Protein parenterals

Polysorbate 80 is a surfactant commonly used in protein parenteral formulations to minimize denaturation at the air-water interface. Polysorbate 80 is also sometimes used in injectable solution formulations of small molecules for the purpose of solubility enhancement owing to micelle formation. Docetaxel, a first-line therapeutic to treat breast and small cell lung cancer, is practically insoluble in water and is solubilized in Taxotere to 40mg/ml in 100% polysorbate 80, and is diluted four-fold with the supplied diluent of 13% ethanol in water, then further diluted to 0.3-0.74mg/ml with saline or dextrose 5% prior to administration by rV infusion. The dose of Taxotere is up to 5 ml of polysorbate 80 per dose, representing the estimated maximum amount administered intravenously. 

Therapeutic proteins and peptides have gained a significant market interest owing to their increased development and applicability to multiple disease conditions (Chin et al., 2012 Park et al., 2011). For the systemic delivery of therapeutic peptides and proteins, parenteral administration is currently believed to be the most efficient route and also the delivery method of choice to achieve therapeutic activity compared with transdermal, pulmonary, nasal, oral, and buccal delivery routes (Fig. 11.4) (Muranishi, 1985 Lennemas, 1995 Ghilzai, 2004). But, for the usually faced chronic conditions, patients find the use of daily injections both unpleasant and difficult to be self-administered. 

O. Mayura, M. Rhishikesh, and S. Jagdish, Smart polymers for peptide and protein parenteral sustained delivery. Drug Discovery Today Technologies, 9,2,2012. 

Penicillamine (29) can be effective in patients with refractory RA and may delay progression of erosions, but adverse effects limit its useflilness. The most common adverse side effects for penicillamine are similar to those of parenteral gold therapy, ie, pmritic rash, protein uria, leukopenia, and thrombocytopenia. Decreased or altered taste sensation is a relatively common adverse effect for penicillamine. A monthly blood count, platelet count, and urinalysis are recommended, and also hepatic and renal function should be periodically monitored. Penicillamine is teratogenic and should not be used during pregnancy. 

In Parenteral and Enteral Nutrition. Amino acid transfusion has been widely used since early times to maintain basic nitrogen metaboHsm when proteinaceous food caimot be eaten. It was very difficult to prepare a pyrogen-free transfusion from protein hydrolysates. Since the advances in L-amino acid production, the crystalline L-amino acids have been used and the problem of pyrogen in transfusion has been solved. The formulation of amino acid transfusion has been extensively investigated, and a solution or mixture in which the ratio between essential and nonessential amino acid is 1 1, has been widespread clinically. Special amino acid mixtures (eg, branched chain amino acids-enriched solution) have been developed for the treatment of several diseases (93). 

Some polymyxins are sold for second-line systemic therapy. Polymyxin B sulfate and colistimethate sodium can be used for intravenous, intramuscular, or intrathecal administration, especially for Pseudomonas aerupinosa mP QXiosis, but also for most other gram-negative organisms, such as those resistant to first-line antibiotics. Nephrotoxicity and various neurotoxicities are common in parenteral, but not in topical, use. Resistance to polymyxins develops slowly, involves mutation and, at least in some bacteria, adaptation, a poorly understood type of resistance that is rapidly lost on transfer to a medium free of polymyxin. Resistance can involve changes in the proteins, the lipopolysaccharides, and lipids of the outer membrane of the cell (52). Polymyxin and colistin show complete cross-resistance. 

Insulin must be administered via the parenteral route, usually the subcutaneous (SC) route Insulin cannot be administered orally because it is a protein and readily destroyed in the gastrointestinal tract. Regular insulin is the only insulin preparation given intravenously (IV). Regular insulin is given 30 to 60 minutes before a meal to achieve optimal results. 

The composition of body fluids remains relatively constant despite the many demands placed on the body each day. On occasion, these demands cannot be met, and electrolytes and fluids must be given in an attempt to restore equilibrium. The solutions used in the management of body fluids discussed in this chapter include blood plasma, plasma protein fractions, protein substrates, energy substrates, plasma proteins, electrolytes, and miscellaneous replacement fluids. Electrolytes are electrically charged particles (ions) that are essential for normal cell function and are involved in various metabolic activities. This chapter discusses the use of electrolytes to replace one or more electrolytes that may be lost by the body. The last section of this chapter gives a brief overview of total parenteral nutrition (TPN). 

When normal enteral feeding in not possible or is inadequate to meet an individual s nutritional needs, intravenous (IV) nutritional therapy or total parenteral nutrition (TPN) is required. Products used to meet the IV nutritional requirements of the patient include protein substrates (amino acids), energy substrates (dextrose and fat emulsions), fluids, electrolytes, and trace minerals (see the Summary Drug Table Electrolytes). 

In vivo studies in animals suggest that endosulfan may disrupt normal reproductive hormone levels in male animals, but that it is not an endocrine disrupter in females. Persistent depressed testicular testosterone was seen in male rats after intermediate duration oral exposures to endosulfan. In ovariectomized female rats, orally administered endosulfan did not induce normal development of female reproductive tissues, and in female mice and immature female rats, acute parenteral exposure to endosulfan did not affect several endocrine-related end points. In vitro studies have evaluated endosulfan for estrogen receptor (ER) and cytosolic protein binding affinity, ER-mediated reporter gene expression, estrogenic induction of cell proliferation, and alteration of relative abundance of active estradiol metabolites. Overall, in vitro evidence in favor of endosulfan estrogenicity indicates relatively weak potency compared to 17[3-estradiol. Apparently contradictory results were reported in different... 

Delivery of peptides and proteins via the gastrointestinal tract has not been successful because of poor penetration through the intestinal epithelium and high levels of proteolytic activity in the gastrointestinal tract. Liposomal encapsulation of proteins and peptides will not improve the efficiency and capacity of this absorption pathway considerably (e.g., Ryman et al., 1982 Machy and Leserman, 1987 Weiner and Chia-Ming Chiang, 1988). These difficulties in delivery via the oral route caused the parenteral route to remain the preferred route for the administration of therapeutic peptides... 

Table 24.3 Specification of therapeutic proteins to be administered parenterally... 

O Parenteral nutrition (PN), also called total parenteral nutrition (TPN), is the intravenous administration of fluids, macronutrients, electrolytes, vitamins, and trace elements for the purpose of weight maintenance or gain, to preserve or replete lean body mass and visceral proteins, and to support anabolism and nitrogen balance when the oral/enteral route is not feasible or adequate. 

S Harnisch, RH Muller. Adsorption kinetics of plasma proteins on oil-in-water emulsions for parenteral nutrition. Eur J Pharm Biopharm 49(l) 41-46, 2000. 

As pharmaceutical scientists gain experience and tackle the primary challenges of developing stable parenteral formulations of proteins, the horizons continue to expand and novel delivery systems and alternative routes of administration are being sought. The interest in protein drug delivery is reflected by the wealth of literature that covers this topic [150-154]. Typically, protein therapeutics are prepared as sterile products for parenteral administration, but in the past several years, there has been increased interest in pulmonary, oral, transdermal, and controlled-release injectable formulations and many advances have been made. Some of the more promising recent developments are summarized in this section. 

Y. J. Wang and M. A. Hanson, Parenteral formulations of proteins and peptides Stability and stabilizers. 

D. Bodmer, T. Kissel, and E. Traechslin, Factors influencing the release of peptides and proteins from biodegradable parenteral depot systems, J. Controlled Release, 21, 129 (1992). 

---