RESUMO
Aim: Benznidazole (BNZ), a class-II drug, is the primary treatment for Chagas disease, but its low aqueous solubility presents challenges in formulation and efficacy. Nanosuspensions (NS) could potentially address these issues.Methods: BNZ-NS were prepared using a simple, organic solvents-free nano-milling approach. Physicochemical characterizations were conducted on both NS and lyophilized solid-state BNZ-nanocrystals (NC).Results: BNZ-NS exhibited particle size <500 nm, an acceptable polydispersity index (0.23), high Z-potential, and physical stability for at least 90 days. BNZ-NC showed tenfold higher solubility than pure BNZ. Dissolution assays revealed rapid BNZ-NS dissolution. BNZ-NC demonstrated biocompatibility on an eukaryotic cell and enhanced BNZ efficacy against trypomastigotes of Trypanosoma cruzi.Conclusion: BNZ-NS offers a promising alternative, overcoming limitations associated with BNZ for optimized pharmacotherapy.
[Box: see text].
Assuntos
Doença de Chagas , Nanopartículas , Nitroimidazóis , Tamanho da Partícula , Solubilidade , Tripanossomicidas , Trypanosoma cruzi , Nitroimidazóis/química , Nitroimidazóis/administração & dosagem , Doença de Chagas/tratamento farmacológico , Trypanosoma cruzi/efeitos dos fármacos , Nanopartículas/química , Tripanossomicidas/administração & dosagem , Tripanossomicidas/química , Tripanossomicidas/farmacologia , Animais , Humanos , Suspensões , Estabilidade de Medicamentos , Química Farmacêutica/métodos , Solventes/química , LiofilizaçãoRESUMO
3D printing technology is revolutionizing pharmaceuticals, offering tailored solutions for solid dosage forms. This innovation is particularly significant for conditions like Chagas disease, which require weight-dependent treatments. In this work, a formulation of benznidazole (BNZ), the primary treatment for this infection, was developed to be utilized with the Melting Solidification Printing Process (MESO-PP) 3D printing technique. Considering the limited aqueous solubility of BNZ, an interpolyelectrolyte complex (IPEC), composed of chitosan and pectin, was integrated to improve its dissolution profile. The formulations, also called inks in this context, with and without IPEC were integrally characterized and compared. The printing process was studied, the release of BNZ from 3D-prints (3DP) was exhaustively analyzed and a physiologically based pharmacokinetic model (PKPB) was developed to forecast their pharmacokinetic performance. 3DP were successfully achieved loading 25, 50 and 100 mg of BNZ. The presence of the IPEC in the ink caused a decrease in the crystalline domain of BNZ and facilitated the printing process, reaching a print success rate of 83.3 %. Interestingly, 3DP-IPEC showed accelerated release dissolution profiles, releasing over 85 % of BNZ in 90 min, while 3DP took up to 48 h for doses above 25 mg. The PBPK model demonstrated that 3DP-IPEC tablets would present high bioavailability (0.92), higher than 3DP (0.36) and similar to the commercial product. This breakthrough holds immense potential for improving treatment outcomes for neglected diseases.
Assuntos
Doença de Chagas , Liberação Controlada de Fármacos , Nitroimidazóis , Impressão Tridimensional , Comprimidos , Tripanossomicidas , Nitroimidazóis/química , Nitroimidazóis/administração & dosagem , Nitroimidazóis/farmacocinética , Doença de Chagas/tratamento farmacológico , Tripanossomicidas/química , Tripanossomicidas/administração & dosagem , Tripanossomicidas/farmacocinética , Solubilidade , Quitosana/química , Medicina de Precisão/métodos , Composição de Medicamentos/métodos , Química Farmacêutica/métodosRESUMO
Polyelectrolyte-drug complexes are interesting alternatives to improve unfavorable drug properties. Vancomycin (VAN) is an antimicrobial used in the treatment of methicillin-resistant Staphylococcus aureus pulmonary infections in patients with cystic fibrosis. It is generally administered intravenously with a high incidence of adverse side effects, which could be reduced by intrapulmonary administration. Currently, there are no commercially available inhalable formulations containing VAN. Thus, the present work focuses on the preparation and characterization of an ionic complex between hyaluronic acid (HA) and VAN with potential use in inhalable formulations. A particulate-solid HA-VAN25 complex was obtained by spray drying from an aqueous dispersion. FTIR spectroscopy and thermal analysis confirmed the ionic interaction between HA and VAN, while an amorphous diffraction pattern was observed by X-ray. The powder density, geometric size and morphology showed the suitable aerosolization and aerodynamic performance of the powder, indicating its capability of reaching the deep lung. An in vitro extended-release profile of VAN from the complex was obtained, exceeding 24 h. Microbiological assays against methicillin-resistant and -sensitive reference strains of Staphylococcus aureus showed that VAN preserves its antibacterial efficacy. In conclusion, HA-VAN25 exhibited interesting properties for the development of inhalable formulations with potential efficacy and safety advantages over conventional treatment.
