Water Soluble Synthetic Polymers
PEG
Introduction:
Water soluble synthetic polymers have been used for protein stabilizing agents.s Poly-(ethylene glycol) (PEG) is one such polyer that has been extensively studies both as a protein stabilizer and a protein precipitant. The polymer, at high concentraiton of more than 10% can lead to precipitation but at concentrations less than 1% binds to proteins upon denaturation and can stabilize them against aggregation. Gombotz (Pharm Res. 1994, 11(5), 624-32)
Polyethylene glycol (PEG) conjugation (see also “polymers” under “biochemistry”) is used to alter the pharmacokinetic profiles of a variety of drugs and thus improve their therapeutic potential. PEG conjugation increases retention of drugs in the circulation by protecting against enzymatic digestion, slowing filtration by the kidneys and reducing the generation of neutralizing antibodies (Fishburn, J. Pharma. Sciences, 2008, p. 1). PEG has mainly be used to reduce the immunogenicity and increase the circulating half-lives of antibodies (Chapman, Advanced Drug Delivery Reviews 54 (2002) 531-545).
PEG is a polymer having the properties of solubility in water and in many organic solvents, lacks toxicity and immunogenicity. One of of PEG strategies is to covalently attached the polymer to insoluble molecules to make the resulting PEG molecule “conjugate” soluble. For example, it has been shown that the water insoluble drug paclitaxel when coupled to PEG becomes water soluble. (Roberts, US 6,436,386). The polymer modificaiton tends to reduce needed dosage and dosing frequency and development of drug directed immune responses, thus improving both short and longer term patient tolerance to treatment. In some cases (e.g., PEG insulin, it may also allow for the drug to be taken orally, parenterally or other routes than by injection. The result is PEGylated drug formualtions which have greater chance of FDA approval, patient tolerance, ease of application, wider patient population (e.g., sales base) and longer safety and efficacy. (Van Alstine (WO2011/035282).
Poly (vinylpyrrolidone) (PVP):
Gombotz (Pharm Res. 1994, 11(5), 624-32) discloses using size exclusion high performance liquid chromatogrpahy (HPLC), differential scanning calorimetry (DSC) and ELISA to evaluation of different concentraitons of PVP as a stabilizing agent for an antibody against heat induced aggregation. Higher concentration of PVP increased aggregation and eventually lead to precipitation but low concentraiton stabilized the antibody against heat induced aggregation.
Examples:
There are now several “PEGylated” proteins which are FDA approved and have yearly sales in excess of one billion dollars. Examples include “EGINTRON (PEGylated INTRON) from Schering, PEGASYS (PEGylated ROFERON) from Roche and NEULASTA (PEGylated Nuepogen) from Amgen.
Other Hydrophilic polymers
In addition to PEG other hydrophilic polymers such as those containing mixtures of propylene glycol and ethylene glycol units may also be useful for modificaiton of biopharmaceuticals. So too these netural hydorphilic polymers appear to mimic hydrophilic carbohydroate polymers which might occur as a result of glycosylation and also increase the serum half life of biopharmaceuticals. There are also polymer conjugates of ethylene glycol units and carbohydrate units which are like PEG useful as nonimmunogenic polymers in formulations. One well known example is ethylhydroxyethylcellulose (EHEC). Another is use of dextran (polyglucose) polymer. (Van Alstine (WO2011/035282)
Block Polymers:
Antibody stabilization by addition of block polymers composed of polyoxypropylene and polyoxyethylene in combination with phospholipids is described in EP-A 0318081.
Antibody Fragment PEGylation
Fab’ fragment PEGylation:
Antigen-binding fragmetns (Fab’) of antibodies can be site specifically PEGylated at thiols using cystein-reactive PEG-maleimide conjugates. For therapeutic Fab–PEG, conjugation with 40 kDa of PEG at a single hinge cystein has been found to confer appropriate pharmacokinetic properties to enable infrequent dosing. (Humphreys, Protein Engineering Design & Selection, 20, 5, pp. 227-234, 2007).