Comparison of impact of the different hydrophilic carriers on the properties of piperazine-containing drug.

The objective of this study was to determine the impact of a series of nonionic surfactants on the solubility of piperazine-containing drug (meclizine, MZ) in comparison to that of natural cyclodextrins (alpha-CD and beta-CD) and dimethyl-beta-cyclodextrin (DM-beta-CD). The solubility of the drug was studied in either CDs solutions or nonionic surfactant solutions. Three classes of nonionic surfactants were used namely; polyoxyethylene (POE) sorbitan fatty acid esters (polysorbates), POE fatty acid esters (Myrjs) and polyethylene oxide (PEO) fatty alcohol ethers (Brijs and Eumulgins). The solubility of MZ was increased linearly with the increasing surfactant concentration, indicating that micellar solubilization follows the partition model. It was found that the longer the hydrocarbon chain in a homologous series, the more efficient is the solubilizing power of surfactant. For example, polysorbate 80 (Tween-80) is a more efficient solubilizer than polysorbate 20 (Tween-20), indicating that the drug was incorporated in the core of micelle more than the capsular region of the micelle. On the other hand, in case of POE fatty acid esters, the solubilizing power increased with decreasing polyoxyethylene chain as Myrj 53 was more efficient than Myrj 59. In class of PEO fatty alcohol ethers, the shorter the hydrophilic chain and longer lipophilic chain, the more efficient was the solubilizing capacity. Thus, Brij 58 was more efficient solubilizer than Brij 35 and Eumulgin C1000 was more active than Eumulgin C1500. Comparatively, Eumulgin C1000 had the highest solubilizing power for MZ among the studied PEO fatty alcohol ethers and other groups of surfactants. The solubility action of surfactants toward MZ was increased by raising the temperature of the surfactant solutions from 30 to 45 degrees C. Hydrophilic macromolecules (PEG 1000 and PEG 6000) or cosolvents (glycerol and propylene glycol) have a very slight effect on the solubility of MZ and confirm the predominance of hydrophobic interaction between the drug and nonionic surfactants. A(L)-type phase solubility diagrams were obtained for the drug with alpha-, beta- and DM-beta-CDs showing that the solubility of MZ was enhanced through inclusion complexation. Comparatively, DM-beta-CD had the highest solubilizing efficiency for the drug among the investigated CDs, which could be attributed to its larger hydrophobic cavity size.     

Effect of structural variations of non-ionic surfactants on micellar properties and solubilization: surfactants with semi-polar hydrophobes

Novel non-ionic surfactants have been synthesized in which a polar group (either an ether or a keto group) has been introduced into the hydrocarbon chain of an octadecylpolyoxyethylene glycol monoether (C18En) with an oxyethylene chain length, n, of 17-18 units. Light scattering studies have indicated aggregation numbers for these semi-polar surfactants in aqueous solution of between 55-65% of that of an unsubstituted octadecylpolyoxyethylene glycol monoether, C18E22. The solubilizing capacities of the semi-polar surfactant micelles for test compounds which were mainly solubilized at the polyoxyethylene/core interface were lower than those of C18E22 whilst solubilizates which exhibited a reasonable degree of solubility in both the interface and the micellar core showed an increased solubilization.     

Study of the solubilization of gliclazide by aqueous micellar solutions

It was of interest to increase the solubility of gliclazide in aqueous media. Therefore, solubilization of gliclazide in a variety of surfactants was investigated. Anionic and cationic surfactants exhibited dramatic solubilizing ability for gliclazide, whereas nonionic surfactants showed significantly lower solubilizing ability. It was found that gliclazide solubility increases with increasing the carbon chain length of cationic surfactants and decreases with increasing the carbon chain length of anionic surfactants. The solubilization data were analyzed on the basis of a pseudo-phase model with gliclazide exhibiting moderate partition coefficients into the micellar phase. The possible sites of solubilization of gliclazide in the micelle were examined by studying the effect of NaCl on solubilization and by comparing the absorption spectra of gliclazide in different solvents. The results obtained from these two experiments indicated that gliclazide is solubilized mainly in the inner core of the cationic surfactant micelles and in the outer regions of the anionic surfactant 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.     

