The Molecular Weight Dependence of Nasal Absorption: The Effect of Absorption Enhancers

A series of polyethylene glycols (PEGs) ranging in molecular weight from near 600 to over 2000 daltons was used to study the effects of three absorption enhancers (sodium glycocholate, sodium lauryl sulfate, and polyoxyethylene 9 lauryl ether) on the molecular weight permeability profile of the nasal mucosa of the rat. Molecular weight–permeability properties were studied both by following changes in the excretion of the polyethylene glycols as a function of their molecular size and by examining the nasal mucosa for morphologic changes following exposure to the PEG/enhancer mixtures. Each absorption enhancer was found to affect the mucosa and its permeability in a unique manner. At a 1% concentration, sodium glycocholate only slightly affects tissue morphology and does not significantly alter the molecular weight permeability profile of the mucosa. In contrast, 1% sodium lauryl sulfate causes severe alteration of the mucosa and also greatly increases the absorption of both the PEG 600 and the PEG 2000 oligomers. Polyoxyethylene 9 lauryl ether was found to exert its action in a concentration-dependent manner. At a concentration of 0.1%, few changes were seen in either mucosal integrity or permeability. At a 1% concentration, however, a significant alteration in the structure of the mucosal tissues as well as a profound increase in the permeability of the mucosa to the PEGs was observed. Correlation of mucosal integrity with the effectiveness of an enhancer indicates that some of these compounds appear to be acting by altering the structure of the mucosa. Others, which appear to exert a less damaging effect on the mucosal cells themselves, achieve their greatest absorption enhancement when changes in cell-to-cell adhesion in the mucosa are observed. These results indicate that the paracellular routes may play an important role in large molecule absorption through the nasal mucosa.     

Measurement of ileal permeability with different-sized polyethylene glycols (PEG 400, 600, and 1000)

Polyethylene glycols (PEGs; 400, 600, and 1000) were used to study the molecular weight (MW) permeability dependence in the rat ileal mucosa. Absorption of the PEGs was measured by following their recirculation perfusion over a 3 hr collection period. HPLC methods were used to separate and quantitate the individual oligomers present in the solution of PEGs mixtures (MW range 330 to 1122 D). In the range studied, a distinct molecular weight cutoff was not identified. Corrected for the length of ileum used in the study, over the molecular weight range 330 to 1122 D, the apparent permeability (P_app) of PEG ranged from 3.2±0.06×10^?5 cm/sec (mean±SEM, n=7) to 0.1±0.02×10^?5 cm/sec. Also, it was observed that the apparent permeability was inversely proportional to approximately MW^2.4.     

Modulation of intestinal P-glycoprotein function by polyethylene glycols and their derivatives by in vitro transport and in situ absorption studies

We examined the effect of polyethylene glycols (PEGs) with different molecular weights and their derivatives on the intestinal absorption of rhodamine123, a P-glycoprotein (P-gp) substrate, across the isolated rat intestinal membranes by an in vitro diffusion chamber system. The serosal to mucosal (secretory) transport of rhodamine123 was greater than its mucosal to serosal (absorptive) transport, indicating that the net movement of rhodamine123 across the intestinal membranes was preferentially secretory direction. The secretory transport of rhodamine123 was inhibited by the addition of PEGs with average molecular weights of 400, 2000 and 20,000, irrespective of its molecular weight. The inhibitory effects of these PEGs for the intestinal P-gp function were concentration dependent over the range 0.1-20% (v/v or w/v). Similar inhibitory effect for the intestinal P-gp function was observed when PEG derivatives including PEG monolaurate, PEG monooleate and PEG monostearate were added to the mucosal site of the chambers. Furthermore, we also examined effect of PEG20,000 on the intestinal absorption of rhodamine123 by an in situ closed loop method. The intestinal absorption of rhodamine123 was enhanced in the presence of PEG20,000. These findings suggest that PEGs and their derivatives are useful excipients to inhibit the function of intestinal P-gp, thereby improving the intestinal absorption of P-gp substrates, which are secreted by a P-gp-mediated efflux system.     

