An Electrochemical Sensor of Theophylline on a Boron-Doped Diamond Electrode Modified with Nickel Nanoparticles.

Theophylline is a drug with a narrow therapeutic range. Electrochemical sensors are a potentially effective method for detecting theophylline concentration to prevent toxicity. In this work, a simple modification of a boron-doped diamond electrode using nickel nanoparticles was successfully performed for a theophylline electrochemical sensor. The modified electrode was characterized using a scanning electron microscope and X-ray photoelectron spectroscopy. Square wave voltammetry and cyclic voltammetry methods were used to study the electrochemical behavior of theophylline. The modified nickel nanoparticles on the boron-doped diamond electrode exhibited an electrochemically active surface area of 0.0081 cm2, which is larger than the unmodified boron-doped diamond's area of 0.0011 cm2. This modified electrode demonstrated a low limit of detection of 2.79 µM within the linear concentration range from 30 to 100 µM. Moreover, the modified boron-doped diamond electrode also showed selective properties against D-glucose, ammonium sulfate, and urea. In the real sample analysis using artificial urine, the boron-doped diamond electrode with nickel nanoparticle modifications achieved a %recovery of 105.10%, with a good precision of less than 5%. The results of this work indicate that the developed method using nickel nanoparticles on a boron-doped diamond electrode is promising for the determination of theophylline.

Fabrication of dissolving microneedles for transdermal delivery of protein and peptide drugs: polymer materials and solvent casting micromoulding method.

Proteins and peptides are rapidly developing pharmaceutical products and are expected to continue growing in the future. However, due to their nature, their delivery is often limited to injection, with drawbacks such as pain and needle waste. To overcome these limitations, microneedles technology is developed to deliver protein and peptide drugs through the skin. One type of microneedles, known as dissolving microneedles, has been extensively studied for delivering various proteins and peptides, including ovalbumin, insulin, bovine serum albumin, polymyxin B, vancomycin, and bevacizumab. This article discusses polymer materials used for fabricating dissolving microneedles, which are poly(vinylpyrrolidone), hyaluronic acid, poly(vinyl alcohol), carboxymethylcellulose, GantrezTM, as well as other biopolymers like pullulan and ulvan. The paper is focused solely on solvent casting micromoulding method for fabricating dissolving microneedles containing proteins and peptides, which will be divided into one-step and two-step casting micromoulding. Additionally, future considerations in the market plan for dissolving microneedles are discussed in this article.

Elucidating the Impact of Surfactants on the Performance of Dissolving Microneedle Array Patches.

The need for biocompatible polymers capable of dissolving in the skin while exhibiting reasonable mechanical features and delivery efficiency limits the range of materials that could be utilized in fabricating dissolving microneedle array patches (MAPs). The incorporation of additives, such as surfactants, during microneedle fabrication might be an alternative solution to overcome the limited range of materials used in fabricating dissolving MAPs. However, there is a lacuna in the knowledge on the effect of surfactants on the manufacture and performance of dissolving MAPs. The current study explores the role of surfactants in the manufacture and performance of dissolving MAPs fabricated from poly(vinyl alcohol) (PVA) and poly(vinyl pyrrolidone) (PVP) loaded with the model drugs, ibuprofen sodium and itraconazole. Three nonionic surfactants, Lutrol F108, Pluronic F88, and Tween 80, in solutions at varying concentrations (0.5, 1.0, and 2.0% w/w) were loaded into these dissolving MAPs. It was discovered that all of the dissolving MAPs that incorporated surfactant displayed a lower reduction in the microneedle height (≈10%) relative to the control formulation (≈20%) when subjected to a compressive force of 32 N. In addition, the incorporation of surfactants in some instances enhanced the insertion profile of these polymeric MAPs when evaluated using ex vivo neonatal porcine skin. The incorporation of surfactant into ibuprofen sodium-loaded dissolving MAPs improved the insertion depth of MAPs from 400 µm down to 600 µm. However, such enhancement was not apparent when the MAPs were loaded with the model hydrophobic drug, itraconazole. Skin deposition studies highlighted that the incorporation of surfactant enhanced the delivery efficiency of both model drugs, ibuprofen sodium and itraconazole. The incorporation of surfactant enhanced the amount of ibuprofen sodium delivered from 60.61% up to ≈75% with a majority of the drug being delivered across the skin and into the receptor compartment. On the other hand, when surfactants were added into MAPs loaded with the model hydrophobic drug itraconazole, we observed enhancement in intradermal delivery efficiency from 20% up to 30%, although this did not improve the delivery of the drug across the skin. This work highlights that the addition of nonionic surfactant is an alternative formulation strategy worth exploring to improve the performance and delivery efficiency of dissolving MAPs.

