复方祛白喷雾剂的皮肤毒性和安全性研究

目的 研究复方祛白喷雾剂的皮肤毒性和经皮肤用药的安全性。方法 采用家兔急性皮肤毒性试验、豚鼠皮肤过敏试验、家兔皮肤刺激性试验,观察复方祛白喷雾剂经皮肤用药的急性毒性、过敏性和刺激性。结果 复方祛白喷雾剂对家兔完整皮肤与破损皮肤无急性毒性反应;对豚鼠皮肤无致敏作用;对家兔破损皮肤有轻度刺激性反应,但给药48 h后该刺激性反应消失。结论 复方祛白喷雾剂无明显急性皮肤毒性,经皮肤用药的安全性良好。     

红栀骨通凝胶膏对家兔皮肤刺激性的研究

目的:研究红栀骨通凝胶膏经皮给药的安全性。方法:分别取家兔行完整皮肤单次给药刺激性实验(n=4)、破损皮肤单次给药刺激性实验(n=4)、完整皮肤多次给药刺激性实验(n=4)。各家兔左右两侧皮肤分别贴3 cm×3 cm空白基质和红栀骨通凝胶膏24 h(按生药计为0.14 g)。前2项实验家兔分别于去除胶布1、24、48、72 h后观察去毛部位的红斑和水肿情况;第3项实验家兔给药24 h后,暴露给药区域1 h后再次给药,重复3次,分别观察第1、2次去除胶布后及第3次去除胶布1、24、48、72 h后去毛部位的红斑和水肿情况。结果:3项实验中,各组家兔的红斑和水肿评分均为0分,皮肤刺激性均评价为无刺激。结论:红栀骨通凝胶膏对家兔皮肤无刺激性。     

咪喹莫特乳膏对家兔皮肤的刺激性研究

目的 考察咪喹莫特乳膏对家兔皮肤的刺激性作用。方法 分别进行单次和多次给药对家兔皮肤的刺激性实验。单次给药实验时，取家兔8只，随机平均分成实验组1和实验组2，均对称脱去脊柱两侧毛，将每只家兔脱毛皮肤自上而下平均分为4块，脊柱两侧共8块，下部4块制作破损皮肤模型。所有家兔脊柱左侧均给予赋形剂1 g，实验组1脊柱右侧给予1%咪喹莫特乳膏1 g，实验组2脊柱右侧给予5%咪喹莫特乳膏1 g。涂药后用医用手术巾包扎8 h，观察并记录除去咪喹莫特乳膏及赋形剂后1，24，48，72 h给药部位皮肤的红斑、水肿、焦痂等刺激反应情况。多次给药实验时，分组、给药方法、剂量及包扎时间均同单次给药实验，每日给药1次，连续7 d。每次给药后8 h，用温水洗去药物及赋形剂。结果 1%和5%咪喹莫特乳膏在家兔完整及破损皮肤单次给药时未见皮肤刺激性反应；1%咪喹莫特乳膏在家兔完整皮肤多次给药未见明显刺激反应，破损皮肤多次给药有轻度刺激反应；5%咪喹莫特乳膏在家兔完整皮肤多次给药有轻度刺激反应，破损皮肤多次给药有中度刺激反应。但停药后刺激反应消失，皮肤恢复正常。未见赋形剂对家兔皮肤的明显刺激作用。结论咪喹莫特乳膏单次给药对家兔完整和破损皮肤无刺激性，多次给药对家兔破损和完整皮肤的刺激反应小。预期咪喹莫特乳膏临床可用。     

