Microencapsulação de enterocina e oleo de oregano em leitelho / Microencapsulation of the enterocin and essential oil oregano in buttermilk / Microencapsulación de enterocina y aceite esencial de orégano en suero de leche

A pesquisa busca técnicas alternativas para expansão da vida de prateleira dos alimentos, isto tem impulsionado estudos sobre a utilização de conservantes naturais, tais como as bacteriocinas e óleos essenciais, que são considerados agentes antimicrobianos naturais. No entanto estes antimicrobianos naturais, não são adicionados diretamente em produtos alimentícios, devido a alterações sensoriais e em suas características físico e química. Com avanço tecnológico da microencapsulação, tem sido um potencial em fornecer sistemas que garantem estabilidade para os antimicrobianos naturais desta forma podendo compor a matriz de alimentos. Portanto, o objetivo desse trabalho foi microencapsular a enterocina produzida por Enterococcus durans MF5 e óleo de orégano usando leitelho. Para a microencapsulação, foram realizados três tratamentos: T1 controle leitelho, T2 leitelho/enterocina (LE), e T3 leitelho/enterocina/óleo (LEO). O material foi submetido ao processo de spray dryer e foram realizados ensaios para determinar a atividade antimicrobiana do material encapsulado contra as bactérias Listeria monocytogenes, Listeria innocua e Listeria ivanovi. O rendimento da microencapsulação foi de 13,01% e 11,63% para LE e LEO, respectivamente. Os resultados apresentados nos microencapsulados LE e LEO mostraram inibição contra todas as bactérias teste, foi constatado que a microencapsulação de enterocina e óleo de orégano mantiveram seu poder antimicrobiano. A efetividade da microencapsulação foi realizada por (FTIR), onde picos de intensidade entre as amostras na região 1000 a 930 cm-¹ e 1800 a 1500 cm-¹ foram observadas. Os resultados apontam para mudança no perfil químico das amostras encapsuladas, corroborando com a hipótese que o leitelho apresentou papel encapsulante da bactericiona e óleo de orégano.Portanto a microencapsulação aumenta a eficácia antimicrobiana dos antimicrobianos.

The research seeks alternative techniques for expanding the shelf life of foods, this has driven studies on the use of natural preservatives, such as bacteriocins and essential oils, which are considered natural antimicrobial agents. However, these natural antimicrobials are not directly added to food products due to sensory changes and their physical and chemical characteristics. With technological advancement of microencap- sulation, it has been a potential to provide systems that ensure stability for natural anti- microbials in this way can compose the food matrix. Therefore, this study has an objective microencapsulated the interocin and essencial oil, used buttermilk as a encapsulating ma- terial where, T1 Buttermilk Control, T2 buttermilk/enterocin (LE), e T3 Buttermilk/en- terocin/oil (LEO). The product has been submitted to spray drier process, were conducted trials to determine antimicrobial activity. Was observed with mass yield 13,01% e 11,63% para LE e LEO. These results the microencapsulate indicate then LE e LEO there was inihibiton against bacteria tests. Was observed that the microencapsulated between enter- ocin and essential oil oregano maintained antimicrobial power. The effectiveness of the microencapsulated was performed by Fourier transform infrared (FTIR) analysis, where a sample in the region 1000 to 930 cm-¹ and 1800 to 1500 cm-¹ was observed. Therefore microencapsulation increases antimicrobial efficacy of antimicrobials.

La investigación busca técnicas alternativas para ampliar la vida útil de los alimentos, esto ha impulsado estudios sobre el uso de conservantes naturales, como las bacteriocinas y los aceites esenciales, que se consideran agentes antimicrobianos naturales. Sin embargo, estos antimicrobianos naturales no se añaden directamente a los productos alimentarios debido a los cambios sensoriales y a sus características físicas y químicas. Con el avance tecnológico de la microencapsulación, ha sido un potencial para proporcionar sistemas que garanticen la estabilidad de los antimicrobianos naturales de esta manera puede componer la matriz alimentaria. Por lo tanto, este estudio tiene como objetivo microencapsular la interocina y el aceite esencial, utilizando suero de leche como material encapsulante donde, T1 Suero de leche Control, T2 Suero de leche/enterocina (LE), e T3 Suero de leche/enterocina/aceite (LEO). El producto ha sido sometido al proceso de secado por pulverización, se realizaron ensayos para determinar la actividad antimicrobiana. Se observó con rendimiento de masa 13,01% e 11,63% para LE e LEO. Estos resultados indican que el microencapsulado LE e LEO fue inhibido contra las pruebas bacterianas. Se observó que el microencapsulado entre enterocina y aceite esencial de orégano mantuvo el poder antimicrobiano. La eficacia del microencapsulado fue realizada por análisis de infrarrojo transformado de Fourier (FTIR), donde fue observada una muestra en la región de 1000 a 930 cm-¹ y de 1800 a 1500 cm-¹. Por lo tanto, la microencapsulación aumenta la eficacia antimicrobiana de los antimicrobianos. PALABRAS CLAVE: Bacteriocina; Enterococcus durans; Suero de Leche; Origanum vulgare; Spray Dryer.