A New and Sensitive HPLC-UV Method for Rapid and Simultaneous Quantification of Curcumin and D-Panthenol: Application to In Vitro Release Studies of Wound Dressings.

Curcumin (CUR) and D-panthenol (DPA) have been widely investigated for wound-healing treatment. In order to analyse these two compounds from a dosage form, such as polymer-based wound dressings or creams, an analytical method that allows the quantification of both drugs simultaneously should be developed. Here, we report for the first time a validated high-performance liquid chromatographic (HPLC) method coupled with UV detection to quantify CUR and DPA based on the standards set by the International Council on Harmonization (ICH) guidelines. The separation of the analytes was performed using a C18 column that utilised a mobile phase consisting of 0.001% v/v phosphoric acid and methanol using a gradient method with a run time of 15 min. The method is linear for drug concentrations within the range of 0.39-12.5 µg mL-1 (R2 = 0.9999) for CUR and 0.39-25 µg mL-1 for DPA (R2 = 1). The validated method was found to be precise and accurate. Moreover, the CUR and DPA solution was found to be stable under specific storage conditions. We, therefore, suggest that the HPLC-UV method developed in this study may be very useful in screening formulations for CUR and DPA within a preclinical setting through in vitro release studies.

In Vitro Permeation Studies on Carvedilol Containing Dissolving Microarray Patches Quantified Using a Rapid and Simple HPLC-UV Analytical Method.

Analytical method validation is a vital element of drug formulation and delivery studies. Here, high-performance liquid chromatography in conjunction with UV detection (HPLC-UV) has been used to produce a straightforward, quick, yet sensitive analytical approach to quantify carvedilol (CAR). A C18 column was used to isolate the analyte from the mixture by isocratic elution with a mobile phase comprising a mixture of 0.1% v/v trifluoroacetic acid in water and acetonitrile in a ratio of 65:35 v/v at a flow rate of 0.6 mL min-1. Linearity was observed for CAR concentrations within the range of 1.5-50 µg mL-1 (R2 = 0.999) in phosphate buffer saline and within the range of 0.2-6.2 µg mL-1 (R2 = 0.9999) in methanol. The International Council on Harmonization (ICH) requirements were followed throughout the validation of the isocratic approach, rendering it specific, accurate, and precise. Moreover, robustness tests indicated that the method remained selective and specific despite small deliberate changes to environmental and operational factors. An efficient extraction procedure was also developed to extract and quantify CAR from excised neonatal porcine skin, resulting in recovery rates ranging from 95 to 97%. The methods reported here have been successfully utilised to evaluate CAR permeation, both transdermally and intradermally following application of a dissolving microarray patch (MAP) to excised neonatal porcine skin.

Development, Evaluation, and Pharmacokinetic Assessment of Polymeric Microarray Patches for Transdermal Delivery of Vancomycin Hydrochloride.

