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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.

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In vitro skin percutaneous studies of FK506 from different concentrations of NIC solution.Notes: The percutaneous studies were performed with vertical Franz diffusion cell at 32°C±1°C. Data represent mean ± SD, n=4 per group. *P<0.05 in comparison with FK506 aqueous suspension. The concentration of FK506 in each formulation was 1 mg/mL.Abbreviations: FK506, tacrolimus; h, hours; NIC, nicotinamide; 10% NIC, FK506 dissolved in 10% nicotinamide aqueous solution; 20% NIC, FK506 dissolved in 20% nicotinamide aqueous solution; 30% NIC, FK506 dissolved in 30% nicotinamide aqueous solution; SD, standard deviation.
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f2-ijn-11-4037: In vitro skin percutaneous studies of FK506 from different concentrations of NIC solution.Notes: The percutaneous studies were performed with vertical Franz diffusion cell at 32°C±1°C. Data represent mean ± SD, n=4 per group. *P<0.05 in comparison with FK506 aqueous suspension. The concentration of FK506 in each formulation was 1 mg/mL.Abbreviations: FK506, tacrolimus; h, hours; NIC, nicotinamide; 10% NIC, FK506 dissolved in 10% nicotinamide aqueous solution; 20% NIC, FK506 dissolved in 20% nicotinamide aqueous solution; 30% NIC, FK506 dissolved in 30% nicotinamide aqueous solution; SD, standard deviation.

Mentions: As NIC improved the solubility of FK506, it was supposed that NIC could enhance the percutaneous permeation of FK506. The cumulative amount of FK506 permeated, retention, and flux from in vitro permeation are listed in Table 2, and the cumulative permeated amount of FK506 through the skin is plotted as a function of time (Figure 2). Based on Table 2, the cumulative permeated amount, retention, and flux of FK506 were enhanced in comparison with FK506 suspension when 10% (w/v) or 20% (w/v) NIC was used as the hydrotropic agent (P<0.05). It was possibly attributed to the increased solubility of FK506 in NIC solution, which increased FK506 concentration gradient and partition of skin/vehicle. Moreover, NIC could easily permeate into skin when 20% NIC solution without FK506 was performed in in vitro permeation studies (data not shown). When the complex of FK506–NIC formed or self-aggregated NIC segregated FK506 from water in the NIC hydrotropic system, FK506 permeation might have enhanced due to the driving force from NIC permeation. Interestingly, when FK506 was present in 20% NIC solution, the cumulative permeated amount, retention, and flux were higher than that in 10% NIC solution or 30% NIC solution. Therefore, 20% NIC solution was chosen as the hydrotropic solution for preparing NPs.


Combination of hydrotropic nicotinamide with nanoparticles for enhancing tacrolimus percutaneous delivery
In vitro skin percutaneous studies of FK506 from different concentrations of NIC solution.Notes: The percutaneous studies were performed with vertical Franz diffusion cell at 32°C±1°C. Data represent mean ± SD, n=4 per group. *P<0.05 in comparison with FK506 aqueous suspension. The concentration of FK506 in each formulation was 1 mg/mL.Abbreviations: FK506, tacrolimus; h, hours; NIC, nicotinamide; 10% NIC, FK506 dissolved in 10% nicotinamide aqueous solution; 20% NIC, FK506 dissolved in 20% nicotinamide aqueous solution; 30% NIC, FK506 dissolved in 30% nicotinamide aqueous solution; SD, standard deviation.
© Copyright Policy
Related In: Results  -  Collection

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

f2-ijn-11-4037: In vitro skin percutaneous studies of FK506 from different concentrations of NIC solution.Notes: The percutaneous studies were performed with vertical Franz diffusion cell at 32°C±1°C. Data represent mean ± SD, n=4 per group. *P<0.05 in comparison with FK506 aqueous suspension. The concentration of FK506 in each formulation was 1 mg/mL.Abbreviations: FK506, tacrolimus; h, hours; NIC, nicotinamide; 10% NIC, FK506 dissolved in 10% nicotinamide aqueous solution; 20% NIC, FK506 dissolved in 20% nicotinamide aqueous solution; 30% NIC, FK506 dissolved in 30% nicotinamide aqueous solution; SD, standard deviation.
Mentions: As NIC improved the solubility of FK506, it was supposed that NIC could enhance the percutaneous permeation of FK506. The cumulative amount of FK506 permeated, retention, and flux from in vitro permeation are listed in Table 2, and the cumulative permeated amount of FK506 through the skin is plotted as a function of time (Figure 2). Based on Table 2, the cumulative permeated amount, retention, and flux of FK506 were enhanced in comparison with FK506 suspension when 10% (w/v) or 20% (w/v) NIC was used as the hydrotropic agent (P<0.05). It was possibly attributed to the increased solubility of FK506 in NIC solution, which increased FK506 concentration gradient and partition of skin/vehicle. Moreover, NIC could easily permeate into skin when 20% NIC solution without FK506 was performed in in vitro permeation studies (data not shown). When the complex of FK506–NIC formed or self-aggregated NIC segregated FK506 from water in the NIC hydrotropic system, FK506 permeation might have enhanced due to the driving force from NIC permeation. Interestingly, when FK506 was present in 20% NIC solution, the cumulative permeated amount, retention, and flux were higher than that in 10% NIC solution or 30% NIC solution. Therefore, 20% NIC solution was chosen as the hydrotropic solution for preparing NPs.

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&ndash;NPs&ndash;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&ndash;NPs&ndash;NIC. Hyaluronic acid (HA) was chemically conjugated with cholesterol (Chol) to obtain amphiphilic conjugate of HA&ndash;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%&plusmn;4.2%, and the combination of NPs with NIC exhibited a significantly synergistic effect on FK506 deposition within the skin (2.39&plusmn;0.53 &mu;g/cm2) and penetration through the skin (13.38&plusmn;2.26 &mu;g/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&ndash;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&ndash;Chol&ndash;NPs&ndash;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.


Related in: MedlinePlus