The approaches of Mr Lau and Mr Vickers to formulating a combination injectable
207 In his first affidavit, Mr Lau stated that he was instructed to assume that in June 2010, he was given the task of formulating a combination injectable product containing: (a) a macrocyclic lactone; and (b) levamisole. It is apparent from the heading to the relevant section of the affidavit that the product was for cattle. He stated that he, together with his Chemistry and Quality teams, would work with the Biology, Regulatory Affairs, Marketing and Sales, and Technical teams to develop a product that was effective, stable, safe, sterile and syringeable.
208 Mr Lau stated that for the combination injectable, he would select levamisole HCl rather than levamisole base or levamisole phosphate (for the reasons set out at [199] above). In relation to the macrocyclic lactone in the combination injectable, Mr Lau stated that he would prefer to use ivermectin or abamectin (for the reasons set out at [199] above).
209 Mr Lau stated in his first affidavit that, due to the chemical incompatibility of levamisole and macrocyclic lactones (see [200] above), he would have explored strategies for formulating the combination injectable wherein the levamisole and the macrocyclic lactone were separated. Two main strategies for formulating the combination injectable that he would have considered would have been:
(a) micellar formulations; and
(b) suspension formulations.
210 In each of these types of formulations, Mr Lau explained, the two active ingredients would be physically separated. Mr Lau stated that he would have also considered it possible to try formulating the combination injectable as an emulsion formulation, but this would be a less attractive option.
211 In relation to the micellar formulation approach, Mr Lau stated that a micellar solution forms when the concentration of a surfactant in water reaches the critical micellar concentration, resulting in the formulation of micelles. He stated that a micellar solution is a common way to stabilise macrocyclic lactones in an aqueous environment. He stated that, on this approach, the abamectin or ivermectin would be dissolved in an organic co-solvent and reside in the hydrophobic interior of the micelle; the levamisole HCl would be dissolved in the aqueous environment outside the micelles.
212 In relation to the suspension formulation approach, Mr Lau stated that a suspension formulation is one that contains solid particulates suspended in an aqueous or organic carrier. Mr Lau provided the following description and explanation of the approach he would take:
(a) If he formulated the combination injectable as a suspension, he would dissolve the abamectin or ivermectin in the carrier, and keep the levamisole HCl in suspension. This is because, compared with levamisole HCl, macrocyclic lactones such as abamectin and ivermectin are generally administered at very low doses and are therefore present in the formulation at low concentrations. If an active ingredient is present at a low concentration, it is preferable to formulate it as a solution so that the active ingredient is uniform throughout the formulation. If an active ingredient is present at a low concentration and it is formulated as a suspension, there is a greater risk that it will not be dispersed evenly throughout the formulation, which means that each injection may not deliver the required amount of that active ingredient.
(b) Because he would be dissolving the abamectin or ivermectin, due to the chemical instability of macrocyclic lactones in aqueous environments, he would use an oil or organic carrier as the base, rather than an aqueous base. He would also use a co-solvent, such as benzyl alcohol, which he knew to be a very good solubiliser of macrocyclic lactones, in order to speed up the rate of dissolution of the macrocyclic lactone. The benzyl alcohol would also act as a preservative. He might use more than two organic carriers, depending on the viscosity of the preliminary formulations he made and whether the viscosity was suitable for accommodating the suspended levamisole HCl. If necessary, he would adjust the viscosity of the formulation. This could be done by adjusting the amounts of lower-viscosity and higher-viscosity solvents and/or by using a suspending agent.
(c) A suspending agent is a type of viscosity modifier that can increase the viscosity of a carrier solvent. When included in a suspension formulation, suspending agents can help to maintain the suspendability and reduce the rate of settling of the solid particles. By "suspendability", he meant the ability of a carrier media to suspend any solid particles, and to minimise sedimentation of those particles. The suspendability of a carrier is affected by the density and the viscosity of the media that makes up the carrier, as well as the density and the size of the solid particles. Aluminium stearate is an example of a suspending agent that he and his team commonly used for an oil-based or an organic carrier-based suspension formulation.
(d) If he formulated the combination injectable as a suspension, he would expect the macrocyclic lactone and the levamisole HCl to be chemically stable. This is because having the different active ingredients in different physical states minimises the interaction between them. pH incompatibility is also not an issue when oils or organic carriers are used as a formulation base. This is because the concept of pH refers to the hydrogen ion concentration of an aqueous solution, and oils and organic solvents do not dissociate in the same way that water does.
213 Although Mr Lau's evidence was that, in developing a new formulation, he would usually receive relevant information from his biology colleagues about issues of dose and efficacy, it does not appear that this occurred in relation to the hypothetical development project described in his first affidavit. Mr Lau said in oral evidence that he was not provided with the affidavits of Dr Martin.
