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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

Comparison of kinetic solubility profiles of indomethacin between experimental and predicted results as a function of supersaturation rate generated with various drug solution (indomethacin in ethanol) infusion rates under nonsink dissolution condition (SI=0.1). Figure adapted in part from reference 47 (reproduced with permission from Molecular Pharmaceutics, Copyright American Chemical Society 2013).
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f0030: Comparison of kinetic solubility profiles of indomethacin between experimental and predicted results as a function of supersaturation rate generated with various drug solution (indomethacin in ethanol) infusion rates under nonsink dissolution condition (SI=0.1). Figure adapted in part from reference 47 (reproduced with permission from Molecular Pharmaceutics, Copyright American Chemical Society 2013).

Mentions: As discussed above, a sustained level of supersaturation can be achieved by gradual drug dissolution from ASD based on crosslinked PHEMA hydrogels, later surpassing that based on water-soluble polymer carriers as the drug concentration in the latter case declines due to more rapid de-supersaturation12. Similar observations showing more sustained supersaturation resulting from a more gradual drug release under nonsink dissolution conditions have also been reported for drug release from swelling clay minerals44 and ordered mesoporous silica materials14 in the absence of any crystallization inhibitor. In addition, Six et al.45 have demonstrated that Sporanox®, an ASD formulation of itraconazole in polymeric carrier HPMC having a slower in vitro dissolution rate than ASD prepared in Eudragit E100 and Eudragit E100/PVPVA64, actually produces a better oral bioavailability enhancement for itraconazole. In fact, fast dissolution of a supersaturating drug delivery system does not always translate to an optimal in vivo performance14,46. These observations suggest that the rate of supersaturation generation may play an important role in determining the overall kinetic solubility profiles and the level of supersaturation achieved. Although the degree of supersaturation is well recognized as the driving force for the nucleation and crystallization processes, the effect of rate of supersaturation generation on the time evolution of the overall kinetic solubility profiles was not recognized and had not been explored prior to our work. We have recently shown for the first time that the rate of supersaturation generation plays an important role in determining the level of transient solubility enhancement, thereby affecting the overall kinetic solubility profiles in a dissolution medium free of any crystallization inhibition47. We also proposed a comprehensive mechanistic model based on the classical nucleation theory taking into account both the particle growth and ripening processes to predict experimental kinetic solubility profiles under varying rates of supersaturation generation and recrystallization. This semi-quantitative analysis elucidates the dependency of the overall time-concentration profiles on the rate of supersaturation generation from the dissolution of non-equilibrium amorphous drugs. In the absence of any dissolved polymer or crystallization inhibitor, both of the experimental data and predicted results confirm that the faster rise of supersaturation will inevitably lead to an earlier but higher maximum kinetic solubility and a sharper decline in the de-supersaturation phase. Conversely, a slower rate of supersaturation generation results in a lower maximum kinetic solubility followed by a more gradual decline in drug concentration. These trends are clearly illustrated in Fig. 6 where experimental data at different rates of supersaturation generation (through drug infusion) are compared with simulated results based on our comprehensive mechanistic model47. Given the fact that the mechanistic model simulation was based solely on physical parameters reported in the literature without employing any curve fitting, the agreement between the experimental data and model prediction can be considered as quite good. These trends are also consistent with our results on ASDs based on crosslinked PHEMA hydrogels as reported in Figs. 4 and 5 where a slower drug release from the hydrogel results in a lower but broader and more sustained drug supersaturation.


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)

Comparison of kinetic solubility profiles of indomethacin between experimental and predicted results as a function of supersaturation rate generated with various drug solution (indomethacin in ethanol) infusion rates under nonsink dissolution condition (SI=0.1). Figure adapted in part from reference 47 (reproduced with permission from Molecular Pharmaceutics, Copyright American Chemical Society 2013).
© Copyright Policy - CC BY-NC-ND
Related In: Results  -  Collection

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

f0030: Comparison of kinetic solubility profiles of indomethacin between experimental and predicted results as a function of supersaturation rate generated with various drug solution (indomethacin in ethanol) infusion rates under nonsink dissolution condition (SI=0.1). Figure adapted in part from reference 47 (reproduced with permission from Molecular Pharmaceutics, Copyright American Chemical Society 2013).
Mentions: As discussed above, a sustained level of supersaturation can be achieved by gradual drug dissolution from ASD based on crosslinked PHEMA hydrogels, later surpassing that based on water-soluble polymer carriers as the drug concentration in the latter case declines due to more rapid de-supersaturation12. Similar observations showing more sustained supersaturation resulting from a more gradual drug release under nonsink dissolution conditions have also been reported for drug release from swelling clay minerals44 and ordered mesoporous silica materials14 in the absence of any crystallization inhibitor. In addition, Six et al.45 have demonstrated that Sporanox®, an ASD formulation of itraconazole in polymeric carrier HPMC having a slower in vitro dissolution rate than ASD prepared in Eudragit E100 and Eudragit E100/PVPVA64, actually produces a better oral bioavailability enhancement for itraconazole. In fact, fast dissolution of a supersaturating drug delivery system does not always translate to an optimal in vivo performance14,46. These observations suggest that the rate of supersaturation generation may play an important role in determining the overall kinetic solubility profiles and the level of supersaturation achieved. Although the degree of supersaturation is well recognized as the driving force for the nucleation and crystallization processes, the effect of rate of supersaturation generation on the time evolution of the overall kinetic solubility profiles was not recognized and had not been explored prior to our work. We have recently shown for the first time that the rate of supersaturation generation plays an important role in determining the level of transient solubility enhancement, thereby affecting the overall kinetic solubility profiles in a dissolution medium free of any crystallization inhibition47. We also proposed a comprehensive mechanistic model based on the classical nucleation theory taking into account both the particle growth and ripening processes to predict experimental kinetic solubility profiles under varying rates of supersaturation generation and recrystallization. This semi-quantitative analysis elucidates the dependency of the overall time-concentration profiles on the rate of supersaturation generation from the dissolution of non-equilibrium amorphous drugs. In the absence of any dissolved polymer or crystallization inhibitor, both of the experimental data and predicted results confirm that the faster rise of supersaturation will inevitably lead to an earlier but higher maximum kinetic solubility and a sharper decline in the de-supersaturation phase. Conversely, a slower rate of supersaturation generation results in a lower maximum kinetic solubility followed by a more gradual decline in drug concentration. These trends are clearly illustrated in Fig. 6 where experimental data at different rates of supersaturation generation (through drug infusion) are compared with simulated results based on our comprehensive mechanistic model47. Given the fact that the mechanistic model simulation was based solely on physical parameters reported in the literature without employing any curve fitting, the agreement between the experimental data and model prediction can be considered as quite good. These trends are also consistent with our results on ASDs based on crosslinked PHEMA hydrogels as reported in Figs. 4 and 5 where a slower drug release from the hydrogel results in a lower but broader and more sustained drug supersaturation.

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