Enhancing the nail permeability of topically applied drugs

The topical therapy of nail diseases, especially of onychomycosis, and to a smaller extent, of nail psoriasis, is desirable to avoid the side effects associated with their systemic therapy, to increase patient compliance and reduce the cost of treatment. Systemic therapy is however the mainstay of treatment due to the poor permeability of the nail plate to topically applied drugs. For effective topical therapy, ungual drug permeation must be enhanced. This can be achieved by disrupting the nail plate using physical techniques or chemical agents. Alternatively, drug permeation into the intact nail plate may be encouraged, for example, by iontophoresis or by formulating the drug within a vehicle which enables high drug partition out of the vehicle and into the nail plate. The physical techniques (manual and electrical nail abrasion, acid etching, ablation by lasers, microporation, application of low-frequency ultrasound and electric currents) and chemicals (thiols, sulphites, hydrogen peroxide, urea, water, enzymes) that have shown ungual enhancer activity are discussed in this review. Optimal drug formulation, while crucial to ungual drug delivery, is only briefly reviewed due to the limited literature.     

无痛微针透皮贴片对局部应用利多卡因的促渗作用

目的评价NS-TP-5B型无痛微针透皮贴片对局部应用利多卡因的透皮促渗效果及安全性.方法入选30名健康志愿者,采用随机、双盲、自身对照试验设计.每名志愿者左右臂随机分为试验组和对照组,分别采用无痛微针透皮贴片和模拟贴片处理,测定局部应用2%利多卡因注射液前后的疼痛评分.结果试验组20 min测定的疼痛评分与基线相比下降,且具有统计学意义(4.7±1.5 vs 6.1±1.5,P＜0.001).对照组20 min结果与基线相比无显著差异.结论无痛微针透皮贴片对局部应用利多卡因具有一定的透皮促渗作用.     

Simultaneous two-probe laser doppler velocimetric assessment of topically applied drugs in rats

A simple, noninvasive method for the determination of cutaneous blood flow in anesthetized rats is presented. Simultaneous two-probe laser dopplervelocimetry is shown to be a useful preclinical tool for the assessment of topically applied drugs.     

In vitro permeation of several drugs through the human nail plate: relationship between physicochemical properties and nail permeability of drugs.

The objectives of the present study are to clarify the relationship between the physicochemical properties and the nail permeability of drugs through human nail plates. Homologous p-hydroxybenzoic acid esters were used to investigate the relationship between the octanol/water partition coefficient and the permeability coefficient of several drugs. The nail permeability was found to be independent of the lipophilicity of a penetrating drug. However, the nail permeability of several model drugs was found to markedly decrease as their molecular weights increased. The nail permeability of an ionic drug was found to be significantly lower than that of a non-ionic drug, and the nail permeability of these drugs markedly decreased as their molecular weights increased. The permeation of a model drug, 5-fluorouracil (5-FU), through healthy nail plates was also determined and compared with that through nail plates with fungal infections. The drug permeation through a nail plate decreased with an increase in nail plate thickness. Nail plates with fungal infections exhibited approximately the same 5-FU permeation as healthy nail plates. We suggest that the permeability of a drug is mainly influenced by its molecular weight and permeability through nails with fungal infection can be estimated from data on healthy nail permeability.     

The effect of systemically and topically applied drugs on ultraviolet-induced erythema in the rat.

1. Exposure of the skin of rats to u.v. light (greater than 295 nm) for 30 s or longer elicited a delayed erythema response, the rate of onset increasing with period of irradiation. The erythema was still present at 24 h and was replaced by scab formation in 48 hours. 2. Both topically applied steroidal and non-steroidal anti-inflammatory drugs reduced the erythema formation when administered immediately after u.v. exposure. Propyl gallate, an antioxidant with sun screening properties in man, also possessed topical anti-erythemic activity. 3. Both steroidal and non-steroidal anti-inflammatory drugs, systemically administered 1 h before u.v. exposure, reduced and erythema. However, the steroidal compounds were less effective than the non-steroids and reduced the intensity of erythema by less than 50%. Antagonists of 5-hydroxytryptamine (5-HT) reduced the erythema but several other drugs with different pharmacological activities were ineffective. 4. Neither topical nor systemic treatments of any of the drugs examined suppressed the scab formation at 48 hours. 5. These results and those using other selective blocking agents indicate that in the mediation of the erythema reaction prostaglandins may play a major role and 5-HT perhaps a minor one but that H1 histamine receptors and alpha- and beta-adrenoceptors have no significant role.     

