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.     

The application and mechanisms of polyethylene glycol 8000 on stabilizing lactate dehydrogenase during lyophilization

The purpose of this paper is to explore the application and mechanisms of polyethylene glycol 8000 (PEG 8000) on stabilizing lactate dehydrogenase (LDH) during lyophilization. In earlier freeze-thawing experiments, different molecular weights and concentrations of PEGs were formulated with LDH, and ultraviolet (UV) enzymatic activity and circular dichroism (CD) wavelength scanning studies were conducted. In lyophilization studies, different molecular weights of saccharides, e.g., glucose, sucrose, dextran 37,000 (D 37K), and dextran 160,000 (D 160K), with or without PEG 8000, were formulated with LDH at various molar ratios. UV assays, size exclusion chromatography -high performance liquid chromatography (SEC-HPLC), CD, fourier transform infrared spectroscopy (FTIR) were conducted for LDH. Upon lyophilization, enzymatic activity and tetrameric structure recoveries of LDH-saccharide formulations reached over 90% with PEG 8000 vs. 60-80% without PEG 8000. LDH-PEG 8000-saccharide formulations shifted the melting temperature (Tm) to higher temperatures than did LDH-saccharide formulations. Most LDH-PEG 8000-saccharide formulations at 1:100:1000 molar ratio showed better preservation of LDH secondary structures than did LDH-saccharide formulations at 1:1000 molar ratio. Since PEG 8000 was confirmed an effective cryoprotectant, saccharides were assumed to be protecting LDH from destabilization during drying. However, LDH-PEG 8000-dextran formulations preserved more LDH secondary structure than did LDH-dextran formulations, but preserved less LDH secondary structures than did LDH-PEG 8000 formulations. This indicated that dextrans not only did not stabilize LDH during drying, but they disrupted the stabilization effect of PEG 8000 on LDH during freezing. After reconstitution, CD wavelength scanning showed that some of the unfolded or denatured structures of LDH were refolded. Based on the steric hindrance of the bulky dextrans and the "water replacement mechanism", sucrose with PEG 8000 had synergistic protective effects, and dextrans with PEG 8000 had antagonistic effects, on stabilization of LDH during lyophilization.     

Effect of polyols on polyethylene glycol (PEG)-induced precipitation of proteins: Impact on solubility, stability and conformation

Effect of polyols on the solubility of bovine serum albumin (BSA) in the presence of polyethylene glycols (PEGs) was investigated in order to strengthen the understanding of the observed effects of polyols and PEGs on protein properties in solution. Effect of polyols and/or PEGs on the thermodynamic (conformational) stability of BSA was measured using DSC and circular dichroism (CD). Glucose, sucrose, raffinose, glycerol and sorbitol, all reduced the extent of protein precipitation. Solubility of BSA in the presence of ethylene glycol increased in the case of PEG 1450 and PEG 8000, but was unaffected in the case of PEG 400. DSC studies indicated that smaller PEGs have destabilizing influence on protein structure. CD studies showed that smaller PEGs (ethylene glycol) induce subtle unfolding while stabilizing polyols induce subtle compaction. Results show that, effect of polyols on the apparent solubility of the protein correlates with their effect on the thermodynamic stability of the protein, smaller PEGs are not appropriate for estimating the activity of proteins in saturated solutions, and subtle changes in protein conformation can significantly affect protein precipitation. Though smaller PEGs have weak attractive interactions with protein molecules, perturbation of protein structure by PEGs can be balanced by utilizing appropriate stabilizing solutes.     

A comparison between the protection of LDH during freeze-thawing by PEG 6000 and Brij 35 at low concentrations

The protection of lactate dehydrogenase (LDH) by low concentrations of the non-surface-active polyethylene glycol (PEG 6000) or the non-ionic surfactant PEG dodecyl ether (Brij 35) was investigated during freeze-thawing. The freeze-thawing process was performed with a controlled temperature history, and the protective mechanisms were elaborated. The systems were examined by differential scanning calorimetry (DSC), fluorescence spectroscopy and surface tension measurements. LDH activity assays were performed spectrophotometrically. Very low concentrations of PEG 6000 (8 x 10(-5) mM) or Brij 35 (4 x 10(-3) mM) protected LDH during freeze-thawing with a low cooling rate. With an increased freezing rate, higher concentrations of the additives were needed for full protection. No interaction was detected between LDH and Brij molecules. The strong interaction between LDH and PEG molecules disappeared with a small change in the protein structure, using a hybrid of LDH. The protein was nevertheless completely protected. The amount of Brij required for complete protection at high cooling rates correlated with the created ice surface area. The protection by PEG indicated a certain correlation with the ice crystal size and with the formation of a PEG hydrate. Brij or PEG hydrate molecules might compete with the protein for adsorption at the ice surface and thereby protect the protein during freeze-thawing.     

