Accelerated stability study of sustained-release nifedipine tablets prepared with Gelucire

This paper describes an investigation of the chemical and physical stability of nifedipine sustained release dosage forms prepared with Gelucire® 53/10. Three formulations differing only in the applied tabletting force were stored for 6 months under four different controlled conditions of relative humidity (RH) and temperature (20°C/0% RH, 20°C/80% RH, 40°C/0% RH, 40°C/80%). It was found that nifedipine in the sustained release formulations was chemically stable against the effects of temperature and humidity. However, the variables, tabletting force, RH and storage time, exerted a significant influence on the dissolution behavior of nifedipine. The changes in dissolution behavior after storage under conditions of high humidity and temperature might be related to the formation of nifedipine microcrystals and to structural changes in the wax vehicle during storage. It is predicted that acceptable shelf-lives should result when moisture-resistant packaging is used for pharmaceutical formulations of this type.     

抗骨结核载药缓释支架的研究进展

骨结核是除肺结核以外发病率最高的结核,占全部结核发病率的3％～5％,占肺外结核发病率的35％～50％.目前,临床治疗一般是用手术清除病灶部位的坏死组织,然后再放置抗结核药物以杀死残留的结核杆菌,但是放置的抗结核药物粉末易被体液冲走.载药骨支架既具有充填重建、诱导成骨作用,又能立体局部持续缓慢释放抗结核药物,能够大大提高抗结核药物的疗效并降低副作用,具有很高的临床价值.本文对抗骨结核载药缓释支架的最新研究进展进行综述,为新型抗结核载药缓释骨支架的设计提供思路.     

低分子肝素钠自微乳缓释胶囊的制备及其药效学的初步研究

目的:制备低分子肝素钠自微乳缓释胶囊,并初步考察该制剂体外释放特征及抗凝血效果.方法:采用天青A法测定缓释胶囊体外释放度,用毛细玻管法测定其凝血时间.结果:该缓释胶囊能达到12 h的缓释效果,其体外释放呈Higuchi方程,r=0.9975,凝血时间延长百分率最大可达到(297±21)%.结论:自微乳缓释胶囊能显著延长抗凝血时间.     

烟酸凝胶骨架缓释片的稳定性考察

目的：考察烟酸凝胶骨架缓释片贮存期间稳定性。方法：采用加速试验和长期试验方法，考察外观性状、含量和释放度。结果：密封包装条件下，36个月内外观性状、含量和释放度检查结果没有显著性变化。结论：该制剂密封条件下贮存，有效期可以定为2年。     

Fabrication and in vivo evaluation of Nelfinavir loaded PLGA nanoparticles for enhancing oral bioavailability and therapeutic effect

Nelfinavir mesylate (NFV) is an anti-viral drug, used in the treatment of Acquired Immunodeficiency Syndrome (AIDS). Poor oral bioavailability and shorter half-life (3.5–5 h) remain a major clinical limitation of NFV leading to unpredictable drug bioavailability and frequent dosing. In this context, the objective of the present study was to formulate NFV loaded poly (lactic-co-glycolic acid) (PLGA) nanoparticles (NPs), which can increase the solubility and oral bioavailability along with sustained release of the drug. NFV loaded PLGA-NPs were prepared by nanoprecipitation method using PLGA and Poloxomer 407. The prepared NPs were evaluated for particle size, zeta potential, morphology, drug content, entrapment efficiency (EE) and in vitro dissolution studies. Oral bioavailability studies were carried out in New Zealand rabbits by administering developed NFV PLGA-NPs and pure drug suspension. PLGA-NPs prepared by using 1:4 ratio of drug and PLGA, with a stirring rate of 1500 rpm for 4 h. The prepared NPs were in the size of 185 ± 0.83 nm with a zeta potential of 28.7 ± 0.09 mV. The developed NPs were found to be spherical with uniform size distribution. The drug content and EE of the optimized formulation were found to be 36 ± 0.19% and 72 ± 0.47% respectively. After oral administration of NFV PLGA-NPs, the relative bioavailability was enhanced about 4.94 fold compared to NFV suspension as a control. The results describe an effective strategy for oral delivery of NFV loaded PLGA NPs that helps in enhancing bioavailability and reduce the frequency of dosing.     