701跌打镇痛膏安全性实验研究

的 研究701 跌打镇痛膏经皮给药急性毒性、皮肤刺激性和过敏性,为其临床应用和推广提供实验依据。 方法 选用新西兰兔和 Hartley 豚鼠为研究对象,分别采用最大耐受量法和同体左右侧对照给药的方法考察701 跌打镇痛膏经皮给药的急性毒性、皮肤刺激性和过敏性。 结果 701 跌打镇痛膏经皮给药后对新西兰兔未见明显毒性反应;对新西兰兔破损皮肤会产生刺激性反应,但此刺激性可于停药后14 d 完全恢复;对新西兰兔完整皮肤也会产生轻度刺激性,但此刺激性是一过性反应;对 Hartley 豚鼠未产生明显过敏反应。 结论 701 跌打镇痛膏具有良好的安全性,经皮单次和多次给药后除轻微的皮肤刺激性外未见其他明显毒性反应,且所产生的皮肤刺激性均为可逆性反应,值得进一步推广应用。 但在临床应用中701 跌打镇痛膏应尽量在损伤局部皮肤无明显破损时使用,尽量避免在破损皮肤上使用,以减少药物对皮肤的刺激性。     

黑膏药风湿骨痛贴的皮肤安全性评价

目的:考察黑膏药风湿骨痛贴经皮给药的安全性.方法:采用健康家兔皮肤刺激性试验、健康豚鼠皮肤过敏性试验,观察风湿骨痛贴对动物经皮给药的刺激性和过敏性.结果:风湿骨痛贴对家兔完整皮肤和破损皮肤均无刺激性,对豚鼠皮肤无致敏性.结论:在本试验条件下风湿骨痛贴经皮给药无明显不良反应.     

温面散对兔皮肤刺激性试验研究

目的 观察温面散对新西兰家兔完整皮肤及破损皮肤单次和多次接触受试物后所产生的局部刺激反应.方法 取温面散（相当于人用量的6倍）和赋形剂（60%乙醇）单次和多次于家兔完整皮肤和破损皮肤处给药后,肉眼观察皮肤红斑、水肿、色素沉着、出血点、皮肤粗糙或皮肤菲薄等情况.结果 肉眼观察未见皮肤红斑、水肿、色素沉着、出血点、皮肤粗糙或皮肤菲薄等情况.结论 温面散对皮肤基本无刺激性反应.     

血余炭纳米纤维膜皮肤刺激性和过敏性实验研究

目的:观察血余炭纳米纤维膜外用对皮肤的刺激性和过敏性反应,为评价其安全性提供参考。方法:采用家兔皮肤刺激实验,分完整皮肤组和损伤皮肤组,分别在给药1 d、连续给药7 d后,观察皮肤有无红斑、水肿等刺激反应;采用豚鼠皮肤过敏实验,每周贴敷血余炭纳米纤维膜致敏1次,连续3周,于首次致敏后的第28天皮肤再次给药进行攻击,观察皮肤有无红斑、水肿等过敏反应。结果:血余炭纳米纤维膜对家兔的完整皮肤和破损皮肤,经单次给药或多次给药24 h后去除敷料,分别于1、24、48、72 h观察,均未见红斑及水肿,刺激反应平均分值均<0.5,无刺激性;豚鼠皮肤过敏实验中,未出现皮肤明显红斑、水肿等皮肤过敏反应及其他全身性过敏反应。结论:血余炭纳米纤维膜对家兔完整皮肤和损伤皮肤不会引起刺激性反应,对豚鼠皮肤无过敏性反应,具有良好的皮肤用药安全性。     

十一方药酒急性毒性、皮肤刺激性和过敏性试验

目的:考察十一方药酒的急性毒性、皮肤刺激性和过敏性。方法:采用健康家兔进行急性毒性和皮肤刺激性试验,采用健康豚鼠进行皮肤过敏性试验。结果:家兔完整皮肤及破损皮肤单次用药(临床等效剂量的53,27,13倍),14 d内无中毒表现,呼吸、进食等活动正常,体重分别增长6.97%和6.67%;家兔完整皮肤和破损皮肤单次给药,连续7 d,均未见刺激性;十一方药酒对豚鼠皮肤无致敏性。结论:十一方药酒对家兔皮肤无急性毒性和刺激作用,对豚鼠皮肤无致敏作用。     

