FLUID PROPERTIES, SOLVENT EXCHANGE AND TRANSFORMATION OF IN SITU FORMING GEL AND MICROPARTICLES USING BETA-CYCLODEXTRIN AS A MATRIX FORMER

Abstract

β-cyclodextrin (β-CD) is interesting for using as a matrix former of the solvent exchange-induced in situ forming drug delivery system because of its apparent high solubility in some injectable solvents including 2-pyrrolidone (PYR), N-methyl pyrrolidone (NMP) and dimethyl sulfoxide (DMSO) while it exhibits limited aqueous solubility. The objective of this research was to investigate the fluid properties of β-CD solutions, physicochemical properties of β-CD precipitates prepared from three injectable solvents, physical properties of various solvents and oils used for in situ forming gel (ISG) and in situ forming microparticles (ISM) preparations. In addition, this research aimed to develop and evaluate the meloxicam (Mex)-loaded β-CD solvent exchange-induced ISG and ISM using β-CD as a matrix former for periodontitis treatment. Fluid properties of β-CD solution in NMP, DMSO and PYR were evaluated for pH, density, surface and interfacial tensions, contact angle, apparent viscosity and rheological behavior, water resistantance, matrix formation rate and injectability. The higher the concentration of β-CD resulted in the increased viscosity with the higher force and energy of injectability. β-CD in DMSO exhibited the highest ease of injectability and highest rate of matrix formation. The study of physicochemical properties of β-CD dried precipitates from above three solvents with different techniques revealed that there was a partial complexation of β-CD with respective solvents. According to the fluid and physicochemical properties, DMSO was more suitable for formulation development because of high concentrated β-CD loading capacity. The understanding of properties of solvents and oils used in ISM was also important. Therefore, the characterization of fluid and physicochemical properties of NMP, PYR, DMSO, glycofurol, triacetin, olive oil, camellia oil and isopropyl myristate (IPM) were also evaluated. The intrinsic viscosity of β-CD solution in DMSO was the lowest value of 0.07 dL/g while that in NMP was 0.084 dL/g. The high viscosity dissipation of PYR and triacetin slowed the diffusion of the amaranth solution. The miscibility test revealed the phase separation between DMSO and oils including camellia oil, olive oil and IPM. DMSO showed antibacterial activities against E.coli and C. albicans whereas all tested solvents exhibited the larger inhibition zones against C. albicans than bacteria. PYR inhibited methicillin-resistant Staphylococcus aureus (MRSA) such as S. aureus ATCC 43300 strain more effectively than NMP and glycofurol, respectively. DMSO showed its lowest cytotoxic activity against colorectal HCT 116 cell line which was followed by PYR, NMP, triacetin and glycofurol, respectively. β-CD solution in DMSO was used as the in situ forming system for Mex and used as the internal phase for Mex-loaded ISM whereas the camellia oil comprising 5% glycerol monostearate (GMS) was used as the external phase. Mex/β-CD solution showed the phase inversion into the matrix like after exposure to simulated crevicular fluid by solvent exchange. The attained prolonged release of Mex with minimized initial burst was achieved for Mex-loaded ISG. In addition, the external phase provoked the slower drug release of ISM than ISG. The drug release obeyed the Fickian diffusion in both Mex-loaded ISG and ISM systems comprising 40% β-CD. Upon exposure to simulated crevicular fluid, the ISM system comprising 40% β-CD with 5% GMS of external phase could initiate the system transforming into the microparticles. Therefore, the prepared Mex-loaded ISM system comprising 40% β-CD exhibited the potential controlled release delivery system for periodontitis.

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