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Journal ArticleDOI: 10.1016/J.IJPHARM.2021.120455

Hollow microneedles: A perspective in biomedical applications.

04 Mar 2021-International Journal of Pharmaceutics (Elsevier)-Vol. 599, pp 120455-120455
Abstract: Microneedles (MN) have the potential to become a highly progressive device for both drug delivery and monitoring purposes as they penetrate the skin and pierce the stratum corneum barrier, allowing the delivery of drugs in the viable skin layers and the extraction of body fluids. Despite the many years of research and the different types of MN developed, only hollow MN have reached the pharmaceutical market under the path of medical devices. Therefore, this review focuses on hollow MN, materials and methods for their fabrication as well as their application in drug delivery, vaccine delivery and monitoring purposes. Furthermore, novel approaches for the fabrication of hollow MN are included as well as prospects of microneedle-based products on the market.

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Topics: Drug delivery (54%), Transdermal (50%)
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14 results found


Journal ArticleDOI: 10.1016/J.MSEC.2021.112226
Abstract: In this work, we introduce, for the first time, novel hybrid microneedle patches with implantable poly(lactic-co-glycolic acid) (PLGA) tips aligned with hydrogel-forming microneedle bases (HFMB) using a dissolvable material. A model dye, Nile red, and an antifungal drug, amphotericin B, were loaded into the PLGA tips in a controlled manner by multiple castings. Three different types of pre-formed microneedle bases including conventional dissolving baseplates (MN0), HFMB with needle heights of 600 μm (MN6) and HFMB with needle heights of 800 μm (MN8) were investigated. Compared to the conventional dissolving baseplate (MN0)-based PLGA tipped implantable microneedle design, the addition of the pre-formed HFMB (MN8) improved in vitro and ex vivo insertion capacities of the patches, increased ex vivo drug delivery efficiency up to 80% of the loaded drug and speeded up the implantation process to within 1 min. An adhesion test indicated that the hydrogel baseplate used in this study was easier to peel off from the skin than the dissolving baseplate. In vitro release studies demonstrated that the release of amphotericin B from the drug loading PLGA tips lasts for a week. Antifungal tests of the inserted amphotericin B loaded PLGA tips revealed their antifungal effects against Candida albicans. The MN8 did not dissolve, leaving no viscous residue but absorbed water and disintegrated after immersion into water. The hybrid PLGA-tipped microneedle system will be ideal for rapid implantation and sustained release of amphotericin B for dermal fungal infections. This hybrid patch design is a novel promising technology for delivering drug-eluting microimplants into the skin while ensuring easy and complete removal of the HFMB. It could have many potential applications in implantable intradermal drug delivery.

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Topics: Antifungal drug (58%), PLGA (54%), Controlled release (52%)

6 Citations


Journal ArticleDOI: 10.1016/J.EJPB.2021.05.022
Yu Wu1, Lalitkumar K. Vora1, Yujing Wang1, Muhammad Faris Adrianto1  +4 moreInstitutions (1)
Abstract: Treatment of neovascular ocular diseases involves intravitreal injections of therapeutic proteins using conventional hypodermic needles every 4–6 weeks. Due to the chronic nature of these diseases, these injections will be administrated to patients for the rest of their lives and their frequent nature can potentially pose a risk of sight-threatening complications and poor patient compliance. Therefore, we propose to develop nanoparticle (NP)-loaded bilayer dissolving microneedle (MN) arrays, to sustain delivery of protein drugs in a minimally invasive manner. In this research, a model protein, ovalbumin (OVA)-encapsulated PLGA NPs were prepared and optimised using a water-in-oil-in-water (W/O/W) double emulsion method. The impact of stabilisers and primary sonication time on the stability of encapsulated OVA was evaluated using an enzyme-linked immunosorbent assay (ELISA). Results showed that the lower primary sonication time was capable of sustaining release (77 days at 28.5% OVA loading) and improving the OVA bioactivity. The optimised NPs were then incorporated into a polymeric matrix to fabricate bilayer MNs and specifically concentrated into MN tips by high-speed centrifugation. Optimised bilayer MNs exhibited good mechanical and insertion properties and rapid dissolution kinetics (less than 3 min) in excised porcine sclera. Importantly, ex vivo transscleral distribution studies conducted using a multiphoton microscope confirmed the important function of MN arrays in the localisation of proteins and NPs in the scleral tissue. Furthermore, the polymers selected to prepare bilayer MNs and OVA NPs were determined to be biocompatible with retinal cells (ARPE-19). This delivery approach could potentially sustain the release of encapsulated proteins for more than two months and effectively bypass the scleral barrier, leading to a promising therapy for treating neovascular ocular diseases.

