丙二醇对补骨脂黑色黏稠物的溶解度的影响

目的 优选丙二醇对补骨脂经醇提水沉后所得的不溶于水的黑色黏稠物的溶解条件。方法 正交试验法，以补骨脂素和异补骨脂素为指标，考察丙二醇的用量、丙二醇的浓度和吐温-80的用量3个因素。结果 丙二醇对补骨脂的水不溶物的最佳溶解条件为用6倍量50％的丙二醇溶解补骨脂的黑色黏稠物，所得溶液中补骨脂素和异补骨脂素的含量最高，吐温-80以不加入为佳。结论 丙二醇对补骨脂黑色黏稠物有较好的溶解度。吐温-80的加入不利于补骨脂素和异补骨脂素的溶出。     

Physicochemical properties of valsartan and the effect of ethyl alcohol, propylene glycol and pH on its solubility

The aqueous solubility and partition coefficient of valsartan were determined at room temperature. The effect of ethyl alcohol, propylene glycol and pH on its solubility was also investigated. It was found that both solvents increased the solubility of the drug in water. The solubilizing power of ethyl alcohol was found to be higher than that of propylene glycol. Valsartan solubility was also observed to increase at high pH values and its lipophilicity wasdemonstrated by the high positive value of the logarithm of partition coefficient.     

Effect of surfactants on the solubility and intrinsic dissolution rate of sparfloxacin

The effect of surfactants on the solubility and intrinsic dissolution rate of sparfloxacin was investigated at room temperature. The surfactants used in the study were anionic sodium lauryl sulfate (SLS) and nonionic polysorbate 80 (Tween 80). Sodium lauryl sulfate showed very significant increase in solubility Tween 80 at the highest concentration studied. The intrinsic dissolution rates were determined compared to at the same surfactant concentrations used in the solubility study by rotating disk method. Diffusion coefficient (D) of sparfloxacin was evaluated to be 7.19 x 10(-6) cm2S(-1) and the apparent mean diffusion coefficient for sparfloxacin-loaded micelle was estimated to 3.98 x 10(-6) and 2.21 x 10(-6) cm2S(-1) in Tween 80 and SLS respectively.     

Enhancement of transdermal delivery of progesterone using medium-chain mono and diglycerides as skin penetration enhancers

We evaluated whether medium-chain mono and diglycerides (MCG) can be utilized to optimize the transdermal delivery of progesterone (PGT). MCG was studied at 10–70% (w/w) in propylene glycol (a polar solvent) or Myvacet oil (nonpolar solvent); PGT was used at 1% (w/w). The topical (to the skin) and transdermal (across the skin) delivery of PGT were evaluated in vitro using porcine ear skin. When incorporated in propylene glycol, MCG at 10% enhanced the topical and transdermal delivery of PGT by 2.5- and 7-fold, respectively. At 20–50%, topical delivery was further enhanced while transdermal delivery gradually returned towards baseline. At 70%, MCG enhanced neither the delivery to viable skin nor the transdermal delivery of PGT. Similar concentration-dependent effects were observed when MCG was incorporated in Myvacet oil, but their magnitudes were 2- to 3-fold smaller. The relative safety of MCG was assessed in cultured fibroblasts and compared to propylene glycol (regarded as safe) and sodium lauryl sulfate (moderate-to-severe irritant). Both MCG and propylene glycol were substantially less cytotoxic than sodium lauryl sulfate. We conclude that formulations containing 10% MCG in propylene glycol may be a simple and safe method to improve the transdermal delivery of progesterone and promote its use in hormone replacement therapy.     

Micellar Solubilization of Timobesone Acetate in Aqueous and Aqueous Propylene Glycol Solutions of Nonionic Surfactants

The micellar solubilization of timobesone acetate, a novel topical corticosteroid, was studied in aqueous and aqueous propylene glycol solutions of 1 to 5% nonionic surfactants at 25°C. The surfactants used were polyoxyethylene (POE) sorbitan monofatty acid esters (polysorbates), fatty acid esters (Myrj), and fatty alcohol ethers (Brij), as well as sucrose monolaurate (Crodesta SL40). The increase in the solubility of timobesone acetate in the micellar solutions was dependent on the type and concentration of surfactant. The solubilizing capacity of the surfactant micelles and the distribution coefficient of timobesone acetate in aqueous micellar solutions were found (1) to increase with increasing length of the hydrophobic fatty acid group; (2) to increase according to the structure of the hydrophilic group in the order of POE sorbitan ester, sucrose ester, POE ester, and POE ether; (3) to be unaffected by the increase in POE chain length; and (4) to tend to decrease in surfactant containing unsaturated fatty acid groups. In aqueous propylene glycol solution, the solubilizing capacity increased slightly, i.e., up to 1.5-fold in 50% propylene glycol solution, for the ester-type surfactants (polysorbates and Myrj). But this increase was not observed in the ether-type surfactant (Brij) solution. The distribution coefficient decreased logarithmically with increasing concentrations of propylene glycol in the solution. This was caused by the logarithmic increase in the timobesone acetate solubility in the bulk phase, while the solubility in the micellar phase was practically unchanged. The results support the equilibrium distribution model of micellar solubilization.     

