The Influence of Liquid Crystalline Phases on Drug Percutaneous Absorption. II. Permeation Studies Through Excised Human Skin

The influence of liquid crystalline (LC) phases on the percutaneous absorption of a model compound (ploxicromil; PXC) was studied with the use of the phase diagram for the surfactant, oil, and water comprising the vehicles. Two separate sets of vehicles, representing two different tie lines lying in the Ll + LC phase region, were prepared in which the concentration of LC was varied over the range 0 to 100% along each tie line. In vitro permeation studies of PXC from these systems were conducted using excised human skin and the flux values determined as a function of the percentage LC present in the vehicles. In virtually all cases, the flux reached a peak at 5-10% LC and then decreased significantly as the fraction of LC present increased further. The pattern of behavior observed is discussed in terms of current theories describing membrane-controlled and vehicle-controlled diffusion, none of which adequately model the results obtained.     

Percutaneous Penetration of Acyclovir Through Excised Hairless Mouse and Rat Skin: Effect of Vehicle and Percutaneous Penetration Enhancer

The effects of vehicle and percutaneous penetration enhancer on the penetration of acyclovir through excised hairless mouse and rat skin were investigated. Four solvents, propylene glycol (PG), ethanol (ET), isopropanol (IPA), and isopropyl myristate (IPM), were employed as vehicles, in combination with four enhancers, l-farnesylazacycloheptan-2-one (7FU), l-geranylazacycloheptan-2-one (7GU), l-geranylazacyclopentan-2-one (5GU), and l-dodecylazacycloheptan-2-one (Azone). Acyclovir was suspended in vehicles to avoid the effect of the thermodynamic activity of acyclovir in the vehicle. The penetration of acyclovir through hairless mouse skin from IPA was enhanced by 7GU, whereas that from IPM was not affected. All combinations of vehicle and penetration enhancer were examined using rat skin. No effect of the enhancers was observed in the IPM vehicle. The estimated solubility parameters of vehicles and enhancers indicated that the polarities of IPM and the enhancers are similar, which prevents effective penetration of the enhancers from IPM. However, the penetration of acyclovir from the other vehicles was increased by the enhancers. The combination of hydrophilic vehicle and hydrophobic enhancer resulted in a large enhancing effect. The disappearance of the enhancers from the vehicle correlated with their enhancing activity, but other factors also seemed to affect the penetration enhancement of acyclovir.     

The Influence of Urea on Percutaneous Absorption

The release characteristics of aqueous and oily creams (BP) containing urea up to concentrations of 10% have been studied. The results show that the urea has little influence on the ability of the formulation to release its active ingredient, in this case, hexyl nicotinate. The preparations were then assessed in an in vivo experiment by measuring the time of onset of erythema induced by the hexyl nicotinate. The urea influenced the time of onset of erythema, and a mechanism for its action is proposed.     

不同透皮促进剂对丹参贴膏离体透皮吸收的影响

本文报道了4种透皮促进剂3％月桂氮卓酮（Azone）＋5％丙二醇，3％Azone，5％丙二醇和5％二甲基亚砜（DMSO）对丹参贴膏中两种主要有效成分丹参素和原几条醛透皮吸收的影响。采用离体鼠皮为皮肤模型，实验装置应用自行设计的单室透皮扩散池，检测方法为高效液相色谱法。结果表明，4种透皮促进剂均可不同程度地促进丹参贴膏的透皮吸收效果，其中3％Azone＋5％丙二醇组成的二元透皮促进剂作用最显著。     

Absorption and Disposition of Colloidal Drug Delivery Systems. I. High-Performance Liquid Chromatographic (HPLC) Analysis of a Cyclosporin Emulsion

The amount of cyclosporin A in an oil-in-water emulsion drug delivery system was determined by HPLC. The direct extraction and analysis of an intact emulsion were compared to the analysis of a cracked emulsion and an olive oil solution of the drug. The intra- and interday variability for the intact emulsion was less than 10% from 35 to 150 µg/ml, with recovery of 94%. Comparison of the assay results obtained with the emulsion and the olive oil solution gave a highly correlated regression line with a small intercept and a slope close to unity. Thus, the direct extraction and HPLC analysis of drugs in emulsions may be a viable approach to evaluate drug content     

Absorption of Sunscreens and Other Compounds Through Human Skin in Vivo: Derivation of a Method to Predict Maximum Fluxes

Purpose. The goal of this study was to quantify the transdermally absorbed amounts of the sunscreens octyl dimethyl p-aminobenzoic acid, oxybenzone, 4-isopropyl-dibenzoylmethane, 3-(4-methylben-zylidene)-camphor, isoamyl-4-methoxycinnamate, the repellent and plasticizer dibutyl phthalate, the antioxidant 3.5-di-t-butyl-4-hydroxyanisol, and the antimicrobial compounds butyl-4-hydroxybenzoate, biphenyl-2-ol, and 2,4,4-tri-chlor-2-hydroxydiphenylether (tri-closane). Permeabilities P _B and maximum fluxes J _max should be correlated with relevant physicochemical properties. Methods. Saturated solutions of the above-mentioned compounds in a propylene glycol/water mixture were applied to the skin using glass chambers which were fixed to the upper arms of volunteers. Maximum fluxes were calculated from concentration decreases in the vehicle. Results. A linear relationship between the logarithms of permeabilities P _B of the penetrants (0.02–0.28 cm h^–l) and the corresponding octanol/vehicle partition coefficients PC _Oct/v (166–186,208) was found. Consequently, the influence of aqueous boundary layers could be neglected. However, the slope of the resulting straight line of 0.38 is considerably smaller than unity indicating that PC _Oct/v does not represent the lipophilicity of the stratum corneum adequately. Maximum fluxes range from 0.5 to 130 µg cm^–2 h^–1. A general equation for the calculation of J _max was derived based on experimental data taking into account the PC _Oct/v and the solubilities c _sV of the respective penetrants in the vehicle.     

