扎托洛芬凝胶剂的制备及体外研究

目的制备扎托洛芬凝胶剂,考察其体外渗透性、释放性和稳定性。方法采用紫外分光光度法测定扎托洛芬的含量,采用Franz扩散池分别考察载药凝胶剂体外渗透性和释放性,采用正交试验设计筛选处方,探讨了氮酮、卡波姆浓度及丙二醇用量对扎托洛芬凝胶剂经皮渗透的影响,并对凝胶剂初步稳定性进行了考察。结果扎托洛芬的线性范围为16.0~56.0μg/mL,日内日间精密度的RSD均小于0.6%,平均回收率为98.67%,RSD为1.45%;凝胶剂外观细腻,黏度适宜,pH 6.8~7.0,最佳处方含0.75%卡波姆、15%丙二醇、1%月桂氮卓酮,其体外经皮渗透(以小鼠皮为屏障)符合Higuchi方程,体外释放(以赛璐芬膜为屏障)符合零级动力学方程;室温留样3个月稳定性良好。结论扎托洛芬凝胶剂制备工艺简单,体外渗透性良好,制剂稳定性好。     

左氧氟沙星热敏型眼用凝胶的研制及体外释放研究

目的:制备左氧氟沙星热敏型眼用凝胶,并对其体外释放行为进行考察。方法:以泊洛沙姆407为热敏型材料制备左氧氟沙星眼用凝胶,根据胶凝温度筛选泊洛沙姆407的最佳处方浓度,采用无膜溶出模型对该制剂的体外释放行为进行考察。结果:左氧氟沙星检测浓度线性范围为3～11μg/ml(r=0.9991,n=6),回收率为99.62%;泊洛沙姆407在处方中的最佳浓度为18%;药物释放呈零级动力学特征,释放量取决于凝胶溶蚀量。结论:该制剂制备方法简单,用药剂量易于控制,极具开发前景。     

替硝唑原位固化缓释凝胶的处方研究

目的:应用Box-Behnken法设计并优化替硝唑原位固化缓释凝胶处方.方法:通过体外释放度的单因素影响试验确定考察因素与水平,以凝胶粘度、遇水固化时间、释放时间为响应变量,应用Box-Behnken法进行处方筛选与优化.结果:优化处方为35.3%(w/w)单甲氧基聚乙二醇-聚乳酸(mPEG-PDLLA 10/90),5.9% (w/w)替硝唑和58.8% (w/w)N-甲基-2-吡咯烷酮(NMP).该凝胶体外释放时间达192 h,无突释现象.结论:通过Box-Behnken法成功实现了替硝唑原位固化缓释凝胶的处方筛选.     

总姜黄素脂质体的包封率和体外释药测定

目的:研究总姜黄素脂质体的包封率测定方法,初步考察其体外释放规律。方法:用乙醇注入法制备了总姜黄素脂质体,葡聚糖凝胶 G-50柱分离方法测定脂质体的包封率,并用溶出度第三法考察脂质体的体外释放过程。分析柱为岛津 C_(18)色谱柱(150 mm×4.6 mm,5μm),乙腈-水-冰醋酸(45:55:2)为流动相,流速1mL·min~(-1),检测波长430nm。结果:总姜黄素脂质体的平均包封率为64.4%,体外释放符合一室模型。结论:该方法简便、易操作,可作为总姜黄素脂质体包封率和体外释药的研究。     

马来酸噻吗洛尔眼用温敏凝胶的处方筛选与体外释放评价

目的:筛选马来酸噻吗洛尔眼用温敏型凝胶优化处方,并对其体外释放进行评价。方法:选用泊洛沙姆P407、P188为载体材料制备眼用温敏凝胶,测定不同处方的凝胶前体溶液分别在未经处理和经人工泪液稀释条件下,从溶液态转变为凝胶态的胶凝温度,通过星点设计-效应面法筛选优化处方,并考察胶凝时间和释放行为。结果:根据温敏凝胶保存和使用的温度要求,筛选出优化处方为P407:P188(24.25%:1.56%)。前体溶液能够在34℃人工泪液中迅速形成凝胶,并在体外缓慢释放6 h以上。结论:经过筛选并制备出的噻吗洛尔温敏型凝胶具有良好的载药能力、稳定性及释放性能,满足眼用制剂质量要求和实际应用要求。     

