antioxidantes/efeitos adversos , Hidroxitolueno Butilado/análise , Aromaterapia/métodos , NanopartículasRESUMO
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.
Assuntos
Praziquantel , Esquistossomose/terapia , Composição de MedicamentosRESUMO
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.
Assuntos
Comprimidos/farmacologia , Cetoprofeno , Sistemas de Liberação de Medicamentos/métodosRESUMO
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.
Assuntos
Ratos , Ibuprofeno/análise , Liberação Controlada de Fármacos , Microesferas , Polímeros/análise , Técnicas In Vitro/classificação , Liberação Controlada de FármacosRESUMO
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.
Assuntos
Cápsulas/farmacologia , Celulose/farmacologia , Composição de Medicamentos , PiroxicamRESUMO
No presente trabalho foram desenvolvidos comprimidos de captopril revestidos com hidroxipropilmetilcelulose (HPMC), Opadry®, polvinilpirrolidona (PVP), Eudragil® E e goma laca. Foi realizado estudo termoanalítico do fármaco e das formulações através de termogravimetria(TG) e calorimetria exploratória diferencial (DSC). Através da análise das curvas DSC verificou-se quenão houve a ocorrência de interação entre fármacos e os excipientes lactose, celulose microcristalina, croscarmelose sódica, Aerosil® e talco, utilizados na formulação do comprimido. Através desta técnica detectou-se a possibilidade de interação entre captopril e estearato de magnésio. De acordo com os resultados obtidos através de DSC não foram observadas alterações...