Microencapsulação de enterocina e oleo de oregano em leitelho / Microencapsulation of the enterocin and essential oil oregano in buttermilk / Microencapsulación de enterocina y aceite esencial de orégano en suero de leche

A pesquisa busca técnicas alternativas para expansão da vida de prateleira dos alimentos, isto tem impulsionado estudos sobre a utilização de conservantes naturais, tais como as bacteriocinas e óleos essenciais, que são considerados agentes antimicrobianos naturais. No entanto estes antimicrobianos naturais, não são adicionados diretamente em produtos alimentícios, devido a alterações sensoriais e em suas características físico e química. Com avanço tecnológico da microencapsulação, tem sido um potencial em fornecer sistemas que garantem estabilidade para os antimicrobianos naturais desta forma podendo compor a matriz de alimentos. Portanto, o objetivo desse trabalho foi microencapsular a enterocina produzida por Enterococcus durans MF5 e óleo de orégano usando leitelho. Para a microencapsulação, foram realizados três tratamentos: T1 controle leitelho, T2 leitelho/enterocina (LE), e T3 leitelho/enterocina/óleo (LEO). O material foi submetido ao processo de spray dryer e foram realizados ensaios para determinar a atividade antimicrobiana do material encapsulado contra as bactérias Listeria monocytogenes, Listeria innocua e Listeria ivanovi. O rendimento da microencapsulação foi de 13,01% e 11,63% para LE e LEO, respectivamente. Os resultados apresentados nos microencapsulados LE e LEO mostraram inibição contra todas as bactérias teste, foi constatado que a microencapsulação de enterocina e óleo de orégano mantiveram seu poder antimicrobiano. A efetividade da microencapsulação foi realizada por (FTIR), onde picos de intensidade entre as amostras na região 1000 a 930 cm-¹ e 1800 a 1500 cm-¹ foram observadas. Os resultados apontam para mudança no perfil químico das amostras encapsuladas, corroborando com a hipótese que o leitelho apresentou papel encapsulante da bactericiona e óleo de orégano.Portanto a microencapsulação aumenta a eficácia antimicrobiana dos antimicrobianos.

The research seeks alternative techniques for expanding the shelf life of foods, this has driven studies on the use of natural preservatives, such as bacteriocins and essential oils, which are considered natural antimicrobial agents. However, these natural antimicrobials are not directly added to food products due to sensory changes and their physical and chemical characteristics. With technological advancement of microencap- sulation, it has been a potential to provide systems that ensure stability for natural anti- microbials in this way can compose the food matrix. Therefore, this study has an objective microencapsulated the interocin and essencial oil, used buttermilk as a encapsulating ma- terial where, T1 Buttermilk Control, T2 buttermilk/enterocin (LE), e T3 Buttermilk/en- terocin/oil (LEO). The product has been submitted to spray drier process, were conducted trials to determine antimicrobial activity. Was observed with mass yield 13,01% e 11,63% para LE e LEO. These results the microencapsulate indicate then LE e LEO there was inihibiton against bacteria tests. Was observed that the microencapsulated between enter- ocin and essential oil oregano maintained antimicrobial power. The effectiveness of the microencapsulated was performed by Fourier transform infrared (FTIR) analysis, where a sample in the region 1000 to 930 cm-¹ and 1800 to 1500 cm-¹ was observed. Therefore microencapsulation increases antimicrobial efficacy of antimicrobials.

La investigación busca técnicas alternativas para ampliar la vida útil de los alimentos, esto ha impulsado estudios sobre el uso de conservantes naturales, como las bacteriocinas y los aceites esenciales, que se consideran agentes antimicrobianos naturales. Sin embargo, estos antimicrobianos naturales no se añaden directamente a los productos alimentarios debido a los cambios sensoriales y a sus características físicas y químicas. Con el avance tecnológico de la microencapsulación, ha sido un potencial para proporcionar sistemas que garanticen la estabilidad de los antimicrobianos naturales de esta manera puede componer la matriz alimentaria. Por lo tanto, este estudio tiene como objetivo microencapsular la interocina y el aceite esencial, utilizando suero de leche como material encapsulante donde, T1 Suero de leche Control, T2 Suero de leche/enterocina (LE), e T3 Suero de leche/enterocina/aceite (LEO). El producto ha sido sometido al proceso de secado por pulverización, se realizaron ensayos para determinar la actividad antimicrobiana. Se observó con rendimiento de masa 13,01% e 11,63% para LE e LEO. Estos resultados indican que el microencapsulado LE e LEO fue inhibido contra las pruebas bacterianas. Se observó que el microencapsulado entre enterocina y aceite esencial de orégano mantuvo el poder antimicrobiano. La eficacia del microencapsulado fue realizada por análisis de infrarrojo transformado de Fourier (FTIR), donde fue observada una muestra en la región de 1000 a 930 cm-¹ y de 1800 a 1500 cm-¹. Por lo tanto, la microencapsulación aumenta la eficacia antimicrobiana de los antimicrobianos. PALABRAS CLAVE: Bacteriocina; Enterococcus durans; Suero de Leche; Origanum vulgare; Spray Dryer.

Manufacturing classification system for oral solid dosage forms of traditional Chinese medicines (Ⅱ): classification of tablets disintegration behavior / 中国中药杂志

In this paper, 50 batches of representative traditional Chinese medicine tablets were selected and the disintegration time was examined with the method in Chinese Pharmacopoeia. The disintegration time and disintegration phenomenon were recorded, and the dissolution behaviors of water-soluble and ultraviolet-absorbent components during the disintegration process of tablets were characterized by self-control method. The results revealed that coating type and raw material type influenced the disintegration time of tablets. It was found that only 4% of traditional Chinese medicine tablets had obvious fragmentation during the disintegration process, while 96% of traditional Chinese medicine tablets showed gradual dissolution or dispersion. Furthermore, according to the disintegration speed, disintegration phenomenon, and whether the cumulative dissolution of measured components was > 90% at complete disintegration, a disintegration behavior classification system(DBCS) was created for the regular-release traditional Chinese medicine tablets. As a result, the disintegration behaviors of 50 batches of traditional Chinese medicine tablets were classified into four categories, i.e. ⅠA_2, ⅠB_1, ⅡB_1, and ⅡB_2. traditional Chinese medicine tablets(Class I) with disintegration time ≤ 30 min were defined to be rapid in disintegration, which can be the objective of optimization or improvement of Chinese herbal extract(semi extract) tablets. Different drug release models were used to fit the dissolution curve of traditional Chinese medicine tablets with gradual dissolution or dispersion phenomenon(i.e. Type B tablets). The results showed that the dissolution curves of water-soluble components in the disintegration process conformed to the zero order kinetics and the Ritger-Peppas model. It could be inferred that the disintegration mechanisms of type B tablets were a combination of dissolution controlled and swelling controlled mechanisms. This study contributes to understanding the disintegration behavior of traditional Chinese medicine tablets, and provides a reference for the design and improvement of disintegration performance of traditional Chinese medicine tablets.

