Drug Delivery Technology

AUTO-INJECTOR
EVOLUTION

1. The Original Auto-Injector
Platform

In 1973, the US FDA approved an auto-injector filled with atropine, a modified version of the original ACE auto-injector. Like the ACE auto-injector, the atropine auto-injector is aimed at delivering small volumes in a single chamber, less than 1 mL of drug, in battlefield-like situations. The original atropine auto-injector, which has been in constant use over the past 35 years, delivered a 2-mg dose of atropine in a 0.7-mL solution. Today, atropine doses are available for use in homeland defense settings in 2-, 1-, 0.5-, and 0.25-mg auto-injectors. The same style of auto-injector also is used to deliver morphine to treat pain in wounded soldiers.

2. The ComboPen Platform

The need for a new style of military auto-injector arose in the 1970s. The military discovered that an antidote cocktail of atropine, benactyzine, and the oxime N,N’- trimethylenebis-[pyridine-4-aldoxime bromide] - referred to as TAB - was more effective than atropine alone in reducing lethality of the nerve agent sarin. ⁴However, use of the TAB meant the US military needed an auto-injector that could accommodate the three-drug cocktail, which required a glass container and capacity for 2-mL drug volume.

At the time, STI was developing an auto-injector capable of delivering up to 3 mL of solution. STI modified the new auto-injector, which was originally aimed at delivering lidocaine for the treatment of cardiac arrhythmias, to deliver the new TAB antidote. The auto-injector was dubbed the ComboPen because the new antidote was a combination of drugs in a single chamber. The US Department of Defense fielded the ComboPen filled with TAB for several years in the 1970s. However, the antidote cocktail reportedly caused anticholinergic effects in the absence of nerve agents and was associated with adverse events inappropriate for the battlefield. Therefore, the Department of Defense eventually discontinued its use. ⁴

THE MARK I NERVE AGENT ANTIDOTE KIT: STI and the military ultimately used the ComboPen

platform to field a TAB replacement drug called pralidoxime chloride. This drug and the ComboPen platform are still in use today. Beginning in 1982, the two original platforms were packaged together by the Department of Defense in the Mark I Nerve Agent Antidote Kit (atropine injection and pralidoxime chloride injection). The new kit provided a two-drug nerve agent antidote consisting of atropine and the oxime pralidoxime chloride. The antidote combination counteracts the effects of excess build-up of acetylcholine caused by nerve agent exposure. ⁸^{, 9}Atropine, the primary antidote for nerve agent poisoning, works by competing with excess acetylcholine (ACh) - a neurotransmitter that stimulates breathing, intestinal function, vascular function, and muscle movement - blocking the effects until normal function can return. ⁸Pralidoxime chloride helps reactivate the enzyme acetylcholinesterase, which is inactivated during exposure to most organophosphorous nerve agents, thereby halting the continued build-up of ACh at receptors and restoring normal function to nerves, muscles, and glands. ⁹To administer the antidote using the Mark I Kit, individuals followed the numbered directions on the auto-injectors, first injecting 2 mg of atropine, followed by 600 mg of pralidoxime chloride.

NEW BATTLEFIELD OPTIONS: In the 1990s, STI merged with a medical device company and became Meridian Medical Technologies, Inc. At about the same time, Meridian began supplying the US Armed Forces an auto-injector filled with diazepam based on the ComboPen platform. Because the diazepam auto-injector was and still is used as an adjunct treatment of seizures caused by nerve agent poisoning, soldiers now had three Meridian products to counteract the effects of nerve agent poisoning. ⁴Over the years, the ComboPen platform also has been used to successfully field a number of other nerve agent antidotes and treatments for allied governments.

USE IN CIVILIAN MEDICINE: In 1986, the FDA approved an auto-injector filled with lidocaine HCl based on the original ComboPen

platform. ¹⁰With the lidocaine HCl atuo-injector, emergency medical services (EMS) personnel could deliver intramuscular lidocaine for the treatment of cardiac arrhythmias. Moreover, individuals who had suffered a heart attack and were at risk for arrhythmia could carry the lidocaine HCl auto-injector if they participated in a telephone-based monitoring and intervention program. ¹¹(Note, this product is no longer available.) Use of the ComboPen auto-injector platform by civilian patients expanded further the following year, with the FDA approval of an auto-injector loaded with epinephrine. The epinephrine auto-injector enabled adults and children to self-administer drug to quickly treat a critical allergic reaction to insect stings or bites, foods, drugs, and other allergens, as well as idiopathic or exercise-induced anaphylaxis. ¹²With increasing prevalence of reported peanut and tree nut allergies, availability of the device quickly grew. ¹³Today, the epinephrine auto-injectors (0.3/0.15 mg) remain mainstays of the Meridian product line and are marketed worldwide. In 2003, Meridian was acquired by King Pharmaceuticals, Inc. Today, King continues to develop new products aimed at the civilian market. For example, King currently is conducting a pivotal Phase III clinical study evaluating the efficacy of diazepam when delivered in the ComboPen auto-injector platform for the treatment of acute repetitive epileptic seizures. ¹⁴

3. The BinaJect Platform

Further evolution of the auto-injector occurred through collaboration between Meridian and the US military, which wanted to lighten the load carried by its soldiers and reduce the number of injections that were required to administer the nerve agent antidotes contained in the Mark I Kit.

Beginning in the 1980s, the US military worked with Meridian to develop an auto-injection system that would store and deliver both atropine and pralidoxime from a single device. The two drugs would need to be delivered in a single continuous intra-muscular injection using a single needle, while maintaining separation of the two drugs in the auto-injector and at the human injection site.