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1
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Moawad F, Pouliot R, Brambilla D. Dissolving microneedles in transdermal drug delivery: A critical analysis of limitations and translation challenges. J Control Release 2025:113794. [PMID: 40319916 DOI: 10.1016/j.jconrel.2025.113794] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/19/2025] [Revised: 04/25/2025] [Accepted: 04/28/2025] [Indexed: 05/07/2025]
Abstract
Microneedles (MNs) have emerged as an innovative approach for transdermal drug delivery, offering an efficient and minimally invasive alternative to conventional injections and oral delivery systems. While their potential has been widely recognized and extensively studied, the translation of MN technology into clinical practice remains limited. Despite the vast amount of published research, much of it involves over-complexification without addressing the core barriers to practical application. For example, dissolving/degradable MNs face key limitations such as poor drug loading capacity, low dosing consistency, and challenges in delivering effective therapeutic concentrations. These constraints restrict their utility to niche applications, such as vaccination or delivering potent drugs that require minimal doses. Additionally, the lack of standardized quality control measures, the complex manufacturing processes, and the high costs associated specifically with sterile/aseptic production further impede clinical translation. Regulatory frameworks for MNs remain vague, slowing the development of products that meet approval standards. This review critically examines the fundamental barriers to dissolving/degradable MN commercialization, as the most studied type of MN, while exploring promising strategies to overcome them. Advances in formulation science, fabrication techniques, and material engineering have demonstrated potential in enhancing drug loading efficiency and delivery consistency. Moreover, the establishment of clearer regulatory guidelines and scalable production strategies could significantly accelerate the commercialization of MN technology. By shifting focus toward pragmatic and clinically relevant solutions, this review aims to bridge the gap between research innovations and real-world applications, paving the way for broader implementation of MN technology in medicine.
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Affiliation(s)
- Fatma Moawad
- Faculté de Pharmacie, Université de Montréal, 2940 Chemin de Polytechnique, Montréal, Québec H3T 1J4, Canada; Faculty of Pharmacy, Beni-Suef University, Beni-Suef 625617, Egypt
| | - Roxane Pouliot
- Faculté de Pharmacie, Université Laval, Québec G1V 0A6, Canada
| | - Davide Brambilla
- Faculté de Pharmacie, Université de Montréal, 2940 Chemin de Polytechnique, Montréal, Québec H3T 1J4, Canada.
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2
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Pajzderska A, González MA, Jarek M, Mielcarek J, Wąsicki J. Physical Stability and Molecular Mobility of Resveratrol in a Polyvinylpyrrolidone Matrix. Molecules 2025; 30:1909. [PMID: 40363721 PMCID: PMC12073277 DOI: 10.3390/molecules30091909] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/13/2025] [Revised: 04/11/2025] [Accepted: 04/21/2025] [Indexed: 05/15/2025] Open
Abstract
The physical stability, molecular mobility, and appearance of nanocrystalline resveratrol in a polyvinylpyrrolidone (PVP) matrix were investigated. Two formulations with resveratrol loadings of 30% and 50% were prepared and characterized using powder X-ray diffraction (PXRD) and time-domain nuclear magnetic resonance (TD-NMR). Samples were studied over time (up to 300 days post-preparation), across temperatures (80-300 K), and under varying humidity conditions (0% and 75% relative humidity). The results demonstrate that the 30% resveratrol-PVP sample is a homogeneous amorphous solid dispersion (ASD), while the 50% resveratrol-PVP sample contained resveratrol nanocrystals measuring about 40 nm. NMR measurements and molecular dynamics (MD) simulations revealed that incorporation of resveratrol into the polymer matrix modifies the system's dynamics and mobility compared to the pure PVP polymer. Additionally, MD simulations analyzed the hydrogen bonding network within the system, providing insights for a better understanding of the physical stability of the ASD under different conditions.
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Affiliation(s)
- Aleksandra Pajzderska
- Faculty of Physics, Adam Mickiewicz University, Uniwersytetu Poznanskiego 2, 61-614 Poznan, Poland
| | | | - Marcin Jarek
- NanoBioMedical Centre, Adam Mickiewicz University, Wszechnicy Piastowskiej 3, 61-614 Poznan, Poland;
| | - Jadwiga Mielcarek
- Department of Inorganic and Analytical Chemistry, University of Medical Sciences, Grunwaldzka 6, 60-780 Poznan, Poland;
| | - Jan Wąsicki
- Faculty of Physics, Adam Mickiewicz University, Uniwersytetu Poznanskiego 2, 61-614 Poznan, Poland
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3
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Shang P, Li G, Yang R, Wang L, Zhou H. Hydrogel microspheres based on aggregation induction to improve the solubility of insoluble drugs promoting bone repair. Colloids Surf B Biointerfaces 2025; 253:114686. [PMID: 40279815 DOI: 10.1016/j.colsurfb.2025.114686] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/21/2025] [Revised: 03/30/2025] [Accepted: 04/05/2025] [Indexed: 04/29/2025]
Abstract
Insoluble organic molecule drugs often accumulate in vivo, diminishing their efficacy. This study explores the utilization of cage oligosiloxane (POSS-SH) as a carrier for insoluble drugs. POSS-SH exhibits disaggregation properties and enhances cell phagocytosis. Using a thermodynamic approach, kartogenin (KGN) and diclofenac (DS) were covalently bonded via acrylyl chloride. Subsequently, a "one-pot method" was employed to graft double-bonded KGN, DS, and PEG onto POSS-SH, forming organic-inorganic POSS hybrid drugs. In the target molecule, water-soluble polyethylene glycol was introduced to enhance solubility and inhibit organic molecule aggregation within the target molecule. The resulting POSS nanoparticles were coated with methacrylate hyaluronic acid, generating hydrogel microspheres (MHS@PSD) for slow release in situ within the bone joint cavity using microfluidic technology. Slow release of PSD can ameliorate local joint inflammation and promote mesenchymal stem cell differentiation into chondrocytes. Compared to unmodified KGN and DS, our designed materials expedite and enhance cartilage regeneration. In summary, POSS-based hydrogel microspheres with deaggregation properties hold promise for cartilage regeneration, offering a framework for enhancing the efficacy of insoluble organic drugs.
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Affiliation(s)
- Peiyang Shang
- Department of Orthopaedics, The Second Affiliated Hospital of Soochow University, Suzhou, Jiangsu 215004, China; Department of Orthopaedics, Putuo Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai 200062, China
| | - Gen Li
- Department of Orthopaedics, Clinic Center for Sports Medicine, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China
| | - Renhao Yang
- Department of Orthopaedics, Clinic Center for Sports Medicine, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China
| | - Lei Wang
- Department of Orthopaedics, Clinic Center for Sports Medicine, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China.
| | - Haibin Zhou
- Department of Orthopaedics, The Second Affiliated Hospital of Soochow University, Suzhou, Jiangsu 215004, China.
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4
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Fandiño OE, Hutton ARJ, Zhang C, Abbate MTA, Naser YA, Li Y, Paredes AJ, Donnelly RF. Application of microarray patches for the transdermal administration of psychedelic drugs in micro-doses. Eur J Pharm Biopharm 2025; 207:114603. [PMID: 39643092 DOI: 10.1016/j.ejpb.2024.114603] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/09/2024] [Revised: 11/18/2024] [Accepted: 12/03/2024] [Indexed: 12/09/2024]
Abstract
Throughout history, psychedelic compounds have been used for religious, spiritual and recreational purposes. A plethora of studies have reported the use of psychedelic compounds in the treatment of various conditions, such as alcoholism, addictions, depressive state to borderline schizophrenia, personality disorder, among other mental disorders. Psychedelic microdosing, a common technique in recent years, involves the consumption of small doses of psychedelic drugs for therapeutic purposes. This study investigated the potential of hydrogel-forming microarray patches (HF-MAPs) to deliver N,N-dimethyltryptamine (DMT), 5-methoxy-N,N-dimethyltryptamine (5-MeO-DMT), and mescaline (MES) in small doses through the skin. To this purpose, HF-MAPs were prepared using poly(vinyl alcohol) (PVA) and poly(vinyl pyrrolidone) (PVP), using citric acid as the crosslinker. Two different reservoirs, containing PVP and PVA as the main components and poly(ethylene)glycol 400 (PEG400) and glycerol as plasticising agents, were used to deliver all the drugs from the HF-MAPs. Franz cells studies in excised neonatal porcine skin demonstrated that the permeation of DMT, 5-MeO-DMT and MES was better from the PEG400 reservoir, showing a permeation of 60.71 %, 59.61 % and 41.85 % respectively. Pharmacokinetic studies in rats showed that HF-MAP technology as a strategy for microdosing psychedelic compounds was also demonstrated with DMT. AUCt0-final for the HF-MAP cohort (7186 ± 1296 ng/mL*h) was significantly greater than the IM cohort (1803 ± 53.25 ng/mL*h) (p = 0.0020), with a relative bioavailability of ∼ 72 %. Considering their pharmacokinetic profile, the frequency of DMT dosing could be reduced with HF-MAP when compared to the IM route.
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Affiliation(s)
- Octavio E Fandiño
- School of Pharmacy, Queen's University Belfast, Medical Biology Centre, 97 Lisburn Road, Belfast BT9 7BL, UK
| | - Aaron R J Hutton
- School of Pharmacy and Pharmaceutical Sciences, Ulster University, Coleraine BT52 1SA, UK
| | - Chunyang Zhang
- School of Pharmacy, Queen's University Belfast, Medical Biology Centre, 97 Lisburn Road, Belfast BT9 7BL, UK
| | - Marco T A Abbate
- School of Pharmacy, Queen's University Belfast, Medical Biology Centre, 97 Lisburn Road, Belfast BT9 7BL, UK
| | - Yara A Naser
- School of Pharmacy, Queen's University Belfast, Medical Biology Centre, 97 Lisburn Road, Belfast BT9 7BL, UK
| | - Yaocun Li
- School of Pharmacy, Queen's University Belfast, Medical Biology Centre, 97 Lisburn Road, Belfast BT9 7BL, UK
| | - Alejandro J Paredes
- School of Pharmacy, Queen's University Belfast, Medical Biology Centre, 97 Lisburn Road, Belfast BT9 7BL, UK.
| | - Ryan F Donnelly
- School of Pharmacy, Queen's University Belfast, Medical Biology Centre, 97 Lisburn Road, Belfast BT9 7BL, UK.
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5
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Kapoor DU, Sharma D, Gaur M, Prajapati BG, Limmatvapirat S, Sriamornsak P. Overcoming Solubility Challenges: Self-emulsifying Systems for Enhancing the Delivery of Poorly Water-Soluble Antiviral Drugs. Pharm Nanotechnol 2025; 13:117-132. [PMID: 38192138 DOI: 10.2174/0122117385280541231130055458] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/04/2023] [Revised: 10/13/2023] [Accepted: 10/16/2023] [Indexed: 01/10/2024]
Abstract
The primary goal of drug formulation is to improve a drug's bioavailability in the body. However, poorly water-soluble drugs present challenging issues related to their solubility and bioavailability factors. Emerging technologies, such as lipid-based drug delivery systems, including micro- or nanoemulsifying drug delivery systems, have become increasingly relevant to address the above challenges. This review presents a thorough overview of self-emulsifying drug delivery systems (SEDDS). It covers the properties, principles, self-emulsification mechanism, formulation strategies, and characterization methods of SEDDS. This review also addresses the delivery of antiviral agents through SEDDS. Moreover, it summarizes the marketed formulations of SEDDS consisting of antiviral agents. This review offers a comprehensive and valuable resource for future perspectives on SEDDS and their potential applications in antiviral drug delivery.
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Affiliation(s)
- Devesh U Kapoor
- Dr. Dayaram Patel Pharmacy College, Bardoli, 394601, Gujarat, India
| | - Deepak Sharma
- Institute of Pharmacy, Assam Don Bosco University, Tapesia, Sonapur Gaon, 78240, Assam, India
| | - Mansi Gaur
- Integrity Healthcare Solutions Pvt Ltd., Ahmedabad, 380054, Gujarat, India
| | - Bhupendra G Prajapati
- Shree S. K. Patel College of Pharmaceutical Education and Research, Ganpat University, Kherva, 384012, India
| | - Sontaya Limmatvapirat
- Department of Industrial Pharmacy, Faculty of Pharmacy, Silpakorn University, Nakhon Pathom, 73000, Thailand
| | - Pornsak Sriamornsak
- Department of Industrial Pharmacy, Faculty of Pharmacy, Silpakorn University, Nakhon Pathom, 73000, Thailand
- Academy of Science, The Royal Society of Thailand, Bangkok, 10300, Thailand
- Faculty of Pharmaceutical Sciences, Chulalongkorn University, Bangkok, 10330, Thailand
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6
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Nyavanandi D, Mandati P, Vidiyala N, Parupathi P, Kolimi P, Mamidi HK. Enhancing Patient-Centric Drug Development: Coupling Hot Melt Extrusion with Fused Deposition Modeling and Pressure-Assisted Microsyringe Additive Manufacturing Platforms with Quality by Design. Pharmaceutics 2024; 17:14. [PMID: 39861666 PMCID: PMC11769097 DOI: 10.3390/pharmaceutics17010014] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/05/2024] [Revised: 12/22/2024] [Accepted: 12/24/2024] [Indexed: 01/27/2025] Open
Abstract
In recent years, with the increasing patient population, the need for complex and patient-centric medications has increased enormously. Traditional manufacturing techniques such as direct blending, high shear granulation, and dry granulation can be used to develop simple solid oral medications. However, it is well known that "one size fits all" is not true for pharmaceutical medicines. Depending on the age, sex, and disease state, each patient might need a different dose, combination of medicines, and drug release pattern from the medications. By employing traditional practices, developing patient-centric medications remains challenging and unaddressed. Over the last few years, much research has been conducted exploring various additive manufacturing techniques for developing on-demand, complex, and patient-centric medications. Among all the techniques, nozzle-based additive manufacturing platforms such as pressure-assisted microsyringe (PAM) and fused deposition modeling (FDM) have been investigated thoroughly to develop various medications. Both nozzle-based techniques involve the application of thermal energy. However, PAM can also be operated under ambient conditions to process semi-solid materials. Nozzle-based techniques can also be paired with the hot melt extrusion (HME) process for establishing a continuous manufacturing platform by employing various in-line process analytical technology (PAT) tools for monitoring critical process parameters (CPPs) and critical material attributes (CMAs) for delivering safe, efficacious, and quality medications to the patient population without compromising critical quality attributes (CQAs). This review covers an in-depth discussion of various critical parameters and their influence on product quality, along with a note on the continuous manufacturing process, quality by design, and future perspectives.
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Affiliation(s)
- Dinesh Nyavanandi
- Small Molecule Drug Product Development, Cerevel Therapeutics, Cambridge, MA 02141, USA;
| | - Preethi Mandati
- Department of Pharmaceutics and Drug Delivery, School of Pharmacy, The University of Mississippi, University, MS 38677, USA; (P.M.); (P.K.)
| | - Nithin Vidiyala
- Small Molecule Drug Product Development, Cerevel Therapeutics, Cambridge, MA 02141, USA;
| | - Prashanth Parupathi
- Division of Pharmaceutical Sciences, Arnold & Marie Schwartz College of Pharmacy and Health Sciences, Long Island University, Brooklyn, NY 11201, USA;
| | - Praveen Kolimi
- Department of Pharmaceutics and Drug Delivery, School of Pharmacy, The University of Mississippi, University, MS 38677, USA; (P.M.); (P.K.)