Risk assessment of topically applied products

The human risk of harmful substances in semisolid topical dosage forms applied topically to normal skin and broken skin, respectively, was assessed. Bisphenol A diglycidyl ether (BADGE) and three derivatives of BADGE previously quantified in aqueous cream and the UV filters 3-BC and 4-MBC were used as model compounds. Tolerable daily intake (TDI) values have been established for BADGE and derivatives. Endocrine disruption was chosen as endpoint for 3-BC and 4-MBC. Skin permeation of the model compounds was investigated in vitro using pig skin membranes. Tape stripping was applied to simulate broken skin associated with various skin disorders. BADGE and derivatives had a tendency to permeate pig skin membranes in vitro with higher fluxes in the tape stripped membranes compared to the non-treated membranes. Data from the in vitro skin permeation study and from the literature were used as input parameters for estimating the risk. The immediate human risk of BADGE and derivatives in topical dosage forms was found to be low. However, local treatment of broken skin may lead to higher exposure of BADGE and derivatives compared to application to normal skin. 3-BC permeated skin at higher flux than 4-MBC. Both UV filters are endocrine disrupting compounds with 3-BC being the more potent. UV filters in sunscreen are often present in high concentrations, which potentially may lead to high systemic exposure dosages. Thus, the risk associated with use of 3-BC and 4-MBC containing sunscreen with regards to endocrine disrupting effects was found to be high and more data is urgently needed in order to fully assess the human risk of 3-BC and 4-MBC in commercial sunscreen.     

Analgesic effect of topically applied pranoprofen-gel

The analgesic effect of topically applied pranoprofen-gel (1% and 3%) was investigated in comparison with indomethacin-gel in experimental animals. Applied topically, 1% and 3% pranoprofen-gel inhibited the inflammatory pain induced by Randall and Selitto's method and the pain response (abnormal gait) of concanavalin A-induced arthritis in rats dose-dependently. Furthermore, in antigen (methylated bovine serum albumin)-induced arthritis in rats, pranoprofen-gel had a concentration and application-dependent therapeutic effect on knee joint swelling and the pain response. Pranoprofen-gel had a stronger analgesic effect than indomethacin-gel in these experimental models. Both drugs inhibited the flexor reflexes of the hind limb induced by injecting bradykinin (BK) in combination with arachidonic acid into the common iliac artery of the spinal rat, but failed to do so with BK combined with prostaglandin E2 (PGE2). Moreover, pranoprofen-gel inhibited the BK-induced increase in the firing rate of the saphenous nerve of the spinal cat. These results show that pranoprofen-gel, applied topically, permeates well from the skin to the nociceptor site, relieving the hyperalgesia caused by PGs-induced sensitization of pain receptors by inhibiting their production. As a topical anti-inflammatory and analgesic agent, pranoprofen-gel is at least as effective as indomethacin-gel, so that it should have good clinical potential.     