Pegylated nanoparticles based on poly(methyl vinyl ether-co-maleic anhydride): preparation and evaluation of their bioadhesive properties

Pegylated nanoparticles based on poly(methyl vinyl ether-co-maleic anhydride) (PVM/MA) were prepared by simple solvent displacement method, in the absence of catalysts or specific chemical conditions. Pegylation efficiency increased with the increasing of molecular weight and bulk concentration of poly(ethylene glycols) (PEGs) investigated. In fact, the use of PEG with molecular weight less than 1000 Da did not lead to its attachment. ¹H NMR spectroscopy was performed in order to estimate the conformation state of PEG-chains and to predict the nanoparticle structure. Pegylation with PEG 2000 gave surface modified nanoparticles (“brush” conformation), while the chains of PEG 1000 were distributed either in the core or physically adsorbed on the nanoparticle surface. The capacity of nanoparticles to adsorb mucin at pH 7.4 was significantly higher for PEG 1000-NP than for PEG 2000-NP. The “brush” layer seemed to decrease the interaction between PEG 2000-NP and mucin, which facilitated their penetration through the mucus gel. As a consequence, PEG 2000-NP displayed higher capacity to develop adhesive interactions with rat intestinal mucosa in vivo. Independent on the weaker bioadhesive potential of PEG 1000-NP, both types of pegylated nanoparticles demonstrated very high affinity to the intestinal mucosa rather than to the stomach wall, which could be established for drug targeting to the small intestine.     

Effects of polyethylene glycol molecular weight and concentration on lactate dehydrogenase activity in solution and after freeze-thawing

Lactate dehydrogenase (LDH) is a tetrameric enzyme that has been used as a model for labile protein drugs. Polyethylene glycols (PEGs) have been proposed as excipients to stabilize labile proteins in solution and during the freezing portion of the lyophilization cycle. The aim of this study was to determine the effects of PEG molecular weight and concentration on the activity of LDH. In general, PEG protection increases with PEG molecular weight and concentration. PEGs slow the loss of activity in LDH solutions stored at 4 degrees C, but are not sufficiently effective to allow for a solution product. PEGs 8000, 10,000, and 20,000 show full freezing protection at less than 0.01%, while lower molecular weight PEGs need higher concentrations to produce protection upon freezing. Circular dichroism (CD) studies of LDH solutions before and after freezing with PEG 400 and PEG 8000 confirm the activity studies. The CD spectrum of LDH before freezing shows the classic alpha helix pattern. After unprotected LDH solution is frozen and thawed, the CD spectrum erodes. Low concentrations of PEG 8000 (1% or less) preserve the alpha helix profile after freezing of the samples. PEG 400 preserves the alpha helix CD profile in a stepwise fashion with increasing concentrations. The CD and activity data suggest that PEGs can protect alpha helix structures and activity of LDH through the freezing process.     

低分子肝素纳米脂质体经家兔鼻腔吸收的研究

目的研究低分子肝素 (LMWH)纳米脂质体制剂及其家兔的鼻腔吸收。方法用超声波分散法制备LMWH纳米脂质体 ,以正交实验设计确定最佳制备工艺 ;电镜观察其形态及粒径分布 ,以家兔用药前后血液凝固时间的变化研究其吸收促进作用。结果LMWH纳米脂质体在电镜下为圆形或椭圆形 ,平均粒径为 89.6nm ,包封率为 36 .1% ;家兔用药后血液凝固时间明显延长。结论纳米脂质体对LMWH经鼻黏膜吸收有良好的促进作用     

Study of phase behavior of poly(ethylene glycol)-polysorbate 80 and poly(ethylene glycol)-polysorbate 80-water mixtures

Mixtures of poly(ethylene glycols) (PEGs) with polysorbate 80 are often used to dissolve poorly water-soluble drugs in dosage forms, where polysorbate 80 helps either in enhancing dispersion or in inhibiting precipitation of drugs once the solution is mixed with water. Binary phase diagrams of polysorbate 80 with several low molecular weight PEGs and a ternary phase diagram of polysorbate 80 with PEG 400 and water are presented. Two phases were observed in the binary mixtures when the concentration of PEG 200, PEG 300, PEG 400, or PEG 600 was >55%(w/w). The miscibility of the binary mixtures increases with an increase in temperature; the upper consolute temperatures of PEG 200-polysorbate 80, PEG 300-polysorbate 80, PEG 400-polysorbate 80, and PEG 600-polysorbate 80 mixtures were 100, 85, 75, and 40 degrees C, respectively. The upper consolute temperature of PEG 1000-polysorbate 80 could not be determined because the melting temperature of the mixtures is approximately 40 degrees C and the consolute temperature appeared to be less than this temperature. The decrease in upper consolute temperature with an increase in PEG molecular weight indicated a greater miscibility of the two components. In the ternary system, phase separation of polysorbate 80 was observed when the concentration of PEG 400 was >50-60 % (w/w), possibly because of the high exclusion volume of PEG 400.     

