Use of DMPC and DSPC lipids for verapamil and naproxen permeability studies by PAMPA

Verapamil and naproxen Parallel Artificial Membrane Permeability Assay (PAMPA) permeability was studied using lipids not yet reported for this model in order to facilitate the quantification of drug permeability. These lipids are 1,2-distearoyl-sn-glycero-3-phosphatidylcholine (DSPC), 1,2-dimyristoyl-sn-glycero-3-phosphocholine (DMPC) and an equimolar mixture of DMPC/DSPC, both in the absence and in the presence of 33.3?mol% of cholesterol. PAMPA drug permeability using the lipids mentioned above was compared with lecithin-PC. The results show that verapamil permeability depends on the kind of lipid used, in the order DMPC?>?DMPC/DSPC?>?DSPC. The permeability of the drugs was between 1.3 and 3.5-times larger than those obtained in lecithin-PC for all the concentrations of the drug used. Naproxen shows similar permeability than verapamil; however, the permeability increased with respect to lecithin-PC only when DMPC and DMPC/DSPC were used. This behavior could be explained by a difference between the drug net charge at pH 7.4. On the other hand, in the presence of cholesterol, verapamil permeability increases in all lipid systems; however, the relative verapamil permeability respect to lecithin-PC did not show any significant increase. This result is likely due to the promoting effect of cholesterol, which is not able to compensate for the large increase in verapamil permeability observed in lecithin-PC. With respect to naproxen, its permeability value and relative permeability respect lecithin-PC not always increased in the presence of cholesterol. This result is probably attributed to the negative charge of naproxen rather than its molecular weight. The lipid systems studied have an advantage in drug permeability quantification, which is mainly related to the charge of the molecule and not to its molecular weight or to cholesterol used as an absorption promoter.     

In Vivo Skin Permeation of Sodium Naproxen Formulated in Pluronic F-127 Gels: Effect of Azone® and Transcutol®

The objective of this study was to determine the penetration of sodium naproxen, formulated in Pluronic F-127 (PF-127) gels containing Azone® and Transcutol® as penetration enhancers, through human skin in vivo. It was found that the combination of Azone® and Transcutol® in PF-127 gels enhanced sodium naproxen penetration, with enhancement ratios of up to two fold compared with the formulation containing only Transcutol®. These results were confirmed by TEWL and ATR-FTIR spectroscopy, suggesting a synergic action for Azone® and Transcutol®. Because of the thermo-reversible behavior of Pluronic gels, the influence of the components added to the gel formulations on viscosity, as a function of temperature, was also studied.     

Solubility and Apparent Specific Volume of Some Pharmaceutical Salts in Propylene Glycol + Water Mixtures at 298.15 K

The equilibrium solubility of three pharmaceutical salts, namely, sodium naproxen (Na.NAP), procaine hydrochloride (PC.HCl), and lysine clonixinate (Lys.Clon), was determined in propylene glycol (PG) + water mixtures at 298.15 K. If the mole fraction concentration scale is considered, the mixtures’ composition-dependence on solubility was different for these drugs. Thus, the solubility of Na.NAP increased nonlinearly from pure water to pure PG. By contrast, the solubility of PC.HCl decreased nonlinearly from pure water to pure PG. In a different way, the solubility of Lys.Clon increased from pure water to the mixture with mass fraction of PG, w₁ = 0.80, and later, it decreased to reach a lower value in pure PG. A good correlation of the solubility data was obtained by using the modified NIBS/R-K model. Otherwise, the apparent specific volumes at saturation of these drugs were also calculated in all the mixtures under study.     

Enhancing Effect of Calix[4]arene Amide Derivatives on Lipase Performance in Enantioselective Hydrolysis of Racemic Arylpropionic Acid Methyl Esters

Calix[4]arene amide derivatives were employed as new additives within the sol-gel encapsulation of lipase from Candida rugosa (CRL) to improve its catalytic properties. Evaluation of catalytic activity of the encapsulated lipases was acheived by enantioselective hydrolysis of both racemates, Naproxen methyl ester and 2-phenoxypropionic acid methyl ester, in aqueous buffer solution/isooctane reaction system. Results show that enantioselectivity was improved by using calix[4]arene amide derivatives-based encapsulated lipases. The reaction of naproxen methyl ester resulted in 47.6% conversion (x) in 24 h with 88.9% enantiomeric excess of substrate (ee_s), analogous to an enantioselectivity (E) value of 297 (E = 137 for the encapsulated free enzyme). The conversion of 2-phenoxypropionic acid methyl ester, obtained was 48.4% with E value of 327, enantiomeric excess of substrate (ee_s) of 92% for the reaction time of 1 h (E = 211 for the encapsulated free enzyme).     

