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Crosslinked hydrogels-a promising class of insoluble solid molecular dispersion carriers for enhancing the delivery of poorly soluble drugs.

Sun DD, Lee PI - Acta Pharm Sin B (2014)

Bottom Line: Water-insoluble materials containing amorphous solid dispersions (ASD) are an emerging category of drug carriers which can effectively improve dissolution kinetics and kinetic solubility of poorly soluble drugs.So far, ASD systems based on glassy PHEMA have been shown to be very effective in retarding precipitation of amorphous drugs in the solid state to achieve a robust physical stability.This review summarizes recent research efforts in investigating the potential of developing crosslinked PHEMA hydrogels as a promising alternative to conventional water-soluble ASD carriers, and a related finding that the rate of supersaturation generation does affect the kinetic solubility profiles implications to hydrogel based ASDs.

View Article: PubMed Central - PubMed

Affiliation: Department of Pharmaceutical Sciences, Leslie Dan Faculty of Pharmacy, University of Toronto, Toronto M5S 3M2, Ontario, Canada.

ABSTRACT
Water-insoluble materials containing amorphous solid dispersions (ASD) are an emerging category of drug carriers which can effectively improve dissolution kinetics and kinetic solubility of poorly soluble drugs. ASDs based on water-insoluble crosslinked hydrogels have unique features in contrast to those based on conventional water-soluble and water-insoluble carriers. For example, solid molecular dispersions of poorly soluble drugs in poly(2-hydroxyethyl methacrylate) (PHEMA) can maintain a high level of supersaturation over a prolonged period of time via a feedback-controlled diffusion mechanism thus avoiding the initial surge of supersaturation followed by a sharp decline in drug concentration typically encountered with ASDs based on water-soluble polymers. The creation of both immediate- and controlled-release ASD dosage forms is also achievable with the PHEMA based hydrogels. So far, ASD systems based on glassy PHEMA have been shown to be very effective in retarding precipitation of amorphous drugs in the solid state to achieve a robust physical stability. This review summarizes recent research efforts in investigating the potential of developing crosslinked PHEMA hydrogels as a promising alternative to conventional water-soluble ASD carriers, and a related finding that the rate of supersaturation generation does affect the kinetic solubility profiles implications to hydrogel based ASDs.

No MeSH data available.


Related in: MedlinePlus

SEM images showing surface morphology (A–C) and cross section (D–F) of PHEMA beads (crosslinked with 0.66 mol% EDGMA) at different indomethacin loading levels: (A) 48.1% w/w, (B) 26.1% w/w, (C) 0% w/w, (D) 41.4% w/w, (E) 26.1% w/w and (F) 0% w/w. Images adapted from reference 12 (reproduced with permission from the European Journal of Pharmaceutics and Biopharmaceutics, Copyright Elsevier 2012).
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f0015: SEM images showing surface morphology (A–C) and cross section (D–F) of PHEMA beads (crosslinked with 0.66 mol% EDGMA) at different indomethacin loading levels: (A) 48.1% w/w, (B) 26.1% w/w, (C) 0% w/w, (D) 41.4% w/w, (E) 26.1% w/w and (F) 0% w/w. Images adapted from reference 12 (reproduced with permission from the European Journal of Pharmaceutics and Biopharmaceutics, Copyright Elsevier 2012).

