Various Solvent Systems for Solubility Enhancement of Enrofloxacin

Solubility enhancement of antimicrobial drug enrofloxacin has been studied using a series of co-solvents and surfactants. Aqueous solubility of enrofloxacin could be increased up to 26 times. Co-solvents alone produced only small increase in solubility. However, the combined effect of co-solvents and buffer was synergistic and a large increase in solubility could be attained. Ionic surfactants were found to be much better solubilizing agents than non-ionic surfactant. Amongst ionic surfactants, solubility was found to be very high in anionic surfactant, sodium dodecylsulphate as compared to the cationic surfactant, cetyltrimethylammonium bromide. Up to 3.8 mg/ml of enrofloxacin could be dissolved in sodium dodecylsulphate. Mechanism of solubilization has been proposed and surfactant solubilization parameters have been calculated.     

Enhancement of the Solubility and Efficacy of Poorly Water-Soluble Drugs by Hydrophobically-Modified Polysaccharide Derivatives

Purpose This work was intended to develop and evaluate a new polymeric system based on amphiphilic carboxymethylpullulans (CMP₄₉C₈ and CMP₁₂C₈) that can spontaneously self-assemble in aqueous solutions and efficiently solubilize hydrophobic drugs. Methods The self-assembling properties of CMP₄₉C₈ and CMP₁₂C₈ were characterized by fluorescence spectroscopy and surface tension measurements. The solubilization of benzophenone and docetaxel was assessed from surface tension measurements, UV spectrometry and HPLC assays. The in vitro cytoxicity of CMP₄₉C₈ solutions and the docetaxel commercial vehicle (Tween 80?/Ethanol–water) were evaluated in the absence and in the presence of docetaxel. Results Compared to CMP₁₂C₈, CMP₄₉C₈ in aqueous solutions appeared to self-organize into monomolecular aggregates containing hydrophobic nanodomains, and to significantly increase the apparent solubility of benzophenone. Docetaxel solubility could also be improved in the presence of CMP₄₉C₈ but to a lower extent due to the surface properties of the drug. Nevertheless, in vitro, the cytotoxicity studies revealed that against cancer cells, the CMP₄₉C₈-docetaxel formulation was equipotent to the commercial docetaxel one. Furthermore, in the absence of the drug, CMP₄₉C₈ appeared less cytotoxic against macrophages than the Tween? 80/Ethanol–water. Conclusions CMP₄₉C₈ is a good candidate for solubilizing hydrophobic drugs and could be applied to docetaxel formulations.     

提高克拉维酸发酵产量研究进展

克拉维酸是目前发现的最优秀的β－内酰胺酶抑制剂,其与β－内酰胺类抗生素组成的复合制剂,被广泛用于对抗产β－内酰胺酶耐药菌的感染。国内、外对如何提高克拉维酸的发酵水平一直在不断的探索,本文从产生菌的改良、培养基的优化及发酵工艺的改进等方面主要对国内外近5年来发表的有关提高克拉维酸发酵产量的文献进行了综述。     

Study and Computational Modeling of Fatty Acid Effects on Drug Solubility in Lipid-Based Systems

Lipid-based systems have many advantages in formulation of poorly water-soluble drugs but issues of a limited solvent capacity are often encountered in development. One of the possible solubilization approaches of especially basic drugs could be the addition of fatty acids to oils but currently, a systematic study is lacking. Therefore, the present work investigated apparently neutral and basic drugs in medium chain triglycerides (MCT) alone and with added either caproic acid (C6), caprylic acid (C8), capric acid (C10) or oleic acid (C18:1) at different levels (5 – 20%, w/w). A miniaturized solubility assay was used together with X-ray diffraction to analyze the residual solid and finally, solubility data were modeled using the conductor-like screening model for real solvents (COSMO-RS). Some drug bases had an MCT solubility of only a few mg/ml or less but addition of fatty acids provided in some formulations exceptional drug loading of up to about 20% (w/w). The solubility changes were in general more pronounced the shorter the chain length was and the longest oleic acid even displayed a negative effect in mixtures of celecoxib and fenofibrate. The COSMO-RS prediction accuracy was highly specific for the given compounds with root mean square errors (RMSE) ranging from an excellent 0.07 to a highest value of 1.12. The latter was obtained with the strongest model base pimozide for which a new solid form was found in some samples. In conclusion, targeting specific molecular interactions with the solute combined with mechanistic modeling provides new tools to advance lipid-based drug delivery.     

