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Finally, PK studies in rabbits showed that Ciclosporin A (CsA) cationic nanoemulsion exhibit a twice higher bioavailability than CsA anionic emulsion. (Restasis ...

Novasorb® from bench to bedside: the successful development of cationic nanoemulsion for ophthalmic diseases Mathieu Schmitt, Frederic Lallemand, Philippe Daull, Mourad Amrane Jean-Sébastien Garrigue; Santen SAS, Novagali Innovation Center, 91058 Evry, France

Introduction

Ophthalmic diseases of of the eye anterior segment are usually treated by topical applications of eye drops. However, it is known that most of the instilled dose is washed away within seconds following administration because reflex blinking and extensive drainage through the nasolacrimal duct. This leads to a poor ocular bioavailability and for the patient to increase the number of instillations per day. This could trigger adverse effects and poor compliance finally resulting in an overall poor treatment efficacy. Therefore, there is a need for ocular products that tackle the ocular bioavailability issues by enhancing the retention time on ocular surface. In the course of 2000’s Novagali Pharma (acquired by Santen Pharmaceutical in 2011) has successfully developed the Novasorb® platform, an ocular drug delivery system, based on idea research work from Pr.Benita (University of Jerusalem, Israel). With two products on the market using this technology (Cationorm® and Ikervis®), the access to nanotechnology-based product has become real for patients suffering from dry eye disease. This poster recounts the successful development of Novasorb® based products from bench to bedside, highlighting the benefits of cationic nanoemulsions for the development of innovative treatments for ocular surface diseases..

Formulation Development

The theory behind the development rationale of cationic nanoemulsions is based on the fact that the the mucin layer overlaying the ocular surface epithelium and is negatively charged. Hence, thanks to the electrostatic attractions between the cationic oil nanodroplets and the negatively-charged mucins, the retention time of formulation on the ocular surface is increased. Along the development of Novasorb®, several cationic agents were evaluated, among which cetalkonium chloride (CKC) was finally selected. Cetalkonium chloride is the most lipophilic subcomponent of benzalkonium chloride, a surfactant commonly used as a preservative in ophthalmic products. Owing to its highly lipophilic features, CKC acts exclusively as a cationic surfactant by being fully located at the interface between the oily core of the nanoemulsion droplets and the aqueous phase. Concentration of CKC, ranging from 0.002% to 0.005% w/w was adjusted to target a zeta potential above +15 mV, enabling both long-term stability of emulsion and electrostatic attraction of the oil nanodroplets towards mucins. Novasorb® nanoemulsions were developed to be sterilized by moist heat (steam sterilization) and easily scaled up. The manufacturing process of the bulk emulsion is a very simple 4 steps process, (i) gentle mixing of aqueous and oily phase, (ii) high shear mixing to decrease the droplet size down to micrometer range, (iii) high pressure homogenization to decrease the droplet diameter to 100-200 nm and (iv) bulk sterilization by moist heat.

Function in emulsion

Ingredients Medium Chaim Triglycerides / Mineral oil Tyloxapol Poloxamer 188

Oil Non ionic surfactant Cationic surfactant

Cetalkonium chloride

Osmotic adjustment pH adjuster Diluent, Aqueous phase

Glycerol NaOH Water for injections

Mechanical role on the ocular surface Restoration of tear film lipid layer Enhance spreading properties of drops onto the ocular surface Help in the stabilization of the TFFL/aqueous phase interface Enhanced residence time on the negatively charged ocular Enhance spreading properties of drops onto ocular surface Emollient agent Ensure osmolality compatible with tear fluid Ensure pH compatibility with tear fluid Hydratation of ocular surface by restoration of aqueous layer of the tear film Correction of the

Non clinical development

Non-clinical testing played a key role in the development of Cationorm® and Ikervis®, as it demonstrated the excellent safety profile of the cationic nanoemulsions. In addition, non-clinical results helped understand the behavior of the cationic nanoemulsion on the ocular surface: showing immediate spreading properties over the cornea; hence improving patients’ comfort. Finally, PK studies in rabbits showed that Ciclosporin A (CsA) cationic nanoemulsion exhibit a twice higher bioavailability than CsA anionic emulsion (Restasis, Allergan) (Figure 1). In addition, PK profiles showed a sustained release of CsA over 72h, suggesting a combination of mechanism of actions of cationic nanoemulsions. A fraction of cationic nanodroplets likely migrated to corneal mucus layer due to electrostatic attraction, whereas another migrates to the lipid layer of tear film, thus limiting the evaporation of water and playing a role of reservoir for lipophilic drugs.

Solubilization of lipophilic drugs Life Cycle Management option

Enhanced bioavailability

Drug controlled release

Strong IP protection

Figure 1: Comparative PK data in rabbits between Ciclosporin A loeaded novasrob® emulsion (Nova22007) and a commercial anionic Ciclosporin emulsion (Restasis, Allergan)

Clinical Development

500 nm

Picture 1: Cryo-TEM picture of a Novasorb® emulsion

Conclusion

Easy scale-up and sterilization

Long-term stability

Picture 2: Features of the Novasorb® delivery platform

Several clinical trials were conducted in dry eye disease (DED) patients and demonstrate the efficacy and the safety of the Novasorb® based emulsions with or without CsA. Cationorm® significantly improved DED signs and symptoms in patients suffering from mild to moderate DED. Ikervis® (the cationic nanoemulsion of CsA) has proven its efficacy on severe keratitis in patients suffering from DED in two Phase III clinical trials.

Novasorb® is a perfect example of the successful development of a nanomedicine platform; starting from an academic idea and finally leading to treatments addressing an important unmet medical need. It has been concrete with Cationorm® available as a medical device since 2008 in Europe and 2010 in the USA (Retaine MGD®). In 2015, the European Medicine Agency granted the marketing authorization for Ikervis®, allowing severely impaired DED patients to have access to a unique ready-to-use CsA treatment for severe keratitis. This success story also proved that regulatory authorities are open to innovative drug delivery platforms.

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