Drug-loaded Patches Research Articles

Double-crosslinkable poly(urethane)-based hydrogels relying on supramolecular interactions and light-initiated polymerization: promising tools for advanced applications in drug delivery.

Physical and chemical hydrogels are promising platforms for tissue engineering/regenerative medicine (TERM). In particular, physical hydrogels are suitable for use in the design of drug delivery systems owing to their reversibility and responsiveness to applied stimuli and external environment. Alternatively, the use of chemical hydrogels represents a better strategy to produce stable 3D constructs in the TERM field. In this work, these two strategies were combined to develop multi-functional formulations integrating both drug delivery potential and TERM approaches in a single device. Specifically, a novel photo-sensitive poly(ether urethane) (PEU) was developed to form supramolecular networks with α-cyclodextrins (α-CDs). The PEU was successfully synthesized using Poloxamer® 407, 1,6-diisocyanatohexane and 2-hydroxyethyl methacrylate, as assessed by infrared spectroscopy, size exclusion chromatography and proton nuclear magnetic resonance (1H NMR) spectroscopy. Subsequently, PEU thermo-responsiveness was characterized through critical micelle temperature evaluation and dynamic light scattering analyses, which suggested the achievement of a good balance between molecular mass and overall hydrophobicity. Consequently, the formation of supramolecular domains with α-CDs was demonstrated through X-ray diffraction and 1H NMR spectroscopy. Supramolecular hydrogels with remarkably fast gelation kinetics (i.e., few minutes) were designed using a low PEU concentration (≤5% w/v). All formulations were found to be cytocompatible according to the ISO 10993-5 regulation. Notably, the hydrogels were observed to possess mechanical properties and self-healing ability, according to rheological tests, and their fast photo-crosslinking was evidenced (<60 s) by photo-rheology. A high curcumin payload (570 μg mL-1) was encapsulated in the hydrogels, which was released with highly tunable and progressive kinetics in a physiological-simulated environment for up to 5 weeks. Finally, a preliminary evaluation of hydrogel extrudability was performed using an extrusion-based bioprinter, obtaining 3D-printed structures showing good morphological fidelity to the original design. Overall, the developed hydrogel platform showed promising properties for application in the emerging field of regenerative pharmacology as (i) easily injectable drug-loaded formulations suitable for post-application stabilization through light irradiation, and (ii) biomaterial inks for the fabrication of patient-specific drug-loaded patches.

A Straightforward Method to Produce Multi-Nanodrug Delivery Systems for Transdermal/Tympanic Patches Using Electrospinning and Electrospray.

The delivery of drugs through the skin barrier at a predetermined rate is the aim of transdermal drug delivery systems (TDDSs). However, so far, TDDS has not fully attained its potential as an alternative to hypodermic injections and oral delivery. In this study, we presented a proof of concept of a dual drug-loaded patch made of nanoparticles (NPs) and ultrafine fibers fabricated by using one equipment, i.e., the electrospinning apparatus. Such NP/fiber systems can be useful to release drugs locally through the skin and the tympanic membrane. Briefly, dexamethasone (DEX)-loaded poly(3-hydroxybutyrate-co-3-hydroxyvalerate) (PHBHV) fiber meshes were decorated with rhodamine (RHO)-loaded poly(lactic-co-glycolic acid) (PLGA) NPs, with RHO representing as a second drug model. By properly tuning the working parameters of electrospinning, DEX-loaded PHBHV fibers (i.e., by electrospinning mode) and RHO-loaded PLGA NPs (i.e., by electrospray mode) were successfully prepared and straightforwardly assembled to form a TDDS patch, which was characterized via Fourier transform infrared spectroscopy and dynamometry. The patch was then tested in vitro using human dermal fibroblasts (HDFs). The incorporation of DEX significantly reduced the fiber mesh stiffness. In vitro tests showed that HDFs were viable for 8 days in contact with drug-loaded samples, and significant signs of cytotoxicity were not highlighted. Finally, thanks to a beaded structure of the fibers, a controlled release of DEX from the electrospun patch was obtained over 4 weeks, which may accomplish the therapeutic objective of a local, sustained and prolonged anti-inflammatory action of a TDDS, as is requested in chronic inflammatory conditions, and other pathological conditions, such as in sudden sensorineural hearing loss treatment.

Formulation and Characterization of Polymeric Cross-Linked Hydrogel Patches for Topical Delivery of Antibiotic for Healing Wound Infections.