Hydrophobic Derivatives of Sulfated Hyaluronic Acid as Drug Delivery Systems for Multi-Target Intra-Articular Treatment of Post-Traumatic Osteoarthritis

During osteoarthritis (OA) development, chondrocytes progressively decompensate, upregulating proteolytic enzymes and reducing the key growth factors involved in promoting chondrocyte anabolism. A combined therapeutic approach is needed to address this multifactorial pathology, which affects the whole joint. Based on the literature, three promising targets for OA treatment have been selected: MMP3 (matrix metallopeptidase 3), TRPV4 (transient receptor potential cation channel subfamily V member 4) and mTOR (mammalian target of rapamycin). In this study, a novel water-soluble and biocompatible amphiphilic polymer named “sHA-oleylamide” was synthesized and screened from a series of hyaluronic acid derivatives for its anticatabolic activity. This MMP inhibitor showed no cytotoxicity, and in an in vitro model of inflammatory OA, it reversed the inflammatory outcome at a concentration of 0.011 mg/mL. The ability of sHA-oleylamide to form 20–50 nm micelles in water with a critical micelle concentration of 0.27±0.1 mg/mL, was confirmed by TEM images and measured by Nile red staining. RN-1747 and rapamycin molecules were successfully loaded in sHA-oleylamide, previously prepared at 12 mg/mL in PBS; both formulations were stable, sterile and confirmed in vitro to have mTOR inhibition by rapamycin and TRPV4 activation activity by RN-1747.The controlled release of RN-1747 from the micellar formulation with sHA-oleylamide showed that only approximately 60% of the total loaded RN-1747 was released within 7 days. These micellar formulations can potentially increase the bioavailability and pharmaceutical efficacy of the selected active molecules, combining their anti-catabolic and pro-anabolic activities and making them suitable for i.a. administration as OA treatments.     

介孔硅材料提高托伐普坦溶解性的研究

目的:研究介孔硅作为难溶性药物托伐普坦(TOL)的载体材料在提高其溶解性方面的作用。方法:取TOL 6.60 g,溶解于173.40 g甲醇溶液中,分别加入给药硅土8.80、26.40、44.00 g,采用溶液吸附法制备托伐普坦-介孔硅载药物,记为TOL/SLC-1-a、TOL/SLC-1-b、TOL/SLC-1-c;加入给药硅土8.80 g,采用吸附平衡挥干法制备托伐普坦-介孔硅载药物,记为TOL/SLC-2。对比TOL原料药、TOL和给药硅土物理混合物及载药物在0.22%十二烷基硫酸钠水溶液中60 min内的溶出曲线,并采用X射线粉末衍射法和示差扫描量热法表征载药物的性质。结果:与原料药和物理混合物比较,TOL/SLC-1-a、TOL/SLC-1-b、TOL/SLC-1-c和TOL/SLC-2的溶出速度均增加,其中TOL/SLC-1-a、TOL/SLC-1-b、TOL/SLC-1-c的溶出速度明显快于TOL/SLC-2,且前三者的溶出速度比较接近。TOL/SLC-1-a、TOL/SLC-1-b、TOL/SLC-1-c中的药物为无定形态,TOL/SLC-2中的药物为无定形和结晶态混合形式。结论:介孔硅可成为提高TOL溶出速度的载体材料。     

New Formulation Technique for Solubility and Dissolution Rate Enhancement of Poorly Soluble Drugs

Pharmaceutical Chemistry Journal - Ebastine (EBS) is a second-generation non-sedating antihistamine used for the prevention and treatment of allergic rhinitis and chronic idiopathic urticaria. It...     

Solubility Advantage of Amorphous Pharmaceuticals: II. Application of Quantitative Thermodynamic Relationships for Prediction of Solubility Enhancement in Structurally Diverse Insoluble Pharmaceuticals

Purpose  

To quantitatively assess the solubility advantage of amorphous forms of nine insoluble drugs with a wide range of physico-chemical properties utilizing a previously reported thermodynamic approach.     

