Scaffolds for Sustained Release of Ambroxol Hydrochloride, a Pharmacological Chaperone That Increases the Activity of Misfolded β‐Glucocerebrosidase

• Published in: Macromolecular bioscience 2019-08, Vol.19 (8), p.e1900130-n/a
• Main Authors: Enshaei, Hamidreza, Molina, Brenda G., del Valle, Luis J., Estrany, Francesc, Arnan, Carme, Puiggalí, Jordi, Saperas, Núria, Alemán, Carlos
• Format: Article
• Language: English
• Subjects: Ambroxol - chemistry; Ambroxol - pharmacology; Biological activity; Coatings; Controlled release; Delayed-Action Preparations - chemistry; Drug Compounding - methods; Drug delivery; Drug Liberation; Electrochemical Techniques; electrospinning; Gaucher's disease; Glucosylceramidase; Glucosylceramidase - chemistry; Hot Temperature; Immersion coating; Kinetics; lysosomal storage disorders; Microfibers; misfolding diseases; Pharmacology; poly(ε‐caprolactone); polyester; Polyesters - chemistry; Protective Agents - chemistry; Protective Agents - pharmacology; Protective coatings; Protein Folding - drug effects; Protein Stability; release regulation; Scaffolds; Sustained release; Thermal denaturation
• ISSN: 1616-5187; 1616-5195
• DOI: 10.1002/mabi.201900130

Ambroxol is a pharmacological chaperone (PC) for Gaucher disease that increases lysosomal activity of misfolded β‐glucocerebrosidase (GCase) while displaying a safe toxicological profile. In this work, different poly(ε‐caprolactone) (PCL)‐based systems are developed to regulate the sustained release of small polar drugs in physiological environments. For this purpose, ambroxol is selected as test case since the encapsulation and release of PCs using polymeric scaffolds have not been explored yet. More specifically, ambroxol is successfully loaded in electrospun PCL microfibers, which are subsequently coated with additional PCL layers using dip‐coating or spin‐coating. The time needed to achieve 80% release of loaded ambroxol increases from ≈15 min for uncoated fibrous scaffolds to 3 days and 1 week for dip‐coated and spin‐coated systems, respectively. Furthermore, it is proven that the released drug maintains its bioactivity, protecting GCase against induced thermal denaturation. The release of bioactive ambroxol, a pharmacological chaperone for Gaucher disease, from polyester scaffolds is regulated (from a few hours to months) by controlling their geometry. For this purpose, the utilization of electrospun fibers (release rate: few hours) is combined with dip‐coating and spin‐coating techniques (release rate: weeks and months, respectively).