The hydrolysis of indomethacin in aqueous solutions of polysorbates

The effect of surfactants on the rate of hydrolysis of indomethacin is reported for homologous series of polyoxyethylene (20) sorbitan fatty acid esters (polysorbates). The degradation of the solubilized drug follows a first-order process in which the rate decreases with the increasing surfactant concentration. The increasing length of hydrophobic chain of surfactant molecule has little effect on the rate of reaction. The solubilized solutions of indomethacin can be stored for at least one year. The influence of pH on the solubilizing power of polysorbate 80 is also studied.     

Solubilization of valsartan by aqueous glycerol, polyethylene glycol and micellar solutions

To increase the solubility of valsartan in aqueous solutions was considered of interest. This study therefore investigated the solubilization of valsartan by cosolvency and micellization. Of the solubilization agents used, sodium lauryl sulfate was found to be the most effective. The increase in solubility at the maximum concentration studied was in the following order: sodium lauryl sulfate > polysorbate-80 > polyethylene glycol 400 > glycerol. The effect of propylene glycol on the solubility of valsartan in a 2% w/v polysorbate-80 solution was also investigated and was found that propylene glycol decreased the solubilizing power of polysorbate-80 at the concentrations studied.     

Polysorbates 20 and 80 used in the formulation of protein biotherapeutics: structure and degradation pathways

Polysorbates 20 and 80 (Tween 20 and Tween 80) are used in the formulation of biotherapeutic products for both preventing surface adsorption and as stabilizers against protein aggregation. The polysorbates are amphipathic, nonionic surfactants composed of fatty acid esters of polyoxyethylene sorbitan being polyoxyethylene sorbitan monolaurate for polysorbate 20 and polyoxyethylene sorbitan monooleate for polysorbate 80. The polysorbates used in the formulation of biopharmaceuticals are mixtures of different fatty acid esters with the monolaurate fraction of polysorbate 20 making up only 40-60% of the mixture and the monooleate fraction of polysorbate 80 making up >58% of the mixture. The polysorbates undergo autooxidation, cleavage at the ethylene oxide subunits and hydrolysis of the fatty acid ester bond. Autooxidation results in hydroperoxide formation, side-chain cleavage and eventually formation of short chain acids such as formic acid all of which could influence the stability of a biopharmaceutical product. Oxidation of the fatty acid moiety while well described in the literature has not been specifically investigated for polysorbate. This review focuses on the chemical structure of the polysorbates, factors influencing micelle formation and factors and excipients influencing stability and degradation of the polyoxyethylene and fatty acid ester linkages.     

Solubilization of flavopiridol by pH control combined with cosolvents, surfactants, or complexants.

This study investigates the roles of both ionized and un-ionized species of flavopiridol in solubilization by complexation, micellization, and cosolvency. Control of pH was used in combination with surfactants (polysorbate 20 and polysorbate 80), cosolvents (ethanol and propylene glycol), as well as uncharged and anionic complexing agents [hydroxypropyl beta-cyclodextrin (HPbetaCD) and sulfobutyl ether beta-cyclodextrin (SBEbetaCD)] to solubilize flavopiridol. These combined techniques increase not only the solubility of the un-ionized flavopiridol but also the solubility of the ionized drug. This study confirms that previously developed equations effectively characterize the roles of pH, pK(a), and either complexation constant, micelle partition coefficient, or cosolvent solubilizing power in determining drug total aqueous solubility.     

Solubilization of rapamycin

The solubilization of rapamycin, a poorly water soluble investigational immunosuppressive drug, by facilitated hydrotropy is presented. Partially water-miscible aromatic solutes (such as benzyl alcohol, benzoate, or benzoic acid) can be solubilized by water-miscible cosolvents, such as ethanol and propylene glycol. Once solubilized, the partially miscible aromatic solute becomes a solubilizing agent. This technique yielded a dramatic (>1000-fold) increase in the aqueous solubility of rapamycin.     

Solubilization of the lichen metabolite (+)-usnic acid for testing in tissue culture

