ABSTRACT Generic drugs play an important role in healthcare systems as they represent an effective and more affordable alternative for the population. In Peru, a regulation of interchangeability of generic drugs (also called multisource drugs) was stablished to define the procedures and requirements for developing in vivo and in vitro therapeutic equivalence studies, following the gradual application approach and sanitary risk criteria. Compliance with the new regulation will allow greater access to effective, safe and quality generic drugs. Meanwhile, drugs continue to be marketed in the absence of therapeutic equivalence studies. Findings show that some drugs failed in in vivo and in vitro comparisons with the reference product. This regulation represents a great challenge for manufacturers and holders of sanitary registrations in order to demonstrate the interchangeability of their pharmaceutical products with the reference product.

RESUMEN Los medicamentos genéricos desempeñan un papel importante en los sistemas de atención de salud, ya que representan una alternativa eficaz más asequible para la población. En el Perú, se estableció un reglamento que regula la intercambiabilidad de medicamentos genéricos (también llamados multifuentes), que define los procedimientos y requisitos a seguir para desarrollar estudios de equivalencia terapéutica in vivo e in vitro, siguiendo el enfoque de aplicación gradual y el criterio de riesgo sanitario. El cumplimiento de este reglamento permitirá un mayor acceso a medicamentos genéricos eficaces, seguros y de calidad. Mientras tanto, se siguen comercializando genéricos en ausencia de estudios de equivalencia terapéutica. Los estudios demuestran que algunos medicamentos fallaron en las comparaciones in vivo e in vitro con el medicamento de referencia. Esta implementación representa un gran desafío para los laboratorios fabricantes y los titulares de registros sanitarios a fin de demostrar la intercambiabilidad de sus productos farmacéuticos con el medicamento de referencia.

ABSTRACT Generic drugs play an important role in healthcare systems as they represent an effective and more affordable alternative for the population. In Peru, a regulation of interchangeability of generic drugs (also called multisource drugs) was stablished to define the procedures and requirements for developing in vivo and in vitro therapeutic equivalence studies, following the gradual application approach and sanitary risk criteria. Compliance with the new regulation will allow greater access to effective, safe and quality generic drugs. Meanwhile, drugs continue to be marketed in the absence of therapeutic equivalence studies. Findings show that some drugs failed in in vivo and in vitro comparisons with the reference product. This regulation represents a great challenge for manufacturers and holders of sanitary registrations in order to demonstrate the interchangeability of their pharmaceutical products with the reference product.

RESUMEN Los medicamentos genéricos desempeñan un papel importante en los sistemas de atención de salud, ya que representan una alternativa eficaz más asequible para la población. En el Perú, se estableció un reglamento que regula la intercambiabilidad de medicamentos genéricos (también llamados multifuentes), que define los procedimientos y requisitos a seguir para desarrollar estudios de equivalencia terapéutica in vivo e in vitro, siguiendo el enfoque de aplicación gradual y el criterio de riesgo sanitario. El cumplimiento de este reglamento permitirá un mayor acceso a medicamentos genéricos eficaces, seguros y de calidad. Mientras tanto, se siguen comercializando genéricos en ausencia de estudios de equivalencia terapéutica. Los estudios demuestran que algunos medicamentos fallaron en las comparaciones in vivo e in vitro con el medicamento de referencia. Esta implementación representa un gran desafío para los laboratorios fabricantes y los titulares de registros sanitarios a fin de demostrar la intercambiabilidad de sus productos farmacéuticos con el medicamento de referencia.

The main aim of this study was to develop scaffolds based on alginate, chitosan and hybrid fibers with and without glycerol. The scaffolds developed underwent assessments for tensile property, swelling ratio and weight loss, cellular viability, degradation and biomineralization, as well as DSC/TGA thermal analysis. Tenacity values showed that use of glycerol and the interaction between alginate and chitosan as a hybrid fiber were associated with increasing tenacity values. In the swelling and weight loss study, the scaffolds containing glycerol presented lower weight loss and higher water absorption values in all scaffolds, compared to scaffolds without glycerol, indicating that glycerol acted as a stabilizer. None of the alginate, chitosan and hybrid scaffolds, with or without glycerol, decreased cell viability. On the third day of the biomineralization assay, chitosan without glycerol indicated the presence of apatite crystals. The degradation study showed that glycerol may have acted as a stabilizer.

