Evaluation of microneedles-assisted in situ depot forming poloxamer gels for sustained transdermal drug delivery

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Abstract

In this study, for the first time, we have reported a sustained transdermal drug delivery from thermoresponsive poloxamer depots formed within the skin micropores following microneedle (MN) application. Firstly, we have investigated the sol–gel phase transition characteristics of poloxamers (PF®127, P108, and P87) at physiological conditions. Rheological measurements were evaluated to confirm the critical gelation temperature (CGT) of the poloxamer formulations with or without fluorescein sodium (FS), as a model drug, at various concentrations. Optimized poloxamer formulations were subjected to in vitro release studies using a vial method. Secondly, polymeric MNs were fabricated using laser-engineered silicone micromolds from various biocompatible polymeric blends of Gantrez S-97, PEG 10000, PEG200, PVP K32, and PVP K90. The MN arrays were characterized for mechanical strength, insertion force determination, in situ dissolution kinetics, moisture content, and penetration depth. The optimized MN arrays with good mechanical strength and non-soluble nature were used to create micropores in the neonatal porcine skin. Microporation in neonatal porcine skin was confirmed by dye-binding study, skin integrity assessment, and histology study. Finally, the in vitro delivery of FS from optimized poloxamer formulations was conducted across non-porated vs microporated skin samples using vertical Franz diffusion cells. Results concluded that permeation of FS was sustained for 96 h across the MN-treated skin samples containing in situ forming depot poloxamer formulations compared to non-microporated skin which sustained the FS delivery for 72 h. Confocal microscopic images confirmed the distribution of higher florescence intensity of FS in skin tissues after permeation study in case of MN-treated skin samples vs intact skin samples.

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Microneedles for transdermal drug delivery.

Mark Prausnitz (2004)

The success of transdermal drug delivery has been severely limited by the inability of most drugs to enter the skin at therapeutically useful rates. Recently, the use of micron-scale needles in increasing skin permeability has been proposed and shown to dramatically increase transdermal delivery, especially for macromolecules. Using the tools of the microelectronics industry, microneedles have been fabricated with a range of sizes, shapes and materials. Most drug delivery studies have emphasized solid microneedles, which have been shown to increase skin permeability to a broad range of molecules and nanoparticles in vitro. In vivo studies have demonstrated delivery of oligonucleotides, reduction of blood glucose level by insulin, and induction of immune responses from protein and DNA vaccines. For these studies, needle arrays have been used to pierce holes into skin to increase transport by diffusion or iontophoresis or as drug carriers that release drug into the skin from a microneedle surface coating. Hollow microneedles have also been developed and shown to microinject insulin to diabetic rats. To address practical applications of microneedles, the ratio of microneedle fracture force to skin insertion force (i.e. margin of safety) was found to be optimal for needles with small tip radius and large wall thickness. Microneedles inserted into the skin of human subjects were reported as painless. Together, these results suggest that microneedles represent a promising technology to deliver therapeutic compounds into the skin for a range of possible applications.

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Dissolving Polymer Microneedle Patches for Influenza Vaccination

Sean P. Sullivan, Dimitrios Koutsonanos, María Martín Montero … (2010)

Influenza prophylaxis would benefit from a vaccination method enabling simplified logistics and improved immunogenicity without the dangers posed by hypodermic needles. Here, we introduce dissolving microneedle patches for influenza vaccination using a simple patch-based system that targets delivery to skin’s antigen-presenting cells. Microneedles were fabricated using a biocompatible polymer encapsulating inactivated influenza virus vaccine for insertion and dissolution in the skin within minutes. Microneedle vaccination generated robust antibody and cellular immune responses in mice that provided complete protection against lethal challenge. Compared to conventional intramuscular injection, microneedle vaccination resulted in more efficient lung virus clearance and enhanced cellular recall responses after challenge. These results suggest that dissolving microneedle patches can provide a novel technology for simpler and safer vaccination with improved immunogenicity that could facilitate increased vaccination coverage.

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Dissolving microneedles for transdermal drug delivery.

Jeong Lee, Jung-Hwan Park, Mark Prausnitz (2008)

Microfabrication technology has been adapted to produce micron-scale needles as a safer and painless alternative to hypodermic needle injection, especially for protein biotherapeutics and vaccines. This study presents a design that encapsulates molecules within microneedles that dissolve within the skin for bolus or sustained delivery and leave behind no biohazardous sharp medical waste. A fabrication process was developed based on casting a viscous aqueous solution during centrifugation to fill a micro-fabricated mold with biocompatible carboxymethylcellulose or amylopectin formulations. This process encapsulated sulforhodamine B, bovine serum albumin, and lysozyme; lysozyme was shown to retain full enzymatic activity after encapsulation and to remain 96% active after storage for 2 months at room temperature. Microneedles were also shown to be strong enough to insert into cadaver skin and then to dissolve within minutes. Bolus delivery was achieved by encapsulating molecules just within microneedle shafts. For the first time, sustained delivery over hours to days was achieved by encapsulating molecules within the microneedle backing, which served as a controlled release reservoir that delivered molecules by a combination of swelling the backing with interstitial fluid drawn out of the skin and molecule diffusion into the skin via channels formed by dissolved microneedles. We conclude that dissolving microneedles can be designed to gently encapsulate molecules, insert into skin, and enable bolus or sustained release delivery.

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Author and article information

Contributors

Raghu Raj Singh Thakur:

ORCID: http://orcid.org/0000-0001-7582-2082

+44 (0) 28 9097 5814 , r.thakur@qub.ac.uk

Journal

Journal ID (nlm-ta): Drug Deliv Transl Res

Journal ID (iso-abbrev): Drug Deliv Transl Res

Title: Drug Delivery and Translational Research

Publisher: Springer US (New York )

ISSN (Print): 2190-393X

ISSN (Electronic): 2190-3948

Publication date (Electronic): 23 January 2019

Publication date PMC-release: 23 January 2019

Publication date (Print): 2019

Volume: 9

Issue: 4

Pages: 764-782

Affiliations

[1 ]ISNI 0000 0004 0636 6599, GRID grid.412496.c, Faculty of Pharmacy and Alternative Medicine, , The Islamia University of Bahawalpur, ; Bahawalpur, Punjab 63100 Pakistan

[2 ]ISNI 0000 0004 0374 7521, GRID grid.4777.3, School of Pharmacy, Medical Biology Centre, , Queen’s University Belfast, ; 97 Lisburn Road, Belfast, BT9 7BL UK

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Raghu Raj Singh Thakur http://orcid.org/0000-0001-7582-2082

Article

Publisher ID: 617

DOI: 10.1007/s13346-019-00617-2

PMC ID: 6606675

PubMed ID: 30675693

SO-VID: 3205f5b1-2390-4403-a28c-427c3b7b102a

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OpenAccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made.

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Funding

Funded by: International Research Scholarship Initiative Program

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ScienceOpen disciplines: Pharmacology & Pharmaceutical medicine

Keywords: microneedles,poloxamers,microporation,in situ depots,transdermal,confocal microscopy

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ScienceOpen disciplines: Pharmacology & Pharmaceutical medicine

Keywords: microneedles, poloxamers, microporation, in situ depots, transdermal, confocal microscopy

Evaluation of microneedles-assisted in situ depot forming poloxamer gels for sustained transdermal drug delivery

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RNA drug delivery

Most cited references 45

Microneedles for transdermal drug delivery.

Dissolving Polymer Microneedle Patches for Influenza Vaccination

Dissolving microneedles for transdermal drug delivery.

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