RESUMO
The FDA-approved anthelmintic flubendazole has shown potential to be repositioned to treat cancer and dry macular degeneration; however, its poor water solubility limits its use. Amorphous solid dispersions may overcome this challenge, but the balance of excipients may impact the preparation method and drug release. The purpose of this study was to evaluate the influence of adjuvants and drug loading on the development of an amorphous solid dispersion of flubendazole-copovidone by hot-melt extrusion. The drug, copovidone, and adjuvants (magnesium stearate and hydroxypropyl cellulose) mixtures were statistically designed, and the process was performed in a twin-screw extruder. The study showed that flubendazole and copovidone mixtures were highly extrudable, except when drug loading was high (>40%). Furthermore, magnesium stearate positively impacted the extrusion and was more effective than hydroxypropyl cellulose. The extruded materials were evaluated by modulated differential scanning calorimetry and X-ray powder diffraction, obtaining positive amorphization and physical stability results. Pair distribution function analysis indicated the presence of drug-rich domains with medium-range order structure and no evidence of polymer-drug interaction. All extrudates presented faster dissolution (HCl, pH 1.2) than pure flubendazole, and both adjuvants had a notable influence on the dissolution rate. In conclusion, hot-melt extrusion may be a viable option to obtain stable flubendazole:copovidone amorphous dispersions.
Assuntos
Química Farmacêutica , Excipientes , Varredura Diferencial de Calorimetria , Portadores de Fármacos , Composição de Medicamentos , Temperatura Alta , Mebendazol/análogos & derivados , Pirrolidinas , Solubilidade , Compostos de VinilaRESUMO
The high incidence and costs of chronic wounds in the elderly have motivated the search for innovations to improve product performance and the healing process while reducing costs. In this study, bioadhesive nanostructured lipid carriers (NLC) were developed for the co-encapsulation of compounds with antioxidant (α-tocopherol and quercetin) and antimicrobial (tea tree oil) activity for management of wounds. The NLC was produced with shea butter and argan oil, and modified with sodium alginate or chitosan to confer bioadhesive properties. Spherical nanoparticles of ~307-330 nm and zeta potential varying from -21.2 to +11.8 mV were obtained. Thermal analysis demonstrated that the lipid matrix reduced tea tree oil thermal loss (~1.8-fold). Regardless of the type of polysaccharide employed, the NLCs promoted cutaneous localization of antioxidants in damaged (subjected to incision) skin, with a ~74 to 180-fold higher delivery into the skin compared to percutaneous delivery. This result is consistent with the similar bioadhesive properties of chitosan or sodium alginate-modified NLC. Nanoencapsulation of tea tree oil did not preclude its antimicrobial effects against susceptible and resistant strains of S. aureus and P. aeruginosa, while co-encapsulation of antioxidants increased the NLC-induced fibroblasts migration, supporting their potential usefulness for management of wounds.
Assuntos
Alginatos/química , Anti-Infecciosos/farmacologia , Antioxidantes/farmacologia , Quitosana/química , Portadores de Fármacos , Lipídeos/química , Nanopartículas , Cicatrização/efeitos dos fármacos , Animais , Anti-Infecciosos/química , Antioxidantes/química , Movimento Celular/efeitos dos fármacos , Células Cultivadas , Embrião de Galinha , Composição de Medicamentos , Fibroblastos/efeitos dos fármacos , Humanos , Lipídeos/isolamento & purificação , Óleos de Plantas/química , Pseudomonas aeruginosa/efeitos dos fármacos , Pseudomonas aeruginosa/crescimento & desenvolvimento , Quercetina/química , Quercetina/farmacologia , Sapotaceae/química , Pele/efeitos dos fármacos , Pele/metabolismo , Staphylococcus aureus/efeitos dos fármacos , Staphylococcus aureus/crescimento & desenvolvimento , Óleo de Melaleuca/química , Óleo de Melaleuca/farmacologia , alfa-Tocoferol/química , alfa-Tocoferol/farmacologiaRESUMO
The levitation of samples in an acoustic field has been of interest in the preparation and study of amorphous solid dispersions (ASD). Here, niclosamide-polymer solutions were levitated in a multi-emitter single-axis acoustic levitator and analyzed for 10 min at a High-resolution synchrotron X-ray powder diffraction beamline. This assembly enabled high-quality and fast time-resolved measurements with microliter sample size and measurement of solvent evaporation and recrystallization of niclosamide (NCL). Polymers HPMCP-55S, HPMCP-50, HPMCP-55, Klucel®, and poloxamers were not able to form amorphous dispersions with NCL. Plasdone® and Soluplus® demonstrated excellent properties to form NCL amorphous dispersions, with the last showing superior solubility enhancement. Furthermore, this fast levitation polymer screening showed good agreement with results obtained by conventional solvent evaporation screening evaluated for five days in a stability study, carried out at 40 °C/75% RH. The study showed that acoustic levitation and high-resolution synchrotron combination opens up a new horizon with great potential for accelerating ASD formulation screening and analysis.
