Stability of Benzoyl Peroxide in Aromatic Ester-Containing Topical Formulations

The chemical stability of benzoyl peroxide (BPO) was studied in solutions and gels. The solutions (1% w/v) were prepared in single solvents (alcohol USP, isopropyl alcohol USP, ethyl benzoate, C_12–15 alkyl benzoate, dimethyl isosorbide, propylene carbonate, and acetone) and in binary and tertiary combinations of these solvents, with and without the addition of antioxidant(s) (BHT, BHA, eugenol, tert-butyl hydroquinone, Tenox-2?, vitamin E, and vitamin C). The solutions were stored at 37°C for 5 weeks, and each week were analyzed for remaining BPO. Using first-order kinetics, the stability of BPO in solution was found to decrease in the order: ternary >binary >single solvent systems. Regardless of the number of solvents present, the highest stability of BPO (t_1/2 >7.5 weeks) was attained in the presence of ethyl benzoate and C_12–15 alkyl benzoate. The stability of BPO in solution did not change significantly with the addition of most antioxidants. The solutions in which BPO remained most stable were one in alcohol USP-ethyl benzoate-C_12–15 alkyl benzoate (60:20:20; t_1/2 = 18.15 weeks) and another in alcohol USP-C_12–15 alkyl benzoate-isopropanol plus 0.1% BHT (65:20:15; t_1/2 = 12.44 weeks). In turn, these two solutions were converted to homogeneous gels by the addition of Cab-O-Sil?. The chemical stability of BPO in these gels was evaluated at 37°, 45°, 50°, and 55°C for 5 weeks. Parallel experiments were conducted with two commercial BPO products, a 2.5% tinted gel and 5% vanishing lotion. BPO was less stable in commercial products (t_1/2 ≤ 13 weeks) than in the extemporaneously prepared gels (mean t_1/2 ～23 weeks). The present results suggest that aromatic esters can enhance the chemical stability of BPO in solutions and gel formulations to a significant extent.     

Benzoyl peroxide: a review of its current use in the treatment of acne vulgaris

Background: Owing to the use of topical and systemic antibiotics for acne vulgaris, the incidence of antibiotic-resistant Propionibacterium acnes is increasing worldwide. Topical benzoyl peroxide (BPO) is an alternative to antibiotics in the treatment of acne vulgaris. Objective: This review describes and evaluates recent clinical literature regarding the efficacy and tolerability of BPO. Methods: A PubMed literature search was conducted using the keywords benzoyl peroxide, acne, and combination therapy. Results: BPO is equally effective at concentrations of 2.5, 5.0 and 10%. However, a concentration-dependent irritant dermatitis can occur with higher concentrations. The efficacy of BPO can be enhanced when used in combination with topical retinoids, antibiotics and tertiary amines. BPO-containing combinations do not induce bacterial resistance and are important first-line treatments for mild to moderate acne vulgaris.     

丹参酮胶囊联合5%过氧苯甲酰凝胶治疗寻常型痤疮的疗效观察

目的:观察丹参酮胶囊联合5%过氧苯甲酰凝胶治疗寻常型痤疮的疗效与安全性。方法:将84例寻常型痤疮患者根据就诊次序随机均分为治疗组和对照组。治疗组口服丹参酮胶囊,每次4粒,tid,同时外用5%过氧苯甲酰凝胶,每日早、晚各1次;对照组仅外用5%过氧苯甲酰凝胶,每日早、晚各1次。2组疗程均为6周。结果:治疗组和对照组有效率分别为92.8%和71.4%,2组比较有显著性差异(P<0.01)。2组不良反应均较轻微,组间比较差异无统计学意义(P>0.05)。结论:丹参酮胶囊联合5%过氧苯甲酰凝胶治疗寻常型痤疮疗效显著,未见明显不良反应。     

Kinetics and Mechanism for the Reaction of Cysteine with Hydrogen Peroxide in Amorphous Polyvinylpyrrolidone Lyophiles