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7
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Catlin EJ, Fandiño OE, Lopez-Vidal L, Sangalli M, Donnelly RF, Palma SD, Paredes AJ. A novel temperature-controlled media milling device to produce drug nanocrystals at the laboratory scale. Int J Pharm 2024; 666:124780. [PMID: 39349227 DOI: 10.1016/j.ijpharm.2024.124780] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2024] [Revised: 09/27/2024] [Accepted: 09/27/2024] [Indexed: 10/02/2024]
Abstract
Poor aqueous solubility of preexisting and emerging drug molecules is a common issue faced in the field of pharmaceutics. To address this, particle size reduction techniques, including drug micro- and nanonisation have been widely employed. Nanocrystals (NCs), drug particles with particle sizes below 1 µm, offer high drug content, improved dissolution, and long-acting capabilities. Media milling is the most used method to prepare NCs using of-the-shelf machinery, both at the laboratory and industrial scales. However, early NCs development, especially when limited amounts of the active are available, require the use of milligram-scale media milling. This study introduces a novel mini-scale milling device (Mini-mill) that incorporates temperature control through a water-cooled jacket. The device was used to produce NCs of three model hydrophobic drugs, itraconazole, ivermectin and curcumin, with lowest particle sizes of 162.5 ± 0.4 nm, 178 ± 2 nm, and 116.7 ± 0.7 nm, respectively. Precise control of milling temperature was achieved at 15, 45, and 75°C, with drug dependent particle size reduction trends, with no adverse effects on the milling materials or polymorphic changes in the NCs, as confirmed by calorimetric analysis. Finally, a scale-up feasibility study was carried out in a lab-scale NanoDisp®, confirming that the novel Mini-mills are a material-efficient tool for early formulation development, with potential for scale-up to commercial mills.
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Affiliation(s)
- Elise J Catlin
- School of Pharmacy, Queen's University Belfast, Medical Biology Centre, 97 Lisburn Road, Belfast BT9 7BL, UK
| | - Octavio E Fandiño
- School of Pharmacy, Queen's University Belfast, Medical Biology Centre, 97 Lisburn Road, Belfast BT9 7BL, UK
| | - Lucía Lopez-Vidal
- School of Pharmacy, Queen's University Belfast, Medical Biology Centre, 97 Lisburn Road, Belfast BT9 7BL, UK; Faculty of Chemical Sciences, National University of Córdoba (FCQ-UNC), Haya de la Torre y Medina Allende, X5000XHUA, Córdoba, Argentina
| | - Martina Sangalli
- School of Pharmacy, Queen's University Belfast, Medical Biology Centre, 97 Lisburn Road, Belfast BT9 7BL, UK
| | - Ryan F Donnelly
- School of Pharmacy, Queen's University Belfast, Medical Biology Centre, 97 Lisburn Road, Belfast BT9 7BL, UK
| | - Santiago D Palma
- Faculty of Chemical Sciences, National University of Córdoba (FCQ-UNC), Haya de la Torre y Medina Allende, X5000XHUA, Córdoba, Argentina
| | - Alejandro J Paredes
- School of Pharmacy, Queen's University Belfast, Medical Biology Centre, 97 Lisburn Road, Belfast BT9 7BL, UK.
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8
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Rossier B, Jordan O, Allémann E, Rodríguez-Nogales C. Nanocrystals and nanosuspensions: an exploration from classic formulations to advanced drug delivery systems. Drug Deliv Transl Res 2024; 14:3438-3451. [PMID: 38451440 PMCID: PMC11499347 DOI: 10.1007/s13346-024-01559-0] [Citation(s) in RCA: 11] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 02/21/2024] [Indexed: 03/08/2024]
Abstract
Nanocrystals and nanosuspensions have become realistic approaches to overcome the formulation challenges of poorly water-soluble drugs. They also represent a less-known but versatile platform for multiple therapeutic applications. They can be integrated into a broad spectrum of drug delivery systems including tablets, hydrogels, microneedles, microparticles, or even functionalized liposomes. The recent progresses, challenges, and opportunities in this field are gathered originally together with an informative case study concerning an itraconazole nanosuspension-in-hydrogel formulation. The translational aspects, historical and current clinical perspectives are also critically reviewed here to shed light on the incoming generation of nanocrystal formulations.
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Affiliation(s)
- Benjamin Rossier
- School of Pharmaceutical Sciences, University of Geneva, Rue Michel-Servet 1, 1211, Geneva 4, Switzerland
- Institute of Pharmaceutical Sciences of Western Switzerland, Rue Michel-Servet 1, 1211, Geneva 4, Switzerland
| | - Olivier Jordan
- School of Pharmaceutical Sciences, University of Geneva, Rue Michel-Servet 1, 1211, Geneva 4, Switzerland
- Institute of Pharmaceutical Sciences of Western Switzerland, Rue Michel-Servet 1, 1211, Geneva 4, Switzerland
| | - Eric Allémann
- School of Pharmaceutical Sciences, University of Geneva, Rue Michel-Servet 1, 1211, Geneva 4, Switzerland.
- Institute of Pharmaceutical Sciences of Western Switzerland, Rue Michel-Servet 1, 1211, Geneva 4, Switzerland.
| | - Carlos Rodríguez-Nogales
- School of Pharmaceutical Sciences, University of Geneva, Rue Michel-Servet 1, 1211, Geneva 4, Switzerland.
- Institute of Pharmaceutical Sciences of Western Switzerland, Rue Michel-Servet 1, 1211, Geneva 4, Switzerland.
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9
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Qin N, Li M, Vora LK, Peng K, Sabri AHB, Tao Y, Paredes AJ, McCarthy HO, Donnelly RF. Enhanced long-acting simvastatin delivery via effervescent powder-carrying hollow microneedles and nanocrystal-loaded microneedles. Int J Pharm 2024; 665:124691. [PMID: 39278288 DOI: 10.1016/j.ijpharm.2024.124691] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2024] [Revised: 09/07/2024] [Accepted: 09/08/2024] [Indexed: 09/18/2024]
Abstract
Hyperlipidemia and its associated cardiovascular complications are the major causes of mortality and disability worldwide. Simvastatin (SIM) is one of the most commonly prescribed lipid-lowering drugs for the treatment of hyperlipidemia by competitive inhibition of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase. However, the extensive first-pass metabolism leading to low oral bioavailability and frequent daily doses may lead to poor patient compliance and adverse effects caused by plasma fluctuations. To overcome these challenges, this work purposed two microneedle (MN) delivery strategies for the potential enhancement of SIM delivery. Firstly, nanocrystal (NC) formulations of SIM were investigated, followed by incorporation into a trilayer dissolving microneedle (DMN) design. Furthermore, a novel effervescent powder-carrying MN (EMN) design was developed to enhance intradermal delivery by incorporating the effervescent agents into the drug powder. Both MN approaches exhibited significantly improved permeation and in-skin deposition ability in the Franz cell study, with the ex vivo delivery efficiency of 64.33 ± 6.17 % and 40.11 ± 4.53 % for EMNs and DMNs, respectively. Most importantly, in vivo studies using a female Sprague-Dawley rat model confirmed the successful delivery of SIM from NCs-loaded DMNs (Cmax = 287.39 ± 106.82 ng/mL) and EMNs (Cmax = 203.05 ± 17.07 ng/mL) and maintain therapeutically relevant plasma concentrations for 15 days following a single application. The enhanced bioavailabilities of DMNs and EMNs were 24.28 % and 103.82 %, respectively, which were both significantly higher than that of conventional oral administration.
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Affiliation(s)
- Nuoya Qin
- School of Pharmacy, Queen's University Belfast, Medical Biology Centre, 97 Lisburn Road, Belfast BT9 7BL, UK
| | - Mingshan Li
- School of Pharmacy, Queen's University Belfast, Medical Biology Centre, 97 Lisburn Road, Belfast BT9 7BL, UK
| | - Lalitkumar K Vora
- School of Pharmacy, Queen's University Belfast, Medical Biology Centre, 97 Lisburn Road, Belfast BT9 7BL, UK
| | - Ke Peng
- School of Pharmacy, Queen's University Belfast, Medical Biology Centre, 97 Lisburn Road, Belfast BT9 7BL, UK
| | - Akmal Hidayat Bin Sabri
- School of Pharmacy, Queen's University Belfast, Medical Biology Centre, 97 Lisburn Road, Belfast BT9 7BL, UK
| | - Yushi Tao
- School of Pharmacy, Queen's University Belfast, Medical Biology Centre, 97 Lisburn Road, Belfast BT9 7BL, UK
| | - Alejandro J Paredes
- School of Pharmacy, Queen's University Belfast, Medical Biology Centre, 97 Lisburn Road, Belfast BT9 7BL, UK
| | - Helen O McCarthy
- School of Pharmacy, Queen's University Belfast, Medical Biology Centre, 97 Lisburn Road, Belfast BT9 7BL, UK
| | - Ryan F Donnelly
- School of Pharmacy, Queen's University Belfast, Medical Biology Centre, 97 Lisburn Road, Belfast BT9 7BL, UK.
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10
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Abu Ershaid JM, Zhang H, Tayyem M, Sabri AH, Donnelly RF, Vora LK. Sodium Alginate Microneedles Loaded with Vancomycin for Skin Infections. J Funct Biomater 2024; 15:316. [PMID: 39590520 PMCID: PMC11595082 DOI: 10.3390/jfb15110316] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/11/2024] [Revised: 09/24/2024] [Accepted: 10/21/2024] [Indexed: 11/28/2024] Open
Abstract
BACKGROUND Skin and soft tissue infections (SSTIs) present significant treatment challenges. These infections often require systemic antibiotics such as vancomycin, which poses a risk for increased bacterial resistance. Topical treatments are hindered by the barrier function of the skin, and microneedles (MNs) offer a promising solution, increasing patient compliance and negating the need for traditional needles. METHODS This study focused on the use of sodium alginate MNs for vancomycin delivery directly to the site of infection via a cost-effective micromolding technique. Dissolving polymeric MNs made of sodium alginate and loaded with vancomycin were fabricated and evaluated in terms of their physical properties, delivery ability, and antimicrobial activity. RESULTS The MNs achieved a 378 μm depth of insertion into ex vivo skin and a 5.0 ± 0 mm zone of inhibition in agar disc diffusion assays. Furthermore, in ex vivo Franz cell experiments, the MNs delivered 34.46 ± 11.31 μg of vancomycin with around 35% efficiency, with 9.88 ± 0.57 μg deposited in the skin after 24 h. CONCLUSIONS These findings suggest that sodium alginate MNs are a viable platform for antimicrobial agent delivery in SSTIs. Future in vivo studies are essential to confirm the safety and effectiveness of this innovative method for clinical use.
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Affiliation(s)
- Juhaina M. Abu Ershaid
- School of Pharmacy, Queen’s University Belfast, 97 Lisburn Road, Belfast BT9 7BL, UK; (J.M.A.E.); (H.Z.); (A.H.S.)
- School of Pharmacy, Department of Applied Pharmaceutical Sciences and Clinical Pharmacy, Isra University, Amman 11622, Jordan
| | - Han Zhang
- School of Pharmacy, Queen’s University Belfast, 97 Lisburn Road, Belfast BT9 7BL, UK; (J.M.A.E.); (H.Z.); (A.H.S.)
| | - May Tayyem
- School of Pharmacy, Department of Pharmaceutical Technology and Cosmetics, Middle East University, Airport Road, Amman 11831, Jordan;
| | - Akmal H. Sabri
- School of Pharmacy, Queen’s University Belfast, 97 Lisburn Road, Belfast BT9 7BL, UK; (J.M.A.E.); (H.Z.); (A.H.S.)
- School of Pharmacy, University of Nottingham, University Park, Nottingham NG7 2RD, UK
| | - Ryan F. Donnelly
- School of Pharmacy, Queen’s University Belfast, 97 Lisburn Road, Belfast BT9 7BL, UK; (J.M.A.E.); (H.Z.); (A.H.S.)
| | - Lalitkumar K. Vora
- School of Pharmacy, Queen’s University Belfast, 97 Lisburn Road, Belfast BT9 7BL, UK; (J.M.A.E.); (H.Z.); (A.H.S.)
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11
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Faizi HS, Nasiri MI, Wu Y, Mishra D, Donnelly RF, Minhas MU, Vora LK, Singh Thakur RR. Deferasirox nanosuspension loaded dissolving microneedles for ocular drug delivery. Int J Pharm 2024; 664:124614. [PMID: 39168286 DOI: 10.1016/j.ijpharm.2024.124614] [Citation(s) in RCA: 5] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/17/2024] [Revised: 08/16/2024] [Accepted: 08/17/2024] [Indexed: 08/23/2024]
Abstract
Deferasirox (DFS) is an oral iron chelator that is employed in retinal ailments as a neuroprotectant against retinal injury and thus has utility in treating disorders such as excitoneurotoxicity and age-related macular degeneration (AMD). However, the conventional oral route of administration can present several disadvantages, e.g., the need for more frequent dosing and the first-pass effect. Microneedles (MNs) are minimally invasive systems that can be employed for intrascleral drug delivery without pain and can advantageously replace intravitreal injections therapy (IVT) as well as conventional oral routes of delivery for DFS. In this study, DFS was formulated into a nanosuspension (NS) through wet media milling employing PVA as a stabilizer, which was successfully loaded into polymeric dissolving MNs. DFS exhibited a 4-fold increase in solubility in DFS-NS compared to that of pure DFS. Moreover, the DFS-NSs exhibited excellent short-term stability and enhanced thermal stability, as confirmed through thermogravimetric analysis (TGA) studies. The mechanical characterization of the DFS-NS loaded ocular microneedles (DFS-NS-OcMNs), revealed that the system was sufficiently strong for effective scleral penetration. Optical coherence tomography (OCT) images confirmed the insertion of 81.23 ± 7.35 % of the total height of the MN arrays into full-thickness porcine sclera. Scleral deposition studies revealed 64 % drug deposition after just 5 min of insertion from DFS-NS-loaded ocular microneedles (OcMNs), which was almost 5 times greater than the deposition from pure DFS-OcMNs. Furthermore, both DFS and DFS-NS-OcMN exhibited remarkable cell viability when evaluated on human retinal pigment (ARPE) cells, suggesting their safety and appropriateness for use in the human eye. Therefore, loading DFS-NS into novel MN devices is a promising technique for effectively delivering DFS to the posterior segment of the eye in a minimally invasive manner.
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Affiliation(s)
- Hafsa Shahid Faizi
- School of Pharmacy, Medical Biology Centre, Queen's University Belfast, 97 Lisburn Road, Belfast BT9 7BL, Northern Ireland, United Kingdom; College of Pharmacy, University of Sargodha, University Road, Sargodha, Punjab 40100, Pakistan
| | - Muhammad Iqbal Nasiri
- School of Pharmacy, Medical Biology Centre, Queen's University Belfast, 97 Lisburn Road, Belfast BT9 7BL, Northern Ireland, United Kingdom; Faculty of Pharmacy, Plot No 4, Hamdard University, Park link Rd, Chak Shahzad, Islamabad Capital Territory, Pakistan
| | - Yu Wu
- School of Pharmacy, Medical Biology Centre, Queen's University Belfast, 97 Lisburn Road, Belfast BT9 7BL, Northern Ireland, United Kingdom
| | - Deepakkumar Mishra
- School of Pharmacy, Medical Biology Centre, Queen's University Belfast, 97 Lisburn Road, Belfast BT9 7BL, Northern Ireland, United Kingdom
| | - Ryan F Donnelly
- School of Pharmacy, Medical Biology Centre, Queen's University Belfast, 97 Lisburn Road, Belfast BT9 7BL, Northern Ireland, United Kingdom
| | - Muhammad Usman Minhas
- College of Pharmacy, University of Sargodha, University Road, Sargodha, Punjab 40100, Pakistan
| | - Lalitkumar K Vora
- School of Pharmacy, Medical Biology Centre, Queen's University Belfast, 97 Lisburn Road, Belfast BT9 7BL, Northern Ireland, United Kingdom.
| | - Raghu Raj Singh Thakur
- School of Pharmacy, Medical Biology Centre, Queen's University Belfast, 97 Lisburn Road, Belfast BT9 7BL, Northern Ireland, United Kingdom.
