RESUMEN
The retinoid fenretinide (FENR) is a promising compound for preventing breast cancer recurrence but faces challenges due to poor solubility and low bioavailability. This study explores the development of dissolving microneedles (MNs) containing FENR-loaded ethosomes for minimally invasive breast cancer chemoprevention, aiming to enhance local drug distribution. Ethosomes were formulated using ethanol, propylene glycol, soya lecithin, water, and polysorbate 80 micelles. MNs were created from poly(vinyl alcohol) and poly(vinylpyrrolidone) hydrogels by adding polymer powder directly into ethosomes suspensions, reducing manufacturing time and cost. Two methods were used to load ethosomes into high-density moulds: 1) only in the needle area, and 2) in both the needle area and baseplate. Dynamic light scattering confirmed nanostructures in the hydrogels and MNs. Micelle-based ethosomes dissolved MNs in 15 min, compared to 30 min for other MNs. Skin deposition studies showed greater drug deposition (up to 10 µg/patch) and enhanced skin permeation of FENR (up to 40 µg) with Method 2. In-vivo studies in rats demonstrated that oral administration resulted in plasma FENR levels below 10 ng/g in the first three hours, whereas MN administration delayed delivery, reaching a maximum plasma concentration of 52 ng/g at 48 h. Skin deposition of FENR from MNs decreased from 3 µg/g on day 1 to <0.3 µg/g by the last day. This study indicates that MNs are a potential minimally invasive dosage form for delivering FENR, offering a new approach for breast cancer chemoprevention.
RESUMEN
Hydrogel-forming microneedle array patches (HFMAPs) are microneedles that create microconduits upon insertion and swelling in the skin, potentially allowing prolonged drug delivery without generating sharps waste. Delivering hydrophobic drugs using HFMAPs poses challenges, which can be addressed using solubility enhancers such as cyclodextrins (CDs). This study aimed to deliver risperidone (RIS) transdermally using HFMAPs. To enhance the aqueous solubility of RIS hydroxypropyl-beta-cyclodextrin (HP-ß-CD) and hydroxypropyl-gamma-cyclodextrin (HP-γ-CD) were utilised and their performance was tested using phase solubility studies. The aqueous solubility of RIS was enhanced by 4.75-fold and 2-fold using HP-ß-CD and HP-γ-CD, respectively. RIS-HP-ß-CD complex (CX) and physical mixture (PM) directly compressed tablets were prepared and combined with HFMAPs. Among the tested formulations, RIS-HP-ß-CD PM reservoirs with 11 x 11 PVA/PVP HFMAPs exhibited the best performance in ex vivo studies and were further evaluated in in vivo experiments using female Sprague Dawley rats. The extended wear time of the MAPs resulted in the sustained release of RIS and its active metabolite 9-hydroxyrisperidone (9-OH-RIS) in plasma samples, lasting from 3 to 5 days with a 1-day application and up to 10 days with a 5-day application. For a 1-day application, HFMAPs showed greater systemic exposure to RIS compared to intramuscular control (AUC0-t: 13330.05 ± 2759.95 ng/mL/hour versus 2706 ± 1472 ng/mL/hour). Moreover, RIS exposure was extended to 5 days (AUC0-t: 12292.37 ± 1801.94 ng/mL/hour). In conclusion, HFMAPs could serve as an alternative for delivering RIS in a sustained manner, potentially improving the treatment of schizophrenia.
