For many of today's biologic drugs, formulation and delivery options can present multiple dilemmas when determining product
attributes, including frequency of dosing, dose volume, number of treatments, and delivery mechanism. This article discusses
potential opportunities to improve the patient exerperience through formulation and delivery device technologies.
In an ideal world, patients with chronic conditions could take a single pill once a year, or undergo a one-time noninvasive
treatment that is administered without the need for a hospital or doctor visit. Unfortunately, treatment regimens for many
of today's most prevalent chronic conditions, such as cancer, diabetes, and autoimmune diseases, require multiple, repeated
doses of drug at frequent and regular intervals.
There are opportunities, however, to improve the patient experience using formulation and delivery device technologies. Treatment
regimens can be optimized, for example, by: formulating drugs to higher concentrations to reduce dosing frequency; using higher-volume
delivery systems to deliver a larger volume and reduce dosing frequency; and using higher-volume systems.
To give an example, monoclonal antibody (mAb) drug products have been approved for human therapeutic use for more than 20
years and affect a diverse range of therapeutics targets, including indications for prophylaxis of organ rejection following
transplant, cancer, and various autoimmune diseases (e.g., rheumatoid arthritis, multiple sclerosis, Crohn's disease, and
psoriasis). Most of these approved mAb products are intended for use in an acute care setting and must be administered through
intravenous (IV) infusion. These accommodations are necessary because of the need for weight-based dosing of some products
due to the potential for toxicity at higher doses; the potential for anaphylaxis or other adverse reaction; and the need for
concurrent administration of other drugs intravenously, as with certain chemotherapeutic regimens.
There are, however, approved products intended for self-injection by patients, usually for autoimmune diseases like those
previously mentioned. These include several TNF-α antibody products such as Johnson & Johnson's Simponi and Abbott Laboratories'
Humira. These injections are typically designed for delivery into the subcutaneous space. Attributes of these products have
allowed for self-administration, including a relatively low dose (< 100 mg) for efficacy and a reduced risk of life-threatening
adverse reaction. Both Simponi and Humira are packaged in 1-mL in length prefilled syringes and dosed on a weekly, semi-monthly,
or monthly basis, depending on the patient's particular indication.
In the case of most TNF-α therapies, the therapeutic target and properties of the antibodies used have allowed for relatively
easy formulation and manufacturing because the final product viscosity is low (less than five centipoise) and because the
product can be delivered through commonly available and well-characterized prefillable syringe systems. However, as pharmaceutical
companies develop and test antibodies for new therapeutic products, often in the search for better efficacy and reduced side
effects, challenges can arise. In cases where the dose required for efficacy is significantly higher than currently approved
self-injected products, for example, one must choose between more frequent subcutaneous injections and clinically administered
IV infusion.
Potential solutions would be to increase the dose concentration to fit within the classic 1-mL volume limitation, or to expand
the dose to a larger volume. Concentration has apparently been the choice for many products to date because dosages have increased
in the cases of products like Bristol-Myers Squibb's Orencia, although the 1-mL paradigm has not been broken. In fact, some
recently introduced self-injected products, such as UCB's Cimzia, have concentrations of up to 200 mg/mL.
The exponential relationship between product concentration and viscosity, which often becomes readily apparent above 100 mg/mL,
may limit this strategy significantly because the product either may not be deliverable by self-injection or may not be amenable
to existing fill/finish processes if it is too viscous. Concentration to the necessary level in the final product may not
be possible for all products, because in many cases, upstream purification and manufacturing processes may limit the maximum
concentration for the final drug product more than delivery and fill/finish process concerns. Additionally, drug-product properties,
such as pH and osmolality, along with the use of certain excipients, may limit the most appropriate drug-product concentration.
These properties may need to be kept within certain ranges to prevent patient discomfort and site reaction upon injection.
Certain emerging formulation technologies, including the use of nonaqueous solutions, have shown promise towards mitigating
such concerns, but are awaiting regulatory approval.