硫酸软骨素眼用温敏凝胶的制备与质量考察

摘要：目的:制备硫酸软骨素眼用温敏凝胶,并考察其体外释放度和房水动力学。方法:选用泊洛沙姆407(P407)、泊洛沙姆188(P188)和聚卡波菲为凝胶基质,正交试验L9(34)确定处方组成,通过含量测定、胶凝温度(T1)、人工泪液稀释后的胶凝温度(T2)、凝胶黏度(P)、眼部刺激性试验考察其质量,体外释放度和房水动力学考察其体内疗效。结果:最佳处方组成为硫酸软骨素3%,P407 16%,P188 3%,聚卡波菲1%。凝胶制剂的T1为27.38℃,T2为34.28℃,P为740 cpa,眼部刺激性符合要求,体外释放度和房水动力学均优于溶液剂。结论:所制备的硫酸软骨素眼用温敏凝胶各项质量指标符合要求。     

溶菌酶眼用凝胶剂的制备及体外性质考察

目的通过制备溶菌酶眼用凝胶制剂提高溶菌酶的稳定性,延长溶菌酶与眼部的作用时间。方法按照部颁标准测定了溶菌酶活性,通过对基质的筛选,确定了最优处方及工艺,考察了溶菌酶眼用凝胶剂的基本性质如:黏度、表面张力、渗透压、体外释放、稳定性,以及眼用凝胶剂的体外抑菌性。结果以质量分数1%HPMC K4M为凝胶基质,制备的溶菌酶眼用凝胶剂的黏度为95.83 m Pa·s,表面张力为39.696 m N·m-1,渗透压为277 m Osm·kg-1,p H为6.56,效价为10 300 U·m L-1,溶菌酶凝胶剂体外释放5 h时,累计释放率接近100%。溶菌酶眼用凝胶剂对革兰氏阳性菌抑菌效果较好,而对革兰氏阴性菌抑菌效果较差。加速试验和长期稳定性试验表明该制剂性质稳定。结论制备的溶菌酶眼用凝胶制剂相关性质均符合眼用制剂标准。     

星点设计-效应面法优化葫芦素口服脂质纳米乳剂的处方

目的借助星点设计-效应面法确定葫芦素口服脂质纳米乳剂的最优处方。方法提出了2个量化乳剂稳定性的常数:灭菌稳定性常数KS和冻融稳定性常数KF。用微射流仪制备葫芦素口服脂质纳米乳剂,采用星点设计-效应面法,以葫芦素口服脂质纳米乳剂的平均粒径(Y1)、灭菌稳定性常数KS(Y2)及冻融稳定性常数KF(Y3)为评价指标,考察了葫芦素口服脂质纳米乳剂处方中聚氧乙烯40氢化蓖麻油的用量(X1)、大豆卵磷脂的用量(X2)及中链脂肪酸甘油三酯的用量(X3)对制剂的影响,以效应面法预测最佳处方。结果优选的最优处方为:m(聚氧乙烯40氢化蓖麻油)∶m(大豆卵磷脂)∶m(中链脂肪酸甘油三酯)=1.15∶0.50∶5.52。采用优化处方制得的葫芦素口服脂质纳米乳剂的平均粒径为(113.6±2.1)nm,灭菌稳定性常数KS为2.92±0.7,冻融稳定性常数KF为5.14±0.2,同预测值的偏差均较低,最大偏差为4.6%。结论星点设计-效应面法所建立的模型能较好地应用于葫芦素口服脂质纳米乳剂处方的优化。     

乳酸环丙沙星眼用即型凝胶的研制

目的 研制乳酸环丙沙星眼用即型凝胶。方法 以泊洛沙姆407为温敏型材料制备乳酸环丙沙星眼用即型凝胶,通过对胶凝温度的考察确定处方,考察了乳酸环丙沙星眼用即型凝胶的黏度,采用无膜溶出模型对药物的体外释放机制进行研究,对制剂的眼刺激性进行评价。结果 确定18%的泊洛沙姆407作为乳酸环丙沙星眼用即型凝胶的基质。药物的体外释放呈零级动力学特征,释放量取决于凝胶溶蚀量。该制剂对兔眼无刺激。结论     

处方因素对黄体酮缓释凝胶体外释放性质和黏度的影响

目的:研究处方的组成和制备工艺对黄体酮阴道凝胶体外释放性质和黏度的影响.方法:用旋转黏度计测定凝胶的动态黏度,凝胶的体外释放度采用自制样品池和标准的药物溶出度仪测定.结果:黄体酮的释放为一级过程;随着聚卡波菲含量增加,凝胶的黏度增大,药物释放速率稍降低;液体石蜡含量增加,凝胶的黏度出现最小值,但药物释放速率无明显变化;凝胶的混合方法和水化时间对黏度和药物释放无明显影响.结论:改变处方组成和药物含量,可以获得具有适宜黏度和药物释放速率的黄体酮缓释凝胶.     