Wound healing faces significant challenges in clinical settings. It often contains a series of dynamic and complex physiological healing processes. Instead of creams, ointments and solutions, alternative treatment approaches are needed. The main objective of the study was to formulate bacitracin zinc-loaded topical patches as a new therapeutic agent for potential wound healing. A free radical polymerization technique was optimized for synthesis. Polyethylene glycol-8000 (PEG-8000) was chemically cross-linked with acrylic acid in aqueous medium, using Carbopol 934 as a permeation enhancer and tween 80 as surfactant. Ammonium persulfate and N,N'-Methylenebisacrylamide (MBA) were utilized as initiator and cross-linker. FTIR, DSC, TGA, and SEM were performed, and patches were evaluated for swelling dynamics, sol-gel analysis, in vitro drug release in various media. A Franz diffusion cell was used for the permeation study. Irritation and wound healing with the drug-loaded patches were also studied. The characterization studies confirmed the formation of a cross-linked hydrogel network. The highest swelling and drug release were observed in formulations containing highest Polyethylene glycol-8000 and lowest N,N'-Methylenebisacrylamide concentrations. The pH-sensitive behavior of patches was also confirmed as more swelling, drug release and drug permeation across skin were observed at pH 7.4. Fabricated patches showed no sign of irritation or erythema as evaluated by the Draize scale. Faster wound healing was also observed with fabricated patches compared to marketed formulations. Therefore, such a polymeric network can be a promising technology for speeding up wound healing and minor skin injuries through enhanced drug deposition.

Natural rubber-based pressure sensitive adhesive as a drug carrier

Natural rubber (NR) has been utilized in several products from its interesting unique properties. This study aimed to develop the pressure-sensitive adhesives (PSA) as the transdermal patches from NR by two-roll mill kneading technique. Hydroxyethyl cellulose (HEC) was blended as a tackifier agent. The propranolol HCl and ibuprofen at different parts per hundred of rubber (phr) were loaded into this developed PSA. The appearance, thickness, crystallinity, contact angle, water sorption and erosion, adhesion, and in vitro drug permeation of these patches were evaluated. The thickness of all patches was in the range of 0.46–1.07 mm. The drug-loaded patches showed diverse unique topographies depended on both type and amount of drug incorporation. From powder X-ray diffraction analysis, the plain NR-PSA showed the amorphous structure, while the halo pattern inserted with sharp drug peaks were observed on drug-loaded PSA. The contact angle of all samples was in the range of 80–90° indicating their hydrophobic surface. However, they displayed an increased % water sorption with the time of soaking. The 2–4 N adhesion force was evident for all fabricated drug-loaded PSAs. The propranolol HCl permeated from PSA notably lower than ibuprofen. The residual of the drugs in patches was about 85–90 %. These results provided the basic physicochemical properties for the further development of PSA as the transdermal patch.[copyright information to be updated in production process]

Drug‐Loaded Mucoadhesive Patch with Active Delivery and Controlled Releasing Ability

Drug-Loaded Mucoadhesive Patch In article number 2100203, Sukho Park and co-workers demostrate a drug-loaded patch equipped in wireless capsule, which is delivered to the gastrointestinal tract rapidly and accurately by an external magnetic field. The patch has excellent mucoadhesive properties even in a wet gastrointestinal environment. Since magnetic nanoparticles and doxorubicin are also loaded in the patch, it generates heat under an external alternating magnetic field and treats cancer cells through hyperthermia and drug release promotion.

Development and optimization of metoclopramide containing polymeric patches: impact of permeation enhancers

The study is aimed to develop a monolithic controlled matrix transdermal patches containing Metoclopramide as a model drug by solvent casting method. Eudragit L100, Polyvinylpyrrolidone K-30, and Methylcellulose were used in different ratios and Polyethylene glycol 400 added as a plasticizer. Resulting patches were evaluated for their physicochemical characters like organoleptic characters, weight variation, folding endurance, thickness, swelling index, flatness, drug content, swelling index, percentage erosion, moisture content, water vapor transmission rate and moisture uptake. Formed patches were also evaluated through Fourier transform spectroscopy (FT-IR), X-ray diffraction (XRD), Differential Scanning calorimetry (DSC) and Scanning Electron Microscopy (SEM). Results of SEM unveiled smooth surface of drug-loaded patches. In-vitro dissolution studies were conducted by using dissolution medium phosphate buffer saline pH 7.4. Effect of natural permeation enhancers was elucidated on two optimized formulations (Z4 and Z9). Different concentrations (5%-10 %) of permeation enhancers i.e. Olive oil, Castor oil and Eucalyptus oil were evaluated on Franz diffusion cell using excised abdominal rat skin. Z4-O2 (Olive oil 10%) had enhanced sustain effect and flux value (310.72) close to the desired flux value. Z4-O2 followed Higuchi release model (R2= 0.9833) with non-fickian diffusion release mechanism (n=0.612).

