Nose-to-brain nimodipine formulation bypassing blood-brain barrier
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Solution Overview
Problem
Nimodipine has poor brain transmission rates due to its low solubility and inability to effectively cross the blood-brain barrier, leading to low brain exposure and high risks of cardiovascular and hepatotoxicity.
Innovation Solution
A nose-to-brain delivery formulation of nimodipine is developed, comprising nimodipine, diethylene glycol monoethyl ether as a solvent, a diluent, and an absorption enhancer such as phospholipids or n-dodecyl-β-D-maltoside, which enhances absorption and bypasses the blood-brain barrier.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Quantity of substance
If nimodipine is administered orally, then the drug can be delivered to the systemic circulation, but the first-pass effect is strong and bioavailability is low
Solution Approach 1:
The patent uses the nasal mucosa as an intermediary pathway to bypass the hepatic first-pass metabolism. By formulating nimodipine for nasal administration, the drug can be absorbed through the nasal mucosa and enter the systemic circulation directly, avoiding the liver's first-pass metabolic effect that significantly reduces oral bioavailability.
Solution Approach 2:
The patent segments the drug delivery pathway by separating the absorption site from the metabolic processing site. Instead of oral administration where the drug must pass through the gastrointestinal tract and liver, the nasal route divides the pathway into nasal mucosa absorption and direct systemic entry, bypassing the hepatic first-pass effect.
2Quantity of substance
If ethanol is used as a solvent to improve solubility, then the drug can be dissolved and administered, but irritation and thrombophlebitis increase
Solution Approach 1:
The patent changes the solvent parameter from ethanol to water, fundamentally altering the chemical properties of the formulation. This parameter change maintains the ability to dissolve nimodipine through appropriate formulation techniques while eliminating the irritation and thrombophlebitis associated with ethanol-based solutions.
Solution Approach 2:
The patent converts the challenge of poor water solubility into a benefit by developing water-based formulations that not only eliminate ethanol-related irritation but also potentially improve safety profiles. The formulation strategies used to overcome solubility limitations in water create a safer, non-irritating delivery system.
3Quantity of substance
If conventional injection formulations are used, then the drug can be delivered systemically, but cardio-toxicity and hepatotoxicity increase
Solution Approach 1:
The patent uses the nasal mucosa as an intermediary absorption site that allows for controlled, localized delivery of the drug. This intermediary pathway enables systemic delivery of nimodipine while avoiding the high peak plasma concentrations associated with conventional IV injections, thereby reducing cardio-toxicity and hepatotoxicity.
Solution Approach 2:
The patent introduces dynamic control over drug absorption kinetics through the nasal formulation. The nasal mucosa provides a controlled absorption rate that prevents sudden spikes in plasma drug concentration, dynamically adjusting the delivery profile to reduce toxicity while maintaining therapeutic efficacy.
4Quantity of substance
If nimodipine is administered to achieve therapeutic brain concentrations, then the drug can treat brain diseases, but the blood-brain barrier prevents effective crossing
Solution Approach 1:
The patent uses the nasal mucosa and olfactory nerve pathway as intermediary routes to deliver drugs directly to the brain. This intermediary pathway bypasses the blood-brain barrier by allowing drug molecules to travel through the nasal mucosa, enter the olfactory epithelium, and reach the brain directly via the olfactory nerve, thereby achieving brain exposure without relying on blood-brain barrier penetration.
5Quantity of substance
If the nasal olfactory region is used for drug delivery, then direct brain delivery is achieved, but conventional devices cannot effectively deliver to this region
Solution Approach 1:
The patent changes the physical parameters of the formulation (viscosity, surface tension, particle size) to enable effective delivery to the nasal olfactory region. These parameter changes allow the drug formulation to be appropriately delivered using adapted nasal administration devices that can reach the upper nasal tract and olfactory region, overcoming the limitations of conventional delivery devices.
Applied Scientific Principles
This section explains which scientific principles are used to turn an abstract innovation direction into a practical engineering solution.
Function Achieved in This Case
The formulation achieves high cerebrospinal fluid, olfactory bulb, and cortical brain tissue concentrations, is non-nasally toxic and irritating, and maintains a high cerebral-to-blood ratio, effectively reducing toxic side effects and improving therapeutic efficacy.
Implementation Method 1
the solvent is diethylene glycol monoethyl ether
Implementation Method 2
an absorption enhancer such as phospholipids or n-dodecyl-β-D-maltoside, which enhances absorption
Implementation Method 3
Nose-to-brain delivery system is mainly for upper nasal tract drug delivery, as a non-invasive drug delivery
Data Source
AI summary
The present disclosure provides a nose-to-brain delivery formulation of nimodipine. The present disclosure also provides a method of preventing or treating ischemic disorders in a patient, in particular cerebral ischemic disorders, cerebral vasospasm due to subarachnoid hemorrhage, and sudden deafness, comprising administering said nimodipine nose-to-brain delivery formulation. The present disclosure also provides a composition, comprising a nose-to-brain delivery formulation of nimodipine and pharmaceutically acceptable excipient.