In vitro evaluation of the effect of cyclodextrin complexation on pulmonary deposition of a peptide, cyclosporin A

The effect of hydroxypropyl-alpha-cyclodextrin (HP-alpha-CD) complexation on in vitro pulmonary deposition of a cyclic peptide cyclosporin A (CsA) was studied. In addition, the effect of storage (32 days, 40 degrees C, 75% RH) on CsA/HP-alpha-CD complexes was studied. The complexation of CsA with CDs was evaluated by a phase-solubility method. Solid CsA/HP-alpha-CD complexes were prepared by freeze drying. Three inhalation formulations were prepared: CsA/lactose reference formulation (LF) (drug:carrier 1:364, w/w), CsA/HP-alpha-CD complex formulation (CDF) (drug:CD 1:269, w/w) and CsA/HP-alpha-CD complex/lactose formulation (CDLF) (complex:carrier 100:114, w/w). The inhalation studies were performed in vitro using Andersen Sampler (Ph. Eur.) and Taifun multi-dose dry powder inhalers (DPIs). Before the storage, the respirable fraction value (RF%) of CsA was 19.8+/-0.7%, 33.0+/-7.0% and 34.6+/-1.1% (mean+/-S.D., n=4 x 20) with LF, CDF and CDLF, respectively. When exposed to moisture (storage in a permeable polystyrene tube), the RF% values of CsA from formulations containing CsA/HP-alpha-CD complexes were lower than before the storage. However, when stored in the Taifun DPI, the RF% value of CsA from any of the formulations did not decrease. In conclusion, an acceptable RF% value of a peptide CsA from freeze-dried, simply micronized CsA/HP-alpha-CD complex powder was achieved before and after storage in the DPI.     

Stable bioavailability of cyclosporin A, regardless of food intake, from soft gelatin capsules containing a new self-nanoemulsifying formulation

AIM: We recently succeeded in preparing soft gelatin capsules containing a new self-nanoemulsifying formulation consisting of cyclosporin A (CsA), triacetin, polyoxyl 40 hydrogenated castor oil, polysorbate 20, medium chain triglycerides and medium chain mono- and diglycerides. The soft capsules containing the new formulation exhibited a significantly improved physical stability in terms of the appearance of the gelatin capsule shells and the composition of the fill mass during long-term storage, compared to commercially available soft capsules containing CsA, in which ethanol was employed as a cosolvent of CsA. In the present study, the influence of a fat-rich meal on the bioavailability of CsA from the soft capsule containing the new formulation (test drug) was evaluated and the results compared to those obtained with a representative soft capsule of CsA. VOLUNTEERS AND METHODS: A randomized, open-label, 3-way crossover study was performed in the test capsules and reference soft capsules, in a fasted state or after a fat-rich breakfast. 18 healthy male volunteers received a single dose of the reference formulation (Neoral, Novartis AG, Basel, Switzerland) or test formulation (2 capsules each, 200 mg as CsA) with 240 ml of water with a 1-week washout period between the treatments, after a fat-rich (670 kcal, 45 g fat) breakfast (for the test drug, Treatment A; for the reference drug, Treatment B) or a 12-h fasting (for the test drug, Treatment C). Serial blood samples, collected over a 24-h period after the administration, were assayed for blood CsA concentrations using a specific monoclonal radioimmunoassay. RESULTS: The differences in bioavailability parameters (i.e., AUC(0-24h), AUC(0-infinity) and C(max)) between the treatments were within the range of 80-125% of the reference treatment. An analysis of variance (ANOVA) revealed no significant differences (p > 0.05) between subjects, formulations or periods. The 90% confidence intervals (CI) indicated that the differences between the treatments (Treatments A and B, Treatments A and C) were also within the criteria. CONCLUSION: These results indicate that the bioavailability of CsA from the test drug is equivalent to reference in the fed state, and is likely to be less influenced by a fat-rich meal. Therefore, the new formulation of CsA using triacetin appears to have an advantage over the commercial soft capsules of CsA using a volatile cosolvent such as ethanol.     

