Mitsuhiko Hori

Optimization of Topical Therapy: Partitioning of Drugs into Stratum Corneum

To optimize a topical formulation for therapeutic effect generally implies that the flux of drug into the skin be maximized. This requirement means that the product of drug concentration in the vehicle (Cv) and drug partition coefficient (PC) between stratum corneum (SC) and vehicle be as large as possible. While Cv is a formulation variable which can be easily manipulated up to the drugs saturation solubility, PC is a parameter that is difficult to predict a priori. However, there is no question that an ability to evaluate PC would greatly facilitate the efficient screening of drugs and formulations. We have measured the SC/water and SC/isopropylmyristate (a model lipophilic vehicle) PCs of seven drugs: acitretin, progesterone, testosterone, diazepam, estradiol, hydrocortisone, and caffeine. SC/ water PCs were determined as a function of the following variables: (i) initial drug concentration in the vehicle, (ii) length of equilibrium, (iii) SC source and preparation technique, and (iv) SC delipidization. The data obtained were reproducible and physicochemically consistent, and they show that useful partitioning information from both aqueous and nonaqueous vehicles can be obtained with the biological tissue of greatest relevance. The SC/water PCs of the steroids were in reasonable agreement with previous measurements. A facile approach to an integral determinant of formulation optimization is suggested, therefore, by these observations.

Classification of percutaneous penetration enhancers: a conceptional diagram

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A Lipopolysaccharide from Pantoea Agglomerans Is a Promising Adjuvant for Sublingual Vaccines to Induce Systemic and Mucosal Immune Responses in Mice via TLR4 Pathway

A lipopolysaccharide from Pantoea agglomerans (LPSpa) has been applied to various fields for human use as a Toll-like receptor 4 ligand and its safety has been confirmed. Here, we showed for the first time the application of LPSpa as an effective mucosal adjuvant for activating vaccine-induced antigen specific immune responses. Mice sublingually immunized with influenza vaccine (HA split vaccine) with LPSpa induced both HA-specific IgG (systemic) and IgA (mucosal) antibody responses, which led to a significant increase in survival rate against lethal influenza virus challenge compared with subcutaneous vaccination. After sublingual administration of ovalbumin with LPSpa, ovalbumin-specific mucosal IgA responses were induced at both mucosal surfaces close to the immunized site and at remote mucosal surfaces. Sublingual administration of LPSpa evoked local antigen-uptake by dendritic cells in cervical lymph nodes. LPSpa induced cytokine production and the maturation and proliferation of innate immune cells via Toll-like receptor 4 in dendritic cells. Collectively, these results suggest that LPSpa can be used as an effective mucosal adjuvant to stimulate and activate local innate immune cells to improve and enhance mucosal vaccine potency against various pathogens.

Nonane enhances propranolol hydrochloride penetration in human skin

We compared propranolol hydrochloride penetration through human skin in the presence and absence of a putative enhancer, nonane. During in vivo experiments, l mg of propranolol hydrochloride was administered in l-methyl-2-pyrrolidone, under occlusive conditions to seven human volunteers. Seven others received the same dose and vehicle in the presence of 4% nonane. Propranolol hydrochloride penetration was determined from recovery of tritiated material following urinary excretion; propranolol penetration increased from 0.705 ± 0.3878 to 1.402 ± 0.8358% (mean ± SE) of the applied dose (1 mg/2.5 cm2) in the presence of nonane (p < 0.05). Of clinical interest, all seven subjects receiving the enhancer sustained moderate to severe erythema and slight edema at the application site. Slight eschar formation was observed in two of these seven volunteers after 24 h of exposure. It is postulated that the reactions were a result of stratum corneum disruption due to vehicle, enhancer or both. For comparison, penetration of propranolol HC1 from the same formulations was tested during an in vitro experiment using excised human cadaver skin and phosphate buffered saline receptor fluid. Penetration through a 1 cm2 surface area was determined by recovery of tritiated propranolol from the receptor fluid; propranolol bioavailability was increased from 1.03 ± 0.61 to 2.28 ± 0.17% (p < 0.05) of the applied dose (1 mg/1 cm2).

Cutaneous Pharmacodynamics of Transdermally Delivered Isosorbide Dinitrate

Laser doppler velocimetry (LDV) has been used to assess the cutaneous pharmacodynamics of isosorbide dinitrate (ISDN) following transdermal delivery of the drug from prototypal patches. The delivery systems, which were saturated with ISDN, (a) produced various degrees of skin occlusion and (b) spanned a six-fold range of adhesiveness. The patches were applied to the ventral forearm skin of 10 healthy volunteers and the local ISDN-induced increase in local skin blood flow was determined using LDV by locating the probe in a central hole in the delivery system. Measurements were made for 1.5 hr and the pharmacodynamics were quantified by (i) the maximum LDV response and (ii) the area under the LDV response versus time curve. These parameters were not sensitive to patch occlusivity. They were significantly (P < 0.01) dependent on patch adhesiveness, though, and decreased with increasing adhesion. Although this observation suggested that ISDN diffusion through the adhesive could determine, at least in part, the rate of drug delivery, it was subsequently demonstrated that ISDN release (in vitro, into a perfect sink”) was unaffected by the level of cross-linking in the adhesive polymer. Because the drug was present in all systems at unit thermodynamic activity, these results cannot be explained on the basis of altered ISDN partitioning at the device–stratum coraeum interface. We speculate that the in vivo-in vitro discrepancy may be due to the efficiency of skin contact achieved by different adhesives: that is, the more adhesive, less flexible systems make poorer contact with the skin surface, thereby decreasing the effective surface area of drug delivery. These results indicate that the noninvasive procedure of LDV contributes to the screening of transdermal formulations.

Lineweaver-Burk analysis of skin penetration enhancement

Abstract The transdermal penetration of propranolol hydrochloride across hairless mouse skin in vitro has been enhanced using n-nonane (C9), 1-nonanol (C9OH), 1-dodecylazacycloheptan-2-one (AZ), and oleic acid (OA). For each enhancer, the maximum rate of drug permeation (Jm) was determined as a function of enhancer concentration in the vehicle (ethanol). It was found, that, in all cases, skin penetration enhancement was saturable; that is, the augmentation of propranolol flux reached a maximum at higher enhancer concentrations that could not be increased by further increase in the amount of enhancer applied. The data were analyzed using a technique borrowed from enzyme kinetics, the Lineweaver-Burk plot, in which 1/Jm was plotted against the reciprocal of the enhancer concentration used. It was found that the y-axis intercepts, which correspond to the reciprocal of the maximum rate (1/Vmax), were remarkably consistent between the 4 enhancers considered. The slopes (equivalent to Km/Vmax), however, were enhancer-dependent, and indicated that the Km values for AZ and OA were about an order of magnitude less than those for C9 and C9OH. The results imply, therefore, that AZ and OA are significantly more effective enhancers than C9 and C9OH. These results suggest that the data analytical approach employed may have practical utility for classifying the relative potency of putative skin penetration enhancers.