Methicillin-resistant Staphylococcus aureus (MRSA) can cause harmful and potentially deadly infections. Vancomycin remains the first-line antibiotic treatment for MRSA-derived infections. Nevertheless, as a peptide drug, it is poorly absorbed when administered orally because of its high molecular weight and low permeability in the gastrointestinal tract and is therefore administered intravenously for the treatment of systemic diseases. In order to circumvent some of the many drawbacks associated with intravenous injection, other routes of drug delivery should be investigated. One of the strategies which has been employed to enhance transdermal drug delivery is based on microarray patches (MAPs). This work, for the first time, describes successful transdermal delivery of vancomycin hydrochloride (VCL) using dissolving MAPs (DMAPs) and hydrogel-forming MAPs (HFMAPs). VCL was formulated into DMAPs and reservoirs [film dosage forms, lyophilized wafers, and compressed tablets (CSTs)] using excipients such as poly(vinyl pyrrolidone), poly(vinyl alcohol), sodium hyaluronate, d-sorbitol, and glycerol. In this study, HFMAPs were manufactured using aqueous blends containing poly(methylvinyl ether-co-maleic acid) cross-linked by esterification with poly(ethylene glycol). The VCL-loaded CSTs (60% w/w VCL) were the most promising reservoirs to be integrated with HFMAPs based on the physicochemical evaluations performed. Both HFMAPs and DMAPs successfully delivered VCL in ex vivo studies with the percentage of drug that permeated across the neonatal porcine skin recorded at 46.39 ± 8.04 and 7.99 ± 0.98%, respectively. In in vivo studies, the area under the plasma concentration time curve from time zero to infinity (AUC0-∞) values of 162.04 ± 61.84 and 61.01 ± 28.50 µg h/mL were achieved following the application of HFMAPs and DMAPs, respectively. In comparison, the AUC0-∞ of HFMAPs was significantly greater than that of the oral administration control group, which showed an AUC0-∞ of 30.50 ± 9.18 µg h/mL (p < 0.05). This work demonstrates that transdermal delivery of VCL is feasible using DMAPs and HFMAPs and could prove effective in the treatment of infectious diseases caused by MRSA, such as skin and soft tissue infections, lymphatic-related infections, and neonatal sepsis.

An isocratic RP-HPLC-UV method for simultaneous quantification of tizanidine and lidocaine: application to in vitro release studies of a subcutaneous implant.

Implantable devices have been widely investigated to improve the treatment of multiple diseases. Even with low drug loadings, these devices can achieve effective delivery and increase patient compliance by minimizing potential side effects, consequently enhancing the quality of life of the patients. Moreover, multi-drug products are emerging in the pharmaceutical field, capable of treating more than one ailment concurrently. Therefore, a simple analytical method is essential for detecting and quantifying different analytes used in formulation development and evaluation. Here, we present, for the first time, an isocratic method for tizanidine hydrochloride (TZ) and lidocaine (LD) loaded into a subcutaneous implant, utilizing reversed-phase high-performance liquid chromatography (RP-HPLC) coupled with a UV detector. These implants have the potential to treat muscular spasticity while providing pain relief for several days after implantation. Chromatographic separation of the two drugs was accomplished using a C18 column, with a mobile phase consisting of 0.1% TFA in water and MeOH in a 58 : 42 ratio, flowing at 0.7 ml min-1. The method exhibited specificity and robustness, providing accurate and precise results. It displayed linearity within the range of 0.79 to 100 µg ml-1, with an R2 value of 1 for the simultaneous analysis of TZ and LD. The developed method demonstrated selectivity, offering limits of detection and quantification of 0.16 and 0.49 µg ml-1 for TZ, and 0.30 and 0.93 µg ml-1 for LD, respectively. Furthermore, the solution containing both TZ and LD proved stable under various storage conditions. While this study applied the method to assess an implant device, it has broader applicability for analysing and quantifying the in vitro drug release of TZ and LD from diverse dosage forms in preclinical settings.

Efficacy of quercetin-like compounds from the mistletoe plant of Dendrophthoe pentandra L. Miq, as oral random blood sugar lowering treatment in diabetic rats.

