Permeation Pathway of Macromolecules and Nanospheres through Skin

Todo, Hiroaki; Kimura, Eriko; Yasuno, Hirotaka; Tokudome, Yoshihiro; Hashimoto, Fumie; Ikarashi, Yoshiaki; Sugibayashi, Kenji

doi:10.1248/bpb.33.1394

Cited by 50 publications

(27 citation statements)

References 22 publications

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“…The reduction ratio of permeability coefficients by hair follicle-plugging for 99.5% EtOH was slightly lower than that for 0% or 20% EtOH because of the intrinsically very low permeabilities of FL and FD-4 for 99.5% EtOH. We previously reported that FL and FD-4 permeabilities through three-dimensional cultured skin were markedly lower than those through hairless rat skin, 28) and concluded that this may have been due to the absence of appendages in the cultured skin. The results of the present study, in which FL and FD-4 preferentially permeated through skin appendages, support our previous conclusion.…”

Section: Discussionmentioning

confidence: 97%

“…Many studies on the transdermal deliveries of hydrophilic compounds have been performed using excised skin. 28,40,42,43,45,49) Evaluations of skin permeation parameters using excised skin are very useful for developing transdermal formulations. The skin permeation ratios of drugs through hair follicles against those through the whole permeation area should be considered to clarify the contribution of the hair follicle route.…”

Section: Discussionmentioning

confidence: 99%

“…The permeation pathway of hydrophilic drugs may be skin appendages as well as the aqueous region of the stratum corneum. [26][27][28] Therefore, we developed a method for hair follicle infundibulum-plugging with a mixture of silicone grease, cyanoacrylate adhesive and nile red, referred to as the hair follicle-plugging method, to analyze drug permeability through skin appendages. 29) This method revealed that the hair follicle could be the primary permeation pathway for watersoluble compounds such as ionized lidocaine (ionized LC) and fluorescein isothiocyanate-dextran 4 kDa (FD-4).…”

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Analysis of the Pretreatment Effect of Ethanol on the Stratum Corneum- and Hair Follicular-Penetration of Drugs Using the Hair Follicle-Plugging Method

Horita

Todo

Sugibayashi

2014

CHEMICAL & PHARMACEUTICAL BULLETIN

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The hair follicle-plugging method was used to analyze the effects of EtOH on skin permeation pathways. Methods: In vitro permeation experiments were performed on 4 model drugs [isosorbide mononitrate (ISMN), ionized lidocaine (ionized LC), fluorescein (FL), and fluorescein isothiocyanate (FITC)-dextran 4 kDa (FD-4)] using excised pig ear skin. The skin permeations of ionized LC, FL, and FD-4 were decreased by hair follicle-plugging. Hair follicle-plugging prevented the skin permeation of FL and FD-4 in EtOHpretreated skin, but did not prevent that of ISMN. On the other hand, the effect of hair follicle-plugging on the permeation of ionized LC was different among the pretreatment conditions. These results indicate that the EtOH pretreatment greatly affected the aqueous pathway in the stratum corneum and hair follicles.Key words skin permeation; aqueous pathway; hair follicle-plugging; EtOH pretreatment; permeation route; enhancer Drug delivery systems (DDSs) have been investigated extensively to provide drug formulations with sustained release and/or targeting properties. Transdermal therapeutic systems (TTSs) are a typical example of DDSs. Therapeutic medicines in TTSs that have already been marketed include tulobuterol for the treatment of bronchial asthma, 1) clonidine for hypertension,2) nitroglycerin and isosorbide dinitrate for angina pectoris, 3,4) and rivastigmine for Alzheimer's disease. 5) However, the enhancement of skin permeation is sometimes required for drugs. Skin penetration enhancers are one of the methods used to increase the skin permeation of drugs.Skin penetration enhancers include alcohols, 6,7) fatty acids, 8,9) fatty acid esters, 10,11) terpenes, 12,13) pyrrolidones, 14,15) surfactants, 16,17) and Azone. 18,19) Among these enhancers, ethanol (EtOH) is the most commonly used additive in topical formulations. It is applied not only as a skin penetration enhancer, but also a solvent, such as water, for skin disinfection, as well as a solubilizer for poorly-soluble drugs. Estradiol and fentanyl dermal patches are typical examples that contain EtOH to enhance their absorption into the skin. [20][21][22] The mechanisms underlying the penetration-enhancement effect of EtOH on the stratum corneum barrier were previously reported to be lipid extraction, an increase in lipid fluidity, the enhancement of drug solubility in stratum corneum lipids, changes in skin hydration, effects on the putative pore pathway, alterations in keratinized proteins, and effects on solvent drugs. 23,24) Although many studies have already examined skin permeability with the simultaneous application of EtOH and drugs, few have investigated the effects of an EtOH pretreatment on the skin permeation of drugs. EtOH-containing formulations are frequently applied to the skin surface for the purpose of preventing disinfection and other therapeutic treatments. Other topical formulations may also be applied following treatments with EtOH-containing formulations.We previously investigated the effects of an EtOH pretreatment on th...

