Excipient polyethylene glycols

Huang et al. [59] evaluated some common excipients for residual levels of hydrogen peroxide. They found levels of H2O2 in the range 0-244 ppm, but perhaps of more concern, they showed quite pronounced differences between different batches of the same vendor and between different vendors of the same excipient. For example, although there is some variability of residual peroxide levels in PEG 400 (polyethylene glycol) from vendor B (5-16 ppm), the differences were small, in contrast with those seen from vendor C (2-59 ppm). Similarly, the differences in residual peroxide in the binder PVP (polyvinyl pyroli-done) from two different vendors were quite marked (73 vs 244 ppm). Formulations optimised for excipients from specific sources could well be sub-optimal if the... 

Protein drugs have been formulated with excipients intended to stabilize the protein in the milieu of the pharmaceutical product. It has long been known that a variety of low molecular weight compounds have the effect of preserving the activity of proteins and enzymes in solution. These include simple salts, buffer salts and polyhydroxylated compounds such as glycerol, mannitol, sucrose and polyethylene glycols. Certain biocompatible polymers have also been applied for this purpose such as polysaccharides and synthetic polymers such as polyvinyl pyrrolidone and even nonionic surfactants. 

Polyethylene glycol (PEG), a hygroscopic polymer, was the first molecule to be considered for modifying the surface of proteins. It has proved to be very successful. PEG, available in molecular weights ranging from a few hundred to several thousand daltons, have been used as parenteral excipients for decades with proven clinical safety. 

Permeation enhancement by excipients has generated some interest, but there is still much research that needs to be done to elucidate the mechanism of these excipients. PEG-400 (and many other excipients such as polyethylene glycol, poloxamers, polysorbates, and vitamin E) is known to inhibit p-glycoprotein, which may increase the bioavailability of the API, which was a substrate for this efflux pump. On the other hand, it has been demonstrated that PEG-400 can accelerate small intestinal transit, and thereby reduce the bioavailability of some drugs (e.g., ranitidine) (5). 

Some excipients such as tocophersolan polyethylene glycol succinates (17) or polyethylene glycol hydroxystearates (18) that are used as antioxidants or to increase the solubility of hydrophobic drugs also possess the pharmacological property to attenuate the P-glycoprotein-mediated multidrug resistance (19,20). 

H. Suppositories Solid preparations which melt at body temperature delivering medication for at-site treatment or for absorption at that point (usually rectal, vaginal, or urethral). Excipients include cocoa butter, waxy fatty acids, and derivatives, polyethylene glycol, theobroma oil, as well as many ingredients found in G. 

The permeability of two peptides, P-gp substrate and non P-gp substrate, across caco-2 cells in the presence or absence of polysorbate 80 and cremophor EL, commonly used surfactants in pharmaceutical formulations, was investigated. The permeability of the P-gp substrate peptide across caco-2 cells was enhanced in the presence of polysorbate 80 and cremophor EL, whereas the non-P-gp substrate peptide was not affected by these surfactants [94]. Another commonly used lipidic excipient that has been shown to inhibit P-gp mediated efflux is D-a-tocopheryl polyethylene glycol 1000 succinate (TPGS) [95]. The insertion of a known CYP3A4 and P-gp inhibitor to the formulation is another approach to elevate bioavailability. 

Formaldehyde, along with other short-chain aldehydes such as acetaldehyde, is a low molecular weight, volatile, reactive contaminant that can be present at low levels from a variety of sources (e.g., excipients such as polyethylene oxide, polyethylene glycol (64,65), or from carbohydrate degradation (66), solvent contamination (51), packaging materials (52), etc.). Formaldehyde is known to react with amines (Fig. 33) to form a reactive N-hydroxymethyl compound (a hemiaminal) that can further react with other nucleophiles. Reaction of formaldehyde with amino acids (67) can cause... 

Polyethylene glycol (PEG) is an excipient used in the formulation of liquid pharmaceutical forms of poorly soluble drugs. As an ether, PEG is easily oxidized, and its degradation often facilitates the oxidation of otherwise stable drug substances. 

Higher levels of hydroperoxide (HPO) impurities have been found in several commonly used excipients (Table 2.5),26 including povidone, polysorbate 80, polyethylene glycol 400, and hydroxypropyl cellulose. The level of HPO may vary... 

One of the critical factors in excipient selection and concentration is the effect on preferential hydration of the biopharmaceutical product [53, 54], Preferential hydration refers to the hydration layers on the outer surface of the protein and can be utilized to thermodynamically explain both stability enhancement and denatur-ation. Typical excipients used in protein formulations include albumin, amino acids, carbohydrates, chelating and reducing agents, cyclodextrins, polyhydric alcohols, polyethylene glycol, salts, and surfactants. Several of these excipients increase the preferential hydration of the protein and thus enhance its stability. Cosolvents need to be added in a concentration that will ensure their exclusion from the protein surface and enhance stability [54], A more comprehensive review of excipients utilized for biopharmaceutical drug products is available elsewhere [48],... 

Cryo- and Lyoprotectants and Bulking Agents Various mechanisms are proposed to explain why excipients serve as cryo- or lyoprotectants. The most widely accepted mechanism to explain the action of cryoprotection is the preferential exclusion mechanism [177]. Excipients that will stabilize proteins against the effects of freezing do so by not associating with the surface of the protein. Such excipients actually increase the surface tension of water and induce preferential hydration of the protein. Examples of solutes that serve as cryoprotectants by this mechanism include amino acids, polyols, sugars, and polyethylene glycol. 

Powders intended for nasal administration have to be optimized in terms of particle size and morphology as these properties are related to potential irritation in the nasal cavity [23], Certain procedures (e.g., spray drying process) can modify the particle size of the drug powder raw material, but in order to optimize the morphology and flowability properties of some pure drug powders, excipients need to be used. Sacchetti et al. [28] reported that the use of mannitol as a filler and hydroxy-propylmethyl cellulose (HPMC) as a shaper of spray-dried caffeine microparticles modified the typical needle shape of spray-dried caffeine to a more convenient roundish shape. Further addition of polyethylene glycol (PEG) resulted in increased... 

---