Development of microparticles and microparticulated tablets containing piperine

Abstract Piper nigrum (black pepper) is used in Indian traditional medicine and its main alkaloid, Piperine (PIP), presents antioxidant, antitumor and neuroprotective pharmacological properties. This substance is insoluble in aqueous media and can irritate the gastrointestinal tract. Aiming to avoid these inconvenient characteristics and enable PIP oral administration, this study suggested the PIP microencapsulation through the emulsion-solvent evaporation method and the preparation of microparticulated tablets by direct compression. An UV-spectroscopy method was validated to quantify PIP. Microparticles and microparticulated tablets were successfully obtained and the microparticles exhibited excellent flow. The scanning electron microscopy images showed that PIP microparticles were intact after compression. The in vitro release showed a controlled release of PIP from microparticles and PIP microparticles from tablets in comparison to PIP and PIP tablets. The release profiles of PIP microparticles and the microparticulated tablets were similar. Therefore, tablets containing PIP microparticles are promising multiparticulated dosage forms because a tablet allows microparticles administration and the intact ones promote a controlled release, decreasing its irritating potential on the mucosa.

Development of a validated stability-indicating HPLC- DAD method for dasabuvir and the characterization of its degradation products using LC-QToF-MS/MS

Abstract A stability-indicating HPLC-DAD method was developed and validated for the simultaneous determination of dasabuvir and its degradation products in the pharmaceutical formulation. The proposed method utilized a Symmetry® C18 (4.6 x 75 mm, 3.5 µm) column, and the mobile phase consisted of an isocratic elution of formic acid (0.1%) and acetonitrile (55:45, v/v), at a flow of 1 mL min-1; analytes were detected at 244 nm. Dasabuvir was submitted to different stress degradation conditions, such as acidic, alkaline, neutral, thermal, oxidative and photolytic, and the structural elucidation of degradation products was performed using LC-QToF-MS/MS. The HPLC-DAD stability-indicating method was validated for selectivity, linearity, limit of detection and quantification, accuracy, precision and robustness, according to ICH guidelines. Dasabuvir produced two degradation products (DP1 and DP2) from the alkaline stress conditions, which were characterized in negative ion mode. Dasabuvir was linear in the range 9.78 to 136.92 µg mL-1, and DP and DP were linear in the range 2.9 to 20.2 µg mL-1 and 1.3 to 14.9 µg mL-1, respectively. The 1 2 recovery ranged between 99.16 and 100.86%, while precision ranged from 1.02 to 2.89%. As the method can effectively separate the dasabuvir from its degradation products and quantitate them, it may be employed as a stability-indicating method for the pharmaceutical formulation.

Assessment of cytotoxicity, genotoxicity, and mutagenicity of the dexchlorpheniramine reference standard and pharmaceutical formula in human peripheral blood mononuclear cells

Abstract Dexchlorpheniramine is a first-generation classical antihistamine, clinically used to treat allergies. The main objective of our study was to evaluate the effects of the dexchlorpheniramine reference standard (DCPA Ref. St) and a pharmaceutical formula on DNA in human peripheral blood mononuclear cells (PBMCs). We exposed PBMCs to five different concentrations (0.5, 2.5, 5, 10, and 50 ng/mL) of DCPA Ref. St DCPA Ref. St and pharmaceutical formula in order to evaluate their cytotoxic, genotoxic, and mutagenic potential. The results showed that both dexchlorpheniramine formulations did not affect PBMC viability and CD3+, CD4+, or CD8+ lymphocyte subpopulations. The DCPA Ref. St and pharmaceutical formula neither induced genotoxic or mutagenic effects nor numerical or structural chromosomal alterations in PBMCs after 24 hours of exposure.

Sustained release matrix tablet of 100 mg losartan potassium: Formulation development and in vitro characterization

Abstract Sustained release matrix tablets of 100 mg losartan potassium HCl were fabricated with two release retarding polymers namely HPMC K100 M and affinisol by direct compression method. Nine trial formulations were prepared by varying content of these polymers, each from 50 mg to 100 mg; keeping the total weight of the tablet 310 mg. The best formulation was selected based on in vitro drug release profile for 12 hours conducted in Type II dissolution apparatus at 50 rpm and water as dissolution medium. Pre-compression parameters such as bulk density, tap density, Carr's index and Hausner ratio were evaluated for the selected tablet. The tablets were subjected to thickness, weight variation test, drug content, hardness and friability. Drug release kinetics, surface morphology and accelerated stability study were investigated for that selected formulation. Formulation F4 with the composition of 75 mg HPMC K100M and 100 mg affinisol was selected as the best formulation that extended the drug release up to 12 hours. Pre-compression parameters and other tableting properties were within the Pharmacopoeia limit. Release kinetics analysis proved non-fickian zero-order drug release and that was further confirmed by surface morphology of the tablets before and after dissolution study visualized by SEM. The developed formulation was found to be stable for one month stored at 60 ○C.

Volume residual de frascos-ampola e subdosagens de medicamentos preparados pela equipe de enfermagem / Residual volume of ampoule-vials and underdosing of medications prepared by a nursing staff / Volumen residual de frascos ampolla y subdosificación de medicamentos preparados por el equipo de enfermería

RESUMO Objetivo: Identificar o volume residual em frascos-ampola, após o preparo de injetáveis, associando os erros relacionados a subdoses com as classes dos medicamentos. Método: Estudo descritivo, de abordagem quantitativa. Os dados foram coletados no período de dezembro de 2020 a setembro de 2021, em um serviço ambulatorial privado de um município brasileiro localizado a nordeste do Estado de São Paulo. Foram analisados 562 frascos-ampola de medicamentos preparados pela equipe de enfermagem. Utilizou-se formulário contendo o nome comercial do medicamento, classe/indicação terapêutica, data e horário de reconstituição, volume utilizado para reconstituição do medicamento e volume residual de cada frasco. Os dados foram tabulados e analisados por estatística descritiva e teste ANOVA. Resultados: 462 (82,2%) frascos-ampola continham volume residual que variou de 0,1 ml a 1,5 ml e 165 (29,4%) continham 0,2 ml de solução residual, com perda média de 4,5% da solução. Não houve diferença na perda de solução entre as diferentes classes de medicamentos. Conclusão: Os achados destacam a necessidade de intervenções para a redução de falhas, nas fases de preparo dos medicamentos, com ênfase nos erros associados às subdosagens terapêuticas.