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12
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Naser YA, Vora LK, Tekko IA, Peng K, Volpe-Zanutto F, Greer B, Paredes A, McCarthy HO, Donnelly RF. Atorvastatin-Loaded Dissolving Microarray Patches for Long-Acting Microdepot Delivery: Comparison of Nanoparticle and Microparticle Drug Formulations. ACS APPLIED MATERIALS & INTERFACES 2024; 16. [PMID: 39356645 PMCID: PMC11492242 DOI: 10.1021/acsami.4c05517] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/04/2024] [Revised: 08/28/2024] [Accepted: 09/01/2024] [Indexed: 10/04/2024]
Abstract
The increasing popularity of prolonged-release dosage forms, owing to their ability to provide continuous drug release after administration, has significantly improved patient compliance and overall quality of life. However, achieving prolonged release beyond 24 h frequently requires the use of invasive methods, including injections or implants, which may prove challenging for people suffering from needle phobia. This study introduces atorvastatin (ATR) microparticles (MPs) or nanocrystal (NCs) dissolving microarray patches (D-MAPs) as a noninvasive alternative for intradermal drug delivery over a two-week period for the management of hyperlipidemia. The MP-loaded D-MAPs exhibited an average drug loading of 5.15 ± 0.4 mg of ATR per patch, surpassing the 2.4 ± 0.11 mg/patch observed with NC-loaded D-MAPs. Skin deposition studies demonstrated the superior performance of MP D-MAPs, which delivered 2.0 ± 0.33 mg of ATR per 0.75 cm2 patch within 24 h, representing 38.76% of the initial amount of drug loaded. In contrast, NC D-MAPs delivered approximately 0.89 ± 0.12 mg of ATR per 0.75 cm2 patch at 24 h, equivalent to 38.42 ± 5.13% of the initial ATR loaded. Due to their favorable results, MP D-MAPs were chosen for an in vivo study using Sprague-Dawley rats. The findings demonstrated the capacity of D-MAPs to deliver and attain therapeutically relevant ATR concentrations (>20 ng/mL) for 14 days after a single 24-h application. This study is the first to successfully demonstrate the long-acting transdermal delivery of ATR using MP-loaded D-MAPs after a 24-h single-dose application. The innovative D-MAP system, particularly when loaded with MP, arises as a promising, minimally invasive, long-acting substitute for ATR delivery. This technology has the potential to improve patient compliance and therapeutic outcomes while also significantly advancing the field of transdermal drug delivery.
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Affiliation(s)
- Yara A. Naser
- School
of Pharmacy, Queen’s University Belfast,
Medical Biology Centre, 97 Lisburn Road, Belfast BT9 7BL, Northern Ireland, U.K.
| | - Lalitkumar K. Vora
- School
of Pharmacy, Queen’s University Belfast,
Medical Biology Centre, 97 Lisburn Road, Belfast BT9 7BL, Northern Ireland, U.K.
| | - Ismaiel A. Tekko
- School
of Pharmacy, Queen’s University Belfast,
Medical Biology Centre, 97 Lisburn Road, Belfast BT9 7BL, Northern Ireland, U.K.
- Department
of Pharmaceutics and Pharmaceutical Technology, Faculty of Pharmacy, Aleppo University, Aleppo 00 963, Syria
| | - Ke Peng
- School
of Pharmacy, Queen’s University Belfast,
Medical Biology Centre, 97 Lisburn Road, Belfast BT9 7BL, Northern Ireland, U.K.
| | - Fabiana Volpe-Zanutto
- School
of Pharmacy, Queen’s University Belfast,
Medical Biology Centre, 97 Lisburn Road, Belfast BT9 7BL, Northern Ireland, U.K.
- School
of Biomedical Sciences, Ulster University, Cromore Road, Coleraine BT52 1SA, Northern Ireland, U.K.
| | - Brett Greer
- Institute
for Global Food Security, School of Biological Science, Queen’s University Belfast, 19 Chlorine Gardens, Belfast BT9 5DL, Northern Ireland, U.K.
| | - Alejandro Paredes
- School
of Pharmacy, Queen’s University Belfast,
Medical Biology Centre, 97 Lisburn Road, Belfast BT9 7BL, Northern Ireland, U.K.
| | - Helen O. McCarthy
- School
of Pharmacy, Queen’s University Belfast,
Medical Biology Centre, 97 Lisburn Road, Belfast BT9 7BL, Northern Ireland, U.K.
| | - Ryan F. Donnelly
- School
of Pharmacy, Queen’s University Belfast,
Medical Biology Centre, 97 Lisburn Road, Belfast BT9 7BL, Northern Ireland, U.K.
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13
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Blinov A, Orobets V, Kastarnova E, Gvozdenko A, Golik A, Rekhman Z, Prasolova A, Askerova A, Kuznetsov E, Nagdalian A. Chitosan-ricobendazole complex: Synthesis, characterization and anthelmintic activity. Int J Biol Macromol 2024; 280:135572. [PMID: 39270894 DOI: 10.1016/j.ijbiomac.2024.135572] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/24/2024] [Revised: 09/06/2024] [Accepted: 09/10/2024] [Indexed: 09/15/2024]
Abstract
Synthesis, characterization and assessment of therapeutic efficacy of chitosan-ricobendazole complex were carried out for the first time in this work. Study of physico-chemical properties revealed the optimal ratio of chitosan: ricobendazole (30:4). Quantum chemical modeling set the optimal parameters for the formation of the chitosan-ricobendazole molecular system (E = -3765.26 kcal/mol, η = 0.127 eV), which was confirmed by Fourier-transform infrared spectroscopy. Scanning electron microscopy showed spherical particles of chitosan-ricobendazole complex ranging in size from 100 to 200 μm. Study of therapeutic efficiency was conducted on sheep with dicroceliosis. Notably, the therapeutic efficiency of the chitosan-ricobendazole complex (4 mg/kg of ricobendazole) reached 89 %, while the therapeutic efficiency of the commercial preparation ricazole (8 mg/kg of ricobendazole) was 92 %. Biochemical blood test indicated equivalent normalization of hematological parameters in sheep after treatment with ricazole and the chitosan-ricobendazole complex. Histological examination of infected sheep liver revealed that treatment with the chitosan-ricobendazole complex leads to a decrease in the number of helminth eggs with subsequent therapeutic effect on the severity of the disease. This proves the enhanced solubility of ricobendazole at a dosage of 4 mg/kg, active interaction of the components and relatively high bioavailability without increasing the release rate of ricobendazole.
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Affiliation(s)
- Andrey Blinov
- North-Caucasus Federal University, Stavropol 355017, Russia
| | | | | | | | - Alexey Golik
- North-Caucasus Federal University, Stavropol 355017, Russia
| | - Zafar Rekhman
- North-Caucasus Federal University, Stavropol 355017, Russia
| | | | - Alina Askerova
- North-Caucasus Federal University, Stavropol 355017, Russia
| | - Egor Kuznetsov
- North-Caucasus Federal University, Stavropol 355017, Russia
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14
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Achmad AA, Tangdilintin F, Stephanie, Enggi CK, Sulistiawati, Rifai Y, Aliyah, Permana AD, Manggau MA. Development of dissolving microneedles loaded with fucoidan for enhanced anti-aging activity: An in vivo study in mice animal model. Eur J Pharm Biopharm 2024; 202:114362. [PMID: 38871091 DOI: 10.1016/j.ejpb.2024.114362] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/02/2024] [Revised: 05/30/2024] [Accepted: 06/10/2024] [Indexed: 06/15/2024]
Abstract
Skin aging occurs naturally as essential skin components gradually decline, leading to issues such as fine lines, wrinkles, and pigmentation. Fucoidan, a natural bioactive compound, holds potential for addressing these age-related concerns. However, its hydrophilic nature and substantial molecular weight hinder its absorption into the skin. In this study, we utilized polyvinyl pyrrolidone K30 (PVP) and polyvinyl alcohol (PVA) as polymers to fabricate dissolving microneedles loaded with fucoidan (DMN-F). The DMN-F formulations were examined for physical characteristics, stability, permeability, toxicity, and efficacy in animal models. These formulations exhibited consistent polymer blends with a conical structure and uniform cone-shaped design. Microneedle structure and penetration capability gradually decreased with increasing fucoidan concentration, with storage recommended at approximately 33 % relative humidity (RH). Ex vivo studies showed that DMN-F efficiently delivered up to 95.03 ± 2.36 % of the total fucoidan concentration into the skin. In vivo investigations revealed that DMN-F effectively reduced wrinkles, improved skin elasticity, maintained moisture levels, and increased epidermal thickness. Histological images provided additional evidence of DMN-F's positive effects on these aging parameters. The results confirm that the DMN-F formulation effectively delivers fucoidan into the skin, allowing it to treat and mitigate signs of aging.
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Affiliation(s)
| | | | - Stephanie
- Faculty of Pharmacy, Hasanuddin University, Makassar 90245, Indonesia
| | | | - Sulistiawati
- Faculty of Pharmacy, Hasanuddin University, Makassar 90245, Indonesia
| | - Yusnita Rifai
- Faculty of Pharmacy, Hasanuddin University, Makassar 90245, Indonesia
| | - Aliyah
- Faculty of Pharmacy, Hasanuddin University, Makassar 90245, Indonesia
| | - Andi Dian Permana
- Faculty of Pharmacy, Hasanuddin University, Makassar 90245, Indonesia.
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15
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Han H, Li B, Yang R, Guo HL, Li Q, Wang H, Zheng B, Bai Y, Yu Y. NIR-Remote Selectively Triggered Buprenorphine Hydrochloride Release from Microneedle Patches for the Treatment of Neuropathic Pain. ACS Biomater Sci Eng 2024; 10:5001-5013. [PMID: 39013076 DOI: 10.1021/acsbiomaterials.4c00733] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 07/18/2024]
Abstract
Neuropathic pain is a prevalent form of intermittent chronic pain, affecting approximately 7-10% of the global population. However, the current clinical administration methods, such as injection and oral administration, are mostly one-time administration, which cannot achieve accurate control of pain degree and drug dose. Herein, we developed near-infrared (NIR) light-responsive microneedle patches (MNPs) to spatiotemporally control the drug dose released to treat neuropathic pain according to the onset state. The mechanism of action utilizes upconversion nanoparticles to convert NIR light into visible and ultraviolet light. This conversion triggers the rapid rotation of the azobenzene molecular motor in the mesoporous material, enabling the on-demand controlled release of a drug dose. Additionally, MNs are used to overcome the barrier of the stratum corneum in a minimally invasive and painless manner, effectively promoting the transdermal penetration of drug molecules. The effectiveness of these patches has been demonstrated through significant results. Upon exposure to NIR light for five consecutive cycles, with each cycle lasting 30 s, the patches achieved a precise release of 318 μg of medication. In a mouse model, maximum pain relief was observed within 1 h of one cycle of NIR light exposure, with the effects lasting up to 6 h. The same level of precise treatment efficacy was maintained for subsequent pain episodes with similar light exposure. The NIR-controlled drugs precision-released MNPs provide a novel paradigm for the treatment of intermittent neuropathic pain.
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Affiliation(s)
- Huanzhi Han
- Department of Anesthesiology, Tianjin Medical University General Hospital, Tianjin 300052, China
- Qilu Hospital of Shandong University Dezhou Hospital, Dezhou 253000, China
| | - Bowen Li
- Academy of Medical Engineering and Translational Medicine, Tianjin University, Tianjin 300072, China
| | - Run Yang
- Academy of Medical Engineering and Translational Medicine, Tianjin University, Tianjin 300072, China
| | - Hao-Lin Guo
- School of Traditional Chinese Medicine, Beijing University of Chinese Medicine, Beijing 102401, China
| | - Qiuya Li
- Academy of Medical Engineering and Translational Medicine, Tianjin University, Tianjin 300072, China
| | - Hua Wang
- Academy of Medical Engineering and Translational Medicine, Tianjin University, Tianjin 300072, China
| | - Bin Zheng
- Academy of Medical Engineering and Translational Medicine, Tianjin University, Tianjin 300072, China
- School of Biomedical Engineering and Technology, Tianjin Medical University, Tianjin 300070, China
| | - Yang Bai
- Department of Anesthesiology, Tianjin Medical University General Hospital, Tianjin 300052, China
| | - Yonghao Yu
- Department of Anesthesiology, Tianjin Medical University General Hospital, Tianjin 300052, China
- Tianjin Research Institute of Anesthesiology, Tianjin 300052, China
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16
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Dai X, Permana AD, Li M, Habibie, Nur Amir M, Peng K, Zhang C, Dai H, Paredes AJ, Vora LK, Donnelly RF. Calcipotriol Nanosuspension-Loaded Trilayer Dissolving Microneedle Patches for the Treatment of Psoriasis: In Vitro Delivery and In Vivo Antipsoriatic Activity Studies. Mol Pharm 2024; 21:2813-2827. [PMID: 38752564 DOI: 10.1021/acs.molpharmaceut.3c01223] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 06/04/2024]
Abstract
Psoriasis, affecting 2-3% of the global population, is a chronic inflammatory skin condition without a definitive cure. Current treatments focus on managing symptoms. Recognizing the need for innovative drug delivery methods to enhance patient adherence, this study explores a new approach using calcipotriol monohydrate (CPM), a primary topical treatment for psoriasis. Despite its effectiveness, CPM's therapeutic potential is often limited by factors like the greasiness of topical applications, poor skin permeability, low skin retention, and lack of controlled delivery. To overcome these challenges, the study introduces CPM in the form of nanosuspensions (NSs), characterized by an average particle size of 211 ± 2 nm. These CPM NSs are then incorporated into a trilayer dissolving microneedle patch (MAP) made from poly(vinylpyrrolidone) and w poly(vinyl alcohol) as needle arrays and prefrom 3D printed polylactic acid backing layer. This MAP features rapidly dissolving tips and exhibits good mechanical properties and insertion capability with delivery efficiency compared to the conventional Daivonex ointment. The effectiveness of this novel MAP was tested on Sprague-Dawley rats with imiquimod-induced psoriasis, demonstrating efficacy comparable to the marketed ointment. This innovative trilayer dissolving MAP represents a promising new local delivery system for calcipotriol, potentially revolutionizing psoriasis treatment by enhancing drug delivery and patient compliance.