The pharmacological testing of natural products can often be hampered by the poor solubility of such compounds in non-toxic solvents. There is thus a need for a suitable agent for solubilization of natural substances to allow testing on a variety of cell lines in-vitro. Such an agent should ideally have no direct effects on any of the commonly used cell lines from a variety of tissues and mammalian species to allow proper comparison. In this study, the lichen metabolite (+)-usnic acid, a dibenzofuran derivative, was used as a prototype for an insoluble natural product with the aim of finding a solvent that was both capable of solubilizing usnic acid and was free of direct activity against a test cell line. Solubilization was measured at different pH values in various concentrations of co-solvents (glycofurol 75, propylene glycol, polyethylene glycol 400), surfactants (polysorbate 20 and Cremophor RH40), and the complexing agent 2-hydroxypropyl-beta-cyclodextrin. The solubility achieved in a 20% aqueous solution was 0.11 mg mL(-1) for propylene glycol, 0.19 for PEG 400, 0.27 for glycofurol 75, 0.57 for Cremophor RH40, 0.68 for 2-hydroxypropyl-beta-cyclodextrin and 0.84 for polysorbate 20. The direct effects of the various solvent systems were tested on the human leukaemia cell line K-562 in a standard proliferation assay. Most of the solvents proved toxic with the exception of propylene glycol, PEG 400 and 2-hydroxypropyl-beta-cyclodextrin. Anti-proliferative activity of usnic acid could be demonstrated with an ED50 (amount of substance required to reduce thymidine uptake to 50% of uptake by untreated control culture) of 4.7 microg mL(-1) using PEG 400 and 2-hydroxypropyl-beta-cyclodextrin but only the latter gave satisfactory solubility. 2-Hydroxypropyl-beta-cyclodextrin was thus identified as a solubilizing agent that fulfilled both set criteria of solubility and lack of toxicity against the test cells.     

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.     

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.     

Some considerations about the hydrophilic-lipophilic balance system

The methods and results obtained by Griffin et al. in the determination of the hydrophilic-lipophilic balance (HLB) values of non-ionic surfactants and of required HLB values of oil mixtures are reviewed in the present work. HLB values published by Griffin were compared with those obtained by calculations from theoretic chemical formulas. Griffin HLB values of polyoxyethylene alkyl ethers, polyoxyethylene monoesters and propylene glycol monoesters coincide with those obtained from such theoretical chemical formulations. These results demonstrate that, for these surfactants, Griffin did not experimentally obtain their HLB values, but instead calculated them from theoretic formulae. For the calculation of the HLB values of glycerol monostearate, sorbitan fatty acid esters and polyoxyethylene sorbitan fatty acid esters, Griffin's assumptions were possibly based upon the mean saponification values of the ester and the acid of the fatty acid. It is concluded that the HLB values of non-ionic surfactants were not rigorously defined. Moreover, Griffin could not demonstrate the validity of the assumption that individual required HLB values can be added up to obtain the overall required HLB value of an oil mixture. The HLB and required HLB values published by Griffin should only be taken as approximate guidelines.     

Development of parenteral formulations and evaluation of the biological activity of the trypanocide drug benznidazole

Chagas disease, caused by Trypanosoma cruzi, is a major public health problem in Latin America. According to the World Health Organization, around 20 million people are infected and another 40 million are at risk of acquiring the disease. One of the drugs most frequently used for the treatment of Chagas disease is benznidazole (BZL). It is practically insoluble in water (0.4 mg/ml), which precludes the preparation of liquid dosage forms, in particular, parenteral formulations. Thus, the aim of this work was to investigate the solubilization of BZL at two pH values using various cosolvents such as ethyl alcohol, propylene glycol, polyethylene glycol 400, benzyl alcohol, diethylene glycol monoethyl ether (Transcutol) and surfactants such as polysorbates (Tween) 40 and 80, and sodium dioctyl sulfosuccinate (AOT). Solvent systems based on PEG 400, with the addition ethyl alcohol and/or potassium biphthalate buffer solution, increased the BZL solubility up to 10 mg/ml. These alcoholic vehicles showed no toxicity against parasite when assayed at 1%. Physical and chemical stability studies showed that the formulations were stable for at least 1.5 years. In agreement with the biological activity results, the selected formulations are suitable for further clinical studies. Moreover, increasing the aqueous solubility of BZL reduced the problems in vitro testing techniques and bioassays leading to more reliable results and/or reproducibility.     

