Research and development in novel injectable formulations and devices

On an international scale, injectable medicines feature as the second most used class of drugs following oral medicines on the global market. The evolution of these systems is evidenced by the shift from traditional needles and syringes to the recently developed needle-free injectors. Improving patient acceptability, experience and device usability have also been accompanied with the increasing trend from administration of injections in clinical settings to people’s homes.

With regard to drug delivery, novel technologies and applications of nanotechnologies have yielded advancements in targeted drug delivery carriers such as liposomes, microspheres and polymeric micelles. The drive for this market is fuelled by the need for targeted and sustained drug delivery in the treatment of chronic diseases and the need for cost-efficient delivery of high-priced medicines. Examples of such are the biologics and biosimilars, whose presence in the market is increasing.¹

Patient safety and usability

The drive to improve usability has led to the main insulin manufacturers replacing their injection pen devices — the reusable disposable (prefilled) pens and syringes (PFSs) — with those enhanced with new features such as digital dose memory and recording, new dosing mechanisms and a user-friendly design interface that allows easier dose dialling or lower force to deliver the drug.²

With the exponential rise in the use of PFSs due to the benefits of safety, accuracy, security, anti-tampering and counterfeit protection, there is a move within the industry to incorporate the auto-injector. The auto-injector has been shown to reduce primary healthcare costs by up to 95 per cent because patients are able to self-administer at home. The auto-injectors also offer pharmaceutical companies extensions on their products’ lifecycles.³

The growing proportion of patients self-administering has added to the need for increased safety of devices and reduction in needlestick injuries. Safety devices that can be attached to standard PFSs have been developed to reduce needle exposure. The two classes that exist are passive, where the needle is automatically shielded without user intervention, and active, if the shield needs to be activated when the injection is complete.

has developed Safe’n’Sound, a platform of passive safety devices that can be attached by a  simple clip-on to standard PFSs available on the market. Just before the end of the injection, a minimal additional force applied by the user on the plunger activates the safety feature. This additional force is not felt by the user, who continues to push on the plunger to complete the injection. A spring is then released which pulls the syringe back, while the user’s finger is still pushing on the plunger. These two opposing forces help to empty the syringe. Studies have shown that Safe’n’Sound allows the delivery of a more complete and consistent drug dose compared with other commercially available passive safety devices. It also reduces the cost associated with drug overfill volume and increases treatment compliance.⁴

Developments in novel devices

A small group of device development companies have recently been attempting to commercialise drug delivery products based on arrays of microneedles. These devices create channels in the stratum corneum to deliver drugs across the skin and into the dermal layers. Several products focused on achieving a local anaesthetic effect, while other products were pursued to ensure that the drug migrated via interstitial fluid to the vasculature to achieve systemic delivery. As development has proceeded, three main strategic approaches exist:

• Arrays mounted on the end of syringes to effect an injection with minimal discomfort
• Standalone drug-containing devices (eg, coated microneedles, microneedle reservoir patch) designed to be applied or attached to the skin directly
• Two-step delivery systems that use an array to create microchannels through the skin followed by a drug-containing patch designed to deliver the drug through the newly formed microchannels

The recent commercialisation of microneedle drug delivery devices such as Sanofi-Aventis Intanza influenza vaccine, which is based on the Becton Dickson Soluvia syringe-mounted microneedle array device, is a milestone in the transition of microneedle drug delivery from development to the market place.⁶ This vaccination via the intradermal (ID) route involves the administration of the antigen into the dermal layer of the skin. Due to the high concentrations of specialised immune cells in this skin layer and their ability to stimulate an immune response effectively, ID vaccination provides direct and efficient access to the immune system.⁷

Another direction in improving patient adherence and acceptability of injectable therapies is the development of needle-free devices. Early 2010 saw the introduction of the first disposable needle-free device. Sumavel DosePro (Zogenix Inc.) is a single dose, prefilled, needle-free system that delivers subcutaneously 0.5ml of sterile solution containing 6mg sumatriptan for the acute treatment of migraine attacks. This system has been reported to have increased patient satisfaction, confidence and acceptability.^2,5