Inhalable dry-emulsion formulation of cyclosporine A with improved anti-inflammatory effects in experimental asthma/COPD-model rats

The main purpose of the present study was to develop a novel respirable powder (RP) formulation of cyclosporine A (CsA) using a spray-dried O/W-emulsion (DE) system. DE formulation of CsA (DE/CsA) was prepared by spray-drying a mixture of erythritol and liquid O/W emulsion containing CsA, polyvinylpyrrolidone, and glyceryl monooleate as emulsifying agent. The DE/CsA powders were mixed with lactose carriers to obtain an RP formulation of DE/CsA (DE/CsA-RP), and its physicochemical, pharmacological, and pharmacokinetic properties were evaluated. Spray-dried DE/CsA exhibited significant improvement in dissolution behavior with ca. 4500-fold increase of dissolution rate, and then, nanoemulsified particles were reconstituted with a mean diameter of 317 nm. Laser diffraction analysis on the DE/CsA-RP suggested high dispersion of DE/CsA on the surface of the lactose carrier. Anti-inflammatory properties of the inhaled DE/CsA-RP were characterized in antigen-sensitized asthma/COPD-model rats, in which the DE/CsA-RP was more potent than the RP formulation of physical mixture containing CsA and erythritol in inhibiting inflammatory responses, possibly due to the improved dissolution behavior. Pharmacokinetic studies demonstrated that systemic exposure of CsA after intratracheal administration of the DE/CsA-RP at a pharmacologically effective dose (100 μg-CsA/rat) was 50-fold less than that of the oral CsA dosage form at a toxic dose (10 mg/kg). From these findings, use of inhalable DE formulation of CsA might be a promising approach for the treatment of airway inflammatory diseases with improved pharmacodynamics and lower systemic exposure.     

正交设计优化复方酮康唑凝胶剂的处方配比

目的:优化复方酮康唑凝胶剂的处方配比.方法:以正交设计,通过改良Franz扩散池筛选最佳处方配比,以HPLC法测定其中酮康唑的含量.结果:优化所得处方为酮康唑5%,月桂氮(艹卓)酮1%,尿素10%,卡波姆-940 1%,甘油20%.结论:该凝胶剂配方合理,制备的复方酮康唑凝胶剂细腻、光洁,稳定性好,释药速度快,且含量测定简便易行.     

In vivo characterisation of a novel water-soluble Cyclosporine A prodrug for the treatment of dry eye disease

Cyclosporine A (CsA) has been demonstrated to be effective for the treatment of a variety of ophthalmological conditions, including ocular surface disorders such as the dry eye disease (DED). Since CsA is characterised by its low water solubility, the development of a topical ophthalmic formulation represents an interesting pharmaceutical question. In the present study, two different strategies to address this challenge were studied and compared: (i) a water-soluble CsA prodrug formulated within an aqueous solution and (ii) a CsA oil-in-water emulsion (Restasis®, Allergan Inc., Irvine, CA). First, the prodrug formulation was shown to have an excellent ocular tolerance as well as no influence on the basal tear production; maintaining the ocular surface properties remained unchanged. Then, in order to allow in vivo investigations, a specific analytical method based on ultra high pressure liquid chromatography coupled with triple quadrupole mass spectrometer (UHPLC–MS/MS) was developed and optimised to quantify CsA in ocular tissues and fluids. The CsA ocular kinetics in lachrymal fluid for both formulations were found to be similar between 15 min and 48 h. The CsA ocular distribution study evidenced the ability of the prodrug formulation to penetrate into the eye, achieving therapeutically active CsA levels in tissues of both the anterior and posterior segments. In addition, the detailed analysis of the in vivo data using a bicompartmental model pointed out a higher bioavailability and lower elimination rate for CsA when it is generated from the prodrug than after direct application as an emulsion. The interesting in vivo properties displayed by the prodrug solution make it a safe and suitable option for the treatment of DED.     