RESUMO
Mathematical models are an important tool in pharmaceutical formulations development, to evaluate in vitro and in vivo drug release processes and to optimize the design of new systems. Dome Matrix technology allows the combination of modules with different types of drugs, doses, and releases kinetics. This work aimed to design drug release systems based on Dome Matrix technology, with different swelling and erosion properties, to obtain complex drug release profiles and analyze them with simple mathematical models. Most of the release profiles followed a sigmoid curve, with an inflection point corresponding to a change in the release rate behavior. The experimental data were fitted with a simple model recently developed, named the Dual Release model, which consists in the combination of a modified Korsmayer-Peppas model from the beginning to the inflection point and the Lumped model from there until the end. This approach allowed determining relevant pharmaceutical parameters, such as the maximum release rate and the dissolution efficiency, among others. The use of the Dual Release model and the pharmaceutical parameters that characterize the different Dome Matrix modules allows optimizing the choice of the composition and the configuration during the development of a drug delivery system.
Assuntos
Sistemas de Liberação de Medicamentos , Tecnologia , Preparações de Ação Retardada , Composição de Medicamentos , Liberação Controlada de Fármacos , Cinética , Solubilidade , ComprimidosRESUMO
BACKGROUND: Mathematical modeling in modified drug release is an important tool that allows predicting the release rate of drugs in their surrounding environment and elucidates the transport mechanisms involved in the process. OBJECTIVE: The aim of this work was to develop a mathematical model that allows evaluating the release profile of drugs from polymeric carriers in which the swelling phenomenon is present. METHODS: Swellable matrices based on ionic complexes of alginic acid or carboxymethylcellulose with ciprofloxacin were prepared and the effect of adding the polymer sodium salt on the swelling process and the drug release was evaluated. Experimental data from the ciprofloxacin release profiles were mathematically adjusted, considering the mechanisms involved in each stage of the release process. RESULTS: A proposed model, named "Dual Release" model, was able to properly fit the experimental data of matrices presenting the swelling phenomenon, characterized by an inflection point in their release profile. This entails applying the extended model of Korsmeyer-Peppas to estimate the percentage of drug released from the first experimental point up to the inflection point and then a model called Lumped until the final time, allowing to adequately represent the complete range of the drug release profile. Different parameters of pharmaceutical relevance were calculated using the proposed model to compare the profiles of the studied matrices. CONCLUSION: The "Dual Release" model proposed in this article can be used to predict the behavior of complex systems in which different mechanisms are involved in the release process.
Assuntos
Ácido Algínico/química , Ciprofloxacina/química , Preparações de Ação Retardada/química , Polieletrólitos/química , Liberação Controlada de Fármacos , Humanos , Modelos TeóricosRESUMO
In this work, we report the synthesis of graft copolymers based on casein and N-isopropylacrylamide, which can self-assemble into biodegradable micelles of approximately 80 nm at physiological conditions. The obtained copolymers were degraded by trypsin, an enzyme that is overexpressed in several malignant tumors. Moreover, graft copolymers were able to load doxorubicin (Dox) by ionic interaction with the casein component. In vitro release experiments showed that the in situ assembled micelles can maintain the cargo at plasma conditions but release Dox immediately after their exposition at pH 5.0 and trypsin. Cellular uptake and cytotoxicity assays revealed the efficient delivery to the nucleus and antiproliferative efficacy of Dox in the breast cancer cell line MDA231. Both delivery and therapeutic activity were enhanced in presence of trypsin. Overall, the prepared micelles hold a great potential for their utilization as dual responsive trypsin/pH drug delivery system.