基质pH及促渗剂对阿昔洛韦水凝胶贴剂体外透皮性能的影响

分别制备了基质pH为5.0、6.0、7.5的不含促渗剂的阿昔洛韦水凝胶贴剂,在基质pH 6.0的处方中加入不同浓度的月桂氮革酮、Ⅳ.甲基吡咯烷酮(NMP)、薄荷醇、吐温-80、聚乙二醇(PEG)400作为促渗荆,以考察基质pH及促渗剂对阿昔洛韦透过离体小鼠皮肤的影响.结果表明,基质pH升高,阿昔洛韦的透皮速率增大.与不含促渗剂的基质pH6.0处方组对照,NMP、PEG 400单用不能提高阿昔洛韦的渗透速率,4%的吐温-80、薄荷醇和月桂氮革酮均可提高阿昔洛韦的经皮渗透.     

Liquid Crystalline Systems Based on Glyceryl Monooleate and Penetration Enhancers for Skin Delivery of Celecoxib: Characterization,In Vitro Drug Release,and In Vivo Studies

Celecoxib (CXB) is a widely used anti-inflammatory drug that also acts as a chemopreventive agent against several types of cancer, including skin cancer. As the long-term oral administration of CXB has been associated with severe side effects, the skin delivery of this drug represents a promising alternative for the treatment of skin inflammatory conditions and chemoprevention of skin cancer. We prepared and characterized liquid crystalline systems based on glyceryl monooleate and water containing penetration enhancers which were primarily designed to promote skin delivery of CXB. Analysis of their phase behavior revealed the formation of cubic and hexagonal phases depending on the systems' composition. The systems' structure and composition markedly affected the in vitro CXB release profile. Oleic acid reduced CXB release rate, but association oleic acid/propylene glycol increased the drug release rate. The developed systems significantly reduced inflammation in an aerosil-induced rat paw edema model. The systems' composition and liquid crystalline structure influenced their anti-inflammatory potency. Cubic phase systems containing oleic acid/propylene glycol association reduced edema in a sustained manner, indicating that they modulate CXB release and permeation. Our findings demonstrate that the developed liquid crystalline systems are potential carriers for the skin delivery of CXB.     

Investigation of Drug Delivery by Iontophoresis in a Surgical Wound Utilizing Microdialysis

PURPOSE: This study investigated the penetration of lidocaine around and through a sutured incision following the application of iontophoretic and passive patches in the CD Hairless rat. MATERIALS AND METHODS: Concentrations in localized areas (suture, dermis, subcutaneous, and vascular) were determined using microdialysis sampling followed by analysis using liquid chromatography with UV detection. RESULTS: Iontophoresis significantly enhanced the dermal penetration of lidocaine. In an intact skin model, dermal concentrations were 40 times greater following iontophoretic delivery compared to passive delivery. In a sutured incision model, iontophoresis enhanced localized concentrations in the dermis, suture, and subcutaneous regions by 6-, 15-, and 20-fold, respectively. Iontophoretic delivery to a region containing a sutured incision was focused to the incision resulting in a greater increase in the suture concentration and in the subcutaneous region directly below the incision. CONCLUSIONS: The four microdialysis probe design was successful in the determination of localized drug penetration in a sutured incision model. Iontophoresis enhanced skin penetration and allowed for site specific delivery when applied to a sutured incision.     

Solubilization of Cyclosporine in Topical Ophthalmic Formulations: Preformulation Risk Assessment on a New Solid Form

Owing to the discovery of a less soluble crystalline form (form 2) of cyclosporine (CsA), risks in solubility and physical stability of these formulations need to be revisited. This work focused on understanding the solubility behavior of various CsA forms in different media, including water, castor oil, and selected cosolvent micellar systems. In water, form 2 was approximately 8-9 times less soluble than form 1 (aka. tetragonal dihydrate). In neat nonaqueous solvent, for example, castor oil, form 3 (aka. orthorhombic hydrate) was found to have the lowest solubility and therefore the most stable form. In addition, the solubility-temperature relationship of CsA is complex and solvent-dependent. In aqueous vehicles, retrograde temperature dependence of solubility was observed in aqueous vehicles, that is, the solubility of CsA decreased with temperature, which was attributed to the effect of temperature on the strength of hydrogen bonding interactions; conversely, the solubility of CsA increased with temperature in nonaqueous solvents. In addition, the solubility of these CsA forms was very sensitive to temperature. Temperature-dependent form transformation was also observed in the media studied, with faster form conversion occurring at elevated temperatures. These studies provided key information to support the risk assessment for topical ophthalmic formulation development of CsA.