Background: Mistletoe is an herb that grows on duku plants (Lancium demosticum) and is known as benalu duku (BD) in Indonesia. It is predicted to have benefits such as anticancer or antiviral properties, and it is also thought to have anti-diabetic pharmacological activity. Quercetin-like compounds (QLCs) are secondary metabolites with antidiabetic activity that are expected to lower blood sugar levels in animals after oral administration.Objective: This study aimed to analyze the ability of QLCs to reduce random blood sugar levels using experimental animals as clinical models.Material and methods: The research method used was exploratory, which used a before-after test model, and observations were made on the random blood sugar levels after treatment. Secondary metabolites were extracted from BD leaves, which were then screened. Diabetes was induced in 30 rats (Rattus norvegicus) by the administration of streptozotocin at 0.045 mg/g body weight daily for 2 days. The antidiabetic effects of the secondary metabolite at doses of 0.5 mg/kg body weight (twice a day) when administered orally for up to 5 days were tested in diabetic rats. The random sugar levels (mg/dL) were measured using a One Touch Ultra Plus medical device for observation of randomized blood sugar levels. Results and novelty: The results revealed that the secondary metabolite, as an analyte from the BD leaf extract, can significantly reduce random blood sugar levels.Conclusion: The secondary metabolite extracted from BD, could be used to treat diabetes in rats.

Dissolvable microarray patches of levodopa and carbidopa for Parkinson's disease management.

Carbidopa and levodopa remain the established therapeutic standard for managing Parkinson's disease. Nevertheless, their oral administration is hindered by rapid enzymatic degradation and gastrointestinal issues, limiting their efficacy, and necessitating alternative delivery methods. This work presents a novel strategy employing dissolving microarray patches (MAPs) loaded with carbidopa and levodopa, formulated with Tween® 80 to improve their transdermal delivery. The fabricated MAPs demonstrated an acceptable mechanical strength, resisting pressures equivalent to manual human thumb application (32 N) onto the skin. Additionally, these MAPs exhibited an insertion depth of up to 650 µm into excised neonatal porcine skin. Ex vivo dermatokinetic studies could achieve delivery efficiencies of approximately 53.35 % for levodopa and 40.14 % for carbidopa over 24 h, demonstrating their significant potential in drug delivery. Biocompatibility assessments conducted on human dermal fibroblast cells corroborated acceptable cytocompatibility, confirming the suitability of these MAPs for dermal application. In conclusion, dissolving MAPs incorporating carbidopa and levodopa represent a promising alternative for improving the therapeutic management of Parkinson's disease.

Novel SmartReservoirs for hydrogel-forming microneedles to improve the transdermal delivery of rifampicin.

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.

Parafilm® M and Strat-M® as skin simulants in in vitro permeation of dissolving microarray patches loaded with proteins.

In vitro permeation studies play a crucial role in early formulation optimisation before extensive animal model investigations. Biological membranes are typically used in these studies to mimic human skin conditions accurately. However, when focusing on protein and peptide transdermal delivery, utilising biological membranes can complicate analysis and quantification processes. This study aims to explore Parafilm®M and Strat-M® as alternatives to dermatomed porcine skin for evaluating protein delivery from dissolving microarray patch (MAP) platforms. Initially, various MAPs loaded with different model proteins (ovalbumin, bovine serum albumin and amniotic mesenchymal stem cell metabolite products) were prepared. These dissolving MAPs underwent evaluation for insertion properties and in vitro permeation profiles when combined with different membranes, dermatomed porcine skin, Parafilm®M, and Strat-M®. Insertion profiles indicated that both Parafilm®M and Strat-M® showed comparable insertion depths to dermatomed porcine skin (in range of 360-430 µm), suggesting promise as membrane substitutes for insertion studies. In in vitro permeation studies, synthetic membranes such as Parafilm®M and Strat-M® demonstrated the ability to bypass protein-derived skin interference, providing more reliable results compared to dermatomed neonatal porcine skin. Consequently, these findings present valuable tools for preliminary screening across various MAP formulations, especially in the transdermal delivery of proteins and peptides.

Quercetin loaded polymeric dissolving microarray patches: fabrication, characterisation and evaluation.