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Affiliation(s)
- Xianbing Dai
- School of Pharmacy, Medical Biology Centre, Queen's University Belfast, 97 Lisburn Road, Belfast BT9 7BL, U.K
- School of Pharmacy, Jinzhou Medical University, Jinzhou, Liaoning 121001, China
| | - Andi Dian Permana
- Faculty of Pharmacy, Universitas Hasanuddin, Makassar 90245, Indonesia
| | - Mingshan Li
- School of Pharmacy, Medical Biology Centre, Queen's University Belfast, 97 Lisburn Road, Belfast BT9 7BL, U.K
| | - Habibie
- Faculty of Pharmacy, Universitas Hasanuddin, Makassar 90245, Indonesia
| | - Muhammad Nur Amir
- Faculty of Pharmacy, Universitas Hasanuddin, Makassar 90245, Indonesia
| | - Ke Peng
- School of Pharmacy, Medical Biology Centre, Queen's University Belfast, 97 Lisburn Road, Belfast BT9 7BL, U.K
| | - Chunyang Zhang
- School of Pharmacy, Medical Biology Centre, Queen's University Belfast, 97 Lisburn Road, Belfast BT9 7BL, U.K
| | - Haodong Dai
- School of Chemistry and Chemical Engineering, Queen's University Belfast, David Keir Building, Stranmillis Road, Belfast BT9 5AG, U.K
| | - Alejandro J Paredes
- School of Pharmacy, Medical Biology Centre, Queen's University Belfast, 97 Lisburn Road, Belfast BT9 7BL, U.K
| | - Lalitkumar K Vora
- School of Pharmacy, Medical Biology Centre, Queen's University Belfast, 97 Lisburn Road, Belfast BT9 7BL, U.K
| | - Ryan F Donnelly
- School of Pharmacy, Medical Biology Centre, Queen's University Belfast, 97 Lisburn Road, Belfast BT9 7BL, U.K
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17
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Cheng A, Zhang S, Meng F, Xing M, Liu H, Yang G, Gao Y. Nanosuspension-Loaded Dissolving Microneedle Patches for Enhanced Transdermal Delivery of a Highly Lipophilic Cannabidiol. Int J Nanomedicine 2024; 19:4061-4079. [PMID: 38736651 PMCID: PMC11088408 DOI: 10.2147/ijn.s452207] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/01/2023] [Accepted: 04/11/2024] [Indexed: 05/14/2024] Open
Abstract
Purpose Transdermal Drug Delivery System (TDDS) offers a promising alternative for delivering poorly soluble drugs, challenged by the stratum corneum's barrier effect, which restricts the pool of drug candidates suitable for TDDS. This study aims to establish a delivery platform specifically for highly lipophilic drugs requiring high doses (log P > 5, dose > 10 mg/kg/d), to improve their intradermal delivery and enhance solubility. Methods Cannabidiol (CBD, log P = 5.91) served as the model drug. A CBD nanosuspension (CBD-NS) was prepared using a bottom-up method. The particle size, polydispersity index (PDI), zeta potential, and concentration of the CBD-NS were characterized. Subsequently, CBD-NS was incorporated into dissolving microneedles (DMNs) through a one-step manufacturing process. The intradermal dissolution abilities, physicochemical properties, mechanical strength, insertion depth, and release behavior of the DMNs were evaluated. Sprague-Dawley (SD) rats were utilized to assess the efficacy of the DMN patch in treating knee synovitis and to analyze its skin permeation kinetics and pharmacokinetic performance. Results The CBD-NS, stabilized with Tween 80, exhibited a particle size of 166.83 ± 3.33 nm, a PDI of 0.21 ± 0.07, and a concentration of 46.11 ± 0.52 mg/mL. The DMN loaded with CBD-NS demonstrated favorable intradermal dissolution and mechanical properties. It effectively increased the delivery of CBD into the skin, extended the action's duration in vivo, and enhanced bioavailability. CBD-NS DMN exhibited superior therapeutic efficacy and safety in a rat model of knee synovitis, significantly inhibiting TNF-α and IL-1β compared with the methotrexate subcutaneous injection method. Conclusion NS technology effectively enhances the solubility of the poorly soluble drug CBD, while DMN facilitates penetration, extends the duration of action in vivo, and improves bioavailability. Furthermore, CBD has shown promising therapeutic outcomes in treating knee synovitis. This innovative drug delivery system is expected to offer a more efficient solution for the administration of highly lipophilic drugs akin to CBD, thereby facilitating high-dose administration.
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Affiliation(s)
- Aguo Cheng
- Key Laboratory of Photochemical Conversion and Optoelectronic Materials, Technical Institute of Physics and Chemistry of Chinese Academy of Sciences, Beijing, People’s Republic of China
- University of Chinese Academy of Sciences, Beijing, People’s Republic of China
| | - Suohui Zhang
- Key Laboratory of Photochemical Conversion and Optoelectronic Materials, Technical Institute of Physics and Chemistry of Chinese Academy of Sciences, Beijing, People’s Republic of China
- Beijing CAS Microneedle Technology Ltd, Beijing, People’s Republic of China
| | - Fanda Meng
- School of Clinical and Basic Medical Sciences, Shandong First Medical University & Shandong Academy of Medical Sciences, Jinan, Shandong Province, People’s Republic of China
| | - Mengzhen Xing
- Key Laboratory of New Material Research Institute, Department of Pharmaceutical Research Institute, Shandong University of Traditional Chinese Medicine, Jinan, Shandong Province, People’s Republic of China
| | - Han Liu
- Beijing CAS Microneedle Technology Ltd, Beijing, People’s Republic of China
| | - Guozhong Yang
- Beijing CAS Microneedle Technology Ltd, Beijing, People’s Republic of China
| | - Yunhua Gao
- Key Laboratory of Photochemical Conversion and Optoelectronic Materials, Technical Institute of Physics and Chemistry of Chinese Academy of Sciences, Beijing, People’s Republic of China
- University of Chinese Academy of Sciences, Beijing, People’s Republic of China
- Beijing CAS Microneedle Technology Ltd, Beijing, People’s Republic of China
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18
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Kim JC, Choi JA, Park H, Yang E, Noh S, Kim JS, Kim MJ, Song M, Park JH. Pharmaceutical and Immunological Evaluation of Cholera Toxin A1 Subunit as an Adjuvant of Hepatitis B Vaccine Microneedles. Pharm Res 2023; 40:3059-3071. [PMID: 37914841 DOI: 10.1007/s11095-023-03623-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/28/2023] [Accepted: 10/11/2023] [Indexed: 11/03/2023]
Abstract
PURPOSE For successful delivery of a solid vaccine formulation into the skin using microneedles, the solubility of an adjuvant should be considered because the decrease in the dissolution rate by the addition of adjuvant decreases the delivery efficiency of the vaccine. METHODS In this study, cholera toxin A subunit 1 (CTA1) was examined as an adjuvant to Hepatitis B vaccine (HBV) microneedles because of its good water solubility, improved safety, and positive effect as shown in intramuscular administration of a liquid vaccine. RESULTS All solid formulations with CTA 1 dissolved in in vivo mouse skin within 30 min, and they were successfully delivered into the skin. In experiments with mice, the addition of CTA1 led to improved IgG immune response compared to the use of an aluminum hydroxide-based formulation and intramuscular administration of HBV. In addition, CTA1 induced CD8 + T cell response as much as in which the aluminum hydroxide-based formulation induced. CONCLUSIONS CTA1 is an adjuvant that satisfies both the delivery efficiency and the immunological characteristics required for vaccine microneedles. CTA1 will be used as a potential adjuvant through vaccine microneedles.
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Affiliation(s)
- Jong-Chan Kim
- Department of BioNano Technology, Gachon BioNano Research Institute, Gachon University, Seongnam, South Korea
| | - Jung-Ah Choi
- Science Unit, International Vaccine Institute, Seoul, South Korea
| | - Hayan Park
- Science Unit, International Vaccine Institute, Seoul, South Korea
| | - Eunji Yang
- Science Unit, International Vaccine Institute, Seoul, South Korea
| | - Shinyoung Noh
- Science Unit, International Vaccine Institute, Seoul, South Korea
| | - Ji-Seok Kim
- Department of BioNano Technology, Gachon BioNano Research Institute, Gachon University, Seongnam, South Korea
| | - Moon-Jin Kim
- Department of BioNano Technology, Gachon BioNano Research Institute, Gachon University, Seongnam, South Korea
| | - Manki Song
- Science Unit, International Vaccine Institute, Seoul, South Korea.
| | - Jung-Hwan Park
- Department of BioNano Technology, Gachon BioNano Research Institute, Gachon University, Seongnam, South Korea.
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19
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Huang H, Zhang Y, Liu Y, Guo Y, Hu C. Influence of Intermolecular Interactions on Crystallite Size in Crystalline Solid Dispersions. Pharmaceutics 2023; 15:2493. [PMID: 37896253 PMCID: PMC10610461 DOI: 10.3390/pharmaceutics15102493] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/19/2023] [Revised: 10/17/2023] [Accepted: 10/18/2023] [Indexed: 10/29/2023] Open
Abstract
Crystalline solid dispersions (CSDs) represent a thermodynamically stable system capable of effectively reducing the crystallite size of drugs, thereby enhancing their solubility and bioavailability. This study uses flavonoid drugs with the same core structures but varying numbers of hydroxyl groups as model drugs and poloxamer 188 as a carrier to explore the intrinsic relationships between drug-polymer interactions, crystallite size, and in vitro dissolution behavior in CSDs. Initially, we investigate the interactions between flavonoid drugs and P188 by calculating Hansen solubility parameters, determination of Flory-Huggins interaction parameters, and other methods. Subsequently, we explore the crystallization kinetics of flavonoid drugs and P188 in CSD systems using polarized optical microscopy and powder X-ray diffraction. We monitor the domain size and crystallite size of flavonoids in CSDs through powder X-ray diffraction and a laser-particle-size analyzer. Finally, we validate the relationship between crystallite size and in vitro dissolution behavior through powder dissolution. The results demonstrate that, as the number of hydroxyl groups increases, the interactions between drugs and polymers become stronger, making drug crystallization in the CSD system less likely. Consequently, reductions in crystalline domain size and crystallite size become more pronounced, leading to a more significant enhancement in drug dissolution.
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Affiliation(s)
- Hua Huang
- Medical College, Qinghai University, Xining 810001, China; (H.H.); (Y.Z.); (Y.L.); (Y.G.)
| | - Yong Zhang
- Medical College, Qinghai University, Xining 810001, China; (H.H.); (Y.Z.); (Y.L.); (Y.G.)
| | - Yao Liu
- Medical College, Qinghai University, Xining 810001, China; (H.H.); (Y.Z.); (Y.L.); (Y.G.)
| | - Yufei Guo
- Medical College, Qinghai University, Xining 810001, China; (H.H.); (Y.Z.); (Y.L.); (Y.G.)
| | - Chunhui Hu
- State Key Laboratory of Plateau Ecology and Agriculture, Qinghai University, Xining 810001, China
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20
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Vora LK, Sabri AH, Naser Y, Himawan A, Hutton ARJ, Anjani QK, Volpe-Zanutto F, Mishra D, Li M, Rodgers AM, Paredes AJ, Larrañeta E, Thakur RRS, Donnelly RF. Long-acting microneedle formulations. Adv Drug Deliv Rev 2023; 201:115055. [PMID: 37597586 DOI: 10.1016/j.addr.2023.115055] [Citation(s) in RCA: 49] [Impact Index Per Article: 24.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/08/2023] [Revised: 08/09/2023] [Accepted: 08/16/2023] [Indexed: 08/21/2023]
Abstract
The minimally-invasive and painless nature of microneedle (MN) application has enabled the technology to obviate many issues with injectable drug delivery. MNs not only administer therapeutics directly into the dermal and ocular space, but they can also control the release profile of the active compound over a desired period. To enable prolonged delivery of payloads, various MN types have been proposed and evaluated, including dissolving MNs, polymeric MNs loaded or coated with nanoparticles, fast-separable MNs hollow MNs, and hydrogel MNs. These intricate yet intelligent delivery platforms provide an attractive approach to decrease side effects and administration frequency, thus offer the potential to increase patient compliance. In this review, MN formulations that are loaded with various therapeutics for long-acting delivery to address the clinical needs of a myriad of diseases are discussed. We also highlight the design aspects, such as polymer selection and MN geometry, in addition to computational and mathematical modeling of MNs that are necessary to help streamline and develop MNs with high translational value and clinical impact. Finally, up-scale manufacturing and regulatory hurdles along with potential avenues that require further research to bring MN technology to the market are carefully considered. It is hoped that this review will provide insight to formulators and clinicians that the judicious selection of materials in tandem with refined design may offer an elegant approach to achieve sustained delivery of payloads through the simple and painless application of a MN patch.
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Affiliation(s)
- Lalitkumar K Vora
- School of Pharmacy, Queen's University Belfast, 97 Lisburn Road, Belfast BT9 7BL, UK
| | - Akmal H Sabri
- School of Pharmacy, Queen's University Belfast, 97 Lisburn Road, Belfast BT9 7BL, UK
| | - Yara Naser
- School of Pharmacy, Queen's University Belfast, 97 Lisburn Road, Belfast BT9 7BL, UK
| | - Achmad Himawan
- School of Pharmacy, Queen's University Belfast, 97 Lisburn Road, Belfast BT9 7BL, UK; Department of Pharmaceutical Science and Technology, Faculty of Pharmacy, Universitas Hasanuddin, Makassar 90245, Indonesia
| | - Aaron R J Hutton
- School of Pharmacy, Queen's University Belfast, 97 Lisburn Road, Belfast BT9 7BL, UK
| | - Qonita Kurnia Anjani
- School of Pharmacy, Queen's University Belfast, 97 Lisburn Road, Belfast BT9 7BL, UK
| | - Fabiana Volpe-Zanutto
- School of Pharmacy, Queen's University Belfast, 97 Lisburn Road, Belfast BT9 7BL, UK
| | - Deepakkumar Mishra
- School of Pharmacy, Queen's University Belfast, 97 Lisburn Road, Belfast BT9 7BL, UK
| | - Mingshan Li
- School of Pharmacy, Queen's University Belfast, 97 Lisburn Road, Belfast BT9 7BL, UK
| | - Aoife M Rodgers
- The Wellcome-Wolfson Institute for Experimental Medicine, Queen's University of Belfast, 97 Lisburn Road, Belfast BT9 7BL, UK
| | - Alejandro J Paredes
- School of Pharmacy, Queen's University Belfast, 97 Lisburn Road, Belfast BT9 7BL, UK
| | - Eneko Larrañeta
- School of Pharmacy, Queen's University Belfast, 97 Lisburn Road, Belfast BT9 7BL, UK
| | | | - Ryan F Donnelly
- School of Pharmacy, Queen's University Belfast, 97 Lisburn Road, Belfast BT9 7BL, UK.
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21
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Shabbir M, Barkat K, Ashraf MU, Nagra U, Shah SNH. Assessment of formulation variables of poor water soluble diacerein for its improved loading and anti-inflammatory activity. Drug Deliv Transl Res 2023; 13:1780-1798. [PMID: 36735216 DOI: 10.1007/s13346-023-01293-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 01/04/2023] [Indexed: 02/04/2023]
Abstract
Dissolving microneedles have become a popular method for percutaneous administrationof drugs. However, loading poorly soluble drugs into water-based dissolving microneedles remains a challenge. In view of this, we aimed to improve Diacerein (DCN) solubility formulating dissolving microneedles. DCN microsuspension was created by high-speed homogenization with organic solvents or wet milling with Tween 80 as a stabilizer (LD1). They were analyzed for particle size and saturation solubility. Subsequently, the organic solvent-based microneedles were prepared under vacuum, whereas LD1 was mixed with HPMC (8% w/w) and PVP (30% w/w) matrix to concentrate the drug in acral fraction through centrifugation. DCN microsuspension in DMSO had the highest drug solubility with an average particle size of 6 µm, whereas LD1 had a particle size of 3.28 µm showing improved solubility. TD-3 had the highest drug loading and the least amount of drug migration into the blank baseplate. Within 5 min, these microneedles dissolved completely in an agarose-gel block. LD1 was likewise put in the baseplate to generate TD3-B. Within 24 h, 74.39% of the medication was released from TD3-B, with only a small amount remaining in the baseplate. TLC examination indicated the conversion of DCN to Rhein in the skin, whereas DSC and TGA studies revealed amorphous features. DCN microneedles showed no sign of skin irritancy but showed anti-inflammatory response on carrageenan-induced paw edema model. Microneedles remained stable during accelerated stability testing. Wet milling in the presence of a stabilizer can be an effective approach for enhancing DCN solubility for improved drug loading in dissolving microneedles. Improvement in solubility of Diacerein for subsequent loading in Dissolving Microneedle for percutaneous delivery.
