Research

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15 pages, 10732 KiB

Open AccessArticle

Smart Microneedles with Porous Polymer Layer for Glucose-Responsive Insulin Delivery

by Asad Ullah, Hye Jin Choi, Mijin Jang, Sanghyun An and Gyu Man Kim

Pharmaceutics 2020, 12(7), 606; https://doi.org/10.3390/pharmaceutics12070606 - 30 Jun 2020

Cited by 30 | Viewed by 3825

A closed-loop system imitating the function of pancreatic cells, connected to microneedles (MNs) that automatically “release” insulin in response to the blood glucose (BG) levels would be highly satisfactory for improving the quality of life and health for diabetes patients. This paper describes [...] Read more.

A closed-loop system imitating the function of pancreatic cells, connected to microneedles (MNs) that automatically “release” insulin in response to the blood glucose (BG) levels would be highly satisfactory for improving the quality of life and health for diabetes patients. This paper describes an easy, fast and simple technique of coating a porous polymer layer on stainless steel (SS) MNs that release insulin in a glucose-responsive fashion. It was fabricated by sealing insulin, sodium bicarbonate (a pH-sensitive element [NaHCO₃]) and glucose oxidase (glucose-specific enzymes [GOx]) into the pores of a porous polymer coating. Glucose can passively diffuse into the pores and become oxidized to gluconic acid by GOx, thereby causing a decrease in local pH. The subsequent reaction of protons with NaHCO₃ forms carbon dioxide (CO₂) which creates pressure inside the pores, thereby rupturing the thin polymer film and releasing the encapsulated insulin. Field emission scanning electron microscopy (FE-SEM) images displayed that upon the exposure of MNs to glucose-free phosphate buffer saline (PBS) with pH 7.4, the pores of the porous MNs were closed, while in MNs exposed to a hyperglycemic glucose level, the pores were opened and the thin film burst. These MNs demonstrated both in vitro (in porcine skin and PBS) and in vivo (in diabetic rats) glucose-mediated insulin release under hyperglycemic conditions with rapid responsiveness. This study validated that the release of insulin from porous MNs was effectively correlated with glucose concentration. Full article

(This article belongs to the Special Issue Advances in Microneedle-Based Drug Delivery Systems)

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11 pages, 1695 KiB

Open AccessArticle

Rapidly Separable Micropillar Integrated Dissolving Microneedles

by Chung-ryong Jung, Shayan Fakhraei Lahiji, Youseong Kim, Hyeonjun Kim and Hyungil Jung

Pharmaceutics 2020, 12(6), 581; https://doi.org/10.3390/pharmaceutics12060581 - 23 Jun 2020

Cited by 21 | Viewed by 4015

Abstract

Dissolving microneedle (DMN) patches were developed as efficient and patient-friendly transdermal delivery systems for biopharmaceuticals. However, recent studies have confirmed that the efficiency of DMNs to deliver biopharmaceuticals is highly reduced because of incomplete insertion caused by the stiffness and elastic properties of [...] Read more.

Dissolving microneedle (DMN) patches were developed as efficient and patient-friendly transdermal delivery systems for biopharmaceuticals. However, recent studies have confirmed that the efficiency of DMNs to deliver biopharmaceuticals is highly reduced because of incomplete insertion caused by the stiffness and elastic properties of the skin. Therefore, micropillar integrated DMNs were developed to overcome the insertion limitations of DMN patches. Although micropillars were designed as integrated applicators to implant DMNs across the skin, they can also become inserted into the skin, leading to skin injury and inflammation. Herein, we have developed a separable micropillar integrated DMN (SPDMN) capable of inserting DMNs across the skin with high efficiency while minimizing skin injury risk through the introduction of a safety ring feature. Unlike previously developed systems, the SPDMN does not require continuous skin attachment and can be detached immediately post-application, leaving DMNs implanted inside the skin. Altogether, the findings of this study lead to the development of a quick, safe, and efficient DMN-based drug delivery platform. Full article

(This article belongs to the Special Issue Advances in Microneedle-Based Drug Delivery Systems)

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14 pages, 4024 KiB

Open AccessArticle

Characterization of Hepatitis B Surface Antigen Loaded Polylactic Acid-Based Microneedle and Its Dermal Safety Profile

by Young-Guk Na, Minki Kim, Mingu Han, Hyun Wook Huh, Ji-Seok Kim, Jong Chan Kim, Jung-Hwan Park, Hong-Ki Lee and Cheong-Weon Cho

Pharmaceutics 2020, 12(6), 531; https://doi.org/10.3390/pharmaceutics12060531 - 09 Jun 2020

Cited by 14 | Viewed by 2840

Abstract

A surge of interest in microneedle (MN) vaccines as a novel vaccination system has emerged. Before the clinical application of MN vaccine, an assessment of potential biological risks to skin and quality control of MN must be performed. Therefore, the present study aims [...] Read more.

