N2B-Patch – Development of an intranasal form of therapy for the treatment of multiple sclerosis

Biomaterials for treatment of demyelination disorders of the central nervous system

Effective drugs for the treatment of diseases of the central nervous system (CNS) exist. However, the blood-brain barrier (BBB), which protects the brain as the body's control center, makes it difficult for therapeutic biomolecules in particular to pass through. This can be remedied by nose-to-brain transport via the olfactory nerve, which enables the direct passage of therapeutic antibodies into the CNS. In the N2B-patch project coordinated by Fraunhofer IGB, an intranasal application platform for CNS-active biopharmaceuticals has been developed for this purpose. To do so, an innovative galenical formulation based on biomaterials has been combined with a special applicator and applied as a hydrogel bandage on the olfactory epithelium.

N2B-patch.
Flow-through cell.
© Fraunhofer IGB
Flow-through cell for determination of drug release according to USP 4.

Effective drugs for the treatment of diseases of the central nervous system (CNS) – in addition to multiple sclerosis (MS) these can be the consequences of a stroke, neurodegenerative diseases or tumors – do exist. However, the blood-brain barrier (BBB), which protects the brain as the body's control center, makes it difficult for therapeutic biomolecules to pass through. This can be remedied by nose-to-brain transport via the olfactory nerve, which allows the direct passage of therapeutic antibodies into the CNS [1].

For patients, this innovative form of therapy may provide a less burdensome treatment available to patients, as fewer side effects can be expected and the drug can be administered at longer intervals and without the need for hospitalization.

Acting as project coordinator as part of the EU-funded joint project “N2B-patch”, Fraunhofer IGB has been involved in the development of a medicine-based treatment form for drug delivery over the regio olfactoria. At this position, the brain and the fluids surrounding it are separated from the nasal cavity by only the ethmoid bone and a few layers of cells.  

 

Novel gel patch for nose-to-brain transport

The new therapy form developed in the EU project N2B-Patch consists of different components: the active ingredient itself, a formulation containing the active ingredient, a hydrogel as a carrier material and a suitable applicator for insertion of the gel patch. The active ingredient contained in the gel patch is released over a longer period of time. The patch dissolves and does not need to be removed again. For a long-term treatment, a new patch will be applied.

 

Rasterelektronenmikroskopische (REM) Aufnahme von sprühgetrockneten Chitosan-Partikeln, Vergrößerung 25 000 X
© Fraunhofer IGB
Scanning electron microscope (SEM) image of spray-dried chitosan particles, magnification 25,000 X

Formulation of the active ingredient

Fraunhofer IGB developed the final formulation of the clinical antibody and was involved in the development of the incorporation process into the gel. The active ingredients, monoclonal antibodies (mAbs), were encapsulated in chitosan as matrix material by spray drying. This process allowed us to achieve high encapsulation efficiencies of up to 90 percent while maintaining the bioactivity and structural integrity of the drug. The storage stability of the formulation at room temperature is up to four weeks. In experiments with porcine epithelium, it was shown that tight junctions opened 15 minutes after ex-vivo application of the formulation to porcine olfactory mucosa when chitosan was used as the capsule material [2]. Preclinical proof-of-concept studies in minipigs showed a controlled release profile of the patch and demonstrated CNS bioavailability.

The application of chitosan particles (NiM) causes an opening of the tight junctions in the olfactory mucosa and enables a paracellular transport.
© Fraunhofer IGB
The application of chitosan particles (NiM) causes an opening of the tight junctions in the olfactory mucosa and enables a paracellular transport.

 

Novel formulation with high encapsulation efficiency as a platform technology for therapy of CNS diseases

Here, Fraunhofer IGB has developed a formulation with high encapsulation efficiency that is storage stable at room temperature and whose production can be transferred to industrial scale. This represents a promising new system for improving the formulation of biologics and the associated therapeutic challenges, and may be used in the future (with and without gel patches) as a potential platform technology for other CNS diseases such as stroke and Alzheimer's – or even for certain cancers.

 

Outlook   

Basic research also goes beyond this specific project, as part of the Marie Sklodowska Curie Network "Bio2Brain" coordinated by Fraunhofer IGB. Young scientists from all over the world are involved in this network.

References

[1] Stützle, M.; Flamm, J.; Carle, S.; Schindowski, K. (2015) Nose-to-brain delivery of insulin for Alzheimer's disease, ADMET and DMPK 3(3), DOI: 10.5599/admet.3.3.184

[2] Spindler, L. M. et al. (2021) Nano-in-micro-particles consisting of PLGA, nanoparticles embedded in chitosan microparticles via spray drying enhances their uptake in the olfactory mucosa, Frontiers in Pharmacology 12, DOI: 10.3389/fphar.2021.732954

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In a final project video, the consortium sheds light on the objectives, the challenges and the advantages that a direct transport route from the nasal cavity to the brain, bypassing the blood-brain barrier, could potentially offer for central nervous system drug delivery. Moreover, the latest results of the proof of concept study are presented by the N2B-patch team.

The further development of platform technology for the treatment of other CNS disorders continues beyond the end of the project.

Project information

Project title

N2B-Patch – Nose to Brain Delivery of an API via the Olfactory Region for the Regenerative Treatment of Multiple Sclerosis Using Novel Multifunctional Biomaterials Combined with a Medical Device

 

Project duration

January 2017 – December 2020

 

Project partners

  • Fraunhofer IGB, coordination
  • Contipro a.s. (Czech Republic)
  • MJR PharmJet GmbH (Germany)
  • Fachhochschule Biberach (Germany)
  • Centre for Research and Technology Hellas - CERTH (Greece)
  • Beiter GmbH & Co. KG (Germany)
  • Laboratorio Europeo di Spettroscopie Non Lineari (Italy)
  • JensonR+ Limited (United Kingdom)
  • LGI Consulting Sàrl (France)
  • The European Multiple Sclerosis Platform aisbl (Belgium)
  • University of Bern (Switzerland)

Funding

This project has received funding from the European Union’s Horizon 2020 research and innovation programme under grant agreement No 721098.