Hydrogel-based ultra-moisturizing cream formulation for skin hydration and enhanced dermal drug delivery.

To develop an external vehicle for skin hydration and enhanced dermal drug delivery, a hydrogel-based ultra-moisturizing cream (HUMC) was successfully formulated with carbopol 934P, urea, Tinocare GL, grape seed oil, and other excipients. The HUMC showed plastic flow behavior due to a gel structure with a cream base. Different types of drug-free vehicles such as a hydrogel, conventional cream (CC), and three HUMCs were prepared and subjected to an in vivo skin hydration test on a hairless mouse using a corneometer. Hydration effect (∆AU) was in the order of HUMC2>HUMC1 ≥ CC>HUMC3>hydrogel. Using nile red (NR) and 5-carboxyfluorescein (5-CF) as lipophilic and hydrophilic fluorescent probes, respectively, in vitro skin permeation and accumulation studies were conducted using Franz diffusion cells. The values of steady-state flux (Jss, ng/h/cm(2)) were obtained: 74.8 (CC), 145.6 (HUMC1), and 161.9 (HUMC2) for NR delivery; 6.8 (CC), 8.3 (HUMC1), and 10.9 (HUMC2) for 5-CF delivery. The amounts retained in the skin at 12 h (Qr, ng/cm(2)) were determined: 86.4 (CC) and 102.0 (HUMC2) for NR; and 70.1 (CC) and 195.6 (HUMC2) for 5-CF. Confocal microscopy was used to visualize the distribution of the fluorescent probes. NR tended to be localized into the deeper part of the skin with adipose tissue whereas 5-CF localized in the upper layer of the skin. Thus we propose that HUMC2 is an efficacious vehicle for skin hydration and enhances dermal delivery of lipophilic and hydrophilic drugs.

A retinyl palmitate-loaded solid lipid nanoparticle system: effect of surface modification with dicetyl phosphate on skin permeation in vitro and anti-wrinkle effect in vivo.

Surface-modified solid lipid nanoparticles (SLNs) containing retinyl palmitate (Rpal) were prepared by the hot-melt method using Gelucire 50/13(®) and Precirol ATO5(®). Dicetyl phosphate (DCP) was added to negatively charge the surfaces of the SLNs and thereby enhance the skin distribution properties of Rpal. In vitro skin permeation and in vivo anti-aging studies were performed using SLNs dispersed in a hydrogel. The SLNs were under 100 nm in size with an even polydispersity index (PDI), and the high absolute zeta-potential value was sufficient to maintain the colloidal stability of the SLNs. DCP-modified negative SLNs (DCPmod-SLNs) enhanced the skin distribution of Rpal 4.8-fold and delivered Rpal to a greater depth than did neutral SLNs. The in vivo anti-wrinkle effect of the DCPmod-SLN formulation was Rpal dose-dependent. However, the anti-wrinkle effects of the DCPmod-SLN formulations were significantly different from that of the negative control and effectively prevented the reduction of elastin and superoxide dismutase by UV irradiation. In conclusion, the DCPmod-SLN system presented is a good candidate for topical Rpal delivery.

Folic acid-tethered Pep-1 peptide-conjugated liposomal nanocarrier for enhanced intracellular drug delivery to cancer cells: conformational characterization and in vitro cellular uptake evaluation.

BACKGROUND: A novel dual ligand-modified liposome, folic acid-tethered Pep-1 peptide-conjugated liposomal nanocarrier (FP-Lipo), was designed to overcome the nonselectivity of conventional penetrating peptide-tagged nanoparticulates and to provide the advantage of selective targeting of the folic acid receptor, which is frequently overexpressed on epithelial cancer cells. METHODS: FP-Lipo was prepared by a sequential process of formation of a maleimide-derivatized small unilamellar vesicle, postinsertion of distearoyl phosphatidyl ethanolamine-polyethylene glycol 2000-folate to the vesicle, and Pep-1 peptide conjugation via thiol-maleimide linkage. Conformational and physical characteristics of the FP-Lipo nanocarriers were investigated for the extent of Pep-1 peptide and folic acid on the surface, vesicle size, and zeta potential. In vitro cellular uptake behaviors of the novel carrier containing a fluorescein dextran isothiocyanate probe were examined by spectrophotometry or by confocal laser scanning microscopy. RESULTS: A novel nanocarrier bearing approximately 750 folate ligands and 100 penetrating peptides per vesicle was successfully prepared. The physical properties were as follows: 140 nm in size; 5 mV in zeta potential; less than 0.3 in polydispersity index. An in vitro cellular uptake study revealed that the FP-Lipo nanocarrier system exhibited more than twofold enhanced translocation into the folic acid receptor-positive HeLa cells compared with the single Pep-1 peptide-modified liposome. Meanwhile, its cellular association and internalization into the folic acid receptor-negative normal HaCaT cells was comparable with that of Pep-1 peptide-modified liposome. CONCLUSION: An advanced dual ligand-modified liposome is potentially useful for the treatment of folic acid receptor-positive tumors with high translocation capability of the penetrating peptide-modified liposome.

