Periodic Reporting for period 3 - N2B-patch (Nose to Brain Delivery of Antibodies via the Olfactory Region for the Treatment of Multiple Sclerosis Using Novel Multi-functional Biomaterials Combined with a Medical Device)
Okres sprawozdawczy: 2020-01-01 do 2021-06-30
N2B-patch stands for Nose-to-Brain-patch. The goal of the project was the development of an innovative technology for multiple sclerosis (MS) treatment by developing a ‘nose to brain’ (N2B) delivery system which will avoid the need for injections and oral medicine. The long-term objective is to improve treatment of MS patients. The therapy of central nervous system (CNS) diseases like MS is still an unmet medical need due to the low CNS bioavailability of innovative drugs like antibodies. On the other hand, the N2B transport of substances is scientifically well-known and a recently clinically proven alternative route of administration as the so-administered substances can bypass the blood-brain barrier (BBB). Nevertheless until now, highly efficient technologies for olfactory uptake and direct brain delivery are missing.
The direct transport route from the nasal cavity to the brain, bypassing the BBB, could potentially offer an exciting method for central nervous system drug delivery.
The N2B-patch partners have developed a promising and innovative N2B drug delivery technology which may improve the treatment of MS based on the synthesis of a biomaterial-based innovative galenic formulation, a novel class of hydrogel matrix-patch and a medical applicator device system. The establishment of pilot manufacturing batches which are cost and resource effective demonstrators and representatives of commercial batches was successful and the transfer of the lead formulations from lab to good manufacturing practices (GMP) environment was efficient. Moreover, the innovative multifunctional galenic formulation is stable. The application has been successfully investigated via mathematical modeling and numerical simulations. The output of the integrated interface computational modeling generated the required input for the design and development of the multifunctional ensemble. Experimental work on the application process by using the 3D casts was performed. The demonstration of the feasibility and biocompatibility of the nasal patch and its application in-vivo was successful.
The international consortium has demonstrated the proof of concept and has therefore shown that a nasal delivery system for biopharmaceuticals in the upper region of the nasal cavity via the olfactory mucosa, the regio olfactoria, is possible.
The direct transport route from the nasal cavity to the brain, bypassing the BBB, could potentially offer an exciting method for central nervous system drug delivery.
The N2B-patch partners have developed a promising and innovative N2B drug delivery technology which may improve the treatment of MS based on the synthesis of a biomaterial-based innovative galenic formulation, a novel class of hydrogel matrix-patch and a medical applicator device system. The establishment of pilot manufacturing batches which are cost and resource effective demonstrators and representatives of commercial batches was successful and the transfer of the lead formulations from lab to good manufacturing practices (GMP) environment was efficient. Moreover, the innovative multifunctional galenic formulation is stable. The application has been successfully investigated via mathematical modeling and numerical simulations. The output of the integrated interface computational modeling generated the required input for the design and development of the multifunctional ensemble. Experimental work on the application process by using the 3D casts was performed. The demonstration of the feasibility and biocompatibility of the nasal patch and its application in-vivo was successful.
The international consortium has demonstrated the proof of concept and has therefore shown that a nasal delivery system for biopharmaceuticals in the upper region of the nasal cavity via the olfactory mucosa, the regio olfactoria, is possible.
The project addresses the development of a biomaterial-based galenic formulation in combination with a medical device for the treatment of MS.
The development of the formulation including an ensemble composed of particles and hydrogel started with the beginning of the project. Various particles had been manufactured for further testing. The lead matrix was selected and for the final formulation the particle development started. Novel techniques to evaluate adhesion and spreading of the formulation at the olfactory region were set-up further one. The technology transfer of the galenic formulation was demonstrated by using previously prepared batch production documentation at pilot scales. The pilot scale manufacturing protocol of the antibody-loaded particles and the hydrogel as a product for the application to olfactory region for nose-to-brain delivery of antibodies is ready. The first large scale manufacturing was realized at MyBiotech and Contipro facilities for a batch size representative of industrial scales.
The validity of the end product including the applicator and the galenic formulation is a very important step. Therefore, the setting of the user-requirement specifications (URS) started where the product quality related all relevant attributes and their specifications are defined for safe medicinal product development. This URS has served as the basis for the further evaluation of the assigned properties ensuring the consolidation of an aligned development, once it has been transmuted in a functional design specification. The experimental work on the application process was supported by using 3D casts. The moulding design for the applicator was completed. The respective functional design specifications were based on the URS requirements, matching the physical, the chemical and the mechanical properties as well as the functionality of the CCS together with the N2B matrix patch generated by the computational model output to the experimental feasibility.
A battery of tests was established to determine, if the developed biomaterial and the constructed application system meet the needs and functions needed for a successful intranasal delivery of antibodies. The mechanism of action of the nose to brain transport was investigated, which enables us to rationally design the galenic formulation and potential drug candidates for an optimal central bioavailability. In-vivo models were established, which were successfully used to show proof of concept in an MS model. A profound understanding of drug absorption, uptake, pharmacokinetics (PK) and pharmacodynamics (PD) after intranasal delivery via the olfactory region is vital for a successful development of the N2B-patch platform technique for other CNS active drugs with low central availability.
