RESUMEN
Most medicines are white bitter powders that are formulated as tablets and capsules but cough medicines are an exception where the taste and appearance of the medicine are more important to the patient than the pharmacology of the active ingredient. Excipients are generally defined as any ingredient in a medicine other than the active ingredient. In most medicines excipients play a supportive role in delivering the medicine, but in the case of cough medicines, excipients have more important and complex roles and they can also be the main active ingredient of the cough medicine as menthol, glycerol, and sugars, which are declared as active ingredients. This review searched the United Kingdom electronic medicines compendium (emc) and found over 100 excipients in 60 different liquid formulations of over the counter cough medicines. The excipients were divided into functional groups: sweeteners, thickeners, flavors, colors, antimicrobials, and buffers, and the incidence and function of the different excipients is discussed. When considering the efficacy of a cough medicine, clinicians and pharmacists tend to think of the pharmacology of antitussives such as dextromethorphan or expectorants such as guaifenesin, and they rarely consider the role of excipients in the efficacy of the medicine. This review discusses the functions and importance of excipients in cough medicines and provides some new information for clinicians, pharmacists, and all interested in the treatment of cough when considering the composition and efficacy of a cough medicine.
Asunto(s)
Antitusígenos , Tos , Humanos , Antitusígenos/clasificación , Antitusígenos/farmacología , Tos/tratamiento farmacológico , Composición de Medicamentos/métodos , Excipientes/clasificación , Excipientes/farmacología , Medicamentos sin Prescripción/farmacología , Soluciones Farmacéuticas , Resultado del TratamientoRESUMEN
The increasing number of new chemical entities is bringing new challenges to the field of drug delivery. These drugs present bioavailability issues that are frequently associated with intestinal metabolism or efflux mechanisms. Some excipients, particularly surfactants, have demonstrated a capacity to interfere with these mechanisms, improving drug bioavailability. Consequently, these excipients can no longer be considered as inert and should be subject to special considerations from a regulatory perspective. In the present manuscript, the state-of-the-art research related to these abilities of excipients to interfere with intestinal metabolism and efflux mechanisms are presented and discussed. Here, a biopharmaceutical classification system of excipients is proposed for the first time as a tool in the development of new products and for regulatory purposes.
Asunto(s)
Excipientes/química , Excipientes/clasificación , Disponibilidad Biológica , Sistemas de Liberación de Medicamentos , Humanos , Preparaciones Farmacéuticas , TensoactivosRESUMEN
This work reports the preparation of tablets by direct compression of sodium alendronate-loaded microparticles, using pullulan as filler. The tableting properties of pullulan were compared with those of microcrystalline cellulose and lactose. Pullulan tablets showed low variations in average weight, thickness and drug content. Moreover, these tablets exhibited a higher hardness compared to the other excipients. In vitro release studies showed that only pullulan was capable to maintain gastroresistance and release properties of microparticles, due to its ability to protect particles against damage caused by compression force. Thus, pullulan was considered an advantageous excipient to prepare tableted microparticles.
Neste trabalho relata-se a preparação de comprimidos pela compressão direta de micropartículas contendo alendronato de sódio, utilizando o pullulan como diluente. As propriedades dos comprimidos de pullulan foram comparadas com as de comprimidos de celulose microcristalina e de lactose. Os comprimidos de pullulan mostraram baixa variação no peso médio, espessura e teor. Por outro lado, estes apresentaram altos valores de dureza comparados aos preparados com os outros excipientes. Através dos estudos de liberação in vitro pode-se observar que apenas o pullulan foi capaz de manter a gastrorresistência e as propriedades de liberação das micropartículas, o que se deve à sua capacidade de proteger as partículas do dano causado pela força de compressão. Dessa forma, o pullulan foi considerado um excipiente vantajoso para a preparação de comprimidos microparticulados.