雷公藤内酯醇缓释微球的制备及体内外释放规律研究

目的:制备雷公藤内酯醇缓释微球,并考察其体内外释放规律。方法:采用液中干燥法制备雷公藤内酯醇缓释微球,以静止法研究其体外释放规律,以大鼠药动学实验研究其体内释药规律。结果:制备的缓释微球外观呈规则的球形,粒径分布均匀((38.2±1.7)μm),包封率为(74.7±3.2)%。雷公藤内酯醇缓释微球在体外恒速释放;在大鼠体内的Cmax为(114.7±31.90)ng.mL-1,tmax为(8.32±4.43)h,AUC为(1774282±1046152)ng.h.mL-1,MRT为(596±165)h;在体内外的相关系数为0.9553(P<0.01)。结论:本制备工艺可行;雷公藤内酯醇有制备成缓释注射微球的可行性。     

Preparation and evaluation of temperature sensitive liposomes containing adriamycin and cytarabine

Temperature sensitive liposomes (TSL) containing adriamycin (ADM) and cytarabine (Ara-C) were prepared. ADM and Ara-C were selected as model compounds of amphiphilic and hydrophilic drug, respectively. Encapsulation efficiency of ADM entrapped into TSL was about twice greater than that of Ara-C. It might be due to different polarity of the drugs. Lipid compositions of TSL had no effect on the encapsulation efficiency of drugs. Thermal behavior of TSL using a differential scanning calorimetry (DSC) was also investigated. Phase transition temperature (T_c) of TSL was dependent on the lipid compositions of TSL.ADM broadened thermogram of TSL but Ara-C did not. However, T_c of TSL was not changed by any drug. Release rate of drugs was highly dependent on temperature. The release profile of ADM was similar to that of Ara-C. The maximum release rate of drugs from TSL was occurred at the near T_c and observed at 39–41°C for DPPC (Dipalmitoylphosphatidylcholine) only, 52–54°C for DSPC (Distearoylphosphatidylcholine) only, 41–43°C for DPPC and DSPC (3∶1), and 43–45°C for DPPC and DSPC (1∶1), respectively. Effect of human serum albumin (HSA) on the release rate of ADM was investigated. HSA had no significant effect on the release of ADM below T_c. However, ADM release from TSL was increased at the near and above T_c. The HSA-induced leakage of drug may result from the interaction of liposomal constituents with HSA structure at the near T_c. From the fact that the release profiles of ADM from freshly prepared TSL and stored TSL for 1 week at 4°C was not changed, the TSL was considered to be stable for at least 1 week at 4°C. Based on these findings, TSL may be useful to deliver drugs to preheated target sites due to its thermal behaviors.     

Sustained release of brimonidine from BRI@SR@TPU implant for treatment of glaucoma

Glaucoma is the leading cause of irreversible vision loss worldwide, and reduction of intraocular pressure (IOP) is the only factor that can be interfered to delay disease progression. As the first line and preferred method to treat glaucoma, eye drops have many shortcomings, such as low bioavailability, poor patient compliance, and unsustainable therapeutic effect. In this study, a highly efficient brimonidine (BRI) silicone rubber implant (BRI@SR@TPU implant) has been designed, prepared, characterized, and administrated for sustained relief of IOP to treat glaucoma. The in vitro BRI release from BRI@SR@TPU implants shows a sustainable release profile for up to 35 d, with decreased burst release and increased immediate drug concentration. The carrier materials are not cytotoxic to human corneal epithelial cells and conjunctival epithelial cells, and show good biocompatibility, which can be safely administrated into rabbit’s conjunctival sac. The BRI@SR@TPU implant sustainably released BRI and effectively reduced IOP for 18 d (72 times) compared to the commercial BRI eye drops (6 h). The BRI@SR@TPU implant is thus a promising noninvasive platform product for long-term IOP-reducing in patients with glaucoma and ocular hypertension.     

曲尼司特缓释片的制备及其释药影响因素研究

目的　制备了曲尼司特凝胶骨架片。方法　采用HPMCK4M、K15M为凝胶骨架材料 ,进行了处方研究 ;通过测定制剂体外释放度 ,评价了该缓释片处方。结果　曲尼司特缓释片体外释药符合Higuchi方程 ,其释药速率常数Kr为 0 193h-1/ 2 。影响缓释片体外释药的因素有骨架材料的种类、用量、粘合剂的种类和释药介质的pH等。结论　缓释片具有明显的缓释作用 ,可缓慢释药 12h。     

Polyoxyethylene-polyoxypropylene block copolymer gels as sustained release vehicles for subcutaneous drug administration