214 In his affidavit, Mr Vickers also described the approach he would have undertaken if given the task of trying to formulate a new combination injectable product containing levamisole and a macrocyclic lactone as at the priority date. He stated that his preferred starting point would have been to base a proposed formulation on the commercially available injectable products, although (to his knowledge) there were no injectable products as at June 2010 that combined levamisole and a macrocyclic lactone. The basis for Mr Vickers's preference was that the commercially available injectable products were known to contain excipients suitable for injectable products, and their properties, including efficacy, safety, residues and tolerance at the injection site, were known.
215 For reasons set out in his affidavit, Mr Vickers would prefer levamisole phosphate as the form of levamisole that he would use if formulating a combination injectable as described above.
216 Mr Vickers stated that his preferred option in developing a combination formulation would have been to have the levamisole dissolved in an aqueous phase, to try to have its release profile match as closely as possible the release profile of the existing levamisole injectable products. He stated that he would have tried having the macrocyclic lactone present in an organic solvent as a micellar or micro-emulsion formulation, and investigated stability at different pH levels. Only if that were unsuccessful, Mr Vickers stated, would he have considered using a different carrier system for the levamisole that did not involve water.
217 Mr Vickers stated that, using a partition formulation, which physically separates the solubilised active ingredients, was how the problem was addressed in the Switch oral drench product, although this was an oral liquid drench and not an injectable product. For the reasons set out in his affidavit, Mr Vickers stated that it would not be straightforward to adjust an oral formulation to a formulation for injection administration.
218 Mr Vickers stated that, as at the priority date, he was unaware of any levamisole injectables that did not contain water, and so developing a non-aqueous formulation would involve trialling different solvents or solvent systems (mixtures of different solvents).
219 Mr Vickers referred in his affidavit to exploring possible non-aqueous formulations. He stated that, in that regard, he would need to conduct tests as to the stability of the two active ingredients over time and the efficacy of the product. He stated that he would be concerned at the impact of changing the levamisole from an aqueous formulation to a non-aqueous formulation, as he considered this to be likely to affect the rate of absorption from the injection site into the animal, and hence the product's efficacy. Mr Vickers stated that:
(a) levamisole is quick acting, with peak blood levels within about two hours and total elimination within about 24 hours;
(b) if an insufficient dose is delivered or absorbed, it may not sufficiently paralyse the worms to result in them being killed and expelled; and
(c) he would have been less concerned at the impact on the abamectin or other macrocyclic lactone, as macrocyclic lactones are longer acting, and a variety of short and long acting formulations containing abamectin and other macrocyclic lactones were known and registered.
220 In his affidavit, Mr Vickers responded to the evidence in Mr Lau's first affidavit as to the approach he would have taken to the formulation task. Mr Vickers stated that, in general, suspensions are not good for injectable products because of the difficulty of injection and because the solid particles can settle in either or both of the container or the syringe and so require resuspension. For this reason, in Mr Vickers's opinion, for an injectable product, a solution is preferable. Mr Vickers stated that, by "solution", he was referring to a clear liquid, typically with lower viscosity, and where the actives remain homogenous and evenly distributed or dispersed through the formulation; this could include a solution where all components are fully dissolved, but also a solution that included micelles.
221 In response to Mr Lau's two main strategies for formulating levamisole and a macrocyclic lactone, Mr Vickers stated that he would not have considered a suspension for an injection. This was because, for an injectable product, either he would have wanted something solubilised or a clear solution that was easily injectable; these formulations also typically remain homogenous and do not require shaking and resuspension. Mr Vickers stated that he was not aware of any liquid product for any administration route that included levamisole as a suspension.
222 Mr Vickers also stated that he would have concerns about the use of a suspension because of the high loading of levamisole that would be needed to achieve the required dose rate. He stated that he would also have concerns that Mr Lau's second approach could change the release profile of the levamisole, making it different from the known release profile. Mr Vickers stated that he had no knowledge of how a levamisole particle would be tolerated as an injection as at June 2010.
223 Mr Vickers stated in [131] of his affidavit that, normally, when levamisole HCl is in an injectable formulation, it is a solution; in this form, once injected, it is freely absorbed into the animals' system. Mr Vickers stated that a particle will take longer to be absorbed and this is problematic for the following reasons:
(a) When an aqueous levamisole solution is injected into an animal, the rapid absorption allows for the rapid onset and high peak of levamisole, which is important in its mode of action; the injected levamisole would also be rapidly excreted. By contrast, a particulate form of levamisole, having a slower rate of absorption, could make the levamisole less effective. The required peak blood levels may not be achieved, leading to a failure to kill the parasites, and it may also be less rapidly excreted. While micronisation of the levamisole particles may possibly assist with the rate of absorption, the rate of absorption may still be limited by the use of an oil or organic carrier. This could only be determined by testing.
(b) Levamisole HCl is an irritant at the injection site. Given the severity of injection site reactions encountered when delivered as a solution, which is rapidly absorbed from the injection site, he would expect injection site reactions to be much worse where the injection involves levamisole HCI in particulate form, because the levamisole is less rapidly dispersed from the site. Further, given that levamisole is immunostimulatory, this may further promote injection site reactions.
(c) The use of levamisole HCI as a particle may also adversely affect syringeability.