Assuntos
Niclosamida , Síncrotrons , Acústica , Química Farmacêutica , Pós , Solubilidade , Difração de Raios X , Raios XRESUMO
This work describes an exploratory experimental and in silico study of the influence of polymorphism, particle size, and physiology on the pharmacokinetics of lercanidipine hydrochloride (LHC). Equilibrium and kinetic solubility studies were performed on LHC forms I and II, as a function of pH and buffer composition. GastroPlus® was used to evaluate the potential effect of solubility differences due to polymorphism, particle size, and physiological conditions, on the drug pharmacokinetics. The results indicated that solubilities of LHC polymorphs are strongly dependent on the composition and pH of the buffer media. The concentration ratio (CI/CII) is particularly large for chloride buffer (CI/CII = 3.3-3.9) and exhibits a slightly decreasing tendency with the pH increase for all other buffers. Based on solubility alone, a higher bioavailability of form I might be expected. However, exploratory PBPK simulations suggested that (i) under usual fasted (pH 1.3) and fed (pH 4.9) gastric conditions, the two polymorphs have similar bioavailability, regardless of the particle size; (ii) at high gastric pH in the fasted state (e.g., pH 3.0), the bioavailability of form II can be considerably lower than that of form I, unless the particle size is < 20 µm. This study demonstrates the importance of investigating the effect of the buffer nature when evaluating the solubility of ionizable polymorphic substances. It also showcases the benefits of using PBPK simulations, to assess the risk and pharmacokinetic relevance of different solubility and particle size between crystal forms, for diverse physiological conditions.
Assuntos
Di-Hidropiridinas/química , Disponibilidade Biológica , Di-Hidropiridinas/farmacocinética , Humanos , Concentração de Íons de Hidrogênio , Tamanho da Partícula , SolubilidadeRESUMO
Considering the increased incidence of sporotrichosis and other fungal infections in rural and urban areas, and the limitations and adverse effects of oral itraconazole therapy, we studied nanostructured lipid carriers (NLC) as topical delivery systems to increase itraconazole localization in skin lesions and associate efficacy with reduced systemic exposure. Unloaded and itraconazole-loaded NLC showed nanometric size (~216-340 nm), negative zeta potential (~ -17 mV), and high entrapment efficiency (~97%). NLC treatment decreased transepidermal water loss, an index of cutaneous barrier function, in intact skin and in tissues damaged with a linear incision (to mimic lesions) by 23-36%, and reduced drug transdermal delivery by ~2-fold, demonstrating its ability to localize itraconazole within the skin. The unloaded and itraconazole-loaded NLC were considered safe, as indicated by scores of 0.5 and 0.6 in HET-CAM models, respectively, and lack of toxicity (measured by survival and health index) on the Galleria mellonella larvae. The values obtained for minimum inhibitory concentration and minimum fungicidal concentration on Sporothrix brasiliensis yeasts were 0.25 and 32 µg/mL, respectively. The drug in solution displayed similar values, indicating that encapsulation does not hinder itraconazole antifungal effect. NLC treatment improved the survival rate and health index of G. mellonella larvae infected with S. brasiliensis yeasts and C. albicans, demonstrating antifungal efficacy. Taken together, itraconazole encapsulation in NLC represents a viable strategy to optimize cutaneous localization without compromising its efficacy against fungal infections.
RESUMO
As a new strategy for treatment of ductal carcinoma in situ, biocompatible and bioadhesive nanoemulsions for intraductal administration of the cytotoxic agent piplartine (piperlongumine) were optimized in this study. To confer bioadhesive properties, the nanoemulsion was modified with chitosan or hyaluronic acid. Tricaprylin was selected as the nanoemulsion non-polar phase due to its ability to dissolve larger drug amounts compared to isopropyl myristate and monocaprylin. Use of phosphatidylcholine as sole surfactant did not result in a homogeneous nanoemulsion, while its association with polysorbate 80 and glycerol (in a surfactant blend) led to the formation of nanoemulsions with droplet size of 76.5⯱â¯1.2â¯nm. Heating the aqueous phase to 50⯰C enabled sonication time reduction from 20 to 10â¯min. Inclusion of either chitosan or hyaluronic acid resulted in nanoemulsions with similar in vitro bioadhesive potential, and comparable ability to prolong mammary tissue retention (to 120â¯h) in vivo without causing undesirable histological alterations. Piplartine was stable in both nanoemulsions for 60â¯days; however, the size of loaded NE-HA was maintained at a similar range for longer periods of time, suggesting that this nanoemulsion may be a stronger candidate for intraductal delivery.