Asunto(s)
Polisacáridos/clasificación , Comprimidos/farmacocinética , Alendronato/farmacocinética , Excipientes/clasificación , Trituración de Residuos SólidosRESUMEN
The present study was planned to investigate the influence of polyethylene glycols (PEGs) on the activity and expression of P-glycoprotein (P-gp). Sub-toxic concentrations of PEGs in Caco-2 cells were determined using the MTT test assay. Then the measurement of Rhodamine-123 (Rho-123) uptake, a P-gp fluorescence substrate, in Caco-2 cells confronting PEG 400 (1% and 2% w/v), PEG 4000 (2% and 4% w/v), PEG 6000 (2% and 4% w/v), PEG 10000 (2% and 4% w/v), PEG 15000 (1% and 2% w/v), and PEG 35000 (2% and 4% w/v) overnight was taken to elucidate whether non-toxic concentrations of PEGs are able to impact P-gp activity. Furthermore, western blotting was carried out to investigate P-gp protein expression. The results showed that PEG 400 at concentrations of 1% (w/v) and 2% (w/v) and PEG 6000 at the concentration of 4% (w/v) are notably capable of blocking P-gp. Based on the obtained results it is concluded that the mentioned excipients could be used to obstruct P-gp efflux transporter in order to increase the bioavailability of co-administered substrate drug.
O presente estudo foi planejado para investigar a influência de polietileno glicóis sobre a atividade e expressão da P- glicoproteína (P-gp) . Concentrações sub-tóxicas de PGPs e em células Caco-2 foram determinadas por meio do ensaio de MTT. Em seguida, efetuou-se a a medida de captura de Rodamina-123 (Rho-123), um substrato fluorescente de P-gp, em células Caco-2, confrontando com PEG 400 (1% e 2% m/v), PEG 4000 (2% e 4% m/v) e PEG 6000 (2% e 4% m /v), PEG 10000 (2% e 4% w/v), PEG 15000 (1% e 2% m/v), e PEG 35000 (2% e 4% m/v). Essa medida foi efetuada durante a noite, para saber se as concentrações não tóxicas de excipientes são capazes de influenciar a actividade da P-gp. Além disso, realizou-se o western blotting para investigar a expressão da proteína P-gp. Os resultados mostraram que o PEG 400, nas concentrações de 1% (m/v) e 2% (m/v), e PEG 6000, na concentração de 4% (m/v) são capazes de bloquear P-gp. Com base nos resultados conclui-se que os excipientes mencionados poderiam ser utilizados para obstruir o efluxo por P-gp, a fim de aumentar a biodisponibilidade de do fármaco co-administrado.
Asunto(s)
Polietilenglicoles/análisis , Miembro 1 de la Subfamilia B de Casetes de Unión a ATP/análisis , Células CACO-2 , Disponibilidad Biológica , Rodamina 123 , Excipientes/clasificaciónRESUMEN
The freezing stress and cryoprotectants were known to be the crucial factors for solidification formability of nanosuspensions during freeze-drying. However, there has been controversy as to whether an aggressive or conservative freezing stress (freezing temperature or freezing rate) prevents from irreversible aggregation of nanosuspensions. And the screening of cryoprotectants for solidification formability of nanosuspensions has largely relied on empirical approaches. A systematic investigation was presented herein regarding the effect of both the freezing stress and property of cryoprotectants on solidification formability of drug nanosuspensions during freeze-drying. It was found that at different freezing stresses (-20 °C, -80 °C, and -196 °C), the redispersibility of BCN, NGN, RCN, and RVL nanosuspensions stabilized, respectively, by seven stabilizers, was RDI(-20 °C)>RDI(-80 °C)>RDI(-196 °C). But the redispersibility of UDCA and OCA nanosuspensions stabilized, respectively, by seven stabilizers, was RDI(-20 °C)Asunto(s)
Crioprotectores/química
, Portadores de Fármacos
, Excipientes/química
, Nanopartículas/química
, Estrés Mecánico
, Fenómenos Químicos
, Química Farmacéutica
, Frío/efectos adversos
, Crioprotectores/clasificación
, Estabilidad de Medicamentos
, Excipientes/clasificación
, Estudios de Factibilidad
, Liofilización
, Interacciones Hidrofóbicas e Hidrofílicas
, Cinética
, Microscopía Electrónica de Rastreo
, Nanopartículas/ultraestructura
, Presión Osmótica
, Tamaño de la Partícula
, Transición de Fase
, Sacarosa/química
, Sacarosa/clasificación
, Suspensiones
, Temperatura de Transición
RESUMEN
Hypersensitivity reactions to excipients contained in drugs are rare but can be severe or confusing. With regard to generic versus brand drug, often the ingredients are different; for each DHR, we recommend that the physician exercises caution in considering which brand drug or generic was administered and in listing all medicine components and not only the active drug.
