Formulating for Needle-free Jet Injection

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Needle-free drug delivery systems provide advantages to patients, clinicians, and biopharmaceutical manufacturers that range from reduced needle-stick injuries and needle waste-to improved patient adherence and convenience-to product differentiation in a competitive marketplace.

Needle-free systems are based on a wide range of technologies, including high velocity, ultrasound, iontophoresis, thermo ablation, and electrophoresis. Jet-injection technology involves the delivery of a high-pressure stream of liquid through the skin and has been increasingly used for vaccine delivery in non-clinical settings (i.e., pharmacies) for self-administration by patients with chronic diseases such as diabetes and arthritis, and more recently for emergency treatment of anaphylactic shock. The first-generation devices used in these applications are, however, more complex than standard needle-injection technology and can cost more.

Newer, second-generation needle-free jet-injection technologies that have been recently commercialized or are under development combine the ease of prefilled syringes with the benefits associated with needle-free technology and are anticipated to experience rapid growth in the coming years. The initial key to success will be developing versions of existing, generic parenteral formulations that are compatible with the technology and require minimal reformulation.

These technologies are coming to market as differentiated branded drug products delivering off-patent, small-molecule formulations via the FDA 505(b)(2) regulatory pathway, thus validating and de-risking the injection systems.

Many market drivers
The number and total market value of parenteral drug products has risen dramatically in recent years as the portion of biologic drugs in development has grown. In 2013, according to Datamonitor Healthcare, 35% of global prescription sales for the top 50 pharmaceutical companies (excluding generic-drug companies) were attributed to injectable drugs, with sales growing 43% from 2010 to 2015.

“This increase in parenterally-administered biopharmaceuticals has driven an increased interest in differentiated injection technologies across the board,“ says John Turanin, vice-president and general manager of San Diego, Calif.-based Zogenix Technologies. Two good examples are prefilled syringes and autopen injectors (the needle is enclosed inside the device), according to Patrick Alexandre, CEO of France-based Crossject.

In addition, as differences in the safety and efficacy of these drugs narrow--particularly with the emergence of biosimilars--biologics manufacturers are looking for other meaningful product-based attributes that might bring a sustainable competitive advantage to their brands. Patients with chronic diseases that also prefer to self-administer their drugs are also looking for alternatives to injectables. There is also growing interest in the reduction of needle-stick injuries and concern about reuse and disposal of needles, particularly in developing countries.

Furthermore, as the push to increase influenza vaccination continues, there is expanding interest in offering “needle-free” vaccines at retail pharmacies to attract in-store traffic, according to Turanin.

Needle-free technologies have been around for many decades and have been widely used in the agricultural setting for the rapid vaccination of large numbers of livestock at a given time. Similarly, human drug delivery using needleless technology was largely limited to mass vaccinations by trained healthcare workers.

Second-generation technologies
The first generation of needle-free systems were approved as medical devices via the 510(k) pathway, with the earliest devices on the market in the 1990s. Confirmation of the delivery depth for a specific drug requires clinical trials. Typically the devices have a durable, multi-use actuating mechanism (often a spring) to dispense a liquid drug from a disposable plastic cartridge that has been filled from a vial by the user. The patient must load the spring or prime a gas reservoir and then load the drug into the cartridge; this complex process can be quite difficult for patients compared with using a standard needle-based system with an autoinjector, according to Alexandre.

Second-generation technologies have only recently been brought on the market or are still in the commercialization stages. These needle-free jet injection systems are single-use technologies that are simple for patients to use and come with a pre-measured dose. The patient only needs to place the injector at the proper location and push the barrel.

Many practical advantages
Needle-free jet injection technology offers advantages to patients, healthcare workers, payers, and biopharmaceutical manufacturers. “For a patient or family caregiver, the opportunity to inject without a needle can overcome the lack of confidence typically faced by someone who has to inject for the first time and then on a regular basis,” observes Turanin. He adds that while needle-phobes are generally thought of as the target patient segment, most people prefer not to have injections if given an alternative. The option to have needle-free injections can also help overcome a patient’s reluctance to accept drug therapy that requires injections, especially if the drug must be taken over a long period of time.

In fact, patient adherence to the prescribed medication schedule may be greater with needle-free injections than standard injections because they are easier to use and of very short duration, according to both Alexandre and Turanin.

A dose is completely delivered using jet-injection technology within 50 microseconds, according to Alexandre. As a result, it is not possible for the patient to halt an injection and receive only a partial dose. He also notes that the ease of use and rapid delivery that jet injectors provide can be particularly beneficial when a patient needs to receive treatment immediately, such as in the case of anaphylactic shock due to an allergic reaction. “Even patients in distress can give themselves the needed medication and have it distributed in their systems in a very short period of time,” he explains.

Additional benefits of needle-free jet injection technology include avoidance of accidental skin punctures, high reproducibility, and potentially improved immune responses to vaccines.

Biopharmaceutical manufacturers, and particularly biosimilar developers, can benefit from differentiation of their products. “Branded and generic/biosimilar producers have the opportunity to apply the intellectual property of needle-free technology within a drug/device combination and extend the value of a brand nearing the end of its patent life with a highly-differentiated technology versus standard needle-based systems,” states Turanin. He also notes that the physics of needle-free injection permits the delivery of highly concentrated, viscous formulations that cannot be delivered by autoinjectors.