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.     

Interaction of polyethylene glycol (PEG) with the membrane-binding domains following spinal cord injury (SCI): introduction of a mechanism for SCI repair

Lipid-binding domains regulate positioning of the membrane proteins via specific interactions with phospholipid’s head groups. Spinal cord injury (SCI) diminishes the integrity of neural fiber membranes at nanoscopic level. In cases that the ruptured zone size is beyond the natural resealing ability, there is a need for reinforcing factors such as polymers (e.g. Polyethylene glycol) to patch the dismantled axoplasm. Certain conserved sequential and structural patterns of interacting residues specifically bind to PEGs. It is also found that PEG600, PEG400 and PEG200 share the strongest interaction with the lipid-binding domains even more successful than phospholipid head groups. The alpha helix structure composed of hydrophobic, neutral and acidic residues prepares an opportunity for PEG400 to play an amphipathic role in the interaction with injured membrane. This in-silico study introduces a mechanism for PEG restorative ability at the molecular level. It is believed that PEG400 interrelates the injured membrane to their underneath axoplasm while retaining the integrity of ruptured membrane via interaction with ENTH domains of membrane proteins. This privilege of PEG400 in treating injured membrane must be considered in designing of polymeric biomaterials that are introduced for SCI repair.     

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.     

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.     

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.     

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.     

Maltodextrins as Lyoprotectants in the Lyophilization of a Model Protein,LDH

Purpose. Maltodextrins, partially hydrolysed starches, were evaluated as potential lyoprotectants and the effect of combinations of maltodextrins and PEG 8000 on the protection of lactate dehydro genase (LDH) was examined. Methods. LDH activity assays were performed immediately before freezing and after reconstitution. The activity recovery was used as the parameter to evaluate the lyoprotectants. Differential Scanning Calorimetry (DSC) was used to measure the glass transition temperature (Tg′) of the solutions. DSC and X ray diffraction were used to characterise the freeze-dried products. Results. Maltodextrins were found to protect LDH againt inactivation during freeze-drying. The lyoprotection obtained by these maltodextrins is dependent on their D.E. value and the concentration used. The maltodextrin formulations performed as good or better than those containing sucrose and maltose, depending on the concentration used. Freeze dried cakes of maltodextrin formulations were amorphous. In the case of low D.E. maltodextrins, lyoprotection was improved by the addition of PEG 8000 as a cryoprotectant. Conclusions. Maltodextrins could be considered as potential lyoprotectants in lyophilization of proteins.     

Lyophilization of polyethylene glycol mixtures

Lyophilization of cosolvent systems may be a beneficial way of enhancing both physical and chemical stability of a drug product. The objective of this research is to establish whether cosolvent systems commonly used in the formulation of poorly water-soluble drugs can be successfully lyophilized. Polyethylene glycol (PEG) 400 was selected because it is widely used and can be easily frozen. The addition of PEG 400 to commonly used bulking agents, such as mannitol, sucrose, or polyvinylpyrrolidone, caused a significant change in the thermal properties of the bulking agents as observed by modulated differential scanning calorimetry. In addition, PEG 8000 was evaluated as a bulking agent because it also can function as a cosolvent in solution and forms an acceptable cake after lyophilization. Addition of PEG 400 to PEG 8000 caused negligible changes in the thermogram of this bulking agent. Surprisingly, the combination of PEG 8000 and PEG 400 forms a solid lyophilized cake. The current system can be best described as the lyophilization of a miscible solution of PEG 8000 and PEG 400 resulting in a lyophile that has a crystalline structure of PEG 8000 which is able to support PEG 400.     