布地奈德鼻喷雾剂的局部安全性评价

目的：通过家兔鼻刺激性和豚鼠皮肤过敏性试验考察布地奈德鼻喷雾剂对皮肤用药的安全性。方法：参照《化学药物刺激性、过敏性和溶血性研究技术指导原则》,采用最大给药量试验观察鼻腔给药后动物短期内出现的毒性反应及其程度,并结合组织病理学检查综合判断呼吸道黏膜发生的局部刺激性反应;对豚鼠皮肤多次局部涂抹致敏,观察其过敏反应。结果：家兔鼻腔在最大给药量为102μg/Kg·d后,短期内未见毒性反应及死亡情况,给药局部鼻黏膜未见充血、水肿等刺激反应。组织病理学检查未见明显鼻、喉、气管、支气管等呼吸道黏膜损伤性变化及大量炎性细胞浸润;对豚鼠皮肤的多次刺激致敏试验未显示明显红斑及水肿等过敏反应。结论：布地奈德鼻喷雾剂局部用药无明显毒性及刺激性,符合外用制剂的安全性要求,临床使用安全可靠。     

碳糊电极阳极吸附伏安法测定雷贝拉唑

目的:考察乳癖消巴布膏皮肤用药的安全性.方法:用健康家兔分别进行完整与破损皮肤的皮肤刺激性试验;用健康豚鼠进行皮肤过敏试验;用健康大鼠进行慢性经皮毒性试验.结果与结论:乳癖消巴布膏对家兔无皮肤刺激性.对豚鼠无致敏性,对大鼠无经皮毒性.     

Transdermal contraceptive patches

Many contraceptive methods have been developed for fertility regulation, either reversible or irreversible, in males and females. Oral contraceptives have been considered the most popular form of reversible contraception. However, they must be taken consistently, on a daily basis for 21 or 28 days of each menstrual cycle, in order to achieve the maximal outcomes of contraception. Moreover, their contraceptive efficacy has been reportedly affected by their interactions with many drug products taken concurrently for other conditions. To resolve the dilemma of daily compliance and the risk of potential interactions with drugs taken orally, several non-traditional delivery systems have been developed to permit contraceptive agents and their combinations to be administered via a non-oral route, and also at a lesser frequency of administration, so as to enhance treatment compliance, maximize therapeutic outcomes, and minimize adverse effects. One typical example is the successful development of the ethinylestradiol/norelgestromin patch for achieving contraception in females via transdermal delivery. With topical application on intact skin, each patch delivers a combination of norelgestromin and ethinylestradiol for a week. With a treatment schedule of 3 weeks with a patch on and 1 week without a patch for each menstrual cycle, the ethinylestradiol/norelgestromin patch has achieved a clinical efficacy that is considered bioequivalent to oral contraceptives (with an unintended pregnancy rate of 0.8% per woman-year for the patch versus 0.1% per woman-year for the combined oral contraceptive). Stimulated by the marketing success of the ethinylestradiol/norelgestromin transdermal contraceptive patch, and a growing recognition of the therapeutic benefits realized by delivering an orally inactive progestin via a transdermal route, other transdermal drug delivery systems (DDS), such as transdermal gels and a metered-dose transdermal spray system, have also been developed. Further transdermal contraceptive patches have also been developed. One of these is similar to the ethinylestradiol/norelgestromin patch, in that it is fabricated from an adhesive polymer matrix diffusion-controlled DDS; however, it has a two times smaller patch size (to minimize localized reactions at the application site). This was made possible by substituting norelgestromin with a more potent progestin called gestodene, that has a higher skin permeation rate. The other transdermal patch that has been developed employs a microreservoir partition-controlled delivery system, to provide dual-controlled delivery of estradiol (a natural estrogen) and levonorgestrel (another potent synthetic progestin) at constant rates (zero-order kinetics). Clinical studies have demonstrated that these two new patch systems may be attractive alternative forms of contraception, since ovulation inhibition has been achieved in all subjects who wear the transdermal patch for 3 weeks, replacing it on a weekly basis. A transdermal gel has been formulated to contain elcometrine, which has a progestational potency that is 100 times that of progesterone but is orally inactive, in an alcoholic solution. Preliminary clinical studies have indicated that suppression of ovulation was achieved in the majority of subjects receiving daily application of the transdermal gel. To address the problems associated with the dosing accuracy of the transdermal gel, due to difficulty controlling the area and size of the application site, the feasibility of delivering the transdermal gel from a metered-dose transdermal spray system is currently under evaluation by the Population Council.     

