Exploring the feasibility of the use of biopolymers as a carrier in the formulation of amorphous solid dispersions – Part I: Gelatin

Biopolymers have rarely been used so far as carriers in the formulation of amorphous solid dispersions (ASD) to overcome poor solubility of active pharmaceutical ingredients (APIs). In an attempt to enlarge our knowledge on this topic, gelatin, type 50PS was selected. A screening study was initiated in which twelve structurally different poorly soluble biopharmaceutical classification system (BCS) Class II drugs (carbamazepine, cinnarizine, diazepam, itraconazole, nifedipine, indomethacin, darunavir (ethanolate), ritonavir, fenofibrate, griseofulvin, ketoconazole and naproxen) were selected for evaluation. Solid dispersions of five different drug loadings of these twelve compounds were prepared by lyophilization and evaluated for their solid state properties by mDSC and XR(P)D, and in vitro dissolution performance. Even without any process optimization it was possible to form either fully amorphous or partially amorphous systems, depending on the API and API to carrier ratio. Hence in this respect, gelatin 50PS behaves as any other carrier. Dissolution of the API from the solid dispersions significantly exceeded that of their crystalline counterparts. This study shows the potential of gelatin as a carrier to formulate amorphous solid dispersions.     

噻托溴铵粉雾剂联合沙美特罗替卡松粉吸入剂治疗慢性阻塞性肺疾病急性加重期伴呼吸衰竭的临床研究

目的观察噻托溴铵粉雾剂联合沙美特罗替卡松粉吸入剂治疗慢性阻塞性肺疾病(COPD)急性加重期伴呼吸衰竭的临床疗效及安全性。方法将76例COPD急性加重期伴呼吸衰竭患者随机分为对照组38例和试验组38例。对照组予以常规治疗配合呼吸机辅助通气治疗;试验组在对照组治疗的基础上,予以沙美特罗替卡松粉吸入剂每次1吸,bid,吸入治疗+噻托溴铵粉雾剂每次18μg,qd,吸入治疗。2组患者均治疗2周。比较2组患者的临床疗效、动脉血气指标、降钙素原和免疫功能,以及药物不良反应的发生情况。结果治疗后,试验组和对照组的总有效率分别为92.11%(35例/38例)和73.68%(28例/38例),差异有统计学意义(P<0.05)。治疗后,试验组和对照组的动脉血氧分压分别为(86.35±7.04)和(77.49±6.85)mm Hg,氧合指数分别为(310.89±29.87)和(281.34±27.53)mm Hg,降钙素原分别为(1.42±0.54)和(1.93±0.61)ng·m L^-1,肿瘤坏死因子-α分别为(275.49±48.62)和(310.05±54.73)ng·L^-1,白细胞介素-8分别为(312.62±75.64)和(389.75±78.76)pg·m L^-1,超敏C-反应蛋白分别为(4.73±2.45)和(8.34±2.53)mg·L^-1,差异均有统计学意义(均P<0.05)。2组患者治疗期间均未发生药物不良反应。结论噻托溴铵粉雾剂联合沙美特罗替卡松粉吸入剂治疗COPD急性加重期伴呼吸衰竭的临床疗效确切,其能显著降低患者的降钙素原水平,改善患者的血气指标和免疫功能,且安全性较好。     

扎那米韦鼻用粉雾剂粉体性质研究

目的 考察3种方法制备扎那米韦鼻用粉雾剂粉体的性质。方法 分别采用研磨法、气流粉碎法和喷雾干燥法制备不同粒径扎那米韦的粉体,并与吸入乳糖混合,对混合粉体的粒径、微观形态、流动性、堆密度和吸湿性进行考察。结果 研磨法、喷雾干燥法和气流粉碎法得到的扎那米韦原料粉末粒径依次减小;与乳糖相比,3种混合粉体松密度逐渐减小,振实密度依次增加,流动性仅喷雾干燥略增加,研磨法和气流粉碎法无影响; 3种方式得到的混合粉末均没有明显的吸湿性。结论 研磨筛分法比较适合扎那米韦鼻用粉雾剂的进一步开发。     

Low density,good flowability cyclodextrin-raffinose binary carrier for dry powder inhaler: anti-hygroscopicity and aerosolization performance enhancement

Background: The hygroscopicity of raffinose carrier for dry powder inhaler (DPI) was the main obstacle for its further application. Hygroscopicity-induced agglomeration would cause deterioration of aerosolization performance of raffinose, undermining the delivery efficiency.