Kinetics of the Esterification of Active Pharmaceutical Ingredients Containing Carboxylic Acid Functionality in Polyethylene Glycol: Formulation Implications

Polyethylene glycols (PEGs) are attractive as excipients in the manufacture of drug products because they are water soluble and poorly immunogenic. They are used in various pharmaceutical preparations. However, because of their terminal hydroxyl groups, PEGs can participate in esterification reactions. In this study, kinetics of two active pharmaceutical ingredients, cetirizine and indomethacin possessing carboxylic acid functionality, has been studied in PEG 400 and PEG 1000 at 50°C, 60°C, 70°C, and 80°C. HPLC–UV was applied for the determination of concentrations in the kinetic studies, whereas HPLC–MS was used to identify reaction products. The esterification reactions were observed to be reversible. A second-order reversible kinetic model was applied and rate constants were determined. The rate constants demonstrated that cetirizine was esterified about 240 times faster than indomethacin at 80°C. The shelf-life for cetirizine in a PEG 400 formulation at 25°C expressed as t_95% was predicted to be only 30 h. Further, rate constants for esterification of cetirizine in PEG 1000 in relation to PEG 400 decreased by a factor of 10, probably related to increased viscosity. However, it is important to be aware of this drug–excipient interaction, as it can reduce the shelf-life of a low-average molecular weight PEG formulation considerably. © 2014 Wiley Periodicals, Inc. and the American Pharmacists Association J Pharm Sci 103:2424–2433, 2014     

Absorption of Polyethylene Glycols 600 Through 2000: The Molecular Weight Dependence of Gastrointestinal and Nasal Absorption

Polyethylene glycols (PEGs) 600,1000, and 2000 were used to study the molecular weight permeability dependence in the rat nasal and gastrointestinal mucosa. Absorption of the PEGs was measured by following their urinary excretion over a 6-hr collection period. HPLC methods were used to separate and quantitate the individual oligomeric species present in the PEG samples. The permeabilities of both the gastrointestinal and the nasal mucosae exhibited similar molecular weight dependencies. The steepest absorption dependence for both mucosae occurs with the oligomers of PEG 600, where the extent of absorption decreases from approximately 60% to near 30% over a molecular weight range of less than 300 daltons. Differences in the absorption characteristics between the two sites appear in the molecular weight range spanned by PEG 1000. For these oligomers, the mean absorption from the nasal cavity is approximately 14%, while that from the gastrointestinal tract is only 9%. For PEG 2000, mean absorption decreases to 4% following intranasal application and below 2% following gastrointestinal administration. Within the PEG 1000 and 2000 samples, however, very little molecular weight dependency is seen among the oligomers. In the range studied, a distinct molecular weight cutoff was not apparent at either site.     

Investigation of the adjuvant effect of polyethylene glycol (PEG) 400 in BALB/c mice.

In the formulation of peptide- and protein-based drugs, it is important that the pharmaceutical excipients used do not potentiate possible immunogenic properties of the drug substance. Polyethylene glycols (PEGs) are widely used excipients e.g. in parenteralia and in formulations for nasal application. The immunomodulating properties of PEG 400 were investigated in this study using hen egg ovalbumin (OA) as the model immunogen. OA was dissolved in saline, 10% PEG 400 in saline or undiluted PEG 400 and injected subcutaneously into the neck region of BALB/cJ mice. The levels of OA-specific IgE, IgG1 and IgG2a antibodies were measured. The 10% solution of PEG 400 did not have any immunomodulating properties, whereas the undiluted product gave rise to immunosuppression when compared with the saline control. Neither 10% nor the 100% PEG 400 preparation possessed adjuvant activity under the conditions of the study.     

Structural properties of polyethylene glycol-polysorbate 80 mixture, a solid dispersion vehicle.

The structural properties of the mixtures of polysorbate 80 with various polyethylene glycols (PEG), viz., PEG 1000, PEG 1450, PEG 3350, and PEG 8000, have been investigated by powder X-ray diffraction (XRD) and differential scanning calorimetric studies. These mixtures may be used as solid dispersion vehicles to insure complete dissolution of poorly water-soluble drugs. Although polysorbate 80 is a liquid at room temperature, the PEG-polysorbate 80 mixtures with up to 75% (w/w) polysorbate 80 were solid. The XRD studies revealed that the crystal structures (d-spacings) of the PEGs (M(r) 1000, 1450, 3350, and 8000) did not change with increasing amounts of polysorbate 80 in the mixture. The intensities of the XRD peaks, however, varied approximately in proportion to the concentration of PEG present. Similarly, the differential scanning calorimetric studies showed that the melting behavior of a PEG-polysorbate 80 mixture was similar to that of the PEG used. The lowering of the mp of a particular PEG due to the presence of 50% (w/w) polysorbate 80 in the mixture was < 6 degrees C, and the decrease in mp was < 12 degrees C in the presence of 75% (w/w) polysorbate 80. When enthalpies of fusion of the mixtures were normalized for the amounts of PEGs present, they were similar to those of pure PEGs. These results indicate that the crystalline structure of PEG in a PEG-polysorbate 80 mixture is substantially the same as that of the pure PEG, and that polysorbate 80 is incorporated into the amorphous region of PEG solid structure.     

