Improved dissolution and pharmacokinetic behavior of cyclosporine A using high-energy amorphous solid dispersion approach

Abstract. Polyvinyl alcohol (PVAL) has not been investigated in a binary formulation as a concentrationenhancing polymer owing to its high melting point/high viscosity and poor organic solubility. Due to the unique attributes of the KinetiSol® dispersing (KSD) technology, PVAL has been enabled for this application and it is the aim of this paper to investigate various grades for improvement of the solubility and bioavailability of poorly water soluble active pharmaceutical ingredients. Solid amorphous dispersions were created with the model drug, itraconazole (ITZ), at a selected drug loading of 20%. Polymer grades were chosen with variation in molecular weight and degree of hydroxylation to determine the effects on performance. Differential scanning calorimetry, powder X-ray diffraction, polarized light microscopy, size exclusion chromatography, and dissolution testing were used to characterize the amorphous dispersions. An in vivo pharmacokinetic study in rats was also conducted to compare the selected formulation to current market formulations of ITZ. The 4-88 grade of PVAL was determined to be effective at enhancing solubility and bioavailability of itraconazole.

show abstract

“…hydroxyethylcellulose (HEC) (22). hydroxypropylcellulose (HPC) (23). polyvinyl acetate phthalate (PVAP) (5).…”

Section: Introductionmentioning

confidence: 99%

Use of Polyvinyl Alcohol as a Solubility-Enhancing Polymer for Poorly Water Soluble Drug Delivery (Part 1)

Brough

Miller²,

Keen³

et al. 2015

AAPS PharmSciTech

View full text Add to dashboard Cite

show abstract

“…[19][20][21] The factors impeding the absorption of CyA include the narrow absorption window in the upper gut, P-glycoprotein efflux from enterocytes, and extensive presystemic metabolism in the wall and liver. 22,23 To date, how to improve CyA's in vivo performance has been a widespread concern, and various oral drug carriers have emerged, such as solid dispersion, 19,24,25 nanosuspension, 26 liposomes, 27 lipid NPs, 28 self-microemulsifying drug-delivery system (SMEDDS), 16 and PLGA NPs. 17 Although each of these were reported to significantly increase CyA oral bioavailability, only the SMEDDS of CyA (Sandimmun Neoral ® ) was High-performance liquid chromatography (HPLC)-grade methanol and acetonitrile were purchased from Tedia (Carson City, CA, USA).…”

Section: Introductionmentioning

confidence: 99%

Enhancement of oral bioavailability of cyclosporine A: comparison of various nanoscale drug-delivery systems

Wang¹,

Qi²,

Weng

et al. 2014

IJN

View full text Add to dashboard Cite

A variety of nanoscale delivery systems have been shown to enhance the oral absorption of poorly water-soluble and poorly permeable drugs. However, the performance of these systems has seldom been evaluated simultaneously. The aim of this study was to compare the bioavailability enhancement effect of lipid-based nanocarriers with poly(lactic-co-glycolic acid) (PLGA) nanoparticles (NPs) to highlight the importance of the lipid composition, with cyclosporine A (CyA) as a model drug. CyA-loaded PLGA NPs, nanostructured lipid carriers (NLCs), and self-microemulsifying drug-delivery systems (SMEDDS) were prepared. The particle size of PLGA NPs (182.2±12.8 nm) was larger than that of NLCs (89.7±9.0 nm) and SMEDDS (26.9±1.9 nm). All vehicles are charged negatively. The entrapment efficiency of PLGA NPs and NLCs was 87.6%±1.6% and 80.3%±0.6%, respectively. In vitro release tests indicated that the cumulative release of CyA was lower than 4% from all vehicles, including Sandimmun Neoral ® , according to the dialysis method. Both NLCs and SMEDDS showed high relative oral bioavailability, 111.8% and 73.6%, respectively, after oral gavage administration to beagle dogs, which was not statistically different from commercial Sandimmun Neoral ® . However, PLGA NPs failed to achieve efficient absorption, with relative bioavailability of about 22.7%. It is concluded that lipid-based nanoscale drug-delivery systems are superior to polymeric NPs in enhancing oral bioavailability of poorly water-soluble and poorly permeable drugs.

show abstract

“…Interaction between DP and Polymer in SD-Eud/DP/TA The interaction of drug and polymer in SD formulation could give rise to attractive effects, including enhancement of the supersaturation of a drug, 17) suppression of the precipitation of a drug, 18) and stabilization of the amorphous state of a drug in SD. 19) FT-IR spectroscopic analysis was performed in order to investigate the possible interaction between DP and polymer in SD-Eud/DP/TA (Fig.…”