Asunto(s)
Hipersensibilidad a las Drogas/diagnóstico , Hipersensibilidad a las Drogas/etiología , Excipientes/efectos adversos , Excipientes/clasificación , HumanosRESUMEN
OBJECTIVE: Water uptake and force development of disintegrating tablets provide a high degree of information about the disintegration mechanisms and process itself. An apparatus for the simultaneous measurement of water uptake and force development of tablets is presented, and the gathered data are analysed. METHODS: Flat faced, 10 mm, dibasic calcium phosphate tablets containing 2% disintegrant are investigated with the newly constructed apparatus. The force is determined with a texture analyser, whereas the water uptake is recorded by a balance. Different measurement regimes are compared with each other. Measured curves are analysed according to their shape and fitted with a modified Hill equation. KEY FINDINGS: Known disintegration mechanisms can be confirmed with the newly constructed apparatus - swelling for sodium starch glycolate and croscarmellose sodium, and shape recovery for crospovidone disintegrants. Different brands of polacrilin potassium act by different mechanisms. All curves could be fitted successfully with a modified Hill equation. A novel classification to facilitate the appropriate disintegrant selection is presented on basis of the fit parameters. CONCLUSION: The new apparatus allows the acquisition of water uptake and force data simultaneously. Parameters calculated with the modified Hill equation provide a simple way to classify disintegrants according to their behaviour.
Asunto(s)
Fosfatos de Calcio/administración & dosificación , Carboximetilcelulosa de Sodio/química , Excipientes/química , Compuestos de Potasio/química , Povidona/química , Almidón/análogos & derivados , Comprimidos/química , Agua/química , Excipientes/clasificación , Cinética , Solubilidad , Almidón/químicaRESUMEN
As a methodology for characterizing substances with regard to its viability in direct compression, the SeDeM Diagram Expert System may be considered a new tool in terms of the number of parameters applied and its optimization. The paper is based on the experimental SeDeM characterization study of 51 directly compressible (DC) excipients. After selecting the parameters, and comparing the corresponding results, the choices available within the SeDeM Expert System could be expanded. Through applied variants, the maximum and optimal values of the DC diluent excipient were precisely defined and the mathematical limits of the parameters, functions and parametric indices that define the level of direct compressibility were established. These studies have allowed us to propose a new classification of excipients CD based on its rheological and compressibility capability, resulting in a periodic table of CD excipients. It has been determined that the best excipient for direct compression should have an index of good compression (IGC) of 8.832.
Asunto(s)
Excipientes/química , Excipientes/clasificación , Sistemas Especialistas , Fuerza Compresiva , Tamaño de la Partícula , Porosidad , ReologíaAsunto(s)
Biofarmacia/métodos , Excipientes/clasificación , Excipientes/metabolismo , Animales , Disponibilidad Biológica , Relación Dosis-Respuesta a Droga , Excipientes/química , Humanos , Ósmosis/efectos de los fármacos , Ósmosis/fisiología , Permeabilidad/efectos de los fármacos , Solubilidad/efectos de los fármacos , Equivalencia TerapéuticaRESUMEN
The main objective of this work was to prepare a self-micro emulsifying drug delivery system (SMEDDS) for enhancement of oral bioavailability of domperidone, a poorly water soluble drug. The solubility of the drug was determined in various vehicles. A pseudo ternary phase diagram was constructed to identify the self-micro emulsification region. The in vitro self-micro emulsification properties and droplet size analysis of SMEDDS were studied following their addition to water under mild agitation. Further, the resultant formulations were investigated for clarity, phase separation, globule size, effect of pH and dilutions (1:100, 1:500, 1:1000) and freeze-thaw stability. The optimized formulation, SMEDDS-B used for in vitro dissolution and bioavailability assessment, contained oil (Labrafac CC, 25 %, m/m), surfactant (Tween 80, 55 %, m/m), and co-surfactant (Transcutol®, 20 %, m/m). The preliminary oral bioavailability of domperidone from SMEDDS was 1.92-fold higher compared to that of domperidone suspension in rats. The AUC0-24 and cmax values were 3.38 ± 0.81 µg h mL-1 and 0.44 ± 0.03 µg mL-1 for SMEDDS-B formulation in comparison with 1.74 ± 0.18 µg h mL-1 and 0.24 ± 0.02 µg mL-1 for domperidone suspension, suggesting a significant increase (p < 0.05) in oral bioavailability of domperidone from SMEDDSS.