Purpose Peroxide impurities play a critical role in drug oxidation. In metal-free aqueous solutions, hydrogen peroxide (H₂O₂) induced thiol oxidation involves a bimolecular nucleophilic reaction to form a reactive sulfenic acid intermediate (RSOH), which reacts with a second thiol to form a disulfide (RSSR). This study examines the reaction of cysteine (CSH) and H₂O₂ in amorphous polyvinylpyrrolidone (PVP) lyophiles to explore the possible relevance of the solution mechanism to reactivity in an amorphous glass.Materials and Methods Amorphous PVP lyophiles containing CSH and H₂O₂ at varying initial ‘pH’ and reactant concentrations were prepared by methods designed to minimize reaction during lyophilization. Kinetic studies were conducted anaerobically at 25°C and reactants and products were monitored by HPLC. Products were characterized and the kinetic data were fit to models adapted from the solution mechanism.Results Key differences in the reactions in aqueous solution and amorphous PVP are: (1) while only cystine (CSSC) forms in solution, three degradants—cysteine sulfinic acid (CSO₂H), cysteine sulfonic acid (CSO₃H) and cystine (CSSC)—form in amorphous PVP; (2) simple bimolecular kinetics govern the solution reaction while initial rates in amorphous PVP suggested more complex kinetics (i.e., non-unity values for reaction order); and (3) heterogeneous (i.e., biphasic) reaction dynamics are evident in amorphous PVP. The differences in product formation and apparent reaction orders in the solid-state could be rationalized by partitioning of the same reactive intermediate to multiple products in the solid-state due to the restricted mobility of CSH. Beyond the initial rate region, the kinetics in amorphous PVP could be described by the Kohlrausch‐Williams‐Watts (KWW) stretched-exponential equation or by assuming two populations of reactant molecules having different reactivities.Conclusions When reactive intermediates are involved, differences in degradant profiles and other characteristics (e.g., rate constants, apparent reaction order) in the amorphous-state may simply reflect altered rates for individual reaction steps due to glass-induced changes in relative reactant mobilities rather than a change in overall mechanism.     

Comparison of tretinoin solution and benzoyl peroxide lotion in the treatment of acne vulgaris

Summary

In a single-blind trial, 44 patients were treated with tretinoin solution and 44 patients were treated with benzoyl peroxide lotion for acne vulgaris for not less than 12 weeks. Both treatments were shown to have a beneficial effect. The improvements, as judged by patients' and clinical assessment and lesion count, were more marked in patients receiving tretinoin solution. Few side-effects were reported with either treatment.     

银杏叶提取物对糖尿病大鼠肾脏保护作用的实验研究

目的 :研究银杏叶提取物 (ExtractofGinkgoBilboa,EGB)对糖尿病大鼠肾脏的保护作用。方法 :应用EGB对四氧嘧啶糖尿病大鼠进行了8wk治疗 ,观察其对糖尿病大鼠肾脏的保护作用。结果 :EGB能明显提高血清及肾组织中超氧化物歧化酶 (SOD)及谷光甘肽过氧化物酶 (GSH -Px)活性 ,改善基底膜增厚及基质增生 ,减少实验大鼠肾脏尿蛋白排泄量 ,减轻肾功能损害。结论 :EGB在预防与治疗糖尿病肾病方面有一定作用。     

不同溶剂与奥美拉唑钠配伍稳定性考察

目的:研究注射用奥美拉唑钠在7种溶剂中的配伍稳定性。方法:将40 mg奥美拉唑加入0.9%氯化钠注射液、5%葡萄糖注射液、10%葡萄糖注射液、果糖、5%碳酸氢钠溶液、10%葡萄糖酸钙溶液、25%硫酸镁溶液中,用高效液相色谱法测定配伍后的奥美拉唑钠的含量,并测定其pH值及观察液体变化,观察温度对0.9%氯化钠注射液、5%葡萄糖注射液、10%葡萄糖注射液中奥美拉唑钠颜色的影响。结果:注射用奥美拉唑钠与7种溶剂配伍后,其中0.9%氯化钠注射液、5%葡萄糖注射液、10%葡萄糖注射液在1 h内未出现颜色的变化,但放置3 h后5%葡萄糖注射液、10%葡萄糖注射液的液体由无色变为淡黄色,而果糖、10%葡萄糖酸钙及25%硫酸镁溶液30 min后即出现了颜色的变化以及沉淀。在37℃下,5%葡萄糖注射液、10%葡萄糖注射液在1 h内就出现了颜色变化。结论:奥美拉唑钠可以与0.9%氯化钠注射液、5%葡萄糖注射液、10%葡萄糖注射液配伍,其中以0.9%氯化钠注射液最佳,但与5%葡萄糖注射液、10%葡萄糖注射液配伍要注意温度以低于25℃为宜,放置时间不宜超过2 h,而果糖、10%葡萄糖酸钙溶液、25%硫酸镁溶液与奥美拉唑钠配伍禁忌。     