Section: )mentioning

confidence: 99%

Improved Dissolution of Dipyridamole with the Combination of pH-Modifier and Solid Dispersion Technology

Kojo

Matsunaga

Suzuki

et al. 2017

CHEMICAL & PHARMACEUTICAL BULLETIN

Self Cite

View full text Add to dashboard Cite

The aim of this study was to develop a pH-independent release formulation of dipyridamole (DP) by the combined use of pH-modifier technology and solid dispersion (SD) technology employing enteric polymer, Eudragit ® S100 (Eud). Tartaric acid (TA) was selected as an appropriate pH-modifier in terms of improving the dissolution behavior of DP under neutral conditions. Upon optimization of the ratio of TA to DP, SD of DP with Eud and TA (SD-Eud/DP/TA) was prepared by a freeze-drying method. Scanning electron microscopic images revealed that DP was dispersed in the polymer in SD-Eud/DP/TA, and DP in SD-Eud/DP/TA was in an amorphous state, supported by powder X-ray diffraction and differential scanning calorimetry analyses. The dissolution behavior of SD-Eud/DP/TA was not dependent on the pH of the medium, although SD-Eud/DP exhibited very limited dissolution behavior under neutral conditions. Spectroscopic analysis suggested that there might be inter-molecular interaction among DP, TA and enteric polymer in SD-Eud/DP/TA, possibly leading to the stable pH-independent dissolution behavior of SD-Eud/DP/TA. TA in SD-Eud/DP/TA promoted the degradation of DP, suggesting that improving the stability of DP in SD-Eud/DP/TA might be key for its practical use. From these results, pH-independent dissolution behavior of SD-Eud/DP/TA could be achieved by an enteric polymer-based solid dispersion with a pH-modifier. Key words dipyridamole; dissolution; enteric polymer; pH-modifier; solid dispersionRecently, a lot of drug candidates with poor solubility have been developed and such drugs constituted about 40% of all drug products. 1) In many cases, low solubility or slow dissolution of a poorly soluble drug in the gastrointestinal (GI) tract causes insufficient absorption of the drug for treatment. In order to improve the dissolution rate and solubility of poorly soluble drugs, various solubilization technologies have been developed, including amorphization, reduction of particle size, emulsification and solid dispersion (SD).2) However, these technologies might not always be effective for improving the dissolution behavior of drugs with pH-dependent solubility. 3)Weak basic drugs are one included among pH-dependent soluble drugs, and exhibit high solubility under gastric pH conditions, but low solubility under intestinal pH conditions. Such pH-dependent solubility of weak basic drugs leads to high variability of absorption among individuals with different GI pH conditions.4) It has been reported that pH-modifier technology could effectively improve the dissolution of drugs with pH-dependent solubility.5) A pH-modifying agent could change the microenvironmental pH of the drug particles to a lower or higher pH at which the drug could dissolve easily. 6) In order to improve the dissolution behavior of weak basic drugs, organic acids have been used as pH-modifying agents. 7)Dipyridamole [2,6-bis(diethanolamino)-4,8-dipiperidinopyrimido[5,4-d] pyrimidine] (DP), widely used as an antiplatelet for its attractive antithrombotic propertie...

show abstract

Improved dissolution and pharmacokinetic behavior of cyclosporine A using high-energy amorphous solid dispersion approach

Cited by 71 publications

References 36 publications

Use of Polyvinyl Alcohol as a Solubility-Enhancing Polymer for Poorly Water Soluble Drug Delivery (Part 1)

Use of Polyvinyl Alcohol as a Solubility-Enhancing Polymer for Poorly Water Soluble Drug Delivery (Part 1)

Enhancement of oral bioavailability of cyclosporine A: comparison of various nanoscale drug-delivery systems

Improved Dissolution of Dipyridamole with the Combination of pH-Modifier and Solid Dispersion Technology

Contact Info

Product

Resources

About

Improved dissolution and pharmacokinetic behavior of cyclosporine A using high-energy amorphous solid dispersion approach

Cited by 71 publications

References 36 publications

Use of Polyvinyl Alcohol as a Solubility-Enhancing Polymer for Poorly Water Soluble Drug Delivery (Part 1)

Use of Polyvinyl Alcohol as a Solubility-Enhancing Polymer for Poorly Water Soluble Drug Delivery (Part 1)

Enhancement of oral bioavailability of cyclosporine A: comparison of various nanoscale&nbsp;drug-delivery systems

Improved Dissolution of Dipyridamole with the Combination of pH-Modifier and Solid Dispersion Technology

Contact Info

Product

Resources

About

Enhancement of oral bioavailability of cyclosporine A: comparison of various nanoscale drug-delivery systems