Methods: Cyclodextrin-raffinose binary carriers (CRBCs) were produced by spray-drying so as to surmount the above issue. Physicochemical attributes and formation mechanism of CRBCs were explored in detail. The flow property of CRBCs was examined by FT4 Powder Rheometer. Hygroscopicity of CRBCs was elucidated by dynamic vapor sorption study. Aerosolization performance was evaluated by in vitro deposition profile and in vivo pharmacokinetic profile of CRBC based DPI formulations.

Results: The optimal formulation of CRBC (R₄) was proven to possess anti-hygroscopicity and aerosolization performance enhancement properties. Concisely, the moisture uptake of R₄ was c.a. 5% which was far lower than spray-dried raffinose (R₀, c.a. 65%). R₄ exhibited a high fine particle fraction value of 70.56 ± 0.61% and it was 3.75-fold against R₀. The pulmonary and plasmatic bioavailability of R₄ were significantly higher than R₀ (p < 0.05).

Conclusion: CRBC with anti-hygroscopicity and aerosolization performance enhancement properties was a promising approach for pulmonary drug delivery, which could provide new possibilities to the application of hygroscopic carriers for DPI.     

Development of a novel quantitative real‐time PCR assay with lyophilized powder reagent to detect African swine fever virus in blood samples of domestic pigs in China

African swine fever (ASF) is a devastating disease, which is causing huge economic losses in China. Therefore, it is urgent to provide a rapid, highly specific and sensitive diagnostic method for the detection of African swine fever virus (ASFV), the ASF infectious agent. In this study, a novel quantitative real‐time polymerase chain reaction (qPCR) assay with lyophilized powder reagents (LPR), targeting the major structural protein p72 gene, was established for the detection of ASFV. This assay had many advantages, such as saving time and money, good sensitivity and repeatability. The sensitivity of this assay was 100 copies/μl of ASFV plasmid templates, and the assay showed 10‐fold greater sensitivity than a qPCR assay recommended by OIE. Furthermore, specificity analysis showed that qPCR with LPR for ASFV had no cross‐reactivity with other important swine pathogens. In clinical diagnoses of 218 blood samples of domestic pigs in China, the positive rate of the diagnosis of ASFV by qPCR with the LPR and commercial kit reached 80.73% (176/218) and 76.61% (167/218) respectively. The coincidence rate between the two assays is 92.20% (201/218), and kappa value is 0.768 (p < .0001) by SPSS analysis. The overall agreement between the two assays was 95.87% (209/218). Further Pearson correlation and linear regression analysis showed a significant correlation between the two assays with an R² value of 0.9438. The entire procedure, from specimen processing to result reporting, can be completed within 2 hr. Our results demonstrated that the qPCR‐LPR assay is a good laboratory diagnostic tool for sensitive and efficient detection of ASFV.     

蒙脱石散联合Vit.Bco治疗对大剂量甲氨蝶呤化疗致口腔溃疡的效果观察

目的 探讨蒙脱石散联合Vit.Bco在治疗急性淋巴细胞白血病（ALL）患者使用甲氨蝶呤化疗致口腔溃疡的临床效果。方法 将2018年1月~2019年12月在本院血液内科住院行大剂量甲氨蝶呤化疗继发口腔溃疡的102例ALL患者作为研究对象,对照组采用常规漱口水漱口,观察组在对照组的基础上加用蒙脱石散联合Vit.Bco糊状物涂抹在溃疡处,对比两组患者口腔溃疡恢复及疼痛评分情况。结果 观察组口腔溃疡治愈率为94.33%,对照组口腔溃疡治愈率为77.55%;观察组疼痛评分为2.29±1.09分,对照组疼痛评分为2.97±1.12分,两组指标对比差异均具有统计学意义（P<0.05）。结论 本研究中,蒙脱石散联合Vit.Bco能有效治疗大剂量甲氨蝶呤化疗引起的口腔溃疡,但确切疗效尚需多中心进一步随机对照研究验证。     