Polyoxyethylene-polyoxypropylene surface-active block copolymers (Pluronic^®) were evaluated as a vehicle for subcutaneous administration of drugs using a phenolsulfophthalein (PR) as a tracer. The type of Pluronic^® copolymer (F108 or F127), and their concentrations, and the effect of solutes (NaOH, NaCl or PR) on gelation properties were studied. Sodium hydroxide and sodium chloride decreased the gel-sol transition temperature, whereas the opposite effect was observed with PR. The ‘in vitro’ release rates obtained for PR were inversely proportional to the concentration of Pluronic used and a zero-order release rate was observed in all preparations assayed. Pluronic^® F127/PR preparations were administered subcutaneously (SC) to Wistar rats and PR plasma levels were compared with those reached after SC or intravenous (i.v.) administration of a PR aqueous solution. The gel formulation produced a sustained plateau level within 15 min that lasted 8–9 h. In vivo data analysis was performed with the JANA and PCNONLIN computer programs. The best fittings for experimental data from Pluronic gels were obtained using a zero-order input and first-order output two-compartment model. The results obtained suggest that PF127 aqueous gels may be of practical use as a vehicle for SC administration of drugs.     

Gastric floating sustained-release tablet for dihydromyricetin: Development,characterization, and pharmacokinetics study

Dihydromyricetin (DHM) is a natural dihydroflavonol compound with quite a number of important pharmacological properties. However, its low solubility in water and poor stability in aqueous environment, have compromised drug efficacy of DHM, thus hindering its clinical use. The present study was to develop DHM-loaded gastric floating sustained-release tablet (DHM-GFT) to improve the bioavailability of DHM. DHM-GFT was prepared via powder direct compression. The formulation of tablet was optimized in terms of the floating ability and drug release rate. The optimized DHM-GFT exhibited short floating lag time of less than 10 s and long floating duration of over 12 h in acidic medium. It had a 12-hour sustained release of DHM, which proved its potential to develop as a twice-a-day dosing preparation. The physicochemical properties of DHM-GFT well satisfied the pharmacopoeial requirements. In addition, the results from pharmacokinetic studies demonstrated that, DHM-GFT could considerably prolong the in vivo residence time of drug and improve the bioavailability via good gastric floating ability and sustained drug release when compared to DHM powder. Therefore, DHM-GFT is promising to promote the application of DHM and merits studies for further development.     

不同剂量阿糖胞苷维持治疗对老年急性髓系白血病预后的影响

目的 探讨不同剂量阿糖胞苷巩固维持治疗在老年急性髓系白血病(AML)患者的疗效及安全性.方法 北京军区总医院血液科2005年1月至2010年1月32例经过诱导化疗取得缓解的老年AML患者,完全随机分为治疗组A(12例)、治疗组B(10例)、治疗组C(10例).3组患者达到完全缓解后,分别给予不同剂量的单药阿糖胞苷(0.5g/次、0.5 g/m2及1.0 g/m2,静脉滴注,每12小时1次,第1～3天)维持巩固治疗,连续6～8个疗程,维持1～2年.结果 治疗组A、B和C患者治疗相关病死率为16.7％(2/12)、10.0％ (1/10)、20.0％ (2/10),复发相关病死率为41.7％ (5/12)、50.0％ (5/10)、40.0％ (4/10),中位生存期分别为15.8(5～60)、16.2(6～60)、15.7(6 ～60)个月,2年总生存率分别为41.7％、40.0％、40.0％.3组差异均无统计学意义(均P＞0.05).结论 不同剂量阿糖胞苷巩固维持治疗对老年AML患者的生存率无明显影响,在剂量增加的情况下治疗相关并发症增多,而总体长期生存率无提高.     

Intracranial drug-delivery scaffolds: biocompatibility evaluation of sucrose acetate isobutyrate gels

INTRODUCTION: Sucrose acetate isobutyrate (SAIB) is a water insoluble, biodegradable gel used for controlled-release oral and subcutaneous drug delivery. We investigated SAIB compatibility in the rat central nervous system (CNS) by implanting solutions of SAIB in adult and in neonatal brains. METHODS: 10-15 microL solutions of SAIB gels in 0-30% ethanol were injected into the cerebral cortex of adult Fischer 344 rats. Control animals were implanted with a 10 mg biodegradable poly anhydride copolymer of poly [bis (p-carboxyphenoxy) propane] anhydride and sebacic acid (PCPP:SA). Adult rats were evaluated for signs of pain and distress, including changes in posture, facial signs, and grooming behavior. 1-2 microL solutions of SAIB gels in 15% ethanol were injected into brains of 12-24 h-old rats. Neonatal rats were evaluated for survival. Adult and neonatal brains were examined by histopathology 3-48 days after implant. RESULTS: Gel implants produced elliptical compression of cortical tissue, cell loss, and inflammation. Cell loss appeared to be confined to the implantation wound and associated neuronal fields. In adult rats, neurophil compression, inflammation, and cell loss appeared similar with the 10-mg PCPP:SA implants and the 10-mg SAIB implants. There was no clinical evidence of pain or distress from SAIB implants. 1-2 microL implants of SAIB-15% ethanol had no effect on survival of neonatal animals. CONCLUSION: Brain implants of SAIB induce a mild to moderate inflammatory response and associated neuronal cell damage. The implants appeared to be biocompatible in adult and neonatal animals. These results suggest that further studies of SAIB as an injectable drug-delivery scaffold for CNS therapeutic agents are warranted.     