Anti-inflammatory effect of topically applied pranoprofen-gel

The anti-inflammatory activity and mode of action of topically applied pranoprofen-gel were investigated in comparison with indomethacin-gel in experimental animals. Applied topically, 0.3 approximately 3% pranoprofen-gel inhibited carrageenin-induced paw edema, fracture-induced paw edema, carrageenin-induced increase in vascular permeability and adjuvant arthritis in rats and ultraviolet ray-induced erythema in guinea pigs dose-dependently, with a potency slightly greater than that of indomethacin-gel. In addition, pranoprofen-gel inhibited dose-dependently the formation of granuloma caused by a cotton pellet implantation, without affecting the weight of the thymus or adrenals and without inducing gastrointestinal lesions. Moreover, applied topically to carrageenin-treated rats, pranoprofen-gel inhibited dose-dependently, and more potently than indomethacin-gel, the production of a prostaglandin E2 (PGE2)-like substance in both the exudate of the carrageenin air pouch and the inflamed synovial membrane. Both drugs inhibited the potentiation of bradykinin-induced vascular permeability in rabbit skin by arachidonic acid, but not by PGE2. Pranoprofen was only one third as potent as indomethacin in inhibiting the production of PGE2 from the phagocytosing of killed bacteria by rat peritoneal leucocytes in vitro. These results show that pranoprofen-gel, applied topically, permeates well from the skin to the deep inflammatory site, relieving potently and long lastingly the inflammation by inhibiting PG production. As a topical anti-inflammatory agent, pranoprofen-gel is at least as effective as indomethacin-gel, so it may have good clinical use.     

The effectiveness of topically applied capsaicin

To undertake a quantitative overview of trials of topical capsaicin for the treatment of diabetic neuropathy, osteoarthritis, post-herpetic neuralgia, and psoriasis.A systematic search of the literature using both computerized and manual methods for identifying clinical trials of capsaicin. The trials identified were abstracted for response data, which then were analysed using established meta-analytic methods for both fixed and random effects modelling.The odds ratio of the response rate of subjects receiving topical capsaicin relative to that of subjects on placebo was used as the main outcome measure. The difference in the response rate was used as the response variable under the random effects model. When dropouts were mentioned and unambiguous assignment could not be made, the analysis was made on the basis of intention to treat.Capsaicin cream give more pain relief to patients with diabetic neuropathy than placebo did. The odds ratio (OR) and corresponding 95% confidence interval (95% CI) in favour of capsaicin cream were OR=2.74 (95% CI=1.73, 4.32). Using a random effect model the rate difference (RD) in favour of capsaicin cream was RD=0.25 (95% CI=0.15, 0.35).Capsaicin cream was also better than placebo in providing pain relief in osteoarthritis: OR=4.36 (95% CI=2.77, 6.88) and RD=0.29 (95% CI=0.20, 0.37) and in psoriasis: OR=2.80 (95% CI=1.69, 4.62) and RD=0.35 (95% CI=0.14, 0.56). There was, however, evidence of heterogeneity in the individual RDs in psoriasis, and complete blinding was difficulty because of the initial discomfort associated with topical capsaicin.In post-herpetic neuralgia the results were even less convincing.Topical capsaicin appears to be effective in the management of a variety of painful clinical conditions affecting the skin. However, totally blind trials are difficult to conduct with this substance. Future trials will need to address this problem more rigorously if a definitive answer about the effectiveness of capsaicin is to be obtained.     

Surface activity profiling of drugs applied to the prediction of blood-brain barrier permeability

The present study describes a novel in vitro platform for physicochemical profiling of compounds, based on their impact on the air/water interfacial tension. Interfacial partitioning coefficient, cross-sectional area, and critical micelle concentration were derived from the Gibbs adsorption isotherms recorded for 76 structurally diverse drugs. An approximation for the membrane partitioning coefficient, K(memb), is introduced and calculated for the measured compounds. This methodology provides a fully automatic, high-throughput screening technique for compound characterization, yielding precise thermodynamic information on the partitioning behavior of molecules at air/water interfaces, which can be directly related to their anisotropic interaction with lipid bilayers in biological membranes. The latter represents the barrier for the passive entry of compounds into cells. The surface activity profiles are shown to correlate to the ability of the compounds to pass passively through the blood-brain barrier.     

