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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: 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.

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

Classification of solid dispersion/solution of drug molecules in polymeric carrier matrix.
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f0005: Classification of solid dispersion/solution of drug molecules in polymeric carrier matrix.

Mentions: Physical instability, such as crystallization on ageing, and manufacturing challenges have limited the success in commercial applications of amorphous pharmaceuticals. Since reduced molecular mobility is crucial for the retardation of drug nucleation and crystallization, the selection of suitable carriers is determined by the confinement properties of amorphous drugs. Entrapped drug molecules in polymeric carrier matrices can be classified as crystalline solid dispersion (2-phase system), amorphous solid dispersion (2-phase system) and solid solution (1-phase system) as illustrated in Fig. 1. Compared to the 1-phase solid solution in which drug molecules are dissolved or molecularly dispersed in the carrier, the 2-phase dispersion systems contain a separated phase of either crystalline (long-range molecular order) or amorphous drugs (short-range molecular order). In reality, formulations based on ASD may also contain a mixture or hybrid of both the 2-phase and 1-phase systems. In the case of nonporous ASD carriers where amorphous drug molecules are completely dissolved (i.e., one-phase solid solution), carriers with extremely low drug diffusivities such as “glassy polymers” (i.e., glass transition temperature, Tg, much higher than the ambient temperature) will exhibit better ASD stability due to hindered drug diffusion and inhibition of drug precipitation in the glassy matrix. The presence of specific drug-carrier intermolecular interactions due to hydrogen bonding, dipole-dipole attraction and van der Waals forces further stabilizes the entrapped amorphous drug preventing it from nucleating and becoming crystalline. On the other hand, in porous carriers where the incorporated bulk amorphous drug is localized in interstitial pore space (i.e., not molecularly dispersed), the nucleation and crystallization of this bulk amorphous drug can give rise to stability issues. However, the drug nucleation and crystallization rates can be reduced if the size of the pore is sufficiently small compared to that of the critical nucleus such that it is energetically unfavorable for nuclei to grow13–15. Table 1 summarizes available water-insoluble carriers utilized to convert poorly water-soluble model drugs into amorphous formulations categorized by their physicochemical characteristics such as porosity, location of amorphous drug and carrier chemical composition.


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)

Classification of solid dispersion/solution of drug molecules in polymeric carrier matrix.
© Copyright Policy - CC BY-NC-ND
Related In: Results  -  Collection

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

f0005: Classification of solid dispersion/solution of drug molecules in polymeric carrier matrix.
Mentions: Physical instability, such as crystallization on ageing, and manufacturing challenges have limited the success in commercial applications of amorphous pharmaceuticals. Since reduced molecular mobility is crucial for the retardation of drug nucleation and crystallization, the selection of suitable carriers is determined by the confinement properties of amorphous drugs. Entrapped drug molecules in polymeric carrier matrices can be classified as crystalline solid dispersion (2-phase system), amorphous solid dispersion (2-phase system) and solid solution (1-phase system) as illustrated in Fig. 1. Compared to the 1-phase solid solution in which drug molecules are dissolved or molecularly dispersed in the carrier, the 2-phase dispersion systems contain a separated phase of either crystalline (long-range molecular order) or amorphous drugs (short-range molecular order). In reality, formulations based on ASD may also contain a mixture or hybrid of both the 2-phase and 1-phase systems. In the case of nonporous ASD carriers where amorphous drug molecules are completely dissolved (i.e., one-phase solid solution), carriers with extremely low drug diffusivities such as “glassy polymers” (i.e., glass transition temperature, Tg, much higher than the ambient temperature) will exhibit better ASD stability due to hindered drug diffusion and inhibition of drug precipitation in the glassy matrix. The presence of specific drug-carrier intermolecular interactions due to hydrogen bonding, dipole-dipole attraction and van der Waals forces further stabilizes the entrapped amorphous drug preventing it from nucleating and becoming crystalline. On the other hand, in porous carriers where the incorporated bulk amorphous drug is localized in interstitial pore space (i.e., not molecularly dispersed), the nucleation and crystallization of this bulk amorphous drug can give rise to stability issues. However, the drug nucleation and crystallization rates can be reduced if the size of the pore is sufficiently small compared to that of the critical nucleus such that it is energetically unfavorable for nuclei to grow13–15. Table 1 summarizes available water-insoluble carriers utilized to convert poorly water-soluble model drugs into amorphous formulations categorized by their physicochemical characteristics such as porosity, location of amorphous drug and carrier chemical composition.

Bottom Line: 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.

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