Ácido rosmarínico : contribuição ao estudo de sua biodisponibilidade oral, complexação com ciclodextrina e pré-formulação de comprimidos

O ácido rosmarínico (AR) é um composto fenólico que possui múltiplas atividades biológicas, porém baixa biodisponibilidade, que pode estar relacionada à sua solubilidade aquosa, estabilidade físico-química e permeabilidade no trato gastrointestinal. A complexação com ciclodextrinas (CD) vem sendo uma alternativa tecnológica amplamente utilizada para propiciar aumento de biodisponibilidade de fármacos e os complexos são encontrados no mercado farmacêutico principalmente na forma farmacêutica de comprimidos. Baseado nisso, este trabalho teve como objetivos realizar levantamento da literatura condizente com o tema, avaliar o efeito da complexação do AR com metil-βCD (MβCD) sobre a sua solubilidade aquosa, estabilidade térmica e gastrointestinal e permeabilidade e realizar estudo de compatibilidade com excipientes comumente utilizados na produção de comprimidos. Inicialmente, revisões de literatura relatando as vias de administração e sistemas de liberação aplicados ao AR e biodisponibilidade oral e estudos de complexação com CDs do AR e seus derivados foram realizadas. Posteriormente, complexo do AR e MβCD foram obtidos por método de suspensão em água seguido de liofilização, caracterizados por cromatografia líquida, infravermelho (FTIR), calorimetria diferencial exploratória (DSC), termogravimetria (TG) e ressonância magnética nuclear de próton (H1 RMN) e submetidos a avaliação de solubilidade aquosa, estabilidade térmica e gastrointestinal e permeabilidade. Para o estudo de compatibilidade, misturas binárias (1:1) entre AR e excipientes foram obtidas e submetidas a análise de DSC, TG, FTIR, ressonância magnética nuclear em estado sólido e estresse isotérmico. As revisões demonstraram que o AR vem sendo administrado por diferentes vias e veiculado a variados sistemas de liberação. Sua biodisponibilidade oral, bem como a de alguns dos seus derivados, é baixa, e a complexação com CDs permanece como uma das alternativas tecnológicas pouco exploradas ao aumento da absorção oral. O complexo obtido apresentou um teor de 0,33 mg/mg e mudanças físico-químicas foram detectadas por FTIR, DSC e TG, sugerindo a complexação do AR com MβCD, a qual foi confirmada pelo método H1 RMN. A complexação foi capaz de aumentar a solubilidade aquosa e estabilidade do AR, sem afetar a sua partição óleo/água, porém os testes de permeabilidade foram inconclusivos. No estudo de compatibilidade, celulose microcristalina e polivinilpirrolidona não apresentaram incompatibilidades com o AR, enquanto croscarmelose de sódio e estearato de magnésio promoveram sua degradação. Desta forma, conclui-se que o AR e seus derivados possuem baixa disponibilidade quando administrados por via oral e poucos estudos, até o momento, utilizaram a complexação com CDs com intenção de melhorar esta característica. A complexação com MβCD se apresenta como uma abordagem tecnológica promissora para aumento da absorção do AR por via oral por propiciar melhores características biofarmacêuticas. Por meio da avaliação de compatibilidade AR-excipientes, pode ser estabelecido que croscarmelose de sódio e estearato de magnésio são excipientes que necessitam mais atenção no processo de manipulação para produção de forma farmacêutica que contenha o AR.Rosmarinic acid (RA) is a phenolic compound that has multiple biological activities, but low bioavailability, which may be related to its aqueous solubility, physicochemical stability, and permeability in the gastrointestinal tract. Complexation with cyclodextrins (CDs) has been a widely used technological alternative to increase the bioavailability of drugs and the complexes are found in the pharmaceutical market, mainly in the pharmaceutical form of tablets. Based on this, this work aimed to survey the literature consistent with the topic, to evaluate the effect of the complexation of RA with methyl-βCD (MβCD) on its aqueous solubility, thermal and gastrointestinal stability, and permeability, and to perform a compatibility study with excipients commonly used in the production of tablets. Initially, literature reviews reporting routes of administration and delivery systems applied to AR and oral bioavailability and complexation studies with CDs of RA and their derivatives were performed. Subsequently, RA and MβCD complex was obtained by suspension in water method followed by freeze-drying, characterized by liquid chromatography, infrared (FTIR), differential scanning calorimetry (DSC), thermogravimetry (TG) and proton nuclear magnetic resonance (H1 NMR) and submitted to evaluation of aqueous solubility, thermal and gastrointestinal stability, and permeability. For the compatibility study, binary mixtures (1:1) between RA and excipients were obtained and submitted to DSC, TG, FTIR, solid-state nuclear magnetic resonance, and isothermal stress analysis. Reviews showed that RA has been administered by different pathways and several delivery systems have been applied to it. Its oral bioavailability, as well as some of its derivatives is low and complexes with CDs remains one of the scarcely-explored technological alternatives to increase oral absorption. The obtained complex had a content of 0.33 mg/mg and physicochemical changes were detected by FTIR, DSC, and TG, suggesting the complexation of RA with MβCD, which was confirmed by the H1 NMR method. The complexation was able to increase the aqueous solubility and stability of the RA, without affecting its oil/water partition, but the permeability tests were inconclusive. In the compatibility study, microcrystalline cellulose and polyvinylpyrrolidone did not show incompatibilities with RA, while croscarmellose sodium and magnesium stearate promoted its degradation. Thus, it is concluded that RA and its derivatives have low availability when administered orally and few studies, so far, have used complexation with CDs with the intention of improving this characteristic. Complexation with MβCD presents itself as a promising technological approach to increase oral absorption of RA by providing better biopharmaceutical characteristics. From the RA-excipient compatibility assessment, it can be established that croscarmellose sodium and magnesium stearate are excipients that need more attention in the handling process for the production of a pharmaceutical form containing RA

