咪喹莫特固体脂质纳米粒包封率的测定

目的:建立咪喹莫特固体脂质纳米粒包封率的测定方法。方法:采用热乳匀法制备咪喹莫特固体脂质纳米粒。用葡聚糖凝胶柱色谱法分离含药固体脂质纳米粒与游离药物,以蒸馏水和1．0×10-3mol·L-1盐酸溶液为洗脱液,用HPLC法测定游离药物量。结果:凝胶柱色谱法能够将包封药物和游离药物分开。游离咪喹莫特在0．335-2．69μg·ml-1浓度范围内,线性关系良好(r=0．999 9)。游离药物柱回收率为98．6％,柱的加样回收率为97．7％。样品的平均包封率为(51．43±0．88)％。结论:该方法操作简便,结果准确,可用于咪喹莫特固体脂质纳米粒包封率测定。     

鸦胆子油微乳的制备及稳定性研究

目的研究鸦胆子油微乳的制备、稳定性及微乳中药物含量的测定方法。方法选用MCT(辛葵酸甘油三脂)为油相,大豆卵磷脂为表面活性剂,乙醇为助表面活性剂,在制备三元相图的基础上,考察微乳的组分对微乳形成的影响。结果大豆卵磷脂为乳化剂形成微乳系统所需表面活性剂的量为20%～30%。结论采用微乳作为药物载体制备口服鸦胆子油微乳是一种很好的药物传递系统。     

以葛根素为模型药物的口服微乳研究

目的以葛根素为模型药物研究口服微乳的处方筛选方法 ,并对其结果进行质量评价。方法查阅文献选取不同极性空白微乳,考察不同处方空白微乳的葛根素的最大载药量,考察载药和矫味剂对微乳稳定性的影响,从而确定葛根素口服微乳的2个最优处方,对其进行质量评价包括载药微乳的理化性质、粒径大小、在人工胃液和人工肠液中的稳定性及载药微乳中葛根素的含量。结果处方B载药微乳为淡黄色澄清液体,平均粒径为61.59nm,葛根素载药量为21.06mg.mL-1;处方G载药微乳为无色澄清液体,平均粒径为23.09nm,葛根素载药量为21.73mg.mL-1。结论本实验优选空白微乳能增加葛根素的溶解度,且载药量大,质量稳定。     

白藜芦醇微乳的制备及表征

目的:采用高压均质法制备白藜芦醇微乳,并对其进行表征。方法:以白藜芦醇微乳粒径分布、多分散系数(Pd I)、包封率为评价指标,考察制备白藜芦醇微乳的各个因素,并对制得的微乳进行表征;初步研究白藜芦醇微乳的稳定性。结果:白藜芦醇微乳的平均粒径为231±37.8 nm,Pd I为0.228±0.047,zeta电位为-42.5±4.3 m V;透射电镜显示微乳粒径均一,成球状分布。长期稳定性研究显示,微乳在25℃条件下放置3个月稳定。结论:高压均质法制备白藜芦醇微乳工艺简单易行。     

利多卡因微乳凝胶剂的制备及初步药效学研究

目的制备利多卡因微乳凝胶剂,并对其药效学及皮肤刺激性进行初步研究。方法以油酸乙酯为油相,聚山梨酯-80为表面活性剂,无水乙醇为助表面活性剂,用水滴定的方法制备利多卡因微乳。以卡波姆940为凝胶骨架,采用直接溶胀法制备利多卡因微乳凝胶。采用Zetasizer Nano-ZS90马尔文激光粒度仪测定微乳的粒径。采用日立H-7650透射电子显微镜观察微乳的形态。采用热板法观察该药对小鼠的镇痛作用。采用连续给药的方法,考察该药对家兔正常皮肤与破损皮肤的刺激性。结果利多卡因微乳凝胶外观为白色透明凝胶态,微乳呈圆球形,微乳粒径<100 nm。利多卡因微乳凝胶剂能延长热板致痛的潜伏期,对家兔皮肤无刺激性。结论利多卡因微乳凝胶剂具有较好的局麻镇痛作用和安全性。     