ABSTRACT The search for new pharmaceutical dosage forms and different drug delivery systems already used in therapeutics is a global trend, serving as an opportunity to expand the portfolio for the pharmaceutical industry. In this context, multiparticulate systems, such as pellets, granules, and minitablets, represent an attractive alternative, given the range of possibilities they provide. Among the methods used in the production of these systems, we highlight the process of extrusion-spheronization for pellet manufacture, wet granulation and hot-melt extrusion for the obtention of granules, and direct compression for minitablets. Although highly versatile, depending on the technology chosen, many processes and formulation variables can influence the ensuing stages of manufacture, as well as the final product. Therefore, the characterization of these small units is of fundamental importance for achieving batch homogeneity and optimal product performance. Analyses, including particle size distribution, morphology, density, porosity, mechanical strength and disintegration, are example tests used in this characterization. The objective of this review was to address the most widely used tests for the physical evaluation of multiparticulate systems.

<p>USP aparato 3 (cilindros recíprocos) é um equipamento bastante versátil para a avaliação das características de liberação <italic>in vitro</italic> de formas farmacêuticas sólidas orais, pois permite que o produto seja submetido a diferentes meios de dissolução e condições de agitação, em um único ensaio. Neste trabalho, são apresentados um breve histórico e a descrição desse sistema, suas aplicações no desenvolvimento de produtos de liberação imediata e modificada, assim como sua utilização na simulação dos estados não alimentado e alimentado com o emprego de meios biorrelevantes. Além disso, uma comparação é estabelecida com o cesto e a pá, com destaque para a hidrodinâmica superior do USP aparato 3, que faz com que os resultados não sejam influenciados por fatores como o uso de sondas de coleta de amostras ou presença de bolhas de ar no meio de dissolução.</p>

<p>USP Apparatus 3 (reciprocating cylinder) is a very versatile device for the <italic>in vitro</italic> assessment of release characteristics of solid oral dosage forms, because it enables the product to be subjected to different dissolution media and agitation speeds in a single run. In this paper, a brief history and a description of this system are presented, along with its applications in the development of immediate and modified release products and in the simulation of fasted and fed states using biorelevant media. Furthermore, a comparison is made with the basket and paddle apparatus, especially highlighting the superior hydrodynamics of USP apparatus 3, since the results are not sensitive to factors such as the presence of sample collection probes or air bubbles in the dissolution medium.</p>

A finalidade do presente trabalho foi avaliar o efeito do meio de dissolução, velocidade de rotação e pressão de compactação na velocidade de dissolução intrínseca (VDI) do fármaco anti-hipertensivo besilato de anlodipino, usando o método do disco rotativo. Dessa forma, foi utilizado um planejamento experimental do tipo fatorial facionado (33-1) utilizando como variáveis independentes o meio de dissolução (água, HCl 0,1M e tampão fosfato pH 6,8), velocidade de rotação (50, 75 e 100 rpm) e pressão de compactação do fármaco (1000, 1500 e 2000 psi). Os ensaios foram randomizados e comparados estatisticamente pelo software Statistica(r) 11. A análise de variância (ANOVA) indicou que o meio de dissolução exerce considerável impacto na VDI do besilato de anlodipino. A análise das variáveis em seus componentes lineares e quadráticos permitiu a proposição de um modelo matemático que descreve a VDI em função dos parâmetros estudados. Por outro lado, os níveis de pressão de compactação e velocidade de rotação empregados exercem efeito menos relevantes, especialmente quando o ensaio é conduzido em HCl 0,1 M.

The aim of this study was to evaluate the effect of dissolution medium, rotation speed and compaction pressure on the intrinsic dissolution rate (IDR) of the antihypertensive drug amlodipine besylate, using the rotating disk method. Accordingly, a fractional factorial design (33-1) was used, employing dissolution media (water, phosphate buffer pH 6.8 and HCl 0.1 M), rotation speed (50, 75 and 100 rpm), and compaction pressure (1000, 1500 and 2000 psi) as independent variables. The assays were randomized and statistically compared using the Statistica(r) 11 software program. Significance testing (ANOVA) indicated that the dissolution medium had a considerable impact on the IDR of amlodipine besylate. Analysis of the linear and quadratic components of the variables led to the proposition of a mathematical model that describes the IDR as a function of the parameters studied. Conversely, the levels of compaction pressure and rotation speed employed during experimental planning were less relevant, especially when the assay was conducted in the HCl 0.1 M medium.