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Section: Discussionmentioning

confidence: 97%

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

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Analysis of the Pretreatment Effect of Ethanol on the Stratum Corneum- and Hair Follicular-Penetration of Drugs Using the Hair Follicle-Plugging Method

Horita

Todo

Sugibayashi

2014

CHEMICAL & PHARMACEUTICAL BULLETIN

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“…Hair follicles are known to be an effective topical drug delivery route for hydrophilic drug and particles, despite the surface area of skin occupied by hair follicles is only about 0.1% of the total skin surface area. 31,32 Recently, follicular penetration of nano-and microparticle has been investigated and showed hair follicles as a primary penetration route for the particle-based deliver system containing macromolecules, chemical drug, vaccine. [33][34][35] The penetration depth depends on the size of the particles and the result isn't very similar because of difference in lipid type, combination of lipid, preparation methods.…”

Section: Discussionmentioning

confidence: 99%

Recombinant Human Epidermal Growth Factor (rhEGF)-loaded Solid Lipid Nanoparticles: Fabrication and Their Skin Accumulation Properties for Topical rhEGF Delivery

Hwang¹,

Han²,

Jeon³

et al. 2014

Bulletin of the Korean Chemical Society

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For the present study, rhEGF was encapsulated into solid lipid nanoparticles (SLNs). The SLNs were prepared by the W 1 /O/W 2 double emulsification method combined with the high pressure homogenization method and the physical properties such as particle size, zeta-potential and encapsulation efficiency were measured. The overall particle morphology of SLNs was investigated using a transmission electron microscopy (TEM). The percutaneous skin permeation and accumulation property of rhEGF was evaluated using Franz diffusion cell system along with confocal laser scanning microscopy (CLSM). The mean particle size of rhEGF-loaded SLNs was 104.00 ± 3.99 nm and the zeta-potential value was in the range of −36.99 ± 0.54 mV, providing a good colloidal stability. The TEM image revealed a spherical shape of SLNs about 100 nm and the encapsulation efficiency was 18.47 ± 0.22%. The skin accumulation of rhEGF was enhanced by SLNs. CLSM image analysis provided that the rhEGF rat skin accumulation is facilitated by an entry of SLNs through the pores of skin.

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“…[29][30][31] Todo et al reported that polystyrene latex nanoparticles (mean particle size 500 nm) penetrated into the hair follicles of porcine skin. 32) On the other hand, Tahara et al reported that a S/O nanosuspension of protein (mean particle size: 214-257 nm) penetrated into the stratum corneum in the in vitro Yucatan micropig skin permeation experiments.…”

Section: )mentioning

confidence: 99%

Characterization of a Riboflavin Non-aqueous Nanosuspension Prepared by Bead Milling for Cutaneous Application

et al. 2015

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The purpose of this study was to characterize the non-aqueous nanosuspension of a hydrophilic drug prepared by bead milling for cutaneous application. Riboflavin was used as the model hydrophilic drug. The non-aqueous nanosuspensions were prepared by grinding riboflavin with zirconia beads using eight nonaqueous bases. The mean particle size of riboflavin in the suspensions ranged from 206 to 469 nm, as determined by the dynamic light scattering method. Among the well-dispersed samples, riboflavin nanosuspension prepared in oleic acid was selected for evaluation of the drug permeability through rat skin. The cumulative amount and permeation rate of riboflavin from the nanosuspension were approximately three times higher than those for unprocessed riboflavin in oleic acid. Fluorescence imaging of the riboflavin nanosuspension suggested improved penetration of riboflavin into the stratum corneum. Furthermore, the addition of polysorbate 65 or polyglyceryl-6 polyricinoleate to the nanosuspension prepared in oleic acid markedly improved the riboflavin dispersibility. These results show that the preparation of a nanosuspension in a non-aqueous base by bead milling is one of the simple methods to improve the skin permeability of hydrophilic drugs.Key words bead milling; riboflavin; non-aqueous nanosuspension; oleic acid; stabilization; skin permeabilityThe skin permeability of hydrophilic drugs is generally known to be low, 1,2) due to the existence of lipophilic stratum corneum. It is difficult to obtain sufficient skin permeation to obtain a pharmacological effect without skin irritation, even with the use of chemical enhancers.3) Application of hydrophilic drugs by iontophoresis 4,5) and microneedle, 6,7) known as physical enhancers, allows dramatic improvement of the skin permeation, but these devices are expensive, and the safety of their long-term use still needs to be evaluated.In recent years, application of the preparations for cutaneous with the use of nanoparticles has been reported. Polymer nanoparticles composed of poly(DL-lactic-co-glycolic acid) 8,9) or chitosan 9,10) are considered to enhance the skin permeation of drugs by improving the polymer penetration into hair follicles. Solid-in-oil (S/O) nanosuspension is reported to enhance the skin permeation of hydrophilic drugs via penetration of the nanoparticles into the stratum corneum, 11) and penetration into the stratum corneum of latex-beads nanoparticles has been confirmed.12) In addition, solid-lipid nanoparticles and nanostructured lipid carriers enhance drug permeation by forming a film on the skin, improving the skin hydration. 13)However, the presence of nanoparticles in the receptor fluid was not shown in these reports.Nanosuspensions are bothersome to produce via as the process involves emulsification, drying/evaporation/centrifugation, and redispersion. Especially, preparation of uniformly dispersed nanosuspensions is difficult because of the agglomeration forces between nanoparticles after the drying/evaporation/centrifugation process. In ...

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Permeation Pathway of Macromolecules and Nanospheres through Skin

Cited by 50 publications

References 22 publications

Analysis of the Pretreatment Effect of Ethanol on the Stratum Corneum- and Hair Follicular-Penetration of Drugs Using the Hair Follicle-Plugging Method

Analysis of the Pretreatment Effect of Ethanol on the Stratum Corneum- and Hair Follicular-Penetration of Drugs Using the Hair Follicle-Plugging Method

Recombinant Human Epidermal Growth Factor (rhEGF)-loaded Solid Lipid Nanoparticles: Fabrication and Their Skin Accumulation Properties for Topical rhEGF Delivery

Characterization of a Riboflavin Non-aqueous Nanosuspension Prepared by Bead Milling for Cutaneous Application

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