Design of dialdehyde cellulose crosslinked poly(vinyl alcohol) hydrogels for transdermal drug delivery and wound dressings.

2,3-Dialdehyde cellulose (DAC) was used as an efficient and low-toxicity crosslinker to prepare thin PVA/DAC hydrogel films designed for topical applications such as drug-loaded patches, wound dressings or cosmetic products. An optimization of hydrogel properties was achieved by the variation of two factors - the amount of crosslinker and the weight-average molecular weight (Mw) of the source PVA. The role of each factor to network parameters, mechanical, rheological and surface properties, hydrogel porosity and transdermal absorption is discussed. The best results were obtained for hydrogel films prepared using 0.25 wt% of DAC and PVA with Mw = 130 kDa, which had a high porosity and drug-loading capacity (high water content), mechanical properties allowing easy handling, best adherence to the skin from all tested samples and improved transdermal drug-delivery. Hydrogel films are biocompatible, show no cytotoxicity and have no negative impact on cell growth and morphology in their presence. Furthermore, hydrogels do not support cell migration and attachment to their surface, which should ensure easy removal of hydrogel patches even from wounded or damaged skin after use.

Flexible, sticky, and biodegradable wireless device for drug delivery to brain tumors

Implantation of biodegradable wafers near the brain surgery site to deliver anti-cancer agents which target residual tumor cells by bypassing the blood-brain barrier has been a promising method for brain tumor treatment. However, further improvement in the prognosis is still necessary. We herein present novel materials and device technologies for drug delivery to brain tumors, i.e., a flexible, sticky, and biodegradable drug-loaded patch integrated with wireless electronics for controlled intracranial drug delivery through mild-thermic actuation. The flexible and bifacially-designed sticky/hydrophobic device allows conformal adhesion on the brain surgery site and provides spatially-controlled and temporarily-extended drug delivery to brain tumors while minimizing unintended drug leakage to the cerebrospinal fluid. Biodegradation of the entire device minimizes potential neurological side-effects. Application of the device to the mouse model confirms tumor volume suppression and improved survival rate. Demonstration in a large animal model (canine model) exhibited its potential for human application.

Physicochemical and Drug Release Characterization of Lidocaine-Loaded Transdermal Patches Prepared from STR-5L Block Rubber

The aims of this study were to formulate 5% lidocaine-loaded transdermal patches using STR-5L block rubber as a main component of the patch base and to investigate their physicochemical characteristics, in vitro drug release, and stability. The results suggested that STR-5L block rubber could be feasibly used as a main component of the base of pharmaceutical transdermal patches with acceptable physicochemical properties. STR-5L block rubber patches containing lidocaine exhibited lower moisture absorption when compared with the blank counterparts because the drug molecules inserted between the polymer chains. Lidocaine still showed its own crystallinity characteristics after crushing and mixing in STR-5L block rubber patches. Additionally, no chemical interaction between the drug and polymer base was found. The drug-loaded patches could provide drug release with the best fitted to Higuchi square root of time. They had good stability during the studied period of 3 months when kept at 4 °C.

Characterization of Lidocaine Transdermal Patches from Natural Rubber Latex

The mucous liquid of Hevea brasiliensis or Para rubber tree, called natural rubber latex (NRL), composes of cis-1,4-polyisoprene which can form a patch under suitable formulation. In this study, blank and 5% lidocaine-loaded NRL patches were formulated and then characterized for physicochemical properties as well as evaluated in vitro drug release and stability. The patches were observed for their appearances. Surface morphology of the patches was investigated using a SEM. XRD was employed to study the crystallinity of the drug, the patch, and the drug-loaded patch. The extractions of lidocaine-loaded patches were analyzed for drug contents by HPLC. In vitro drug release study was performed using modified Franz diffusion cells. The patches at initial preparation and after kept at 4, 25, and 45 °C for 3 months were investigated for the stability determination. The results suggested that NRL could be used as a main component in pharmaceutical transdermal patches with acceptable physicochemical properties. Lidocaine-loaded NRL patches provided desirable drug release but high storage temperatures could age the patches resulting in darken color and lower release amount.