Novel reverse electrodialysis-driven iontophoretic system for topical and transdermal delivery of poorly permeable therapeutic agents

Topical and transdermal drug delivery has great potential in non-invasive and non-oral administration of poorly bioavailable therapeutic agents. However, due to the barrier function of the stratum corneum, the drugs that can be clinically feasible candidates for topical and transdermal delivery have been limited to small-sized lipophilic molecules. Previously, we fabricated a novel iontophoretic system using reverse electrodialysis (RED) technology (RED system). However, no study has demonstrated its utility in topical and/or transdermal delivery of poorly permeable therapeutic agents. In this study, we report the topical delivery of fluorescein isothiocyanate (FITC)–hyaluronic acid (FITC–HA) and vitamin C and the transdermal delivery of lopinavir using our newly developed RED system in the in vitro hairless mouse skin and in vivo Sprague–Dawley rat models. The RED system significantly enhanced the efficiency of topical HA and vitamin C and transdermal lopinavir delivery. Moreover, the efficiency and safety of transdermal delivery using the RED system were comparable with those of a commercial ketoprofen patch formulation. Thus, the RED system can be a potential topical and transdermal delivery system for various poorly bioavailable pharmaceuticals including HA, vitamin C, and lopinavir.     

Dermal Drug Delivery Systems: A Review

Abstract

Systems that deliver drugs through intact skin at a controlled rate are now in routine clinical use. They include a nitroglycerin system for the prophylaxis of angina, and a scopolamine system for the prevention of motion sickness. In addition, there are also published reports on rate-controlled transdermal forms of clonidine and estradiol. Since the trans-dermal mode of drug administration can provide continuity of delivery and precise control of drug plasma concentrations, it offers particular advantages for drugs with short half-lives or narrow therapeutic indices. It is also useful when the oral route is unsuitable. Transdermal rate-controlled therapy appears on the brink of rapid expansion for the administration of potent, nonirritating, nonallergenic agents with suitable physi-cochemical properties. In the case of new agents, rate-controlled transdermal administration may render some drugs routinely usable that otherwise would produce unacceptable side effects or require impractical regimens. Some older agents will gain an increased margin of safety and convenience—as well as expanded therapeutic usefulness—compared with their administration in conventional dosage forms. Owing to constraints arising from drug potency, skin permeability, and/or topical reactions, however, transdermal administration is not expected to become the preferred dosage form for a high percentage of drugs.     

Enhancement of transdermal delivery of progesterone using medium-chain mono and diglycerides as skin penetration enhancers

We evaluated whether medium-chain mono and diglycerides (MCG) can be utilized to optimize the transdermal delivery of progesterone (PGT). MCG was studied at 10–70% (w/w) in propylene glycol (a polar solvent) or Myvacet oil (nonpolar solvent); PGT was used at 1% (w/w). The topical (to the skin) and transdermal (across the skin) delivery of PGT were evaluated in vitro using porcine ear skin. When incorporated in propylene glycol, MCG at 10% enhanced the topical and transdermal delivery of PGT by 2.5- and 7-fold, respectively. At 20–50%, topical delivery was further enhanced while transdermal delivery gradually returned towards baseline. At 70%, MCG enhanced neither the delivery to viable skin nor the transdermal delivery of PGT. Similar concentration-dependent effects were observed when MCG was incorporated in Myvacet oil, but their magnitudes were 2- to 3-fold smaller. The relative safety of MCG was assessed in cultured fibroblasts and compared to propylene glycol (regarded as safe) and sodium lauryl sulfate (moderate-to-severe irritant). Both MCG and propylene glycol were substantially less cytotoxic than sodium lauryl sulfate. We conclude that formulations containing 10% MCG in propylene glycol may be a simple and safe method to improve the transdermal delivery of progesterone and promote its use in hormone replacement therapy.     

Topical delivery of cyclosporin A: an in vitro study using monoolein as a penetration enhancer.