Development of vitamin loaded topical liposomal formulation using factorial design approach: drug deposition and stability

Long-term exposure of the skin to UV light causes degenerative effects, which can be minimized by using antioxidant formulations. The major challenge in this regard is that a significant amount of antioxidant should reach at the site for effective photoprotection. However, barrier properties of the skin limit their use. In the present study, Vitamin E acetate was encapsulated into liposome for improving its topical delivery. However preparation of liposomes is very difficult due to number of formulation variables involved therein. In the present work systematic statistical study for the formulation of liposomes for topical delivery of Vitamin E using the factorial design approach was undertaken. Amount of phospholipid (PL) and cholesterol (CH) were taken at three different levels and liposomes were prepared using ethanol injection method. Liposomes were characterized for encapsulation efficiency, vesicle size, zeta potential, and drug deposition in the rat skin. Gels containing liposomal dispersion (batch with higher skin deposition of VE) were prepared in Carbopol^® 980 NF and were characterized for gel strength, viscosity and drug deposition in the rat skin. Stability of liposome dispersion and gel formulation was studied at 30 °C/65% RH for 3 months. Results of regression analysis revealed that vesicle size and drug deposition in the rat skin were dependant on the lipid concentration and lipid:drug ratio. Drug deposition in rat skin had an inverse relationship with respect to PL and CH concentration. Prepared liposomal dispersion (50 mg PL:6 mg CH) showed seven-fold increase in drug deposition compared to control (plain drug dispersion). Gel formulation demonstrated six-fold and four-fold increase in drug deposition compared to control gel and marketed cream, respectively. Liposome dispersion and gel formulation were found to be stable for 3 months. Factorial design was found to be well suited to identify the key variables affecting drug deposition. Improved drug deposition from liposomal preparations demonstrates its potential for dermal delivery.     

海藻酸钠在盐酸二甲双胍缓释片中的应用

目的：采用海藻酸钠作为缓释材料制备盐酸二甲双胍缓释片。方法通过自制样品与原研药进行体外溶出曲线及稳定性的对比,考察海藻酸钠作为缓释材料在盐酸二甲双胍缓释片中的缓释效果。结果试验处方制得的盐酸二甲双胍缓释片与原研药对比几条关键 pH 溶出介质体外溶出曲线,相似因子（f2）达到70以上;试验处方制得的盐酸二甲双胍缓释片有关物质基本无增加;试验处方制得的盐酸二甲双胍缓释片片重约850 mg,原研药约1000 mg。结论采用海藻酸钠作为缓释材料制备的盐酸二甲双胍缓释片与原研药的体外释放相似度高;处方、工艺稳定可行,质量可控。     

Bioactivity of bone resorptive factor loaded on osteoconductive matrices: Stability post-dehydration

Since calcium phosphate cements were proposed two decades ago, extensive research has been realized to develop and improve their properties. They have proved their efficiency as bone graft substitutes and their ability to incorporate and release drugs. However, to date, all ‘resorbable’ osteoconductive synthetic biomaterials are in fact simply soluble. In order to investigate a synthetic material capable of inducing osteoclast remodelling post-implantation, a formulation of calcium phosphate cement loaded with a pro-resorptive cytokine (RANKL) was studied. Many prior release studies on calcium phosphates did not confirm that the matrix had no detrimental effect on the molecule to be released during storage prior to use or that bioactivity was maintained during storage. In this report, the stability of our protein was tested after loading onto the cement, and various regimens to improve stability were compared. The presence of trehalose was shown to stabilize the bioactivity of RANKL adsorbed to brushite cement. The reduction of both moisture and oxygen in the storage vessel improved osteoclastogenic potential of the matrix compared with that stored in ambient atmosphere and temperature. No loss in activity was observed over the study period for the loaded matrix stored in dry nitrogen.     

