Skin permeation of buflomedil form adhesive matrix patches

The main objective of this research work was to fabricate and evaluate adhesive matrix-type transdermal patches of buflomedil hydrochloride, employing different ratios of pressure sensitive adhesives (PSAs) by solvent casting technique. The adhesive matrix-type transdermal patches were evaluated by their in vitro physicochemical properties such as thickness, moisture content, weight variation, drug content uniformity, etc. The effects of PSAs ratio, drug loading, and concentration of permeation enhancer were evaluated thoroughly. Ex vivo skin permeation studies with kinetic modeling of adhesive matrix patches were systematically evaluated. Based on the above observations, the best optimized buflomedil hydrochloride-loaded adhesive matrix-type transdermal patch was further characterized by scanning electron microscopy, Fourier transform infrared spectroscopy, X-ray diffraction study, and differential scanning calorimetry analyses. Drug containing adhesive matrix patches showed sustained release property without showing any incompatibility in adhesive matrix system. Hence, adhesive matrix-type transdermal patches of buflomedil hydrochloride can be used as a potential carrier for sustained transdermal delivery of hydrophilic drugs like buflomedil hydrochloride.     

Evaluation of the Structural Modification of Ibuprofen on the Penetration Release of Ibuprofen from a Drug-in-Adhesive Matrix Type Transdermal Patch

This study aimed to evaluate the effect of chemical modifications of the structure of active compounds on the skin permeation and accumulation of ibuprofen [IBU] from the acrylic pressure-sensitive adhesive used as a drug-in-adhesives matrix type transdermal patch. The active substances tested were ibuprofen salts obtained by pairing the ibuprofen anion with organic cations, such as amino acid isopropyl esters. The structural modification of ibuprofen tested were Ibuprofen sodium salt, [GlyOiPr][IBU], [AlaOiPr][IBU], [ValOiPr][IBU], [SerOiPr][IBU], [ThrOiPr][IBU], [(AspOiPr)₂][IBU], [LysOiPr][IBU], [LysOiPr][IBU]₂, [PheOiPr][IBU], and [ProOiPr][IBU]. For comparison, the penetration of unmodified ibuprofen and commercially available patches was also investigated. Thus, twelve transdermal patches with new drug modifications have been developed whose adhesive carrier is an acrylate copolymer. The obtained patches were characterized for their adhesive properties and tested for permeability of the active substance. Our results show that the obtained ibuprofen patches demonstrate similar permeability to commercial patches compared to those with structural modifications of ibuprofen. However, these modified patches show an increased drug permeability of 2.3 to even 6.4 times greater than unmodified ibuprofen. Increasing the permeability of the active substance and properties such as adhesion, cohesion, and tack make the obtained patches an excellent alternative to commercial patches containing ibuprofen.     

Controlled Transdermal Iontophoresis of Insulin from Water-Soluble Polypyrrole Nanoparticles: An In Vitro Study

The iontophoresis delivery of insulin (INS) remains a serious challenge due to the low permeability of the drug through the skin. This work aims to investigate the potential of water-soluble polypyrrole nanoparticles (WS-PPyNPs) as a drug donor matrix for controlled transdermal iontophoresis of INS. WS-PPyNPs have been prepared via a simple chemical polymerization in the presence of sodium dodecyl sulfate (SDS) as both dopant and the stabilizing agent. The synthesis of the soluble polymer was characterized using field emission scanning electron microscopy (FESEM), dynamic light scattering (DLS), fluorescence spectroscopy, and Fourier transform infrared (FT–IR) spectroscopy. The loading mechanism of INS onto the WS-PPyNPs is based on the fact that the drug molecules can be replaced with doped dodecyl sulfate. A two-compartment Franz-type diffusion cell was employed to study the effect of current density, formulation pH, INS concentration, and sodium chloride concentration on anodal iontophoresis (AIP) and cathodal iontophoresis (CIP) of INS across the rat skin. Both AIP and CIP delivery of INS using WS-PPyNPs were significantly increased compared to passive delivery. Furthermore, while the AIP experiment (60 min at 0.13 mA cm^–2) show low cumulative drug permeation for INS (about 20.48 µg cm⁻²); the CIP stimulation exhibited a cumulative drug permeation of 68.29 µg cm⁻². This improvement is due to the separation of positively charged WS-PPyNPs and negatively charged INS that has occurred in the presence of cathodal stimulation. The obtained results confirm the potential applicability of WS-PPyNPs as an effective approach in the development of controlled transdermal iontophoresis of INS.     

