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Combination of hydrotropic nicotinamide with nanoparticles for enhancing tacrolimus percutaneous delivery

View Article: PubMed Central - PubMed

ABSTRACT

Tacrolimus (FK506), an effective immunosuppressant for treating inflammatory skin diseases, hardly penetrates into and through the skin owing to its high hydrophobicity and molecular weight. The aim of this study was to develop a hybrid system based on nicotinamide (NIC) and nanoparticles (NPs) encapsulating FK506, such as FK506–NPs–NIC, for facilitating percutaneous delivery, which exploited virtues of both NIC and NPs to obtain the synergetic effect. Solubility and percutaneous permeation studies were carried out. The results showed that NIC could increase the solubility and permeability of FK506 and that 20% (w/v) NIC presented higher FK506 permeability and was thus chosen as the hydrotropic solution to solubilize FK506 and prepare FK506–NPs–NIC. Hyaluronic acid (HA) was chemically conjugated with cholesterol (Chol) to obtain amphiphilic conjugate of HA–Chol, which self-assembled NPs in 20% NIC solution containing FK506. The particle size, zeta potential, and morphology of NPs were characterized. The encapsulation efficiency and in vitro percutaneous permeation of NPs were evaluated in the presence and absence of NIC. The results demonstrated that hydrotropic solubilizing FK506 was readily encapsulated into NPs with a higher encapsulation efficiency of 79.2%±4.2%, and the combination of NPs with NIC exhibited a significantly synergistic effect on FK506 deposition within the skin (2.39±0.53 μg/cm2) and penetration through the skin (13.38±2.26 μg/cm2). The effect of the combination of NPs with NIC on drug permeation was further visualized by confocal laser scanning microscope through in vivo permeation studies, and the results confirmed that NPs–NIC synergistically enhanced the permeation of the drug into the skin. The cellular uptake performed in HaCaT cells presented a promoting effect of NPs on cellular uptake. These overall results demonstrated that HA–Chol–NPs–NIC can synergistically improve the percutaneous delivery of FK506, and it is a novel potential strategy based on a nano-sized carrier for FK506 to treat skin diseases.

No MeSH data available.


The plot of fluorescence intensity ratio (I388/I375) to the logarithmic of concentration (LogC) of HA–Chol conjugates with different DSs.Note: The CAC of HA–Chol with different DSs was the concentration under the inflection point of the curve.Abbreviations: CAC, critical aggregation concentration; DS, degree of substitution; HA–Chol, hyaluronic acid–cholesterol conjugates.
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f3-ijn-11-4037: The plot of fluorescence intensity ratio (I388/I375) to the logarithmic of concentration (LogC) of HA–Chol conjugates with different DSs.Note: The CAC of HA–Chol with different DSs was the concentration under the inflection point of the curve.Abbreviations: CAC, critical aggregation concentration; DS, degree of substitution; HA–Chol, hyaluronic acid–cholesterol conjugates.

Mentions: The CAC of HA–Chol was determined using the fluorescence excitation spectra method. Figure 3 shows the plot of fluorescence intensity ratio (I388/I375) to the logarithmic of concentration of HA–Chol conjugates. The CAC was determined by the HA–Chol threshold concentration to form self-assembled NPs. As shown in Figure 3, the CAC decreased with the increase in Chol DS. It was 43.7 μg/mL for HA–Chol 1, 11.5 μg/mL for HA–Chol 2, and 2.04 μg/mL for HA–Chol 3. Based on these data, HA–Chol could self-assemble to be NPs to incorporate poorly water-soluble drugs into their hydrophobic inner core.


Combination of hydrotropic nicotinamide with nanoparticles for enhancing tacrolimus percutaneous delivery
The plot of fluorescence intensity ratio (I388/I375) to the logarithmic of concentration (LogC) of HA–Chol conjugates with different DSs.Note: The CAC of HA–Chol with different DSs was the concentration under the inflection point of the curve.Abbreviations: CAC, critical aggregation concentration; DS, degree of substitution; HA–Chol, hyaluronic acid–cholesterol conjugates.
© Copyright Policy
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC4998035&req=5

f3-ijn-11-4037: The plot of fluorescence intensity ratio (I388/I375) to the logarithmic of concentration (LogC) of HA–Chol conjugates with different DSs.Note: The CAC of HA–Chol with different DSs was the concentration under the inflection point of the curve.Abbreviations: CAC, critical aggregation concentration; DS, degree of substitution; HA–Chol, hyaluronic acid–cholesterol conjugates.
Mentions: The CAC of HA–Chol was determined using the fluorescence excitation spectra method. Figure 3 shows the plot of fluorescence intensity ratio (I388/I375) to the logarithmic of concentration of HA–Chol conjugates. The CAC was determined by the HA–Chol threshold concentration to form self-assembled NPs. As shown in Figure 3, the CAC decreased with the increase in Chol DS. It was 43.7 μg/mL for HA–Chol 1, 11.5 μg/mL for HA–Chol 2, and 2.04 μg/mL for HA–Chol 3. Based on these data, HA–Chol could self-assemble to be NPs to incorporate poorly water-soluble drugs into their hydrophobic inner core.

View Article: PubMed Central - PubMed

ABSTRACT

Tacrolimus (FK506), an effective immunosuppressant for treating inflammatory skin diseases, hardly penetrates into and through the skin owing to its high hydrophobicity and molecular weight. The aim of this study was to develop a hybrid system based on nicotinamide (NIC) and nanoparticles (NPs) encapsulating FK506, such as FK506–NPs–NIC, for facilitating percutaneous delivery, which exploited virtues of both NIC and NPs to obtain the synergetic effect. Solubility and percutaneous permeation studies were carried out. The results showed that NIC could increase the solubility and permeability of FK506 and that 20% (w/v) NIC presented higher FK506 permeability and was thus chosen as the hydrotropic solution to solubilize FK506 and prepare FK506–NPs–NIC. Hyaluronic acid (HA) was chemically conjugated with cholesterol (Chol) to obtain amphiphilic conjugate of HA–Chol, which self-assembled NPs in 20% NIC solution containing FK506. The particle size, zeta potential, and morphology of NPs were characterized. The encapsulation efficiency and in vitro percutaneous permeation of NPs were evaluated in the presence and absence of NIC. The results demonstrated that hydrotropic solubilizing FK506 was readily encapsulated into NPs with a higher encapsulation efficiency of 79.2%±4.2%, and the combination of NPs with NIC exhibited a significantly synergistic effect on FK506 deposition within the skin (2.39±0.53 μg/cm2) and penetration through the skin (13.38±2.26 μg/cm2). The effect of the combination of NPs with NIC on drug permeation was further visualized by confocal laser scanning microscope through in vivo permeation studies, and the results confirmed that NPs–NIC synergistically enhanced the permeation of the drug into the skin. The cellular uptake performed in HaCaT cells presented a promoting effect of NPs on cellular uptake. These overall results demonstrated that HA–Chol–NPs–NIC can synergistically improve the percutaneous delivery of FK506, and it is a novel potential strategy based on a nano-sized carrier for FK506 to treat skin diseases.

No MeSH data available.