Solubilization of water by hydrotropic salts

The effect of some electrolytes, nonelectrolytes, surfactants, and hydrotropic salts on the solubility of water in 1-butanol and 1-hexanol was investigated. While sodium chloride and sodium acetate decrease the solubility of water in 1-butanol, urea has no significant effect. The ionic surfactants, sodium lauryl sulfate and cetrimide, cause an initial decrease in the solubility of water in 1-butanol followed by an increase at high surfactant concentrations. The nonionic surfactant, polysorbate 20, does not show the initial decrease in water solubility. On the other hand, the hydrotropic salts, sodium benzoate, sodium salicylate, and sodium gentisate, are shown to be the best water solubilizers in 1-butanol. Sodium salicylate showed the maximum solubilizing power. The effect of sodium benzoate, sodium salicylate, and sodium lauryl sulfate on the solubility of water in 1-hexanol was also investigated. Similar results were obtained.     

Studies on the adsorption and solubility of nalidixic acid

The adsorption of nalidixic acid on certain pharmaceutical additives was investigated and its extent estimated. Also, the effects of various surface-active agents and hydrophilic polymers on the solubility of the drug was determined. The adsorption isotherms have revealed that the degree of adsorption increased in the order; microcrystalline cellulose < ethyl cellulose < silicon dioxide < aluminium magnesium silicate. Studies on the solubility of nalidixic acid at 37°C using different concentrations of hydrophilic polymers have demonstrated that methyl cellulose, polvinylpyrrolidone and polyethylene glycol 6000 have comparable effects. Polyvinyl alcohol caused only a marginal increase in solubility. The surface-active agents, sodium lauryl sulphate and polysorbate 80, also increased solubility of the drug. The values of the heat of solution and the free energy changes were calculated from the Van't Hoff plots. The values of heat of solution for all systems were comparable, but the free energy changes indicate that sodium lauryl sulphate causes the most marked effect on solubility.     

Development of an ethyl laurate-based microemulsion for rapid-onset intranasal delivery of diazepam

An ethyl laurate-based microemulsion system with Tween 80 as surfactant, propylene glycol and ethanol as cosolvents was developed for intranasal delivery of diazepam. Phase behavior and solubilization capacity of the microemulsion system were characterized and in vivo nasal absorption of diazepam from microemulsion formulations was investigated in rabbits. A single isotropic region, which is considered as a bicontinuous microemulsion, was found in the pseudo-ternary phase diagrams developed at various Tween 80: propylene glycol: ethanol ratios. With the increase of Tween 80 concentration, the microemulsion region area, microemulsion viscosity, and the amount of H(2)O and ethyl laurate solubilized into the microemulsion system increased; however, the increase of ethanol percentage produced opposite effects. Diazepam, a practically water-insoluble drug, displayed a high solubility of 41 mg/ml in a microemulsion consisting of 15% ethyl laurate, 15% H(2)O, and 70% (w/w) surfactant/cosurfactant (Tween 80:propylene glycol:ethanol at 1:1:1 weight ratio). Nasal absorption of diazepam from this microemulsion was found to be fairly rapid. At 2 mg/kg dose, the maximum drug plasma concentration was arrived within 2-3 min, and the bioavailability (0-2 h) after nasal spray compared with intravenous injection was about 50%. These results suggest that this ethyl laurate-based microemulsion may be a useful approach for the rapid-onset delivery of diazepam during the emergency treatment of status epilepticus.     

Stabilization of solid dispersions of nimodipine and polyethylene glycol 2000.

