Technology

Polymeric PDC Technology : An Integrated Approach To Autoinjector Design

PDC components can be moulded with features that directly interact with device mechanisms which can overcome issues such as device recoil, variable use forces and injection speed. Ultimately this reduces the impact on the user, whilst ensuring all required user interface features are present without compromise to overall device size or usability. Approaches to solving common user interface pitfalls through high-risk needle-less systems or ‘power-source’ innovations, form distractions which can detract from fully user-centric devices which could be better resolved through increased design freedoms. A polymeric PDC provides these freedoms which allow engineers to design-out user interface weaknesses typically observed within glass -based PDC autoinjectors.

During the development of a combination device, two main streams of development occur; 1) the drug, and 2) the delivery device. It is imperative that any device development process places equal importance on the delivery requirements of the drug, as well as the requirements of the user interface.

For optimal device design and performance, the user interface should not be influenced by the forces required to deliver the drug and similarly, the drug delivery mechanism should not be influenced by any force the user applies through the user interface. Regularly, these two sets of requirements conflict; biologics may require high delivery forces, whereas specific user populations may require low operation forces from the user interface. Part of the challenge for engineers is to accept this conflict and design around it effectively.

It is possible to ‘decouple’ the conflicting requirements between the user interface and drug delivery mechanism through use of a polymer PDC. To do this effectively, it is imperative that both the needs of the user and the delivery requirements of the drug are fully understood at an early stage in the design process.

AN APPROACH TO COMPLEX FORMULATIONS

The characterisation of a drug is an important step towards designing a fully-integrated device. Oval have developed an Injection Characterisation System (ICS) to thoroughly analyse a range of complex formulations and their properties, allowing an improved understanding of how they must be delivered. This facilitates the correct autoinjector mechanism specification (e.g. needle bore, spring force and container type), and also identifies factors with the potential to affect the user.

The ICS includes sensing capabilities at key positions (Figure 2) to allow feedback on forces and pressures within an autoinjector system during drug delivery.

Figure 2 : ICS Schematic

A load cell reports on the amount of force produced by the chosen power source. The pressure sensor detects the pressure within the drug container and the linear encoder provides data on the location of the plunger which can then be extrapolated into delivery speed. Figure 3 shows the outputs of these sensors which can then be used to inform the design of the delivery system.

Figure 3 : Output plots from the IGS during an injection plunger position in mm (green), delivery force in
Newtons (blue) and container pressure in bar (pink) against time in seconds.

Observing the relationship between internal pressure, P, and the speed of the plunger during delivery, V, reveals information about the formulation properties. By using the modified form of the Hagen-Poiseuille equation2, the viscosity of any formulation can then be evaluated :

Testing the same formulation under different conditions (e.g. speed, needle gauge, temperature), allows full characterisation of drug viscosity and the uniformity between conditions.

Many simple drug formulations are Newtonian (their viscosity will not change with shear force), however, complex formulations are becoming more common. These formulations may take the form of suspensions, emulsions or highly viscous fluids, often displaying many non-Newtonian characteristics (e.g. shear thinning, shear-thickening or pseudo-plastic behaviour). Comparison between the viscosity of the formulation and other characteristics will reveal any non-Newtonian behaviour, allowing it to be modelled accurately.

The power law equation is the most common function used to model non-Newtonian fluids. It is assumed that rather than a direct correlation between shear stress, t, and shear rate, ?, as in a Newtonian fluid, the shear stress is proportional to a power of the shear rate.

Characterising formulations is a vital step towards developing an accurate numerical model for the behaviour of an autoinjector. It allows prediction of both delivery characteristics, and the potential effects of external factors (e.g. environmental conditions and device tolerances).

The culmination of this characterisation process is that for each formulation tested, the delivery mechanism can be optimised through the appropriate specification of required functions and components, such as needle gauge and length, container dimensions, and power source. Extensive knowledge of drug delivery requirements allows for this aspect of the device to be decoupled from that of the user interface. This results in a fully integrated solution which has been developed with consideration to both the user and drug requirements, offering reduced risk, quicker development times and a competitive advantage to glass-based systems.

COMBINING USER AND DRUG REQUIREMENTS

Oval’s subcutaneous platform embodies this integrated philosophy to device design (Figure 4). Combining both user and drug requirements into its development, the platform provides a patient-centric device for delivery of Sumatriptan to migraine and cluster headache sufferers.

