Hydrocortisone Delayed Release Polymer Circadian Rhythm
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Solution Overview
Problem
Current drug delivery methods for hydrocortisone fail to replicate the natural circadian rhythm of cortisol secretion, leading to adrenal insufficiency, inflammatory disease suppression, and depression, as they either cause excessive suppression of the hypothalamo-pituitary-adrenal axis or do not effectively mimic the physiological release of cortisol.
Innovation Solution
A pharmaceutical composition comprising hydrocortisone with a delayed release polymer layer made of a mixture of poly(methacrylic acid and methyl methacrylate) and microcrystalline cellulose particles, designed to release hydrocortisone in a manner that replicates the natural cortisol rhythm, maintaining cortisol levels above 100nmol/l from approximately 06:00 to 19:00 hours, thereby avoiding suppression of the HPA axis and aligning with the patient's circadian rhythm.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If immediate release glucocorticoid is given at night, then the HPA axis activation is prevented, but the natural cortisol rhythm is suppressed
Solution Approach 1:
The patent applies periodic action by designing a controlled release formulation that releases hydrocortisone in a time-dependent manner to mimic the natural circadian rhythm of cortisol secretion. The formulation releases drug primarily during daytime hours (when cortisol is naturally high) and minimizes release at night, thereby maintaining HPA axis control while avoiding suppression of the natural cortisol rhythm.
Solution Approach 2:
The patent changes the release parameter of hydrocortisone from immediate release to controlled release with time-dependent release characteristics. By modifying the release rate and timing parameters to match physiological cortisol patterns, the formulation achieves both HPA axis control and preservation of natural cortisol rhythm.
2Duration of action of moving object
If long acting potent synthetic glucocorticoids are used, then anti-inflammatory effect is enhanced, but adrenal suppression is increased
Solution Approach 1:
The patent changes the temporal distribution parameter of drug delivery from prolonged constant exposure to pulsatile release matching circadian rhythm. This parameter change allows use of potent glucocorticoids while reducing adrenal suppression by aligning drug exposure with physiological patterns, thereby maintaining anti-inflammatory efficacy with reduced HPA axis suppression.
Solution Approach 2:
The formulation employs periodic action by releasing glucocorticoid in a circadian-rhythm-synchronized pattern rather than continuous release. This periodic delivery maintains therapeutic anti-inflammatory levels during daytime while allowing nighttime HPA axis recovery, thereby reducing overall adrenal suppression compared to long-acting continuous release formulations.
3Object-generated harmful factors
If hydrocortisone is given in low dose, then HPA recovery is maximized, but the natural cortisol rhythm cannot be reproduced
Solution Approach 1:
The patent changes the release kinetics parameter of hydrocortisone from immediate release to controlled release with circadian-synchronized release pattern. This parameter transformation allows low dose administration to be temporally distributed to match physiological cortisol rhythms, thereby achieving both HPA recovery and accurate cortisol rhythm replication simultaneously.
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 composition effectively replicates the natural cortisol rhythm, reducing the risk of adrenal insufficiency, inflammatory disease flare-ups, and depression by providing a controlled release of hydrocortisone that aligns with the body's natural circadian secretion, thereby maintaining physiological balance and minimizing side effects.
Implementation Method 1
a layer comprising a delayed release polymer wherein said delayed release polymer consists essentially of a mixture of poly(methacrylic acid, methyl methacrylate) in a ratio of 1:2 and poly(methacrylic acid, methyl methacrylate) in a ratio of 1:1 and is adapted to delay release of hydrocortisone from said core
Data Source
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AI summary
The disclosure relates to a pharmaceutical formulation comprising hydrocortisone and its use in the treatment of conditions that would benefit from a delayed release of hydrocortisone, in particular conditions such as adrenal insufficiency, inflammatory conditions and depression.