Sustainable UV-Crosslinkable Acrylic Pressure-Sensitive Adhesives for Medical Application

This study aimed to investigate the potential of photoreactive acrylate patches as systems for transdermal drug delivery, in particular, using more renewable alternatives and more environmentally friendly synthesis routes of transdermal patches. Therefore, the aim of this study was to develop a transdermal patch containing ibuprofen and investigate its performance in vitro through the pigskin. Transparent patches were prepared using four acrylate copolymers with an incorporated photoinitiator. Two types of transdermal patches based on the photocrosslinking acrylic prepolymers with isobornyl methacrylate as biocomponent and monomer increasing Tg (“hard”) were manufactured. The obtained patches were characterized for their adhesive properties and tested for permeability of the active substance. It turns out that patches whose adhesive matrix is photoreactive polyacrylate copolymers have a higher cohesion than patches from commercial adhesives, while the modification of the copolymers with isobornyl methacrylate resulted in an improvement in adhesion and tack. This study demonstrates the feasibility of developing photoreactive acrylic-based transdermal patches that contain biocomponents that can deliver a therapeutically relevant dose of ibuprofen.     

Elasticity Determination of Adhesive Patches With Filler Inclusion

Patches can be used for topical and transdermal drug delivery as well as for cosmetic purposes. Their mechanical properties (i.e. strength, brittleness, elasticity, etc.) are important features that can influence their therapeutic success. Most of the drug-in-adhesive (DIA) patches adhere well to the skin or other surfaces. However, their degree of elasticity cannot be accurately determined since during the compression–decompression cycle(s), the patches adhere to the moving plate (and sensor), resulting in under the x-axis forces (and “negative” areas in the stress–strain curves). We overcame this limitation using two different approaches: gluing thin non-adhesive plates to both sides of the patch or applying talc granules to both surfaces. These treatments rendered the patch surfaces non-adhesive, thereby eliminating the “negative” force (and area) and permitting testing of adhesive materials as well as determination of their degree of elasticity. The general level of calculated recoverable work was ～60–80% of the total work for the patches, i.e., they can be considered elastic entities. When the strain rate was 100 mm/s, the calculated recoverable work “jumped” to ～92% and changed in a significant manner. Inclusion of fillers (corn or potato starch) in the patch reduced the percent recoverable work and degree of elasticity. For the first compression–decompression cycle, there was an increase in the degree of elasticity of the compressed–decompressed patches; while in the third and fourth cycles, there were no statistical differences in the extents of percent recoverable work. Recoverable work vs cycle number was almost a mirror image of total work.     

Characterization, in vitro release and permeation studies of nicotine transdermal patches prepared from deproteinized natural rubber latex blends

The nicotine transdermal patches (NTPs) are available used for smoking cessation; however, they still should be developed for high efficacy and low cost. In this study, deproteinized natural rubber latex (DNRL) blended with hydroxypropylmethyl cellulose (HPMC) and dibutylphthalate (DBP) were used as matrix membrane for nicotine (NCT) delivery. Several techniques, i.e., FT-IR, XRD, DSC, and SEM were used to characterize the compatibility of each ingredient in the blended patches. A backing layer was used to protect NCT from volatilization. Five different types of backing layer were evaluated for their effects on in vitro release and skin permeation of NCT from the formulated matrix membranes. The backing layer with highest moisture vapor transmission rate (MVTR) and lowest oxygen transmission (OT) supposed to give higher NCT release and skin permeation due to increasing of skin hydration and its occlusive effect. The kinetic of in vitro release and permeation was demonstrated the monophasic slow release pattern which confirmed by first order and zero order kinetics, respectively. Therefore, the backing layer could be appropriated and used conveniently in the preparation of NTPs.     