氯霉素凝胶滴眼剂的制备及含量测定

目的:制备氯霉素凝胶滴眼剂并建立其含量测定方法。方法:以卡波姆-940为基质制备凝胶;采用紫外联立方程法测定其中主药含量。结果:所制制剂pH适中,透明度良好;平均回收率为99.67%(RSD=1.23%),样品标示含量为98.6%～101.2%。结论:本处方设计合理,含量测定方法简单易行、重现性好。     

左氧氟沙星凝胶的制备及质量控制

目的:制备左氧氟沙星凝胶剂并制定质控标准.方法:以卡波姆940为基质,三乙醇胺为中和剂制成凝胶剂;采用反相高效液相色谱法测定凝胶中左氧氟沙星的含量.结果:含量测定线性回归方程为A=7.51×104C 3.71×104(r=0.999 9),线性范围4.0～20μg·ml-1.平均回收率99.7%,RSD0.57%.结论:该凝胶剂处方合理,质量稳定,适于临床应用.     

人胚腺垂体移植病人环孢霉素药代动力学研究

目的：测定环抱霉素A在5例人胚腺垂体移植患者体内的药-时曲线，据此测算其体内代谢动力学参数。方法：采用荧光偏振免疫法，测定环孢霉素A血药浓度，用MCPKP序计算药动学参数。结果：CSA在人胚腺垂体移植患者体内的过程呈二室模型，其动力学参数是t1/2Ka=0．6±0．16h，t1/2α=0．96±0．32h，t1/2β=8．69±263h，Tmax=1.73±0.31h。结论：该研究为休儒症患者合理使用CSA，制定给药方案提供一定科学依据。     

Comparative in vivo bioequivalence and in vitro dissolution of two cyclosporin A soft gelatin capsule formulations

OBJECTIVE: A study was conducted to establish the bioequivalence between a newly developed cyclosporin A (CsA) oral formulation, Deximune soft-gelatin capsules (Dexcel Ltd.) and Sandimmune Neoral (Novartis Inc.). MATERIALS AND METHODS: The clinical investigation was designed as a randomized, open-labeled, two-period, two-treatment crossover study, in 24 healthy fasted male volunteers. The subjects were administered a single 200 mg CsA dose of either formulation. Serial venous blood samples were obtained over 24 hours after each administration to measure CsA in whole blood by a specific TDx-immunoassay. In addition, the comparative drug release rate was assessed using a dissolution apparatus test according to the USP-24 method. RESULTS: For both treatments, a mean maximum blood concentration (Cmax) of approximately 1,200 ng/ml was obtained at about 1.6 hours (tmax) after administration and the geometric mean of the area under the blood concentration-time curve (AUC) both for test and reference was approximately 4,900 ng x h/ml. Bioequivalence was conclusively demonstrated for both rate (Cmax and tmax) and extent (AUC) of CsA absorption, between the two treatments. Moreover, the CsA blood concentration measurement at 2 hours after administration (C2), demonstrated equivalent results between the two products. The point estimates and their 90% confidence intervals were within the respective equivalence ranges for the pharmacokinetic parameters and were included in the range for drugs with a narrow therapeutic index. The comparative dissolution test for both formulations showed an in vitro release rate of more than 90% within 15 minutes. CONCLUSIONS: Based on the results, the two oral CsA formulations compared are bioequivalent and can be interchanged without need for dosage adjustment.     

Improvement of cyclosporine A bioavailability by incorporating ethyl docosahexaenoate in the microemulsion as an oil excipient

The aims of this study were to determine the effect of ethyl docosahexaenoate (DHA-EE) on cyclosporine A (CsA) bioavailability, while also examining the effect of DHA-EE on CsA when DHA-EE was incorporated into a microemulsion formulation as an oil ingredient. The oral co-administration of DHA-EE and CsA increased the blood CsA concentration in a dose-dependent manner, and the AUC and C_max both increased by about 2-fold with 100 mg/kg DHA-EE. The microemulsion formulation of CsA consisted of Tween-20, ethanol, water, and DHA-EE (53.3/6.5/35.9/3.3 w/w%) (namely DHA-ME) was transparent and stable with an average particle size of 50 nm, which was similar to that of the control formulation incorporating vitamin E instead of DHA-EE (namely VE-ME). The permeabilities of CsA from DHA-ME, VE-ME and Neoral^® formulations across an artificial membrane were not significantly different. The C_max and AUC_0–∞ of CsA in rats administered DHA-ME significantly increased by approximately 2-fold in comparison to that of VE-ME. The relative oral bioavailability (F_r) of DHA-ME in comparison to Neoral^® was determined to be 114%, while the F_r of VE-ME was only 60%. It was, therefore, suggested that the use of DHA-EE as an oil excipient may be promising for the development of a microemulsion formulation of CsA with an improved oral bioavailability.