Previous investigations revealed that solid dispersions consisting of 20% (m/m) nimodipine and 80% (m/m) polyethylene glycol 2000 prepared by the melting method, represent supersaturated solid solutions of nimodipine recrystallizing upon storage at +25 degrees C. The objective of this study was the improvement of the storage stability by preventing recrystallization. The first approach in order to prevent recrystallization was the development of thermodynamically stable solid solutions by using solvents aiming to enhance the solubility of nimodipine in the carrier material. As potential solubility enhancing additives, polyethylene glycol 300, poly(ethylene/propylene glycol) copolymer, polypropylene glycol 1020, propylene glycol, glycerol and ethyl acetate were evaluated. The second approach enhancing storage stability was the addition of recrystallization inhibitors to supersaturated solid solutions, thereby delaying the transformation of the metastable supersaturated system to the thermodynamically stable state. Macrogol cetostearyl ether, macrogol glycerol monostearate, polysorbate 60, cetostearyl alcohol, glycerol monostearate and sodium lauryl sulphate as well as hydroxypropylcellulose, butylmethacrylat-(2-dimethylaminoethyl)methacrylat-methylmethacrylat-copolymer, polyacrylic acid, polyvinyl alcohol and povidone K17 were included in the study. It could be shown that povidone K17 effectively prevents recrystallization in solid solutions containing 20% (m/m) of nimodipine during storage at +25 degrees C over silica gel thereby ensuring a substantial increase in the dissolution rate and degree of supersaturation in water. On the contrary, stabilization by solubility enhancement was only successful at drug loadings not exceeding 1% (m/m) using polyethylene glycol 300 as solubility enhancing additive.     

Solubility studies on valdecoxib in the presence of carriers,cosolvents, and surfactants

Enhancement of the solubility of valdecoxib was examined using a series of hydrophilic carriers (mannitol, polyethylene glycol (PEG) 4000, PEG 6000, PEG 8000, and urea), surfactants (Tween‐20, Tween‐80, and sodium lauryl sulfate [SLS]) and cosolvents (ethanol, methanol, and glycerol) at 37°C. The solubility of valdecoxib could be enhanced significantly using PEG 4000 as a carrier, ethanol as cosolvent, and SLS as a surfactant. Because the solubility of valdecoxib increased dramatically in the presence of polyethylene glycols, these are suitable dispersing agents for preparing solid dispersions containing valdecoxib. Gibbs free energy (ΔG) values were all negative for all hydrophilic carriers tested, indicating the spontaneous nature of valdecoxib solubilisation. Among the cosolvents, ethanol exhibited higher solubilization potential than methanol and glycerol. As the dielectric constant of the cosolvent–water mixtures decreased, the solubility of valdecoxib increased. Finally, SLS exerted maximum solubilization of valdecoxib when compared to Tween‐20 or Tween‐80. The crystallinity of valdecoxib was explored by X‐ray diffraction study and showed numerous crystalline peaks. Examination of surface morphology by scanning electron microscopy depicted a near spherical shape of valdecoxib with irregular surface characteristics. Drug Dev. Res. 62:41–48, 2004. © 2004 Wiley‐Liss, Inc.     

Solubilization behavior of a poorly soluble drug under combined use of surfactants and cosolvents.

The solubilization behavior of a poorly soluble model drug, phenytoin (PHT), under combined use of surfactants (sodium dodecyl sulfate (SDS), Tween 80) and cosolvents (dimethylacetoamide (DMA), ethanol, poly(ethylene glycol) 400 (PEG), glycerol) was examined. The solubility of PHT in the aqueous surfactant solutions increased linearly with increase of the surfactant concentration. The solubility of PHT in water-cosolvent mixtures roughly followed the log-linear model, which is widely accepted to explain the solubilization behavior of poorly soluble compounds in water-cosolvent mixtures, except for the case of glycerol, in which the solubility was minimal at 10% (w/v) of glycerol. When the cosolvents were added to the aqueous surfactant solutions, their effect on the solubility depended on the combination of the surfactant and the cosolvent. The most striking increase in solubility was observed with DMA, regardless of the type of surfactant. When ethanol was added, an increase in the solubility was observed with the Tween 80 solution, while a dramatic decrease was found with the SDS solution. The addition of glycerol or PEG to the surfactant solutions had only a minor impact on the solubility. These solubilization behaviors of PHT in the surfactant-cosolvent mixtures were partially explained by the solubility model introduced in our previous paper [Kawakami, K., Miyoshi, K., Ida, Y., 2004. Solubilization behavior of poorly soluble drugs with combined use of Gelucire 44/14 and cosolvent. J. Pharm. Sci. 93, 1471-1479]. Addition of the cosolvents to the surfactant solutions generally offered only a small advantage from the viewpoint of improving solubility because of the decrease in the solubilization capacity of the micelles.     