Proliposomes of lisinopril dihydrate for transdermal delivery: Formulation aspects and evaluation

We formulated and evaluated proliposomal gel of relatively low bioavailable drug lisinopril dihydrate (LDH) for transdermal delivery. Several proliposomal gel formulations of lisinopril dihydrate were prepared by modified coacervation phase separation method and examined for formation of liposomes by optical microscope and characterized by transmission electron microscopy. The formulations were evaluated for size, zeta potential, entrapment efficiency, rheological behavior, ex vivo drug permeation, skin irritation and stability. Differential scanning calorimetry (DSC) and Fourier transform infrared (FTIR) studies were performed to understand the phase transition behavior and mechanism for skin permeation, respectively. The microscopic examination revealed the formation of liposomes from proliposomal gel, and the size of the vesicles was found to be in the range of 385 nm to 635 nm. Entrapment efficiency was high for the formulation containing greater amounts of phosphatidylcholine. The DSC studies indicated the amorphous form of LDH in proliposomal gel formulation. Ex vivo permeation studies revealed sustained permeation of drug from proliposomal gels studied. The stability studies reveal that the proliposomal formulations are more stable when stored at refrigeration temperature (4 °C). In conclusion, proliposomal gels offer potential and prove to be efficient carriers for improved and sustained transdermal delivery of lisinopril dihydrate.     

Ceramide-based nanostructured lipid carriers for transdermal delivery of isoliquiritigenin: Development,physicochemical characterization,and <Emphasis Type="Italic">in vitro</Emphasis> skin permeation studies

An optimized, ceramide-based, nanostructured lipid carrier (NLC) formulation was developed for isoliquiritigenin (ILTG), and its potential as a transdermal delivery system was evaluated. ILTG-loaded NLCs were prepared by blending solid (ceramide, cholesterol) and liquid lipids (caprylic/capric triglyceride) in various proportions using a hot homogenization and ultrasonication method. The physicochemical characteristics were investigated by DLS, ZP, EE%, TEM, DSC and XRD analyses and in vitro skin permeation studies. The results showed that the particle size of the formulation was 150.19–251.69 nm with a ZP>?20mV. The EE% was 56.45–89.97%. The NLC structure was influenced by lipid ratio, and increasing the caprylic/capric triglyceride ratio caused a less ordered structure, as confirmed by DSC. The XRD analysis indicated that ILTG was not in the crystalline state in all formulations. The skin permeation study showed that the ILTG-NLCs promoted ILTG permeation. In conclusion, ceramide-based NLCs could be a promising vehicle for the ILTG transdermal delivery of ILTG.     

Preparation of macroporous chitosan patch using co-solvent as a transdermal drug-delivery system

As a simple method, bio-patches of band type have been widely used in various medical areas for more than 70 years. Despite their numerous advantages, drawbacks such as a lack of adhesive strength and low efficiency of transdermal drug delivery have limited their application. To improve the convenience of use, a 3D porous chitosan patch was prepared simply by phase separation of a solvent (acidic water)/co-solvent [dimethyl carbonate (DMC)]. As a tackifìer of low cytotoxicity, allyl 2-cyanoacrylate bio-glue was prepolymerized and coated onto the porous chitosan patch. Various properties were examined, such as mechanical strength, efficiency of drug-delivery, morphology, cytotoxicity and degradability. We ascertained that the optimal ratio of co-solvent for achieving a highly porous chitosan patch was DMC at a ratio of 5 %. The resultant drug release by the optimal highly porous chitosan patch was approximately twofold faster than that of the untreated control. The porous patch showed improved efficiency of cell adhesion after culturing in cells for 4 h. After 72 h, the cultured cells showed increased cell proliferation on the porous patches. These results strongly suggest that the chitosan-based porous patches covered with modified cyanoacrylate can be widely used as good adhesive patches in various incidents.     

Refining natural rubber matrix for electrically stimulated transdermal drug delivery

This work focuses on the enhancement of transdermal delivery of indomethacin (IN) from natural rubber matrix by deproteinization, the addition of ethylene glycol (EG) as a plasticizer, and the enlarged matrix size under electrical field. The starting double-centrifuge natural rubber (DCNR) was deproteinized to produce the deproteinized natural rubber (DPNR). Both DCNR and DPNR patches were fabricated by the UV curing method, and blended with EG to enhance the IN loading and release–permeation. Using a pig skin to simulate the human skin, the IN release–permeation was found to increase with increasing plasticizer, removed protein, and applied electrical potential.     