Developments in novel formulations

The concept of lipid nanoparticles for injectable delivery originated from submicron-sized parenteral fat oil-in-water emulsion used for parenteral nutrition. This led to the idea of encapsulating lipophilic drugs into oil droplets. Much research has been invested into developing stable and sustained release systems for a variety of diseases (eg, treatment of cancers and cardiovascular diseases, targeting to the liver and central nervous system, etc).⁸

FluidCrystal NP injection nanoparticles, developed by Camurus, is a high drug payload liquid crystal nanoparticle system developed for intravenous bolus injection and infusion products, as well as for subcutaneous injection products. The extensive internal surface area can encapsulate both lipophilic and amphiphilic drug compounds and some capacity to carry some peptides and proteins and protect them from degradation from endogenous enzymes.⁹

An attractive alternative to microspheres and implants as parenteral depot systems are biodegradable injectable in situ forming drug delivery systems.
QLT Inc has developed the Atrigel technology which is based on a water-insoluble and biodegradable polymer dissolved in a biocompatible organic solvent to which a drug is added, which then forms a solution or suspension on mixing. On injection into the body, the water-miscible organic solvent dissipates and water penetrates into the organic phase. The phase separation that results in precipitation of the polymer facilitates the formation of a depot at the site of injection.⁸

This drug delivery system is currently used for the delivery of Eligard, a treatment for prostate cancer, and is approved for one-, three-, four- and six-month time-release formulation.¹⁰

MacroMed has investigated thermally induced gelling systems, and developed OncoGel, which contains paclitaxel 6mg/g RelGel (a polymeric system that has an abrupt change in solubility in response to environmental temperature) for intratumoral injection. This system has shown prolonged release of the drug for more than 50 days, with good biocompatibility and toxicity data reported.
Much research has been invested in liposomes as carriers for anticancer agents, vaccine adjuvants and anti-infective agents, where drugs are carried within the phospholipid molecules within an aqueous environment. AmBisome is the first licensed liposomal preparation used for the treatment of systemic fungal infection. It has been reported that the liposomal amphotericin B, by passively targeting the liver and spleen, reduces the renal and general toxicity of the drug at normal doses.¹¹

Conclusion

Although injectable medicines are generally more reliable and predictable because variability of absorption and local degradation is minimal, they are not well accepted by all patients because of the problems associated with using a needle (pain) and sometimes there are complications associated with a high risk of dosage errors. This has added momentum to non-invasive routes for delivery of the therapeutics and has been mentioned and discussed in some of the previous articles in this series.

However, the benefits of this route are substantial enough to ensure further research and development is invested in improving the devices and the formulations to minimise problems and enhance usability and acceptability.

References

1 Global injectabal drug delivery market 2010–15. Industry Analysis Report, February 2011.
2 Romacker M. Latest developments in injectable drug delivery. Available at: www.americanpharmaceuticalreview.com (accessed 18 September 2012).
3 Sharp B, Whyte P. The requirements of an injection device: a clinical perspective. Available at: www.ondrugdelivery.com (accessed 18 September 2012).
4 Dugand P. Impact of passive safety devices on prefilled syringes dose delivery. Available at: www.ondrugdelivery.com (accessed 18 September 2012).
5 Cady R, Aurora S, Brandes J et al. Satisfaction with and confidence in needle-free subcutaneous sumatriptan in patients currently treated with triptans. Headache: The Journal of Head and Face Pain (article first published online 3 August 2011).
6 Greystone Research Associates. Microneedle drug delivery systems moving toward commercailsation by converging with existing delivery technologies. Medical News Today 5 May 2011.
7 Sanofi Pasteur. INTANZA/IDflu, first intradermal influenza vaccine recommended in the European Union. Sanofi Aventis Press Release 18 December 2008.
8 Patel R, Patel K. Advances in novel parenteral drug delivery systems. Asian Jounral of Pharmaceutics 2010;4:193–9.
9 Camurus. FluidCrystal NP injection nanoparticles, Innovative nanoscale technologies. Available at: www.camurus.com (accessed 18 September 2012).
10 QLT Inc. Atrigel technology: punctal drug delivery system. Available at: www.qltinc.com (accessed 18 September 2012).
11 Astellas. Ambisome. Available at:?www.ambisome.com (accessed 18 September 2012).

Hamde Nazar is senior lecturer in pharmacy practice at the University of Sunderland (email hamde.nazar@sunderland.ac.uk)