苦参碱口服微乳的制备及含量测定

目的制备苦参碱口服微乳,并对微乳进行含量测定和理化性质考察。方法通过滴定法绘制伪三元相图,考察不同因素对微乳区域的影响,筛选合适的微乳处方;采用稀释法和染色法鉴别微乳的类型。结果确定了油酸乙酯-cremophor EL-无水乙醇-蒸馏水的苦参碱微乳,所制备微乳为O/W型;理化性质:pH值为8.23、平均粒径为61.3 nm、黏度为0.022 mPa.s、电导率为0.183 2 S.m-1z、eta电位为-3.72 mV;HPLC法测定微乳中苦参碱的平均质量浓度为39.94 g.L-1。结论所制备的苦参碱微乳粒径较小,分布均匀,理化性质稳定,为进一步研究奠定了基础。     

微乳色谱应用研究进展

微乳(Microemulsion,ME)是由乳化剂、助乳化剂、油相和水相组成的光学上各向同性,热力学稳定的液-液分散体[1],只要组分的比例合适即可自发形成均匀透明或微呈乳光的体系并保持稳定。以微乳为流动相进行的色谱称为微乳色谱[2]。微乳色谱近年来得到广泛研究和应用,其中微乳电动色谱的研究应用较多。本文简单介绍微乳的色谱行为,并就近年来微乳色谱的应用研究进展进行综述,主要介绍微乳电动色谱、微乳液相色谱、微乳薄层色谱、微乳毛细管电泳。1微乳的色谱行为微乳体系中由于引入表面活性剂,其亲水亲油性使得较大范围极性的物质都能在微乳中…     

不同链长油相对葛根素微乳经淋巴转运吸收的影响

目的：以实验室前期研究得到的微乳处方为基础,采用乳糜微粒阻断法研究微乳处方中不同链长度油相对葛根素微乳经淋巴转运的影响。方法：采用乳糜微粒阻滞技术阻断药物淋巴转运,高效液相色谱法测定大鼠血浆中葛根素浓度,比较阻断组与未阻断组生物利用度来计算淋巴转运的比例。结果：长链油微乳的淋巴转运比例为49.7%,中链油微乳、及短链油微乳为29.8%、22.5%。长链油微乳的淋巴转运比例高于中链油微乳及短链油微乳,且其生物利用度也高于中链油微乳及短链油微乳,差异具有统计学意义。结论：长链油微乳更能促进葛根素经肠道吸收,增加其在血浆中的浓度,从而提高生物利用度。     

丁香酚微乳凝胶的制备及其体外释放特性研究

目的制备高载药量、高黏附性的丁香酚微乳凝胶,以提高丁香酚的透皮渗透性和相对生物利用度。方法通过表观溶解度评价丁香酚在油、表面活性剂和助表面活性剂中的溶解度,以筛选微乳的处方组成。以油酸乙酯为油相,Solutol HS15为表面活性剂和PEG 400为助表面活性剂,纯化水为水相构建伪三元图。评价微乳的pH值、电导率、黏度、粒径和药物浓度。通过甘油润湿的卡波姆940配制成微乳凝胶,并评价微乳凝胶的pH值、粒径、黏度和药物浓度。采用改良Franz扩散池法对丁香酚微乳凝胶的体外释放性能进行考察。结果表面活性剂和助表面活性剂之比为1∶1时,形成的微乳区域最大;微乳(F3)的球体尺寸为83.27 nm,含量稳定。加入0.5%卡波姆940和6%甘油制得外观均匀、透明的微乳凝胶,微乳(F3)黏度为106.8 mPa·s,微乳凝胶(FG3)黏度增加到15.7 Pa·s。体外经皮渗透试验表明丁香酚对照品溶液、微乳和微乳凝胶的经皮累积渗透率依次增大,微乳凝胶(FG3)渗透12h后丁香酚经皮累积渗透量为55.08%。家兔刺激试验结果表明其在家兔皮肤上没有刺激或诱导炎症。结论丁香酚微乳凝胶比丁香酚对照品溶液、丁香酚微乳具有更好的应用性和稳定性,有望成为丁香酚的新型给药制剂。     

