Solubilization of indomethacin by polysorbate 80 in mixed water-sorbitol solvents

The effect of indomethacin on the micellar properties of the non-ionic surfactant, polysorbate 80, in water-sorbitol mixtures containing up to 25% w/v sorbitol has been investigated by light scattering, photon correlation spectroscopy and viscometric techniques. The molecular weight of polysorbate 80 micelles containing solubilized indomethacin increased linearly with increase of sorbitol concentration. Solubilization of indomethacin resulted in an increase of micellar weight due not only to the incorporation of solubilizate but also to an increase in the number of polysorbate molecules per micelle. The micelles in all systems were most satisfactorily represented as oblate ellipsoids, the asymmetry and hydration of which increased with increase of sorbitol concentration. Indomethacin solubilization caused a restructuring of the micelle to produce a more symmetrical micelle of increased hydration.     

INDUCED HELICAL CONFORMATION OF IONIC POLYPEPTIDES BY PHOSPHOLIPIDS SOLUBILIZED IN A NONIONIC SURFACTANT SOLUTION

Phosphatidylcholine that has been solubilized in hexadecylpoly (oxyethylene) ether can induce a coil-to-helix transformation for poly(l -glutamic acid) in neutral solution. Similarly, solubilized phosphatidylserine promotes a helical conformation of poly(l -lysine) at neutral pH through complex formation. The mixed micelles of a phospholipid and a nonionic surfactant are thermodynamically stable and do not separate on standing. The nonionic surfactant here has no effect on the conformation of the two polypeptides.     

Effect of micellar solubilization on the gastrointestinal absorption of indomethacin in the rat

The absorption of indomethacin used as a test substance from the micellar polysorbate 80 solution was investigated and compared with that in the true solution, solutions in 60% PEG 400 and suspension. All liquid formulations were tested at different pH values comprising the range at which the indomethacin molecule was unionized (pH 2), partly ionized (pH 4) and completely ionized (pH 8). The concentration of surfactant added was 5% and 10%.The availability parameters (AUC_o^∞, C_max, T_max) were calculated for all formulations investigated. The values of the area under the serum concentration-time curve show that the presence of surfactant does not retard absorption of drug. The enhancement of maximum serum concentration (C_max) is particularly distinct in case of ionized forms of indomethacin. Two-fold increase of surfactant concentration has practically no effect on the availability parameters.     

Dissolution of a poorly water-soluble drug dry coated with magnesium and sodium stearate

The purpose of this research was to investigate the influence of dry coating micronized cohesive powders of a poorly water-soluble drug, indomethacin with force control agents, on its dissolution performance. A dry mechanical fusion method (mechanofusion) was used to coat indomethacin powders with magnesium stearate (0.25%, 1%, 5%) and sodium stearate (5%). After mechanofusion, significantly increased bulk and tapped densities and decreased intrinsic cohesion were observed for all samples. X-ray photoelectron spectroscopy analysis confirmed that a thicker magnesium stearate surface coating was achieved with increasing concentrations of the material. Dissolution was studied using the USP paddle method in buffer pH 5.0; several modelling approaches were used to explore the dissolution mechanisms. Whilst the bi-exponential equation represented dissolution of mechanofused indomethacin powders occurring from dispersed and agglomerated particles, it provided unrealistic parameter estimates for the two coating materials of contrasting properties. Initial increases in indomethacin dissolution were dependent on the concentration of magnesium stearate mechanofused onto the drug powders. The dissolution enhancing effect of indomethacin powders mechanofused with 5% sodium stearate was attributed to its surfactant properties that increased dispersion of indomethacin agglomerates. Initial drug release from the coated powders was described by a matrix-diffusion system according to the Higuchi model.     

Buffer controlled release of indomethacin from ethylcellulose microcapsules

The rate of release of indomethacin from ethylcellulose microcapsules prepared by coacervation was studied using internal buffer, dibasic sodium phosphate (DSP), to increase the solubility of the core. The dissolution rate of the drug was determined in phosphate buffer solutions of varying pH and concentration. The role of the stagnant diffusion layer at the microcapsule surface was also evaluated by changing the mixing in the dissolution test. Indomethacin release was accelerated considerably with increasing amounts of DSP in the core. DSP increases the pH inside the microcapsules, thus enhancing the release of the acidic drug. Increasing bulk solution pH increased the release rate of indomethacin, the enhancing effect being more pronounced with buffered microcapsules. Neither increasing phosphate concentration of the bulk solution nor increasing mixing of the microcapsules influenced the rate of release of indomethacin from unbuffered capsules. With buffered capsules the increase in phosphate concentration of bulk solution prevented leaching out of internal phosphate increasing the release rate of indomethacin. The release of indomethacin also accelerated slightly with increasing mixing.     