Assuntos
Acrilamidas/química , Antineoplásicos/química , Caseínas/química , Doxorrubicina/química , Portadores de Fármacos/química , Polímeros/química , Temperatura , Antineoplásicos/farmacologia , Transporte Biológico , Linhagem Celular Tumoral , Portadores de Fármacos/metabolismo , Humanos , Concentração de Íons de Hidrogênio , Polímeros/metabolismoRESUMO
The aim of the present work was to study the main formulation variables that influence attributes of bioadhesive emulgels based on a combination of polymers, using response surface methodology (RSM). Bioadhesive products continue to gain attention in topical cutaneous administration as they allow long residence times on the application site, which is important when a long dermal action and a reduced product administration frequency are desired. A Box-Behnken design of experiments (DoE) was introduced to study the effect of formulation variables on quality attributes of the emulgels. The effects of concentration of carbomer interpolymer type A (Polym1), xanthan gum (Polym2) and mineral oil (Oil) on detachment force (Fdetch), spreadability (Spread), and phase separation by mechanical stress (PhSep) were investigated. RSM and desirability functions were applied for data analysis. Emulgels were further characterized by viscosity and extrudability measurements. Polym1 showed a positive effect on Fdetch, while the increase in concentrations of Polym2 and Oil decreased this property. Polym1 and Polym2 favored emulgel PhSep. However, their interaction effect decreased it. The combination of 0.4-0.6% of carbomer and 0.2-0.3% of gum was able to produce easy-to-spread bioadhesive emulgels with mineral oil as discontinuous phase in the presence of a low surfactant concentration. Based on the DoE results, value ranges for the variables, which could achieve for the experimental domain to get the critical quality attributes of emulgels jointly within the specification limits, were able to be identified using RSM supported by desirability functions.
Assuntos
Emulsões/química , Hidrogéis/química , Resinas Acrílicas/química , Interpretação Estatística de Dados , Composição de Medicamentos , Polímeros/química , ViscosidadeRESUMO
ABSTRACT 6-Methylcoumarin (6MC) is a semisynthetic coumarin with important in vitro and in vivo anti-inflammatory activity. In order to continue the pre-clinical characterization of this molecule, in vitro intestinal permeability, plasma profile and tissue distribution after oral administration in rats were studied. The permeability of 6MC was evaluated by the Caco-2 cellular model in both the apical-basal (A-B) and basal-apical (B-A) directions. The pharmacokinetics and biodistribution were evaluated in rats after oral and intraperitoneal administration at doses of 200 mg/kg. Transport experiments with Caco-2 cells showed that 6MC presented high permeability at all concentrations evaluated. This finding suggested that 6MC could be transported across the gut wall by passive diffusion. The plasma concentration-time curve showed that the maximum concentration (Cmax) was 17.13 ± 2.90 µg/mL at maximum time (Tmax) of 30 min for the oral route and Cmax 26.18 ± 2.47 µg/mL at 6.0 min for the intraperitoneal administration, with elimination constant of (Ke ) 0.0070 min-1 and a short life half time of (T1/2 ) lower that 120 min. The distribution study showed that 6MC has high accumulation in the liver, and widespread distribution in all the organs evaluated.
Assuntos
Animais , Masculino , Feminino , Ratos , Permeabilidade , Técnicas In Vitro/instrumentação , Administração Oral , Ratos Wistar/classificação , Cumarínicos/análise , Farmacocinética , Absorção Peritoneal , Enteropatias/classificaçãoRESUMO
The development and characterization of a novel, gel-type material based on a dendronized polymer (DP) loaded with ciprofloxacin (CIP), and the evaluation of its possible use for controlled drug release, are presented in this work. DP showed biocompatible and non-toxic behaviors in cultured cells, both of which are considered optimal properties for the design of a final material for biomedical applications. These results were encouraging for the use of the polymer loaded with CIP (as a drug model), under gel form, in the development of a new controlled-release system to be evaluated for topical administration. First, DP-CIP ionic complexes were obtained by an acid-base reaction using the high density of carboxylic acid groups of the DP and the amine groups of the CIP. The complexes obtained in the solid state were broadly characterized using FTIR spectroscopy, XRP diffraction, DSC-TG analysis and optical microscopy techniques. Gels based on the DP-CIP complexes were easily prepared and presented excellent mechanical behaviors. In addition, optimal properties for application on mucosal membranes and skin were achieved due to their high biocompatibility and acute skin non-irritation. Slow and sustained release of CIP toward simulated physiological fluids was observed in the assays (in vitro), attributed to ion exchange phenomenon and to the drug reservoir effect. An in vitro bacterial growth inhibition assay showed significant CIP activity, corresponding to 38 and 58% of that exhibited by a CIP hydrochloride solution at similar CIP concentrations, against Staphylococcus aureus and Pseudomonas aeruginosa, respectively. However, CIP delivery was appropriate, both in terms of magnitude and velocity to allow for a bactericidal effect. In conclusion, the final product showed promising behavior, which could be exploited for the treatment of topical and mucosal opportunistic infections in human or veterinary applications.