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Topics: Bilayer (52%)

4 Citations


Journal ArticleDOI: 10.1007/S13346-021-00981-Y
Qida Zong1, Ranran Guo1, Naijun Dong1, Guixia Ling1  +1 moreInstitutions (1)
Abstract: As a painless and minimally invasive method of self-administration, microneedle is very promising to replace subcutaneous injection of insulin for type I diabetes treatment. Since the introduction of microneedles, many scholars have paid attention to and studied this technology, which has made it developed rapidly. However, there is no product on the market or in clinical trials at present. The reason is that there are still many technical problems in microneedle drug delivery system, such as the perfect integration of stable, controllable, fast, long-lasting, safe, and other necessary conditions. Here, we review the achievements that researchers have made that contain one or more of the above factors, and put some ideas to solve the limitations of insulin delivery by microneedles for reference.

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3 Citations


Open accessJournal ArticleDOI: 10.1007/S13346-021-01032-2
Alyaa Albadr1, Alyaa Albadr2, Ismaiel Tekko1, Ismaiel Tekko3  +5 moreInstitutions (3)
Abstract: Chronic fungal infection of the cornea could lead to blindness if not treated properly. Topical amphotericin B (AMP-B) is considered the first treatment of choice for ocular fungal infection. However, factors related to its poor solubility and penetration through intact cornea lead to poor bioavailability. Microneedles (MNs) are emerging as a minimally invasive method to enhance ocular drug delivery. This study aims to investigate the potential use of biodegradable poly(vinylpyrrolidone) (PVP) and hyaluronic acid (HA)-based rapidly dissolving MNs for delivery of AMP-B to treat fungal infection. The data obtained illustrates PVP/HA MN arrays' reproducibility, good mechanical strength, and faster dissolution with 100% drug recovery. Multiphoton microscopic results revealed that MNs successfully penetrate the corneal tissue and enhance AMP-B permeation through corneal layers. Furthermore, PVP/HA MN arrays showed high solubility. Both PVP and HA successfully decreased AMP-B cytotoxicity when compared to free drug. More interestingly, the biocompatible MN formulations preserved the antifungal activity of AMP-B, as demonstrated by significant inhibition of fungal growth. Therefore, this study shows the feasibility of ocular delivery of the poorly soluble AMP-B using a fast-dissolving MN patch.

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Topics: Drug delivery (51%)

2 Citations


Journal ArticleDOI: 10.1016/J.JCONREL.2021.10.001
Ke Peng1, Lalitkumar K. Vora1, Ismaiel Tekko1, Andi Dian Permana2  +6 moreInstitutions (3)
Abstract: Fungal infections affect millions of people globally and are often unreceptive to conventional topical or oral preparations because of low drug bioavailability at the infection site, lack of sustained therapeutic effect, and the development of drug resistance. Amphotericin B (AmB) is one of the most potent antifungal agents. It is increasingly important since fungal co-infections associated with COVID-19 are frequently reported. AmB is only administered via injections (IV) and restricted to life-threatening infections due to its nephrotoxicity and administration-related side effects. In this work, we introduce, for the first time, dissolving microneedle patches (DMP) loaded with micronised particles of AmB to achieve localised and long-acting intradermal delivery of AmB for treatment of cutaneous fungal infections. AmB was pulverised with poly (vinyl alcohol) and poly (vinyl pyrrolidone) to form micronised particles-loaded gels, which were then cast into DMP moulds to form the tips. The mean particle size of AmB in AmB DMP tips after pulverisation was 1.67 ± 0.01 μm. This is an easy way to fabricate and load microparticles into DMP, as few steps are required, and no organic solvents are needed. AmB had no covalent chemical interaction with the excipients, but the crystallinity of AmB was reduced in the tips. AmB was completely released from the tips within 4 days in vitro. AmB DMP presented inhibition of Candida albicans (CA) and the killing rate of AmB DMP against CA biofilm inside porcine skin reached 100% within 24 h. AmB DMP were able to pierce excised neonatal porcine skin at an insertion depth of 301.34 ± 46.86 μm. Ex vivo dermatokinetic and drug deposition studies showed that AmB was mainly deposited in the dermis. An in vivo dermatokinetic study revealed that the area under curve (AUC0-inf) values of AmB DMP and IV (Fungizone® bolus injection 1 mg/kg) groups were 8823.0 d∙μg/g and 33.4 d∙μg/g, respectively (264-fold higher). AmB remained at high levels (219.07 ± 102.81 μg/g or more) in the skin until 7 days after the application of AmB DMP. Pharmacokinetic and biodistribution studies showed that AmB concentration in plasma, kidney, liver, and spleen in the AmB DMP group was significantly lower than that in the IV group. Accordingly, this system addressed the systemic side effects of intravenous injection of AmB and localised the drug inside the skin for a week. This work establishes a novel, easy and effective method for long-acting and localised intradermal drug delivery.