In this study, fluid bed granulation was applied to improve the dissolution of nimodipine and spironolactone, two very poorly water-soluble drugs. Granules were obtained with different amounts of sodium dodecyl sulfate and croscarmellose sodium and then compressed into tablets. The dissolution behavior of the tablets was studied by comparing their dissolution profiles and dissolution efficiency with those obtained from physical mixtures of the drug and excipients subjected to similar conditions. Statistical analysis of the results demonstrated that the fluid bed granulation process improves the dissolution efficiency of both nimodipine and spironolactone tablets. The addition of either the surfactant or the disintegrant employed in the study proved to have a lower impact on this improvement in dissolution than the fluid bed granulation process.

Ciclodextrinas (CDs) são oligossacarídeos cíclicos, compostos por unidades D-glicopiranosídicas ligadas entre si por meio de ligações glicosídicas e sua principal propriedade está na capacidade de alterar as características físico-químicas e biológicas de fármacos com baixa solubilidade por meio da formação de complexos de inclusão fármaco:CD. Para a formação dos complexos de inclusão a molécula hospedeira necessita ajustar-se total ou parcialmente no interior da cavidade da CD, onde este ajuste está diretamente ligado a propriedades físico-químicas da molécula hóspede e hospedeira, facilidade de alojamento da molécula hóspede no interior da cavidade da CD, estequiometria, dose terapêutica e toxicidade. No entanto, as formas farmacêuticas podem atingir um elevado volume, em função da quantidade de CD requerida, sendo necessário aumentar sua eficiência de solubilização para que seja possível utilizar menores quantidades das mesmas. Isso pode ser obtido com a inclusão de pequenas quantidades de polímeros hidrossolúveis ao sistema. Nessa revisão, são abordados aspectos relacionados à complexação de fármacos com ciclodextrinas empregando-se polímeros hidrossolúveis para otimização da quantidade de CD utilizada na formulação, com a finalidade de aumentar a solubilidade do fármaco e reduzir o volume das preparações.

Cyclodextrins (CDs) are cyclic oligosaccharides composed of D-glucopyranoside units linked by glycosidic bonds. Their main property is the ability to modify the physicochemical and biological characteristics of low-soluble drugs through the formation of drug:CD inclusion complexes. Inclusion complexation requires that host molecules fit completely or partially within the CD cavity. This adjustment is directly related to the physicochemical properties of the guest and host molecules, easy accommodation of guest molecules within the CD cavity, stoichiometry, therapeutic dose, and toxicity. However, dosage forms may achieve a high volume, depending on the amount of CD required. Thus, it is necessary to increase solubilization efficiency in order to use smaller amounts of CD. This can be achieved by adding small amounts of water-soluble polymers to the system. This review addresses aspects related to drug complexation with CDs using water-soluble polymers to optimize the amount of CD used in the formulation in order to increase drug solubility and reduce dosage form volume.

The combined effect of hydroxypropyl-β-cyclodextrin (HPβCD) and polyvinylpyrrolidone (PVP) or sodium carboxymethylcellulose (CMC) on the solubility of pyrimethamine (PYR) was studied. Equimolar PYR-HPβCD solid systems, in the presence or the absence of 0.25% (w/v) PVP or 0.10% (w/v) CMC were prepared by coevaporation or freeze-drying, and characterized by differential scanning calorimetry, X-ray diffraction analysis and dissolution profile. Phase-solubility analysis was used to investigate the interactions in aqueous solution between PYR and HPβCD, in the absence or presence of polymers, which showed a linear increase of PYR solubility depending on the concentration of HPβCD. The presence of polymer did not alter the stoichiometry of the complexes. DSC results were indicative of complexation, due to the loss of the characteristic endothermic peak of PYR. X-ray diffraction analysis confirmed the DSC results. Binary and ternary complexes showed higher dissolution rate when compared with the pure drug.