Asunto(s)
Domperidona , Sistemas de Liberación de Medicamentos/métodos , Emulsionantes , Aceites/farmacología , Solubilidad/efectos de los fármacos , Administración Oral , Animales , Disponibilidad Biológica , Química Farmacéutica/métodos , Domperidona/administración & dosificación , Domperidona/farmacocinética , Antagonistas de Dopamina/administración & dosificación , Antagonistas de Dopamina/farmacocinética , Emulsionantes/clasificación , Emulsionantes/farmacología , Emulsiones/farmacología , Excipientes/clasificación , Excipientes/farmacología , Concentración de Iones de Hidrógeno , Masculino , Tamaño de la Partícula , Ratas , Ratas WistarRESUMEN
BACKGROUND: In animal studies, some ortho-phthalates, including di(2-ethylhexyl) phthalate (DEHP) and di-n-butyl phthalate (DBP), have been shown to be reproductive and developmental toxicants. Human studies show widespread population exposure to background levels of phthalates. Limited evidence suggests that particularly high exposure levels may result from orally ingested medicinal products containing phthalates as excipients (inactive ingredients). OBJECTIVE: In this study we aimed to identify and describe the scope of prescription (RX) and nonprescription (over-the-counter; OTC) medicinal products and dietary supplements marketed in the United States and Canada since 1995 that include phthalates as excipients. METHODS: We used lists of modified-release drug products to identify potential drug products. Inclusion of phthalates was verified using available electronic databases, print references, published package inserts, product packages, and direct communication from manufacturers. Additional products were identified using Internet searches utilizing keywords for phthalates. RESULTS: Based on labeling information, 6 RX drug products included DBP as an excipient, and 45 specified the use of diethyl phthalate (DEP). Phthalate polymers with no known toxicity--hypromellose phthalate (HMP), cellulose acetate phthalate (CAP), and polyvinyl acetate phthalate (PVAP)--were included in 75 RX products. Three OTC drug and dietary supplement products listed DBP, 64 listed DEP, and > 90 indicated inclusion of polymers. CONCLUSIONS: Numerous RX and OTC drug products and supplements from a wide range of therapeutic categories may use DBP or DEP as excipients in oral dosage forms. The potential effects of human exposure to these phthalates through medications are unknown and warrant further investigation.
Asunto(s)
Suplementos Dietéticos/análisis , Exposición a Riesgos Ambientales , Excipientes/análisis , Medicamentos sin Prescripción/análisis , Ácidos Ftálicos/análisis , Medicamentos bajo Prescripción/análisis , Canadá , Preparaciones de Acción Retardada/análisis , Excipientes/clasificación , Preparaciones Farmacéuticas/análisis , Ácidos Ftálicos/química , Ácidos Ftálicos/toxicidad , Estados UnidosRESUMEN
Antioxidants are currently used as efficient excipients that delay or inhibit the oxidation process of molecules. Excipients are often associated with adverse reactions. Stability studies can guide the search for solutions that minimize or delay the processes of degradation. The ability to predict oxidation reactions in different drugs is important. Methods: This study was conducted to assess the rational use of butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), sodium metabisulfite (SMB), propyl gallate (PG) and cysteine (CYS) in tablet formulations of simvastatin and ketoconazole. These antioxidants were evaluated according to stability parameters and the relationship between efficiency of the antioxidant and chemical structure of the drugs. Results were compared with DPPH tests and computational simulations. BHT was most efficient regarding simvastatin stability, and the most effective BHT concentrations for maintaining stability were 0.5 and 0.1%. In relation to ketoconazole, SMB was most efficient for maintaining content and dissolution profile. The evaluation by DPPH showed that the largest percentage of absorbance reduction was observed for PG, while SMB proved most efficient and had lower consumption of DPPH. The same pattern was observed, albeit with lower efficiency, for the other lipophilic antioxidants such as BHT and BHA. The results of the molecular modeling study demonstrated that electronic properties obtained were correlated with antioxidant activity in solution, being useful for the rational development of liquid pharmaceutical formulations but not for solid oral formulations. This study demonstrated the importance of considering stability parameters and molecular modeling to elucidate the chemical phenomena involved in antioxidant activity, being useful for the rational use of antioxidants in the development of pharmaceutical formulations.