Mentions: ASD in PHEMA hydrogels with various levels of drug loading can be achieved by equilibrating purified PHEMA beads in a concentrated drug solution prepared in a good swelling solvent (e.g., ethanol). Subsequent filtration, rinsing and vacuum drying after the equilibrium sorption process result in glassy hydrogel beads containing uniformly dissolved or dispersed drug. This preparation method involving swelling, drug sorption, followed by solvent evaporation requires the evaporative removal of only a limited amount of solvent imbibed into the hydrogels during the drug loading process, thereby significantly reducing the amount of organic solvent usage comparing to that of the conventional spray drying process for ASDs based on water-soluble polymers where the removal of 90% w/w or more organic solvent is typically required. Thus far, ASDs of model poorly water-soluble drugs such as diclofenac sodium, naproxen, piroxicam and indomethacin have been successfully incorporated in PHEMA hydrogels with a maximum drug loading up to approximately 40–50% w/w11,12. For example, indomethacin-loaded PHEMA hydrogel beads at various drug loading levels as a function of crosslinking agent concentration and loading solution concentration are shown in Fig. 2, where a transition of physical appearance from being pale yellow and transparent (i.e., containing dissolved drug) to opaque (i.e., containing precipitated drug) when the drug loading exceeds a threshold of approximately 40% w/w indomethacin. Representative surface and cross-sectional SEM images of Fig. 3 illustrate that both pure PHEMA and indomethacin-loaded PHEMA hydrogel beads appear to be homogenous and nonporous in morphology in the interior without any significant surface irregularities. The physical state (e.g., amorphous or crystalline polymorph) of the loaded drug can be confirmed by the presence of certain characteristic peaks in the X-ray diffraction (XRD) patterns of the drug-loaded hydrogel beads. A threshold drug loading level of up to 30%–40% w/w typically exists in PHEMA hydrogels above which amorphous-to-crystalline transition tends to occur11,12. No drug melting endotherms were detected from the differential scanning calorimetry (DSC) thermograms of drug-PHEMA ASD samples below such threshold drug loading level, reflecting the existence of a completely amorphous phase of dissolved drug in the hydrogel matrix. The thermal analysis by DSC also shows that the Tg of drug-PHEMA ASD decreases as the drug loading increases due to the plasticizing effect of dissolved drug on the polymer network (i.e., PHEMA has a Tg much higher than that of the model drugs). In addition, spectroscopic analysis by fourier transformed inferred (FTIR) was used to confirm the presence of hydrogen bonding between the drug and the polymer in diclofenac sodium-, naproxen- and indomethacin-PHEMA ASD samples. A robust physical stability has also been demonstrated in indomethacin-PHEMA ASD by using polarized light microscopy to detect the onset of drug precipitation and no drug precipitation was observed for up to 8 months under direct exposure to an accelerated storage condition (40 °C/75% RH) for indomethacin loading levels below 16.7% w/w12.


Crosslinked hydrogels-a promising class of insoluble solid molecular dispersion carriers for enhancing the delivery of poorly soluble drugs.

Sun DD, Lee PI - Acta Pharm Sin B (2014)

SEM images showing surface morphology (A–C) and cross section (D–F) of PHEMA beads (crosslinked with 0.66 mol% EDGMA) at different indomethacin loading levels: (A) 48.1% w/w, (B) 26.1% w/w, (C) 0% w/w, (D) 41.4% w/w, (E) 26.1% w/w and (F) 0% w/w. Images adapted from reference 12 (reproduced with permission from the European Journal of Pharmaceutics and Biopharmaceutics, Copyright Elsevier 2012).
© Copyright Policy - CC BY-NC-ND
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4590291&req=5