Assuntos
Antibacterianos/química , Ciprofloxacina/química , Dendrímeros/química , Portadores de Fármacos/química , Géis/química , Polímeros/química , Animais , Antibacterianos/metabolismo , Antibacterianos/farmacologia , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Ciprofloxacina/metabolismo , Ciprofloxacina/farmacologia , Portadores de Fármacos/toxicidade , Liberação Controlada de Fármacos , Humanos , Concentração de Íons de Hidrogênio , Íons/química , Testes de Sensibilidade Microbiana , Pseudomonas aeruginosa/efeitos dos fármacos , Coelhos , Reologia , Pele/efeitos dos fármacos , Espectroscopia de Infravermelho com Transformada de Fourier , Staphylococcus aureus/efeitos dos fármacosRESUMO
Chagas disease is an important public health problem in Latin America, and its treatment by chemotherapy with benznidazole (BZ) or nifurtimox remains unsatisfactory. In order to design new alternative strategies to improve the current etiological treatments, in the present work, we comprehensively evaluated the in vitro and in vivo anti-Trypanosoma cruzi effects of clomipramine (CMP) (a parasite-trypanothione reductase-specific inhibitor) combined with BZ. In vitro studies, carried out using a checkerboard technique on trypomastigotes (T. cruzi strain Tulahuen), revealed a combination index (CI) of 0.375, indicative of a synergistic effect of the drug combination. This result was correlated with the data obtained in infected BALB/c mice. We observed that during the acute phase (15 days postinfection [dpi]), BZ at 25 mg/kg of body weight/day alone decreased the levels of parasitemia compared with those of the control group, but when BZ was administered with CMP, the drug combination completely suppressed the parasitemia due to the observed synergistic effect. Furthermore, in the chronic phase (90 dpi), mice treated with both drugs showed less heart damage as assessed by the histopathological analysis, index of myocardial inflammation, and levels of heart injury biochemical markers than mice treated with BZ alone at the reference dose (100 mg/kg/day). Collectively, these data support the notion that CMP combined with low doses of BZ diminishes cardiac damage and inflammation during the chronic phase of cardiomyopathy. The synergistic activity of BZ-CMP clearly suggests a potential drug combination for Chagas disease treatment, which would allow a reduction of the effective dose of BZ and an increase in therapeutic safety.
Assuntos
Doença de Chagas/tratamento farmacológico , Clomipramina/farmacologia , Nitroimidazóis/farmacologia , Parasitemia/tratamento farmacológico , Tripanossomicidas/farmacologia , Trypanosoma cruzi/efeitos dos fármacos , Animais , Doença de Chagas/parasitologia , Modelos Animais de Doenças , Esquema de Medicação , Combinação de Medicamentos , Sinergismo Farmacológico , Coração/efeitos dos fármacos , Coração/fisiopatologia , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Parasitemia/parasitologia , Testes de Sensibilidade Parasitária , Resultado do Tratamento , Trypanosoma cruzi/crescimento & desenvolvimento , Trypanosoma cruzi/patogenicidadeRESUMO
OBJECTIVE: To develop an extemporaneous 1% benznidazole (BNZ) suspension, with masked taste and adequate stability starting from available commercial tablets. The quality of compounding was evaluated through content uniformity measurement and physical and microbiological stability evaluation, under different storage conditions during 90 days. METHODS: Six batches of 1% BNZ suspension were prepared using safe excipients currently available in a galenic area of Hospital Pharmacy and then stored at 5 and 25 °C for 90 days. The BNZ content was determined by UV spectrophotometry. Physical stability was defined as the absence of colour, odour and/or flavour changes and the re-suspension of solid phase by a reasonable amount of simple 15-s shaking. The compliance with microbiological attributes of non-sterile pharmaceutical products was also evaluated. RESULTS: An oral liquid suspension, containing 1% of BNZ, was developed from commercially available BNZ tablets. The formulations stored for 90 days were easily re-dispersed after a simple 15-s shaking, ensuring the pouring of a liquid volume containing the desired dose of BNZ. All samples were within the acceptable range of BNZ concentration with minimal standard deviations. There were no detectable changes in colour, odour, viscosity, pH and microbial growth, complying with official quality requirements. The quality attributes were not affected by storage, room or refrigeration conditions or by the frequent opening or closing of the multidose containers. CONCLUSION: Paediatric oral liquid suspension containing 1.0% of BNZ was easily prepared starting from commercial tablets, being an interesting alternative for optimising the paediatric treatment of Chagas disease.