Atualmente, antioxidantes são usados como excipientes eficientes, que retardam ou inibem o processo de oxidação de moléculas. Excipientes são frequentemente associados a efeitos adversos. Estudos de estabilidade podem ajudar na busca por possíveis soluções para minimizar ou retardar os processos de degradação. A habilidade de prever as reações de oxidação em diferentes fármacos é importante. O estudo foi conduzido com o objetivo de avaliar o uso racional de hidroxianisol butilado (BHA), hidroxitolueno butilado (BHT), metabissulfito sódico (SMB), galato de propila (PG) e cisteína (CYS) em formulações de comprimidos de sinvastatina e cetoconazol. Eles foram avaliados por parâmetros de estabilidade e pela relação entre a eficiência dos antioxidantes e a estrutura química do fármaco. Os resultados foram comparados com testes de DPPH e simulações em computador. BHT foi mais eficiente com relação a estabilidade da sinvastatina e às concentrações mais eficientes para manutenção de estabilidade foram 0,5 e 0,1%. Com relação ao cetoconazol, SMB foi mais eficiente em manter o conteúdo e o perfil de dissolução. A avaliação por DPPH mostrou que o maior percentual de redução de absorção foi observado para PG, enquanto que SMB mostrou ser mais eficiente e consumir menos DPPH. A mesma tendência foi observada com menos eficiência em todos os outros antioxidantes lipofílicos como o BHT e BHA. Os resultados do estudo de modelagem molecular demonstraram que as propriedades eletrônicas obtidas podem ser correlacionadas com a atividade antioxidante em solução, sendo útil para o desenvolvimento racional de formulações farmacêuticas líquidas, mas não para formulações sólidas orais. Este estudo demonstrou a importância de considerar parâmetros de estabilidade e modelagem molecular para elucidar os fenômenos químicos envolvidos na atividade antioxidante, sendo úteis para o uso racional de antioxidantes no desenvolvimento de formulações farmacêuticas.
Asunto(s)
Preparaciones Farmacéuticas , Administración Oral , Utilización de Medicamentos/clasificación , Antioxidantes/análisis , Galato de Propilo/farmacocinética , Hidroxianisol Butilado/farmacocinética , Hidroxitolueno Butilado/farmacocinética , Simvastatina/análisis , Cisteína/farmacocinética , Excipientes/clasificación , Cetoconazol/análisisRESUMEN
Ibuprofen is one of the most important non-steroidal anti-inflammatory drugs used in the treatment of inflammatory diseases. In its pure state, ibuprofen presents poor physical and mechanical characteristics and its use in solid dosage forms needs the addition of excipients that improve these properties. The selection of the best excipients and the most suitable pharmaceutical dosage form to carry ibuprofen is very important for the industrial success of this drug. Given these factors, lipid microparticles and solid dispersions of ibuprofen with cetyl alcohol, stearic acid, and hydrogenated castor oil were prepared. These formulations were intended to improve the physical and mechanical characteristics and to sustain the release of this drug. Physical mixtures were also prepared with the same ingredients in similar proportions. The solid dispersions of ibuprofen/stearic acid and ibuprofen/hydrogenated castor oil showed the best flow characteristics compared with pure ibuprofen. Further, gelatin capsules filled with lipid microparticles and solid dispersions were submitted to dissolution tests in order to study the influence of the prepared systems in the release profiles of ibuprofen. Prolonged release of ibuprofen was achieved with the lipid microparticles and solid dispersions prepared with the different types of excipients.
