Preparation, characterization and evaluation of the in vivo trypanocidal activity of ursolic acid-loaded solid dispersion with poloxamer 407 and sodium caprate

Abstract

Ursolic acid is a promising candidate for treatment of Chagas disease; however it has low aqueous solubility and intestinal absorption, which are both limiting factors for bioavailability. Among the strategies to enhance the solubility and dissolution of lipophilic drugs, solid dispersions are growing in popularity. In this study, we employed a mixture of the surfactants poloxamer 407 with sodium caprate to produce a solid dispersion containing ursolic acid aimed at enhancing both drug dissolution and in vivo trypanocidal activity. Compared to the physical mixture, the solid dispersion presented higher bulk density and smaller particle size. Fourier Transform Infrared Spectroscopy results showed hydrogen bonding intermolecular interactions between drug and poloxamer 407. X-ray diffractometry experiments revealed the conversion of the drug from its crystalline form to a more soluble amorphous structure. Consequently, the solubility of ursolic acid in the solid dispersion was increased and the drug dissolved in a fast and complete manner. Taken together with the oral absorption-enhancing property of sodium caprate, these results explained the increase of the in vivo trypanocidal activity of ursolic acid in solid dispersion, which also proved to be safe by cytotoxicity evaluation using the LLC-MK2 cell line. O ácido ursólico é um candidato promissor para o tratamento da doença de Chagas, contudo este fármaco possui baixa solubilidade aquosa e limitada absorção intestinal, ambos os fatores limitantes da biodisponibilidade. Entre as estratégias para potencializar a solubilidade e a dissolução de fármacos lipofílicos, as dispersões sólidas estão crescendo em popularidade. Neste estudo, empregamos mistura dos tensoativos, poloxamer 407 e caprato de sódio, para produzir dispersão sólida contendo ácido ursólico, com o objetivo de aumentar tanto a dissolução do fármaco quanto a atividade tripanocida in vivo. Comparada à mistura física, a dispersão sólida apresentou maior densidade e menor tamanho de partícula. Os resultados da análise de espectroscopia no infravermelho com transformada de Fourier mostraram interações intermoleculares do tipo ligações de hidrogênio entre o fármaco e o poloxamer 407. Os experimentos de difratometria de raio-X revelaram a conversão do fármaco de sua forma cristalina para a forma amorfa, mais solúvel. Consequentemente, a solubilidade do ácido ursólico em dispersão sólida foi aumentada e o fármaco dissolveu-se de maneira mais rápida e completa. Em conjunto com as propriedades promotoras de absorção oral do caprato de sódio, estes resultados explicaram o aumento da atividade tripanocida in vivo do ácido ursólico em dispersão sólida, que também se provou segura após avaliação de citotoxicidade empregando a linhagem celular LLC-MK2.Unitermos: Ácido ursólico/atividade tripanocida. Doença de Chagas/tratamento. Tensoativos. Dispersões sólidas/dissolução. Poloxamer 407. Caproato de sódio.

Ursolic acid: Pharmacokinetics process in vitro and in vivo, a mini review

“…However, UA is almost insoluble in water and its bioavailability is poor. According to the biopharmaceutical classification system, UA is classified as a class IV drug in the biopharmaceutics classification system owing to its limited pharmacological effects due to low solubility in water and difficulty in permeating biological membranes . This type of drugs not only had slow dissolution, but also limited penetration through the gastrointestinal mucosa, therefore, these drugs' oral bioavailability was low.…”

“…According to the biopharmaceutical classification system, UA is classified as a class IV drug in the biopharmaceutics classification system owing to its limited pharmacological effects due to low solubility in water and difficulty in permeating biological membranes. [8] This type of drugs not only had slow dissolution, but also limited penetration through the gastrointestinal mucosa, there-fore, these drugs' oral bioavailability was low. For these reasons, some new approaches have been introduced to enhance the biopharmaceutical properties of this compound of UA, particularly drug delivery technologies.…”

A Review on Ursolic Acid: A Naturally Obtained Pentacyclic Triterpene

“…Lately, the search for biologically active substances from natural sources has boosted interest in its investigation. Studies show that UA has many pharmacological activities, including anti-inflammatory, hepatoprotective, antitumor, cardioprotective, neuroprotective, antimicrobial, antihyperlipidemic, antidiabetic, antifungal, antiviral, and trypanocidal [9]. But, it is classified as a class IV drug in the Biopharmaceutics Classification System thanks to its restricted pharmacological effects because of low solubility in water and problems in permeating biological membranes [10].…”

Ursolic acid nanoparticles for oral delivery prepared by emulsion solvent evaporation method: characterization, in vitro evaluation of radical scavenging activity and bioavailability

“…The main reason for this is hydrophobic nature and poor membrane permeability of UA [8]. The conditions are attracting more and more attention to explore, such as preparing self-microemulsifying [9], liposome [10], solid dispersion [11], inclusion compound [12] of UA, and these methods achieve certain effects. But these preparations still have some defects, which need high-level equipment and complex process.…”