A surge of interest in microneedle (MN) vaccines as a novel vaccination system has emerged. Before the clinical application of MN vaccine, an assessment of potential biological risks to skin and quality control of MN must be performed. Therefore, the present study aims to evaluate the physicochemical properties of MN and to evaluate the histological changes and inflammatory cell infiltrations after the application of MN with hepatitis B surface antigen (HBsAg). During in vitro and in vivo release testing, HBsAg MN released over 70% of HBsAg at 30 min. During the pyrogen test of HBsAg MN in rabbit, no rabbit showed an individual rise in temperature of 0.5 °C or more. MN with HBsAg produced the moderate immunization in mice. MN application did not alter the thickness of dermal and epidermal layers in mice. In addition, the topical applications of MN and MN for hepatitis B vaccine did not acutely induce the inflammation, allergic reaction, dermal toxicity and skin irritation. Thus, the MN system for the delivery of HBsAg could be the promising technology in the hepatitis B vaccination. Full article

(This article belongs to the Special Issue Advances in Microneedle-Based Drug Delivery Systems)

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19 pages, 1792 KiB

Open AccessArticle

Design and Characterization of Spray-Dried Chitosan-Naltrexone Microspheres for Microneedle-Assisted Transdermal Delivery

by Abayomi T. Ogunjimi, Jennifer Fiegel and Nicole K. Brogden

Pharmaceutics 2020, 12(6), 496; https://doi.org/10.3390/pharmaceutics12060496 - 29 May 2020

Cited by 14 | Viewed by 3268

Abstract

Naltrexone (NTX) hydrochloride is a potent opioid antagonist with significant first-pass metabolism and notable untoward effects when administered orally or intramuscularly. Microneedle (MN)-assisted transdermal delivery is an attractive alternative that can improve therapeutic delivery to deeper skin layers. In this study, chitosan-NTX microspheres [...] Read more.

Naltrexone (NTX) hydrochloride is a potent opioid antagonist with significant first-pass metabolism and notable untoward effects when administered orally or intramuscularly. Microneedle (MN)-assisted transdermal delivery is an attractive alternative that can improve therapeutic delivery to deeper skin layers. In this study, chitosan-NTX microspheres were developed via spray-drying, and their potential for transdermal NTX delivery in association with MN skin treatment was assessed. A quality-by-design approach was used to evaluate the impact of key input variables (chitosan molecular weight, concentration, chitosan-NTX ratio, and feed flow rate) on microsphere physical characteristics, encapsulation efficiency, and drug-loading capacity. Formulated microspheres had high encapsulation efficiencies (70–87%), with drug-loading capacities ranging from 10–43%. NTX flux through MN-treated skin was 11.6 ± 2.2 µg/cm²·h from chitosan-NTX microspheres, which was significantly higher than flux across intact skin. Combining MN-assisted delivery with the chitosan microsphere formulation enabled NTX delivery across the skin barrier, while controlling the dose released to the skin. Full article

(This article belongs to the Special Issue Advances in Microneedle-Based Drug Delivery Systems)

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18 pages, 3449 KiB

Open AccessArticle

In Situ Gel Formation in Microporated Skin for Enhanced Topical Delivery of Niacinamide

by Sonalika Bhattaccharjee, Moritz Beck-Broichsitter and Ajay K. Banga

Pharmaceutics 2020, 12(5), 472; https://doi.org/10.3390/pharmaceutics12050472 - 21 May 2020

Cited by 20 | Viewed by 5973

Abstract

Although used widely in cosmetic formulations, topical delivery of niacinamide (LogP = −0.35) is unfavorable by conventional means. Poly(lactide-co-glycolide) (PLGA) formulations, can undergo a sol-gel transition triggered by solvent exchange, entrapping molecules and sustaining their release. The current study aims to [...] Read more.