Production of insulin-loaded poly(ethylene glycol)/poly(l-lactide) (PEG/PLA) nanoparticles by gas antisolvent techniques.

Insulin and insulin/poly(ethylene glycol) (PEG)-loaded poly(l-lactide) (PLA) nanoparticles were produced by gas antisolvent (GAS) CO(2) precipitation starting from homogeneous polymer/protein organic solvent solutions. Different amounts of PEG 6000 (0, 10, 30, 50, 100, and 200% PEG/PLA w/w) or concentration of 30% PEG/PLA with PEGs with different molecular weight (MW; 350, 750, 1900, 6000, 10,000, and 20,000) were used in the preparations. The process resulted in high product yield, extensive organic solvent elimination, and maintenance of > 80% of the insulin hypoglycemic activity. Nanospheres with smooth surface and compact internal structure were observed by scanning electron microscopy. The nanospheres presented a mean particle diameter in the range 400-600 nm and narrow distribution profiles. More than 90% of drug and PEG were trapped in the PLA nanoparticles when low MW PEGs were used in the formulation, whereas the addition of high MW PEGs significantly reduced the loading yield. In all cases, in vitro release studies showed that only a little amount of drug was released from the preparations. However, formulations containing low MW PEGs allowed for a slow but constant drug release throughout 1500 h, whereas a burst was obtained by increasing the PEG MW. In conclusion, the GAS process offers a mean to produce protein-loaded nanoparticles possessing the prerequisites for pharmaceutical applications. The PEG added to the formulation was found to play a key role in the simultaneous solute precipitation phenomena and in determining the release behavior and the chemical-physical properties of the formulation.     

Enhancement of Nasal Absorption of Insulin Using Chitosan Nanoparticles

Purpose. To investigate the potential of chitosan nanoparticles as a system for improving the systemic absorption of insulin following nasal instillation. Methods. Insulin-loaded chitosan nanoparticles were prepared by ionotropic gelation of chitosan with tripolyphosphate anions. They were characterized for their size and zeta potential by photon correlation spectroscopy and laser Doppler anemometry, respectively. Insulin loading and release was determined by the microBCA protein assay. The ability of chitosan nanoparticles to enhance the nasal absorption of insulin was investigated in a conscious rabbit model by monitoring the plasma glucose levels. Results. Chitosan nanoparticles had a size in the range of 300–400 nm, a positive surface charge and their insulin loading can be modulated reaching values up to 55% [insulin/nanoparticles (w/w): 55/100]. Insulin association was found to be highly mediated by an ionic interaction mechanism and its release in vitro occurred rapidly in sink conditions. Chitosan nanoparticles enhanced the nasal absorption of insulin to a greater extent than an aqueous solution of chitosan. The amount and molecular weight of chitosan did not have a significant effect on insulin response. Conclusions. Chitosan nanoparticles are efficient vehicles for the transport of insulin through the nasal mucosa.     

Solidification Studies of Polyethylene Glycols,Gelucire 44/14 or their Dispersions with Triamterene or Temazepam

The solidification of polyethylene glycols (PEG 1500, PEG 2000, PEG 4000, PEG 6000), gelucire 44/14 or their dispersions containing triamterene or temazepam were studied to assess the feasibility of using these dispersions to liquid-fill hard gelatin capsules. Solidification from melts, investigated by differential scanning calorimetry using cooling cycles, showed a tendency of the drugs, carriers or their dispersions to supercool. The degree of supercooling depended on the rate of cooling, the drug content and, for the PEGs, on the molecular weight. PEG 1500 and PEG 2000 gave one morphological form, irrespective of cooling rate; PEG 4000 and PEG 6000 solidified into at least two forms, depending on the cooling rate. Incorporation of drugs affected the morphology of the PEGs during solidification. The rate of crystal growth was, furthermore, influenced by the fusion temperature, molecular weight and the degree of supercooling. The degree of crystallinity, as measured by the enthalpies of solidification, decreased with increasing cooling rate. The results show that reducing the rate of solidification could lead to incomplete solidification, giving products that are liable to change on storage.     