Solubility and stability of curcumin in solutions containing alginate and other viscosity modifying macromolecules. Studies of curcumin and curcuminoids. XXX

The solubility, chemical- and photochemical stability of curcumin in aqueous solutions containing alginate, gelatin or other viscosity modifying macromolecules have been investigated in order to obtain an alternative to the use of surfactants or cyclodextrins. The solubility of curcumin in aqueous solution at pH 5 increased by a factor > or = 10(4) in the presence of 0.5% (w/v) alginate (various qualities) or gelatin compared to plain buffer, while propylene glycol alginate ester, cesapectin and sodium carboxymethyl cellulose did not have a similar solubilizing effect. The solubilization was slightly influenced by pH, ionic strength and type and concentration of buffer salts. The macromolecules do, however, not stabilize towards hydrolytic- or photolytic degradation of curcumin.     

Molar solubility of felodipine in different aqueous systems

The molar solubility of felodipine in water was calculated and experimentally determined. A polyoxyethylene-polyoxypropylene block copolymer (Synperonic T304) and sodium lauryl sulfate as surfactants and ethanol as cosolvent were used as solubilizing agents. Significantly different molar solubilities were determined for felodipine according to the approach used to achieve solubilization. Such differences are the result of the different mechanisms of solubilization of the additives.     

The preservation of Lanette Wax Cream (FNA)

Factors influencing the free concentration methylparaben in Lanette Wax Cream (fna) were studied. These factors are the partitioning of the preservative between oil and water phase and solubilisation by the micelles of emulsifier, sodium lauryl sulphate. Solubilisation could be described as simple partitioning provided that the free concentration of methylparaben did not exceed 0.1% (w/v). The influence of propylene glycol on partitioning and solubilisation was also studied. Microbiological studies were performed on five creams differing only in preservative system viz. 0.2% and 0.4% methylparaben, 20% propylene glycol, 0.4% methylparaben + 20% propylene glycol, and 0.15% sorbic acid. A formulation containing 0.15% sorbic acid was preferred.     

The effect of sorption promoters on percutaneous permeation of a model zwitterion baclofen

In vitro percutaneous penetration of baclofen, a model zwitterion, in the presence of penetration enhancers was investigated to better characterize a porous polar pathway of diffusion across the stratum corneum. The following sorption promoters were studied: DMSO, urea, propylene glycol (PG), sodium lauryl sulphate (SLS), ethanol 95%, Azone, oleic acid (OA) and OA/PG system. No significant increase of penetration or skin accumulation of baclofen was observed when DMSO, urea, PG, Azone or OA were used. The presence of SLS or OA/PG in the vehicle resulted in high penetration rates and uptake of baclofen but this effect was observable only after 30 h and was accompanied with signs of the barrier damage. Ethanol 95% was the only vehicle which promoted baclofen penetration despite its lower solubility in this solvent which is attributed to new pore formation. Penetration rate and skin accumulation of the zwitterion depend on its solubility in the vehicle.     

Simultaneous solubilization of steroid hormones II: androgens and estrogens.

The simultaneous solubilization of some androgens and estrogens in aqueous polysorbate 40, tetradecyltrimethylammonium bromide, and sodium lauryl sulfate was studied. The solubilizations of estradiol and testosterone were independent of each other in all three association colloids. However, if the estrogen component was ethinyl estradiol, the solubilization was dependent on the addition order. The estrogen precipitates more readily than testosterone in polysorbate 40 and tetradecyltrimethylammonium bromide, but the opposite is true in sodium lauryl sulfate. The simultaneous solubilizations of methyltestosterone or ethisterone with the estrogens tested were different from those of testosterone. The solubilization behavior of the steroids is discussed, starting with the pseudophase model and different solubilization loci. Results indicated that the free energy change of micellar binding, delta Gb, decreases with increased steroid polarity. The simultaneous solubilization cannot be predicted by delta Gb but may be explained by differences in the solubilization mechanism.     

Physicochemical characterization of tacrolimus-loaded solid dispersion with sodium carboxylmethyl cellulose and sodium lauryl sulfate

To develop a novel tacrolimus-loaded solid dispersion with improved solubility, various solid dispersions were prepared with various ratios of water, sodium lauryl sulfate, citric acid and carboxylmethylcellulose-Na using spray drying technique. The physicochemical properties of solid dispersions were investigated using scanning electron microscopy, differential scanning calorimetery and powder X-ray diffraction. Furthermore, their solubility and dissolution were evaluated compared to drug powder. The solid dispersion at the tacrolimus/CMC-Na/sodium lauryl sulfate/citric acid ratio of 3/24/3/0.2 significantly improved the drug solubility and dissolution compared to powder. The scanning electron microscopy result suggested that carriers might be attached to the surface of drug in this solid dispersion. Unlike traditional solid dispersion systems, the crystal form of drug in this solid dispersion could not be converted to amorphous form, which was confirmed by the analysis of DSC and powder X-ray diffraction. Thus, the solid dispersion system with water, sodium lauryl sulfate, citric acid and CMC-Na should be a potential candidate for delivering a poorly water-soluble tacrolimus with enhanced solubility and no convertible crystalline.     