Asunto(s)
2-Hidroxipropil-beta-Ciclodextrina , Administración Cutánea , Sistemas de Liberación de Medicamentos , Hidrogeles , Risperidona , Solubilidad , Risperidona/administración & dosificación , Risperidona/farmacocinética , Risperidona/química , Animales , Hidrogeles/química , Sistemas de Liberación de Medicamentos/métodos , Sistemas de Liberación de Medicamentos/instrumentación , 2-Hidroxipropil-beta-Ciclodextrina/química , Ratas , Agujas , Ratas Sprague-Dawley , Absorción Cutánea , Ciclodextrinas/química , Antipsicóticos/administración & dosificación , Antipsicóticos/farmacocinética , Femenino , Piel/metabolismoRESUMEN
Human immunodeficiency virus (HIV) continues to pose a serious threat to global health. Oral preexposure prophylaxis (PrEP), considered highly effective for HIV prevention, is the utilisation of antiretroviral (ARV) drugs before HIV exposure in high-risk uninfected individuals. However, ARV drugs are associated with poor patient compliance and pill fatigue due to their daily oral dosing. Therefore, an alternative strategy for drug delivery is required. In this work, two dissolving microneedle patches (MNs) containing either bictegravir (BIC) or tenofovir alafenamide (TAF) solid drug nanoparticles (SDNs) were developed for systemic delivery of a novel ARV regimen for potential HIV prevention. According to ex vivo skin deposition studies, approximately 11% and 50% of BIC and TAF was delivered using dissolving MNs, respectively. Pharmacokinetic studies in Sprague Dawley rats demonstrated that BIC MNs achieved a long-acting release profile, maintaining the relative plasma concentration above the 95% inhibitory concentration (IC95) for 3 weeks. For TAF MNs, a rapid release of drug and metabolism of TAF into TFV were obtained from the plasma samples. This work has shown that the proposed transdermal drug delivery platform could be potentially used as an alternative method to systemically deliver ARV drugs for HIV PrEP.
Asunto(s)
Administración Cutánea , Alanina , Fármacos Anti-VIH , Infecciones por VIH , Agujas , Profilaxis Pre-Exposición , Ratas Sprague-Dawley , Tenofovir , Animales , Tenofovir/administración & dosificación , Tenofovir/farmacocinética , Tenofovir/análogos & derivados , Alanina/farmacocinética , Alanina/administración & dosificación , Alanina/química , Fármacos Anti-VIH/administración & dosificación , Fármacos Anti-VIH/farmacocinética , Profilaxis Pre-Exposición/métodos , Infecciones por VIH/prevención & control , Masculino , Adenina/administración & dosificación , Adenina/farmacocinética , Adenina/análogos & derivados , Adenina/química , Ratas , Nanopartículas/administración & dosificación , Nanopartículas/química , Liberación de Fármacos , Compuestos Heterocíclicos de 4 o más Anillos/farmacocinética , Compuestos Heterocíclicos de 4 o más Anillos/administración & dosificación , Compuestos Heterocíclicos de 4 o más Anillos/química , Piridonas/administración & dosificación , Piridonas/farmacocinética , Sistemas de Liberación de Medicamentos , Piperazinas/farmacocinética , Piperazinas/administración & dosificación , Piperazinas/química , Ciclopropanos/administración & dosificación , Ciclopropanos/farmacocinética , Compuestos Heterocíclicos con 3 Anillos/farmacocinética , Compuestos Heterocíclicos con 3 Anillos/administración & dosificación , Amidas/administración & dosificación , Amidas/farmacocinética , Amidas/químicaRESUMEN
Schizophrenia is a psychiatric disorder that results from abnormal levels of neurotransmitters in the brain. Risperidone (RIS) is a common drug prescribed for the treatment of schizophrenia. RIS is a hydrophobic drug that is typically administered orally or intramuscularly. Transdermal drug delivery (TDD) could potentially improve the delivery of RIS. This study focused on the development of RIS nanocrystals (NCs), for the first time, which were incorporated into dissolving microneedle array patches (DMAPs) to facilitate the drug delivery of RIS. RIS NCs were formulated via wet-media milling technique using poly(vinylalcohol) (PVA) as a stabiliser. NCs with particle size of 300 nm were produced and showed an enhanced release profile up to 80 % over 28 days. Ex vivo results showed that 1.16 ± 0.04 mg of RIS was delivered to both the receiver compartment and full-thickness skin from NCs loaded DMAPs compared to 0.75 ± 0.07 mg from bulk RIS DMAPs. In an in vivo study conducted using female Sprague Dawley rats, both RIS and its active metabolite 9-hydroxyrisperidone (9-OH-RIS) were detected in plasma samples for 5 days. In comparison with the oral group, DMAPs improved the overall pharmacokinetic profile in plasma with a â¼ 15 folds higher area under the curve (AUC) value. This work has represented the novel delivery of the antipsychotic drug, RIS, through microneedles. It also offers substantial evidence to support the broader application of MAPs for the transdermal delivery of poorly water-soluble drugs.