Physical Stability of Solid Dispersions Containing Triamterene or Temazepam in Polyethylene Glycols

The effect of storage on the physical stability of solid dispersions of triamterene or temazepam in polyethylene glycols was studied using differential scanning calorimetry (DSC), particle-size analysis and dissolution methods. The enthalpies of fusion of the carriers, without included drug and previously fused and crystallized, increased on storage. Analysis of similarly treated solid dispersions, containing either 10% temazepam or 10% triamterene, showed that each drug influenced the morphology of the polyethylene glycol (PEG). The enthalpies and melting points of the solidus components of the dispersions' carriers were initially reduced after preparation, but on storage these increased. The particle sizes of the drugs dispersed in the PEGs increased on storage. The changes in dissolution after storage of triamterene or temazepam dispersions were smaller for dispersions in PEG 1500 than for dispersions in PEGs of higher molecular weight (PEG 2000, PEG 4000 or PEG 6000) in which the reduction in dissolution was particularly marked during the first month of storage. The rank order of changes in dissolution were PEG 1500 ? PEG 2000 < PEG 4000 ～ PEG 6000.     

Absorption Characteristics of Dextrans with Different Molecular Weights from the Liver Surface Membrane in Rats: Implications for Targeting to the Liver

Abstract

We examined the importance of molecular weight on the absorption from the liver surface in rats using fluorescein isothiocyanate-dextrans (FDs) with molecular weights of 4,400 (FD-4), 9,300 (FD-10), 40,500 (FD-40) or 69,000 (FD-70). After application of FDs (5 mg) to the rat liver surface employing a cylindrical glass cell (i.d. 9 mm), each FD appeared gradually in the plasma, and the in vivo behavior was explained by two-compartment model with first-order absorption. The absorption ratios of FDs from the rat liver surface at 6 h, calculated from the amount recovered from the glass cell, decreased with an increase in the molecular weight (44.5% for FD-4, 29.3% for FD-10, 5.1% for FD-40 and 2.2% for FD-70). A linear relationship was observed between the absorption rate constant and the reciprocal value with square root of molecular weight of the model compounds. The limit of absorption from the rat liver surface was extrapolated to be at a molecular weight of 70,000. Furthermore, absorbed FDs were accumulated in the liver, as high liver/plasma concentration ratio as compared with that of i.v. administration.

We clarified the molecular weight dependence of drug absorption from the liver surface in rats. Moreover, the liver surface application appeared to be a promising route with enhancing the efficacy of drug targeting to the liver.     

Effect of polyethylene glycols on the trans-ungual delivery of terbinafine

Topical nail drug delivery could be improved by identifying potent chemical penetration enhancers. The purpose of this study was to assess the effect of polyethylene glycols (PEGs) on the trans-ungual delivery of terbinafine. In vitro permeation studies were carried out by passive and iontophoresis (0.5 mA/cm2) processes for a period of 1 h using gel formulations containing different molecular weight PEGs (30%w/w). The release of drug from the loaded nail plates and the possible mechanisms for the enhanced delivery was studied. Passive delivery using formulation with low molecular weight PEGs (200 and 400 MW) indicated moderate enhancement in the permeation and drug load in the nail plate, compared to the control formulation. However, the effect of low molecular weight PEGs was predominant during iontophoresis process with greater amount of terbinafine being permeated (≈35 μg/cm2) and loaded into the nail plate (≈2.7 μg/mg). However, little or no effect on drug delivery was observed with high molecular weight PEGs (1000- 3350 MW) in passive and iontophoresis processes. Release of drug from the nail plates loaded by iontophoresis using low molecular weight PEG (400 MW) exhibited sustain effect which continued over a period of 72 days. The enhancement in drug permeation by low molecular weight PEGs is likely due to their ability to lead to greater water uptake and swelling of nail. This study concluded that the low molecular weight PEGs are indeed a promising trans-ungual permeation enhancer.     

Formulation and Evaluation of Tramadol hydrochloride Rectal Suppositories

Rectal suppositories of tramadol hydrochloride were prepared using different bases and polymers like PEG, cocoa butter, agar and the effect of different additives on in vitro release of tramadol hydrochloride was studied. The agar-based suppositories were non-disintegrating/non-dissolving, whereas PEGs were disintegrating/dissolving and cocoa butter were melting suppositories. All the prepared suppositories were evaluated for various physical parameters like weight variation, drug content and hardness. The PEG and cocoa butter suppositories were evaluated for macromelting range, disintegration and liquefaction time. In vitro release study was performed by USP type I apparatus. The prepared suppositories were within the permissible range of all physical parameters. In vitro drug release was in the order of PEG>Agar>cocoa butter. Addition of PVP, HPMC in agar suppositories retards the release. The mechanism of drug release was diffusion controlled and follows first order kinetics. The results suggested that blends of PEG of low molecular weight (1000) with high molecular weight (4000 and 6000) in different percentage and agar in 10% w/w as base used to formulate rapid release suppositories. The sustained release suppositories can be prepared by addition of PVP, HPMC in agar-based suppositories and by use of cocoa butter as base.     