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Affiliation(s)
- Maryam Shabbir
- Faculty of Pharmacy, University of Lahore, Lahore, Punjab, Pakistan
| | - Kashif Barkat
- Faculty of Pharmacy, University of Lahore, Lahore, Punjab, Pakistan.
| | | | - Uzair Nagra
- Faculty of Pharmacy, University of Lahore, Lahore, Punjab, Pakistan
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22
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Yuan J, Yang H, Liu C, Shao L, Zhang H, Lu K, Wang J, Wang Y, Yu Q, Zhang Y, Yu Y, Shen Z. Microneedle Patch Loaded with Exosomes Containing MicroRNA-29b Prevents Cardiac Fibrosis after Myocardial Infarction. Adv Healthc Mater 2023; 12:e2202959. [PMID: 36739582 DOI: 10.1002/adhm.202202959] [Citation(s) in RCA: 40] [Impact Index Per Article: 20.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/15/2022] [Revised: 01/18/2023] [Indexed: 02/06/2023]
Abstract
Myocardial infarction (MI) is a cardiovascular disease that poses a serious threat to human health. Uncontrolled and excessive cardiac fibrosis after MI has been recognized as a primary contributor to mortality by heart failure. Thus, prevention of fibrosis or alleviation of fibrosis progression is important for cardiac repair. To this end, a biocompatible microneedle (MN) patch based on gelatin is fabricated to load exosomes containing microRNA-29b (miR-29b) mimics with antifibrotic activity to prevent excessive cardiac fibrosis after MI. Exosomes are isolated from human umbilical cord mesenchymal stem cells and loaded with miR-29b mimics via electroporation, which can be internalized effectively in cardiac fibroblasts to upregulate the expression of miR-29b and downregulate the expression of fibrosis-related proteins. After being implanted in the infarcted heart of a mouse MI model, the MN patch can increase the retention of loaded exosomes in the infarcted myocardium, leading to alleviation of inflammation, reduction of the infarct size, inhibition of fibrosis, and improvement of cardiac function. This design explored the MN patch as a suitable platform to deliver exosomes containing antifibrotic biomolecules locally for the prevention of cardiac fibrosis, showing the potential for MI treatment in clinical applications.
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Affiliation(s)
- Jianping Yuan
- Department of Cardiovascular Surgery of the First Affiliated Hospital and Institute for Cardiovascular Science, Suzhou Medical College of Soochow University, Soochow University, Suzhou, 215007, P. R. China
- Department of Thoracic and Cardiovascular Surgery, Baotou Central Hospital, Baotou, 014040, P. R. China
| | - Hong Yang
- Department of Cardiovascular Surgery of the First Affiliated Hospital and Institute for Cardiovascular Science, Suzhou Medical College of Soochow University, Soochow University, Suzhou, 215007, P. R. China
| | - Chunxia Liu
- Department of Cardiovascular Surgery of the First Affiliated Hospital and Institute for Cardiovascular Science, Suzhou Medical College of Soochow University, Soochow University, Suzhou, 215007, P. R. China
| | - Lianbo Shao
- Department of Cardiovascular Surgery of the First Affiliated Hospital and Institute for Cardiovascular Science, Suzhou Medical College of Soochow University, Soochow University, Suzhou, 215007, P. R. China
| | - Haixin Zhang
- State and Local Joint Engineering Laboratory for Novel Functional Polymeric Materials, College of Chemistry, Chemical Engineering and Materials Science, Soochow University, Suzhou, 215123, P. R. China
| | - Kunyan Lu
- State and Local Joint Engineering Laboratory for Novel Functional Polymeric Materials, College of Chemistry, Chemical Engineering and Materials Science, Soochow University, Suzhou, 215123, P. R. China
| | - Jingjing Wang
- Department of Cardiovascular Surgery of the First Affiliated Hospital and Institute for Cardiovascular Science, Suzhou Medical College of Soochow University, Soochow University, Suzhou, 215007, P. R. China
| | - Yuanyuan Wang
- Department of Cardiovascular Surgery of the First Affiliated Hospital and Institute for Cardiovascular Science, Suzhou Medical College of Soochow University, Soochow University, Suzhou, 215007, P. R. China
| | - Qian Yu
- State and Local Joint Engineering Laboratory for Novel Functional Polymeric Materials, College of Chemistry, Chemical Engineering and Materials Science, Soochow University, Suzhou, 215123, P. R. China
| | - Yanxia Zhang
- Department of Cardiovascular Surgery of the First Affiliated Hospital and Institute for Cardiovascular Science, Suzhou Medical College of Soochow University, Soochow University, Suzhou, 215007, P. R. China
| | - Yunsheng Yu
- Department of Cardiovascular Surgery of the First Affiliated Hospital and Institute for Cardiovascular Science, Suzhou Medical College of Soochow University, Soochow University, Suzhou, 215007, P. R. China
| | - Zhenya Shen
- Department of Cardiovascular Surgery of the First Affiliated Hospital and Institute for Cardiovascular Science, Suzhou Medical College of Soochow University, Soochow University, Suzhou, 215007, P. R. China
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23
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Mudjahid M, Meidianto Asri R, Nainu F, Dian Permana A. Validation of spectrophotometric method to quantify chloramphenicol in fluid and rat skin tissue mimicking infection environment: Application to in vitro release and ex vivo dermatokinetic studies from dissolving microneedle loaded microparticle sensitive bacteria. SPECTROCHIMICA ACTA. PART A, MOLECULAR AND BIOMOLECULAR SPECTROSCOPY 2023; 291:122374. [PMID: 36682254 DOI: 10.1016/j.saa.2023.122374] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/03/2022] [Revised: 12/15/2022] [Accepted: 01/12/2023] [Indexed: 06/17/2023]
Abstract
Cellulitis is a common dermis/subcutaneous tissue skin infection and shared global disease burden, with a higher incidence for males and people aged 45-64 years. Application therapy of chloramphenicol (CHL) has been hindered because of its toxicity and limited penetration into the skin. In this research, CHL was developed into a bacterially sensitive microparticles which were further incorporated into a microneedle system to increase penetration. To support this formulation, in this study, UV-vis spectrophotometry method was validated in methanol, polyvinyl alcohol (PVA) 1%, phosphate buffered saline (PBS), tryptic soy broth (TSB) (fluid-mimicking infection), and skin tissue to quantify amount of CHL. The developed analytical method was subsequently validated according to ICH guidelines. The results obtained showed that the correlation coefficients were linear ≥0.9934. The values of LLOQ inside the methanol, PVA 1%, PBS, TSB, and skin tissue were 7.20 µg/mL, 4.40 µg/mL, 8.18 µg/mL, 387.48 µg/mL, and 7.27 µg/mL, respectively. The accuracy and precision of the developed method were prominent. These methods were successfully applied to quantify the amount of CHL in microparticle and microneedle system in fluid and tissue skin infection. The result showed the high drug release microparticle sensitive bacteria, and high drug retention in ex vivo dermatokinetic evaluation in rat skin tissue containing bacterial infection. This was due to the presence of Staphylococcus aureus bacteria culture that produced lipase enzymes, playing a role in lysing microparticle matrix to develop selectively delivery antimicrobials. A further analytical method needs to be matured to quantify CHL inside the in vivo studies.
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Affiliation(s)
- Mukarram Mudjahid
- Faculty of Pharmacy, Hasanuddin University, Makassar 90245, Indonesia
| | | | - Firzan Nainu
- Faculty of Pharmacy, Hasanuddin University, Makassar 90245, Indonesia
| | - Andi Dian Permana
- Faculty of Pharmacy, Hasanuddin University, Makassar 90245, Indonesia.
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24
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Aly NSM, Matsumori H, Dinh TQ, Sato A, Miyoshi SI, Chang KS, Yu HS, Kim HS. Formulation and evaluation of the antimalarial N-89 as a transdermal drug candidate. Parasitol Int 2023; 93:102720. [PMID: 36516945 DOI: 10.1016/j.parint.2022.102720] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/12/2022] [Revised: 12/09/2022] [Accepted: 12/09/2022] [Indexed: 12/14/2022]
Abstract
The discovery of new effective and safe antimalarial drugs is mandatory. In this report, we formulate and evaluate transdermal (td) 1,2,6,7-tetraoxaspiro[7.11]nonadecane (N-89) using the Plasmodium berghei rodent malaria parasite in vivo model. The selected solvent for the ointment type of td N-89 was polyethylene glycol (PEG) [PEG400:PEG 4000 = 8:1 (v/w)]. We tested different application areas of 4, 6, and 8 cm2 on the shaved backs of mice. Pharmacokinetic (PK) analysis of N-89 parameters after a single 4 cm2 transdermal application revealed that the Tmax was 2 h, the T1/2 was 1.9 h, and the AUC was 1951.1 ng.h/mL. More than 10 ng/mL of plasma concentration was maintained for 12 h. The ED50 values for the 4, 6, and 8 cm2 application areas in a 4-day suppressive test were 18.9, 25.1, and 26.8 mg/kg, respectively. We additionally tested the cure effect of td N-89 in mice at a dose of 60 mg/kg, twice daily for 4 days at 0.2% parasitemia. Parasites disappeared following day 7 post-treatment in all td N-89 treated groups. Mice were cured without any parasite recurrence or dermal irritation. In conclusion, this study determined for the first time the PK parameters and effect of a new ointment type of td N-89. This suggests that transdermal treatment with N-89 is an effective and safe alternative route for the treatment of malaria, especially in children.
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Affiliation(s)
- Nagwa S M Aly
- Division of International Infectious Diseases Control, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, Okayama 700-8530, Japan; Parasitology Department, Faculty of Medicine, Benha University, Benha13511, Egypt
| | - Hiroaki Matsumori
- Division of International Infectious Diseases Control, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, Okayama 700-8530, Japan
| | - Thi Quyen Dinh
- Division of International Infectious Diseases Control, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, Okayama 700-8530, Japan
| | - Akira Sato
- Division of International Infectious Diseases Control, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, Okayama 700-8530, Japan; Department of Biochemistry, Faculty of Pharmaceutical Sciences, Tokyo University of Science, Noda, Chiba 278-8530, Japan
| | - Shin-Ich Miyoshi
- Department of Sanitary Microbiology, Faculty of Pharmaceutical Sciences, Okayama University, Tsushima-Naka, Kita-Ku, Okayama 700-8530, Japan
| | - Kyung-Soo Chang
- Department of Clinical Laboratory Science, College of Health Sciences, Catholic University of Pusan, Busan 46252, Republic of Korea
| | - Hak Sun Yu
- Department of Parasitology and Tropical Medicine, School of Medicine, Pusan National University, Beomeo-ri, Mulgeum-eup, Yangsan-si, Gyeongsangnam-do, 626-870, Republic of Korea
| | - Hye-Sook Kim
- Division of International Infectious Diseases Control, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, Okayama 700-8530, Japan.
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25
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Aly NSM, Matsumori H, Dinh TQ, Sato A, Miyoshi SI, Chang KS, Yu HS, Cao DT, Kim HS. Pioneer Use of Antimalarial Transdermal Combination Therapy in Rodent Malaria Model. Pathogens 2023; 12:pathogens12030398. [PMID: 36986320 PMCID: PMC10056811 DOI: 10.3390/pathogens12030398] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/11/2022] [Revised: 01/25/2023] [Accepted: 02/23/2023] [Indexed: 03/06/2023] Open
Abstract
We have previously reported 1,2,6,7-tetraoxaspiro [7.11]nonadecane (N-89) as a promising antimalarial compound. In this study, we evaluated the effect of transdermal therapy (tdt) of N-89 in combination (tdct) with other antimalarials as an application for children. We prepared ointment formulas containing N-89 plus another antimalarial drug, specifically, mefloquine, pyrimethamine, or chloroquine. In a 4-day suppressive test, the ED50 values for N-89 alone or combined with either mefloquine, pyrimethamine, or chloroquine were 18, 3, 0.1, and 3 mg/kg, respectively. Interaction assays revealed that N-89 combination therapy showed a synergistic effect with mefloquine and pyrimethamine, but chloroquine provoked an antagonistic effect. Antimalarial activity and cure effect were compared for single-drug application and combination therapy. Low doses of tdct N-89 (35 mg/kg) combined with mefloquine (4 mg/kg) or pyrimethamine (1 mg/kg) gave an antimalarial effect but not a cure effect. In contrast, with high doses of N-89 (60 mg/kg) combined with mefloquine (8 mg/kg) or pyrimethamine (1 mg/kg), parasites disappeared on day 4 of treatment, and mice were completely cured without any parasite recurrence. Our results indicated that transdermal N-89 with mefloquine and pyrimethamine provides a promising antimalarial form for application to children.
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Affiliation(s)
- Nagwa S. M. Aly
- Division of International Infectious Disease Control, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, Okayama City 700-8530, Okayama, Japan
- Department of Parasitology, Faculty of Medicine, Benha University, Benha 13511, Egypt
| | - Hiroaki Matsumori
- Division of International Infectious Disease Control, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, Okayama City 700-8530, Okayama, Japan
| | - Thi Quyen Dinh
- Division of International Infectious Disease Control, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, Okayama City 700-8530, Okayama, Japan
| | - Akira Sato
- Division of International Infectious Disease Control, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, Okayama City 700-8530, Okayama, Japan
- Department of Biochemistry, Faculty of Pharmaceutical Sciences, Tokyo University of Science, Noda 278-8530, Chiba, Japan
| | - Shin-Ichi Miyoshi
- Department of Sanitary Microbiology, Faculty of Pharmaceutical Sciences, Okayama University, Tsushima-Naka, Kita-Ku, Okayama City 700-8530, Okayama, Japan
| | - Kyung-Soo Chang
- Department of Clinical Laboratory Science, College of Health Sciences, Catholic University of Pusan, Busan 46252, Republic of Korea
| | - Hak Sun Yu
- Department of Parasitology and Tropical Medicine, School of Medicine, Pusan National University, Yangsan-si 626-870, Republic of Korea
| | - Duc Tuan Cao
- Department of Pharmaceutical Chemistry and Quality Control, Faculty of Pharmacy, Hai Phong University of Medicine and Pharmacy, Hai phong, Vietnam
| | - Hye-Sook Kim
- Division of International Infectious Disease Control, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, Okayama City 700-8530, Okayama, Japan
- Correspondence: ; Tel.: +81-86-251-7975
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26
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Choo JJY, McMillan CLD, Young PR, Muller DA. Microarray patches: scratching the surface of vaccine delivery. Expert Rev Vaccines 2023; 22:937-955. [PMID: 37846657 DOI: 10.1080/14760584.2023.2270598] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/25/2023] [Accepted: 10/10/2023] [Indexed: 10/18/2023]
Abstract
INTRODUCTION Microneedles are emerging as a promising technology for vaccine delivery, with numerous advantages over traditional needle and syringe methods. Preclinical studies have demonstrated the effectiveness of MAPs in inducing robust immune responses over traditional needle and syringe methods, with extensive studies using vaccines targeted against different pathogens in various animal models. Critically, the clinical trials have demonstrated safety, immunogenicity, and patient acceptance for MAP-based vaccines against influenza, measles, rubella, and SARS-CoV-2. AREAS COVERED This review provides a comprehensive overview of the different types of microarray patches (MAPs) and analyses of their applications in preclinical and clinical vaccine delivery settings. This review also covers additional considerations for microneedle-based vaccination, including adjuvants that are compatible with MAPs, patient safety and factors for global vaccination campaigns. EXPERT OPINION MAP vaccine delivery can potentially be a game-changer for vaccine distribution and coverage in both high-income and low- and middle-income countries. For MAPs to reach this full potential, many critical hurdles must be overcome, such as large-scale production, regulatory compliance, and adoption by global health authorities. However, given the considerable strides made in recent years by MAP developers, it may be possible to see the first MAP-based vaccines in use within the next 5 years.
