Intracochlear PLGA based implants for dexamethasone release: Challenges and solutions

Lehner, Eric; Gündel, Daniel; Liebau, Arne; Plontke, Stefan K.; Mäder, Karsten

doi:10.1016/j.ijpx.2019.100015

Cited by 22 publications

(27 citation statements)

References 29 publications

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“…45 Finally, the present protocol exhibits some significant benefits as being operationally simple, mild and catalyst-free, making it a promising approach for the synthesis of polyester-based networks with good water uptake capacity, which can be used for potential pharmaceutical applications such as carriers for sustained release of hydrophilic drugs 46 and biodegradable implants for controlled drug delivery. 47…”

Section: Discussionmentioning

confidence: 99%

Network formation by aza‐Michael addition of primary amines to vinyl end groups of enzymatically synthesized poly(glycerol adipate)

Alaneed

Golitsyn

Hauenschild

et al. 2020

Polymer International

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A highly efficient approach for the synthesis of polyester-based networks via aza-Michael addition of primary amines to ⊍,⊎-unsaturated (vinyl) end groups of poly(glycerol adipate) (PGA) was achieved. By acylation of PGA with 6-(Fmoc-amino)hexanoic acid side chains via Steglich esterification, protected amine-functionalized PGA was obtained. This was followed by the removal of fluorenylmethyloxycarbonyl (Fmoc) protecting groups and the synthesis of PGA-based networks under catalyst-free conditions. The successful conjugate addition of primary amines to vinyl end groups and network formation were confirmed using 13 C magic angle spinning NMR and Fourier transform infrared spectroscopy. Network heterogeneity and defects were quantitatively investigated using 1 H double-quantum NMR spectroscopy. Finally, a hydrogel was prepared with potential biomedical applications. Supporting information may be found in the online version of this article.

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Section: Discussionmentioning

confidence: 99%

Network formation by aza‐Michael addition of primary amines to vinyl end groups of enzymatically synthesized poly(glycerol adipate)

Alaneed

Golitsyn

Hauenschild

et al. 2020

Polymer International

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“…The strength of the Ozurdex implant has been reported to be *2.75 N or 280 g. The implant strengths measured in this study are similar or better. 28 Dexamethasone can be detrimental to corneal endothelial cells above concentrations of 10 -4 to 10 -3 M, causing in-creased apoptosis/necrosis and increased Na + K + -ATPase activity. 29 Furthermore, doses of dexamethasone over 1 mg were toxic to the ocular tissues of rabbits.…”

Section: Discussionmentioning

confidence: 99%

Manufacturing of Dexamethasone–Poly(d,l-Lactide-co-Glycolide) Implants Using Hot-Melt Extrusion: Within- and Between-Batch Product Performance Comparisons

Kelley

Ghaffari

Wang

et al. 2020

Journal of Ocular Pharmacology and Therapeutics

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Purpose: Reliable drug therapy with injectable intravitreal implants requires implants of consistent quality. The purpose of this study was to prepare dexamethasone-poly(d,l-lactide-co-glycolide) (PLGA) biodegradable implants and assess implant quality within and between batches for different polymer compositions. Methods: Implants containing 20% w/w dexamethasone with 3 theoretical rates of release (fast, intermediate, and slow) were manufactured with decreasing proportion of acid-terminated PLGA (50:50) and increasing proportion of ester-terminated PLGA (50:50) in a batch process using hot-melt extrusion. The implants were manufactured without and with in-process modification of extrusion/conveyor speed in the late phase of each batch. Implant samples collected at early, middle, and late phases of each batch were analyzed for diameter, drug loading, mechanical properties (strength and toughness), and drug release. Results: With a fixed process, unlike a modified process with an increase in extrusion speed and reduction of conveyor speed in the late phase, all implant formulations tended to decrease in diameter and mechanical properties in the late phase. Drug release profiles for the intermediate and slow release compositions were similar with or without process modification, unlike the fast release composition. Addition of ester-terminated PLGA resulted in a slower drug release. When all formulations are grouped together, the implant diameter exhibited a moderate correlation with mechanical properties, but no correlation was observed with drug release. Conclusions: Within a hot-melt extrusion batch process, the dexamethasone-PLGA implant diameter and hence toughness and strength tend to decline in the latter phase. In-process adjustment of extrusion and conveyor speeds can improve batch consistency and, potentially, implant integrity or performance during or after injection. Process changes did not affect drug release for 2 of the 3 implant compositions.

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“…Newer ideas include introducing a PLGA‐based implant into the scala tympani via a cochleostomy in the basal turn of the cochlea. Simulations predict that the implant can reach constant drug levels within a few hours and last for several weeks . Placement of this implant has been demonstrated ex vivo in guinea pig models and did not result in macroscopic traumatization of inner ear structures based on CT scans.…”

Section: Recent Advances In Inner Ear Deliverymentioning

confidence: 91%

“…Simulations predict that the implant can reach constant drug levels within a few hours and last for several weeks. 86 Placement of this implant has been demonstrated ex vivo in guinea pig models and did not result in macroscopic traumatization of inner ear structures based on CT scans. However, methods involving cochleostomy are known to be traumatic to the inner ear and risk hearing loss; alternative approaches may reduce this risk.…”

Section: Advances With Direct Intracochlear Deliverymentioning

confidence: 95%

Inner ear delivery: Challenges and opportunities

Szeto

Chiang

Valentini

et al. 2019

Laryngoscope Investig Oto

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Objectives The treatment of inner ear disorders remains challenging due to anatomic barriers intrinsic to the bony labyrinth. The purpose of this review is to highlight recent advances and strategies for overcoming these barriers and to discuss promising future avenues for investigation. Data Sources The databases used were PubMed, EMBASE, and Web of Science. Results Although some studies aimed to improve systemic delivery using nanoparticle systems, the majority enhanced local delivery using hydrogels, nanoparticles, and microneedles. Developments in direct intracochlear delivery include intracochlear injection and intracochlear implants. Conclusions In the absence of a systemic drug that targets only the inner ear, the best alternative is local delivery that harnesses a combination of new strategies to overcome anatomic barriers. The combination of microneedle technology with hydrogel and nanoparticle delivery is a promising area for future investigation. Level of Evidence NA

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Intracochlear PLGA based implants for dexamethasone release: Challenges and solutions

Abstract: Graphical abstract

Cited by 22 publications

References 29 publications

Network formation by aza‐Michael addition of primary amines to vinyl end groups of enzymatically synthesized poly(glycerol adipate)

Network formation by aza‐Michael addition of primary amines to vinyl end groups of enzymatically synthesized poly(glycerol adipate)

Manufacturing of Dexamethasone–Poly(d,l-Lactide-co-Glycolide) Implants Using Hot-Melt Extrusion: Within- and Between-Batch Product Performance Comparisons

Inner ear delivery: Challenges and opportunities

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