Entire biopharmaceutical development projects can succeed or fail based on the feasibility of an acceptable dosage form. Therapeutic proteins range in size from a few hundred to over 100,000 Daltons. The biological manufacturing process leads to complex, unstable, and potentially variable products that frequently require novel dosage forms and new patterns of process validation.
By far the most common delivery method used in the biopharmaceutical industry is parenteral dosing; that is, liquid formulations for subcutaneous or intramuscular injection or intravenous drip. "An assured bioavailability will make this route the first development objective," explained D. Ganderton from the Chelsea Department of Pharmacy at King's College in London in Polypeptide and Protein Drugs: Production, Characterization, and Formulation. "Until a consistent bioavailability, which may be acceptable even if low, has been achieved, formulations derived for the oral route should not be included." Bioavailability measures how much of the drug molecule arrives at its site of action compared with how much is in the formulation delivered to the body.
"In exploiting routes other than parenteral administration," Ganderton cautioned, "one encounters barriers for which there is little or no intrinsic permeation of the peptide. Breaching these barriers raises important questions of toxicity and, until massive research is carried out on the mode of action of penetration enhancers and the reversibility of their effects, a major regulatory hurdle will be raised against their use. In the meantime, much can be done to refine parenteral dosage forms, both in terms of the time course of their action and the ease with which they are used."Ganderton wrote those words over a decade ago, but they still apply to most development projects today.
Parental Drugs Scientists are refining injectable delivery forms for better patient comfort, convenience, and compliance with dosage regimens. Three main technologies are under development: high-concentration formulations, needle-free injection devices, and controlled — sustained or targeted — delivery.
High-concentration formulations. Comfort and efficiency of delivery limits the volume of subcutaneous injections to less than one milliliter per injection. The less volume a patient must receive in a single injection, the better. Many biopharmaceutical companies are exploring high-concentration formulations (>100 mg/mL) for protein drugs that require large doses, such as some monoclonal antibodies.
The improper selection of filling equipment for high-concentration proteins will result in sheared, precipitated, aggregated, or adulterated solutions during the actual filling step. Traditional vial-filling methods (see Chapter 4) must be replaced by gentler technologies. For high-concentration formulations, lyophilization may be used to concentrate rather than preserve the formulation. The freeze-drying process removes water, and the formulation may be reconstituted by adding back into it a smaller quantity of water-for-injection.
Questions yet to be answered about high-concentration formulations include the details of loading concentrations and fill volumes. The company's marketing department has a say here: Do end users want to see a vial with hardly anything in it? More technical questions arise over the higher concentrations of excipients in the product. Will stabilizing-excipients impede tonicity at high concentrations?
Another emerging technology is iontophoretic (electrically assisted) delivery. The skin is not naturally permeable to peptides and proteins; its main job (besides acting as the body's largest sensory organ) is precisely this kind of protection: keeping what's outside from getting inside. However, it can be induced to take a certain amount of very specific material — a formulation on the skin, held in place by an adhesive that keeps other substances away from the delivery site — by an electric field that temporarily changes the chemical and physical properties of the skin cells. As soon as that electrical field is switched off, the skin returns to its normal state.