Quercetin, a natural compound, shows promising potential in wound healing by reducing fibrosis, limiting scar formation, and boosting fibroblast proliferation. However, its effectiveness is hindered by poor solubility, resulting in low bioavailability and necessitating high doses for therapeutic efficacy. This study presents a novel approach, fabricating quercetin-loaded microarray patches (MAPs) using widely employed solubility enhancement strategies. Fabricated MAPs exhibited favourable mechanical strength and could be inserted into excised porcine skin to a depth of 650 µm. Furthermore, formulations containing Soluplus® significantly increased the drug loading capacity, achieving up to 2.5 mg per patch and complete dissolution within an hour of application on excised porcine skin. In vitro studies on full-thickness neonatal porcine skin demonstrated that Soluplus®-enhanced MAPs effectively delivered quercetin across various skin layers, achieving a delivery efficiency exceeding 80% over 24 h. Additionally, these prototype MAPs displayed anti-inflammatory properties and demonstrated biocompatibility with human keratinocyte skin cells. Therefore, quercetin-loaded MAPs employing Soluplus® as a solubility enhancer present a promising alternative strategy for wound healing and anti-inflammatory therapy applications.

MAP-box: a novel, low-cost and easy-to-fabricate 3D-printed box for the storage and transportation of dissolving microneedle array patches.

Research on the use of microarray patches (MAPs) has progressed at an unprecedented rate over the years, leading to the development of many novel drug delivery systems. As the technology approaches patients, there are several key aspects that ought to be addressed in order to facilitate the smooth translation of MAPs from bench to bedside. One integral factor includes the choice of devices and packaging for the storage of MAPs. In the current work, a slide-and-seal box, MAP-box, was developed for the storage of dissolving MAPs, using fused-deposition modelling. The device has been designed to act as a pill-box for MAPs not only to provide protection for MAPs from the environment, but also to improve patient's adherence to treatment. The overall design of the MAP-box was simple, yet offers the capability of sealing and protecting dissolving MAPs up to 30 days. Donepezil HCl was formulated into a dissolvable MAP, which was used to treat dementia related to Alzheimer's disease. This compound was used as a model formulation to evaluate the utility of the 3D printed MAP-box when placed under three storage conditions: 5 °C and ambient humidity, 25 °C and 65% relative humidity and 40 °C and 75% relative humidity. It was shown that the slide-and-seal box was able to confer protection to MAPs for up to 30 days under accelerated stability study conditions as the drug loading, mechanical properties and insertion properties of MAPs remained unaffected when compared to the unpackaged MAPs stored under these same parameters. These preliminary data provide evidence that the MAP-box prototype may be of great utility for the storage of single or multiple MAPs. Nevertheless, future work will be needed to evaluate their patient usability and its application to different types of MAP systems to fully validate the overall robustness of the prototype.

Design of a Novel Delivery Efficiency Feedback System for Biphasic Dissolving Microarray Patches Based on Poly(Lactic Acid) and Moisture-Indicating Silica.

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.

Improved pharmacokinetic and lymphatic uptake of Rose Bengal after transfersome intradermal deposition using hollow microneedles.

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.

Carbon nanomaterials as electrochemical sensors for theophylline: a review.

Theophylline (TP) is a methylxanthine derivative, which serves as a valuable compound in treating respiratory disorders and acts as a bronchodilator agent. However, TP has a limited therapeutic range (20-100 µmol L-1), demanding precise monitoring to prevent potential drug toxicity even with slight level fluctuations during treatment. Thus, to overcome this limitation, electrochemical methods have been extensively used due to their efficacy in achieving sensitivity, selectivity, and accuracy. In the context of electrochemical sensors, nanocarbon-based materials have gained widespread recognition for their extensive applications. Therefore, this review aims to explore the latest advancements in carbon-based electrodes particularly used for the precise determination of TP through electrochemical methods. The results are expected to provide insights into the profound significance of the methods in enhancing the accuracy and sensitivity for the detection of TP.

Risperidone-cyclodextrin complex reservoir combined with hydrogel-forming microneedle array patches for enhanced transdermal delivery.

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.

Development of ropivacaine hydrochloride-loaded dissolving microneedles as a local anesthetic agent: A proof-of-concept.