O ibuprofeno é um dos antiinflamatórios não esteróides mais utilizados no tratamento de patologias associadas a processos inflamatórios. Este fármaco, quando no seu estado puro, apresenta características físicas e mecânicas pouco satisfatórias e a sua utilização em formas sólidas só é possível se forem adicionados excipientes que permitam melhorar estas propriedades. A seleção dos excipientes ideais e da forma farmacêutica mais adequada para veicular o ibuprofeno é fundamental para o sucesso industrial deste fármaco. Tendo em conta estes fatores, prepararam-se micropartículas lipídicas e dispersões sólidas de ibuprofeno com cada um dos seguintes excipientes: álcool cetílico, ácido esteárico e óleo de rícino hidrogenado. Estas formulações tinham por finalidade melhorar as características físicas e mecânicas e prolongar a liberação deste fármaco. Foram, também, preparadas misturas físicas do ibuprofeno com os mesmos excipientes e nas mesmas proporções. As dispersões sólidas de ibuprofeno/ácido esteárico e as dispersões sólidas de ibuprofeno/óleo de rícino hidrogenado foram aquelas que apresentaram melhores características de escoamento comparativamente com o ibuprofeno puro. Por outro lado, foram preparadas cápsulas de gelatina com as diferentes micropartículas lipídicas e dispersões sólidas e submetidas a ensaios de dissolução com o objetivo de estudar a influência dos sistemas preparados nos perfis de liberação do ibuprofeno. A liberação prolongada do ibuprofeno foi conseguida nas diferentes micropartículas lipídicas e dispersões sólidas preparadas com os diferentes excipientes.
Asunto(s)
Estudio Comparativo , Ibuprofeno/análisis , Factor de Crecimiento de Hepatocito/clasificación , Gotas Lipídicas/clasificación , Aceite de Ricino/clasificación , Excipientes/clasificaciónRESUMEN
Guidance recommendations by the Committee for Medicinal Products for Human Use (CHMP) and Pharmaceutical Research and Manufacturers of America (PhRMA) acknowledge the presence of potential toxic impurities in some pharmaceutical ingredients and have proposed setting limits on impurities with genotoxic activity as a means to protect patients in clinical trials and for marketing of the approved products. Recently, there have been suggestions that drug excipients, including existing products, should also be subjected to the same testing procedures and intake limits as proposed for active ingredients. This report is an attempt to put such recommendations into the proper perspective regarding the likelihood of protecting or improving public health.
Asunto(s)
Contaminación de Medicamentos/prevención & control , Excipientes/toxicidad , Pruebas de Mutagenicidad/métodos , Mutágenos/toxicidad , Preparaciones Farmacéuticas/química , ADN Bacteriano/efectos de los fármacos , Excipientes/química , Excipientes/clasificación , Contaminación de Alimentos/análisis , Humanos , Mutágenos/química , Mutágenos/clasificación , Salud Pública , Medición de Riesgo , Salmonella typhimurium/efectos de los fármacos , Salmonella typhimurium/genéticaRESUMEN
The ability to incorporate either of the two components of a self-emulsifying system (polysorbate 80 (PSG80) and a mixture of mono- and di-glycerides (MDG)) separately into pellets prepared by extrusion/spheronization and the properties of any resulting pellets has been investigated. The results have established that it is possible to prepare satisfactory pellets thus adding to the range of ingredients that can be included in pellet formulations. For PS80, it was found possible to prepare pellets containing at least 92% of the surfactant/water mixture, but with a mixture of (MDG) and water, however, it was not possible to prepare pellets, which contained more than 46% of MDG. By analysis of variance significant relationships were established between the ratio of lactose to MCC and the ratio of the PS80 or MDG to water and the properties of the pellets. There were both similarities and differences of the two input factors, which provided relationships for the two materials. The quantity of liquid required, the fluid content of the pellets, the tensile strength and porosity of the pellets provided relationships for both systems, whereas the extrusion force and the median pellet size gave relationships for the PS80 systems, but they did not for the MDG systems. The opposite was true for interquartile range (IQR), the yield in the modal fraction and the shape factor. It was possible to identify global relationships for these systems and those reported previously, when the two components were combined as a self-emulsifying system, by the application of perceptual mapping. It was found that, there were relationships between the size range, expressed as the IQR and the fluid level required to make pellets; the quantity of the non-aqueous component of the fluid and the pellet shape factor; the extrusion force and the tensile strength of the pellets and the yield in the modal fraction and the ratio of the non-aqueous to aqueous content of the fluid used to prepare the pellets. The ability to use the materials independently offers further alternatives for the formulation of water insoluble drugs into pellet formulations.