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Administración Cutánea , Antipsicóticos , Ratas Sprague-Dawley , Risperidona , Esquizofrenia , Animales , Risperidona/administración & dosificación , Risperidona/farmacocinética , Esquizofrenia/tratamiento farmacológico , Femenino , Antipsicóticos/administración & dosificación , Antipsicóticos/farmacocinética , Parche Transdérmico , Nanopartículas/química , Nanopartículas/administración & dosificación , Liberación de Fármacos , Absorción Cutánea , Ratas , Sistemas de Liberación de Medicamentos , Piel/metabolismo , Alcohol Polivinílico/química , Palmitato de Paliperidona/administración & dosificación , Palmitato de Paliperidona/farmacocinética , Tamaño de la Partícula , Solubilidad , AgujasRESUMEN
Parkinson's disease (PD) is a debilitating neurodegenerative disease primarily impacting neurons responsible for dopamine production within the brain. Pramipexole (PRA) is a dopamine agonist that is currently available in tablet form. However, individuals with PD commonly encounter difficulties with swallowing and gastrointestinal motility, making oral formulations less preferable. Microneedle (MN) patches represent innovative transdermal drug delivery devices capable of enhancing skin permeability through the creation of microconduits on the surface of the skin. MNs effectively reduce the barrier function of skin and facilitate the permeation of drugs. The work described here focuses on the development of polymeric MN systems designed to enhance the transdermal delivery of PRA. PRA was formulated into both dissolving MNs (DMNs) and directly compressed tablets (DCTs) to be used in conjunction with hydrogel-forming MNs (HFMNs). In vivo investigations using a Sprague-Dawley rat model examined, for the first time, if it was beneficial to prolong the application of DMNs and HFMNs beyond 24 h. Half of the patches in the MN cohorts were left in place for 24 h, whereas the other half remained in place for 5 days. Throughout the entire 5 day study, PRA plasma levels were monitored for all cohorts. This study confirmed the successful delivery of PRA from DMNs (Cmax = 511.00 ± 277.24 ng/mL, Tmax = 4 h) and HFMNs (Cmax = 328.30 ± 98.04 ng/mL, Tmax = 24 h). Notably, both types of MNs achieved sustained PRA plasma levels over a 5 day period. In contrast, following oral administration, PRA remained detectable in plasma for only 48 h, achieving a Cmax of 159.32 ± 113.43 ng/mL at 2 h. The HFMN that remained in place for 5 days demonstrated the most promising performance among all investigated formulations. Although in the early stages of development, the findings reported here offer a hopeful alternative to orally administered PRA. The sustained plasma profile observed here has the potential to reduce the frequency of PRA administration, potentially enhancing patient compliance and ultimately improving their quality of life. This work provides substantial evidence advocating the development of polymeric MN-mediated drug delivery systems to include sustained plasma levels of hydrophilic pharmaceuticals.
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Administración Cutánea , Sistemas de Liberación de Medicamentos , Agujas , Enfermedad de Parkinson , Pramipexol , Ratas Sprague-Dawley , Pramipexol/administración & dosificación , Pramipexol/farmacocinética , Animales , Ratas , Enfermedad de Parkinson/tratamiento farmacológico , Sistemas de Liberación de Medicamentos/métodos , Masculino , Absorción Cutánea/efectos de los fármacos , Piel/metabolismo , Piel/efectos de los fármacos , Antiparkinsonianos/administración & dosificación , Antiparkinsonianos/farmacocinética , Agonistas de Dopamina/administración & dosificación , Agonistas de Dopamina/farmacocinética , Hidrogeles/químicaRESUMEN
Hydrogel-forming microneedles (HF-MNs) are composed of unique cross-linked polymers that are devoid of the active pharmaceutical ingredient (API) within the microneedle array. Instead, the API is housed in a reservoir affixed on the top of the baseplate of the HF-MNs. To date, various types of drug-reservoirs and multiple solubility-enhancing approaches have been employed to deliver hydrophobic molecules combined with HF-MNs. These strategies are not without drawbacks, as they require multiple manufacturing steps, from solubility enhancement to reservoir production. However, this current study challenges this trend and focuses on the delivery of the hydrophobic antibiotic rifampicin using SmartFilm-technology as a solubility-enhancing strategy. In contrast to previous techniques, smart drug-reservoirs (SmartReservoirs) for hydrophobic compounds can be manufactured using a one step process. In this study, HF-MNs and three different concentrations of rifampicin SmartFilms (SFs) were produced. Following this, both HF-MNs and SFs were fully characterised regarding their physicochemical and mechanical properties, morphology, Raman surface mapping, the interaction with the cellulose matrix and maintenance of the loaded drug in the amorphous form. In addition, their drug loading and transdermal permeation efficacy were studied. The resulting SFs showed that the API was intact inside the cellulose matrix within the SFs, with the majority of the drug in the amorphous state. SFs alone demonstrated no transdermal penetration and less than 20 ± 4 µg of rifampicin deposited in the skin layers. In contrast, the transdermal permeation profile using SFs combined with HF-MNs (i.e. SmartReservoirs) demonstrated a 4-fold increase in rifampicin deposition (80 ± 7 µg) in the skin layers and a permeation of approx. 500 ± 22 µg. Results therefore illustrate that SFs can be viewed as novel drug-reservoirs (i.e. SmartReservoirs) for HF-MNs, achieving highly efficient loading and diffusion properties through the hydrogel matrix.