Assuntos
Antineoplásicos Fitogênicos/administração & dosagem , Dioxolanos/administração & dosagem , Glândulas Mamárias Animais/metabolismo , Nanopartículas/administração & dosagem , Piperidonas/administração & dosagem , Adesividade , Animais , Antineoplásicos Fitogênicos/química , Galinhas , Quitosana/administração & dosagem , Quitosana/química , Membrana Corioalantoide/efeitos dos fármacos , Dioxolanos/química , Vias de Administração de Medicamentos , Emulsões , Feminino , Glicerol/administração & dosagem , Glicerol/química , Ácido Hialurônico/administração & dosagem , Ácido Hialurônico/química , Nanopartículas/química , Fosfatidilcolinas/administração & dosagem , Fosfatidilcolinas/química , Piperidonas/química , Polissorbatos/administração & dosagem , Polissorbatos/química , Ratos Wistar , Pele/química , SuínosRESUMO
For many years, the idea of analyzing atom-atom contacts in amorphous drug-polymer systems has been of major interest, because this method has always had the potential to differentiate between amorphous systems with domains and amorphous systems which are molecular mixtures. In this study, local structure of ionic and noninonic interactions were studied by High-Energy X-ray Diffraction and Pair Distribution Function (PDF) analysis in amorphous solid dispersions of lapatinib in hypromellose phthalate (HPMCP) and hypromellose (HPMC-E3). The strategy of extracting lapatinib intermolecular drug interactions from the total PDF x-ray pattern was successfully applied allowing the detection of distinct nearest neighbor contacts for the HPMC-E3 rich preparations showing that lapatinib molecules do not cluster in the same way as observed in HPMC-P, where ionic interactions are present. Orientational correlations up to nearest neighbor molecules at about 4.3 Å were observed for polymer rich samples; both observations showed strong correlation to the stability of the systems. Finally, the superior physical stability of 1:3 LP:HPMCP was consistent with the absence of significant intermolecular interactions in (∆) in the range of 3.0 to 6.0 Å, which are attributed to C-C, C-N and C-O nearest neighbor contacts present in drug-drug interactions.
RESUMO
Objetivo: Analisar medicamentos, incluindo forma de apresentação e preço, visando adequar o produto comercializado à prática de prescrição médica e, conseqüentemente, reduzir gastos governamentais e pessoais.Métodos: Foi realizado um levantamento de drogas prescritas clinicamente incluindo nimesulida, paracetamol+ fosfato de codeína, cefalexina, amoxicilina, ciprofloxacino, omeprazol, loratadina e haloperidol. Foram relacionados o princípio ativo, a apresentação, a indicação terapêutica, a posologia, o tratamento administradoe os desperdícios financeiro e medicamentoso. A análise de custo dos medicamentos foi realizada comparando-se medicamentos genéricos com os de referência. Resultados: Nimesulida 100mg mostrou variação de preço sem torno de 60% em relação ao Nisulid®. Para cefalexina 500mg o custo variou de 37,5 a 62,2% comparado aoKeflex®. Amoxicilina 500mg apresentou variação de 36,5 a 58% do custo do Amoxil®. Para ciprofloxacino500mg o custo foi de 31 a 58,3% do valor do Cipro®. As variações para omeprazol 20mg foram de 52,3 e 67,1%do valor do Peprazol®. Loratadina 10mg variou seu preço de 57,2 a 65% do Claritin®. A apresentação denimesulida, paracetamol + fosfato de codeína, omeprazol, loratadina e haloperidol mostrou-se em desajusteà prescrição médica para as doenças ora associadas, refletindo em desperdício de dois a oito comprimidos evariação do prejuízo de R$ 0,32 a R$ 13,76. Conclusões: A apresentação da maioria dos medicamentosindicados no tratamento de doenças freqüentes na população está em desajuste com a prescrição médica, refletindo em desperdícios medicamentoso e financeiro. Isso confirma a necessidade da elaboração de estratégia para conscientização de indústrias, instituições e profissionais de saúde também na economia terapêutica medicamentosa.