Poloxamer-based in situ hydrogels for controlled delivery of hydrophilic macromolecules after intramuscular injection in rats

Abstract

This study is aimed to investigate the applicability of poloxamer 407 (P407) and 188 (P188)-based temperature-sensitive in situ hydrogel (TSHG) in sustained delivery of hydrophilic macromolecules following intramuscular administration. Polyethylene glycols (PEGs) with molecular weight of 5-, 20-, and 40-kDa were used as model drugs, which can represent the common size range of hydrophilic macromolecular drugs using TSHG. The correlation between the level of poloxamers and thermogelling transition temperatures (T_sol–gel) was established and two formulations “20% P407/10% P188” and “24% P407/10% P188” were chosen for further study. The results showed that the release kinetics of PEGs was close to zero order. Sustained in vivo behaviors were achieved by both of the two formulations for all the PEGs though variations were seen. Lower molecular weight PEG showed more remarkable pharmacokinetic improvements. No significant differences in pharmacokinetics were observed between the two formulations for the same PEG. This suggested that 20–24% P407/10% P188 formulations, with accordingly T_sol–gel in the range of 24.6?°C–31.7?°C, might be freely chosen to achieve comparable pharmacokinetics for hydrophilic macromolecular drugs after intramuscular injection.     

Synthesis, characterization and in situ intestinal absorption of different molecular weight scutellarin-PEG conjugates

Highly water soluble esters of scutellarin with different molecular weight polyethylene glycol (PEG) were synthesized. The physicochemical properties, the stabilities under different conditions and the in situ intestinal absorption of the conjugates in rats were investigated. By PEG modification, greatly increased water solubility and a desirable partition coefficient were obtained. These compounds act as prodrugs i.e. breakdown occurrs in a predictable fashion: in vitro, the t1/2 of them in PBS buffer at pH 7.4 was above 12 h (37 degrees C), while in plasma a more rapid breakdown was observed (t1/2 1.5-3 h). PEGylation could enhance the absorption of scutellarin in rat intestine, and scutellarin, its PEG conjugates are absorbed through intestine mainly via passive transport. When the molecular weight of PEG increased from 200 to 1000 Da, the absorption of the conjugates decreased accordingly. The range of PEG molecular weight used for the PEGylation of scutellarin was about 400-1000 Da based on considerations of the yield, the stability and the absorption.     

Concentration-Dependent Effects of Polyethylene Glycol 400 on Gastrointestinal Transit and Drug Absorption

Purpose. The aim of the study was to investigate the effect of different concentrations of polyethylene glycol 400 (PEG 400) on liquid transit through, and ranitidine absorption from, the gastrointestinal tract. Methods. Six healthy male volunteers received, on four separate occasions, 150 mL water containing 150 mg ranitidine and either 0 (control), 1, 2.5, or 5 g PEG 400. The solutions were radiolabeled with technetium-99m to allow their gastrointestinal transit to be followed using a gamma camera. Urine samples were collected over a 24-h period to assess the amount of ranitidine excreted and hence absorbed. Results. No significant differences in gastric emptying were noted between the four solutions. In contrast, the presence of 1, 2.5, and 5 g PEG 400 reduced the mean small intestinal transit times of the solutions by 9, 20, and 23%, respectively, against the control. In terms of drug absorption, the mean cumulative amount of ranitidine excreted was reduced by 38% in the presence of both 2.5 and 5 g PEG 400, although it was significantly increased by 41% in the presence of 1 g PEG 400. Conclusions. The results show that low concentrations of PEG 400 enhance the absorption of ranitidine possibly via modulation of intestinal permeability, while high concentrations have a detrimental effect on ranitidine absorption presumably via a reduction in the small intestinal transit time.     