Asunto(s)
Administración Cutánea , Sistemas de Liberación de Medicamentos , Hidrogeles , Agujas , Rifampin , Rifampin/administración & dosificación , Rifampin/química , Hidrogeles/química , Animales , Piel/metabolismo , Absorción Cutánea , Interacciones Hidrofóbicas e HidrofílicasRESUMEN
Dissolving microarray patches (DMAPs) represent an innovative approach to minimally invasive transdermal drug delivery, demonstrating efficacy in delivering both small and large therapeutic molecules. However, concerns raised in end-user surveys have hindered their commercialization efforts. One prevalent issue highlighted in these surveys is the lack of clear indicators for successful patch insertion and removal time. To address this challenge, a color-change-based feedback system is devised, which confirms the insertion and dissolution of DMAPs, aiming to mitigate the aforementioned problems. The approach combines hydrophilic needles containing model drugs (fluorescein sodium and fluorescein isothiocyanate (FITC)-dextran) with a hydrophobic poly(lactic acid) baseplate infused with moisture-sensitive silica gel particles. The successful insertion and subsequent complete dissolution of the needle shaft are indicated by the progressive color change of crystal violet encapsulated in the silica. Notably, distinct color alterations on the baseplate, observed 30 min and 1 h after insertion for FITC-dextran and fluorescein sodium DMAPs respectively, signal the full dissolution of the needles, confirming the complete cargo delivery and enabling timely patch removal. This innovative feedback system offers a practical solution for addressing end-user concerns and may significantly contribute to the successful commercialization of DMAPs by providing a visualized drug delivery method.
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Sistemas de Liberación de Medicamentos , Poliésteres , Dióxido de Silicio , Dióxido de Silicio/química , Poliésteres/química , Sistemas de Liberación de Medicamentos/métodos , Fluoresceína-5-Isotiocianato/química , Fluoresceína-5-Isotiocianato/análogos & derivados , Dextranos/química , Administración Cutánea , Interacciones Hidrofóbicas e HidrofílicasRESUMEN
The lymphatic system is active in several processes that regulate human diseases, among which cancer progression stands out. Thus, various drug delivery systems have been investigated to promote lymphatic drug targeting for cancer therapy; mainly, nanosized particles in the 10-150 nm range quickly achieve lymphatic vessels after an interstitial administration. Herein, a strategy to boost the lymphotropic delivery of Rose Bengal (RB), a hydrosoluble chemotherapeutic, is proposed, and it is based on the loading into Transfersomes (RBTF) and their intradermal deposition in vivo by microneedles. RBTF of 96.27 ± 13.96 nm (PDI = 0.29 ± 0.02) were prepared by a green reverse-phase evaporation technique, and they showed an RB encapsulation efficiency of 98.54 ± 0.09%. In vitro, RBTF remained physically stable under physiological conditions and avoided the release of RB. In vivo, intravenous injection of RBTF prolonged RB half-life of 50 min in healthy rats compared to RB intravenous injection; the RB half-life in rat body was further increased after intradermal injection reaching 24 h, regardless of the formulation used. Regarding lymphatic targeting, RBTF administered intravenously provided an RB accumulation in the lymph nodes of 12.3 ± 0.14 ng/mL after 2 h, whereas no RB accumulation was observed after RB intravenous injection. Intradermally administered RBTF resulted in the highest RB amount detected in lymph nodes after 2 h from the injection (84.2 ± 25.10 ng/mL), which was even visible to the naked eye based on the pink colouration of the drug. In the case of intradermally administered RB, RB in lymph node was detected only at 24 h (13.3 ± 1.41 ng/mL). In conclusion, RBTF proved an efficient carrier for RB delivery, enhancing its pharmacokinetics and promoting lymph-targeted delivery. Thus, RBTF represents a promising nanomedicine product for potentially facing the medical need for novel strategies for cancer therapy.
