Bart E. Burgess

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. 

Increasing the administered volume of drug product offers the ability to deliver a larger dose, but this approach can have disadvantages. There are limitations to how rapidly a volume of drug can be injected subcutaneously. Although the optimal injection time may vary greatly by individual drug product, and the literature regarding the relationship between injection volume and speed is limited, the subcutaneous space cannot necessarily tolerate rapidly injecting larger and larger dose volumes as tissue disruption and site reaction may occur. Second, if the injection is rapid and the volume is too large, there is potential for the product to leak back from the injection site, reducing the bioavailability relative to the total dose. Lastly, a larger volume of product may require a larger device for self-delivery, and, potentially, a longer injection time, neither of which is likely to be desirable, especially in a crowded therapeutic class.  

A potential solution to large-volume injection challenges is the development and use of systems that administer the dose into the subcutaneous space more slowly. Such systems have the potential to expand the possibilities for self-injection. Due to the longer duration of injection, the device or system may need to be temporarily attached to the body at an appropriate injection site; thus, the current industry interest in patch-injection technologies.  

Such systems use a bladder, cartridge, or other container for the drug product, which may either be prefilled or user-filled. The mechanism to force the drug product into the body may be purely mechanical or electromechanical. Due to the widely varying properties of drug products, which can influence the optimal injection time, systems should be easily adaptable to the demands of the drug-product developer (e.g., changing the system mechanism or varying the programming of an electromechanical system).  

Patch-injector systems specifically can potentially allow for less frequent administration of products already approved for self-injection and for porting of products approved for IV administration to subcutaneous self-injection. In the case of the former, a larger dose can be given by a single injection less frequently than currently approved, more frequent regimens, except in the case where dose-limiting toxicities may exist. The latter can be performed by concentrating the existing formulation or by using the already formulated dosage strength in conjunction with a larger-volume injection. 

Technologies that allow for delivery of higher drug product doses may be applicable to certain emerging needs for mAb products. For instance, the potential to coformulate (i.e., containing more than one mAb product in a single dose), may be a significant area of investigation to create next-generation therapeutic options. A major limitation for some solutions is viscosity, which can be significantly higher than would be expected for a normal mAb solution. The ability to deliver such products in higher volumes may increase the attractiveness of pursuing combination drug products. 

In conclusion, the development of mAb products to address patient needs is complicated by the many physical and chemical factors inherent to such drug-product solutions. Limitations imposed by existing formulation strategies and the dose volume that can be delivered by devices may make some products less attractive than currently approved therapies or less likely to gain user acceptance, even in areas of unmet need. Innovative delivery systems that address the challenges of higher-volume delivery may enable drug manufacturers to develop products that use more desirable dosing and IV administration regimens. 

 is manager of business development, self-injection systems, at West Pharmaceutical Services,  tel. 610.594.3295, 

Articles

The author discusses potential opportunities to improve the patient experience through formulation and delivery device technologies.