ABSTRACT Objective: Identify the residual volume in ampoule-vials after the preparation of injectables, associating the errors related to underdosing with the classes of drugs. Method: This is a descriptive study with a quantitative approach. Data were collected between December 2020 and September 2021, in a private outpatient service located in a Brazilian municipality in the northeast of the state of São Paulo. A total of 562 ampoule-vials of medications prepared by a nursing staff were analyzed. A form was used containing the commercial name of the medication, therapeutic class/indication, reconstitution date and time, volume used to reconstitute the medication and residual volume of each vial. The data were tabulated and analyzed using descriptive statistics and the ANOVA test. Results: the residual volume of 462 (82.2%) ampoule-vials varied between 0.1 ml and 1.5 ml, whereas 165 (29.4%) ampoule-vials had 0.2 ml of residual volume, with a mean loss of 4.5% of the solution. There was no difference in the loss of solution between the different classes of drugs. Conclusion: The findings highlight the need for interventions to reduce failures in the medication preparation phases, with emphasis on errors associated with therapeutic underdosing.

RESUMEN Objetivo: Identificar volúmenes residuales en frascos ampolla luego de prepararse inyectables, asociando los errores relacionados a subdosificaciones con las clases de los medicamentos. Método: Estudio descriptivo, de abordaje cuantitativo. Datos recolectados entre diciembre de 2020 y setiembre de 2021 en servicio ambulatorio privado de un municipio brasileño del noreste del Estado de São Paulo. Fueron analizados 562 frascos ampolla de medicamentos preparados por el equipo de enfermería. Se utilizó formulario, consignando nombre comercial del medicamento, clase/indicación terapéutica, fecha y hora de reconstitución, volumen utilizado para reconstituir el medicamento y volumen residual de cada frasco. Los datos fueron tabulados y analizados por estadística descriptiva y test ANOVA. Resultados: 462 (82,2%) frascos ampolla contenían volumen residual de entre 0,1 ml y 1,5 ml, y 165 (29,4%) contenían 0,2 ml de solución residual, con una pérdida media del 4,5% de solución. No se observó diferencia de pérdida de solución entre las diferentes clases de medicamentos. Conclusión: Los hallazgos destacan la necesidad de intervenciones para reducir fallos en las fases de preparación de medicamentos, haciendo énfasis en los errores asociados con subdosificaciones terapéuticas.

Formulation, Optimization, in vitro and in-vivo evaluation of levofloxacin hemihydrate Floating Tablets

Abstract The objective of the present investigation was to design, optimize and characterize the gastro retentive floating levofloxacin tablets and perform in-vivo evaluation using radiographic imaging. The floating tablets were prepared by using polymers i.e hydroxy propyl methyl cellulose (HPMC-K4M) and carbopol-940 individually and in combination by nonaquous granulation method. All the Formulations were evaluated for swelling index (S.I), floating behavior and in-vitro drug release kinetics. The compatibility study of levofloxacin with other polymers was investigated by FTIR, DSC, TGA and XRD. Results from FTIR and DSC revealed no chemical interaction amongst the formulation components. The optimized formulation (F11) showed floating lag time (FLT), total floating time (TFT) swelling index (S.I) of 60 sec, >16h and approximately 75 %, respectively. Moreover, F11 showed zero order levofloxacin release in simulated gastric fluid over the period of 6 h. X-ray studies showed that total buoyancy time was able to delay the gastric emptying of levofloxacin floating tablets in rabbits for more than 4 hours. In conclusion the optimized formulation (F11) can be used for the sustained delivery of levofloxacin for the treatment of peptic ulcer.

Novel biopharmaceutical development investigations towards drug and formulation performance optimization

For a drug to excerpt pharmacological action after oral intake, it first needs to be released from the formulation, get into solution (dissolve), be absorbed, and reach the systemic circulation. Since only solubilized drugs can be absorbed, and thus have therapeutic effect, the understanding of the dissolution and drug release processes of a drug product is of primary importance. Such understanding allows a robust formulation development with an ideal in vivo performance. In order to meet set standards, the performance assessment of oral drug products, such as dissolution testing, often applies conditions that are not reflective of the in vivo environment. The use of non-physiologically relevant dissolution method during the drug product development phase can be misleading and give poor mechanistic understanding of the in vivo dissolution process. Hence, we hypothesized that applying physiologically relevant conditions to the dissolution test would result in more accurate in vivo predictability for a robust and precise development process. Since the buffering system in the intestinal lumen operates at low molarity values, phosphate buffer at low buffer capacity was used as a first approach to an in vivo relevant parameter. Furthermore, a biphasic system was used, that is, the low buffer capacity medium was paired with an organic layer (n-octanol) to mimic the concurrent drug absorption that happens with the in vivo dissolution. Both poorly and highly soluble drugs in immediate release formulations (ibuprofen and metronidazole, respectively) were tested in this set-up to assess the dissolution in the aqueous medium and the partitioning to the organic phase. Additionally, enteric coated formulations were tested in bicarbonate buffer at the in vivo reported molarities values to assess the impact of buffer species on drug dissolution. The evaluated parameters were the buffer system (bicarbonate buffer vs. phosphate buffer), buffer capacity and medium pH. In all approaches, dissolution was also carried out in compendial buffer for comparison purposes. Our results demonstrate that the USP-recommended dissolution method greatly lacked discriminatory power, whereas low buffer capacity media discriminated between manufacturing methods. The use of an absorptive phase in the biphasic dissolution test assisted in controlling the medium pH due to the drug removal from the aqueous medium. Hence, the applied noncompendial methods were more discriminative to drug formulation differences and manufacturing methods than conventional dissolution conditions. In this study, it was demonstrated how biphasic dissolution and a low buffer capacity can be used to assess drug product performance differences. This can be a valuable approach during the early stages of drug product development for investigating drug release with improved physiological relevance. Similarly, all the enteric coated formulations displayed a fast release in phosphate buffer and complied with the compendial performance specifications. On the other hand, they all had a much slower drug release in bicarbonate buffer and failed the USP acceptance criteria. Also, the nature of the drug (acid vs base) impacted the dissolution behavior in bicarbonate buffer. This study indicates that compendial dissolution test for enteric coated tablets lacks physiological relevance and it needs to be reevaluated. Thus, an in vivo relevant performance method for EC products is needed. Overall, the findings of this thesis comprehensively demonstrates that meaningful differences in performance and accordance to clinical reports were only obtained when physiological relevant conditions were applied. Hence, our results indicate that the central hypothesis was answered positively