Topical delivery of cyclosporin A (CysA) is of great interest for the treatment of autoimmune skin disorders, but it is frequently ineffective due to poor drug penetration in the skin. The present study was aimed at investigating whether the presence of monoolein (a lipidic penetration enhancer) in a preparation of propylene glycol can improve CysA delivery to the skin. CysA was incorporated in a propylene glycol preparation containing 5-70% (w/w) of monoolein. The topical (to the skin) and transdermal (across the skin) delivery of CysA were evaluated in vitro using porcine ear skin mounted in a Franz diffusion cell. CysA was quantified by UV-HPLC. At 5%, monoolein increased only the transdermal delivery of CysA. At 10%, it increased both topical and transdermal delivery. When the concentration of monoolein was further increased (20-70% w/w), an interesting phenomenon was observed: the topical delivery of CysA was still elevated but its transdermal delivery was substantially reduced. It was concluded that monoolein (in propylene glycol formulations) can promote the topical delivery of CysA, with reduced transdermal delivery.     

Gene expression in an intact ex-vivo skin tissue model following percutaneous delivery of cationic liposome-plasmid DNA complexes

The skin represents an attractive site for the localised gene therapy of dermatological pathologies and as a potential antigen bioreactor following transdermal delivery. Potential also exists for the gene therapy of skin as a cosmetic intervention. The most exploited non-viral gene delivery system involves the complexation of cationic liposomes with plasmid DNA (pDNA) to form lipid:pDNA vectors that protect the DNA from nuclease-mediated degradation and improve transgene-cell interactions. Despite numerous studies examining the potential for these vectors in delivering genes to a variety of keratinocyte models, investigations into the topical application of such complexes to intact skin tissue is limited. This ex-vivo study, conducted with intact skin tissue derived from hairless mice, provides quantitative confirmation that topical administration of cationic lipid:pDNA complexes can mediate uptake and expression of reporter pDNA (33-fold higher compared with control) in viable epidermal tissue. The ex-vivo study design provides for intact skin tissue that has not been subjected to depilatory procedures of potential detriment to stratum corneum barrier function, and can be utilised for the quantitative and efficient examination of a potentially wide range of non-viral gene vectors designed for epidermal expression.     

介孔二氧化硅纳米材料的皮肤安全性研究

目的:评价介孔二氧化硅纳米材料(MSNs)的皮肤渗透性、刺激性及过敏性。方法:在体透皮实验中,将分别载不同量(0.75%和3%,W/W)MSNs和氨基修饰的MSNs(NH2-MSNs)的凝胶涂布于大鼠背部皮肤,考察24 h后皮肤中硅含量及在皮肤组织中的分布(n=4);皮肤刺激性实验中,将分别载3%MSNs和NH2-MSNs的凝胶多次(1次/d,共7 d)涂布于家兔完整皮肤及破损皮肤,采用同体左右侧自身对照,给药期间每日观察局部皮肤红斑及水肿情况(n=4);皮肤过敏性实验中,于实验第1、7、14天将载3%MSNs和NH2-MSNs的凝胶、凝胶基质和1%2,4-二硝基氯代苯溶液(阳性对照)分别涂布于豚鼠背部皮肤左侧致敏,于末次致敏后14 d(第28天)同法涂药于右侧激发接触,以是否出现红斑或水肿为指标,观察局部皮肤的过敏反应(n=6)。结果:载0.75%、3%MSNs的凝胶致皮肤中硅含量分别为(10.812±3.963)、(22.050±5.721)μg/g,载0.75%、3%NH2-MSNs的凝胶致皮肤中硅含量分别为(7.799±2.068)、(16.416±3.221)μg/g,透射电镜显示MSNs能跨过皮肤屏障,进入真皮层;完整皮肤和破损皮肤均未出现红斑或水肿现象;与阳性对照比较,载MSNs及NH2-MSNs的凝胶均未导致豚鼠皮肤出现红斑或水肿。结论:MSNs作为局部施药载体具有良好的皮肤安全性。     

Biopharmaceutics: Effect of Ointment Bases on Topical and Transdermal Delivery of Salicylic Acid in Rats: Evaluation by Skin Microdialysis