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1 Citations


References
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162 results found


Journal ArticleDOI: 10.1111/J.1600-0625.2008.00786.X
Abstract: The skin forms an effective barrier between the organism and the environment preventing invasion of pathogens and fending off chemical and physical assaults, as well as the unregulated loss of water and solutes In this review we provide an overview of several components of the physical barrier, explaining how barrier function is regulated and altered in dermatoses The physical barrier is mainly localized in the stratum corneum (SC) and consists of protein-enriched cells (corneocytes with cornified envelope and cytoskeletal elements, as well as corneodesmosomes) and lipid-enriched intercellular domains The nucleated epidermis also contributes to the barrier through tight, gap and adherens junctions, as well as through desmosomes and cytoskeletal elements During epidermal differentiation lipids are synthesized in the keratinocytes and extruded into the extracellular domains, where they form extracellular lipid-enriched layers The cornified cell envelope, a tough protein/lipid polymer structure, resides below the cytoplasmic membrane on the exterior of the corneocytes Ceramides A and B are covalently bound to cornified envelope proteins and form the backbone for the subsequent addition of free ceramides, free fatty acids and cholesterol in the SC Filaggrin is cross-linked to the cornified envelope and aggregates keratin filaments into macrofibrils Formation and maintenance of barrier function is influenced by cytokines, 3',5'-cyclic adenosine monophosphate and calcium Changes in epidermal differentiation and lipid composition lead to a disturbed skin barrier, which allows the entry of environmental allergens, immunological reaction and inflammation in atopic dermatitis A disturbed skin barrier is important for the pathogenesis of contact dermatitis, ichthyosis, psoriasis and atopic dermatitis

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Topics: Cornified envelope (68%), Corneocyte (59%), Barrier function (57%) ... read more

1,303 Citations


Journal ArticleDOI: 10.1016/S0928-0987(01)00167-1
B.W. Barry1Institutions (1)
Abstract: Optimisation of drug delivery through human skin is important in modern therapy. This review considers drug-vehicle interactions (drug or prodrug selection, chemical potential control, ion pairs, coacervates and eutectic systems) and the role of vesicles and particles (liposomes, transfersomes, ethosomes, niosomes). We can modify the stratum corneum by hydration and chemical enhancers, or bypass or remove this tissue via microneedles, ablation and follicular delivery. Electrically assisted methods (ultrasound, iontophoresis, electroporation, magnetophoresis, photomechanical waves) show considerable promise. Of particular interest is the synergy between chemical enhancers, ultrasound, iontophoresis and electroporation.

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Topics: Drug delivery (56%), Transdermal (54%), Drug carrier (51%) ... read more

1,093 Citations


Open accessJournal ArticleDOI: 10.1073/PNAS.2331316100
Abstract: Arrays of micrometer-scale needles could be used to deliver drugs, proteins, and particles across skin in a minimally invasive manner. We therefore developed microfabrication techniques for silicon, metal, and biodegradable polymer microneedle arrays having solid and hollow bores with tapered and beveled tips and feature sizes from 1 to 1,000 μm. When solid microneedles were used, skin permeability was increased in vitro by orders of magnitude for macromolecules and particles up to 50 nm in radius. Intracellular delivery of molecules into viable cells was also achieved with high efficiency. Hollow microneedles permitted flow of microliter quantities into skin in vivo, including microinjection of insulin to reduce blood glucose levels in diabetic rats.

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731 Citations


Journal ArticleDOI: 10.1016/J.JBIOMECH.2003.12.010
Abstract: As a hybrid between a hypodermic needle and transdermal patch, we have used microfabrication technology to make arrays of micron-scale needles that transport drugs and other compounds across the skin without causing pain However, not all microneedle geometries are able to insert into skin at reasonable forces and without breaking In this study, we experimentally measured and theoretically modeled two critical mechanical events associated with microneedles: the force required to insert microneedles into living skin and the force needles can withstand before fracturing Over the range of microneedle geometries investigated, insertion force was found to vary linearly with the interfacial area of the needle tip Measured insertion forces ranged from approximately 01-3N, which is sufficiently low to permit insertion by hand The force required to fracture microneedles was found to increase with increasing wall thickness, wall angle, and possibly tip radius, in agreement with finite element simulations and a thin shell analytical model For almost all geometries considered, the margin of safety, or the ratio of fracture force to insertion force, was much greater than one and was found to increase with increasing wall thickness and decreasing tip radius Together, these results provide the ability to predict insertion and fracture forces, which facilitates rational design of microneedles with robust mechanical properties

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553 Citations


Journal ArticleDOI: 10.1016/J.ADDR.2003.10.027
Abstract: Electroporation is the transitory structural perturbation of lipid bilayer membranes due to the application of high voltage pulses. Its application to the skin has been shown to increase transdermal drug delivery by several orders of magnitude. Moreover, electroporation, used alone or in combination with other enhancement methods, expands the range of drugs (small to macromolecules, lipophilic or hydrophilic, charged or neutral molecules) which can be delivered transdermally. Molecular transport through transiently permeabilized skin by electroporation results mainly from enhanced diffusion and electrophoresis. The efficacy of transport depends on the electrical parameters and the physicochemical properties of drugs. The in vivo application of high voltage pulses is well tolerated but muscle contractions are usually induced. The electrode and patch design is an important issue to reduce the discomfort of the electrical treatment in humans.

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Topics: Transdermal (59%), Electroporation (57%)

441 Citations