Mixing Pens and the Future of Diabetes Drugs

Abstract

With the availability of a smaller mixing pen, mass marketing of less stable medications is possible. Bidureon is one such medication, and the properties of its pen are discussed along with the prospects for future mixing pens.

This interesting article ¹ raises points in three very interesting areas of diabetes technology: (1) Can we use technology to reduce the burden of taking medications? (2) How is this type of device evaluated by the FDA? and (3) With more medications being proteins (antibodies and receptor inhibitors) and nucleic acids (antisense RNA, hairpin RNA) we will see many more mixing pens; what do we know about the technology?

Weekly exenatide is created by placing exenatide into microspheres that slowly dissolve in water, releasing the exenatide over approximately 7 days. ² The decreased frequency of dosing results in better blood glucose control compared to twice daily exenatide and slightly poorer control than liraglutide given daily. ³ The large size of the particles, 100 µ, requires a 23 gauge needle since the needle inner diameter should be 3-5 times the size of the particle to avoid clogging. Although not described in the publications, pain may become a factor. The pen needle is not a safety needle, limiting its utility in hospitals and nursing homes.

Dulaglutide has recently been approved as a weekly GLP-1 analog. Dimerization and the addition of an Fc fragments of the heavy chain of IgG4 slow the absorption. ⁴ Since the medication is stable in solution for 14 days at room temperature, a very thin pen needle can be used.

Taking medications daily or even twice daily becomes a routine. Once weekly less so. I look forward to studies of adherence and the possible introduction of reminders by smartphone or text message.

The manuscript gives us some insight into the extensive testing that is required for registration of an injection device, although the authors limit the data to some of the most important characteristics. This device is typical of mixing pens that mix a clear liquid with a solid, each in its own chamber. There is an applicable ISO standard for needle based delivery systems (ISO 11608) which was just revised last year. ⁵ In this manuscript they provide us with data on accuracy, torque, forces, and usability. For accuracy, torque, and forces, their prespecified acceptance criteria were at or below those of ISO 11608 and they met them all. It would be nice to know their acceptance criteria for drop testing (will the pen break if it falls off your refrigerator?) and temperature for usage. Personally, I find a take-home test, injecting an orange or equivalent to be of exceptional value. In a study of my first device, my dog sat on our new pen and broke it in half, requiring a redesign.

Several hormones are currently available in mixing pens and others are planned.^6-8 Glucagon is stable in aqueous solution for only a few hours. Thus, a family member or friend must mix glucagon powder with diluent it in a syringe, as required by current glucagon kits. This has led to dramatic under-utilization of glucagon. ⁹ Some nonaqueous formulations seem to have significantly better stability, but have other problems. ¹⁰ Biodel is currently testing a mixing pen for glucagon that appears to be small, accurate and of course stable. ⁸

Biologics, such as those for Rheumatoid Arthritis need to be injected every two weeks, but are stable in a refrigerator and thus do not require mixing pens. ¹¹ As new biologics develop, proteins, polypeptides, and polynucleotides, some will be less stable and we can expect to see a variety of devices, some with new diabetes medications. ¹² High-quality, easy-to-use devices, such as the one described in the LaRue and Malloy article, ¹ will be important for appropriate therapy.