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Affiliation(s)
- Jovin J Y Choo
- School of Chemistry and Molecular Biosciences, The University of Queensland, Brisbane, QLD, Australia
| | - Christopher L D McMillan
- School of Chemistry and Molecular Biosciences, The University of Queensland, Brisbane, QLD, Australia
- Australian Infectious Diseases Research Centre, School of Chemistry and Molecular Biosciences, The University of Queensland, Brisbane, QLD, Australia
| | - Paul R Young
- School of Chemistry and Molecular Biosciences, The University of Queensland, Brisbane, QLD, Australia
- Australian Infectious Diseases Research Centre, School of Chemistry and Molecular Biosciences, The University of Queensland, Brisbane, QLD, Australia
| | - David A Muller
- School of Chemistry and Molecular Biosciences, The University of Queensland, Brisbane, QLD, Australia
- Australian Infectious Diseases Research Centre, School of Chemistry and Molecular Biosciences, The University of Queensland, Brisbane, QLD, Australia
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27
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Faizi HS, Vora LK, Nasiri MI, Wu Y, Mishra D, Anjani QK, Paredes AJ, Thakur RRS, Minhas MU, Donnelly RF. Deferasirox Nanosuspension Loaded Dissolving Microneedles for Intradermal Delivery. Pharmaceutics 2022; 14:pharmaceutics14122817. [PMID: 36559310 PMCID: PMC9784557 DOI: 10.3390/pharmaceutics14122817] [Citation(s) in RCA: 15] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/19/2022] [Revised: 12/01/2022] [Accepted: 12/08/2022] [Indexed: 12/23/2022] Open
Abstract
Microneedles are minimally invasive systems that can deliver drugs intradermally without pain and bleeding and can advantageously replace the hypodermal needles and oral routes of delivery. Deferasirox (DFS) is an iron chelator employed in several ailments where iron overload plays an important role in disease manifestation. In this study, DFS was formulated into a nanosuspension (NSs) through wet media milling employing PVA as a stabilizer and successfully loaded in polymeric dissolving microneedles (DMNs). The release studies for DFS-NS clearly showed a threefold increased dissolution rate compared to pure DFS. The mechanical characterization of DFS-NS-DMNs revealed that the system was sufficiently strong for efficacious skin penetration. Optical coherence tomography images confirmed an insertion of up to 378 µm into full-thickness porcine skin layers. The skin deposition studies showed 60% drug deposition from NS-DMN, which was much higher than from the DFS-NS transdermal patch (DFS-NS-TP) (without needles) or pure DFS-DMNs. Moreover, DFS-NS without DMNs did not deposit well inside the skin, indicating that DMNs played an important role in effectively delivering drugs inside the skin. Therefore, it is evident from the findings that loading DFS-NS into novel DMN devices can effectively deliver DFS transdermally.
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Affiliation(s)
- Hafsa Shahid Faizi
- School of Pharmacy, Queen’s University Belfast, Medical Biology Centre, 97 Lisburn Road, Belfast BT9 7BL, UK
| | - Lalitkumar K. Vora
- School of Pharmacy, Queen’s University Belfast, Medical Biology Centre, 97 Lisburn Road, Belfast BT9 7BL, UK
| | - Muhammad Iqbal Nasiri
- School of Pharmacy, Queen’s University Belfast, Medical Biology Centre, 97 Lisburn Road, Belfast BT9 7BL, UK
- Department of Pharmaceutics, Hamdard Institute of Pharmaceutical Sciences, Hamdard University, Islamabad 45550, Pakistan
| | - Yu Wu
- School of Pharmacy, Queen’s University Belfast, Medical Biology Centre, 97 Lisburn Road, Belfast BT9 7BL, UK
| | - Deepakkumar Mishra
- School of Pharmacy, Queen’s University Belfast, Medical Biology Centre, 97 Lisburn Road, Belfast BT9 7BL, UK
| | - Qonita Kurnia Anjani
- School of Pharmacy, Queen’s University Belfast, Medical Biology Centre, 97 Lisburn Road, Belfast BT9 7BL, UK
| | - Alejandro J. Paredes
- School of Pharmacy, Queen’s University Belfast, Medical Biology Centre, 97 Lisburn Road, Belfast BT9 7BL, UK
| | - Raghu Raj Singh Thakur
- School of Pharmacy, Queen’s University Belfast, Medical Biology Centre, 97 Lisburn Road, Belfast BT9 7BL, UK
| | - Muhammad Usman Minhas
- College of Pharmacy, University of Sargodha, Sargodha 40100, Pakistan
- Correspondence: (M.U.M.); (R.F.D.)
| | - Ryan F. Donnelly
- School of Pharmacy, Queen’s University Belfast, Medical Biology Centre, 97 Lisburn Road, Belfast BT9 7BL, UK
- Correspondence: (M.U.M.); (R.F.D.)
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28
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Rajesh N, Coates I, Driskill MM, Dulay MT, Hsiao K, Ilyin D, Jacobson GB, Kwak JW, Lawrence M, Perry J, Shea CO, Tian S, DeSimone JM. 3D-Printed Microarray Patches for Transdermal Applications. JACS AU 2022; 2:2426-2445. [PMID: 36465529 PMCID: PMC9709783 DOI: 10.1021/jacsau.2c00432] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/04/2022] [Revised: 09/30/2022] [Accepted: 10/03/2022] [Indexed: 05/14/2023]
Abstract
The intradermal (ID) space has been actively explored as a means for drug delivery and diagnostics that is minimally invasive. Microneedles or microneedle patches or microarray patches (MAPs) are comprised of a series of micrometer-sized projections that can painlessly puncture the skin and access the epidermal/dermal layer. MAPs have failed to reach their full potential because many of these platforms rely on dated lithographic manufacturing processes or molding processes that are not easily scalable and hinder innovative designs of MAP geometries that can be achieved. The DeSimone Laboratory has recently developed a high-resolution continuous liquid interface production (CLIP) 3D printing technology. This 3D printer uses light and oxygen to enable a continuous, noncontact polymerization dead zone at the build surface, allowing for rapid production of MAPs with precise and tunable geometries. Using this tool, we are now able to produce new classes of lattice MAPs (L-MAPs) and dynamic MAPs (D-MAPs) that can deliver both solid state and liquid cargos and are also capable of sampling interstitial fluid. Herein, we will explore how additive manufacturing can revolutionize MAP development and open new doors for minimally invasive drug delivery and diagnostic platforms.
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Affiliation(s)
- Netra
U. Rajesh
- Department
of Bioengineering, Stanford University, Stanford, California94305, United States
| | - Ian Coates
- Department
of Chemical Engineering, Stanford University, Stanford, California94305, United States
| | - Madison M. Driskill
- Department
of Chemical Engineering, Stanford University, Stanford, California94305, United States
| | - Maria T. Dulay
- Department
of Radiology, Stanford University, Stanford, California94305, United States
| | - Kaiwen Hsiao
- Department
of Chemical Engineering, Stanford University, Stanford, California94305, United States
| | - Dan Ilyin
- Department
of Mechanical Engineering, Stanford University, Stanford, California94305, United States
| | - Gunilla B. Jacobson
- Department
of Radiology, Stanford University, Stanford, California94305, United States
| | - Jean Won Kwak
- Department
of Radiology, Stanford University, Stanford, California94305, United States
| | - Micah Lawrence
- Department
of Bioengineering, Stanford University, Stanford, California94305, United States
| | - Jillian Perry
- Eshelman
School of Pharmacy, University of North
Carolina at Chapel Hill, Chapel
Hill, North Carolina27599, United States
| | - Cooper O. Shea
- Department
of Mechanical Engineering, Stanford University, Stanford, California94305, United States
| | - Shaomin Tian
- Department
of Microbiology and Immunology, University
of North Carolina at Chapel Hill, Chapel Hill, North Carolina27599, United States
| | - Joseph M. DeSimone
- Department
of Chemical Engineering, Stanford University, Stanford, California94305, United States
- Department
of Radiology, Stanford University, Stanford, California94305, United States
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Wu Y, Vora LK, Mishra D, Adrianto MF, Gade S, Paredes AJ, Donnelly RF, Singh TRR. Nanosuspension-loaded dissolving bilayer microneedles for hydrophobic drug delivery to the posterior segment of the eye. BIOMATERIALS ADVANCES 2022; 137:212767. [PMID: 35929230 DOI: 10.1016/j.bioadv.2022.212767] [Citation(s) in RCA: 38] [Impact Index Per Article: 12.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/18/2021] [Revised: 01/27/2022] [Accepted: 03/14/2022] [Indexed: 06/15/2023]
Abstract
Intravitreal injections (IVT) are regarded as the gold standard for effective delivery of hydrophobic drugs to the back of the eye. However, as a highly invasive procedure, the injection itself may lead to poor patient compliance and severe complications. In this research work, a hybrid system of nanosuspensions (NS) and dissolving microneedles (MNs) was developed as an alternative to conventional hypodermic needles used in IVT for minimally invasive transscleral delivery of hydrophobic drugs. NS of a hydrophobic drug, triamcinolone acetonide (TA), were fabricated using a wet milling technique. TA NS optimised by central composite factorial design had a proven diameter of 246.65 ± 8.55 nm. After optimisation, TA NS were incorporated into MN arrays to form a bilayer structure by high-speed centrifugation. TA NS-loaded MNs were robust enough to pierce excised porcine sclera with insertion depth higher than 80% of the needle height and showed rapid dissolution (<3 min). In contrast, the plain TA-loaded MNs exhibited poor mechanical and insertion performances and took more than 8 min to be fully dissolved in the scleral tissue. Importantly, transscleral deposition studies showed that 56.46 ± 7.76 μg/mm2 of TA was deposited into the sclera after 5 min of NS-loaded MN application, which was 4.5-fold higher than plain drug-loaded MNs (12.56 ± 2.59 μg/mm2). An ex vivo distribution study revealed that MN arrays could promote the transscleral penetration of hydrophobic molecules with higher drug concentrations observed in the deep layer of the sclera. Moreover, the developed TA NS-loaded MN array was biocompatible with ocular tissues, as demonstrated using the hens egg-chorioallantoic membrane assay and cytotoxicity test. The results presented here demonstrate that the hybrid system of NS and dissolving MNs can provide a novel and promising technology to alleviate retinal diseases in a therapeutically effective and minimally invasive manner.
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Affiliation(s)
- Yu Wu
- School of Pharmacy, Medical Biology Centre, Queen's University Belfast, 97 Lisburn Road, Belfast BT9 7BL, UK
| | - Lalitkumar K Vora
- School of Pharmacy, Medical Biology Centre, Queen's University Belfast, 97 Lisburn Road, Belfast BT9 7BL, UK
| | - Deepakkumar Mishra
- School of Pharmacy, Medical Biology Centre, Queen's University Belfast, 97 Lisburn Road, Belfast BT9 7BL, UK
| | - Muhammad Faris Adrianto
- School of Pharmacy, Medical Biology Centre, Queen's University Belfast, 97 Lisburn Road, Belfast BT9 7BL, UK; Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Airlangga University, Surabaya, East Java 60115, Indonesia
| | - Shilpkala Gade
- School of Pharmacy, Medical Biology Centre, Queen's University Belfast, 97 Lisburn Road, Belfast BT9 7BL, UK
| | - Alejandro J Paredes
- School of Pharmacy, Medical Biology Centre, Queen's University Belfast, 97 Lisburn Road, Belfast BT9 7BL, UK
| | - Ryan F Donnelly
- School of Pharmacy, Medical Biology Centre, Queen's University Belfast, 97 Lisburn Road, Belfast BT9 7BL, UK
| | - Thakur Raghu Raj Singh
- School of Pharmacy, Medical Biology Centre, Queen's University Belfast, 97 Lisburn Road, Belfast BT9 7BL, UK.
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Levonorgestrel Microneedle Array Patch for Sustained Release Contraception: Formulation, Optimization and In Vivo Characterization. Molecules 2022; 27:molecules27072349. [PMID: 35408746 PMCID: PMC9000369 DOI: 10.3390/molecules27072349] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/17/2022] [Revised: 03/30/2022] [Accepted: 03/31/2022] [Indexed: 11/16/2022] Open
Abstract
Background: The goal of this work was to develop a levonorgestrel liposome-loaded microneedle array patch for contraception. Methods: Levonorgestrel-loaded liposome was formulated by a solvent injection technique, characterized, and studied. Results: The formulated liposomes were characterized for particle size (147 ± 8 nm), polydispersity index (0.207 ± 0.03), zeta potential (−23 ± 4.25 mV), drug loading (18 ± 3.22%) and entrapment efficiency (85 ± 4.34%). A cryo high-resolution transmission electron microscopy and cryo field emission gun scanning electron microscopy study showed spherical shaped particles with a smooth surface. The in vitro drug release and in vivo pharmacokinetic study showed sustained behaviour of Levonorgestrel for 28 days. Conclusion: The levonorgestrel liposome-loaded microneedle array patch showed better contraception than the drug-loaded microneedle array patch.
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31
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McGuckin MB, Wang J, Ghanma R, Qin N, Palma SD, Donnelly RF, Paredes AJ. Nanocrystals as a master key to deliver hydrophobic drugs via multiple administration routes. J Control Release 2022; 345:334-353. [DOI: 10.1016/j.jconrel.2022.03.012] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/13/2022] [Revised: 03/05/2022] [Accepted: 03/06/2022] [Indexed: 12/14/2022]
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Bletilla striata polysaccharide microneedle for effective transdermal administration of model protein antigen. Int J Biol Macromol 2022; 205:511-519. [PMID: 35217076 DOI: 10.1016/j.ijbiomac.2022.02.116] [Citation(s) in RCA: 24] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/08/2021] [Revised: 02/14/2022] [Accepted: 02/18/2022] [Indexed: 02/03/2023]
Abstract
Traditional vaccination relies on subcutaneous injection or intramuscular injection, which requires professional medical personnel and is accompanied by the risk of needle-related diseases and injuries. Therefore, to promote immunization coverage and reduce costs, it is necessary to provide a new method of vaccine administration. Dissolving microneedle (DMN) has been proposed as an alternative to hypodermic needles, providing prospects for self-inoculation and increasing immunogenicity by directly targeting skin dendritic cells. This study reported the successful preparation and characterization of Bletilla striata polysaccharide microneedles (BMNs) and investigated the potential of this natural material-based DMN as a vaccine carrier. The prepared BMNs exhibited more excellent mechanical properties and stability compared with microneedles made of hyaluronic acid and polyvinyl alcohol. BMNs had good cell compatibility, low bacterial skin permeability, slight irritation to the skin, and no infection or inflammation in the body. In addition, as shown by circular dichroism, the molecular structure of the antigen ovalbumin (OVA) loaded in BMN did not change during storage for 21 days. The Franz diffusion cell experiment showed 76.74% of OVA was released to the skin within 3 h. These encouraging findings indicate that the BMNs can be a promising tool for effective vaccine delivery.
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33
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Long LY, Liu W, Li L, Hu C, He S, Lu L, Wang J, Yang L, Wang YB. Dissolving microneedle-encapsulated drug-loaded nanoparticles and recombinant humanized collagen type III for the treatment of chronic wound via anti-inflammation and enhanced cell proliferation and angiogenesis. NANOSCALE 2022; 14:1285-1295. [PMID: 35006234 DOI: 10.1039/d1nr07708b] [Citation(s) in RCA: 42] [Impact Index Per Article: 14.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/05/2023]
Abstract
Nowadays, diabetic chronic wounds impose a heavy burden on patients and the medical system. Persistent inflammation and poor tissue remodeling severely limit the healing of chronic wounds. For these issues, the first recombinant humanized collagen type III (rhCol III) and naproxen (Nap) loaded poly(lactic-co-glycolic acid) (PLGA) nanoparticle incorporated hyaluronic acid (HA) microneedle (MN) was fabricated for diabetic chronic wound therapy. As the tailored rhCol III was synthesized based on the Gly483-Pro512 segment, which contained the highly adhesive fragments (GER, GEK) in the human collagen type III sequence, it possessed strong cell adhesion. The mechanical strength of the prepared MN was enough to overcome the tissue barrier of necrosis/hyperkeratosis in a minimally invasive way after being applied in wounds. Subsequently, rhCol III and Nap@PLGA nanoparticles were rapidly released to the wound site within a few minutes. The prepared MN possessed favourable biocompatibility and could effectively facilitate the proliferation and migration of fibroblasts and endothelial cells. Furthermore, the regenerative efficacy of the MN was evaluated in vivo using the diabetic rat full-thickness skin wound model. These results illustrated that the prepared MN could accelerate wound closure by reducing the inflammatory response and enhancing angiogenesis or collagen deposition, indicating their significant application value in wound dressings for chronic wound repair.
