Optimized pharmaceutical formulation for the treatment of inflammatory conditions of the esophagus
Inventors
GREINWALD, Roland • Mueller, Ralph • Proels, Markus • Wilhelm, Rudolf
Assignees
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Publication Number
US-11382860-B2
Publication Date
2022-07-12
Expiration Date
Abstract
Disclosed is an optimized pharmaceutical formulation for the treatment of inflammatory conditions of the esophagus. A pharmaceutical formulation in the form of an orodispersible effervescent tablet is stable, easy to produce, and can be used without dissolving same in a liquid. It is not necessary to drink anything with the tablet as this would reduce the time that the budesonide solution remains in the affected regions of the esophagus. The effervescent tablet of the invention surprisingly resulted in an unexpectedly high rate of histological remission in patients with active eosinophilic esophagitis.
Core Innovation
The invention relates to an orodispersible effervescent tablet formulated to release budesonide in an oral cavity for a period of 1.5 minutes to 2 minutes. The tablet comprises 0.25 mg to 5 mg of budesonide and a gas generating system that generates an effervescent reaction upon contact with saliva. The effervescent reaction targets a concentrated distribution of budesonide directly to one or more inflammatory regions of an esophageal mucosa while minimizing undesired absorption of budesonide into systemic circulation and/or through an oral mucosa.
In an embodiment, the gas generating system comprises a weak acid or salt thereof and a salt of an acid that, in conjunction with a further acid, can release a gas and produce an effervescent reaction upon contact with saliva. The tablet disintegrates into a plurality of small budesonide-containing particles that suspend in saliva. The particle-containing saliva, when swallowed, is relatively uniformly distributed on the esophagus to form a budesonide-containing adhesion.
The described formulation and performance constraints support esophageal targeting with short duration exposure, rather than prolonged delivery. The summary reports CO2 generation from a saliva-activated weak-acid/acid-salt gas system and rapid disintegration into small particles. The dissolved or dispersed form and swallowed saliva are described as wetting the esophagus to form a relatively uniform budesonide adhesion for controlled retention of about 1.5 to 2 minutes.
Claims Coverage
The document includes two independent claims. The main inventive concept is an orodispersible effervescent budesonide tablet using a saliva-activated gas generating system to disintegrate into small budesonide-containing particles and provide relatively uniformly distributed esophageal adhesion while minimizing oral and systemic absorption; an additional independent feature constrains budesonide delivery duration to 1.5 to 2 minutes where stated.
Saliva-activated effervescent budesonide targeting with minimized absorption
An orodispersible effervescent tablet formulated to release budesonide in an oral cavity for a period of 1.5 minutes to 2 minutes, comprising 0.25 mg to 5 mg of budesonide and a gas generating system comprising a weak acid or salt thereof and a salt of an acid that can release a gas and produce an effervescent reaction upon contact with saliva, wherein the effervescent reaction provides a concentrated distribution of budesonide targeted directly to one or more inflammatory regions of an esophageal mucosa while minimizing undesired absorption of budesonide into systemic circulation and/or through an oral mucosa.
Particle-containing saliva forms relatively uniform esophageal adhesion
An orodispersible effervescent tablet formulated to deliver budesonide directly to an esophageal mucosa in a subject in need thereof, comprising 0.1 to 20 mg budesonide and a gas generating system comprising a weak acid or salt thereof and a salt of an acid that can release a gas; wherein the gas generating system generates an effervescent reaction upon contact with saliva that causes the tablet to disintegrate into a plurality of small budesonide-containing particles that suspend in saliva, and the particle-containing saliva, when swallowed, is relatively uniformly distributed on the subject's esophagus to form a budesonide-containing adhesion that provides a concentrated distribution of budesonide targeted directly to inflammatory regions of the subject's esophageal mucosa while minimizing absorption through the subject's oral mucosa.
Localized budesonide delivery duration limited to 1.5 to 2 minutes
The tablet is configured so that localized budesonide delivery lasts for 1.5 to 2 minutes.
Across the independent claims, the inventive coverage centers on a saliva-activated weak-acid/acid-salt effervescent gas generating system that disintegrates an orodispersible effervescent budesonide tablet into small budesonide-containing particles suspended in saliva. Swallowed saliva is described as relatively uniformly distributing on the esophagus to form budesonide-containing adhesion that concentrates budesonide at esophageal inflammatory regions while minimizing absorption through the oral mucosa and, in one claim, undesired systemic absorption. A dependent refinement further specifies a localized delivery duration of 1.5 to 2 minutes.
Stated Advantages
Minimizing undesired absorption of budesonide into systemic circulation and/or through an oral mucosa.
Providing a concentrated distribution of budesonide targeted directly to inflammatory regions of an esophageal mucosa.
Disintegrating into a plurality of small budesonide-containing particles that suspend in saliva and are relatively uniformly distributed on the esophagus to form budesonide-containing adhesion.
Localized budesonide delivery is time-limited to 1.5 to 2 minutes.
Documented Applications
Delivering budesonide directly to an esophageal mucosa in a subject in need thereof, in an eosinophilic esophagitis context.
Treatment outcomes described in the summary include histological remission versus placebo, eosinophil load reduction across esophageal segments, improved endoscopic intensity scores, and dysphagia score improvement or maintenance during follow-up.
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