Cyclodextrin-based delivery systems and hydroxycinnamic acids : interactions and effects on crucial parameters influencing oral bioavailability — aReview

Hydroxycinnamic acids (HCAs) are a subclass of phenolic acids presenting caffeic acid (CA), chlorogenic acid (CGA), coumaric acid (COA) isomers, ferulic acid (FA), and rosmarinic acid (RA) as the major representants, being broadly distributed into vegetal species and showing a range of biological potentials. Due to the low oral bioavailability of the HCAs, the development of delivery systems to promote better administration by the oral route is demanding. Among the systems, cyclodextrin (CD)-based delivery systems emerge as an important technology to solve this issue. Regarding these aspects, in this review, CD-based delivery systems containing HCAs are displayed, described, and discussed concerning the degree of interaction and their effects on crucial parameters that affect the oral bioavailability of HCAs

Oral pharmacokinetics of hydroxycinnamic acids : an updated review

Hydroxycinnamic acids (HCAs) such as caffeic acid (CA), chlorogenic acid (CGA), coumaric acid (COA) isomers, ferulic acid (FA) and rosmarinic acid (RA) are natural phenolic acids with widespread distribution in vegetal foods and well-documented pharmacological activities. However, the low bioavailability of HCAs impairs their administration by the oral route. The present review addresses new findings and important factors/obstacles for their oral administration, which were unexplored in the reviews published a decade ago concerning the bioavailability of phenolic acids. Based on this, the article aims to perform an updated review of the water solubility and gastrointestinal stability of HCAs, as well as describe their oral absorption, distribution, metabolism and excretion (ADME) processes by in vitro, ex vivo, in situ and in vivo methods

Compatibility study of rosmarinic acid with excipients used in pharmaceutical solid dosage forms using thermal and non-thermal techniques

Rosmarinic acid (RA) is a phenolic compound that presents well-documented anti-inflammatory, antioxidant and antitumor activities, and based on its pharmacological potential and poor bioavailability, several solid dosage forms have been developed to RA delivery. Therefore, in literature, there are no reports about RA compatibility with excipients. In this regard, the aim of the present study was to evaluate, for the first time, the compatibility of RA with excipients commonly used in solid dosage forms at a 1:1 (RA: excipient) ratio using differential scanning calorimetry (DSC), thermogravimetry (TG), Fourier-transform infrared (FTIR), solid-state nuclear magnetic resonance (ssNMR), and isothermal stress testing (IST) coupled with liquid chromatography (LC). The excipients selected were hydroxypropyl methylcellulose (HPMC), microcrystalline cellulose (MCC), lactose monohydrate (LAC), polyvinylpyrrolidone (PVP), talc (TALC), croscarmellose sodium (CCS), and magnesium stearate (MgSTE). According to DSC results, physical interactions were found between RA and HPMC, LAC, CCS, and MgSTE. The TG analyses confirmed the physical interactions and suggested chemical incompatibility. FTIR revealed physical interaction of RA with TALC and MgSTE and the ssNMR confirmed the physical interaction showed by FTIR and excluded the presence of chemical incompatibility. By IST, the greatest loss of RA content was found to CCS and MgSTE (>15%), demonstrating chemical incompatibilities with RA. High temperatures used in DSC and TG analyses could be responsible for incompatibilities in binary mixtures (BMs) with HPMC and LAC, while temperature above 25 C and presence of water were factors that promote incompatibilities in BMs with CCS and MgSTE. Overall results demonstrate that RA was compatible with MCC and PVP