Correlation between epithelial toxicity and surfactant structure as derived from the effects of polyethyleneoxide surfactants on caco-2 cell monolayers and pig nasal mucosa

The cell toxic effects of nonionic surfactants were investigated by means of two in vitro models, namely pig nasal mucosa mounted in horizontal Ussing chambers, and Caco-2 cell monolayers. A series of homologous polyethyleneoxide (PEO) surfactants with a wide span in hydrophilic head-group size and hydrophobic chain lengths were screened for concentration-dependent effects on the transepithelial electrical resistance (TEER) and mannitol permeability across Caco-2 cell monolayers. Trends in effects on permeability in the presence of increasing surfactant concentration coincided with the effects seen on TEER. Correlation of surfactant molecular structure with cell toxicity showed the size of the PEO group to be a more critical parameter than the size of the hydrocarbon chain. More specifically, the presence of very long PEO groups (>30 EO units) were found to lead to a decrease in cell toxicity. Similar trends were observed in the studies of the effects of PEO surfactants on pig nasal mucosa mounted in horizontal Ussing chambers. However, the nasal mucosa was somewhat more tolerant towards high surfactant concentrations than the Caco-2 cells. The relation between surfactant molecular structure and cell toxic effects is discussed in terms of micellar surface adsorption and micellar solubilization. The effect of the surfactants on the solubility of budesonide was investigated at two different surfactant concentrations (0.01 and 1 mg/mL). At the lower concentration, the solubilizing capacity of all of the surfactants was marginal, and there was no correlation between solubilizing capacity and cmc. At the higher concentration, on the other hand, all surfactants substantially increased the solubility of budesonide. The C18 PEO-ester with 40 EO units in the head group was found to be an efficient micellar solubilizer for budesonide, without causing adverse effects on the Caco-2 cell monolayers.     

Improvement of the bioavailability of colchicine in rats by co-administration of D-alpha-tocopherol polyethylene glycol 1000 succinate and a polyethoxylated derivative of 12-hydroxy-stearic acid

Two surface-active formulation ingredients, a water-soluble derivative of vitamin E (D-alpha-tocopherol polyethylene glycol 1000 succinate, vitamin E-TPGS) as well as a polyethoxylated derivative of 12-hydroxy-stearic acid (Solutol HS 15) were investigated in rats for their potential to increase the oral bioavailability of the p-glycoprotein (p-gp) and cytochrome P450 substrate colchicine. D-alpha-Tocopherol polyethylene glycol 1000 succinate and the polyethoxylated derivative of 12-hydroxy-stearic acid will be referred to as "surfactant 1" and "surfactant 2" in the following. Colchicine was administered to the animals at a dose level of 5 mg/kg in each 10% surfactant containing formulation. A solution of colchicine in isotonic saline was selected as a reference formulation. It was found that the administration of colchicine in the surfactant containing formulations resulted in significantly higher systemic exposures as compared to the aqueous reference vehicle (2-fold increase in AUC in the presence of surfactant 1 and 4-fold increase in AUC in the presence of surfactant 2). The aqueous solubility of colchicine was about 16.7 mg/ml, and the increase in solubility in the presence of 1% surfactant 1 or surfactant 2 to about 20.5 and 18.5 mg/ml was not considered to significantly affect the oral bioavailability. In summary, it was demonstrated that both surfactants are suitable formulation ingredients to improve the systemic exposure of colchicine in the rat. Due to the high aqueous solubility of colchicine the most likely reasons for these findings are inhibition of p-gp and/or metabolism as well as permeability enhancement by interactions of the surfactants with the intestinal membrane.     

维生素D2的增溶与稳定性的研究

3种结构类型不同的增溶剂对维生素D₂的增溶效应,聚氧乙烯蓖麻油类大于聚氧乙烯脱水山梨醇脂肪酸酯类及聚氧乙烯脂肪醇醚类。在聚氧乙烯蓖麻油类C-125中维生素D₂的稳定性亦大于其余的两种增溶剂。在吐瘟80胶团中丁基羟基茴香醚主要位于胶团的栅层深部,由于可与维生素D₂处于胶团的相同部位,故较位于栅层浅部及水相之中的没食子酸丙酯,有效地延缓了维生素D₂的自动氧化作用。     

Micellar solubilization of a new antimalarial drug, beta-arteether

beta-Arteether (1) is a new antimalarial drug derived from artemisinin (2, quinghaosu). Compound 1 is quite water insoluble, but very soluble in a variety of organic solvents. Solubilization in a variety of surfactants was investigated to obtain higher concentrations of 1 in aqueous solutions. Anionic and cationic surfactants exhibited dramatic solubilizing ability for 1, while nonionic surfactants showed significantly lower solubilizing ability. The solubilization data are analyzed on the basis of a pseudo-phase model with 1 exhibiting a high partition coefficient into the micellar phase. An empirical model is presented to identify the possible sites of solubilization of 1 in the micelle.     

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.