Tat peptide-admixed elastic liposomal formulation of hirsutenone for the treatment of atopic dermatitis in NC/Nga mice.

BACKGROUND: The aim of the present study was to enhance a topical delivery of hirsutenone (HST), a naturally occuring immunomodulator, employing Tat peptide-admixed elastic liposomes (EL/T). METHODS: HST-loaded EL, consisting of phosphatidylcholine and Tween 80 (85:15 w/w%), were prepared using thin film hydration method. By adding Tat peptide to EL (0.16 w/w%), EL/T were formulated. The in vitro skin permeation of HST was examined using a Franz diffusion cell mounted with depilated mouse skin. Lesions for atopic dermatitis (AD) were induced by a topical application of diphenylcyclopropenone to NC/Nga mice. Therapeutic improvements of AD were evaluated by clinical skin severity scores. Immunological analyses on inducible nitric oxide synthase and cyclooxygenase-2 levels in the skin and interleukin (IL)-4, IL-13, immunoglobulin E, and eosinophil levels in the blood were also performed. RESULTS: EL systems were superior to conventional cream, revealing greater flux values in a permeation study. The addition of Tat peptide further increased the skin permeation of HST. In an efficacy study with AD-induced NC/Nga mice, an HST-containing EL/T formulation brought a significant improvement in both skin severity score and immune-related responses for the levels of nitric oxide synthase, cyclooxygenase-2, IL-4, IL-13, immunoglobulin E, and eosinophils. CONCLUSION: A novel EL/T formulation was successfully developed for topical delivery of HST to treat AD.

Solid dispersion formulations of megestrol acetate with copovidone for enhanced dissolution and oral bioavailability.

In order to enhance the dissolution profile and oral bioavailability of megestrol acetate (MA), solid dispersions of MA (MASDs) were formulated with copovidone and crystal sugar as a hydrophilic polymeric carrier and an inert core bead, respectively. Solvent evaporation method and fluidized bed coating technique were employed. MASDs were categorized as crystalline solid dispersion by the characterization of differential scanning calorimetry and X-ray diffraction. The mass-median diameters of MASDs were in a range of 1.4 to 2.6 µm. Based on drug to polymer ratio, MASD (1:1) and (1:2) were considered as optimized formulations, resulting in a smooth-surfaced homogeneously coated layer with enhanced dissolution rate. Dissolution of MASD was gradually increased up to 15 min, after which it reached a plateau. For the initial period, dissolution rates were in the decreasing order of MASD (1:2) ≥ MASD (1:1) > MASD (1:3) > MASD (1:5) > MASD (1:0.5) > MA powder. In the comparative pharmacokinetic study with Megace OS, a reference drug product, MASD (1:1) showed improved bioavailability of over 220% with 2-fold higher C(max) and 30% faster T(max). We conclude that MASD (1:1) is a good candidate for the development of oral solid dosage forms.

Pep-1 peptide-conjugated elastic liposomal formulation of taxifolin glycoside for the treatment of atopic dermatitis in NC/Nga mice.

In order to develop topical preparations of taxifolin glycoside (TXG) for the treatment of atopic dermatitis (AD), formulations of Pep-1 peptide-conjugated elastic liposomes (Pep1-EL) were examined for their in vitro skin permeation profile and in vivo therapeutic efficacy. TXG-loaded Pep1-EL - a nanovesicle consisting of phosphatidylcholine, Tween 80, N-[4-(p-maleimidophenyl)butyryl]-phosphatidylethanolamine (MPB-PE), and Pep-1 peptide - is 130nm in size, and has a zeta potential of 25mV and a deformability index value of 60. Here, we examined the skin permeability of several topical preparations using a Franz diffusion cell mounted with depilated mouse skin and found that formulations of Pep1-EL exhibited superior absorption when compared to aqueous solution, EL or Pep-1 peptide-admixed EL formulations. Both transepidermal water loss and skin surface hydration were also measured using AD-induced NC/Nga mice, and the TXG-loaded Pep1-EL treatment group displayed a significantly expedited recovery in skin barrier function when compared to the controls treated with a TXG aqueous solution (p<0.05). AD-associated immune responses - including serum interleukine-4, immunoglobulin E, and interferon-gamma - were also regulated by topical application of TXG-loaded Pep1-EL. In conclusion, the novel Pep1-EL formulation of TXG shows substantial promise in the treatment of AD as a result of its desirable skin delivery-promoting capability.