Development of PVP/PEG mixtures as appropriate carriers for the preparation of drug solid dispersions by melt mixing technique and optimization of dissolution using artificial neural networks

The effect of plasticizer’s (PEG) molecular weight (MW) on PVP based solid dispersions (SDs), prepared by melt mixing, was evaluated in the present study using Tibolone as a poorly water soluble model drug. PEGs with MW of 400, 600, and 2000 g/mol were tested, and the effect of drug content, time and temperature of melt mixing on the physical state of Tibolone, and the dissolution characteristics from SDs was investigated. PVP blends with PEG400 and PEG600 were completely miscible, while blends were heterogeneous. Furthermore, a single T_g recorded in all samples, indicating that Tibolone was dispersed in a molecular lever (or in the form of nanodispersions), varied with varying PEG’s molecular weight, melt mixing temperature, and drug content, while FTIR analysis indicated significant interactions between Tibolone and PVP/PEG matrices. All prepared solid dispersion showed long-term physical stability (18 months in room temperature). The extent of interaction between mixture components was verified using Fox and Gordon–Taylor equations. Artificial neural networks, used to correlate the studied factors with selected dissolution characteristics, showed good prediction ability.     

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.     

Evaluation of HPβCD-PEG microparticles for salmon calcitonin administration via pulmonary delivery

For therapeutic peptides, the lung represents an attractive, noninvasive route into the bloodstream. To achieve optimal bioavailability and control their fast rate of absorption, peptides can be protected by coprocessing with polymers such as polyethylene glycol (PEG). Here, we formulated and characterized salmon calcitonin (sCT)-loaded microparticles using linear or branched PEG (L-PEG or B-PEG) and hydroxypropyl-beta-cyclodextrin (HPβCD) for pulmonary administration. Mixtures of sCT, L-PEG or B-PEG and HPβCD were co-spray dried. Based on the particle properties, the best PEG:HPβCD ratio was 1:1 w:w for both PEGs. In the sCT-loaded particles, the L-PEG was more crystalline than B-PEG. Thus, L-PEG-based particles had lower surface free energy and better aerodynamic behavior than B-PEG-based particles. However, B-PEG-based particles provided better protection against chemical degradation of sCT. A decrease in sCT permeability, measured across Calu-3 bronchial epithelial monolayers, occurred when the PEG and HPβCD concentrations were both 1.6 wt %. This was attributed to an increase in buffer viscosity, caused by the two excipients. sCT pharmacokinetic profiles in Wistar rats were evaluated using a 2-compartment model after iv injection or lung insufflation. The maximal sCT plasma concentration was reached within 3 min following nebulization of sCT solution. L-PEG and B-PEG-based microparticles were able to increase T(max) to 20 ± 1 min and 18 ± 8 min, respectively. Furthermore, sCT absolute bioavailability after L-PEG-based microparticle aerosolization at 100 μg/kg was 2.3 times greater than for the nebulized sCT solution.     

Poly(ethylene glycol) conjugated drugs and prodrugs: a comprehensive review

Low molecular weight Poly(ethylene glycol) (PEG) (< 20,000)-drug conjugates, prepared over a 20-year period, have been scrutinized and their properties and efficacy reviewed. No commercial products have thus far been reported for these types of compounds. However, during the past 5 years a renaissance in the field of PEG-(anticancer) drug conjugates has taken place, initiated by the use of higher molecular weight PEGs (> 20,000), especially 40,000, which is estimated to have a plasma circulating half-life of approximately 8-9 h. This recent resuscitation of small organic molecule delivery by high molecular weight PEG conjugates was founded on meaningful in vivo testing using established tumor models and has led to a clinical candidate. Recent applications of high molecular weight PEG prodrug strategies to amino-containing drugs are also detailed.