Kinetic model to predict the absorption of nasally applied drugs from in vitro transcellular permeability of drugs

The purpose of this study is to propose a kinetic model to predict the absorption of nasally applied drugs from their permeability to the Caco-2 monolayer (P(Caco-2)). Since a drug applied to the nose in an in vivo physiologic condition is translocated to the gastrointestinal (GI) tract by coordinated beats of cilia (mucociliary clearance, MC), the drug undergoes absorption both from the nasal cavity and from the GI tract. The detailed MC of the rat was examined, using inulin as a marker of the applied solution. Inulin disappeared monoexponentially from the nasal cavity, indicating that the MC can be assumed to follow first-order kinetics. From the disappearance of inulin, the first order rate constant for MC (k(MC)) was calculated as 0.0145 min(-1). In the proposed kinetic model, the fractional absorption of the drug following nasal application is predicted as the sum of F(NC) (fractional absorption from the nasal cavity) and F(GI) (fractional absorption from the GI tract), both of which are estimated indirectly from P(Caco-2). F(NC) is calculated according to the equation, k(a)/(k(a)+k(MC)), where k(a) is the absorption rate constant. Nasal drug absorption is assumed to follow first order kinetics. The k(a) of four drugs was initially calculated from k(MC) and their F(NC); thereafter, the linear relationship between k(a) and P(Caco-2), from which k(a) is predicted, was determined. F(GI) is calculated as F(p.o.)(1-F(NC)), where F(p.o.) is fractional absorption after oral administration. F(p.o.) was predicted from the previously determined sigmoid curve between F(p.o.) and P(Caco-2). The proposed kinetic model is the first estimation system for nasal drug absorption based on drug disposition after nasal application and is useful for the development of nasal dosage forms.     

Photoprotective actions of topically applied vitamin E

Topical application of vitamin E has been shown to decrease the incidence of ultraviolet (UV)-induced skin cancer in mice. Vitamin E provides protection against UV-induced skin photodamage through a combination of antioxidant and UV absorptive properties. Topical application of alpha-tocopherol on mouse skin inhibits the formation of cyclobutane pyrimidine photoproducts. However, topically applied alpha-tocopherol is rapidly depleted by UVB radiation in a dose-dependent manner. The photooxidative fate of the alpha-tocopherol depends on the local environment of the vitamin E. alpha-Tocopherol quinone and alpha-tocopherol quinone epoxides are principal photoproducts of vitamin E that has penetrated into the epidermal layer of the skin, whereas tocopherol dimers and trimers are formed from alpha-tocopherol in a bulk phase at the skin surface. Dimer and trimer products may participate in prevention of UV-induced photodamage.     

In vivo effects of different antispasmodic drugs on the rat bladder contractions induced by topically applied KCl.

The model originally proposed by Postius and Szelenyi for in vivo screening of spasmolytic compounds on the rat urinary bladder, has been modified and tested to verify its predictivity. The topically applied KCl induced reproducible contractions of the bladder that were dose dependently inhibited by i.v. administration of calcium antagonists like nifedipine, nicardipine, and verapamil. The other spasmolytics tested (oxybutynin, terodiline, flavoxate, and papaverine), showed a non-dose-related inhibition of the contractions. The in vivo potency of the calcium antagonists was related to their in vitro activity on the agonist-induced contractions of rat bladder strips, whereas the activity of the other spasmolytics appeared higher than that predicted on the basis of their in vitro efficacy. Nicardipine showed a dose-dependent inhibition of KCl-induced contractions also after oral administration, whereas oxybutynin and papaverine behaved as after i.v. administration. The described model represents, therefore, a good, quantitative, and reproducible tool of screening at the bladder level only for antispasmodic drugs endowed with strong calcium antagonistic activity.     

Effect of topically applied flurbiprofen on ultraviolet-induced erythema

The effect of flurbiprofen, a nonsteroidal antiinflammatory agent, on ultraviolet B-induced erythema was studied in normal volunteers. The effect of various concentrations as well as the effect of multiple applications were evaluated at 4, 8, and 24 hours after irradiation with three MEDs of ultraviolet B. Repeated applications of flurbiprofen during the four- and eight-hour periods following ultraviolet B exposure did not increase the blanching response obtained following a single treatment. A concentration dependent effect of flurbiprofen on blanching was observed with suppression of erythema increasing with increasing concentration of flurbiprofen up to 3%. Further increase in concentration up to 5% offered no added advantage. Significant differences in blanching were also observed at different postirradiation time periods. No cutaneous or systemic complications were reported during the entire study.     