Assuntos
Doença de Chagas/tratamento farmacológico , Estabilidade de Medicamentos , Nitroimidazóis/administração & dosagem , Paladar , Administração Oral , Criança , Composição de Medicamentos/métodos , Armazenamento de Medicamentos , Humanos , Nitroimidazóis/uso terapêutico , Pediatria , Espectrofotometria Ultravioleta , Suspensões , ComprimidosRESUMO
The synthesis, characterization and properties of pH/thermosensitive hydrogels based on acrylic acid (AAc) and N-isopropylacrylamide (NIPA) using (+)-N,N'-diallyltartramide (DAT) as cross-linking agent and water as solvent, are presented in this article. Subsequently, the incorporation of ofloxacin (OFL) as model drug to evaluate the drug load capacity of hydrogels and the in vitro release from OFL-polymer conjugate are presented in order to define potential pharmaceutical applications. Interestingly, the incorporation of AAc diversified the properties of NIPA-based hydrogels allowing ionic interaction of these new materials with drugs of opposite charge and produced different release profiles at pH 1.2 and 6.8 simulated physiological media.
Assuntos
Acrilamidas/química , Acrilatos/química , Preparações de Ação Retardada/química , Hidrogéis/química , Polímeros/química , Resinas Acrílicas/química , Concentração de Íons de Hidrogênio , Ofloxacino/química , Solventes/química , Temperatura , Água/químicaRESUMO
INTRODUCCION: En Argentina se emplea el benznidazolcomo terapéutica de primera línea para el tratamiento etiológico del Chagas. Desde su lanzamiento (hace más de 40 años), sólo se dispone de comprimidos convencionales de 100 mg; no se han desarrollado nuevas formas farmacéuticas que aumenten la eficacia y seguridad, ni alternativas con dosis pediátricas. OBJETIVOS: Desarrollar formas farmacéuticas de benznidazol que ofrezcan ventajas farmacoterapéuticas. METODOS: Preformulación y diseño de nuevas formulaciones de benznidazol, con caracterización físico-química y selección de las formulaciones más favorables. Frente a la discontinuidad de producción del ingrediente activo benznidazol, se desarrolló una metodología de extracción a partir de 8520/8520/nica alternativa comercial disponible. RESULTADOS: Se obtuvieron nuevas formulaciones de comprimidos de 50 y 100 mg debenznidazol, con una rápida disolución del producto de referencia. Además, se obtuvieron formulaciones masticables de 50 mg bajo la forma de hidrogeles azucarados, con un efectivo enmascaramiento del mal sabor. Todas las formulaciones cumplieron los ensayos de evaluación de las propiedades farmacotécnicas y biofarmacéuticas, superando los perfiles de referencia. CONCLUSIONES: Se desarrollaron nuevas alternativas farmacéuticas de benznidazol de rápida disolución, que podrían mejorar el tratamiento etiológico de la enfermedad(especialmente en pediatría) y convertirse en herramientas aptas para su explotación comercial (AU)
INTRODUCTION: In Argentina, benznidazole is the drug of choice for the etiological treatment of Chagas disease. Since it was launched (more than 40 years ago), there are only 100 mg tablets available; the development included neither new pharmaceutical forms improving efficacy and safety, nor a pediatric dosage option. OBJECTIVES: To develop pharmaceutical form sof benznidazole with pharmacotherapeutic advantages. METHODS: Preformulation and design of new formulation sof benznidazole, with physicochemical characterization and selection of the most favorable formulations. Due to the discontinuity in the production of the active ingredient benznidazole, a specific methodology was developed in order to obtain it from the only commercially available alternative. RESULTS: New benznidazole tablet formulations were obtained (50 and 100 mg), with a rapid dissolution of the reference product, as well as chewable formulation sof 50 mg as sugar hydrogels featuring an effective taste masking. All formulations passed the evaluation tests for pharmacotechnical and biopharmaceutical properties, out performing the reference profiles. CONCLUSIONS:New fast-dissolving pharmaceutical dosage forms of benznidazole were developed, which could improve the etiological treatment of the disease (especially in the pediatric field) and become a proper tool for its commercial exploitation (AU)
Assuntos