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Sistemas de Liberación de Medicamentos , Agujas , Rosa Bengala , Animales , Rosa Bengala/administración & dosificación , Rosa Bengala/farmacocinética , Inyecciones Intradérmicas , Masculino , Ratas Sprague-Dawley , Ganglios Linfáticos/metabolismo , Ratas , Microinyecciones , Colorantes Fluorescentes/administración & dosificación , Colorantes Fluorescentes/farmacocinéticaRESUMEN
The lymphatic system possesses the main viral replication sites in the body following viral infection. Unfortunately, current antiretroviral agents penetrate the lymph nodes insufficiently when administered orally and, therefore, cannot access the lymphatic system sufficiently to interrupt this viral replication. For this reason, novel drug delivery systems aimed at enhancing the lymphatic uptake of antiretroviral drugs are highly desirable. Dissolving polymeric microarray patches (MAPs) may help to target the lymph intradermally. MAPs are intradermal drug delivery systems used to deliver many types of compounds. The present work describes a novel work investigating the lymphatic uptake of two anti-HIV drugs: cabotegravir (CAB) and rilpivirine (RPV) when delivered intradermally using dissolving MAPs containing nanocrystals of both drugs. Maps were formulated using NCs obtained by solvent-free milling technique. The polymers used to prepare the NCs of both drugs were PVA 10 Kda and PVP 58 Kda. Both NCs were submitted to the lyophilization process and reconstituted with deionized water to form the first layer of drug casting. Backing layers were developed for short application times and effective skin deposition. In vivo biodistribution profiles of RPV and CAB after MAP skin application were investigated and compared with the commercial intramuscular injection using rats. After a single application of RPV MAPs, a higher concentration of RPV was delivered to the axillary lymph nodes (AL) (Cmax 2466 ng/g - Tmax 3 days) when compared with RPV IM injection (18 ng/g - Tmax 1 day), while CAB MAPs delivered slightly lower amounts of drug to the AL (5808 ng/g in 3 days) when compared with CAB IM injection (9225 ng/g in 10 days). However, CAB MAPs delivered 7726 ng/g (Tmax 7 days) to the external lumbar lymph nodes, which was statistically equivalent to IM delivery (Cmax 8282 ng/g - Tmax 7 days). This work provides strong evidence that MAPs were able to enhance the delivery of CAB and RPV to the lymphatic system compared to the IM delivery route.
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Dicetopiperazinas , Infecciones por VIH , Piridonas , Rilpivirina , Animales , Ratas , Preparaciones Farmacéuticas , Distribución Tisular , Antirretrovirales , PolímerosRESUMEN
In the last 20 years, protein, peptide and nucleic acid-based therapies have become the fastest growing sector in the pharmaceutical industry and play a vital role in disease therapy. However, the intrinsic sensitivity and large molecular sizes of biotherapeutics limit the available routes of administration. Currently, the main administration routes of biomacromolecules, such as parenteral, oral, pulmonary, nasal, rectal and buccal routes, each have their limitations. Several non-invasive strategies have been proposed to overcome these challenges. Researchers were particularly interested in microneedles (MNs) and polymeric films because of their less invasiveness, convenience and greater potential to preserve the bioactivity of biotherapeutics. By facilitating with MNs and polymeric films, biomacromolecules could provide significant benefits to patients suffering from various diseases such as cancer, diabetes, infectious and ocular diseases. However, before these devices can be used on patients, how to upscale MN manufacture in a cost-effective and timely manner, as well as the long-term safety of MN and polymeric film applications necessitates further investigation.