Asunto(s)
Diglicéridos/química , Excipientes/química , Glicéridos/química , Tensoactivos/química , Biofarmacia , Fenómenos Químicos , Química Farmacéutica , Química Física , Formas de Dosificación , Composición de Medicamentos , Diseño de Fármacos , Excipientes/clasificación , Dureza , Microscopía Electrónica de Rastreo , Modelos Estadísticos , Peso Molecular , Tamaño de la Partícula , Polisorbatos , Análisis de Regresión , Tensoactivos/clasificación , Resistencia a la TracciónRESUMEN
This study assessed the effect of excipients (sodium taurocholate, 2-hydroxypropyl-f-cyclodextrin, potassium chloride, propylene glycol, 1-methyl-2-pyrrolidone, and polyethylene glycol 400) on the apparent intrinsic solubility properties of eight sparingly soluble drugs (four bases, two neutrals, and two acids): astemizole, butacaine, clotrimazole, dipyridamole, griseofulvin, progesterone, glibenclamide, and mefenemic acid. Over 1,200 UV-based solubility measurements (pH 3-10) were made with a high-throughput instrument. New equations, based on the "shift-in-pKa" method, were derived to interpret the complicated solubility-pH dependence observed, and poorly predicted by the Henderson-Hasselbalch equation. An intrinsic solubility-excipient classification gradient map visualization tool was developed to rank order the compounds and the excipients. In excipient-free solutions, all of the ionizable compounds formed either uncharged or mixed-charge aggregates. Mefenamic acid formed anionic dimers and trimers. Glibenclamide displayed a tendency to form monoanionic dimers. Dipyridamole and butacaine tended to form uncharged aggregates. With strong excipients, the tendency to form aggregates diminished, except in the case of glibenclamide. We conclude that a low-cost, compound-sparing, and reasonably accurate high-throughput assay which can be used in early screening to prioritize candidate molecules by their eventual developability via the excipient route is possible with the aid of the "self-organized" intrinsic solubility-excipient classification gradient maps.
Asunto(s)
Excipientes/química , Excipientes/clasificación , Preparaciones Farmacéuticas/química , Algoritmos , Concentración de Iones de Hidrógeno , Cinética , Estructura Molecular , SolubilidadRESUMEN
In 1996, Bolhuis and Chowhan compiled a review of excipients that were used for the direct compaction of tablets. This article updates that review because since that time there has been considerable activity in this area. New single component and coprocessed filler-binders have been introduced. In addition, there have been advances in the understanding of how such substances act and hence how they can be optimally designed.
Asunto(s)
Composición de Medicamentos , Excipientes/química , Compuestos de Calcio/química , Celulosa/química , Química Farmacéutica , Excipientes/clasificación , Lactosa/química , Oligosacáridos/química , Polímeros/química , Polvos , Almidón/químicaRESUMEN
The aims of this study are (1) to compare the disintegration efficiency, and (2) to develop a discriminating test model for the 3 classes of superdisintegrants represented by Ac-Di-Sol, Primojel, and Polyplasdone XL10. Using a digital video camera to examine the disintegration process of tablets containing the same wt/wt percentage concentration of the disintegrants, Ac-Di-Sol was found to disintegrate tablets rapidly into apparently primary particles; Primojel also apparently disintegrated tablets into primary particles but more slowly; Polyplasdone XL10 disintegrated tablets rapidly but into larger masses of aggregated particles. The differences in the size distribution generated in the disintegrated tablets likely contribute to the drug dissolution rate differences found for aspirin tablets with similar disintegration rates. The aspirin tablet matrix is proposed as a model formulation for disintegrant efficiency comparison and performance consistency testing for quality control purposes.