The Stability and Solubility of Progabide and Its Related Metabolic Derivatives

The stability–pH profile of the -aminobutyric acid prodrug, Progabide, was found to be bell shaped, with maximum stability occurring at pH 6 to 7 with a t _1/2 of 126 min. Of its metabolic derivatives, the deamidated product PGA degraded in a similar fashion to Progabide, whereas the hydrolytic degradation product SL79.182 was, as expected, a stable compound. Progabide behaved as a typical weak base, with its solubility increasing with a decrease in pH. SL79.182 behaved as a typical phenolic weak acid, with its solubility increasing with an increase in pH. Both compounds displayed low intrinsic solubilities of 14.5 × 10^–5 M for Progabide and 33.4 × 10^–6 M for SL79.182. An increase in temperature resulted in an increase in the solubility but a decrease in the stability of Progabide. The data obtained indicate that the gastric pH and gastric emptying rate will have a profound effect on the oral bioavailability of Progabide.     

Solid-State Stability Testing of Drugs by Isothermal Calorimetry

A new technique has been developed to calculate rapidly the solid-state room-temperature degradation rate of drugs and drug candidates. The technique utilizes measurements of the initial rate of heat output at several elevated temperatures by isothermal calorimetry and the degradation rate of the compound determined at a single elevated temperature by chromatography. The activation energies and degradation rates at 25°C calculated by conventional methods and by isothermal calorimetry are compared and discussed. The compounds studied were phenytoin, triamterene, digoxin, tetracycline, theophylline, diltiazem, and several proprietary ICI compounds.     

Chemical Stability of Ethyl Icosapentate Against Autoxidation. I. Effect of Temperature on Oxidation Kinetics

Pharmaceutical Research -     

迷迭香酸在不同溶剂中的热稳定性及其降解产物研究

目的 探讨迷迭香酸对照品在不同溶剂中加热温度和加热时间对其稳定性的影响,并对其在最不稳定的溶剂中的主要降解产物进行定性分析以阐释其降解途径。方法 将迷迭香酸对照品分别溶于水、70%乙醇、甲醇中,分别在不同水浴温度（20~100 ℃）下加热4 h,每隔1 h取样。采用HPLC测定迷迭香酸加热前后色谱峰的峰面积,计算其剩余率,同时采用HPLC-MS对其主要降解产物进行鉴定。结果 当加热温度≤60 ℃时,水溶液、70%乙醇溶液、甲醇溶液中的迷迭香酸剩余率均>95%,且甲醇溶液中的迷迭香酸剩余率高于水溶液和70%乙醇溶液;当迷迭香酸加热时间达到4 h时,水溶液和70%乙醇溶液中的迷迭香酸剩余率显著减小,甲醇溶液中的迷迭香酸剩余率几乎不变。迷迭香酸在水溶液中最不稳定,在水溶液中的降解途径主要有酯键水解、双键加成和氧化反应,降解后产生丹参素、咖啡酸、原儿茶醛、丹参酸C及其异构体等产物。结论 迷迭香酸的稳定性在甲醇中较好,70%乙醇中次之,水中最差;加热温度越高或加热时间越长,迷迭香酸的稳定性越差。因此,在迷迭香酸的研究过程中推荐首选甲醇为溶剂;迷迭香酸及含有该成分的中药在提取分离、加工制备和贮存过程中,温度不宜超过60 ℃,加热时间不宜超过4 h。     

阿达帕林凝胶治疗寻常性痤疮疗效及安全性研究

目的:通过阿达帕林凝胶与5%过氧苯甲酰霜对寻常性痤疮治疗的对照观察,评价阿达帕林凝胶治疗寻常性痤疮的疗效和安全性.方法:采用开放对照临床实验,分别应用阿达帕林凝胶与5%过氧苯甲酰霜对寻常性痤疮病人进行治疗,疗程12周,在治疗的2、4、8和12周进行随访.结果:阿达帕林凝胶治疗寻常性痤疮疗效和安全性均高于5%过氧苯甲酰霜剂.结论:阿达帕林凝胶是治疗寻常性痤疮安全和有效的药物.     

N－（4＇－羧苯基）－4－羟基－3，5－二叔丁基苯甲酰胺对十四烷酰佛波醋酸酯刺激大鼠多形核白细胞生成过氧化氢的影响

Ｎ－（４＇－羧苯基）－４－羟基－３，５－二叔丁基苯甲酰胺对十四烷酰佛波醋酸酯刺激大鼠多形核白细胞生成过氧化氢的影响孙士勇，韩锐（中国医学科学院药物研究所，北京１０００５０）新维甲类化合物Ｎ（４＇－羧苯基）－４－羟基－３，５－二叔丁基苯甲酰胺［Ｎ－（４...     