The aim of this study was to prepare and evaluate the pellets, containing a highly soluble drug (ascorbic acid), by the extrusion-spheronization process and coated with a release controlling polymer. The coating (undertaken in a fluid bed) was applied to three batches of the pellets with a dispersion of Kollicoat® SR 30 D, with each batch of pellets receiving a different level of polymer (5.07; 8.26 and 10.35%). The coated pellets were evaluated for sphericity by imaging analysis and comparative dissolution profile with a product commercially available in Brazil. All of the evaluated samples presented adequate physical properties and the dissolution profile of those coated with 5.07% of polymer proved to be similar to that of the commercially available brand name.

O objetivo deste trabalho foi melhorar as características de fluxo do fluconazol com o emprego da granulação úmida e estudar o efeito desse processo na dissolução do fármaco em cápsulas e comprimidos. O fluconazol foi submetido ao processo de granulação úmida num granulador de alta velocidade empregando Plasdone K29/32 e K90. Foram determinadas as propriedades de fluxo dos grânulos e obtidos os perfis de dissolução de cápsulas e comprimidos obtidos com os granulados em estudo. Os grânulos de fluconazol apresentaram melhores características de fluxo após o processamento, demonstradas por meio das determinações do ângulo de repouso e do índice de compressibilidade, comparativamente à matéria-prima. Adicionalmente, observou-se que o processo de granulação melhorou a eficiência de dissolução (ED) do fluconazol nos comprimidos e cápsulas.

The aim of this work was to improve fluconazole flowability by wet granulation and to study the effect of granulation on drug dissolution from tablets and capsules. Fluconazole was submitted to a process of wet granulation in a high-speed granulator using Plasdone® K29/32 or K90. Flow properties of granules and dissolution profiles for tablets and capsules produced with them were determined. Fluconazole granules demonstrated better flowability, calculated by angle of repose and compressibility index data, compared with powder. Additionally, it was observed that the granulation process improved the dissolution efficiency (ED) of fluconazole from tablets and capsules, which could also suggest an increase in bioavailability. Higher dissolution efficiencies were achieved with Plasdone® K29/32.

A ineficácia clínica de muitos medicamentos tem servido de alerta para estudos mais profundos sobre os componentes da formulação, processos empregados e características físico-químicas dos fármacos. O objetivo deste trabalho foi avaliar a liberação in vitro de comprimidos de fosfato de primaquina disponíveis no Brasil para tratamento da malária, e o desenvolvimento de novas formulações de liberação convencional. Embora os comprimidos de fosfato de primaquina estudados tenham sido aprovados pelos critérios propostos pela Farmacopéia Americana (2006) para o teste de dissolução, não apresentaram desempenho adequado para o perfil de dissolução, mostrando retenção do fármaco durante a liberação. Os resultados indicam a existência de problemas nos comprimidos de fosfato de primaquina analisados, podendo sugerir como um dos fatores responsáveis pelo aparecimento de resistência dos parasitas.

The clinical inefficacy of many medications has served to highlight the need for deeper studies on the formulation components, processes used and physicochemical characteristics of drugs. The objective of this study was to evaluate the in vitro release of primaquine phosphate from tablets available in Brazil for treating malaria, and the development of new formulations for conventional release. Although the primaquine phosphate tablets studied had been approved according to the criteria proposed by the United States Pharmacopoeia (2006) for the dissolution test, they did not present adequate dissolution performance characteristics, in that there was drug retention during the release process. The results indicate the existence of problems in the primaquine phosphate tablets analyzed, and it may suggest that this is one of the factors responsible for the appearance of parasite resistance.

As formas farmacêuticas sólidas orais (FFSO) de liberação prolongada caracterizam-se pela liberação gradual do fármaco e manutenção da sua concentração plasmática em níveis terapêuticos, durante um período de tempo prolongado. Podem ser desenvolvidas como sistemas monolíticos ou multiparticulados, empregando-se tecnologias como matrizes poliméricas, sistemas reservatório ou bombas osmóticas. Este trabalho apresenta uma revisão acerca das tecnologias utilizadas para a obtenção de FFSO de liberação prolongada, destacando os benefícios tecnológicos e biofarmacotécnicos dos sistemas multiparticulados sobre os monolíticos. Os métodos empregados para a avaliação das características de dissolução desses sistemas são também abordados, especialmente o aparato 3 da Farmacopéia Americana. Por fim, são apresentados exemplos de produtos disponíveis no mercado brasileiro, com o objetivo de ilustrar a aplicabilidade das FFSO de liberação prolongada, além de verificar o perfil de utilização desses sistemas pela indústria nacional.