2-甲氧基-6-(2′-萘基)丙酸-(2,″2″-二甲基-3″-溴)丙酯水解反应制备萘普生

用氢氧化钠水溶液水解2-甲氧基-6-(2′-萘基)丙酸-(2,″2″-二甲基-3″-溴)丙酯得到萘普生,以萘普生收率为主要指标,用均匀设计和单因素实验方法,考察了NaOH质量分数,物料摩尔比,水解时间对水解反应的影响。结果表明:在水解温度(110±5)℃,水解反应时间60~90 m in,w(NaOH)=40%,n(氢氧化钠)∶n(原料)=4.4∶1的条件下,萘普生收率可达99.19%。同时确定了高效液相色谱分析萘普生的分析方法。     

Process development for electrocarboxylationof 2-acetyl-6-methoxynaphthalene

Electrochemical carboxylation of 2-acetyl-6-methoxynaphthalene to 2-hydroxy-2-(6-methoxy-2-naphthyl)propionic acid may be carried out in good yield (89% in the electrolysis; 75% as isolated dried product) in an undivided flow cell using lead as the cathode and aluminium as the dissolving anode. Dimethylformamide was found to be the best solvent for the reaction and low cost tetraethylammonium chloride hydrate is a good electrolyte for the system. The best conditions are those that increase carbon dioxide concentration although higher pressure seems to be more effective than low temperature. The reaction may be carried out with good yield at fairly high current density (1150Am–1) and higher current densities are likely attainable. The allowable payload is limited to around 10% because higher payloads (20%) resulted in solution too viscous to pump. Initially it was surmised that trace quantities of water would be detrimental to good yields in these reactions. However, it was found that small amounts of water (that associated with typical quaternary ammonium chloride salts) has the beneficial effect of eliminating the major byproduct which is formed in more nearly anhydrous solutions without resulting in formation of alternative byproducts. Process conditions were evaluated at 0.2L scale, then scaled up to 1L and finally 75L. The best results were attained in the 1L system, solvable operating problems limited the yield in the largest scale electrolysis.     

反溶剂重结晶法制备萘普生超细微粒

在溶剂(丙酮)-反溶剂(水)体系下,采用反溶剂重结晶法制备了超细萘普生微粒。研究了不同溶剂-反溶剂体积比、重结晶温度、表面活性剂用量及陈化条件对重结晶产物粒径和形貌的影响。采用扫描电子显微镜(SEM)、表面吸附(BET)、红外光谱(IR)、X射线衍射(XRD)等检测手段对原料药和重结晶产物进行了对比分析。实验结果表明,当溶剂与反溶剂体积比为1:20,重结晶温度为4～8℃,表面活性剂聚乙烯吡咯烷酮(PVP)的质量分数为0.5%～1.0%,60℃下陈化2 h时。可得到短径300～500 nm,长径1～2μm的超细萘普生粉体。重结晶所得产物的晶型和物理性质均未发生变化,但粒度显著减小,形貌趋于规整且比表面积增加至原料药的5.3倍。     

萘普生稀土(Ce、Gd)配合物的合成及稳定性研究

本文合成了萘普生稀土(Ce、Gd)配合物,测定了配合物配位数并依据徐光宪关于水溶液中配合物的吸附平衡理论求得逐级稳定常数βi.     

Preparation and irradiation of Pluronic F127-based thermoreversible and mucoadhesive hydrogel for local delivery of naproxen

To improve physical properties and modulate the mucoadhesive hydrogel formulation via cross-linking by radiation, hydrogels were prepared using thermoreversible polymer Pluronic F127 (PF127) and mucoadhesive polymer carbopol 934P (C934P). As a model drug, naproxen was loaded in the hydrogel formulation. Sol-gel transition temperatures of hydrogels were measured by the tube-inversion method. The mucoadhesive potential of each formulation was determined by measuring the force required to detach the formulation from oral mucosal tissue. To strengthen the mechanical properties, the formulations were irradiated using an electronic beam. Drug release from the hydrogels and the cytotoxicity of each formulation were investigated. Sol-gel transition temperatures of the formulations were decreased by the addition of carbopol and were close to body temperature. The mucoadhesive force of the PF127 formulation was increased by addition of carbopol. In vitro release was sustained and the release rate was reduced by the addition of carbopol. After irradiation, the mucoadhesive force was increased about five-fold especially in the case of PF127 23% (9.7 kPa) and in vitro release was not sustained further. In conclusion, the use of a PF127 formulation incorporating a mucoadhesive polymer could effectively and safely improve oral residence time and absorption of naproxen. Irradiated formulations showed permanent cross-linking and improved properties.     

Kinetic Study for Biphasic Recognition Chiral Extraction of Naproxen Enantiomers with Hydrophobic L-iso-butyl Tartrate and Hydrophilic Hydroxypropyl-β-Cyclodextrin

The kinetics of biphasic recognition chiral extraction of naproxen (HA) enantiomers was investigated to determine the extraction mechanism, with hydrophobic L-iso-butyl tartrate (L-IBTA) in the organic phase and hydrophilic hydroxypropyl-β-cyclodextrin (HP--CD) in the aqueous phase. The two-phase homogeneous reaction model was selected over the interfacial reaction model, because there is a clear physical solubility of naproxen enantiomers in both the aqueous phase and the organic phase. The reactions between the HA enantiomers and L-iso-butyl tartrate in a stirred cell fall in Regime 3; the extraction is accompanied by two fast chemical reactions in the diffusion film. The reactions have been found to be first order with respect to HA enantiomers and second order with respect to L-IBTA. The forward rate constants for S-HA and R-HA are 1.26?×?10^?4 mol^?2 m⁶ s^?1 and 2.52?×?10^?4 mol^?2 m⁶ s^?1, respectively. With the increase of HP--CD concentration in the aqueous phase, high enantioselectivity was obtained, but the extraction rates decreased. These data will be useful in the design of extraction processes.