过氧化氢对FRTL细胞线粒体膜电位和超氧化物生成的影响

目的:探讨外源性过氧化氢(H2O2)对Fisher大鼠甲状腺细胞系(FRTL)线粒体膜电位(△ψ)和超氧化物生成的影响.方法:用1 mmol/L H_2O_2处理FRTL细胞10 min、30 min、24 h后,利用MitoSOX,通过活细胞影像法、流式细胞术检测线粒体超氧化物生成;利用罗丹明123(rh123),通过荧光分光光度计和荧光显微镜检测△ψ;MTT比色法检测细胞活力;光镜观察细胞形态学变化;吖啶橙(AO)染色检测细胞凋亡.结果:与对照组相比,1 mmol/L H_2O_2处理的FRTL细胞10 min、30 min、24 h,细胞内MitoSOX荧光强度明显增强,rh123荧光强度和MTT吸光度明显下降(P＜0.01),光镜下可见细胞脱壁、破碎,AO染色可见核变小、变圆,染色质浓缩、边集,核碎裂改变.结论:1 mmol/L H_2O_2急性处理(10 min,30 min)和慢性处理(24 h)均能明显增加FRTL细胞线粒体超氧化物生成,降低线粒体膜电位,造成细胞坏死和凋亡.     

常用输液溶剂中注射用乌司他丁稳定性研究

目的考察注射用乌司他丁在2种常用输液溶剂中的稳定性。方法按药品说明书规定的用量及浓度,将注射用乌司他丁10万单位分别溶于5%葡萄糖注射液(500 m L)和0.9%氯化钠注射液(500 m L),定时考察配伍溶液的外观、p H、不溶性微粒和含量变化情况。结果注射用乌司他丁与2种溶剂混合配制12 h内,外观和pH均无明显变化,≥10μm不溶性微粒数和≥25μm不溶性微粒数均符合2015年版《中国药典(四部)》规定的限度,且12 h内乌司他丁的含量基本无改变。结论注射用乌司他丁与2种输液溶剂配伍后,室温条件下12 h内可保持相对稳定,临床可采用输液泵持续给药的方法使用。     

A rapid and sensitive spectrophotometric method for the determination of benzoyl peroxide in wheat flour samples

A simple, rapid, and sensitive spectrophotometric method for the determination of benzoyl peroxide (BPO) in wheat flour samples was developed. The detection principle is based on BPO reacted with 2,2′-azino-bis(3-ethylbenzothiazoline-6-sulfonic acid) (ABTS) to obtain a blue-green colored product that was detected at 415 nm by spectrophotometry. The effect of factors influencing the color reaction was investigated. Under the selected conditions, the linear range for quantification of BPO was observed between 0.2–1.0 mg L⁻¹ with r² = 0.998. The limit of detection (LOD) was 0.025 mg L⁻¹. The developed method obtained superior precision (relative standard deviation < 2%) using 11 repeatability at 0.2 mg L⁻¹, 0.6 mg L⁻¹, and 0.8 mg L⁻¹. The proposed methodology was successfully applied to determine BPO in wheat flour samples.     

Chemical Stability of Ethyl Icosapentate Against Autoxidation. II. Effect of Photoirradiation on Oxidation Kinetics

The effect of ultraviolet (UV) or visible light (VIS) irradiation on the chemical stability of ethyl icosapentate [ethyl-(all-cis)-5,8,l l,14,17-icosapentaenoate] (EPA) was investigated at 45°C by means of HPLC and by measuring the peroxide value (POV). EPA was oxidized to peroxides after an induction period by photoirradiation, and the peroxide subsequently degraded to secondary products. The autoxidation of EPA followed consecutive reaction kinetics including an induction period, and the kinetic parameters of the oxidation were calculated based upon the consecutive reaction model by computer curve fitting. The results of the degradation rate constant, k, and the induction period obtained by HPLC showed that the radical and the peroxide formation rates are affected by UV, but not by VIS light irradiation. The formation rate constant of peroxide, kl, and its degradation rate constant to secondary products, k2, obtained from the POV under UV light irradiation, increased with irradiation intensity, during which the induction period decreased. On the other hand, kl, k2 and the induction period by VIS light irradiation did not change significantly. The relationship between the induction periods obtained by HPLC and POV and the UV light irradiation energy were superimposed in the plots, indicating that these parameters depended on the UV irradiation energy. The relationship between kl/k2 ratio and the UV irradiation energy suggested that the formation of secondary products was more remarkably accelerated by UV energy than that of peroxide.     