Fate of ethanol topically applied to skin.

Ethanol is a major component of many aerosol sprays and consumer products that are designed to contact the skin. It is theoretically possible that small amounts of ethanol from alcohol-based sprays can be absorbed across the skin or inhaled during spraying. In order to assess the potential systemic dose, three parameters were measured: the evaporation of [14C]ethanol from the skin surface, the in vitro penetration of [14C]ethanol through excised pig skin and the ethanol concentration in the blood of human volunteers following simulated use of an alcohol based deodorant spray. The rate of evaporation from Benchkote and whole pig skin was similar (t(1/2)=13.6 sec and 11.7 sec, respectively) while that from glass was longer (t(1/2)=24.8 sec). Ethanol penetration through pig skin in vitro was greater in occluded cells than in non-occluded cells (2.19 mg/cm(2) and 0.10 mg/cm(2) in 24 hours, respectively). At the maximum flux seen in this experiment under occlusion, the amount of ethanol penetrating from a 1 m(2) area of skin would give a blood alcohol level of about 4 mg% in a 70-kg man. In the human use study, none of the blood samples taken from 16 human volunteers exhibited a detectable level of alcohol. These studies provide evidence that a systemic dose of ethanol is likely to be very low after the use of formulations delivering ethanol to the skin.     

Anti-inflammatory activity of hamamelis distillate applied topically to the skin

Summary The anti-inflammatory activity of hamamelis distillate has been evaluated with respect to drug concentration (0.64 mg/2.56 mg hamamelis ketone/100 g) and the effect of the vehicle (O/W emulsion with/without phosphatidylcholine (PC) in an experimental study. The effects were compared with those of chamomile cream, hydrocortisone 1% cream and 4 base preparations. Erythema was induced by UV irradiation and cellophane tape stripping of the horny layer in 24 healthy subjects per test. Skin blanching was quantified by visual scoring and chromametry. Drug effects were compared with one another and with an untreated control area, as well as with any action due to the vehicle.UV-induced erythema at 24 h was suppressed by low dose hamamelis PC-cream and hydrocortisone cream. Hydrocortisone appeared superior to both hamamelis vehicles, hamamelis cream (without PC) and chamomile cream. The latter preparation was also less potent than hamamelis PC-cream. Erythema 4 to 8 h after the stripping of the horny layer was suppressed by hydrocortisone (P0.05). Inflammation was also less pronounced following low dose hamamelis PC-cream and chamomile cream. Hamamelis PC-cream, however, appeared less potent than hydrocortisone. In general, visual scoring was more discriminatory than chromametry.The results have demonstrated an anti-inflammatory activity of hamamelis distillate in a PC-containing vehicle. A fourfold increase of drug concentration, however, did not produce an increase in activity.     

高效液相色谱法测定洛美沙星局部应用的兔眼通透性研究

采用高效液相色谱法（ＨＰＬＣ）测定了洛美沙星在兔眼组织中的通透性。以０．３％滴眼液单次点眼３０ｍｉｎ后，角膜、房水和虹膜睫状体组织的药物浓度分别是８．７５±０．３９μｇ·ｇ－１，０．２１±０．１ｍｇ·Ｌ－１和１．４９±０．３９μｇ·ｇ－１。去除角膜上皮后，多次点眼（１滴／５ｍｉｎ×６）和结膜下注射（０．５ｍｇ，０．５ｍｌ），眼组织达较高药浓度，超出多数病菌的ＭＩＣ９０。实验结果证实，洛美沙星可做为内眼术前的预防用药和治疗由敏感菌引起的眼内炎。