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Sistemas de Liberación de Medicamentos , Péptidos , Humanos , Administración Cutánea , Péptidos/química , Péptidos/metabolismo , Piel/metabolismoRESUMEN
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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Sistemas de Liberación de Medicamentos , Piel , Humanos , Polímeros/farmacología , Agujas , Administración CutáneaRESUMEN
Skin and soft tissue infections (SSTIs) arise from microbial ingress into the skin. In this study, poly(2-acrylamido-2-methyl-1-propanesulfonic acid) (polyAMPS), which has been reported to exhibit antimicrobial properties was synthesised for the manufacture of microarray patches (MAPs). The free acid and sodium salt of polyAMPS with controlled molar masses and narrow dispersity were synthesised via reversible addition - fragmentation chain-transfer (RAFT) polymerisation reaction with a monomer conversion of over 99%, as determined by 1H NMR. The polymers were shown to be biocompatible when evaluated using a fibroblast dermal cell line while agar plating assay using cultures of C. albican demonstrated that the acid form of polyAMPS exhibited antimicrobial inhibition, which is potentiated in the presence of antimicrobial agents. The synthesised polymers were then used to fabricate dissolving MAPs, which were loaded with either ITRA or levofloxacin (LEV). The MAPs displayed acceptable mechanical resistance and punctured ex vivo skin to a depth of 600 µm. Skin deposition studies revealed that the MAPs were able to administer up to â¼ 1.9 mg of LEV (delivery efficiency: 94.7%) and â¼ 0.2 mg of ITRA (delivery efficiency: 45.9%), respectively. Collectively, the synthesis and development of this novel pharmaceutical system may offer a strategy to manage SSTIs.
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Antiinfecciosos , Ácidos Sulfónicos , Antifúngicos/metabolismo , Antibacterianos/metabolismo , Piel/metabolismo , Administración Cutánea , Polímeros/química , Agujas , Sistemas de Liberación de MedicamentosRESUMEN
PURPOSE: Whilst significant progress has been made to defeat HIV infection, the efficacy of antiretroviral (ARV) therapy in the paediatric population is often hindered by poor adherence. Currently, two long-acting (LA) intramuscular injectable nanosuspensions of rilpivirine (RPV) and cabotegravir (CAB) are in clinical development for paediatric populations. However, administration requires access to healthcare resources, is painful, and can result in needle-stick injuries to the end user. To overcome these barriers, this proof-of-concept study was developed to evaluate the intradermal delivery of RPV LA and CAB LA via self-disabling dissolving microarray patches (MAPs). METHODS: Dissolving MAPs of two conformations, a conventional pyramidal and a bilayer design, were formulated, with various nanosuspensions of RPV and CAB incorporated within the respective MAP matrix. MAPs were mechanically robust and were capable of penetrating ex vivo skin with intradermal ARV deposition. RESULTS: In a single-dose in vivo study in rats, all ARV MAPs demonstrated sustained release profiles, with therapeutically relevant plasma concentrations of RPV and CAB detected to at least 63 and 28 d, respectively. In a multi-dose in vivo study, repeated MAP applications at 14-d intervals maintained therapeutically relevant plasma concentrations throughout the duration of the study. CONCLUSIONS: These results illustrate the potential of the platform to repeatedly maintain plasma concentrations for RPV and CAB. As such, these MAPs could represent a viable option to improve adherence in the paediatric population, one that is capable of being painlessly administered in the comfort of the patient's own home on a biweekly or less frequent basis.