Para que um medicamento exerça a ação farmacológica após a ingestão oral, ele primeiro precisa ser liberado da formulação, dissolver, ser absorvido e atingir a circulação sistêmica. Uma vez que apenas medicamentos solubilizados podem ser absorvidos e, assim, ter efeito terapêutico, a compreensão dos processos de dissolução e liberação de um medicamento é de extrema importância. Tal compreensão permite o desenvolvimento de uma formulação robusta com o desempenho in vivo ideal. Para atender aos padrões regulatórios previamente estabelecidos, a avaliação da performance de formulações orais, como por exemplo, o teste de dissolução, frequentemente aplica condições que não refletem o ambiente fisiológico. O uso de métodos de dissolução não fisiologicamente relevante durante a fase de desenvolvimento do medicamento pode gerar resultados equivocados sem uma compreensão mecanistica do processo de dissolução in vivo. Portanto, a hipótese desse trabalho é que a aplicação de condições fisiologicamente relevantes no teste de dissolução resultaria em uma predição mais precisa da dissolução in vivo para um processo de desenvolvimento robusto e preciso. Uma vez que o sistema tampão no lúmen intestinal possui baixa molaridade, o tampão fosfato com baixa capacidade tamponante foi usado como uma primeira abordagem como um meio de dissolução fisiologicamente relevante. Além disso, foi utilizado um sistema bifásico, ou seja, o meio de baixa capacidade tamponante combinado a uma fase orgânica (n-octanol) para imitar a absorção in vivo. Formulações de liberação imediata contendo fármacos de baixa e de alta solubilidade (ibuprofeno e metronidazol, respectivamente) foram testadas no sistema bifásico para avaliar a dissolução no meio aquoso e a partição para a fase orgânica. Ademais, formulações com revestimento entérico foram testadas em tampão bicarbonato nos valores de molaridades fisiológicos para avaliar o impacto da espécie tamponante na dissolução do fármaco. Os parâmetros avaliados foram o sistema tampão (tampão bicarbonato vs. tampão fosfato), capacidade tamponante e pH médio. Em todas as abordagens, a dissolução também foi realizada em tampão farmacopeico para fins de comparação. Nossos resultados demonstraram que o método de dissolução farmacopeico não foi discriminativo, enquanto o meio com menor capacidade tamponante diferenciou entre as formulações obtidas via granulação úmida ou compressão direta. Ademais, a utilização da fase orgânica no teste de dissolução bifásica auxiliou no controle do pH do meio aquoso. Portanto, os métodos não compendiais aplicados foram mais discriminativos do que as condições de dissolução convencionais. Neste estudo, foi demonstrado como a dissolução bifásica e uma baixa capacidade tamponante podem ser usadas para avaliar as diferenças na performance de formulações. Esta pode ser uma abordagem valiosa durante os estágios iniciais do desenvolvimento de medicamentos para investigar a liberação destes sob condições fisiologicamente relevantes. Da mesma forma, todas as formulações com revestimento entérico exibiram uma liberação rápida em tampão de fosfato e atenderam às especificações farmacopeicas. Entretanto, a liberação do fármaco foi muito mais lenta em tampão de bicarbonato e consequentemente não cumpriram com as especificações farmacopeicas. Além disso, a natureza do fármaco (ácido vs. base) impactou o comportamento de dissolução no tampão de bicarbonato. Este estudo indica que o teste de dissolução convencional para comprimidos de liberação retardada não possui relevância fisiológica e precisa ser reavaliado. Portanto, os resultados desta tese demonstram de forma abrangente que diferenças significativas na performance condizentes com relatórios clínicos foram obtidas apenas quando as condições fisiológicas relevantes foram aplicadas. Esses resultados indicam que a hipótese central foi respondida positivamente

Innovative pharmaceutical strategies for niclosamide repositioning / Estratégias farmacêuticas inovadoras para o reposicionamento da niclosamida

The antiparasitic niclosamide has shown promising anticancer activity in preclinical studies against several types of cancer, such as colorectal and prostate. Thus, the objective of this work was to develop innovative formulations for the repositioning of niclosamide as an anticancer agent. In chapter I, a critical review of the literature on the physicochemical properties of the drug was carried out, in addition the results of clinical studies against colorectal and prostate cancer. Besides, a review was carried out on studies that developed formulations containing this drug, as well as hypotheses to improve the biopharmaceutical performance of this molecule. In chapter II, the development of solid amorphous dispersion containing niclosamide was carried out. Drug/polymer solutions were acoustic levitated and characterized by synchrotron X-ray light. This set allowed fast, high quality measurements, as well as the identification of niclosamide recrystallization. Plasdone® and Soluplus® demonstrated better properties to form amorphous dispersions, with the latter showing superior solubility enhancement. The study showed that the developed formulation increased the apparent saturation solubility of niclosamide in water by two times. In chapter III the objective was the development, physicochemical characterization and in vitro anticancer activity of a niclosamide nanoemulsion, having HCT-116 cells as a cellular model. Preliminary results indicated Capmul® MCM C8 as the best liquid lipid for the system, but the first nanoemulsions containing this lipid were not stable to justify its usage. On the other hand, Miglyol® 812 indicated to be a suitable liquid lipid for the system. The niclosamide nanoemulsion (~200 nm) with Miglyol® 812 and poloxamer 188 was stable for 56 days, with a monomodal particle size distribution. Cell viability assay against HCT-116 cells demonstrated that niclosamide cytotoxicity is time and concentration dependent. Results herein obtained encourage further research to understand and optimize niclosamide performance as an anticancer drug substance