The cyclic olefin PDC provides the option to configure component geometry freely, whilst ‘designing-in’ strength to manage high viscosities (>100cP). This permits the delivery of complex drug formulations alongside the inclusion of a full range of features (e.g. automatic needle insertion, end of delivery feedback and passive needle safety), within a simplified and compact form. The subcutaneous autoinjector platform actively decouples the drug delivery challenges from those of the user interface. The use of separate springs for needle insertion and for drug delivery reduces the risk of recoil and excessive force on the patient, whilst retaining the ability to deliver challenging formulations.

Figure 4: Sumalen Ovali 6mg 0.5ml Sumatriptan autoinjector for the treatment of migraine and cluster headaches

This integrated approach is intended to improve clinical outcomes through the greater management of key device aspects such as needle depth. Oval has taken three steps to ensure that the Sumalen Ovali delivers into the correct tissue i.e. subcutaneous:

1. Specify an appropriate needle depth: Informed by ‘state-of-the-art’ population research e.g. ultrasound studies. Correct inserted needle depth is essential to avoid compromising drug pharmacokinetics.

2. Manufacture with controlled tolerances: Enabled through the use of a moulded polymeric container which ensures needle depth and mechanism interface accuracy.

3. Reduce injection depth variability through device design: Promotion of consistent tissue compression during use, reducing needle depth variation e.g. through user technique differences or high activation force requirements.

Overlaying the needle length for 30 Sumalen Ovali devices (pink) with the results of 30 established Sumatriptan reference products (grey), (Figure 5) demonstrates the impact of needle depth on the risk of an intramuscular injection at the thigh. The tissue depth risk profile is derived from two ultrasound studies at the thigh in >400 adult subjects.

In summary, the needle length of the Sumalen Ovali is better specified for the population, achieving tighter manufacturing tolerances than the glass-based reference product (s = 0.09 vs 0.20mm). Tissue compression has the potential to further increase the risk of Intramuscular (IM) injection. It should be noted that the intramuscular risk estimates may be conservative, particularly for the reference product that incorporates a secondary activation button.

Oval’s integrated device design philosophy has ensured that the subcutaneous platform has overcome many inherent issues seen with existing glass-based systems. Combined with Oval’s drug characterisation and user research capabilities, the platform is paving the way towards greater compatibility between autoinjectors and the delivery of biologics.

REFERENCES

1. McDonald C, “Pharm Exec’s 2016 Pipeline Report”. Pharmaceutical Executive, 2015, Vol 35, Issue 11.
2. Sutera S, Skalak R, “The History of Poiseuille’s Law”. Annual Review of Fluid Mechanics, 1993, Vol 25, pp 1-19.
3. Chhabra R P, “Non-Newtonian Fluids: An Introduction”. Rheology of Complex Fluids, 2010, pp 3-34.
4. Gibney M, Arce C, Byron K et al, “Intramuscular Risk at Insulin Injection Sites – Measurement of the Distance from Skin to Muscle and rationale for Shorter-Length Needles for Subcutaneous Insulin Therapy”. Diabetes Technology & Therapeutics, 2014, Vol 16, No 12.
5. Tsai G, Kim L, Nevis IFP et al, “Autoinjector needle length may be inadequate to deliver epinephrine intramuscularly in women with confirmed food allergy”. Allergy, Asthma & Clinical Immunology, 2014, 10:39.

ABOUT OVAL

Oval Medical technologies was founded in 2010 by Matthew Young to provide autoinjectors to meet the needs of patients and a broad range of drugs including biologics. Oval platforms address formulations that are fragile and easily degraded, viscous formulations, some of which exhibit non Newtonian characteristics, and delivery volumes of up to 3ml. Owning the primary drug container allows integrated devices to be designed. This design freedom enables novel mechanisms to be introduced, smaller devices to be developed and the use of polymeric materials gives our Pharma customers complete control over critical component tolerances and control over their supply chain.

Today, Oval is an SMC Ltd. Company adding world class contract manufacturing of medical devices in locations around the world. Oval/SMC can provide customers with a complete service from customisation of our subcutaneous and intramuscular platforms, to production of clinical trials devices, and commercial scale manufacture. SMC also offers integration of filled primary drug containers with secondary packaging and distribution.

Oval Medical Technologies The Innovation Centre, Unit 23 Cambridge Science Park, Cambridge UK CB4 0EY www.ovalmedical.com