Although used widely in cosmetic formulations, topical delivery of niacinamide (LogP = −0.35) is unfavorable by conventional means. Poly(lactide-co-glycolide) (PLGA) formulations, can undergo a sol-gel transition triggered by solvent exchange, entrapping molecules and sustaining their release. The current study aims to exploit the ability of PLGA to gel in situ and enhance the topical delivery of niacinamide in microporated skin. In vitro drug permeation studies were performed using vertical Franz diffusion cells. Microporation was performed using Dr. Pen^TM Ultima A6, where pre-treatment with a 1 mm needle-length for 10 s and a 0.5 mm needle-length for 5 s, both at 13,000 insertions/min were compared. The effect of different grades of PLGA, EXPANSORB^® DLG 50-2A (“low” molecular weight), and EXPANSORB^® DLG 50-8A (“high” molecular weight) on topical delivery was also determined. Formulations containing PLGA resulted in successful gelation in situ on application over microporated skin. A significantly higher amount of drug was found in the skin with the 0.5 mm treatment for 5 s (892 ± 36 µg/cm²) than with 1 mm for 10 s (167 ± 16 µg/cm²). Hence, the different grades of PLGA were evaluated with 0.5 mm, 5 s treatment, and a significantly larger amount was seen in skin with the higher rather than the lower molecular weight polymer (172 ± 53 µg/cm²). Full article

(This article belongs to the Special Issue Advances in Microneedle-Based Drug Delivery Systems)

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13 pages, 2624 KiB

Open AccessArticle

Dissolving Microneedles for Rapid and Painless Local Anesthesia

by Byeong-Min Lee, Chisong Lee, Shayan Fakhraei Lahiji, Ui-Won Jung, Gehoon Chung and Hyungil Jung

Pharmaceutics 2020, 12(4), 366; https://doi.org/10.3390/pharmaceutics12040366 - 17 Apr 2020

Cited by 45 | Viewed by 6091

Abstract

Microneedles are emerging drug delivery methods for painless treatment. The current study tested dissolving microneedles containing lidocaine (Li-DMN) for use in local anesthesia. An Li-DMN patch was fabricated by centrifugal lithography with carboxymethyl cellulose as a structural polymer and assessed for physical properties [...] Read more.

Microneedles are emerging drug delivery methods for painless treatment. The current study tested dissolving microneedles containing lidocaine (Li-DMN) for use in local anesthesia. An Li-DMN patch was fabricated by centrifugal lithography with carboxymethyl cellulose as a structural polymer and assessed for physical properties by optical microscopy and a fracture force analyzer. The biocompatibility was evaluated by a histology section in vitro and by ear thickness in vivo. The efficacy of the Li-DMN patch was assessed by electrophysiological recordings in primary cultured sensory neurons in vitro and a von Frey test on rats’ hind paws in vivo. The physical properties of the microneedle showed enough rigidity for transdermal penetration. The maximal capacity of lidocaine-HCl in the Li-DMN patch was 331.20 ± 6.30 µg. The cytotoxicity of the dissolving microneedle to neuronal cells was negligible under an effective dose of lidocaine for 18 h. Electrophysiological recordings verified the inhibitory effect of the voltage-gated sodium channel current by the Li-DMN patch in vitro. A skin reaction to the edema test and histologic analysis of the rats’ ears after application of the Li-DMN patch were negligible. Also, the application of the Li-DMN patch reduced the nocifensive behavior of the rats almost immediately. In conclusion, the dissolving microneedle patch with carboxymethyl cellulose is a promising candidate method for the painless delivery of lidocaine-HCl. Full article

(This article belongs to the Special Issue Advances in Microneedle-Based Drug Delivery Systems)

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17 pages, 2261 KiB

Open AccessArticle

Characteristic of K3 (CpG-ODN) as a Transcutaneous Vaccine Formulation Adjuvant

by Sayami Ito, Sachiko Hirobe, Takuto Kawakita, Mio Saito, Ying-Shu Quan, Fumio Kamiyama, Ken J. Ishii, Mizuho Nagao, Takao Fujisawa, Masashi Tachibana and Naoki Okada

Pharmaceutics 2020, 12(3), 267; https://doi.org/10.3390/pharmaceutics12030267 - 15 Mar 2020

Cited by 11 | Viewed by 4331

Abstract

Transcutaneous immunization (TCI) is easy to use, minimally invasive, and has excellent efficacy in vaccines against infections. We focused on toll-like receptor (TLR) ligands as applicable adjuvants for transcutaneous formulations and characterized immune responses. TCI was performed using poke-and-patch methods, in which puncture [...] Read more.