甲磺酸倍他司汀中甲磺酸的离子色谱法测定不确定度评定

摘 要 目的：建立离子色谱法测定甲磺酸倍他司汀中甲磺酸的含量,并进行不确定度评定。方法: 采用IonPac AS11 HC（25 mm×4.0 mm,5 μm）阴离子色谱柱,以12 mmol·L^-1氢氧化钠溶液为淋洗液,采用电导检测器,抑制器电压30 mV。结果: 甲磺酸峰与其他离子色谱峰之间分离度良好,在10~30 μg·mL^-1浓度范围内线性关系良好（r=0.999 9）,定量限为0.116 μg·mL^-1,平均加样回收率为100.8%,RSD为1.2%（n=9）。根据试验结果,对离子色谱法测量中影响测量不确定度的因素进行了量化、评定与合成,给出扩展不确定度的结果报告。结论:建立的离子色谱方法简便、准确,专属性好,可用于测定甲磺酸倍他司汀中甲磺酸含量;通过不确定度评定中对各因素分量结果的分析,有助于减小测量不确定度,提高测定结果的准确可靠性。     

Synthesis and Biological Activity of Aliphatic and Aromatic Sulfonic Acid Azolides

Pharmaceutical Chemistry Journal -     

Estimation of Aqueous Solubility for Some Guanine Derivatives Using Partition Coefficient and Melting Temperature

Aqueous solubilities for some guanine derivatives were estimated by semiempirical equations developed by Yalkowsky and Valvani1 using the data for partition coefficient and melting temperature. It was shown that in the case of guanine derivatives examined in this study, the solubility values could not be estimated adequately by these equations.     

肝胆显影鳌合物—氮基三乙酸单酰苯胺及其类似物的合成

本课题合成了四个氮基三乙酸单酰苯胺(IDA)类及其类似物肝胆显影螯合物.(1)用家兔做了肝胆显影扫描实验,其显影效果甚好.(2)～(3)为未见报道的新化合物.     

葛根素-壳寡糖共无定型制备与体外溶出度评价

目的 提高葛根素的生物利用度.方法 采用低温研磨法制备葛根素-壳寡糖共无定型(PUE-COS CM),采用差示扫描量热法、X射线粉末衍射法、傅里叶红外光谱法、扫描电镜法对PUE-COS CM进行固态表征分析;评价PUE-COS CM在漏槽和非漏槽2种条件下的体外溶出行为,并考察其稳定性.结果 差示扫描量热法证实,PUE...     

青藤碱对TNBS诱导的慢性小鼠结肠炎的治疗作用

摘 要 目的：评价青藤碱对2,4,6 三硝基苯磺酸（TNBS）灌肠引起的Th1细胞介导的小鼠实验性结肠炎的治疗作用,并探讨其作用机制。方法: 为评价青藤碱对结肠炎的治疗作用,将Balb/c 小鼠随机分为乙醇对照组,TNBS模型组,青藤碱低（50 mg·kg^-1）、中（100 mg·kg^-1）、高（200 mg·kg^-1）剂量组,每组10只。为观察青藤碱对TNBS结肠炎的治疗作用,第1剂TNBS给药后7 d开始灌胃给予青藤碱,持续给药21 d。第28天处死动物,观察结肠黏膜的损伤程度, 测定结肠髓过氧化物酶（MPO）活性,ELISA法分别测定结肠炎症细胞因子 （TNF-α、IL-17和IL-23）蛋白水平。结果: 与TNBS模型组比较,青藤碱中、高剂量组的体质量、大体损伤评分及组织学表现均显著改善（P<0.05）,MPO酶活性显著降低（P<0.05）,结肠黏膜中TNF-α 、IL-17和IL-23的蛋白水平均较TNBS组下降（P<0.05）。结论:青藤碱对TNBS诱导的慢性小鼠结肠炎具有治疗作用,作用机制与青藤碱对Th1炎症细胞因子的抑制有关。     

Drug Resinates an Attractive Approach of Solubility Enhancement of Atorvastatin Calcium

A substantial number of new chemical entities and marketed drugs show poor solubility characteristics and amorphisation is one of the favorable approaches to enhance solubility characteristics of such poorly soluble drugs. Formulation efforts in the present study were devoted to investigate amorphisation of a model poorly soluble drug, atorvastatin calcium by molecular complexation with anion exchange resin, Duolite^®AP 143/1093 and hence enhancement in its solubility characteristics. Drug resinates in 1:1, 1:2, and 1:4 weight ratios were prepared by simple batch operation and subsequently studied for drug content, residual solvent content, molecular interactions, solid state characterisation and solubility characteristics. During initial characterisation, all the proportions of drug resinates, except 1:1 proportion showed partial amorphisation of the drug, whereas 1:1 proportion showed complete amorphisation of the drug. This proportion reported distinctly enhanced solubility characteristics over pure drug and other proportions. Such amorphisation and solubility enhancement could be attributed to the binding of individual drug molecules to the functional sites of the resin molecules, either partially or completely, resulting in reduction of crystal lattice energy, a main barrier to dissolution. Hydrophilic nature of ion exchange resin matrices also assisted in enhancing dissolution of the drug from the resinates. During accelerated stability study, there was an insignificant decrease in solubility characteristics of the drug and its amorphous form was also found to be stable in 1:1 proportion. Atorvastatin resinates formed in 1:1 weight ratio were in stoichiometric proportion and such drug resinates in stoichiometric proportion showed to have tremendous potential in conversion of crystalline form of drug substances to its amorphous form and subsequent stabilisation. It hence proved to be a very effective, yet simple approach for improving solubility characteristics of poorly soluble actives.     

