Basic rhEPO Intranasal Formulation for CNS Delivery
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Solution Overview
Problem
Current methods for administering rhEPO for treating cerebrovascular, neurodegenerative, and psychiatric diseases face challenges due to the low permeability of the blood-brain barrier and high affinity for sialic acid, requiring large doses and risking increased blood viscosity and thrombolytic events.
Innovation Solution
Development of an intranasal formulation using basic rhEPO with low sialic acid content, combined with bioadhesive polymers and stabilizers, to enhance brain penetration and reduce erythropoiesis induction, thereby providing effective neuron protection without systemic metabolism.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If acid rhEPO with high sialic acid content is administered intravenously, then neuron protection is achieved, but large doses are required which increase blood viscosity and thrombolytic risk
Solution Approach 1:
The patent changes the sialic acid content parameter of rhEPO from high (>40%) to low (<40%), which fundamentally alters the molecule's affinity for blood cells and receptors. This parameter change enables effective neuron protection at lower doses while reducing the harmful effects of blood viscosity and thrombolytic events associated with high-dose acid rhEPO treatment
Solution Approach 2:
The patent uses the intranasal administration route as an intermediary pathway to deliver basic rhEPO directly to the brain, bypassing the bloodstream. This intermediary route avoids the systemic circulation that causes blood viscosity increases and thrombolytic events, while still achieving effective neuron protection through direct brain delivery
2Reliability
If large quantities of rhEPO are administered for a long time to overcome low BBB permeability, then effective pharmacological effect is achieved, but increased blood viscosity and thrombolytic events occur
Solution Approach 1:
The intranasal administration route serves as an intermediary pathway that delivers rhEPO directly to the brain, bypassing the need for prolonged systemic administration. This approach achieves effective pharmacological effect through direct brain delivery while avoiding the cumulative harmful effects of long-term high-dose treatment
3Reliability
If acid rhEPO is administered systemically, then erythropoiesis is stimulated, but this causes increased blood viscosity and thrombolytic risk
Solution Approach 1:
The patent changes the sialic acid content parameter to create basic rhEPO with low sialic acid content, which has reduced affinity for erythroid progenitor cells compared to acid rhEPO. This parameter change allows therapeutic effect to be achieved while minimizing the harmful induction of erythropoiesis that leads to increased blood viscosity and thrombolytic risk
Solution Approach 2:
The intranasal administration route acts as an intermediary that delivers basic rhEPO directly to the brain, bypassing systemic circulation. This approach achieves therapeutic effect through direct brain delivery while avoiding the systemic erythropoiesis stimulation that causes harmful effects
Data Source
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AI summary
The present invention is related to the biopharmaceutical industry and in particular to the development of a medication for the treatment of cerebrovascular, neurodegenerative and psychiatric diseases. Its active principle is recombinant human erythropoietin (rhEPO) with low content of sialic acid. During the production of rhEPO, this glycoprotein is obtained with different contents of sialic acid; if less than 40% of the molecule is protected with (basic) sialic acid, it is not biologically active in the systemic way, as it is then inactivated by hepatic enzymes. Surprisingly, we have found that intranasal administration of basic rhEPO has enhanced therapeutic activity in comparison with acid rhEPO. The nasal formulations of basic rhEPO herein presented incorporate bioadhesive polymers which increase the residence time in the nasal cavity, thereby enhancing their therapeutic effect. They also include other auxiliary substances such as preservatives, tensioactive agents, pH regulators, isotonic agents and protein stabilizers.