Preparatory work for exploitation of project results along the whole value-chain was performed: A targeted survey for patients was prepared and translated in different languages. A generic market study on available MS treatments and nose-to-brain applicators as well as a Freedom-to-operate analysis linked to related patents were performed. The patent application of the project partner Beiter was awarded.
Besides general communication activities (e.g. logo, website, Flyer, video animation), N2B-patch is still present in Social Media, e.g. YouTube and LinkedIn.
The consortium attended relevant scientific conferences, held presentations or presented posters related to N2B-patch, this involves patient-related events. Due to the Covid-19 pandemic, mostly all events have been virtual since March 2020.
The development of the formulation including an ensemble composed of particles and hydrogel started with the beginning of the project. Various particles had been manufactured for further testing. The lead matrix was selected and for the final formulation the particle development started. Novel techniques to evaluate adhesion and spreading of the formulation at the olfactory region were set-up further one. The technology transfer of the galenic formulation was demonstrated by using previously prepared batch production documentation at pilot scales. The pilot scale manufacturing protocol of the antibody-loaded particles and the hydrogel as a product for the application to olfactory region for nose-to-brain delivery of antibodies is ready. The first large scale manufacturing was realized at MyBiotech and Contipro facilities for a batch size representative of industrial scales.
The validity of the end product including the applicator and the galenic formulation is a very important step. Therefore, the setting of the user-requirement specifications (URS) started where the product quality related all relevant attributes and their specifications are defined for safe medicinal product development. This URS has served as the basis for the further evaluation of the assigned properties ensuring the consolidation of an aligned development, once it has been transmuted in a functional design specification. The experimental work on the application process was supported by using 3D casts. The moulding design for the applicator was completed. The respective functional design specifications were based on the URS requirements, matching the physical, the chemical and the mechanical properties as well as the functionality of the CCS together with the N2B matrix patch generated by the computational model output to the experimental feasibility.
A battery of tests was established to determine, if the developed biomaterial and the constructed application system meet the needs and functions needed for a successful intranasal delivery of antibodies. The mechanism of action of the nose to brain transport was investigated, which enables us to rationally design the galenic formulation and potential drug candidates for an optimal central bioavailability. In-vivo models were established, which were successfully used to show proof of concept in an MS model. A profound understanding of drug absorption, uptake, pharmacokinetics (PK) and pharmacodynamics (PD) after intranasal delivery via the olfactory region is vital for a successful development of the N2B-patch platform technique for other CNS active drugs with low central availability.
Preparatory work for exploitation of project results along the whole value-chain was performed: A targeted survey for patients was prepared and translated in different languages. A generic market study on available MS treatments and nose-to-brain applicators as well as a Freedom-to-operate analysis linked to related patents were performed. The patent application of the project partner Beiter was awarded.
Besides general communication activities (e.g. logo, website, Flyer, video animation), N2B-patch is still present in Social Media, e.g. YouTube and LinkedIn.
The consortium attended relevant scientific conferences, held presentations or presented posters related to N2B-patch, this involves patient-related events. Due to the Covid-19 pandemic, mostly all events have been virtual since March 2020.
The N2B transport of substances is scientifically well-known and a recently clinically proven alternative route of administration to let the so-administered substances bypass the BBB. However, until now, highly efficient technologies for olfactory uptake and direct brain delivery are missing.
The N2B-patch project is a brand new approach that aims to develop a delivery technology based on the synthesis of a biomaterial-based innovative galenic formulation, a novel class of hydrogel matrix-patch and a medical applicator device system. Moreover, the innovative multifunctional galenic formulation of N2B-patch aims to shield sensitive drugs and maintain the drug’s bioactivity.
The N2B-patch project aims to deliver the following three outputs:
- An Ensemble composed of biomaterial-based drug particles and an innovative Active Pharmaceutical Ingredient API (biomolecules) for MS treatment (Figure 1).
- The hydrogel formulation as a minimally-invasive carrier (Figure 2).
- The applicator device as integral part of the functional and minimally-invasive system (Figure 3).
The N2B-patch project aims to have considerable impacts on society as a whole, on markets and research. The effective treatment of CNS disorders is still an “unmet medical need” connected with high morbidity, significant side effects, suffering of the patients and their families, as well as an enormous burden on the welfare systems.
N2B-patch perfectly matches market and user needs in a cost effective and thus competitive manner.
The N2B-patch project is a brand new approach that aims to develop a delivery technology based on the synthesis of a biomaterial-based innovative galenic formulation, a novel class of hydrogel matrix-patch and a medical applicator device system. Moreover, the innovative multifunctional galenic formulation of N2B-patch aims to shield sensitive drugs and maintain the drug’s bioactivity.
The N2B-patch project aims to deliver the following three outputs:
- An Ensemble composed of biomaterial-based drug particles and an innovative Active Pharmaceutical Ingredient API (biomolecules) for MS treatment (Figure 1).
- The hydrogel formulation as a minimally-invasive carrier (Figure 2).
- The applicator device as integral part of the functional and minimally-invasive system (Figure 3).
The N2B-patch project aims to have considerable impacts on society as a whole, on markets and research. The effective treatment of CNS disorders is still an “unmet medical need” connected with high morbidity, significant side effects, suffering of the patients and their families, as well as an enormous burden on the welfare systems.
N2B-patch perfectly matches market and user needs in a cost effective and thus competitive manner.