Effect of fatty acid Esters on permeation of ketoprofen through hairless rat skin

Twelve medium to long chain fatty acid Esters (Esters), the total number of carbon atoms of which ranged from 17 to 34, were used to study the effect of the vehicle on the permeation of ketoprofen, and the effect was compared with the case of indomethacin. The solubility of ketoprofen was higher in Esters with a smaller number of carbon atoms. The permeation rate of ketoprofen from the Ester suspension through excised hairless rat skin was proportional to its solubility in the suspension, which was the same in the case of indomethacin. The diffusion constant and partition coefficient were calculated using the computer program MULTI(FILT). The diffusion constant decreased with increasing number of carbon atoms, and the partition coefficient was increased with increasing number of carbon atoms, in both cases of ketoprofen and indomethacin. Esters also penetrated the skin with the concentration of about 10 mg/g, independent of the number of carbon atoms. The Esters in the skin increase the diffusion rate of the drugs, especially in the case of Esters with a small number of carbon atoms. Also the drug solubility in the skin was improved, although the effect was similar for the range of Esters investigated in the present study. Then the permeation rate of ketoprofen and indomethacin increased.     

The Influence of Detergents on Skin Barrier Properties

Abstract: The influence of surfactants on the changes in skin barrier properties was investigated in rats. Various ionic and non-ionic surfactants were assessed using indomethacin as a model penetrant. The surfactants appeared to either increase or decrease the skin permeability, due to the properties of both compound and surfactant. Ionic surfactant sodium dodecylsulfate was the most powerful and exceeded controls by approximately 10 times measured by means of serum levels of indomethacin. Other surfactants caused concentration increase or decrease of indomethacin in serum.     

Microemulsion: a novel transdermal delivery system to facilitate skin penetration of indomethacin

In this study, we aimed to develop thermodynamically stable microemulsion formulations of indomethacin with lower surfactant and cosurfactant contents, to improve drug permeability. Formulations were based on the oil/water microemulsion region of pseudo-ternary phase diagrams. The characteristic parameters (viscosity, diameter, and polydispersity) of the microemulsion formulations were then determined. In vitro permeation studies were performed using Franz diffusion cells. Permeation through mouse skin and skin retention of indomethacin microemulsions and ointment were tested. The cumulative amount of permeated indomethacin and its skin retention were significantly higher in microemulsion formulations compared with ointment. Drug flux and skin retention improved with decreasing droplet diameter of the microemulsions. On the basis of these results, we suggest some possible mechanisms for the enhanced transdermal permeation of drugs in microemulsions, including high drug-loading capacity, permeation enhancement by surfactants and cosurfactants, and smaller droplet diameter. In conclusion, microemulsions represent a novel transdermal delivery vehicle for increasing the solubility and permeability of indomethacin.     

Effect of quercetin, caffeic acid and caffeic acid phenylethyl ester, solubilized in non-ionic surfactants, on histamine release in vivo and in vitro

A practical hindrance in using many therapeutic agents is their limited solubility in aqueous matrixes. This is usually overcome by incorporating the active compounds in a matrix, with the aid of a non-ionic surfactant. Three water-insoluble natural polyphenols with inherent biological activity, quercetin (CAS 117-39-5), caffeic acid and caffeic acid phenylethyl ester, were solubilized in water, with the aid of Tween 80 (an esterified and polyethoxylated derivative of sorbitan), Solutol HS15 (a polyethoxylated derivative of 12-hydroxy-stearic acid), Cremophor RH40 (a ricinoleic acid derivative) or Cremophor EL and the effect of the solubilized polyphenols on histamine release was studied in vitro (mast cells) and in vivo in the rat. In vivo Cremophor EL alone increased, and Tween 80 decreased histamine plasma levels. All four groups injected with solubilized quercetin exhibited a decrease in their plasma histamine levels. Caffeic acid solubilized in Cremophor RH40 decreased histamine levels, too. In vitro Tween 80 increased histamine release in a dose-dependent mode. Quercetin in vitro inhibited histamine release in all solubilizers used. It is concluded that the ability of the studied polyphenols to release histamine is not only depending on the condition of the storage vesicles in the mast cells, but also on the surfactant used to solubilize them.     

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.     