O antiparasitário niclosamida tem apresentado promissora atividade anticâncer em estudos pré- clínicos contra diversos tipos de câncer, como coloretal e próstata. Assim, o objetivo deste trabalho foi desenvolver formulações inovadoras para o reposicionamento da niclosamida como agente anticâncer. No capítulo I foi realizada revisão crítica da literatura sobre as propriedades físico-químicas do fármaco, além de resultados de estudos clínicos da niclosamida contra câncer de coloretal e de próstata. Além disso, foi feita revisão sobre estudos que desenvolveram formulações contendo esse fármaco, bem como hipóteses para melhorar o desempenho biofarmacêutico dessa molécula. No capítulo II foi realizado o desenvolvimento de dispersão solida amorfa contendo niclosamida. Soluções de fármaco/polímero foram levitadas em levitador acústico e caracterizadas por raios-X de luz síncrotron. Este conjunto permitiu medições rápidas e de alta qualidade, bem como identificação de recristalização da niclosamida. Plasdone® e Soluplus® demonstraram melhores propriedades para formar as dispersões amorfas, com o último apresentando aumento de solubilidade superior. O estudo mostrou que a formulação desenvolvida aumentou em duas vezes a solubilidade aparente de saturação da niclosamida em água. No capítulo III o objetivo foi o desenvolvimento, a caracterização físicoquímica e atividade anticâncer in vitro de uma nanoemulsão de niclosamida, tendo células HCT-116 como modelo celular. Resultados preliminares indicaram o Capmul® MCM C8 como o melhor lipídio líquido para o sistema, mas as primeiras nanoemulsões contendo este lipídio não foram estáveis para justificar seu uso. Por outro lado, Miglyol® 812 indicou ser um lipídio líquido adequado para o sistema. A nanoemulsão de niclosamida (~200 nm) com Miglyol® 812 e poloxâmero 188 foi estável por 56 dias, com distribuição monomodal do tamanho de partícula. O ensaio de viabilidade celular contra células HCT-116 demonstrou que a citoxicidade da niclosamida é dependente do tempo e da concentração. Os resultados aqui obtidos encorajam mais pesquisas para entender e otimizar o desempenho da niclosamida como uma substância anticancerígena

Co-amorphous technology to improve dissolution and physical stability of silybin / 中国中药杂志

The present study explored the effect of co-amorphous technology in improving the dissolution rate and stability of silybin based on the puerarin-silybin co-amorphous system prepared by the spray-drying method. Solid-state characterization was carried out by powder X-ray diffraction(PXRD), polarizing microscopy(PLM), Fourier transform infrared spectroscopy(FT-IR), differential scanning calorimetry(DSC), etc. Saturated powder dissolution, intrinsic dissolution rate, moisture absorption, and stability were further investigated. The results showed that puerarin and silybin formed a co-amorphous system at a single glass transition temperature which was higher than that of any crude drug. The intrinsic dissolution rate and supersaturated powder dissolution of silybin in the co-amorphous system were higher than those of the crude drug and amorphous system. The co-amorphous system kept stable for as long as three months under the condition of 40 ℃, 75% relative humidity, which was longer than that of the single amorphous silybin. Therefore, the co-amorphous technology could significantly improve the dissolution and stability of silybin.

Voltammetric Determination of Ascorbic Acid in Pharmaceutical Formulations Using Modified Iodine-Coated Platinum Electrode / Determinación voltamétrica del ácido ascórbico en formulaciones farmacéuticas utilizando un electrodo de platino modificado recubierto de yodo

Background: Despite the high reactivity of the platinum electrode, the iodine-coated platinum electrode shows obvious inertness toward adsorption and surface processes. For that, iodine-coated platinum electrodes accommodate themselves to interesting voltammetric applications. Objectives: This study reports using the modified iodine-coated polycrystalline platinum electrode as a voltammetric sensor for ascorbic acid determination in pharmaceutical formulations. Methods: The developed voltammetric method based on recording cyclic voltammograms of ascorbic acid at iodine-coated electrode The optimized experimental parameters for the determination of ascorbic acid were using 0.1 M KCl as a supporting electrolyte with a scan rate of 50mV/s. Results: The anodic peak related to ascorbic acid oxidation was centered at nearly 0.28V. An excellent and extended linear dependence of the oxidative peak current on the concentration of ascorbic acid was observed in the range 2.84x10-3 - 5.68 mM. The limit of detection (LOD) and limit of quantitation (LOQ) were 1.0 µM and 3.01 µM, respectively, attesting to the method's sensitivity. The investigation for the effect of potential interference from multivitamin tablet ingredients (vitamins B1, B6, B12, folic acid, citric acid, sucrose, glucose, and zinc) indicated specific selectivity toward ascorbic acid and the absence of any electrochemical response toward these components. Recovery results in the range 98.93±2.78 - 99.98±5.20 for spiked standard ascorbic acid in pharmaceutical formulations further confirmed the potential applicability of the developed method for the determination of ascorbic acid in real samples. Conclusions: The developed method was successfully applied to the analysis of ascorbic acid (vitamin C), and the obtained results were in good agreement with the labeled values; besides, the statistical tests indicated no significant difference at p=0.05 with a 95% confidence level