Modified TEWL in vitro measurements on transdermal patches with different additives with regard to water vapour permeability kinetics

Water vapour permeability (WVP) and water absorption capacity (WAC) influence physicochemical properties and wearability of transdermal patches considerably. For determination of WVP, a modified transepidermal water loss (TEWL) measurement was developed. These measurements continuously measure WVP of transdermal patches in vitro along with time required to reach steady state, and its magnitude according to the type of polymer used. Additionally, WAC of the patches was examined and related to WVP. According to literature in the field of WVP determination, usually selected points are taken from the evaporation time curve and averaged over a given time span without knowing whether steady state has already been reached or not. The latter causes errors upon averaging. The advantage of the in vitro TEWL measurement presented includes reproducibly adjustable conditions for every time span desired, thus providing information on the kinetics of the experiment and avoiding biased results from averaging. Knowing the shape of the evaporation time curve and thus the kinetics of the experiment allows for focusing on the relevant part of the measurement, i.e. the determination of the steady state level and the time to reach it. Four different polymers (P1-P4) based on sugar-modified polyacrylates were investigated with regard to WVP and WAC of the matrices prepared thereof along with the influence of drug loading and the incorporation of a variety of additives commonly used for transdermal patches. A clear correlation between WVP and the hydrophilicity in terms of the number of free hydroxyl groups of the polymer was elaborated. Additives of higher hydrophilicity compared to that of the polymer itself led to higher WVPs and vice versa. The combination of the model drug lidocaine in its free base form together with the additive succinic acid (Suc) resulted in ionization of the drug and thus in substantially increased WVPs. Addition of α-tocopherol acetate (Toc) into P3 and P4 and Suc into the drug-free matrix of P3 decreased WVP probably by affecting the structure of the polymer network. The same effects were found for WAC upon incorporation of succinic acid into drug-loaded matrices of P3 and P4 (drug-loaded patches of P1 and P2 were not tested) but not for additives which were likely to modify the polymer network structure.

Poly(hydroxyethyl methacrylate)-based co-polymeric hydrogels for transdermal delivery of salbutamol sulphate

Various co-polymeric hydrogels for transdermal delivery of salbutamol sulphate were synthesized using 2-hydroxyethyl methacrylate (HEMA), methacrylic acid (MAA) and N-[3-(dimethylamino)propyl]methacrylamide (DMAPMA) in the presence of ammonium persulphate (APS) and N,N,N′,N′-tetramethylethylenediamine (TEMED) as redox free radical initiator and ethyleneglycol dimethacrylate (EGDMA) as a cross-linker. The synthesized co-polymeric hydrogels were characterized using FT-IR spectral studies and swelling studies. It was observed that percentage swelling of co-polymeric hydrogel increased with the increasing concentration of DMAPMA and methacrylic acid. Salbutamol sulphate, a well-known vasodilator, was labeled with 99mTc(technetium) and loaded on circular discs of various hydrogels. In vitro permeation of radiolabelled salbutamol sulphate was carried out using a Franz diffusion cell in phosphate-buffered saline (PBS, pH 7.4) as dissolution medium through mice skin. It was observed that drug release from the co-polymeric hydrogel carriers increased on increasing the amount of DMAPMA in the polymeric carriers, while it decreased on increasing the amount of MAA content. The local toxicity studies of DMAPMA-containing hydrogel patches were carried out in rabbits. Drug-loaded patches applied on rabbit skin showed no toxicity, even after 1 week of studies.

Liquid scintillation spectrometry of 5-fluorouracil in cervical tissue following in vitro surface application of a bioadhesive cervical patch.

The potential use of bioadhesive technology for the treatment of cervical intraepithelial neoplasia was investigated. A cervical patch was designed containing 5-fluorouracil in a bioadhesive matrix and polyvinyl chloride as the backing layer. The concentration of 5-fluorouracil at specified tissue depths from the cervical surface was determined in vitro in relation to the ability of the drug to reach precancerous foci in cervical crypts up to 4 mm below the tissue surface. Thus, tissue was exposed to drug-loaded patches spiked with 5-fluorouracil-6-3H and subsequently sectioned to obtain tissue slices at different depths. The concentration of 5-fluorouracil was determined by liquid scintillation spectrometry. Drug penetration into cervical tissue exceeded a depth of 5.5 mm. Furthermore, the concentration in the tissue depended on the drug loading in the patch. Patches containing 10 and 20 mg of 5-fluorouracil produced a linear drug gradient that was established after a 4 hour application of the patch and persisted over 24 hours. However, patches containing 3.5 mg of 5-fluorouracil displayed signs of drug exhaustion after 24 hours. The penetration characteristics of 5-fluorouracil through cervical tissue using the cervical patch delivery system were sufficiently favourable to warrant further clinical investigations.