Humanos , Doença de Chagas/terapia , Antiparasitários/farmacologia , Antiparasitários/uso terapêutico , Comprimidos/farmacologia , Géis/farmacologia , Administração OralRESUMO
INTRODUCCIÓN: En Argentina se emplea el benznidazolcomo terapéutica de primera línea para el tratamiento etiológico del Chagas. Desde su lanzamiento (hace más de 40 años), sólo se dispone de comprimidos convencionales de 100 mg; no se han desarrollado nuevas formas farmacéuticas que aumenten la eficacia y seguridad, ni alternativas con dosis pediátricas. OBJETIVOS: Desarrollar formas farmacéuticas de benznidazol que ofrezcan ventajas farmacoterapéuticas. MÉTODOS: Preformulación y diseño de nuevas formulaciones de benznidazol, con caracterización físico-química y selección de las formulaciones más favorables. Frente a la discontinuidad de producción del ingrediente activo benznidazol, se desarrolló una metodología de extracción a partir de 8520/8520/nica alternativa comercial disponible. RESULTADOS: Se obtuvieron nuevas formulaciones de comprimidos de 50 y 100 mg debenznidazol, con una rápida disolución del producto de referencia. Además, se obtuvieron formulaciones masticables de 50 mg bajo la forma de hidrogeles azucarados, con un efectivo enmascaramiento del mal sabor. Todas las formulaciones cumplieron los ensayos de evaluación de las propiedades farmacotécnicas y biofarmacéuticas, superando los perfiles de referencia. CONCLUSIONES: Se desarrollaron nuevas alternativas farmacéuticas de benznidazol de rápida disolución, que podrían mejorar el tratamiento etiológico de la enfermedad(especialmente en pediatría) y convertirse en herramientas aptas para su explotación comercial
INTRODUCTION: In Argentina, benznidazole is the drug of choice for the etiological treatment of Chagas disease. Since it was launched (more than 40 years ago), there are only 100 mg tablets available; the development included neither new pharmaceutical forms improving efficacy and safety, nor a pediatric dosage option. OBJECTIVES: To develop pharmaceutical form sof benznidazole with pharmacotherapeutic advantages. METHODS: Preformulation and design of new formulation sof benznidazole, with physicochemical characterization and selection of the most favorable formulations. Due to the discontinuity in the production of the active ingredient benznidazole, a specific methodology was developed in order to obtain it from the only commercially available alternative. RESULTS: New benznidazole tablet formulations were obtained (50 and 100 mg), with a rapid dissolution of the reference product, as well as chewable formulation sof 50 mg as sugar hydrogels featuring an effective taste masking. All formulations passed the evaluation tests for pharmacotechnical and biopharmaceutical properties, out performing the reference profiles. CONCLUSIONS:New fast-dissolving pharmaceutical dosage forms of benznidazole were developed, which could improve the etiological treatment of the disease (especially in the pediatric field) and become a proper tool for its commercial exploitation
Assuntos
Humanos , Administração Oral , Antiparasitários/farmacologia , Antiparasitários/uso terapêutico , Comprimidos/farmacologia , Doença de Chagas/terapia , Géis/farmacologiaRESUMO
The interactions between pilocarpine (PIL) and the anionic polyelectrolyte carbomer (CBR) were investigated. The effects of the chemical interactions on the chemical stability of the drug also were evaluated. The binary system was characterized by nuclear magnetic resonance techniques, Fourier-transform infrared spectroscopy (FT-IR), X-ray powder diffraction, scanning electron microscopy (SEM) and thermal analysis. The experiments showed that the complex, prepared by freeze-drying, is a solid amorphous form different from its precursors, thereby offering an interesting alternative for the preparation of extended release matrices. The solution stability of PIL was studied at pH 7 and 8, at 70 °C. The PIL solution stability was evaluated alone and in the presence of CBR. Results indicated that the drug in the presence of the polymer is 3.3 and 3.5 times more stable, at pH 7 and pH 8, respectively, than the drug without CBR. The activation energy and the frequency factor, according to Arrhenius plot, were estimated to be 13.9 ± 0.4 and 14.8 ± 0.5 kcalmol(-1), and 6.1 ± 0.3 and 7.6 ± 0.3, with and without the polymer, respectively.