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.     

Solubility Enhancement of Nucleosides and Structurally Related Compounds by Complex Formation

Water-soluble vitamins, amino acids, and nontoxic pharmaceutical excipients were studied as solubilizing agents for poorly water-soluble adenine (nucleic acid base), guanosine (nucleoside), and structurally related drugs (acyclovir and triamterene). The apparent solubility of the substrates (adenine, guanosine, acyclovir, or triamterene) was appreciably increased by forming complexes with the ligands (vitamins, amino acids, or other ligand). Apparent association constants (K _a ) values were measured at 25°C in pH 7 phosphate buffer using phase solubility analysis. The effect of combination ligands on substrate solubility was also studied. Additive solubility enhancement was obtained for several ligand pairs.     

Thermodynamics of Solutions I: Benzoic Acid and Acetylsalicylic Acid as Models for Drug Substances and the Prediction of Solubility

Purpose. To investigate the solution process of drug substances (exemplified by benzoic acid, BA, and acetylsalicylic acid, ASA), particularly the interrelation between enthalpic and entropic terms of Gibbs energy, in different solvents. To develop an approach for the estimation of standard solution enthalpies based on a self-consistent thermochemical scale. Method. Two independent methods, solubility experiments (concentrations of saturated solutions) and solution calorimetry (standard solution enthalpies) in aliphatic alcohols and individual organic solvents were used. Correlation between the thermodynamic functions in various solvents were analyzed by standard statistical methods. Multiple regression analysis between H ⁰ _sol values and the parameters of the solvents was run on the Koppel-Palm equation. Results. Based on experimental data, a compensation effect between thermodynamic functions was observed. Correlation was found between H ⁰ _sol (BA) and H ⁰ _sol (ASA) [where the H ⁰ _sol (BA)-values were used as a self-consistent thermochemical scale]. Furthermore, H ⁰ _sol correlated with the Koppel-Palm basicity of the solvents. Conclusions. The model based on solubility and solution experiments might be useful for the prediction of solubility or solvation of drug substances in different media. The regression equation based on the self-consistent thermochemical scale makes it possible to approximate the ability to solvate a drug substance in comparison with structure-relative substances.     

美沙拉嗪缓释剂对2，4，6-三硝基苯磺酸诱导大鼠溃疡性结肠炎的治疗作用

目的 研究美沙拉嗪缓释剂对2,4,6 三硝基苯磺酸(2,4,6-trinitro picrylsulfonic acid,TNBS)诱导的溃疡性结肠炎肿瘤坏死因子α(tumor necrosis factor α,TNF-α)、白细胞介素(interleukin,IL) 1β、IL-6表达的影响,探讨美沙拉嗪缓释剂的抗炎机制. 方法 应用TNBS/乙醇建立大鼠溃疡性结肠炎模型,实验设正常对照组、模型组、药物治疗组(给予美沙拉嗪溶液100 mg&#8226;kg^-1&#8226;d^-1), 阳性对照组(给予5-对氨基水杨酸100 mg&#8226;kg^-1&#8226;d^-1),每组10只,每天灌胃2次,给药时间从造模后第1天开始至实验结束,共7 d,观察大鼠疾病活动指数(disease index,DAI)、体质量变化及结肠病理学改变,生化法检查大鼠结肠组织髓过氧化物酶(myeloperoxidase,MPO)活性,逆转录聚合酶链反应(Real-time PCR)检测肠组织TNF-α、IL-1β、IL-6mRNA的表达水平. 结果 与正常对照组比较,模型组大鼠结肠组织MPO活性及TNF-α、IL-1β、IL-6mRNA表达量明显增多(P<0.05).与模型组和阳性对照组比较,药物治疗组MPO活性及结肠组织TNF-α、IL-1β、IL-6mRNA的表达明显减少(P<0.05).模型组和阳性对照组差异无统计学意义. 结论 美沙拉嗪缓释剂对大鼠实验性溃疡性结肠炎具有治疗作用,其机制与通过降低中性粒细胞的浸润、抑制促炎因子TNF-α、IL-1β、IL-6mRNA等的表达有关.