油酸微乳对利多卡因透皮吸收的影响

目的研究油酸微乳对利多卡因透皮吸收的影响。方法在制备相图的基础上，考察了微乳的组分对微乳形成的影响。选择适当的表面活性剂/助表面活性剂比例，制备利多卡因的油酸微乳处方，考察微乳、乳剂、胶束和饱和水溶液在透皮吸收方面的差异。结果以Labrasol为表面活性剂，吐温80为助表面活性剂所得油酸微乳的区域较大，微乳对利多卡因有明显的促透作用，透皮速率依次为微乳＞乳剂＞饱和水溶液＞胶束。结论油酸微乳可促进利多卡因的透皮吸收。     

咪喹莫特乳膏的制备与治疗尖锐湿疣的临床应用

目的：研制治疗尖锐湿疣的新型外用免疫调节药咪喹莫特乳膏，并观察其临床疗效。方法：苯甲醇、异硬脂酸、十八醇等加热融化为油相，甘油、对羟基苯甲酸甲酯、对羟基苯甲酸丙酯等加热融化为水相，将油相加入水相制成乳膏基质，把咪喹莫特细粉加入乳膏基质制备咪喹莫特乳膏。采用紫外分光光度法测定其含量，并观察咪喹莫特乳膏治疗125例尖锐湿疣患者的疗效。结果：该制剂制备简单，质量可控，临床治疗尖锐湿疣患者，治疗8周总有效率97.6%。 结论：咪喹莫特乳膏是治疗尖锐湿疣的有效药物，可作为第一线药物应用于临床。     

Effect of food on the pharmacokinetics and bioavailability of oral imiquimod relative to a subcutaneous dose

OBJECTIVES: The present study, the first clinical pharmacokinetic report of the immune response modifier imiquimod, was conducted to assess the effect of food on the oral absorption of imiquimod, to characterize its pharmacokinetics, and to estimate its oral bioavailability. SUBJECTS AND METHODS: Sixteen healthy male volunteers completed this open-label, randomized, three-period crossover study. Subjects received a 100 mg oral dose of imiquimod after fasting in one period, after a standarized, high fat meal in another, and a 30 mg subcutaneous dose in the third period. RESULTS: The oral bioavailability of imiquimod was on average 47%, and independent of whether imiquimod was administered with or without food. Oral imiquimod was absorbed in both fasted and non-fasted states with an absorption half-life of approximately 1 hour. However, there seemed to be a delay in the initiation of the absorption process when food was administered, which translated in to a Tmax of approximately 2.6 hours while fasting and one hour later in the non-fasted state. Imiquimod was rapidly eliminated with a half-life of approximately 2.5 hours and a total body clearance of approximately 970 ml/hxkg. Although equivalence could not be established due to the large intersubject variability, no significant differences in rate (Cmax) and extent (AUC) of oral absorption were observed between the fasted and non-fasted states. In addition, the Cmax, AUC and bioavailability values for individual subjects were consistent between both oral treatments. CONCLUSION: This study suggests that food does not have a major effect on the rate, extent of absorption or bioavailability of oral imiquimod, and thus, it is suitable to administer imiquimod orally in either the fasted or non-fasted states.     

Evaluation of imiquimod for topical treatment of vaccinia virus cutaneous infections in immunosuppressed hairless mice

Imiquimod is an immune response modifier prescribed as a topical medication for a number of viral and neoplastic conditions. We evaluated the antiviral activity of imiquimod against vaccinia virus (WR strain) cutaneous infections in immunosuppressed (with cyclophosphamide) hairless mice when administered after virus exposure. Primary lesions progressed in severity, satellite lesions developed, and infection eventually killed the mice. Once daily topical treatment with 1% imiquimod cream for 3, 4, or 5 days were compared to twice daily topical treatment with 1% cidofovir cream for 7 days. Survival time of mice in all treated groups was significantly prolonged compared to placebo controls. The mean day of death for the placebo group, 3-day imiquimod, 4-day imiquimod, 5-day imiquimod, and cidofovir groups were 15.5, 20.0, 20.5, 19.5, and 20.5 days post-infection, respectively. All treatment groups showed significant reductions in primary lesion size and in the number of satellite lesions. The cidofovir and 4-day imiquimod treatments delayed the appearance of lung virus titers by 3 and 6 days, respectively, although cutaneous lesion and snout virus titers were not as affected by treatment. Benefits in survival and lesion reduction were observed when imiquimod treatment was delayed from 24, 48, and 72 h post-infection. However, increasing the treatment dose of imiquimod from 1% to 5% led to a significant decrease in antiviral efficacy. These results demonstrate the protective effects of topically administered imiquimod against a disseminated vaccinia virus infection in this mouse model.     