Asunto(s)
Aspirina/farmacocinética , Excipientes/clasificación , Excipientes/farmacocinética , Aspirina/química , Excipientes/química , SolubilidadRESUMEN
Rasburicase (Fasturtec/Elitek) is a new generation of recombinant urate oxidase administred therapeutically by intravenous infusion for the prevention or treatment of hyperuricemia during chemotherapy. To ensure a long storage period, a freeze-dried formulation was developed to guarantee the molecular integrity and enzyme activity. Screening of potential excipients was the first stage of the preformulation study. The selection was based on stability results (rasburicase solution with excipient) obtained with the isoelectric focusing profiles and residual enzyme activity. The different excipients were classified as stabilising, neutral or destabilising. A stability study was then carried out on different freeze-dried formulations containing the usual bulking agents for freeze-drying, excipients with a high glass transition temperature or competitive enzyme inhibitors having a stabilising effect. A mannitol/alanine mixture in phosphate buffer was selected from these preliminary results. Finally, the optimal content of mannitol and alanine in the freeze-dried powder was determined by an experimental design study. The water content and the appearance of the "cake", the osmolality, pH, clarity, and enzyme activity of the reconstituted solution were assessed. The formula with a mannitol/alanine ratio of 0.7 was found to be the best composition. Differential scanning calorimetry and ThermoStimulated Current technique experiments were carried out to study the amorphous phase. A glass transition temperature of about 45-500 degrees C was found. Glassy state is known to preserve stability, which was verified by the real stability data. X-ray diffraction studies have shown that alanine is in a crystallised state and that mannitol remains amorphous. Crystallised excipients participate in forming the structure of the powder and therefore help to prevent any collapse. Amorphous mannitol creates a surrounding medium favourable to the stability of the protein.
Asunto(s)
Química Farmacéutica/métodos , Química Física/métodos , Estabilidad de Medicamentos , Infusiones Intravenosas , Urato Oxidasa/uso terapéutico , Alanina/química , Rastreo Diferencial de Calorimetría/métodos , Combinación de Medicamentos , Incompatibilidad de Medicamentos , Almacenaje de Medicamentos/métodos , Estabilidad de Enzimas , Excipientes/química , Excipientes/clasificación , Excipientes/farmacocinética , Liofilización/métodos , Humanos , Hiperuricemia/inducido químicamente , Manitol/química , Soluciones Farmacéuticas/administración & dosificación , Soluciones Farmacéuticas/química , Soluciones Farmacéuticas/uso terapéutico , Polvos , Proteínas Recombinantes/química , Proteínas Recombinantes/genética , Proteínas Recombinantes/uso terapéutico , Temperatura , Urato Oxidasa/efectos adversos , Urato Oxidasa/químicaRESUMEN
Nitrendipine, a dihydropyridine calcium antagonist, was used as a poorly water-soluble model drug. To improve its dissolution rate and extend the therapeutic period in vivo as well, a novel pH-dependent gradient-release drug delivery system for nitrendipine having a solid dispersed matrix structure was developed. Four factors, i.e. the amount of excipients, the pH of the dissolution medium, the rotating speed of the paddle of the dissolution apparatus and the particle size of the microspheres, all of which affect the drug-release behavior of the pH-dependent microspheres of the system were investigated in detail. The release profiles of the pH-dependent drug delivery system under simulated gastrointestinal tract pH conditions were also investigated. The results showed that the release rate of drug from the microspheres increased on increasing the amount of respective pH-dependent polymers formulated. Due to the fact that the active drug was incorporated in pH-dependent polymers and was present in a solid dispersion state in the microspheres, the release rate of the drug from the microspheres depended on the dissolution rate of the polymers, which was mainly influenced by the pH of dissolution medium, whereas the rotating speed of the paddle and the particle size of the microspheres had only a relatively minor effect. The release behavior of the system under simulated gastrointestinal tract conditions exhibited obvious gradient-release characteristics, showing that the release rate of the active drug could be controlled efficiently before the microspheres reached the appropriate region of the gut for absorption. These findings suggest that the pH-dependent drug delivery system could be fabricated by using present microspheres.