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Fármacos Anti-VIH , Infecciones por VIH , Ratas , Animales , Rilpivirina/uso terapéutico , Infecciones por VIH/tratamiento farmacológico , Antirretrovirales , PiridonasRESUMEN
Heavy chain only binding proteins, such as variable new antigen receptors (VNARs), have emerged as an alternative to the highly successful therapeutic monoclonal antibodies (mAb). Owing to their small size (â¼ 11 kDa) and single chain only architecture, they are amenable to modular reformatting and can be produced using inexpensive expression systems. Furthermore, due to their low molecular weight (MW) and high stability, they may be suitable for alternative delivery strategies, such as microarray array patches (MAPs). In this study, the transdermal delivery of ELN22-104, a multivalent anti-hTNF-α VNAR, was examined using both dissolving and hydrogel-forming MAPs. For dissolving MAPs, the cumulative in vitro permeation of ELN22-104 reached a plateau after 2 h (12.24 ± 0.17 µg). This could be important for bolus dosing. Assessing two hydrogel-forming MAPs in vitro, PVP/PVA hydrogel-forming MAPs delivered significantly higher drug doses when compared to 'super swelling' MAPs, equivalent to 43.13 ± 10.36 µg and 23.13 ± 5.66 µg, respectively (p < 0.05). Consequently, this study has proven that by modifying the MAP system, the transdermal delivery of a VNAR across the skin can be enhanced. Furthermore, this proof-of-concept study has shown that transdermal delivery of 'next generation' biotherapeutics is achievable using MAP technology.
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Receptores de Antígenos , Piel , Prueba de Estudio Conceptual , Anticuerpos Monoclonales , HidrogelesRESUMEN
Microneedles (MNs) are minimally invasive devices, which have gained extensive interest over the past decades in various fields including drug delivery, disease diagnosis, monitoring, and cosmetics. MN geometry and shape are key parameters that dictate performance and therapeutic efficacy, however, traditional fabrication methods, such as molding, may not be able to offer rapid design modifications. In this regard, the fabrication of MNs using 3D printing technology enables the rapid creation of complex MN prototypes with high accuracy and offers customizable MN devices with a desired shape and dimension. Moreover, 3D printing shows great potential in producing advanced transdermal drug delivery systems and medical devices by integrating MNs with a variety of technologies. This review aims to demonstrate the advantages of exploiting 3D printing technology as a new tool to microengineer MNs. Various 3D printing methods are introduced, and representative MNs manufactured by such approaches are highlighted in detail. The development of advanced MN devices is also included. Finally, clinical translation and future perspectives for the development of MNs using 3D printing are discussed.
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Agujas , Impresión Tridimensional , Administración Cutánea , Sistemas de Liberación de Medicamentos/métodosRESUMEN
The antiretroviral agents rilpivirine (RPV) and cabotegravir (CAB) are approved as a combined treatment regimen against human immunodeficiency virus (HIV). To fully understand the biodistribution of these agents and determine their concentration levels in various parts of the body, a simple, selective and sensitive bioanalytical method is essential. In the present study, a high performance liquid chromatography method with mass spectrometry detection (HPLC-MS) was developed for simultaneous detection and quantification of RPV and CAB in various biological matrices. These included plasma, skin, lymph nodes, vaginal tissue, liver, kidneys and spleen, harvested from female Sprague Dawley rats. The suitability of the developed method for each matrix was validated based on the guidelines of the International Council for Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH) on bioanalytical method validation. Analytes were extracted from biological samples employing a simple one-step protein precipitation method using acetonitrile. Samples were analysed using an Apex Scientific Inertsil ODS-3 column (4.6 mm × 250 mm, 5 µm particle size), maintained at 40 °C, on a HPLC system coupled with a single quadrupole MS detector. RPV was detected at a mass-to-charge ratio (m/z) of 367.4 and CAB at 406.3. Separation was achieved using isocratic elution at 0.3 mL/min with a mixture of acetonitrile and 0.1% (v/v) trifluoroacetic acid in water (81:19, v/v) as the mobile phase. The run time was set at 13 min. The presented method was selective, sensitive, accurate and precise for detection and quantification of RPV and CAB in all matrices. The developed and validated bioanalytical method was successfully employed for in vivo samples with both drugs simultaneously.