Sustained release solid oral dosage forms are characterized by the gradual release of the drug and maintenance of its plasmatic concentration in therapeutic levels, during a prolonged period of time. They can be designed as single-unity or multiple-unity dosage forms, using technologies such as matrix, reservoir or osmotic systems. The present work is a review on the technologies used to obtain sustained release oral dosage forms, with a special attention to the technological and biopharmaceutical benefits of multiple-unity over single-unity systems. The methods used in the evaluation of the dissolution characteristics of such systems are also approached. Examples of products available in the Brazilian market are shown with the purpose of illustrating the applicability of sustained release solid oral dosage forms, besides verifying the profile of utilization of these systems by the national industry.

O perfil de dissolução de formas farmacêuticas sólidas contendo palmitato de cloranfenicol 250 mg disponíveis no Brasil foi determinada pelo método da Farmacopéia Americana (United States Pharmacopeia, 2004) e comparado. Duas categorias de métodos para comparação dos perfis de dissolução foram utilizadas: ANOVA e modelo independente. Diferenças entre as formulações foram refletidas nos perfis de dissolução. A presença de polimorfos metaestáveis ou formas amorfas de palmitato de cloranfenicol pode ser responsável pelas variações na concentração do fármaco observada nas formulações.

The dissolution profile for solid pharmaceutical forms containing chloramphenicol 250 mg available in Brazil was determined using a method from the American Pharmacopoeia (United States Pharmacopoeia, 2004) and then compared. Two different methods of dissolution profile comparison were used: ANOVA, and an independent model. Differences between the formulations were reflected in the dissolution profiles. The presence of metastable polymorphs or amorphous forms of chloramphenicol palmitate might be responsible for variations in the concentration of the drug observed within formulations.

A absorção de fármacos a partir de formas farmacêuticas sólidas, administradas por via oral, depende de sua liberação, da dissolução ou solubilização dos mesmos em condições fisiológicas e da permeabilidade das membranas do trato gastrintestinal. Portanto, a dissolução in vitro é fundamental para se prever o desempenho in vivo do fármaco. Pretendeu-se neste trabalho, realizar avaliação biofarmacotécnica in vitro através de testes físico-químicos e avaliação da cinética e eficiência de dissolução de quatro lotes de duas formulações do mercado nacional contendo 100 mg de doxiciclina. Utilizou-se o método descrito pela Farmacopéia Americana para realização do ensaio de dissolução. A análise da cinética de dissolução foi avaliada por meio dos parâmetros k s (constante de velocidade de dissolução) e t50% (tempo necessário para dissolução de 50% do fármaco presente na forma farmacêutica). Calculou-se, também, a eficiência de dissolução (ED%). De acordo com os resultados obtidos, verificou-se que todas as amostras avaliadas apresentaram-se de acordo com os compêndios oficiais no que se referiu a peso médio, teor de fármaco, uniformidade de conteúdo e teste de dissolução. Em relação à cinética de dissolução observou-se que todos os produtos apresentaram cinética de primeira ordem. Para a eficiência de dissolução encontraram-se valores entre 58,48% e 78,39%.

The process of drug absorption from solid dosage forms following oral administration depends on drug delivery from dosage form, its dissolution in gastrointestinal conditions and permeation through the intestinal membrane. Therefore, in vitro dissolution is very important to predict the in vivo performance of a drug contained in a solid dosage form. The purpose of this study was to perform an in vitro biopharmaceutical evaluation, through physicochemical, dissolution kinetics and dissolution efficacy tests of four batches of two commercial products available in the Brazilian market, containing 100 mg of doxycycline. The dissolution method described in the United States Pharmacopeia (USP) was used for the dissolution kinetics analysis. It was evaluated by the parameters k s (dissolution rate constant), t50% (time to promote the dissolution of 50% of the drug in the pharmaceutical dosage form) and dissolution efficacy. According to the results it was verified that all the batches were in accordance with official specifications for average weight, doxyxycline content, uniformity content, and dissolution tests. All produtcts showed first order dissolution kinetics. Dissolution efficacy values ranged from 58,48% to 78,39%.