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Affiliation(s)
- Lin-Yu Long
- National Engineering Research Center for Biomaterials, Chuanda-Jinbo Joint Research Center, Sichuan University, Chengdu, 610064, China.
| | - Wenqi Liu
- National Engineering Research Center for Biomaterials, Chuanda-Jinbo Joint Research Center, Sichuan University, Chengdu, 610064, China.
| | - Li Li
- Institute of Clinical Pathology, West China Hospital of Sichuan University, Chengdu, 610041, China
| | - Cheng Hu
- National Engineering Research Center for Biomaterials, Chuanda-Jinbo Joint Research Center, Sichuan University, Chengdu, 610064, China.
| | - Shuyi He
- National Engineering Research Center for Biomaterials, Chuanda-Jinbo Joint Research Center, Sichuan University, Chengdu, 610064, China.
| | - Lu Lu
- Key Laboratory of Medical Molecular Virology (MOE/NHC/CAMS), School of Basic Medical Sciences and Shanghai Public Health Clinical Center, Fudan-Jinbo Joint Research Center, Fudan University, Shanghai, 200302, China
| | - Jian Wang
- Shanxi Jinbo Bio-Pharmaceutical Co., Ltd, Taiyuan, 030032, China
| | - Li Yang
- National Engineering Research Center for Biomaterials, Chuanda-Jinbo Joint Research Center, Sichuan University, Chengdu, 610064, China.
| | - Yun-Bing Wang
- National Engineering Research Center for Biomaterials, Chuanda-Jinbo Joint Research Center, Sichuan University, Chengdu, 610064, China.
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34
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Lopez-Vidal L, Real JP, Real DA, Camacho N, Kogan MJ, Paredes AJ, Palma SD. Nanocrystal-based 3D-printed tablets: Semi-solid extrusion using melting solidification printing process (MESO-PP) for oral administration of poorly soluble drugs. Int J Pharm 2022; 611:121311. [PMID: 34813905 DOI: 10.1016/j.ijpharm.2021.121311] [Citation(s) in RCA: 29] [Impact Index Per Article: 9.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/22/2021] [Revised: 11/17/2021] [Accepted: 11/18/2021] [Indexed: 01/01/2023]
Abstract
This is the first report on the inclusion of nanocrystals (NCs) within 3D-printed oral solid dosage forms -3D-printed tablets or printlets- produced by the Melting Solidification Printing Process (MESO-PP) 3D printing technique. This method allowed the incorporation of albendazole (ABZ) nanocrystals in a concentration of up to 50% w/w, something not achieved in conventional tablets. An ink of PEG 1500/propylenegycol was used as a carrier and no physicochemical interactions or crystallinity modifications were observed due to the inclusion of ABZ-NCs into the ink, as demonstrated by TGA, DSC, XRD and FT-IR. In particular, the relative crystallinity of the ink loaded with NCs was 97.8% similar to the physical mixture of the components. Moreover, the presence of NCs was observed in the surface and matrix of the printlets by SEM. In addition, the printlet NCs demonstrated to be more effective than NCs included in hard gelatin capsules in improving drug dissolution in HCl 0.1 N. The particle size, crystallinity and chemical stability of the nanocrystals was maintained before and after 180 days of storage. Thus, these findings exhibit relevant pharmaceutical potential for developing stable, fast-release, oral, solid dosage forms of poorly soluble drugs combining 3D printing and nanocrystals. Additionally, this technique could be applied for printing objects using different types of nanocrystals embedded in low melting temperature polymers.
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Affiliation(s)
- Lucía Lopez-Vidal
- Unidad de Investigación y Desarrollo en Tecnología Farmacéutica (UNITEFA), CONICET, Córdoba, Argentina; Departamento de Ciencias Farmacéuticas, Facultad de Ciencias Químicas, Universidad Nacional de Córdoba, Haya de la Torre y Medina Allende, X5000XHUA Córdoba, Argentina
| | - Juan Pablo Real
- Unidad de Investigación y Desarrollo en Tecnología Farmacéutica (UNITEFA), CONICET, Córdoba, Argentina; Departamento de Ciencias Farmacéuticas, Facultad de Ciencias Químicas, Universidad Nacional de Córdoba, Haya de la Torre y Medina Allende, X5000XHUA Córdoba, Argentina
| | - Daniel Andrés Real
- Departamento de Química Farmacológica y Toxicológica, Facultad de Ciencias Químicas y Farmacéuticas, Universidad de Chile, Santos Dumont 964, Independencia, Santiago 8380494, Chile; Advanced Center for Chronic Diseases, ACCDiS, Santiago, Chile
| | - Nahuel Camacho
- Unidad de Investigación y Desarrollo en Tecnología Farmacéutica (UNITEFA), CONICET, Córdoba, Argentina; Departamento de Ciencias Farmacéuticas, Facultad de Ciencias Químicas, Universidad Nacional de Córdoba, Haya de la Torre y Medina Allende, X5000XHUA Córdoba, Argentina
| | - Marcelo J Kogan
- Departamento de Química Farmacológica y Toxicológica, Facultad de Ciencias Químicas y Farmacéuticas, Universidad de Chile, Santos Dumont 964, Independencia, Santiago 8380494, Chile; Advanced Center for Chronic Diseases, ACCDiS, Santiago, Chile
| | - Alejandro J Paredes
- School of Pharmacy, Medical Biology Centre, Queen's University Belfast, 97 Lisburn Road, Belfast BT9 7BL, UK
| | - Santiago Daniel Palma
- Unidad de Investigación y Desarrollo en Tecnología Farmacéutica (UNITEFA), CONICET, Córdoba, Argentina; Departamento de Ciencias Farmacéuticas, Facultad de Ciencias Químicas, Universidad Nacional de Córdoba, Haya de la Torre y Medina Allende, X5000XHUA Córdoba, Argentina.
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35
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Yang L, Yang Y, Chen H, Mei L, Zeng X. Polymeric microneedle-mediated sustained release systems: Design strategies and promising applications for drug delivery. Asian J Pharm Sci 2022; 17:70-86. [PMID: 35261645 PMCID: PMC8888142 DOI: 10.1016/j.ajps.2021.07.002] [Citation(s) in RCA: 47] [Impact Index Per Article: 15.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/13/2020] [Revised: 04/24/2021] [Accepted: 07/03/2021] [Indexed: 12/24/2022] Open
Abstract
Parenteral sustained release drug formulations, acting as preferable platforms for long-term exposure therapy, have been wildly used in clinical practice. However, most of these delivery systems must be given by hypodermic injection. Therefore, issues including needle-phobic, needle-stick injuries and inappropriate reuse of needles would hamper the further applications of these delivery platforms. Microneedles (MNs) as a potential alternative system for hypodermic needles can benefit from minimally invasive and self-administration. Recently, polymeric microneedle-mediated sustained release systems (MN@SRS) have opened up a new way for treatment of many diseases. Here, we reviewed the recent researches in MN@SRS for transdermal delivery, and summed up its typical design strategies and applications in various diseases therapy, particularly focusing on the applications in contraception, infection, cancer, diabetes, and subcutaneous disease. An overview of the present clinical translation difficulties and future outlook of MN@SRS was also provided.
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Affiliation(s)
- Li Yang
- Institute of Pharmaceutics, School of Pharmaceutical Sciences (Shenzhen), Sun Yat-sen University, Shenzhen 518107, China
| | - Yao Yang
- Institute of Pharmaceutics, School of Pharmaceutical Sciences (Shenzhen), Sun Yat-sen University, Shenzhen 518107, China
| | - Hongzhong Chen
- Institute of Pharmaceutics, School of Pharmaceutical Sciences (Shenzhen), Sun Yat-sen University, Shenzhen 518107, China
| | - Lin Mei
- Institute of Pharmaceutics, School of Pharmaceutical Sciences (Shenzhen), Sun Yat-sen University, Shenzhen 518107, China
- Tianjin Key Laboratory of Biomedical Materials, Key Laboratory of Biomaterials and Nanotechnology for Cancer Immunotherapy, Institute of Biomedical Engineering, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin 300192, China
| | - Xiaowei Zeng
- Institute of Pharmaceutics, School of Pharmaceutical Sciences (Shenzhen), Sun Yat-sen University, Shenzhen 518107, China
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36
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Nasiri MI, Vora LK, Ershaid JA, Peng K, Tekko IA, Donnelly RF. Nanoemulsion-based dissolving microneedle arrays for enhanced intradermal and transdermal delivery. Drug Deliv Transl Res 2021; 12:881-896. [PMID: 34939170 PMCID: PMC8694761 DOI: 10.1007/s13346-021-01107-0] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 12/06/2021] [Indexed: 01/20/2023]
Abstract
The development of dissolving microneedles (DMN) is one of the advanced technologies in transdermal drug delivery systems, which precisely deliver the drugs through a rapid dissolution of polymers after insertion into the skin. In this study, we fabricated nanoemulsion-loaded dissolving microneedle (DMN) arrays for intradermal and transdermal drug delivery. For this task, model drug (amphotericin B, AmB)-loaded nanoemulsion (NE) were prepared by the probe-sonication method. AmB-loaded-NE was prepared using Capmul MCM C-8 EP/NF, Tween® 80, poly(vinyl alcohol) (PVA-10 kDa), and poly (vinyl pyrrolidone) (PVP-360 kDa or K29/32) by using SpeedMixer™, followed by probe-sonication and evaluated for particle size and polydispersity index (PDI). Transmission electron microscopy (TEM) was also used to assess the particle size before and after DMN casting. AmB-NE embedded DMN arrays were found to be strong enough, revealed efficient skin insertion, and penetrated down to the fourth layer (depth ≈ 508 μm) of Parafilm M® (validated skin model). Ex vivo skin deposition experiments in full-thickness neonatal porcine demonstrated that after 24 h, AmB-NE-DMN arrays were able to deposit 111.05 ± 48.4 µg/patch AmB into the skin. At the same time, transdermal porcine skin permeation studies showed significantly higher permeability of AmB (29.60 ± 8.23 μg/patch) from AmB-NE-DMN compared to MN-free AmB-NE patches (5.0 ± 6.15 μg/patch) over 24 h. Antifungal studies of optimized AmB-NE-DMN, AmB-loaded discs and drug-free DMN against Candida albicans, confirmed the synergistic activity of Campul-MCM C-8, used in the nanoemulsion formulation. This study establishes that nanoemulsion based dissolving microneedle may serve as an efficient system for intradermal as well as transdermal drug delivery.
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Affiliation(s)
- Muhammad Iqbal Nasiri
- School of Pharmacy, Medical Biology Centre, Queen's University Belfast, 97 Lisburn Road, Belfast, BT9 7BL, UK
- Department of Pharmaceutics, Hamdard Institute of Pharmaceutical Sciences, Hamdard University, Islamabad, Pakistan
| | - Lalitkumar K Vora
- School of Pharmacy, Medical Biology Centre, Queen's University Belfast, 97 Lisburn Road, Belfast, BT9 7BL, UK
| | - Juhaina Abu Ershaid
- School of Pharmacy, Medical Biology Centre, Queen's University Belfast, 97 Lisburn Road, Belfast, BT9 7BL, UK
| | - Ke Peng
- School of Pharmacy, Medical Biology Centre, Queen's University Belfast, 97 Lisburn Road, Belfast, BT9 7BL, UK
| | - Ismaiel A Tekko
- School of Pharmacy, Medical Biology Centre, Queen's University Belfast, 97 Lisburn Road, Belfast, BT9 7BL, UK
| | - Ryan F Donnelly
- School of Pharmacy, Medical Biology Centre, Queen's University Belfast, 97 Lisburn Road, Belfast, BT9 7BL, UK.
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37
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Wang C, Jiang X, Zeng Y, Terry RN, Li W. Rapidly separable microneedle patches for controlled release of therapeutics for long-acting therapies. MEDICINE IN DRUG DISCOVERY 2021. [DOI: 10.1016/j.medidd.2021.100118] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/08/2023] Open
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38
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Chang T, Liu C, Lu K, Wu Y, Xu M, Yu Q, Shen Z, Jiang T, Zhang Y. Biomaterials based cardiac patches for the treatment of myocardial infarction. JOURNAL OF MATERIALS SCIENCE & TECHNOLOGY 2021; 94:77-89. [DOI: 10.1016/j.jmst.2021.03.062] [Citation(s) in RCA: 22] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/06/2025]
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39
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Surface-modified polylactic acid nanospheres with chitosan for antibacterial activity of 1, 2-benzisothiazolin-3-one. Carbohydr Polym 2021; 272:118406. [PMID: 34420704 DOI: 10.1016/j.carbpol.2021.118406] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/26/2021] [Revised: 07/02/2021] [Accepted: 07/04/2021] [Indexed: 11/24/2022]
Abstract
The primary purpose of this study was to develop an innovative chitosan (CS) modified polylactic acid (PLA) nanospheres for enhancing the bioavailability of 1, 2-benzisothiazolin-3-one (BIT). The cellular uptake efficiency was corresponded positively to the quantity of CS coated on BIT-PLA nanospheres against E. coli and S. aureus. The membrane potentials of E.coli and S. aureus treated with BIT-PLA, BIT-PLA-0.1%CS and BIT-PLA-0.5%CS were reduced with the extension of incubation time and the ratio of coated CS. The enhancement of CS modified on BIT-PLA nanospheres was reduced antioxidase activities and generated excessive reactive oxygen species. The lowest EC50 value of the modified BIT-PLA-0.5%CS suggested that its toxicity index was around 2.95-fold and 2.11-fold that of non-modified BIT-PLA against E. coli and S. aureus, respectively. These results revealed that the CS modified BIT-PLA nanospheres had a bright prospect in antibacterial formulation delivery system and improving the bioavailability.
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40
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Balmert SC, Ghozloujeh ZG, Carey CD, Akilov OE, Korkmaz E, Falo LD. Research Techniques Made Simple: Skin-Targeted Drug and Vaccine Delivery Using Dissolvable Microneedle Arrays. J Invest Dermatol 2021; 141:2549-2557.e1. [PMID: 34688405 DOI: 10.1016/j.jid.2021.07.177] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/23/2021] [Revised: 07/11/2021] [Accepted: 07/26/2021] [Indexed: 11/28/2022]
Abstract
Skin-targeted drug delivery is broadly employed for both local and systemic therapeutics and is an important tool for discovery efforts in cutaneous biology. Recently, emerging technologies support efforts toward skin-targeted biocargo delivery for local and systemic therapeutic benefit. Effective targeting of bioactive molecules, including large (molecular weight > 500 Da) or complex (hydrophilic and charged) molecules, to defined cutaneous microenvironments is intrinsically challenging owing to the protective barrier function of the skin. Dissolvable microneedle arrays (MNAs) have proven to be a promising technology to address the unmet need for controlled, minimally invasive, and reliable delivery of a wide range of biocargos to the skin. In this paper, we describe the unique properties of the skin that make it an attractive target for vaccine delivery, for immune-modulating therapies, and for systemic drug delivery and the structural characteristics of the skin that present obstacles to efficient intracutaneous and transdermal delivery of bioactive molecules. We provide an overview of MNA fabrication and the characteristics and mechanisms of dissolvable MNA cargo delivery to the cutaneous microenvironment. We present a representative example of a clinical application of MNAs and discuss future directions for MNA development and applications.
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Affiliation(s)
- Stephen C Balmert
- Department of Dermatology, School of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania, USA
| | | | - Cara Donahue Carey
- Department of Dermatology, School of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania, USA
| | - Oleg E Akilov
- Department of Dermatology, School of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania, USA
| | - Emrullah Korkmaz
- Department of Dermatology, School of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania, USA; Department of Bioengineering, Swanson School of Engineering, University of Pittsburgh, Pittsburgh, Pennsylvania, USA
| | - Louis D Falo
- Department of Dermatology, School of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania, USA; Department of Bioengineering, Swanson School of Engineering, University of Pittsburgh, Pittsburgh, Pennsylvania, USA; Clinical and Translational Science Institute, University of Pittsburgh, Pittsburgh, Pennsylvania, USA; The UPMC Hillman Cancer Center, Pittsburgh, Pennsylvania, USA; The McGowan Institute for Regenerative Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania, USA.