Assuntos
Resinas Acrílicas/química , Agonistas Muscarínicos/química , Pilocarpina/química , Varredura Diferencial de Calorimetria , Cromatografia Líquida de Alta Pressão , Estabilidade de Medicamentos , Liofilização , Hidrogéis , Concentração de Íons de Hidrogênio , Espectroscopia de Ressonância Magnética , Microscopia Eletrônica de Varredura , Peso Molecular , Agonistas Muscarínicos/administração & dosagem , Pilocarpina/administração & dosagem , Espectroscopia de Infravermelho com Transformada de Fourier , Temperatura , Termogravimetria , Difração de Raios XRESUMO
Lidocaine-HCl and procaine-HCl are local anesthetic drugs widely used in minor chirurgic procedures, nevertheless, physicochemical information about their volumetric behavior, as well as for other aqueous properties, is not complete at present. In this context, in this article, densities of aqueous solutions of both drugs have been measured as a function of concentration (from 0.0500 to 0.5000) mol kg1 at several temperatures, i.e. 278.15, 283.15, 288.15, 293.15, 298.15, 303.15, 308.15, and 313.15 K. The apparent molar volumes and partial molar volumes at infinite dilution for the electrolyte drugs were calculated, whereas, the partial molar volumes at infinite dilution and partial molar expansibilities for the molecular forms were also calculated. The dependence of these properties with temperature is shown. The results are interpreted in terms of interaction solute-solvent.
La lidocaína-HCl y procaína-HCl son anestésicos locales ampliamente usados en procedimientos quirúrgicos menores, sin embargo la información fisicoquímica acerca de su comportamiento volumétrico, así como de otras propiedades fisicoquímicas, aún es incompleta en la actualidad. Por esta razón, en este artículo se presentan los valores de densidad de algunas soluciones acuosas de estos dos fármacos en función de la concentración (desde 0,0500 hasta 0,5000) mol kg1 a diferentes temperaturas (278,15, 283,15, 288,15, 293,15, 298,15, 303,15, 308,15 y 313,15 K). Así mismo se presentan los volúmenes molares aparentes y volúmenes molares parciales a dilución infinita de los fármacos como electrolitos, y de otro lado, los volúmenes molares parciales a dilución infinita de los fármacos moleculares y las expansibilidades molares, los cuales fueron calculados a partir de los valores de densidad y composición de las mezclas. Los resultados obtenidos se interpretan en términos de interacciones soluto-solvente.
Assuntos
Lidocaína , Procaína , Soluções , TermodinâmicaRESUMO
The hydrochlorides of the 1:3 aluminum:norfloxacin and aluminum:ciprofloxacin complexes were characterized according to the Biopharmaceutics Classification System (BCS) premises in comparison with their parent compounds. The pH-solubility profiles of the complexes were experimentally determined at 25 and 37 degrees C in the range of pH 1-8 and compared to that of uncomplexed norfloxacin and ciprofloxacin. Both complexes are clearly more soluble than the antibiotics themselves, even at the lowest solubility pHs. The increase in solubility was ascribed to the species controlling solubility, which were analyzed in the solid phases at equilibrium at selected pHs. Additionally, permeability was set as low, based on data reported in the scientific literature regarding oral bioavailability, intestinal and cell cultures permeabilities and also considering the influence of stoichiometric amounts of aluminum. The complexes fulfill the BCS criterion to be classified as class 3 compounds (high solubility/low permeability). Instead, the active pharmaceutical ingredients (APIs) currently used in solid dosage forms, norfloxacin and ciprofloxacin hydrochloride, proved to be BCS class 4 (low solubility/low permeability). The solubility improvement turns the complexes as potential biowaiver candidates from the scientific point of view and may be a good way for developing more dose-efficient formulations. An immediate release tablet showing very rapid dissolution was obtained. Its dissolution profile was compared to that of the commercial ciprofloxacin hydrochloride tablets allowing to dissolution of the complete dose at a critical pH such as 6.8.
