The objective of the present study is to search for a good selection method of phospholipids to design liposome preparations with high skin penetration-enhancing effects.Five kinds of phosphatidylcholines and phosphatidylglycerols each were selected. First, phospholipid aqueous dispersions and liposomes containing caffeine as a model drug were tested for their skin penetration-enhancing effects using excised hairless rat skin. As results, 1,2-distearoyl-sn-glycero-3-phosphocholine (DSPC) and 1,2-dipalmitoyl-sn-glycero-3phosphoglycerol, sodium salt (DPPG) dispersions showed high penetration-enhancing ratio (ER), whereas DPPG, 1,2-dilauroyl-sn-glycero-3-phosphocholine (DLPC) and 1,2dimyristoyl-sn-glycero-3-phosphocholine (DMPC) liposomes showed high ER, suggesting that liposomes had different skin penetration-enhancing mechanisms from phospholipid dispersions. Next, two kinds of experiments were done to clarify the possible mechanism of liposomes as follows: the excised skin was pretreated for 1 h with caffeine-free phospholipid dispersions and liposomes, and caffeine solution was added to determine its skin permeation.Separately, caffeine permeation experiments were done using physical mixture of blank liposomes and caffeine solution (caffeine-spiked liposomes) and caffeine-entrapped liposomes (caffeine was entrapped only in liposomes). As results, DPPG was a promising phospholipid candidate to fabricate liposome formulations with high skin penetration-enhancing effects, since DPPG phospholipid and its liposome vesicles had a combination effect to disrupt the SC lipid barrier as well as could carry both free and entrapped caffeine in the formulation through the skin.
Palmitoyl-glycine-histidine (Pal-GH) is a new low molecular weight gelling agent. It exhibits thixotropic behavior, low viscosity, and high dissolving properties for a wide range of hydrophilic to lipophilic drugs. Orally administered ivermectin (IVM) is used to treat scabies. However, this treatment is associated with well-known side effects, thus a study is awaited to search for alternative routes of administration. Although a topical formulation of IVM could be a candidate, it requires whole body application except the head and face for several hours on a daily basis. Therefore, in this study, we prepared a gel spray formulation containing IVM as an approach for application to large skin areas with a single spray application without further contact with the applied formulation. Pal-GH gel spray formulations were prepared from its aqueous solution by a heating and cooling method. Rheological behavior and physical appearance (spraying, spreading ability, volume of spraying, and homogeneity) of the prepared formulations were evaluated. Pal-GH gel with propylene glycol demonstrated impressive rheological properties (typical thixotropic behavior) with high hysteresis area among all the tested Pal-GH gels and spreading ability. The obtained IVM concentration in the skin after topical application of 0.1% IVM-containing Pal-GH formulation onto hairless rats was much higher than the reported therapeutic concentration obtained from oral administration in humans. These results suggested that topical application of IVM using a Pal-GH gel spray formulation could be an alternative to the conventional oral forms for the scabies treatment.
Highlights• Intranasal delivery of tranilast was enhanced by MGE and GMO liquid crystals • Biodistribution of administered LC formulations was visualized by micro-computed tomography tandem in vivo imaging systems • MGE and GMO formed liquid crystal structures with formulation characteristics supporting brain uptake of lipophilic drugs ABSTRACT Intranasal administration is poised as a competent method in delivering drugs to the brain, because the nasal route has a direct link with the central nervous system bypassing the formidable blood-brain barrier. C17-monoglycerol ester (MGE) and glyceryl monooleate (GMO) as liquid crystal (LC)-forming lipids possess desirable formulation characteristics as drug carriers for intranasally administered drugs. This study investigated the effect of LC formulations on the pharmacokinetics of tranilast (TL), a lipophilic model drug, and its distribution in the therapeutic target regions of the brain in rats. The anatomical biodistribution of LC formulations was monitored using micro-computed tomography tandem in vivo imaging systems. MGE and GMO effectively formed LC with suitable particle size, zeta potential, and viscosity supporting the delivery of TL to the brain. MGE and GMO LC formulations enhanced brain uptake by 10-to 12-fold and 2-to 2.4-fold, respectively, compared with TL solution.The olfactory bulb had the highest TL concentration and fluorescent signals among all the brain regions, indicating a direct nose-to-brain delivery pathway of LC formulations. LC-forming lipids, MGE and GMO, are potential biomaterials in formulations intended for intranasal administration.
N-Palmitoyl-Glycine-Histidine (Pal-GH) is a novel low molecular weight gelator. In our previous report, ivermectin, a lipophilic drug, was effectively delivered to skin tissue after topical application with Pal-GH as a spray gel formulation, and a much higher skin concentration was confirmed than with the administration of a conventional oral formulation. The objective of this study was to increase the skin permeation of metronidazole (MTZ), a hydrophilic drug, after the topical application of Pal-GH gel. An evaluation of the combined effect of chemical penetration enhancers (CPEs), such as isopropyl myristate (IPM), propylene glycol (PG), ethanol, diethylene glycol monoethyl ether, and dimethyl sulfoxide (DMSO), on skin permeation was also conducted. We found that a 5% Pal-GH gel containing 1% MTZ (F5MTZ) exhibited a 2.7-fold higher MTZ permeation through excised hairless rat skin than its solution. Furthermore, F5PG-MTZ and F5IPM-MTZ further increased the skin permeation of MTZ when compared to F5MTZ. Interestingly, F5PG-MTZ enhanced the skin penetration of MTZ, although no enhancement effect was observed for an MTZ solution containing PG. Thus, a Pal-GH formulation containing PG and IPM may enhance the skin permeation of MTZ.
Skin offers an easily accessible and convenient site for the administration of drugs. Therefore, the development of injectable formulations with controlled drug release properties are now expected to deliver middle-and large-size biomolecules. In the present study, formulations mainly composed of a novel polyol ester with an isoprenoid side chain; mono-O-(5,9,13-trimethyl-4-tetradecenyl) glycerol ester (MGE), that was capable of forming a non-lamellar liquid crystal (NLLC), were prepared with different types of phospholipid. Then, factors that affected the release of a model entrapped drug, fluorescein-isothiocyanate dextran (FD-4, M.W. 4,000), from the MGE formulations were analyzed with multi-regression analysis. In addition, self-assembly of the NLLC structure was investigated using small-angle X-ray scattering analysis after contacting the MGE formulations with water. NLLC-forming ability of the formulations after s.c. injection into rats was also confirmed using microscopic observations. FD-4 concentrations in blood were determined after s.c. injection of the MGE formulations. The injectable MGE formulations successfully constructed NLLC structures to form a sponge-like gel after contact with water in vitro and in vivo (in rats) as well. In in vitro conditions, the amount of FD-4 released from the formulations was altered by changing the type and concentration of phospholipid in the MGE formulations and can be expressed with parameters such as MGE content and interplanar spacing of the NLLC. A significantly sustained FD-4 level in the blood was observed after s.c. injection of the formulations.These results suggested that injectable MGE formulations may have the potential to achieve controlled release profiles of drugs after s.c. injection.
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