Numerous applications
Needle-free technologies have been studied both in vitro and clinically with many drugs, including small molecules (e.g., anesthetics and pain medications), vaccines (e.g., influenza), antiretrovirals (enfuvirtide), peptides (e.g., insulin, interferons, somatropin), and biologics (e.g., gonadotropins, erythropoietin, and monoclonal antibodies such as IgG and Humira [adalimumab]).

Commercially, needle-free systems regulated by FDA as 510(k) medical devices are available for use generically for injection; four of these are also included on the labels of specific commercial drug products, including Tev-TropinT-Jet (Teva), Zomacton Zomajet (Ferring), Saizen cool.click-2 (MerckSerono), and Afluria (bioCSL). In addition, two commercially-available products approved as drug-device combinations in the United States use needle-free technologies: Zingo (lidocaine hydrochloride monohydrate, Marathon Pharmaceuticals), a powder intradermal injection system to provide topical local analgesia prior to venipuncture or peripheral intravenous cannulation; and Sumavel DosePro (sumatriptan injection), which is manufactured for Endo by Zogenix, for migraine and cluster headaches.

“Under today’s regulatory climate, any needle-free delivery technology needs to be studied for delivery of a specific drug to ensure safety and effectiveness, and, in particular, delivery of the drug to the target tissue depth (subcutaneous vs. intramuscular) in order to substantiate its label claim,” Turanin says. Suitability for different types of drugs is best determined by the drug’s target product profile. If the final drug product is for self-administration at home, then a prefilled system may be preferred, which would also drive the selection toward a cartridge made of compatible materials. Generally, any stable liquid formulation, and even stable suspensions, can be delivered by needle-free injection technologies.

Formulation challenges
Early in the development of needle-free injection systems, questions were raised about the possibility of damages to biologic molecules due to exposure to the high pressures and high shear forces involved during jet injection. These concerns have largely been addressed and degradation has been shown not to be an issue with currently commercialized second-generation technologies, according to Turanin. He notes that most studies completed by Zogenix have found that when air-fluid interfaces are excluded, the shear forces involved during the jet-injection process have minimal impact on protein structure. In addition, no degradation or aggregation of adalimunab was observed when delivered using Zogenx’s DosePro system. “One of the biggest remaining challenges is actually overcoming misconceptions about second-generation needle-free pharmaceutical technologies that were originally formed based on performance issues with first-generation systems,” Turanin notes.

It is important, however, to demonstrate compatibility/stability of the drug within the needle-free system’s container closure and its integrity post administration, particularly for biologic formulations. In some delivery systems, protein aggregation has been observed at longer exposure time to shear flow. The presence of contaminants and the surface energy and roughness of the syringe are thought to be factors. “More research is needed to understand the dynamic protein structures present in formulations and at interfaces, as well as how an injection event influences structure and activity, particularly at high concentration,” says Turanin.

Current development status
Zogenix has developed data supporting the use of its DosePro technology with a range of formulations, including those that are highly viscous, and, as mentioned, Zogenix currently manufactures a product for Endo Pharmaceuticals. Crossject has also evaluated its ZENEO technology with different types of molecules, completing more than 10,000 tests on human skin, including seven preclinical and seven clinical trials, according to Alexandre. He notes that the company has identified more than 200 injectable molecules that are compatible with its technology. Crossject is due to file for regulatory approval shortly, with an expected launch of commercial methotrexate at the end of 2015, according to Alexandre. Manufacturing capacity of up to 25,000 units/day is being constructed, and he expects the facility will be fully operational within two years. Alexandre also notes that regulatory filing for sumatriptan (for acute migraine) will be completed in the first half of 2016.

Future directions
Both Zogenix and Crossject continue to pursue development projects. Zogenix is looking to increase the volume of its prefilled dose to 1 mL or greater and has partnered with Battelle on the project. The company is currently looking for biopharmaceutical sponsors to drive the remaining development stages with specific drug targets, according to Turanin. A second project is focused on the development of a hand-held, reusable multi-dose actuator for delivery of its single-dose, prefilled disposable drug cartridges. “We think such a system would be ideally suited for in-clinic vaccinations or for frequently-dosed or lower-cost therapeutics in the home setting,” he observes.

Crossject is interested in exploring the jet-injection delivery of drugs that are currently formulated as freeze-dried (lyophilized) products. “Often lyophilization is used because the active biologic substance is not stable in aqueous solution. Therefore, these products will require some level of reformulation in order to enhance their stability,” Alexandre explains.

Whether or not such a formulation challenge can be overcome, the future for needle-free jet injection technology appears to be bright. Both biosimilars and new biologic drugs in development can benefit from the advantages provided by needle-free technologies, and the continued use of needle-free systems in vaccination programs can be expected. “Challenges within the biopharmaceutical industry and competitive market conditions are finally in alignment to stimulate more rapid adoption of needle-free technologies by the industry,” Turanin concludes.

Article DetailsBioPharm International
Vol. 28, Issue 4
Page: 38-41

Citation:
When referring to this article, please cite as R. Peters, “Formulating for Needle-Free Jet Injection,” BioPharm International 28(4) 2015.