Antecedentes: A pesar de su alta reactividad, el electrodo de platino recubierto de yodo muestra una inercia evidente hacia la adsorción y los procesos superficiales. Por ello, los electrodos de platino recubiertos de yodo se adaptan a interesantes aplicaciones voltamétricas. Objetivos: Este estudio informa sobre el uso del electrodo de platino policristalino recubierto de yodo modificado como sensor voltamétrico para la determinación del ácido ascórbico en formulaciones farmacéuticas. Métodos: El método voltamétrico desarrollado se basa en el registro de voltamperogramas cíclicos del ácido ascórbico en el electrodo recubierto de yodo Los parámetros experimentales optimizados para la determinación del ácido ascórbico fueron utilizando KCl 0,1 M como electrolito de soporte con una velocidad de barrido de 50mV/s. Resultados: El pico anódico relacionado con la oxidación del ácido ascórbico se centró en casi 0,28V. Se observó una excelente y extendida dependencia lineal de la corriente del pico oxidativo con respecto a la concentración de ácido ascórbico en el rango 2,84x10-3 - 5,68 mM. El límite de detección (LOD) y el límite de cuantificación (LOQ) fueron 1,0 µM y 3,01 µM, respectivamente, lo que demuestra la sensibilidad del método. La investigación del efecto de la interferencia potencial de los ingredientes de las tabletas multivitamínicas (vitaminas B1, B6, B12, ácido fólico, ácido cítrico, sacarosa, glucosa y zinc) indicó una selectividad específica hacia el ácido ascórbico y la ausencia de cualquier respuesta electroquímica hacia estos componentes. Los resultados de recuperación en el rango de 98,93±2,78 - 99,98±5,20 para el ácido ascórbico estándar adicionado en formulaciones farmacéuticas confirmaron además la potencial aplicabilidad del método desarrollado para la determinación del ácido ascórbico en muestras reales. Conclusiones: El método desarrollado se aplicó con éxito al análisis de ácido ascórbico (vitamina C), y los resultados obtenidos coincidieron con los valores etiquetados; además, las pruebas estadísticas no indicaron diferencias significativas a p=0,05 con un nivel de confianza del 95%

Tratamiento de lesiones apicoperirradiculares con un biomaterial de tercera generación (Licon-D) / Treatment of apicoperiradicular lesions with a third-generation biomaterial (Licon-D)

Biomaterial de tercera generación con una tasa de degradabilidad en la zona perirradicular y del foramen apical, con una velocidad similar a la que emplea el organismo para formar tejido calcificado y sellar biológicamente el extremo apical del diente. Mediante el recurso tecnológico de la microencapsulación se produce la liberación lenta y controlada de Ca2+ retenido en la superficie y en el interior de las microesferas de alginato de calcio, sin que se modifique de manera significativa las propiedades reológicas básicas del biomaterial de obturación de conductos, tales como la compresibilidad, plasticidad, extensibilidad, fluidez, viscosidad cinemática, viscosidad de compresión y endurecimiento por trabajo (AU)

Third-generation biomaterial with a degradability rate in the periradicular area and the apical foramen, with a speed similar to that used by the body to form calcified tissue and biologically seal the apical end of the tooth. Through the technological resource of microencapsulation, the slow and controlled release of Ca2+ retained on the surface and inside the calcium alginate microspheres is produced, without significantly modifying the basic rheological properties of the duct sealing biomaterial, such as compressibility, plasticity, extensibility, flowability, kinematic viscosity, compression viscosity, and work hardening (AU)

Atividades farmacológicas da manteiga de bacuri (Platonia insignis Mart): revisão integrativa / Pharmacological actions of bacuri butter (Platonia insignis Mart): an integrative review

RESUMO Objetivo identificar as atividades farmacológicas da manteiga de bacuri (Platonia insignis Mart.). Métodos revisão integrativa, realizada nas bases de dados Literatura Latino-americana e do Caribe em Ciências da Saúde, Cumulative Index to Nursing and Allied Health Literature, EMBASE, MEDLINE/PubMed, Web of Science, Cochrane Library e SCOPUS, sem delimitação temporal e de idioma. A seleção se constituiu de 13 ensaios pré-clínicos. A avaliação das informações ocorreu de forma descritiva, confrontando com os achados pertinentes. Resultados observou-se que 50,0% das publicações foram indexadas na MEDLINE/PubMed, maioria das publicações ocorreram na Inglaterra (61,5%), seguidas do Brasil e dos Estados Unidos, ambos com 13,3%. Destaca-se que 100,0% dos artigos foram ensaios pré-clínicos; atividades farmacológicas para antioxidante (38,4%) e antileishmanicidas (30,7%). Registrou-se que 38,4% dos ensaios apresentaram testes de toxicidade. Conclusão a manteiga de bacuri (Platonia insignis Mart.) apresentou atividades farmacológicas em ensaios pré-clínicos, como antioxidantes, antileshimaniose, anticonvulsivante e cicatrização de feridas.

ABSTRACT Objective to identify the pharmacological activities of bacuri butter (Platonia insignis Mart.). Methods an integrative review, carried out in the databases of Latin American and Caribbean Literature in Health Sciences, Cumulative Index to Nursing and Allied Health Literature, EMBASE, MEDLINE/PubMed, Web of Science, Cochrane Library and SCOPUS, without the time and language restriction. The selection consisted of 13 pre-clinical trials. The information assessment descriptively took place, comparing with the pertinent findings. Results it was observed that 50.0% of the publications were indexed in MEDLINE/PubMed, most publications were from England (61.5%), followed by Brazil and the United States, both with 13.3%. It is noteworthy that 100.0% of the articles were pre-clinical trials; pharmacological activities for antioxidants (38.4%) and antileishmanicides (30.7%). It was found that 38.4% of the trials presented toxicity tests. Conclusion bacuri butter (Platonia insignis Mart.) Showed pharmacological activities in pre-clinical trials, such as antioxidants, antileshimaniasis, anticonvulsant and wound healing.

