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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.


Confocal laser scanning microscopy of skin sections of Sprague Dawley rats after 4 hours of in vivo administration of (A) C6 aqueous suspension, (B) C6–NIC complex suspension, (C) C6–HA–Chol–NP suspension, and (D) C6–HA–Chol–NPs–NIC suspension.Notes: The concentration of C6 in each formulation was 1 mg/mL, and the green fluorescence represented C6. Scale bar: 50 μm. Magnification ×100.Abbreviations: C6, coumarin 6; C6–HA–Chol–NPs, coumarin 6-loaded hyaluronic acid–cholesterol nanoparticles; C6–HA–Chol–NPs–NIC, coumarin 6-loaded hyaluronic acid–cholesterol nanoparticles containing nicotinamide; C6–NIC complex, coumarin 6–nicotinamide complex; h, hours.
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f6-ijn-11-4037: Confocal laser scanning microscopy of skin sections of Sprague Dawley rats after 4 hours of in vivo administration of (A) C6 aqueous suspension, (B) C6–NIC complex suspension, (C) C6–HA–Chol–NP suspension, and (D) C6–HA–Chol–NPs–NIC suspension.Notes: The concentration of C6 in each formulation was 1 mg/mL, and the green fluorescence represented C6. Scale bar: 50 μm. Magnification ×100.Abbreviations: C6, coumarin 6; C6–HA–Chol–NPs, coumarin 6-loaded hyaluronic acid–cholesterol nanoparticles; C6–HA–Chol–NPs–NIC, coumarin 6-loaded hyaluronic acid–cholesterol nanoparticles containing nicotinamide; C6–NIC complex, coumarin 6–nicotinamide complex; h, hours.

Mentions: The deposition of fluorescently labeled formulations was evaluated using CLSM. C6 was employed as a hydrophobic fluorescent probe. The skin permeation from C6 aqueous suspension, 20% (w/v) NIC solution, C6-loaded HA–Chol–NPs, and C6-loaded HA–Chol–NPs–NIC was observed. The results of CLSM experiments following 4 hours of incubation are illustrated in Figure 6. After 4 hours of application, the confocal images presented that the aqueous suspension delivered very little C6 into the skin (Figure 6A). When C6 was hydrotropically solubilized in 20% NIC solution, C6 could permeate into deeper skin layers (Figure 6B). However, when C6 was loaded in HA–Chol–NPs, the strong fluorescence intensity was only distributed in SC and hair follicles (Figure 6C), which indicated that NPs played predominantly the role of drug carrier after 4 hours of permeation. The fluorescence intensity of C6-loaded HA–Chol–NPs or C6–NIC solution was stronger than that of C6 suspension, indicating that either NIC or HA–Chol–NPs alone could enhance the retention of drugs in the skin. When C6 was loaded in the HA–Chol–NPs–NIC system, the fluorescence intensity within the skin was significantly higher than that of the NIC solution or HA–Chol–NPs alone, especially in the epidermis (Figure 6D). These results supported the results from the in vitro permeation experiments and confirmed the assumption that HA–Chol–NPs–NIC presented a synergistic effect on drug permeation in the skin after the drug incorporated into NPs with a hydrotropic NIC system.


Combination of hydrotropic nicotinamide with nanoparticles for enhancing tacrolimus percutaneous delivery
Confocal laser scanning microscopy of skin sections of Sprague Dawley rats after 4 hours of in vivo administration of (A) C6 aqueous suspension, (B) C6–NIC complex suspension, (C) C6–HA–Chol–NP suspension, and (D) C6–HA–Chol–NPs–NIC suspension.Notes: The concentration of C6 in each formulation was 1 mg/mL, and the green fluorescence represented C6. Scale bar: 50 μm. Magnification ×100.Abbreviations: C6, coumarin 6; C6–HA–Chol–NPs, coumarin 6-loaded hyaluronic acid–cholesterol nanoparticles; C6–HA–Chol–NPs–NIC, coumarin 6-loaded hyaluronic acid–cholesterol nanoparticles containing nicotinamide; C6–NIC complex, coumarin 6–nicotinamide complex; h, hours.
© Copyright Policy
Related In: Results  -  Collection

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

f6-ijn-11-4037: Confocal laser scanning microscopy of skin sections of Sprague Dawley rats after 4 hours of in vivo administration of (A) C6 aqueous suspension, (B) C6–NIC complex suspension, (C) C6–HA–Chol–NP suspension, and (D) C6–HA–Chol–NPs–NIC suspension.Notes: The concentration of C6 in each formulation was 1 mg/mL, and the green fluorescence represented C6. Scale bar: 50 μm. Magnification ×100.Abbreviations: C6, coumarin 6; C6–HA–Chol–NPs, coumarin 6-loaded hyaluronic acid–cholesterol nanoparticles; C6–HA–Chol–NPs–NIC, coumarin 6-loaded hyaluronic acid–cholesterol nanoparticles containing nicotinamide; C6–NIC complex, coumarin 6–nicotinamide complex; h, hours.
Mentions: The deposition of fluorescently labeled formulations was evaluated using CLSM. C6 was employed as a hydrophobic fluorescent probe. The skin permeation from C6 aqueous suspension, 20% (w/v) NIC solution, C6-loaded HA–Chol–NPs, and C6-loaded HA–Chol–NPs–NIC was observed. The results of CLSM experiments following 4 hours of incubation are illustrated in Figure 6. After 4 hours of application, the confocal images presented that the aqueous suspension delivered very little C6 into the skin (Figure 6A). When C6 was hydrotropically solubilized in 20% NIC solution, C6 could permeate into deeper skin layers (Figure 6B). However, when C6 was loaded in HA–Chol–NPs, the strong fluorescence intensity was only distributed in SC and hair follicles (Figure 6C), which indicated that NPs played predominantly the role of drug carrier after 4 hours of permeation. The fluorescence intensity of C6-loaded HA–Chol–NPs or C6–NIC solution was stronger than that of C6 suspension, indicating that either NIC or HA–Chol–NPs alone could enhance the retention of drugs in the skin. When C6 was loaded in the HA–Chol–NPs–NIC system, the fluorescence intensity within the skin was significantly higher than that of the NIC solution or HA–Chol–NPs alone, especially in the epidermis (Figure 6D). These results supported the results from the in vitro permeation experiments and confirmed the assumption that HA–Chol–NPs–NIC presented a synergistic effect on drug permeation in the skin after the drug incorporated into NPs with a hydrotropic NIC system.

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.