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Antirretrovirales , Rilpivirina , Animales , Antirretrovirales/análisis , Antirretrovirales/sangre , Cromatografía Líquida de Alta Presión/métodos , Dicetopiperazinas , Femenino , Preparaciones Farmacéuticas , Piridonas , Ratas , Ratas Sprague-Dawley , Reproducibilidad de los Resultados , Rilpivirina/análisis , Rilpivirina/sangre , Espectrometría de Masas en Tándem/métodos , Distribución TisularRESUMEN
Although microneedle array patch (MAP) technology is reaching ever closer to regulatory approval, it remains imperative that approaches to further improve patient acceptance are still explored. Addressing this perception, a water-filled reservoir was incorporated into a hydrogel-forming MAP system to provide a novel feedback mechanism. To confirm successful MAP skin insertion, the end user would both hear and feel the rupture of the water-filled reservoir. Interestingly, a 50-µL water-filled reservoir ruptured at 30.27 ± 0.39 N, which has previously been shown as the mean application force for MN insertion in human subjects following appropriate instruction. Importantly, no significant difference in % cumulative permeation of FITC-dextran 10 kDa and fluorescein sodium after 24 h was observed between a 50-µL reservoir and the current method of application that has been successfully used in both in vitro and in vivo studies (p > 0.05). Therefore, as drug delivery was not affected, this proof-of-concept study has shown that a water-filled reservoir feedback mechanism has the potential to serve as a viable tool for consistent MAP skin insertion.
Asunto(s)
Hidrogeles , Agujas , Administración Cutánea , Sistemas de Liberación de Medicamentos/métodos , Retroalimentación , Humanos , Microinyecciones/métodos , Piel , AguaRESUMEN
Transdermal microneedle (MN) patches are a promising tool used to transport a wide variety of active compounds into the skin. To serve as a substitute for common hypodermic needles, MNs must pierce the human stratum corneum (~ 10 to 20 µm), without rupturing or bending during penetration. This ensures that the cargo is released at the predetermined place and time. Therefore, the ability of MN patches to sufficiently pierce the skin is a crucial requirement. In the current review, the pain signal and its management during application of MNs and typical hypodermic needles are presented and compared. This is followed by a discussion on mechanical analysis and skin models used for insertion tests before application to clinical practice. Factors that affect insertion (e.g., geometry, material composition and cross-linking of MNs), along with recent advancements in developed strategies (e.g., insertion responsive patches and 3D printed biomimetic MNs using two-photon lithography) to improve the skin penetration are highlighted to provide a backdrop for future research.
RESUMEN
Diabetes affects approximately 450 million adults globally. If not effectively managed, chronic hyperglycaemia causes tissue damage that can develop into fibrosis. Fibrosis leads to end-organ complications, failure of organ systems occurs, which can ultimately cause death. One strategy to tackle end-organ complications is to maintain normoglycaemia. Conventionally, insulin is administered subcutaneously. Whilst effective, this delivery route shows several limitations, including pain. The transdermal route is a favourable alternative. Microneedle (MN) arrays are minimally invasive and painless devices that can enhance transdermal drug delivery. Convincing evidence is provided on MN-mediated insulin delivery. MN arrays can also be used as a diagnostic tool and monitor glucose levels. Furthermore, sophisticated MN array-based systems that integrate glucose monitoring and drug delivery into a single device have been designed. Therefore, MN technology has potential to revolutionise diabetes management. This review describes the current applications of MN technology for diabetes management and how these could prevent diabetes induced fibrosis.
Asunto(s)
Diabetes Mellitus/patología , Hipoglucemiantes/administración & dosificación , Sistemas de Infusión de Insulina , Microinyecciones/instrumentación , Administración Cutánea , Diabetes Mellitus/tratamiento farmacológico , Fibrosis , Humanos , Hipoglucemiantes/uso terapéutico , Microinyecciones/métodosRESUMEN
The success of protein, peptide and antibody based therapies is evident - the biopharmaceuticals market is predicted to reach $388 billion by 2024 [1], and more than half of the current top 20 blockbuster drugs are biopharmaceuticals. However, the intrinsic properties of biopharmaceuticals has restricted the routes available for successful drug delivery. While providing 100% bioavailability, the intravenous route is often associated with pain and needle phobia from a patient perspective, which may translate as a reluctance to receive necessary treatment. Several non-invasive strategies have since emerged to overcome these limitations. One such strategy involves the use of microneedles (MNs), which are able to painlessly penetrate the stratum corneum barrier to dramatically increase transdermal drug delivery of numerous drugs. This review reports the wealth of studies that aim to enhance transdermal delivery of biopharmaceutics using MNs. The true potential of MNs as a drug delivery device for biopharmaceuticals will not only rely on acceptance from prescribers, patients and the regulatory authorities, but the ability to upscale MN manufacture in a cost-effective manner and the long term safety of MN application. Thus, the current barriers to clinical translation of MNs, and how these barriers may be overcome are also discussed.