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Development of novel modified drug delivery systems for improved solubility and oral bioavailability of practically water-insoluble tadalafil

Title
Development of novel modified drug delivery systems for improved solubility and oral bioavailability of practically water-insoluble tadalafil
Author
Dong Shik Kim
Alternative Author(s)
김동식
Advisor(s)
최한곤
Issue Date
2019. 8
Publisher
한양대학교
Degree
Doctor
Abstract
The objective of this research was to develop novel modified drug delivery systems for improved solubility and oral bioavailability of practically water-insoluble tadalafil. Ultimately, based on the research results, the system with maximizing the oral bioavailability of tadalafil has been attempted to be selected. The influence of carriers, such as polymers, surfactants and oils, on tadalafil solubility was evaluated. Among the carriers tested, copovidone and hydroxyl-β-cyclodextrin (HP-β-CD), sodium lauryl sulfate (SLS), D-α-tocopherol polyethylene glycol succinate (TPGS) and Tween 80, and peceol gave most increased drug solubility, resulting in selecting them as a suitable polymers, surfactants and oil, respectively. Afterwards, three modified drug delivery systems, such as solid dispersion, solid self-nanoemulsifying drug delivery system (SNEDDS) and inclusion compound, were chosen via the selected carriers. Their solubility, dissolution, physicochemical properties and pharmacokinetics in rats were assessed compared with tadalafil powder. Numerous solid dispersions were prepared with tadalafil and various ratios of copovidone and SLS via the spray drying technique. As the amount of copovidone and SLS were increased, the solubility and dissolution of drug in solvent evaporated solid dispersions were increased. As the ratio of copovidone/SLS was decreased and the carrier amount was increased, the solubility of drug in surface attached solid dispersions were increased. The formulation composed of tadalafil/copovidone/SLS at the weight ratio of 1/3/1 and 1/1.875/1.125 was selected as an optimized solvent evaporated and surface attached solid dispersion, respectively, because, with the least carrier amount, it gave the highest drug solubility and dissolution. The optimized tadalafil loaded liquid SNEDDS consisted of 50 mg of tadalafil in 1 mL of the mixture of peceol, Tween 80 and TPGS at the volume ratio of 30/20/50 was chosen, due to its smallest emulsion droplet. The effect of solid carrier and solvent on the drug solubility and dissolution of solid SNEDDS was investigated, resulting that calcium silicate and 50 % ethanol provided the highest drug solubility and dissolution. Tadalafil loaded solid SNEDDS formulations were prepared by mixing with 1 mL of the tadalafil loaded liquid SNEDDS, 0.5 g of calcium silicate and 100 mL of 50 % ethanol, subjecting to no treatment, shirasu porous glass (SPG) membrane emulsification and high pressure homogenization (HPH) and then spray drying. Among the solid SNEDDS formulations prepared, the solid SNEDDS treated with HPH presented the smallest and uniform emulsion droplet, leading to excellence in drug solubility and dissolution. Numerous inclusion compounds were prepared with various ratios of tadalafil and HP-β-CD using spray drying technique. As the amount of HP-β-CD increased, the drug solubility and dissolution in inclusion compounds were increased. The optimized inclusion compound was composed of tadalafil and HP-β-CD at the weight ratio of 1/4, showed the highest drug solubility and dissolution. All selected modified drug delivery systems significantly increased the drug solubility and dissolution compared with tadalafil powder. The drug solubility and dissolution at 30 min were enhanced in the order of: solvent evaporated solid dispersion > solid SNEDDS > surface attached solid dispersion > inclusion compound. Solvent evaporated solid dispersion and inclusion compound were observed to be small and spherical particles. Surface attached solid dispersion appeared that the hydrophilic carriers seemed to be attached to the surface of drug. Solid SNEDDS revealed that liquid SNEDDS was absorbed or coated inside the pores and surface of calcium silicate. Except the surface attached solid dispersion, crystalline drug was converted to an amorphous state in all formulations. Furthermore, except the inclusion compound, all systems provided significantly enhanced oral bioavailability of drug compared to tadalafil powder (P<0.05). The oral bioavailability of drug was ranked in order of: solvent evaporated solid dispersion  ≥  solid SNEDDS > surface attached solid dispersion >  inclusion compound. Amongst the modified drug delivery systems developed, the solvent evaporated solid dispersion with the most increased solubility (about 750 folds) and oral bioavailability (about 10 folds), would be recommended as a promising candidate for tadalafil loaded oral pharmaceutical products.
URI
http://dcollection.hanyang.ac.kr/common/orgView/000000110129http://repository.hanyang.ac.kr/handle/20.500.11754/109019
Appears in Collections:
GRADUATE SCHOOL[S](대학원) > PHARMACY(약학과) > Theses (Ph.D.)
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