f0015: SEM images showing surface morphology (A–C) and cross section (D–F) of PHEMA beads (crosslinked with 0.66 mol% EDGMA) at different indomethacin loading levels: (A) 48.1% w/w, (B) 26.1% w/w, (C) 0% w/w, (D) 41.4% w/w, (E) 26.1% w/w and (F) 0% w/w. Images adapted from reference 12 (reproduced with permission from the European Journal of Pharmaceutics and Biopharmaceutics, Copyright Elsevier 2012).
Mentions: ASD in PHEMA hydrogels with various levels of drug loading can be achieved by equilibrating purified PHEMA beads in a concentrated drug solution prepared in a good swelling solvent (e.g., ethanol). Subsequent filtration, rinsing and vacuum drying after the equilibrium sorption process result in glassy hydrogel beads containing uniformly dissolved or dispersed drug. This preparation method involving swelling, drug sorption, followed by solvent evaporation requires the evaporative removal of only a limited amount of solvent imbibed into the hydrogels during the drug loading process, thereby significantly reducing the amount of organic solvent usage comparing to that of the conventional spray drying process for ASDs based on water-soluble polymers where the removal of 90% w/w or more organic solvent is typically required. Thus far, ASDs of model poorly water-soluble drugs such as diclofenac sodium, naproxen, piroxicam and indomethacin have been successfully incorporated in PHEMA hydrogels with a maximum drug loading up to approximately 40–50% w/w11,12. For example, indomethacin-loaded PHEMA hydrogel beads at various drug loading levels as a function of crosslinking agent concentration and loading solution concentration are shown in Fig. 2, where a transition of physical appearance from being pale yellow and transparent (i.e., containing dissolved drug) to opaque (i.e., containing precipitated drug) when the drug loading exceeds a threshold of approximately 40% w/w indomethacin. Representative surface and cross-sectional SEM images of Fig. 3 illustrate that both pure PHEMA and indomethacin-loaded PHEMA hydrogel beads appear to be homogenous and nonporous in morphology in the interior without any significant surface irregularities. The physical state (e.g., amorphous or crystalline polymorph) of the loaded drug can be confirmed by the presence of certain characteristic peaks in the X-ray diffraction (XRD) patterns of the drug-loaded hydrogel beads. A threshold drug loading level of up to 30%–40% w/w typically exists in PHEMA hydrogels above which amorphous-to-crystalline transition tends to occur11,12. No drug melting endotherms were detected from the differential scanning calorimetry (DSC) thermograms of drug-PHEMA ASD samples below such threshold drug loading level, reflecting the existence of a completely amorphous phase of dissolved drug in the hydrogel matrix. The thermal analysis by DSC also shows that the Tg of drug-PHEMA ASD decreases as the drug loading increases due to the plasticizing effect of dissolved drug on the polymer network (i.e., PHEMA has a Tg much higher than that of the model drugs). In addition, spectroscopic analysis by fourier transformed inferred (FTIR) was used to confirm the presence of hydrogen bonding between the drug and the polymer in diclofenac sodium-, naproxen- and indomethacin-PHEMA ASD samples. A robust physical stability has also been demonstrated in indomethacin-PHEMA ASD by using polarized light microscopy to detect the onset of drug precipitation and no drug precipitation was observed for up to 8 months under direct exposure to an accelerated storage condition (40 °C/75% RH) for indomethacin loading levels below 16.7% w/w12.

Bottom Line: Water-insoluble materials containing amorphous solid dispersions (ASD) are an emerging category of drug carriers which can effectively improve dissolution kinetics and kinetic solubility of poorly soluble drugs.So far, ASD systems based on glassy PHEMA have been shown to be very effective in retarding precipitation of amorphous drugs in the solid state to achieve a robust physical stability.This review summarizes recent research efforts in investigating the potential of developing crosslinked PHEMA hydrogels as a promising alternative to conventional water-soluble ASD carriers, and a related finding that the rate of supersaturation generation does affect the kinetic solubility profiles implications to hydrogel based ASDs.

View Article: PubMed Central - PubMed

Affiliation: Department of Pharmaceutical Sciences, Leslie Dan Faculty of Pharmacy, University of Toronto, Toronto M5S 3M2, Ontario, Canada.

ABSTRACT
Water-insoluble materials containing amorphous solid dispersions (ASD) are an emerging category of drug carriers which can effectively improve dissolution kinetics and kinetic solubility of poorly soluble drugs. ASDs based on water-insoluble crosslinked hydrogels have unique features in contrast to those based on conventional water-soluble and water-insoluble carriers. For example, solid molecular dispersions of poorly soluble drugs in poly(2-hydroxyethyl methacrylate) (PHEMA) can maintain a high level of supersaturation over a prolonged period of time via a feedback-controlled diffusion mechanism thus avoiding the initial surge of supersaturation followed by a sharp decline in drug concentration typically encountered with ASDs based on water-soluble polymers. The creation of both immediate- and controlled-release ASD dosage forms is also achievable with the PHEMA based hydrogels. So far, ASD systems based on glassy PHEMA have been shown to be very effective in retarding precipitation of amorphous drugs in the solid state to achieve a robust physical stability. This review summarizes recent research efforts in investigating the potential of developing crosslinked PHEMA hydrogels as a promising alternative to conventional water-soluble ASD carriers, and a related finding that the rate of supersaturation generation does affect the kinetic solubility profiles implications to hydrogel based ASDs.

No MeSH data available.


Related in: MedlinePlus