Application of Hydrogen Peroxide to the Control of Eutrophic Lake Systems in Laboratory Assays

We exposed water samples from a recreational lake dominated by the cyanobacterium Planktothrix agardhii to different concentrations of hydrogen peroxide (H₂O₂). An addition of 0.33 mg·L⁻¹ of H₂O₂ was the lowest effective dose for the decay of chlorophyll-a concentration to half of the original in 14 h with light and 17 h in experiments without light. With 3.33 mg·L⁻¹ of H₂O₂, the values of the chemical oxygen demand (COD) decreased to half at 36 and 126 h in experiments performed with and without light, respectively. With increasing H₂O₂, there is a decrease in the total and faecal coliform, and this effect was made more pronounced by light. Total and faecal coliform were inhibited completely 48 h after addition of 3.33 mg·L⁻¹ H₂O₂. Although the densities of cyanobacterial cells exposed to H₂O₂ did not decrease, transmission electron microscope observation of the trichomes showed several stages of degeneration, and the cells were collapsed after 48 h of 3.33 mg·L⁻¹ of H₂O₂ addition in the presence of light. Our results demonstrate that H₂O₂ could be potentially used in hypertrophic systems because it not only collapses cyanobacterial cells and coliform bacteria but may also reduce chlorophyll-a content and chemical oxygen demand.     

Stabilizing Peptide Fusion for Solving the Stability and Solubility Problems of Therapeutic Proteins

Purpose Protein aggregation is a major stability problem of therapeutic proteins. We investigated whether a novel stabilizing peptide [acidic tail of synuclein (ATS) peptide] could be generally used to make a more stable and soluble form of therapeutic proteins, particularly those having solubility or aggregation problems. Methods We produced ATS fusion proteins by fusing the stabilizing peptide to three representative therapeutic proteins, and then compared the stress-induced aggregation profiles, thermostability, and solubility of them. We also compared the in vivo stability of these ATS fusion proteins by studying their pharmacokinetics in rats. Results The human growth hormone–ATS (hGH–ATS) and granulocyte colony-stimulating factor–ATS (G-CSF–ATS) fusion proteins were fully functional as determined by cell proliferation assay, and the ATS fusion proteins seemed to be very resistant to agitation, freeze/thaw, and heat stresses. The introduction of the ATS peptide significantly increased the storage and thermal stabilities of hGH and G-CSF. The human leptin–ATS fusion protein also seemed to be very resistant to aggregation induced by agitation, freeze/thaw, and heat stresses. Furthermore, the ATS peptide greatly increased the solubility of the fusion proteins. Finally, pharmacokinetic studies in rats revealed that the ATS fusion proteins are also more stable in vivo. Conclusion Our data demonstrate that a more stable and soluble form of therapeutic proteins can be produced by fusing the ATS peptide. E. N. Lee and Y. M. Kim equally contributed to this work.     

Solvent Effects on the Solubility and Physical Stability of Human Insulin-Like Growth Factor I

Purpose. The solubility and physical stability of human Insulin-like Growth Factor I (hIGF-I) were studied in aqueous solutions with different excipients. Methods. The solubility of hIGF-I was determined by UV-absorption and quantification of light blocking particles. The physical stability of hIGF-I was studied with differential scanning calorimetry (DSC) and circular dichroism (CD) spectroscopy. Results. Human IGF-I precipitated at low temperature in the presence of 140 mM benzyl alcohol and 145 mM sodium chloride. CD data showed that the tertiary structure of hIGF-I during these conditions was perturbed compared to that in 5 mM phosphate buffer. In the presence of benzyl alcohol 290 mM mannitol stabilized hIGF-I. Sodium chloride or mannitol by themselves had no effect on either the solubility or the tertiary structure. Benzyl alcohol was attracted to hIGF-I, whereas sodium chloride was preferentially excluded. The attraction of benzyl alcohol was reinforced by sodium chloride leading to salting-out of hIGF-I. The CD-data indicated interactions of benzyl alcohol with phenylalanine in hIGF-I. Thermal denaturation of hIGF-I occurred in all solutions with sodium chloride, whereas mannitol or benzyl alcohol had no effect on the thermal stability. The thermal stability of hlGF-I was thus decreased in 145 mM sodium chloride although it was excluded from hIGF-I. Conclusions. The self-association and thermal aggregation of hIGF-I is driven by hydrophobic interactions. Benzyl alcohol is attracted to hIGF-I and induces changes in the tertiary structure causing hydrophobic attraction of the protein at low temperatures.