UPLC同时测定复方守宫散中核苷类含量

目的 建立UPLC法同时测定复方守宫散中腺嘌呤、腺苷含量的方法。方法 用Acquity BEH C18(2.1 mm×100 mm,1.7 μm),甲醇-水为流动相,梯度洗脱,流速0.25ml/min,柱温26℃,检测波长254nm。结果 腺嘌呤、腺苷的进样量分别在0.0409~0.5115μg(r=0.9999)、0.0578~0.7220μg(r=0.9996)范围内与其峰面积呈良好的线性关系;平均回收率分别为92.83%、94.90%,RSD分别为1.11%、1.70%。结论 该方法快速、可靠、准确,可作为复方守宫散的质量控制方法。     

头孢硫脒与蒙脱石对小儿急性感染性腹泻的临床疗效

目的 探讨头孢硫脒联合蒙脱石对小儿急性感染性腹泻的临床疗效.方法 选取我院儿科住院的173例急性感染性腹泻患儿,采用随机数字表法分为治疗组95例和对照组78例.对照组静脉滴注头孢硫脒,治疗组在对照组基础上口服蒙脱石散.比较两组患儿的临床疗效,临床症状消失时间,以及血清NO、IgG、IgA、IgM水平变化.结果 治疗组总有效率为94.74%,对照组为74.36%,治疗组总有效率明显高于对照组（χ2=15.898,P〈0.05）;治疗组腹痛减轻有效率为86.32%,明显高于对照组（71.79%）,两组比较差异有统计学意义（χ2=5.858,P〈0.05）.治疗组止泻、退热以及体征好转时间均显著低于对照组,两组比较差异有统计学意义（t=4.419、2.436、11.147,P〈0.05）;治疗后,治疗组血清NO水平明显低于对照组,两组比较差异有统计学意义（t=8.724,P〈0.05）;血清IgG、IgA水平显著高于对照组（t=3.795、12.355,P〈0.05）.结论 头孢硫脒联合蒙脱石治疗小儿急性感染性腹泻疗效确切,不仅能降低治疗时间,还能提高患儿的自身免疫功能,值得临床推广应用.     

蜂王浆冻干粉对免疫力低下患者免疫球蛋白及补体水平的影响

目的：研究蜂王浆冻干粉对免疫力低下患者免疫球蛋白IgG、IgA、IgM以及补体C3、C4水平的影响,评价蜂王浆冻干粉治疗免疫力低下综合征的临床疗效。方法采用自身对照临床研究,予确诊的32例免疫力低下患者服用蜂王浆冻干粉,每天2次,1次2粒。于服药28 d后检测患者免疫球蛋白IgG、IgA、IgM和补体C3、C4等指标,并测定AST、ALT水平,评价蜂王浆冻干粉的疗效和安全性。结果服药后患者IgG、IgA、IgM水平[（10．31±2．03）g/L,（1．69±0．55）g/L,（1．51±0．55）g/L]显著高于服药前[（8．52±1.94）g/L,（1．38±0．57）g/L,（1．36±0．55）g/L]（t＝5．21、2．25、1．56,均P＜0．05）;服药后患者血清补体C3、C4水平[（0.93±0．15）g/L,（0．30±0．07）g/L]显著高于服药前[（0．83±0．12）g/L,（0．26±0．08）g/L]（t＝1．94、1.78,均P＜0．05）;服药后AST、ALT水平[（36．13±11．47）U/L,（31．83±12．36）U/L]与服药前[（38．17±12．84）U/L,（32.63±12．81）U/L]差异无统计学意义（t＝0．82、0．44,均P＞0．05）。结论蜂王浆冻干粉通过提高免疫力低下患者免疫球蛋白IgG、IgA、IgM和补体C3、C4,继而改善患者免疫力低下症状。     

肺部吸入给药制剂及临床应用

目的:分析和综述肺吸入制剂的分类、现状及其临床用药。方法:收集国内外发表出版的相关论文及专著,对肺部吸入给药的特点及临床药物制剂进行了分析总结。结果与结论:肺部吸入给药是防治哮喘、慢性阻塞性肺病等呼吸道疾病的首选给药方式。常见的吸入给药制剂包括定量吸入气雾剂、干粉吸入剂和雾化吸入剂,所用药物主要为β2受体激动剂、抗胆碱药物、吸入性糖皮质激素及复方药物等。