The enhancement effect of surfactants on the penetration of lorazepam through rat skin

Lorazepam is an anxiolytic, antidepressant agent, having suitable feature for transdermal delivery. The percutaneous permeation of lorazepam was investigated in rat skin after application of a water:propylene glycol (50:50%v/v). The enhancing effects of various surfactants (sodium lauryl sulfate (SLS), cetyltrimethylammonium bromide (CTAB), benzalkonium chloride or Tween 80) with different concentrations on the permeation of lorazepam were evaluated using Franz diffusion cells fitted with rat skins. Flux, K_p, lag time and enhancement ratios (ERs) of lorazepam were measured over 24 h and compared with control sample. Furthermore, lorazepam solubility in presence of surfactants was determined. The in vitro permeation experiments with rat skin revealed that the surfactant enhancers varied in their ability to enhance the flux of lorazepam. The permeation profile of lorazepam in presence of the cationic surfactant, CTAB, reveals that an increase in the concentration of CTAB results in an increase in the flux of lorazepam in comparison with the control. But an increase in concentration of CTAB or benzalkounium chloride from 0.5 to 1% w/w or from 1 to 2.5% w/w resulted in a reduction in ER, respectively. Benzalkonium chloride which possessed the highest lipophilicity (log P=1.9) among cationic surfactants provided the greatest enhancement for lorazepam flux (7.66-fold over control) at 1% w/w of the surfactant. CTAB (log P<1) and sodium lauryl sulphate at a concentration of 5% w/w (the highest concentration) exhibited the greatest increase in flux of lorazepam compared with control (9.82 and 11.30-fold, respectively, over control). This is attributed to the damaging effect of the cationic and anionic surfactants on the skin at higher concentration. The results also showed that the highest ER was obtained in presence of 1% w/w surfactant with the exception of SLS and CTAB. The increase in flux at low enhancer concentrations is normally attributed to the ability of the surfactant molecules to penetrate the skin and increase its permeability. Reduction in the rate of transport of the drug present in enhancer systems beyond 1% w/w is attributed to the ability of the surfactant molecules to form micelles and is normally observed only if interaction between micelle and the drug occurs.     

In vitro permeation of diclofenac sodium from novel microemulsion formulations through rabbit skin

In order to increase topical penetration of the nonsteroidal anti‐inflammatory drug, diclofenac sodium, new microemulsion formulations were prepared to increase drug solubility and in vitro penetration of the drug. The influence of dimethyl sulfoxide and propylene glycol were also investigated as enhancers on the in vitro penetration of diclofenac sodium using Franz diffusion cells using excised dorsal rabbit skin. Factorial randomized design was performed to analyze the results of in vitro permeation studies. Microemulsions prepared with isopropyl alcohol were superior to those prepared with propanol. Enhancers had different effects depending on the formulation. Propylene glycol was superior to dimethyl sulfoxide when incorporated into isopropyl alcohol microemulsion, whereas dimethyl sulfoxide was superior to propylene glycol in propanol microemulsions. There were no observable histopathological differences between the skin of the control group and the treated groups at the light microscope level due to swelling of the skin tissue. The present study shows that microemulsion formulations containing isopropyl alcohol as co‐surfactant and propylene glycol as enhancer represent a promising approach for a topical vehicle for diclofenac sodium. Drug Dev. Res. 65:17–25, 2005. © 2005 Wiley‐Liss, Inc.     

Hydrotropic solubilization of nimesulide for parenteral administration

Nimesulide is a non-steroidal anti-inflammatory drug (NSAID) that exhibits analgesic, antipyretic and anti-inflammatory activities. It is practically insoluble in water. The effect of various hydrotropes such as nicotinamide, sodium ascorbate, sodium benzoate, sodium salicylate and piperazine on the solubility of nimesulide was investigated. The solubility enhancement of nimesulide by the hydrotropes was observed in decreasing order as piperazine > sodium ascorbate > sodium salicylate > sodium benzoate > nicotinamide. In order to elucidate the probable mechanism of solubilization, various solution properties of hydrotropes such as viscosity, specific gravity, surface tension, refractive index, specific conductance of hydrotropic solutions were studied at 25 +/- 2 degrees C on the basis of earlier studies. The hydrotropic solubilization of nimesulide at lower hydrotrope concentration may be attributed to weak ionic interactions while that at higher hydrotrope concentration may be due to molecular aggregation. Parenteral formulations using piperazine as a hydrotrope were developed and studied for physical and chemical stability.