Comparando técnicas terapêuticas para o manejo da úlcera péptica perfurada a partir de novos ensaios clínicos randomizados

A úlcera péptica pode ser caracterizada como um insulto à mucosa do trato digestivo superior, sendo resultado de um desequilíbrio entre ácido-pepsina do estômago e as barreiras de defesa da mucosa, a qual afeta em torno de 4 milhões de pessoas por ano em todo o mundo e com uma taxa de mortalidade de até 30%. O presente estudo de revisão buscou avaliar técnicas terapêuticas no manejo da úlcera péptica perfurada, documentadas por meio de ensaios clínicos randomizados. Trata-se de uma pesquisa de revisão integrativa realizada por meio da base de dados PubMed, que levou em consideração os seguintes critérios de inclusão: testes controlados e randomizados; artigos publicados nos últimos 05 anos (2018-2023); que possuíam texto completo disponível e que abordassem acerca de técnicas terapêuticas no manejo da úlcera péptica perfurada. Ficou constatado que a abordagem com stent juntamente com lavagem laparoscópica e drenagem se mostrou uma alternativa segura no manejo da úlcera duodenal perfurada. Além disso, verificou-se que a drenagem combinada endoscópica e radiológica intervencionista também se mostrou eficaz no tratamento da úlcera péptica aguda perfurada sem necessidade de anestesia geral e com um curto tempo de realização do procedimento

Ácido rosmarínico : complexação com ciclodextrinas, avaliação do potencial antioxidante in vitro e estudo de compatibilidade com excipientes com vistas ao desenvolvimento de formulação sólida oral

Introdução: O ácido rosmarínico (AR) é um composto fenólico que apresenta inúmeras atividades biológicas, dentre estas, destaca-se a atividade antioxidante. Entretanto, a biodisponibilidade do AR por via oral é de apenas 0,91 a 5,0%, fator que pode estar relacionado à sua solubilidade, estabilidade em meio gastrointestinal e mecanismo de absorção. Ciclodextrinas (CDs) são excipientes farmacêuticos utilizados com o objetivo de promover a absorção oral de fármacos por propiciarem aumento de solubilidade, estabilidade química e permeação pela membrana intestinal a partir da complexação com o fármaco. Tendo em vista o desenvolvimento de uma formulação farmacêutica, estudos de compatibilidade entre a substância e excipientes se fazem necessários. Objetivo: Obter complexo do AR com CDs derivadas, avaliar a atividade antioxidante dos complexos e compatibilidade entre excipientes. Materiais e métodos: Estudo de solubilidade de fase foi realizado para se determinar estequiometria e constante de estabilidade entre o AR e duas CDs: HPβCD e MβCD. Os complexos foram obtidos por liofilização e caracterizados por métodos espectroscópicos, calorimétrico e microscópico. A atividade antioxidante foi determinada pelo método DPPH e estudo de compatibilidade entre excipientes foi realizado por método espectroscópico, calorimétrico e cromatográfico. Resultados: O AR apresentou proporção estequiométrica 2:1 AR:CD e alta constante de estabilidade. Os métodos de caracterização permitiram inferir a presença de formação de complexo de inclusão e complexo de não-inclusão, nos quais uma molécula do AR estaria interagindo com prótons internos e outra estaria interagindo com prótons externos da CD. A atividade antioxidante dos complexos foi superior à apresentada pelo AR não complexado, demonstrando a ação das CDs sobre a doação de prótons do AR e o estudo de compatibilidade de excipientes não demonstrou incompatibilidades viabilizando a obtenção de formas farmacêuticas. Conclusão: Considerando todos os resultados, pode-se inferir que complexos AR:CD podem ser uma alternativa tecnológica para superar a baixa absorção pela via oral, sem ocasionar perda na atividade antioxidante, propiciando também o desenvolvimento de formulações sólidas orais.Introduction: Rosmarinic acid (RA) is phenolic compound which present several biological activities, among these, antioxidant is remarkable. However, oral bioavailability of RA is only 0.91 to 5.0%, a factor that may be related to its solubility, stability in gastrointestinal environment and absorption mechanism. Cyclodextrins (CDs) are pharmaceutical excipients used in oral drug absorption by promoting increased solubility, chemical stability and permeation by the intestinal membrane through complexation with the drug. In view of the development of a pharmaceutical formulation, excipients compatibility studies are also expected. Objective: To obtain RA complex with derivative CDs (HPβCD and MβCD), to evaluate the antioxidant activity of complexes and compatibility between excipients. Materials and methods: Phase-solubility study was performed to determine stoichiometry and constant between RA and CD. The complexes were obtained by lyophilization and characterized by spectroscopic, calorimetric and microscopic techniques. The antioxidant activity was determined by the DPPH method and compatibility study among excipients was performed by spectroscopic, calorimetric and chromatographic methods