咪喹莫特的合成

目的：研究抗病毒药咪喹莫特的合成。方法：以邻氨基苯甲酸为起始原料经缩合、环合、氯化、还原、N-氧化,氨基化等反应合成咪喹莫特。结果：合成的咪喹莫特收率为39％（以3-硝基4-羟基喹啉计）。经元素分析、MS、UV、IR、HNMR等测试确证了结构。结论：本方法合成咪喹莫特原料价廉易得,适合工业化生产。     

Development of a topically active imiquimod formulation

The purpose of this work was to develop a topical formulation of imiquimod, a novel immune response modifier, to induce local cytokine production for the treatment of external genital and perianal warts. A pH-solubility profile and titration data were used to calculate a pKa of 7.3, indicative of a weak base. Solubility experiments were conducted to identify a solvent that dissolves imiquimod to achieve a 5% formulation concentration. Studies to select surfactants, preservatives, and viscosity-enhancing excipients to formulate an oil-in-water cream indicated that fatty acids were the preferred solvent for topical imiquimod formulations, and isostearic acid (ISA) was selected. A relationship existed between the fatty acid composition of four commercially available ISA sources and the solubility of imiquimod. A combination of polysorbate 60, sorbitan monostearate, and xanthan gum was used to produce a physically stable cream. The preservative system included parabens and benzyl alcohol to meet the USP criteria for preservative activity. An in vitro method was developed to demonstrate that imiquimod was released from the formulation. Topical application of the formulation induced local cytokine activity in mice.     

咪喹莫特乳膏和鬼臼毒素酊治疗尖锐湿疣疗效对照观察

目的对比观察咪喹莫特乳膏和鬼臼毒素酊治疗尖锐湿疣的疗效。方法将98例患者分为咪喹莫特乳膏组与鬼臼毒素酊组,咪喹莫特乳膏组肌注重组人干扰素a-2b,口服盐酸伐昔洛韦片,病灶局部涂抹咪喹莫特乳膏;鬼臼毒素酊组：肌注重组人干扰素a－2b,口服盐酸伐昔洛韦片,病灶局部涂抹鬼臼毒素酊。结果咪喹莫特乳膏组痊愈53例,复发5例,有效率为91．2％,鬼臼毒素酊组痊愈30例,复发10例,有效率为75．0％,两组比较差异有显著性（P〈0．05）。结论咪喹莫特乳膏较鬼臼毒素酊治疗尖锐湿疣疗效更理想,复发率低。     

Imiquimod 3.75% cream (Zyclara) for the treatment of actinic keratoses

INTRODUCTION: actinic keratosis is a premalignant disease with a high incidence and is a strong predictor for the development of squamous cell carcinoma. Various treatment options have been established over recent years, including topical treatment with imiquimod, 5-fluorouracil, diclofenac or photodynamic therapy, cryotherapy and surgical procedures. AREAS COVERED: this review covers basic and clinical experiences with imiquimod 3.75% for topical treatment of actinic keratosis of the face and balding scalp and its comparators with special focus on imiquimod 5%. It also covers pharmacology of imiquimod 3.5% and its contribution to the current treatment options of actinic keratoses. EXPERT OPINION: imiquimod 3.75% is an interesting, safe and well-tolerated treatment option for actinic keratoses of the face or balding scalp especially in respect of compliance, as it is indicated for daily use for a shorter time period (2 times, 2-week cycles) and approved for use on larger areas compared with imiquimod 5%. Data from current trials indicate lower efficacy compared with imiquimod 5% cream when applied three times a week for 16 weeks or for two 4-week cycles with a 4-week no-treatment interval, but indicate similar efficacy when compared with a twice-weekly schedule for 16 weeks. An additive effect was observed when combining cryosurgery followed by imiquimod 3.75%.     