Impact of molecular weight on the mechanism of cellular uptake of polyethylene glycols (PEGs) with particular reference to P-glycoprotein

Polyethylene glycols (PEGs) in general use are polydisperse molecules with molecular weight (MW) distributed around an average value applied in their designation e.g., PEG 4000. Previous research has shown that PEGs can act as P-glycoprotein (P-gp) inhibitors with the potential to affect the absorption and efflux of concomitantly administered drugs. However, questions related to the mechanism of cellular uptake of PEGs and the exact role played by P-gp has not been addressed. In this study, we examined the mechanism of uptake of PEGs by MDCK-mock cells, in particular, the effect of MW and interaction with P-gp by MDCK-hMDR1 and A549 cells. The results show that: (a) the uptake of PEGs by MDCK-hMDR1 cells is enhanced by P-gp inhibitors; (b) PEGs stimulate P-gp ATPase activity but to a much lesser extent than verapamil; and (c) uptake of PEGs of low MW (<2000 Da) occurs by passive diffusion whereas uptake of PEGs of high MW (>5000 Da) occurs by a combination of passive diffusion and caveolae-mediated endocytosis. These findings suggest that PEGs can engage in P-gp-based drug interactions which we believe should be taken into account when using PEGs as excipients and in PEGylated drugs and drug delivery systems.     

Cryoprotection mechanisms of polyethylene glycols on lactate dehydrogenase during freeze-thawing

The purpose of this study was to explore the cryoprotection mechanisms of high molecular weight polyethylene glycols (PEGs) (eg, PEG 4000 and PEG 8000) on lactate dehydrogenase (LDH). Ultraviolet activity assays, circular dichroism (CD) spectroscopy, gel filtration, sodium dodecyl sulfate polyacrylamide gel electrophoresis (SDS-PAGE), (14)C-PEG 4000 labeling and binding, and cryostage microscopic study were conducted. Different molecular weights and concentrations of PEGs in LDH formulations were treated by freeze-thawing. Higher molecular weights and concentrations of PEGs in LDH-PEG formulations obtained better activity and secondary structure recoveries of LDH after freeze-thawing. Insoluble aggregation of LDH was not observed in gel filtration studies. SDS-PAGE results suggested surface characteristic modifications of LDH by the larger molecular weight PEGs. The 14C-PEG 4000 labeling and binding study showed extensive nonspecific interactions between the PEG 4000 and LDH molecules in a concentration-dependent manner. The bound LDH-PEG 4000/free PEG 4000 ratio increased when LDH or PEG 4000 concentrations increased. Cryostage microscopic study showed that PEG 8000 delayed the ice crystallization and eutectic transition of LDH formulation. It appeared that multiple mechanisms were at work during PEGs' cryoprotection of LDH. It was unclear whether the delayed eutectic characteristics of PEGs contributed to LDH cryoprotection. The favorable interaction, rather than preferential exclusion, between LDH and PEGs (eg, 4000) cryoprotected LDH.     

Safety assessment on polyethylene glycols (PEGs) and their derivatives as used in cosmetic products

This assessment focusses on polyethylene glycols (PEGs) and on anionic or nonionic PEG derivatives, which are currently used in cosmetics in Europe. These compounds are used in a great variety of cosmetic applications because of their solubility and viscosity properties, and because of their low toxicity. The PEGs, their ethers, and their fatty acid esters produce little or no ocular or dermal irritation and have extremely low acute and chronic toxicities. They do not readily penetrate intact skin, and in view of the wide use of preparations containing PEG and PEG derivatives, only few case reports on sensitisation reactions have been published, mainly involving patients with exposure to PEGs in medicines or following exposure to injured or chronically inflamed skin. On healthy skin, the sensitising potential of these compounds appears to be negligible. For some representative substances of this class, information was available on reproductive and developmental toxicity, on genotoxicty and carcinogenic properties. Taking into consideration all available information from related compounds, as well as the mode and mechanism of action, no safety concern with regard to these endpoints could be identified. Based on the available data it is therefore concluded that PEGs of a wide molecular weight range (200 to over 10,000), their ethers (laureths. ceteths, ceteareths, steareths, and oleths), and fatty acid esters (laurates, dilaurates, stearates, distearates) are safe for use in cosmetics. Limited data were available for PEG sorbitan/sorbitol fatty acid esters, PEG sorbitan beeswax and PEG soy sterols. Taking into account all the information available for closely related compounds, it can be assumed that these compounds as presently used in cosmetic preparations will not present a risk for human health. PEG castor oils and PEG hydrogenated castor oils have caused anaphylactic reactions when used in intravenous medicinal products. Their topical use in cosmetics is, however, considered safe as they are not expected to be systemically available. As all PEGs and PEG derivatives, they must not be applied to damaged skin. Manufacturers of PEGs and PEG derivatives must continue their efforts to remove impurities and by-products such as ethylene oxide and 1,4-dioxane. Overall, it is concluded, that the PEGs covered in this review are safe for use in cosmetics under the present conditions of intended use.