The Effect of Surfactant and Solid Phase Concentration on Drug Aggregates in Model Aerosol Propellent Suspensions

The effect of increasing solid phase concentration on the morphology and flocculation rate of model aerosol suspensions has been investigated. Suspensions of micronized salbutamol sulphate and lactose in trichlorotrifluoroethane (P113) were studied under conditions of increasing shear stress. By use of image analysis techniques, measurement of aggregate size, fractal dimension and rate of aggregation was performed. The effect of the surfactant sorbitan monooleate on morphology and flocculation rate was also studied. Increased solid phase concentration caused an increase in the rate of aggregation and average aggregate size at a given value of shear stress. Surfactant addition retarded the aggregation rate, and caused a shift from a diffusion-limited cluster aggregation to a reaction-limited cluster aggregation mechanism. The aggregate profiles showed a corresponding change from rugged and crenellated without surfactant, to increasingly smooth and Euclidian with increasing surfactant concentration. The morphological changes were characterized by a decrease in the average boundary fractal dimension which also correlated well with the corresponding reduction in aggregation rate.     

Preservation of solubilized and emulsified systems I: Correlation of mathematically predicted preservative availability with antimicrobial activity.

Mathematical models were investigated for the distribution and antimicrobial activity of chlorocresol in solubilized and emulsified systems stabilized with a nonionic surfactant. The concentration of free preservative in the solubilized systems was described adequately by an equation widely used to describe the binding of small molecules to macromolecules. For the emulsions, this equation was combined with an expression for the partitioning of the preservative between the oil and water phases. It was confirmed that short-term antimicrobial activity can be related to the free (unbound) preservative concentration in the aqueous phase and that preservative solubilized within the surfactant micelles or partitioned into the oil phase does not contribute to short-term preservation.     

Stability of indomethacin solubilized system.

Physical and chemical stability testing was carried out for indomethacin in the form of solution, syrup and elixir solubilized by Tween 80 and Brij 99. It was found that sucrose and alcohol markedly stabilize the indomethacin solution.     

Solubilization of indomethacin using hydrotropes for aqueous injection.

Indomethacin 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 urea, nicotinamide, resorcinol, sodium benzoate and sodium p-hydroxy benzoate on the solubility of indomethacin was investigated. The solubility enhancement of indomethacin by the hydrotropes was observed in decreasing order as sodium p-hydroxy benzoate>sodium benzoate>nicotinamide>resorcinol>urea. In order to elucidate the probable mechanism of solubilization, various solution properties of hydrotropes such as viscosity, specific gravity, surface tension, refractive index and specific conductance of hydrotropic solutions were studied at 25+/-2 degrees C. Each solubilized product was characterized by ultraviolet, infrared, powder X-ray diffraction and differential scanning calorimetry techniques. The hydrotropic solubilization of indomethacin at lower hydrotrope concentration may be attributed to weak ionic interactions while that at higher hydrotrope concentration may be due to molecular aggregation. Aqueous injectable formulations using sodium p-hydroxy benzoate, sodium benzoate and nicotinamide as hydrotropes were developed and studied for physical and chemical stability.     

介孔二氧化硅微球的制备及用于吲哚美辛载药与溶出性质

目的制备介孔二氧化硅微球,以期提高吲哚美辛的溶出速率。方法以表面活性剂十六烷基三甲基溴化铵和普兰尼克三嵌段共聚物P123作为双模板,用软膜板法制备具有介孔孔道的介孔二氧化硅微球药物载体,采用扫描电镜及氮气吸附-脱附手段表征载体形貌、比表面积及孔径分布。用吸附平衡挥干法载药制得吲哚美辛固体分散体,并对该固体分散体的溶出性质进行研究。结果制得的介孔二氧化硅载体由粒径相对均一的球形粒子组成。其粒径主要集中在2～5μm,载体的比表面积为502.87 m²·g2·g^(-1),孔容为2.23 cm(-1),孔容为2.23 cm³·g3·g^(-1),孔径为23.75 nm。吲哚美辛/介孔二氧化硅固体分散体的药物溶出速率与累积溶出度与吲哚美辛原料药相比均有了显著提高。结论吲哚美辛已高度分散于微球载体中,药物的溶出速率明显加快,为提高吲哚美辛生物利用度的研究打下了基础。     

Preparation and characterization of indomethacin magnetic nanoparticles

Nanoparticles of polymethylmethacrylate were prepared by the emulsion polymerization technique. The drug was embedded in the nanoparticles. The controlled growth of ferric hydroxide particles in the presence of non-ionic surfactant was effected to obtain nano-size particles and these were subsequently heated to obtain ferroso-ferric oxide (magnetite). The effect of various parameters, i.e. monomer concentration and magnetite concentration, as well as the stirring rate were studied to characterize the particle size and its distribution. Similarly, the factors which affect the total drug payload were assessed. The magno-responsive indomethacin nanoparticles were successfully prepared.     

