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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.


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.


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.


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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