Microdialysis has been used to determine the concentration of salicylic acid in skin tissue and plasma periodically for 4 h to evaluate the effect of ointment bases on topical and transdermal delivery of salicylic acid. The ointment bases examined were solbase (water-soluble), poloid and white petrolatum (oleaginous), hydrophilic poloid (water in oil (w/o) type emulsion lacking water) and absorptive ointment (w/o-type emulsion containing water). The ointments (0.1 g) containing 25 μmol salicylic acid were applied for 2 h to the surface of rat skin (1 cm²) with (intact) or without the stratum corneum. For intact skin, the extent of topical delivery from different ointments, evaluated by the area under the concentration-time curve (AUC) of salicylic acid in the skin tissue (AUCskin), increased in the order solbase. white petrolatum, poloid, hydrophilic poloid. absorptive ointment. The ratio of AUC_skin (topical delivery) to the AUC of salicylic acid in plasma (AUC_plasma, transdermal delivery) varied remarkably among the different bases, the greatest ratio being observed for absorptive ointment. When the ointments were applied to skin surface without stratum corneum, AUC_skin for solbase was much higher (about 45 times that for intact skin), whereas only a small (two-fold) increase was observed for poloid and hydrophilic poloid and the increase was negligible for white petrolatum and absorptive ointment. For skin without the stratum corneum, the ratio AUC_skin/AUC_plasma for the different ointments was comparable, although the magnitudes of AUC_skin and AUC_plasma still varied substantially. The variance of AUC values arises as a result of the different rates of release of salicylic acid from the bases. These results indicate that: the topical and transdermal delivery of salicylic acid in intact skin varies substantially among different ointment bases, and the greatest topical delivery is observed for absorptive ointment; use of absorptive ointment increases the retention of salicylic acid in the stratum corneum; and the stratum corneum functions strongly as a penetration barrier for solbase, moderately for poloid and hydrophilic poloid, and less for absorptive ointment and white petrolatum.     

Bioavailability of propranolol following oral and transdermal administration in rabbits

The systemic bioavailability of propranolol was evaluated following oral and transdermal administration in rabbits. Using a four-way crossover study, the bioavailability of propranolol following oral administration was determined to be 12.3 +/- 5.9%, indicating that propranolol is subject to extensive hepatic first-pass metabolism in rabbits. Transdermal delivery of propranolol, via an adhesive delivery device, resulted in a bioavailability of 74.8 +/- 10.1%, indicating that the transdermal delivery of propranolol can significantly increase systemic bioavailability over oral administration. Skin irritation studies indicated that neither propranolol nor the adhesive used in the device caused any appreciable skin irritation.     

Topical iontophoretic delivery

At present, transdermal iontophoresis is used in the topical delivery of local anesthetics and anti-inflammatory agents. The treatment of hyperhidrosis and the diagnosis of cystic fibrosis are other clinical applications of iontophoresis. Also, a glucose-monitoring device has been developed utilizing the principle of reverse iontophoresis. Commercial iontophoretic systems that would continuously deliver therapeutic agents into the systemic circulation, corresponding to the passive transdermal patches, do not exist at the moment; however, Alza Corporation has announced that it has received an approvable letter from the US FDA regarding a new drug application for Ionsys®, an iontophoretic, fentanyl-containing, transdermal analgesic. There is currently a lot of interest in the potential of closed-loop systems, which not only sense changes in the concentration of the analyte in the skin and in the subdermal tissues, but also administer a drug in response to the fluctuating concentration/need. Thus, self-regulated or patient-regulated systems that allow medication to be administered at home would enable controlled therapy, while accounting for the individual needs of the patient. Predictable and controlled non-invasive drug delivery on the one hand, and putative adverse effects on the other, determine the success of topical iontophoretic systems and methods. The often unavoidable skin sensitization/irritation and other adverse reactions have to be related to the therapeutic benefit(s) of (bio)molecule administration; for example, the potential for skin irritation associated with pain control medication is quite different (in terms of acceptability) to skin irritation associated with cancer treatment. An additional obstacle in the path to successful transdermal delivery is the stability issue of the (bio)molecule in the drug delivery system, skin, and target tissue.