224 In oral evidence, Dr Martin accepted that it would necessary to investigate whether having the levamisole present as a particulate affected the efficacy, bio-availability and safety of a formulation. He said that he did not know whether having an active ingredient present as a particulate could potentially slow the rate of absorption, and that he had not seen evidence to that effect. Dr Martin was asked whether, for an active ingredient to be transported from the injection site to the animal's gut would require the active ingredient first to be dissolved in some appropriate media within the animal. He said that it would need to be absorbed, either by being dissolved or by some other process. In response to a question whether having the levamisole present in particulate form meant that an extra step was required compared with levamisole that is dissolved in water. Dr Martin stated that, if the levamisole salt was in particulate form, it could be possible that it would simply dissolve in the aqueous environment in the subcutaneous area of the animal. He added:
And I don't know, but I would be interested to ask the question as a researched [sic] or how that did impact on its absorption and the blood levels in the animal. I don't know the answer. I would want to explore it.
225 On the basis of the evidence in [131] of Mr Vickers's affidavit and the oral evidence of Dr Martin summarised in the preceding paragraph, I find that, if levamisole was present in particulate form in a formulation, an issue requiring investigation would be whether this affected the rate of absorption of the levamisole (and this formed part of the common general knowledge at the priority date).
226 In his third affidavit, Mr Lau responded to Mr Vickers's affidavit. Mr Lau stated that, to the extent that Mr Vickers was proposing to solubilise both active ingredients in the same solvent (aqueous or non-aqueous), Mr Lau did not agree that this was a viable approach. This was because levamisole and macrocyclic lactones are chemically incompatible, and when solubilised in the same solvent they tend to react with each other. Mr Lau stated that a further reason not to solubilise both active ingredients in an aqueous solution was their pH incompatibility.
227 Mr Lau also stated in his third affidavit that he did not agree with Mr Vickers that a potential change in the release profile or absorption rate of levamisole salt was a reason not to formulate the combination injectable with the levamisole salt in suspension. Mr Lau stated that an active ingredient could be formulated so as to have a different release profile and a different absorption rate from an existing formulation and still be effective. He stated that the efficacy of the levamisole salt as part of the combination injectable would be tested in the ordinary course of product development.
228 In oral evidence, Mr Lau was questioned about the statement in [60] of his first affidavit (summarised in [212(a)] above) regarding the risk that an active ingredient formulated as a suspension will not be dispersed evenly throughout the formulation. Mr Lau had stated in his affidavit that this risk was greater if the active ingredient was present at a low concentration. It was put to Mr Lau that the same would be true where there was a high concentration of the active ingredient. Mr Lau accepted that, theoretically, this was the case, but said that he did not think it was an issue practically. In response to a question whether he had conducted any tests to establish that it was not an issue practically, Mr Lau said that he had not. I am not persuaded that there was a relevant difference in relation to the risk that an active ingredient may not be evenly dispersed as between a low concentration and a high concentration of the active ingredient. Accordingly, I find that this is a risk in both scenarios (and this formed part of the common general knowledge as at the priority date).
229 Mr Lau was asked during oral evidence about issues regarding agglomeration of particles (that is, the formation of larger particles). Mr Lau accepted that if there are more solid particles present, there is a higher chance of agglomeration; he said agglomeration was possible. Mr Lau was asked whether, all other things being equal, for an injectable formulation, it is preferable to have a solution rather than a suspension. Mr Lau responded: "If you take away the compatibility problem and you take away things like - you might want an extended release product, yes." On the basis of this evidence, I find that, all other things being equal, for an injectable formulation, a solution is preferable to a suspension (and this formed part of the common general knowledge as at the priority date).
230 In oral evidence, Mr Vickers accepted that he recognised, as at June 2010, that if he were to adopt a formulation approach that involved including a macrocyclic lactone and levamisole together in an aqueous solution, two issues that would arise were potential instability and the different pH requirements. He accepted that the issue of instability would not arise to the same degree if he adopted a formulation approach where the macrocyclic lactone and levamisole were separated in some way in the formulation.
231 Mr Vickers accepted in oral evidence that whether an impact on the release rate of levamisole was sufficient to indicate that he should not proceed with the formulation would depend on the extent of the impact. He accepted that the release rate may be acceptable, and this was something he would assess through preliminary tests.
232 Mr Vickers was asked about the issue of the slowing down of the release rate in the context of an approach that had the levamisole present in an oily formulation as particles. Mr Vickers stated that he thought the issue "arises even more so" in such a case. He stated that if the levamisole was present in particles, his concern was: "would that even slow it down further and slow the release rate?" Mr Vickers accepted that he would conduct preliminary tests to evaluate such an approach.
233 In oral evidence, Mr Vickers referred to a suspension of levamisole being "very much unknown" and to the potential for toxicity if the particles were not evenly distributed. Mr Vickers stated that these were reasons why he would not initially consider suspension of either of the actives as particles. He accepted, however, that they were approaches he may have considered in the formulation process, having first considered other options.