Assessment of the percutaneous penetration of indomethacin from soybean oil microemulsion: effects of the HLB value of mixed surfactants

The objective of this study was to evaluate the influence of the ratios or the hydrophile-lipophile balance (HLB) values of Cremophor EL and Span 80 on the phase behavior of the O/W microemulsions and the percutaneous absorption and penetration of indomethacin microemulsions. The existence of microemulsion regions is investigated in quaternary systems composed of soybean oil/Cremophor EL and Span 80 (mixed surfactants)/diethylene glycol monoethyl ether (cosurfactant)/water by constructing pseudo-ternary phase diagrams at various Cremophor EL/Span 80 ratios. In addition, five microemulsion formulations with various mixed surfactants HLB values were evaluated by in vitro penetration experiments using mouse skin and Franz diffusion cells. The flux and amount of indomethacin penetration from 5 microemulsion formulations were significantly different from the control, and the enhance ratios ranged from 2.38 to 4.68 and 2.11 to 4.23, respectively. The HLB value of mixed surfactants in the formulations was a principal factor in determining the percutaneous penetration of the drug. The flux and amount of drug penetration increased gradually with increasing content of the lipophilic surfactant Span 80 and skin retention was highest for mixed surfactants with a HLB value of 7.6. Therefore, it is suggested that the presence of mixed surfactants was beneficial in the formation of O/W microemulsions and enhanced percutaneous penetration of indomethacin.     

Micellar interaction of indomethacin and bile salts

In the previous report, it was confirmed that bue salt micelles display a significantly higher affinity for indomethacin as compared to phenylbutazone in pH 7.3 phosphate buffer at 37°C. The extent of micellar solubilization seemed to be influenced by the nature of the solubilized molecule. The difference between indomethacin and phenylbutazone in micellar interaction was investigated. This difference could not be explained on the basis of the lipid solubility and molal volume. It was suggested that the mechanism responsible for the solubilization of indomethacin may be due to the formation of mixed micelles of the bile salts and the drug. On the other hand, the lower of interaction of phenylbutazone with bile salt micelles can probably be attributed to its carbon acid.     

Enhancement of the dissolution of indomethacin in interactive mixtures using added fine lactose.

The objective of the study was to investigate the effect of fine lactose on the in vitro dissolution of indomethacin in interactive mixtures containing spray-dried lactose and lactose monohydrate (106-250 microm). Dissolution of the indomethacin was measured using an automated dissolution apparatus following the USP paddle method at 100 rpm. The particle size distributions of indomethacin mixtures were measured using a Mastersizer S under non-sink conditions. Data fitted bi-exponential or tri-exponential dissolution models, representing dissolution from dispersed and agglomerated particle distributions. The addition of fine lactose (VMD 3.8+/-0.4 microm) to 20% indomethacin-coarse lactose mixtures resulted in significantly increased rates of dissolution caused by increases in the estimated dissolution rate constants for dispersed particles (Kd) and by de-agglomeration. Agglomerates in the mixture showed little tendency to comminute under shear pressure. De-agglomeration in the dissolution medium was attributed to increased porosity of agglomerates, caused by dissolution of water soluble fine lactose in the agglomerate structure. The median particle size (D50) of the dispersed particle distribution decreased with increasing concentrations of added fine lactose, indicating increasing extents of de-agglomeration, and a good correlation between Kd and (D50)2 resulted for the coarse lactose-based mixtures (R2>0.984).     

A diffusion-ordered NMR spectroscopy study of the solubilization of artemisinin by octanoyl-6-O-ascorbic acid micelles

Artemisinin (QHS) is a natural drug with a very low solubility in water. To improve its availability in hydrophilic media, it was solubilized in micellar dispersions of octanoyl-6-O-ascorbic acid (ASC8), a relatively novel surfactant that combines surface activity with powerful performance as radical scavenger. In this article we report a study based on diffusion-ordered NMR spectroscopy (DOSY) measurements carried out on QHS/ASC8 micellar dispersions. QHS is efficiently solubilized by ASC8 micelles, with no significant perturbation of the micellisation.