Ropivacaine hydrochloride (RPL) is a local anesthetic agent that has been widely used for the treatment of pain during or after surgery. However, this drug is only available in parenteral dosage form and may contribute to the infiltration of RPL into the plasma, causing some undesirable side effects. Intradermal delivery of RPL using dissolving microneedles may become a promising strategy to deliver such drugs into the skin. This research aimed to develop RPL-loaded dissolving microneedles (DMN-RPLs) as a proof of the concept of intradermal delivery of a local anesthetic. The DMN-RPLs were fabricated using either centrifugation or air-pressurized chamber methods. Several polymers, such as poly(vinyl pyrrolidone) (PVP), poly(vinyl alcohol) (PVA), and sodium hyaluronate (SH), were utilized for manufacturing the DMN-RPLs. The prepared DMN-RPLs were assessed for their thermal properties, chemical bonds, mechanical strength, insertion ability, skin-dissolution study, and drug content. Furthermore, in-skin deposition and dermatokinetic studies were also performed. The results showed that F9 (30 % w/w PVP-4 % w/w SH) and F10 (30 % w/w PVP-5 % w/w PVA) containing 5 % w/w of RPL were the most promising formulations, as shown by their needle height reduction (<10 %) and insertion depth (∼400 µm). Both formulations were also able to deliver more than 60 % of the RPL contained in the DMNs into the epidermis, dermis, and receiver compartment. This study, for the first time, has provided a proof concept to deliver RPL as a local anesthetic using DMNs and the intradermal route, aiming to minimize pain and discomfort during administration and improve the patient's experience.

Development of a HPLC fluorometric method for the quantification of enfuvirtide following in vitro releasing studies on thermosensitive in situ forming gel.

Due to the presence of peptidase and protease in the gastrointestinal tract, peptides are subjected to digestion and inactivation when administrated orally. To avoid degradation and maintain the desired efficacy of peptide drugs, there is a demand to develop transdermal and intradermal delivery systems. This requires efficient and specific analytical methods to separate and quantify the peptide drugs from the formulation and the skin matrix in the early stages of pharmaceutical development. A high-performance liquid chromatography (HPLC) system equipped with a fluorometric detector was used to quantify enfuvirtide, which is the first fusion inhibitor for HIV treatment. The HPLC method was developed and validated according to the ICH Q2(R1) guidelines. The viability of the method was demonstrated during in vitro studies, where samples were analysed following intradermal administration of a thermosensitive in situ forming gel. Compared with previously reported methods, this assay proved efficient, sensitive and accurate, with a detection limit of 0.74 µg/mL and a run time of 9 min, mitigating the use of any internal standards and detergents. The addition of an organic solvent to the samples successfully solved the problem of low recovery caused by the adsorption of the drug to the plastic consumables in the sample treatment process. The amount of enfuvirtide releasing from the in situ gel through skin after 7 hours was 16.25 ± 7.08 µg, which was significantly lower than the reconstituted FUZEON® itself (26.68 ± 10.45 µg), showing a longer release profile. The results may be beneficial as a constructive input for future enfuvirtide quantification within a preclinical setting through in vitro release studies across the skin.

Microneedle-Mediated Transdermal Delivery of Genetic Materials, Stem Cells, and Secretome: An Update and Progression.

Medical practitioners commonly use oral and parenteral dosage forms to administer drugs to patients. However, these forms have certain drawbacks, particularly concerning patients' comfort and compliance. Transdermal drug delivery presents a promising solution to address these issues. Nevertheless, the stratum corneum, as the outermost skin layer, can impede drug permeation, especially for macromolecules, genetic materials, stem cells, and secretome. Microneedles, a dosage form for transdermal delivery, offer an alternative approach, particularly for biopharmaceutical products. In this review, the authors will examine the latest research on microneedle formulations designed to deliver genetic materials, stem cells, and their derivatives. Numerous studies have explored different types of microneedles and evaluated their ability to deliver these products using preclinical models. Some of these investigations have compared microneedles with conventional dosage forms, demonstrating their significant potential for advancing the development of biotherapeutics in the future.