Advances of enzymes in the applications of disease treatment and drug preparation / 生物工程学报

The development of biotechnology and the in-depth research on disease mechanisms have led to increased application of enzymes in the treatment of diseases. In addition, enzymes have shown great potential in drug manufacturing, particularly in production of non-natural organic compounds, due to the advantages of mild reaction conditions, high catalytic efficiency, high specificity, high selectivity and few side reactions. Moreover, the application of genetic engineering, chemical modification of enzymes and immobilization technologies have further improved the function of enzymes. This review summarized the advances of using enzymes as drugs for disease treatment or as catalysts for drug manufacturing, followed by discussing challenges, potential solutions and future perspectives on the application of enzymes in the medical and pharmaceutical field.

Study on effect of SuperTab 40LL on compression characteristics of musk sustained-release mini-tablets based on mathematical models / 中国中药杂志

In this paper, co-processed lactose SuperTab 40 LL was selected as fillers to study the preparation of musk sustained-release mini-tablets in the Xihuang multiple-unit drug release system. Musk sustained-release tablets containing different proportions of SuperTab 40 LL and MCC were prepared under various pressures, and then the compressibility and compactibility of these prescriptions were evaluated by Walker, Heckel and Ryshkewitch-Duckworth equations. In addition, the fluidity of the prescriptions was evaluated by parameters of Kawakita equation. There was a comprehensive analysis of the effect of SuperTab 40 LL on musk sustained-release mini-tablets combined with the appearance of SuperTab 40 LL and their tensile strength. The results shown that SuperTab 40 LL had better compression process through the Heckel equation, and the direct compression process of drug powders with excipients can be analyzed by the Kawakita and Ryshkewitch-Duckworth equations. As a new type of co-processed lactose, SuperTab 40 LL had a good fluidity and compactibility. SuperTab 40 LL may undergo particle crushing and plastic deformation during the compression process, which increased the contact area and bonding sites between the particles, and aggregated and shaped the mixed powder easy. Moreover, MCC showed a synergistic effect, and the combined application with SuperTab 40 ll could effectively improve the fluidity and compressibility of the musk sustained-release powder. When the ratio of SuperTab 40 LL and MCC was 2∶1, musk sustained-release mini-tablets had a high drug loading capacity and good compactibility in line with the design objectives.

Material manufacturability classification in high shear wet granulation process of Chinese medicine / 中国中药杂志

The high shear wet granulation(HSWG) process of Chinese medicine has a complicated mechanism. There are many influencing factors that contribute to this process. In order to summarize the manufacturability of different kinds of materials in HSWG, this paper constructed a material library composed of 11 materials, including 4 Chinese medicine extracts and 7 pharmaceutical excipients. Each material was described by 22 physical parameters. Several binders were employed, and their density, viscosity and surface tension were characterized. Combining empirical constraints and the principle of randomization, 21 designed experiments and 8 verification experiments were arranged. The partial least squares(PLS) algorithm was used to establish a process model in prediction of the median granule size based on properties of raw materials and binders, and process parameters. The surface tension and density of binders, as well as the maximum pore saturation were identified as key variables. In the latent variable space of the HSWG process model, all materials could be divided into three categories, namely the Chinese medicine extracts, the diluents and the disintegrants. The granulation of Chinese medicine extracts required low viscosity and low amount of binder, and the resulted granule sizes were small. The diluent powders occupied a large physical space, and could be made into granules with different granule sizes by adjusting the properties of binders. The disintegrants tended to be made into large granules under the condition of aqueous binder. The combination use of material database and multivariate modeling method is conducive to innovate the knowledge discovery of the wet granulation process of Chinese medicine, and provides a basis for the formulation and process design based on material attributes.

Formulation of technical guidelines in line with characteristics and principles of traditional Chinese medicine changes to improve quality of such preparations--interpretation of Technical guidelines for the study of pharmaceutical changes in traditional Chinese medicines / 中国中药杂志

In leading the high-quality development of Chinese medicine preparations, it is an important link to formulate the scientific, reasonable, and feasible guidelines for the change of Chinese medicines in accordance with the change characteristics and principles of the Chinese medicines is an important work to promote the Technical guidelines for the study of pharmaceutical changes in traditional Chinese medicines was formed by a broad consensus based on the characteristics and research results of the pharmaceutical changes in Traditional Chinese Medicines(TCM)with the principles of science and risk management. This guideline has clarified the basic principles and requirements for the evaluation of changes in TCM, specified the research and verification work of common change scenarios, defined the boundaries of changes in TCM, and proposed to encourage the use of new technologies, new methods, and new excipients that meet product characteristics. It will definitely promote the quality improvement and the secondary development of TCM. In this article, the revision background and main content of the guideline were introduced, and the main features of the Guideline were analyzed, in order to provide references for the industry.

Errores de enfermería en la preparación y administración de medicamentos / Nursing errors in drug preparation and administration

La preparación y administración de medicamentos, es parte importante en el proceso de recuperación de la salud, se destaca entre las funciones relevantes de los profesionales y auxiliares de enfermería, incluye etapas críticas que deben garantizar la correcta y segura administración de los mismos. Existe carencia de revisiones bibliográficas que aborden la problemática de los errores de enfermería, aunque, investigadores en todo el mundo, han estudiado el impacto que genera el error en la preparación de medicamentos, siendo este uno de los principales problemas en el campo de la enfermería. Objetivo: conocer la relación entre la calidad técnica en la preparación de medicamentos, identificando características y tipos, con la frecuencia en los errores de enfermería. Material y Métodos: se realizó revisión bibliográfica, identificando once artículos científicos en las bases de datos PubMed, Scopus y SciELO. Se incluyeron estudios originales y observacionales, excluyendo revisiones sistemáticas, estudios duplicados y sin acceso libre a la información. Conclusión: los factores predominantes en los errores de enfermería, se deben a la confusión al momento de elegir el fármaco, error en el cálculo de dosis, sobrecarga de trabajo y déficit de conocimiento...(AU)