Protein therapeutics administration

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. 

Test Species Test Article Dose Levels Frequency Administration Beagle dog Protein therapeutic 300, 100, 30 and 10 (ig/kg plus vehicle control Every other day (EOD), 14 doses total Subcutaneous, bolus injection duplicate aliquots of each formulation collected predose and postdose for the F , 7th, and 13lh dose to be analyzed for test article concentration... 

Selection of the appropriate route of administration and delivery device is critical for the commercial success of a drug product. Although injections are the most efficient delivery method for proteins, they are not always the most suitable from the patient s perspective. Few routes of administration (IV, IM, SC, pulmonary, and topical for local delivery) have been successful to date with protein therapeutics because of the size and complexity of the protein structure. Consideration of the bioavailability via a given route must be made when determining the dose required. Use of a delivery device such as an implantable pump, needle-free injector, or dry-powder inhaler may yield a product with a commercial advantage over a competitor s product. 

Some of the key factors in considering specific delivery systems are safety, stability, and efficacy. The parenteral administration of proteins and peptides today offers assured levels of bioavailability and the ability of the product to reach the marketplace first. It is safe to assume that over 95% of the protein therapeutics approved by the Food and Drug Administration (FDA) today are injectable products since parenteral administration avoids physical and enzymatic degradation. 

Another specific problem of protein therapeutics is their relative instability, which calls for strict regimens in storage and handling. In principle, protein drugs need a cold chain that is maintained from the manufacturing plant until administration to the patient. The CHMP has indicated that biosimilar producers need to show that they control the distribution of their products. 

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. 

Disopyr mide. Disopyramide phosphate, a phenylacetamide analogue, is a racemic mixture. The dmg can be adininistered po or iv and is useful in the treatment of ventricular and supraventricular arrhythmias (1,2). After po administration, absorption is rapid and nearly complete (83%). Binding to plasma protein is concentration-dependent (35—95%), but at therapeutic concentrations of 2—4 lg/mL, about 50% is protein-bound. Peak plasma concentrations are achieved in 0.5—3 h. The dmg is metabolized in the fiver to a mono-AJ-dealkylated product that has antiarrhythmic activity. The elimination half-life of the dmg is 4—10 h. About 80% of the dose is excreted by the kidneys, 50% is unchanged and 50% as metabolites 15% is excreted into the bile (1,2). 

EoUowing po administration moricizine is completely absorbed from the GI tract. The dmg undergoes considerable first-pass hepatic metabolism so that only 30—40% of the dose is bioavailable. Moricizine is extensively (95%) bound to plasma protein, mainly albumin and a -acid glycoprotein. The time to peak plasma concentrations is 0.42—3.90 h. Therapeutic concentrations are 0.06—3.00 ]l/niL. Using radiolabeled moricizine, more than 30 metabolites have been noted but only 12 have been identified. Eight appear in urine. The sulfoxide metabolite is equipotent to the parent compound as an antiarrhythmic. Elimination half-life is 2—6 h for the unchanged dmg and known metabolites, and 84 h for total radioactivity of the labeled dmg (1,2). 

Electrotransport technology offers a number of benefits for therapeutic appHcations, including systemic or local adininistration of a wide variety of therapeutic agents with the potential adininistration of peptides and proteins long-term noninvasive administration, improving convenience and compliance controlled release, providing a desired deflvery profile over an extended period with rapid onset of efficacious plasma dmg levels and in some cases reduced side effects and a transport rate relatively independent of skin type or site. Additional benefits include easy inception and discontinuation of treatment, patterned and feedback-controlled deflvery, and avoidance of first-pass hepatic metaboHsm. 

Antihemophilic factor [9001-28-9] (AHF) is a protein found in normal plasma that is necessary for clot formation. It is needed for transformation of prothrombin to thrombin. Administration of AHF by injection or infusion can temporarily correct the coagulation defect present in patients with hemophilia. Antihemophilic factor VIII (Alpha Therapeutic) has been approved by the FDA as replacement therapy in patients with hemophilia B to prevent bleeding episodes, and also during surgery to correct defective hemostasis (178). 

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