小剂量三尖杉酯碱和阿糖胞苷联合粒细胞集落刺激因子治疗老年急性髓细胞白血病疗效观察

目的探讨小剂量三尖杉酯碱（HT,H）和阿糖胞苷（Ara-c,A）联合粒细胞集落刺激因子（G-CSF）治疗老年人急性髓细胞白血病的疗效及不良反应。方法35例AML患者均给予HT1mg·m^-2·d^-1,静脉滴注,第1—14天;Ara—c 10mg·m^-2,静脉滴注,每12h注射1次,第1～14天;G-CSF100—200μg·m^-2·d^-1,皮下注射,在第1次注射Ara—c之前开始使用,至最后1次注射Ara-c之前停用。结果35例AML患者化疗后完全缓解16例（46％）、部分缓解14例（37％）,总有效率83％,未缓解（NR）5例（14％）;2例患者化疗期间死亡。主要不良反应为骨髓抑制。结论小剂量HA方案联合G—CSF治疗老年人急性髓细胞白血病安全、有效。     

阿糖胞苷联合伊马替尼治疗慢性粒细胞白血病的疗效观察

目的探究阿糖胞苷联合伊马替尼治疗慢性粒细胞白血病的临床疗效。方法选取2014年2月—2017年1月石家庄市第一医院收治的慢性粒细胞白血病老年患者84例,随机分为对照组和治疗组,每组各42例。对照组患者口服甲磺酸伊马替尼片,400～600 mg/d,1次/d,根据病情可适当调整剂量。治疗组在对照组基础上静脉滴注注射用盐酸阿糖胞苷,20 mg/m2,6 h滴完,1次/d,每月持续输注10 d,若白细胞(WBC)2.03109/L停止输注。两组患者连续治疗12个月。观察两组患者临床疗效,同时比较治疗前后两组患者骨髓细胞遗传学和血液学缓解率、外周血象变化、ABL1激酶突变率和预后情况。结果治疗后,治疗组患者主要骨髓细胞遗传学缓解率和完全血液学缓解率分别为35.70%、85.72%,均显著高于对照组患者的21.42%、64.28%,两组比较差异具有统计学意义(P0.05)。治疗后,治疗组患者外周血幼稚细胞完全消失时间和血液学完全缓解时间均显著短于对照组,两组比较差异具有统计学意义(P0.05)。治疗组患者ABL1基因突变率为21.42%,对照组患者突变率为35.71%,两组比较差异具有统计学意义(P0.05)。随访12个月,治疗组患者原发耐药、复发和死亡发生率分别为7.14%、4.76%、0.00%,均显著低于对照组患者的21.42%、14.28%、9.52%,两组比较差异具有统计学意义(P0.05)。结论阿糖胞苷联合伊马替尼治疗慢性粒细胞白血病老年患者能够有效提高骨髓细胞遗传学缓解率和完全血液学缓解率,降低ABL1激酶突变率,降低患者原发耐药、复发和死亡发生率,且不良反应低,具有一定的临床推广应用价值。     

Water-in-oil-in-water double emulsions loaded with chlorogenic acid: release mechanisms and oxidative stability

Abstract

Chlorogenic acid (CA) is a natural compound used as an antioxidant in the preparation of food, drugs, and cosmetics. Due to their low stability and bioavailability, many researchers have studied the encapsulation of CA in various delivery colloidal systems. The aim of this study was to evaluate the stability of water-in-oil-in-water (W/O/W) double emulsions loaded with CA and its antioxidant capacity. For this purpose, CA-W/O/W double emulsions were prepared using Span 80 and lecithin as lipophilic emulsifiers, and Tween 20 as a hydrophilic emulsifier. The influence of nature of lipophilic emulsifiers, the presence of chitosan (CH) in the internal and external aqueous phases, pH, temperature and the storage time of W/O/W double emulsions were also investigated. Depending on the preparation conditions, the W/O/W double emulsions showed the droplet size in the range 9.13?±?0.55?μm–38.21?±?1.87?μm, the creaming index 34%–78% and the efficiency encapsulation 79.45?±?1.5%–88.13?±?1.9%. Zeta potential values were negative for the W/O/W double emulsion without CH (?36.8?±?2.02mV; ?27.3?±?1.75mV) and positive for the W/O/W double emulsions with CH in the external aqueous phase (+6.5?±?0.42mV; 28.6?±?0.92mV). The study of the release of CA from W/O/W double emulsions has highlighted two mechanisms: one based on the coalescence between the water inner droplets or between the oil globules as well as a diffusion releasing mechanism. The oxidative stability parameters of the W/O/W double emulsions, such as the peroxide value (POV) and the conjugated diene content (CD) were measured.