Topical imiquimod: a review of its use in genital warts.

Imiquimod is a topically active immunomodulatory agent that is formulated as a 5% cream for application by the patient. It is the first agent of its class, the immune response modifiers, to be used in the treatment of genital warts. In immunocompetent patients with genital warts, imiquimod stimulates the production of interferon-alpha and various other cytokines, and has indirect antiviral activity. In randomised, double-blind, vehicle-controlled clinical trials, complete clearance of warts occurred in 37 to 50% of immunocompetent patients with genital warts treated with imiquimod 5% cream 3 times a week for up to 16 weeks; partial clearance of warts (defined as a reduction in wart area of > or = 50%) was observed in 76% of recipients of imiquimod 5% cream. Rates of complete or partial clearance of warts were significantly higher in patients who applied imiquimod 5% cream 3 times a week than in recipients of imiquimod 1% or vehicle cream, each applied 3 times a week. A between-gender difference in clinical response to imiquimod 5% cream has been reported, with female patients experiencing higher rates of complete clearance of warts than males. Recurrence(s) of > or = 1 wart occurred in 13 to 19% of immunocompetent patients in whom complete clearance of warts had been achieved with imiquimod 5% cream. Imiquimod 5% cream also shows some clearance of warts in immunosuppressed HIV-infected patients with genital warts. Preliminary results of a vehicle-controlled study showed that the rate of partial clearance of warts (defined as a reduction in baseline wart area of >50%) [38%] was significantly higher with imiquimod 5% cream than with vehicle cream; however, the rate of complete clearance was not significantly higher than with vehicle cream. Imiquimod 5% cream is generally well tolerated by immunocompetent and HIV-infected patients. Local skin reactions (mainly mild or moderate), including erythema, itching and burning, are the most commonly reported adverse events, occurring in < or = 67% of patients applying imiquimod 5% cream 3 times a week. The incidence of adverse events is lower in patients applying the cream 3 times a week than with daily application. The incidence of systemic adverse events with imiquimod 5% cream (applied daily or 3 times a week) is similar to that of vehicle cream. The tolerability profile of imiquimod cream appears favourable compared with that of podophyllotoxin. CONCLUSION: Imiquimod 5% cream is a new therapeutic option for patients with genital warts. It produces clearance rates broadly similar to those of other treatment approaches and rates of wart recurrence compare favourably with those reported for established treatments. In contrast to most alternative treatment strategies. which are administered in the physician's office, imiquimod cream is a self-administered therapy for outpatient use.     

Comparison of 5% 5-fluorouracil cream and 5% imiquimod cream in the management of actinic keratoses on the face and scalp

It is timely to compare the efficacy and tolerability of 2 actinic keratosis (AK) therapies--5% 5-fluorouracil (5-FU) cream and imiquimod cream. Thirty-six patients with 4 or more AKs were randomly assigned to receive 5% 5-FU cream twice daily for 2 to 4 weeks or 5% imiquimod cream twice weekly for 16 weeks. Five percent 5-FU was more effective than imiquimod in exposing what were presumed to be subclinical AKs, reducing the final AK count (total AK count declined during the 24-week study by 94% vs. 66%, P < .05), achieving complete clearance (incidence of 84% vs. 24% by week 24, P < .01), and achieving clearance rapidly. Tolerability was similar except for erythema, which was initially significantly higher with 5-FU than imiquimod but resolved rapidly and was significantly lower than imiquimod by week 16. Five percent 5-FU remains the gold standard field therapy for AKs.     

Treatment of locally metastatic melanoma: a novel approach

We report a case of an 83-year-old female with locally metastatic melanoma treated with imiquimod and tazarotene. The patient originally presented to our dermatology clinic with local metastases of malignant melanoma after having undergone multiple surgical procedures and adjuvant radiation therapy for disease recurrence. At this juncture, she refused further surgical management but was interested in topical therapy. A 4-week course of topical imiquimod therapy was initiated. As no clinical response was noted at the end of the treatment period, tazarotene cream was introduced. The patient experienced complete clinical clearance of the treated area after a 6-week course of combination imiquimod and tazarotene therapy. The rationale for using both medications will be discussed.