Assuntos
Biofarmácia , Ciprofloxacina/química , Norfloxacino/química , Ciprofloxacina/análogos & derivados , Ciprofloxacina/classificação , Composição de Medicamentos , Excipientes/química , Norfloxacino/análogos & derivados , Norfloxacino/classificação , Permeabilidade , Solubilidade , ComprimidosRESUMO
The aim of this work was the development of extended release tablets of 500 mg of ciprofloxacin based on swellable drug polyelectrolyte matrices (SDPM). A set of complexes of carbomer, ciprofloxacin and sodium, (CB-Cip)(50)Na( x ), having a molar ratio Cip/CB acid groups of 0.5 and variable proportions of Na(+) was used to prepare SDPM. Characterization of complexes by FT-IR, powder X-ray diffraction and thermal analysis revealed that Cip, in its protonated form, is ionically bonded to the functional groups of CB. Rates of fluid uptake of (CB-Cip)(50)Na( x ) matrices as well as Cip release in simulated gastric fluid were modulated by changes in the proportion of Na(+) incorporated in the complexes. A direct correlation between fluid uptake and delivery rate was observed along the series of matrices. Release rates were modulated from 1.4 mg/min to 25 mg/min in going from (CB-Cip)(50)Na(10) to (CB-Cip)(50)Na(14). The analysis of kinetic data suggest that rates of swelling, ionic pair dissociation and drug diffusion play a role in the kinetic control of delivery. Complexes were satisfactorily prepared and processed together with small amounts of antiadherent and lubricant excipients to obtain a series of extended release SDPM tablets through the current tableting technology processes. Cip release from matrices was widely modulated by the composition of the complexes yielding a flexible system that allows selecting a composition that releases in 120 min 90% of the dose in simulated gastric fluid.
Assuntos
Resinas Acrílicas/química , Resinas Acrílicas/farmacocinética , Ciprofloxacina/química , Ciprofloxacina/farmacocinética , Eletrólitos/química , Eletrólitos/farmacocinética , Química Farmacêutica , Preparações de Ação Retardada/química , Preparações de Ação Retardada/farmacocinética , Portadores de Fármacos/química , Portadores de Fármacos/farmacocinética , Suco Gástrico/química , Suco Gástrico/metabolismo , Polímeros/química , Polímeros/farmacocinética , Espectroscopia de Infravermelho com Transformada de Fourier , ComprimidosRESUMO
The objective of the study is to develop and characterize the delivery properties of swellable drug-polyelectrolyte matrices (SDPM). Solid complexes (C-D)X of carbomer (C) neutralized with different proportions of model basic drugs (D), in which D is atenolol, lidocaine, and metoclopramide, and X=25, 50, 75 and 100 mol of D per 100 equivalents of carboxylic groups of C, were prepared and characterized by DSC-TG, IR, and X-ray diffraction studies. Mechanistic studies with hydrophilic and hydrophobic basic drugs were conducted to explore the drug release patterns of SDPM. Besides, release and up-take studies were carried out in water and NaCl solution to examine the influence of ionic effects. The authors concluded that drugs can be loaded in a high proportion on to the polymer and therefore the resulting (C-D) material could be diluted with other polymers to modulate delivery properties of SDPM. Matrices of atenolol and lidocaine exhibited robust delivery properties with regard to change in proportion of loading D.
Assuntos
Portadores de Fármacos/química , Portadores de Fármacos/farmacocinética , Sistemas de Liberação de Medicamentos/métodos , Resinas Acrílicas/química , Resinas Acrílicas/farmacocinética , Varredura Diferencial de Calorimetria , Espectroscopia de Infravermelho com Transformada de Fourier , Difração de Raios XRESUMO
6-O-Ascorbic acid alkanoates (ASCn, where n is the number of carbon atoms in the alkyl chain) behave as surfactants and form stable supramolecular assemblies in water, depending on chemical structure, concentration and temperature. In concentrated water dispersions, ASCn form liquid crystalline structures ('coagels'), below the critical micellar temperature (CMT), with a typical Krafft phenomenon. Such semisolid systems incorporate and stabilize drugs like anthralin, which is insoluble and unstable in aqueous media. The rheological behavior of coagels obtained from aqueous ASC8, ASC10, ASC11, ASC12, ASC14 and ASC16 was evaluated and related to the coagel structure. For ASC8, ASC12, ASC14 and ASC16 complex rheology was observed and spur values were determined. This behavior is indicative of a high three-dimensional structure. The spur value represents a sharp point of structural breakdown at low shear rate. At this point the semisolids acquire pseudoplastic flow with a very low viscosity. Instead, ASC10 and ASC11 coagels showed pseudoplastic flow and--in the case of ASC11--thixotropy was observed. The ASCn coagel rheological behavior and their capability to load pharmacologically active compounds point to a potentially valuable capacity for such systems as drug carriers.