Cyclodextrin-Based Delivery Systems and Hydroxycinnamic Acids: Interactions and Effects on Crucial Parameters Influencing Oral Bioavailability—A Review

Hydroxycinnamic acids (HCAs) are a subclass of phenolic acids presenting caffeic acid (CA), chlorogenic acid (CGA), coumaric acid (COA) isomers, ferulic acid (FA), and rosmarinic acid (RA) as the major representants, being broadly distributed into vegetal species and showing a range of biological potentials. Due to the low oral bioavailability of the HCAs, the development of delivery systems to promote better administration by the oral route is demanding. Among the systems, cyclodextrin (CD)-based delivery systems emerge as an important technology to solve this issue. Regarding these aspects, in this review, CD-based delivery systems containing HCAs are displayed, described, and discussed concerning the degree of interaction and their effects on crucial parameters that affect the oral bioavailability of HCAs

Poloxamer-enhanced solubility of griseofulvin and its related antifungal activity against Trichophyton spp.

Poorly water-soluble drugs, such as the antifungal drug griseofulvin (GF), exhibit limited bioavailability, despite their high membrane permeability. Several technological approaches have been proposed to enhance the water solubility and bioavailability of GF, including micellar solubilization. Poloxamers are amphiphilic block copolymers that increase drug solubility by forming micelles and supra-micellar structures via molecular self-association. In this regard, the aim of this study was to evaluate the water solubility increment of GF by poloxamer 407 (P407) and its effect on the antifungal activity against three Trichophyton mentagrophytes and two T. rubrum isolates. The GF water solubility profile with P407 revealed a non-linear behavior, well-fitted by the sigmoid model of Morgan-Mercer-Flodin. The polymer promoted an 8-fold increase in GF water solubility. Fourier-transform infrared (FT-IR) spectroscopy, differential scanning calorimetry (DSC), and 2D nuclear magnetic resonance (NMR Roesy) spectroscopy suggested a GF-P407 interaction, which occurs in the GF cyclohexene ring. These results were supported by an increase in the water solubility of the GF impurities with the same molecular structure. The MIC values recorded for GF ranged from 0.0028 to 0.0172 mM, except for T. Mentagrophytes TME34. Notably, the micellar solubilization of GF did not increase its antifungal activity, which could be related to the high binding constant between GF and P407

Compatibility study of rosmarinic acid with excipients used in pharmaceutical solid dosage forms using thermal and non-thermal techniques

Rosmarinic acid (RA) is a phenolic compound that presents well-documented anti-inflammatory, antioxidant and antitumor activities, and based on its pharmacological potential and poor bioavailability, several solid dosage forms have been developed to RA delivery. Therefore, in literature, there are no reports about RA compatibility with excipients. In this regard, the aim of the present study was to evaluate, for the first time, the compatibility of RA with excipients commonly used in solid dosage forms at a 1:1 (RA: excipient) ratio using differential scanning calorimetry (DSC), thermogravimetry (TG), Fourier-transform infrared (FTIR), solid-state nuclear magnetic resonance (ssNMR), and isothermal stress testing (IST) coupled with liquid chromatography (LC). The excipients selected were hydroxypropyl methylcellulose (HPMC), microcrystalline cellulose (MCC), lactose monohydrate (LAC), polyvinylpyrrolidone (PVP), talc (TALC), croscarmellose sodium (CCS), and magnesium stearate (MgSTE). According to DSC results, physical interactions were found between RA and HPMC, LAC, CCS, and MgSTE. The TG analyses confirmed the physical interactions and suggested chemical incompatibility. FTIR revealed physical interaction of RA with TALC and MgSTE and the ssNMR confirmed the physical interaction showed by FTIR and excluded the presence of chemical incompatibility. By IST, the greatest loss of RA content was found to CCS and MgSTE (>15%), demonstrating chemical incompatibilities with RA. High temperatures used in DSC and TG analyses could be responsible for incompatibilities in binary mixtures (BMs) with HPMC and LAC, while temperature above 25 C and presence of water were factors that promote incompatibilities in BMs with CCS and MgSTE. Overall results demonstrate that RA was compatible with MCC and PVP