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41
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Volpe-Zanutto F, Fonseca-Santos B, McKenna PE, Paredes AJ, Dávila JL, McCrudden MTC, Tangerina MMP, Ceccheto Figueiredo M, Vilegas W, Brisibe A, Akira D'Ávila M, Donnelly RF, Chorilli M, Foglio MA. Novel transdermal bioadhesive surfactant-based system for release and solubility improvement of antimalarial drugs artemether-lumefantrine. Biomed Mater 2021; 16. [PMID: 34544052 DOI: 10.1088/1748-605x/ac2885] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/06/2021] [Accepted: 09/20/2021] [Indexed: 01/10/2023]
Abstract
Artemether (ART) and lumefantrine (LUM) are the gold standard antimalarial drugs used for the treatment of malaria in children and pregnant women. Typically, ART and LUM are delivered orally in the form of a combined tablet, however, the appropriateness of this route of administration for these drugs is questionable due to the poor absorption and therefore bioavailability observed unless administered alongside lipid-rich foods. Transdermal drug delivery in the form of a patch-type system has been identified as a viable alternative to the conventional tablet-based therapy. A novel, surfactant-based ART-LUM formulation (S3AL), developed for transdermal delivery, may eliminate the shortcomings associated with oral delivery; namely poor drug absorption which is caused by the inherently low solubility of ART and LUM. Moreover, by successfully delivering these antimalarials transdermally, first-pass metabolism will be avoided leading to enhanced drug bioavailability in both cases. The S3AL formulation contained ART and LUM at equal concentrations (2.5% w/w of each) as well as Procetyl® AWS (30% w/w), oleic acid (10% w/w), 1-methyl-2-pyrrolidone (10% w/w), and water (45% w/w). The addition of LUM to the formulation changed the system from a striae structure to a dark field structure when visualized by a polarized light microscope. Additionally, this system possessed higher viscosity and superior skin bioadhesion, as evidenced by mechanical characterization, when compared to a similar formulation containing ART alone. S3AL was also proven to be biocompatible to human keratinocyte cells. Finally,in vitrostudies demonstrated the propensity of S3AL for successful delivery via the transdermal route, with 2279 ± 295 µg cm-2of ART and 94 ± 13 µg cm-2of LUM having permeated across dermatomed porcine skin after 24 h, highlighting its potential as a new candidate for the treatment of malaria.
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Affiliation(s)
- Fabiana Volpe-Zanutto
- Graduate School of Bioscience and Technology of Bioactive Products, Biology Institute, University at Campinas, Campinas, Sao Paulo, Brazil.,School of Pharmacy, Queen's University Belfast, Belfast, United Kingdom
| | - Bruno Fonseca-Santos
- UNESP- University Estadual Paulista, Faculdade de Ciências Farmacêuticas, UNESP, Araraquara, Sao Paulo, Brazil.,Faculty of Pharmaceutical Science, University at Campinas, Campinas, Sao Paulo, Brazil
| | - Peter E McKenna
- School of Pharmacy, Queen's University Belfast, Belfast, United Kingdom
| | | | - José Luis Dávila
- Centre for Information Technology 'Renato Archer' (CTI), 3D Printing open lab-Laprint, Campinas, Sao Paulo, Brazil
| | | | | | | | - Wagner Vilegas
- UNESP- Univ Estadual Paulista, Instituto de Biociências, São Vicente, Sao Paulo, Brazil
| | | | - Marcos Akira D'Ávila
- School of Mechanical Engineering, University of Campinas, Campinas, Sao Paulo, Brazil
| | - Ryan F Donnelly
- School of Pharmacy, Queen's University Belfast, Belfast, United Kingdom
| | - Marlus Chorilli
- UNESP- University Estadual Paulista, Faculdade de Ciências Farmacêuticas, UNESP, Araraquara, Sao Paulo, Brazil
| | - Mary Ann Foglio
- Faculty of Pharmaceutical Science, University at Campinas, Campinas, Sao Paulo, Brazil
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42
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Weimer P, Rossi RC, Koester LS. Dissolving Microneedles Developed in Association with Nanosystems: A Scoping Review on the Quality Parameters of These Emerging Systems for Drug or Protein Transdermal Delivery. Pharmaceutics 2021; 13:1601. [PMID: 34683895 PMCID: PMC8538119 DOI: 10.3390/pharmaceutics13101601] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/17/2021] [Revised: 09/24/2021] [Accepted: 09/27/2021] [Indexed: 12/20/2022] Open
Abstract
The largest organ of the body provides the main challenge for the transdermal delivery of lipophilic or high molecular weight drugs. To cross the main barrier of the skin, the stratum corneum, many techniques have been developed and improved. In the last 20 years, the association of microneedles with nanostructured systems has gained prominence for its versatility and for enabling targeted drug delivery. Currently, the combination of these mechanisms is pointed to as an emerging technology; however, some gaps need to be answered to transcend the development of these devices from the laboratory scale to the pharmaceutical market. It is known that the lack of regulatory guidelines for quality control is a hindrance to market conquest. In this context, this study undertakes a scoping review of original papers concerning methods applied to evaluate both the quality and drug/protein delivery of dissolving and hydrogel-forming microneedles developed in association with nanostructured systems.
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Affiliation(s)
- Patrícia Weimer
- Programa de Pós-Graduação em Ciências Farmacêuticas, Faculdade de Farmácia, Universidade Federal do Rio Grande do Sul (UFRGS), Porto Alegre 90610-000, Brazil;
| | - Rochele Cassanta Rossi
- Programa de Pós-Graduação em Nutrição e Alimentos, Universidade do Vale do Rio dos Sinos (UNISINOS), São Leopoldo 93022-000, Brazil;
| | - Letícia Scherer Koester
- Programa de Pós-Graduação em Ciências Farmacêuticas, Faculdade de Farmácia, Universidade Federal do Rio Grande do Sul (UFRGS), Porto Alegre 90610-000, Brazil;
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43
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Zhao L, Zhang C, Abu‐Ershaid JM, Li M, Li Y, Naser Y, Dai X, Abbate MTA, Donnelly RF. Smart Responsive Microarray Patches for Transdermal Drug Delivery and Biological Monitoring. Adv Healthc Mater 2021; 10:e2100996. [PMID: 34449129 DOI: 10.1002/adhm.202100996] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/21/2021] [Revised: 07/15/2021] [Indexed: 12/12/2022]
Abstract
Traditional drug delivery routes possess various disadvantages which make them unsuitable for certain population groups, or indeed unsuitable for drugs with certain physicochemical properties. As a result, a variety of alternative drug delivery routes have been explored in recent decades, including transdermal drug delivery. One of the most promising novel transdermal drug delivery technologies is a microarray patch (MAP), which can bypass the outermost skin barrier and deliver drugs directly into the viable epidermis and dermis. Unlike traditional MAPs which release loaded cargo simultaneously upon insertion into the skin, stimuli responsive MAPs based on biological stimuli are able to precisely release the drug in response to the need for additional doses. Thus, smart MAPs that are only responsive to certain external stimuli are highly desirable, as they provide safer and more efficient drug delivery. In addition to drug delivery, they can also be used for biological monitoring, which further expands their applications.
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Affiliation(s)
- Li Zhao
- School of Pharmacy Queen's University Belfast 97 Lisburn Road Belfast BT9 7BL UK
| | - Chunyang Zhang
- School of Pharmacy Queen's University Belfast 97 Lisburn Road Belfast BT9 7BL UK
| | | | - Mingshan Li
- School of Pharmacy Queen's University Belfast 97 Lisburn Road Belfast BT9 7BL UK
| | - Yaocun Li
- School of Pharmacy Queen's University Belfast 97 Lisburn Road Belfast BT9 7BL UK
| | - Yara Naser
- School of Pharmacy Queen's University Belfast 97 Lisburn Road Belfast BT9 7BL UK
| | - Xianbing Dai
- School of Pharmacy Queen's University Belfast 97 Lisburn Road Belfast BT9 7BL UK
| | - Marco T. A. Abbate
- School of Pharmacy Queen's University Belfast 97 Lisburn Road Belfast BT9 7BL UK
| | - Ryan F. Donnelly
- School of Pharmacy Queen's University Belfast 97 Lisburn Road Belfast BT9 7BL UK
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44
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Permana AD, Paredes AJ, Zanutto FV, Amir MN, Ismail I, Bahar MA, Palma SD, Donnelly RF. Albendazole Nanocrystal-Based Dissolving Microneedles with Improved Pharmacokinetic Performance for Enhanced Treatment of Cystic Echinococcosis. ACS APPLIED MATERIALS & INTERFACES 2021; 13:38745-38760. [PMID: 34353029 DOI: 10.1021/acsami.1c11179] [Citation(s) in RCA: 32] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/13/2023]
Abstract
Cystic echinococcosis (CE) is a zoonosis caused by Echinococcus spp., affecting both humans and animals' lives. Current treatment of CE by oral administration of albendazole (ABZ) is hampered by several limitations. The poor aqueous solubility and the rapid metabolism of ABZ in the liver are the main issues, leading to lack of efficacy of the treatment. In the present study, we developed a nanocrystalline (NC) formulation of ABZ to be delivered intradermally using dissolving microneedles (DMNs). The NC formulation was developed using milling in an ultrasmall-scale device. Following several screenings, Pluronic F127 was selected as a suitable stabilizer, producing NCs with around 400 nm in size with narrow particle distribution. The crystallinity of ABZ was maintained as observed by DSC and XRD analysis. The NC approach was able to improve the dissolution percentage of ABZ by approximately three-fold. Furthermore, the incorporation of NCs into DMNs using the combination of poly(vinylpyrrolidone) and poly(vinyl alcohol) formed sharp needles with sufficient mechanical strength and insertion properties. Dermatokinetic studies revealed that >25% of ABZ was localized in the dermis of excised neonatal porcine skin up to 48 h after DMN administration. In in vivo pharmacokinetic studies, the AUC and relative bioavailability values of ABZ delivered by NC-loaded DMNs were found to be significantly higher than those obtained after oral administration of coarse suspension of ABZ or ABZ-NCs, as well as DMNs delivering coarse ABZ as indicated by the relative bioavailability values of >100%. Therefore, the combination approach developed in this study could maintain the systemic circulation of ABZ, which could be possibly caused by avoiding the first-pass metabolism in the liver. This could be beneficial to improve the efficacy of ABZ in CE treatment.
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Affiliation(s)
- Andi Dian Permana
- Department of Pharmaceutics, Faculty of Pharmacy, Hasanuddin University, Makassar 90245, Indonesia
| | - Alejandro J Paredes
- School of Pharmacy, Queen's University Belfast, Medical Biology Centre, 97 Lisburn Road, Belfast BT9 7BL, United Kingdom
| | - Fabiana Volpe Zanutto
- School of Pharmacy, Queen's University Belfast, Medical Biology Centre, 97 Lisburn Road, Belfast BT9 7BL, United Kingdom
- Faculty of Pharmaceutical Sciences, University of Campinas, R. Cândido Portinari, 200 - Cidade Universitária, Campinas, SP 13083-871, Brazil
| | - Muh Nur Amir
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Universitas Hasanuddin, Makassar 90245, Indonesia
| | - Ismail Ismail
- Department of Phytochemistry, Faculty of Pharmacy, Universitas Hasanuddin, Makassar 90245, Indonesia
| | - Muh Akbar Bahar
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Universitas Hasanuddin, Makassar 90245, Indonesia
| | - Santiago Daniel Palma
- Unidad de Investigación y Desarrollo en Tecnología Farmacéutica (UNITEFA), CONICET and Departamento de Ciencias Farmacéuticas, Facultad de Ciencias Químicas, Universidad Nacional de Córdoba, Haya de la Torre y Medina Allende, X5000XHUA, Córdoba, Argentina
| | - Ryan F Donnelly
- School of Pharmacy, Queen's University Belfast, Medical Biology Centre, 97 Lisburn Road, Belfast BT9 7BL, United Kingdom
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45
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Dermatokinetic assessment of luliconazole-loaded nanostructured lipid carriers (NLCs) for topical delivery: QbD-driven design, optimization, and in vitro and ex vivo evaluations. Drug Deliv Transl Res 2021; 12:1118-1135. [PMID: 33895936 DOI: 10.1007/s13346-021-00986-7] [Citation(s) in RCA: 28] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 04/15/2021] [Indexed: 02/07/2023]
Abstract
The present study is concerned with the QbD-based design and development of luliconazole-loaded nanostructured lipid carriers (NLCs) hydrogel for enhanced skin retention and permeation. The NLCs formulation was optimized employing a 3-factor, 3-level Box-Behnken design. The effect of formulation variable lipid content, surfactant concentration, and sonication time was studied on particle size and % EE. The optimized formulation exhibited particle size of 86.480 ± 0.799 nm; 0.213 ± 0.004 PDI, ≥ - 10 mV zeta potential and 85.770 ± 0.503% EE. The in vitro release studies revealed sustained release of NLCs up to 42 h. The designed formulation showed desirable occlusivity, spreadability (0.748 ± 0.160), extrudability (3.130 ± 1.570), and the assay was found to be 99.520 ± 0.890%. The dermatokinetics assessment revealed the Cmax Skin to be ~ 2-fold higher and AUC0-24 to be ~ 3-fold higher in the epidermis and dermis of NLCs loaded gel in contrast with the marketed cream. The Tmax of both the formulations was found to be 6 h in the epidermis and dermis. The obtained results suggested that luliconazole NLCs can serve as a promising formulation to enhance luliconazole's antifungal activity and also in increasing patient compliance by reducing the frequency of application.
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46
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Korkmaz E, Balmert SC, Sumpter TL, Carey CD, Erdos G, Falo LD. Microarray patches enable the development of skin-targeted vaccines against COVID-19. Adv Drug Deliv Rev 2021; 171:164-186. [PMID: 33539853 PMCID: PMC8060128 DOI: 10.1016/j.addr.2021.01.022] [Citation(s) in RCA: 44] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/04/2020] [Revised: 01/10/2021] [Accepted: 01/27/2021] [Indexed: 12/13/2022]
Abstract
The COVID-19 pandemic is a serious threat to global health and the global economy. The ongoing race to develop a safe and efficacious vaccine to prevent infection by SARS-CoV-2, the causative agent for COVID-19, highlights the importance of vaccination to combat infectious pathogens. The highly accessible cutaneous microenvironment is an ideal target for vaccination since the skin harbors a high density of antigen-presenting cells and immune accessory cells with broad innate immune functions. Microarray patches (MAPs) are an attractive intracutaneous biocargo delivery system that enables safe, reproducible, and controlled administration of vaccine components (antigens, with or without adjuvants) to defined skin microenvironments. This review describes the structure of the SARS-CoV-2 virus and relevant antigenic targets for vaccination, summarizes key concepts of skin immunobiology in the context of prophylactic immunization, and presents an overview of MAP-mediated cutaneous vaccine delivery. Concluding remarks on MAP-based skin immunization are provided to contribute to the rational development of safe and effective MAP-delivered vaccines against emerging infectious diseases, including COVID-19.
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Affiliation(s)
- Emrullah Korkmaz
- Department of Dermatology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA; Department of Bioengineering, Swanson School of Engineering, University of Pittsburgh, Pittsburgh, PA 15261, USA.
| | - Stephen C Balmert
- Department of Dermatology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA
| | - Tina L Sumpter
- Department of Dermatology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA; Department of Immunology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261, USA
| | - Cara Donahue Carey
- Department of Dermatology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA
| | - Geza Erdos
- Department of Dermatology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA
| | - Louis D Falo
- Department of Dermatology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA; Department of Bioengineering, Swanson School of Engineering, University of Pittsburgh, Pittsburgh, PA 15261, USA; UPMC Hillman Cancer Center, Pittsburgh, PA 15232, USA; Clinical and Translational Science Institute, University of Pittsburgh, Pittsburgh, PA 15213, USA; The McGowan Institute for Regenerative Medicine, University of Pittsburgh, Pittsburgh, PA 15219, USA.
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