Transcutaneous immunization (TCI) is easy to use, minimally invasive, and has excellent efficacy in vaccines against infections. We focused on toll-like receptor (TLR) ligands as applicable adjuvants for transcutaneous formulations and characterized immune responses. TCI was performed using poke-and-patch methods, in which puncture holes are formed with a polyglycolic acid microneedle on the back skin of mice. Various TLR ligands were applied to the puncture holes and covered with an ovalbumin-loaded hydrophilic gel patch. During the screening process, K3 (CpG-oligonucleotide) successfully produced more antigen-specific antibodies than other TLR ligands and induced T helper (Th) 1-type polarization. Transcutaneously administered K3 was detected in draining lymph nodes and was found to promote B cell activation and differentiation, suggesting a direct transcutaneous adjuvant activity on B cells. Furthermore, a human safety test of K3-loaded self-dissolving microneedles (sdMN) was performed. Although a local skin reaction was observed at the sdMN application site, there was no systemic side reaction. In summary, we report a K3-induced Th1-type immune response that is a promising adjuvant for transcutaneous vaccine formulations using MN and show that K3-loaded sdMN can be safely applied to human skin. Full article

(This article belongs to the Special Issue Advances in Microneedle-Based Drug Delivery Systems)

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12 pages, 2212 KiB

Open AccessArticle

Odorless Glutathione Microneedle Patches for Skin Whitening

by Yechan Lee, Sujeet Kumar, Sou Hyun Kim, Keum-Yong Seong, Hyeseon Lee, Chaerin Kim, Young-Suk Jung and Seung Yun Yang

Pharmaceutics 2020, 12(2), 100; https://doi.org/10.3390/pharmaceutics12020100 - 27 Jan 2020

Cited by 20 | Viewed by 6687

Abstract

Glutathione is a natural anti-aging substance that prevents the oxidation of protein thiols from reactive oxygen species. In the pharmaceutical industry, reduced glutathione (GSH) has been widely used for skin whitening due to its ability to inhibit tyrosinase. However, its poor permeability and [...] Read more.

Glutathione is a natural anti-aging substance that prevents the oxidation of protein thiols from reactive oxygen species. In the pharmaceutical industry, reduced glutathione (GSH) has been widely used for skin whitening due to its ability to inhibit tyrosinase. However, its poor permeability and foul odor limit its use in skin applications. Herein, we report a GSH-loaded dissolving microneedle (MN) patch prepared with hyaluronic acid (HA) that enables enhanced permeation across the skin and reduces the foul odor of GSH. HA was selected to prepare odorless GSH solutions and used for MN fabrications as a carrier of GSH. GSH-loaded MN (GSH-MN) arrays prepared from MN-forming solution containing up to 10% GSH showed good pattern uniformity and appropriate mechanical properties for insertion into the skin. The GSH-MNs with a loading capacity of 17.4% dissolve within 10 min following insertion into porcine skin and release the loaded GSH without being oxidized. This new approach combines functional biopolymers to reduce the characteristic GSH odor and advanced transdermal delivery based on MN technology to enhance skin permeation without pain. We believe this technique could expand the application of GSH in many cosmeceutical fields. Full article

(This article belongs to the Special Issue Advances in Microneedle-Based Drug Delivery Systems)

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Review

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31 pages, 7143 KiB

Open AccessReview

Mathematical Modelling, Simulation and Optimisation of Microneedles for Transdermal Drug Delivery: Trends and Progress

by Prateek Ranjan Yadav, Tao Han, Ololade Olatunji, Sudip K. Pattanayek and Diganta Bhusan Das

Pharmaceutics 2020, 12(8), 693; https://doi.org/10.3390/pharmaceutics12080693 - 22 Jul 2020

Cited by 26 | Viewed by 4800

Abstract

In the last two decades, microneedles (MNs) have received significant interest due to their potential for painless transdermal drug delivery (TDD) and minimal skin damage. MNs have found applications in a range of research and development areas in drug delivery. They have been [...] Read more.

In the last two decades, microneedles (MNs) have received significant interest due to their potential for painless transdermal drug delivery (TDD) and minimal skin damage. MNs have found applications in a range of research and development areas in drug delivery. They have been prepared using a variety of materials and fabrication techniques resulting in MN arrays with different dimensions, shapes, and geometries for delivery of a variety of drug molecules. These parameters play crucial roles in determining the drug release profiles from the MNs. Developing mathematical modelling, simulation, and optimisation techniques is vital to achieving the desired MN performances. These will then be helpful for pharmaceutical and biotechnological industries as well as professionals working in the field of regulatory affairs focusing on MN based TDD systems. This is because modelling has a great potential to reduce the financial and time cost of both the MNs’ studies and manufacturing. For example, a number of robust mathematical models for predicting the performance of the MNs in vivo have emerged recently which incorporate the roles of the structural and mechanical properties of the skin. In addressing these points, this review paper aims to highlight the current status of the MN modelling research, in particular, the modelling, simulation and optimisation of the systems for drug delivery. The theoretical basis for the simulation of MN enhanced diffusion is discussed within this paper. Thus, this review paper provides a better understanding of the modelling of the MN mediated drug delivery process. Full article

(This article belongs to the Special Issue Advances in Microneedle-Based Drug Delivery Systems)

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