Hybrid transdermal drug delivery patch made from poly(p‐phenylene vinylene)/natural rubber latex and controlled by an electric field

A flexible, natural rubber (NR) patch was developed for electrically controllable transdermal drug delivery. NR latex was crosslinked at various crosslinking ratios under the UV curing method. Ibuprofen (Ibu) was the model drug and was used as the dopant for poly(p‐phenylene vinylene) (PPV) acting as the drug encapsulating host. For the pristine Ibu‐loaded NR patch, the amount of Ibu permeation increased with decreasing crosslink density and increasing electrical potential. For the Ibu‐doped PPV/NR patch, the amount of Ibu release?permeation also increased with increasing electrical potential and was higher than that of the pristine NR matrices. Without an applied electric field, the drug remained attached to the PPV during an initial period of 6 h. Under an applied electric field, the oxidation state of the conductive polymer was altered, the iontophoretic effect, pore formation in the NR matrix, expansion of the pore size in hair follicles and PPV chain expansion combined to increase the Ibu release?permeation amount. Thus, the flexible PPV/NR transdermal drug delivery patch was demonstrated to be effective in drug release?permeation based on the strength of the electrical potential, the crosslinking density and the presence of PPV as the encapsulation host. © 2018 Society of Chemical Industry     

桉叶油微乳用于经皮给药的研究与评价

研究与评价了桉叶油作为油相在经皮给药微乳中的有效性。试验以非洛地平作为模型药物。分别以油酸、肉豆蔻酸异丙酯（IPM）和桉叶油为油相制备了9个水包油微乳处方,通过测定各处方物理化学参数和大鼠体外透皮试验研究,通过对比载药量、透皮速率、滞后时间等参数,得到最适宜的处方：w(桉叶油)为5%,、w(吐温-80)为27.5%、w(乙醇)为27.5%和w(水)为40%。最后对该处方进行了兔子在体皮肤刺激性研究。结果表明桉叶油有着显著的优点：乳化能力强、对亲脂药物溶解度大、透皮促进效果明显、稳定性好。但是桉叶油也有一定皮肤刺激性,不宜用量过大。     

Fabrication and Characterization of Matrix-Type Transdermal Patches Loaded with Ramipril and Repaglinide Through Cellulose-based Hydrophilic and Hydrophobic Polymers: In Vitro and Ex Vivo Permeation Studies

Transdermal patches loaded with ramipril and repaglinide were prepared with the ambition to develop matrix-type transdermal drug delivery system for enhanced permeability and hence improved bioavailability. Different formulations were designed by intermittent concentrations of hydroxypropyl methylcellulose K4M as hydrophilic polymer and ethyl cellulose as hydrophobic polymer. Solvent casting method was used for the fabrication of transdermal patches. Oleic acid and propylene glycol were used to enhance permeability along with polyethylene glycol 400 as plasticizer. Newly designed patches were then evaluated for various physicochemical and mechanical properties. Compatibility studies were performed by Fourier transformed infrared spectroscopy which did not reveal any interaction between drug and polymers. Crystalline nature of drugs was confirmed when they were subjected to X-ray diffraction study and surface morphological studies using scanning electron microscopy. Transdermal patches were of good mechanical strength with folding endurance of more than 300-fold and 100% flatness. Percent drug contents of ramipril and repaglinide ranged from 90 to 105%, i.e., analogous to official limits. In vitro and ex vivo permeation studies were executed using franz diffusion cell. The cumulative amount of drug permeated through skin was 55.22–112.72% for repaglinide and 73.14–91.46% for ramipril. The release behavior of the permeated drug was analyzed by the application of model-dependent approaches. The results showed that Korsmeyer–Peppas model was found to be dominating in most of the formulations and drugs followed diffusion mechanism. It could be concluded that hydroxypropyl methylcellulose K4M and ethyl cellulose has great potential for ramipril and repaglinide as a vector for transdermal drug delivery effectively because of the formation of smooth surfaces of patches, high folding endurance, and entrapment efficiency with the ability to release the drugs in sustained manner.     

Deproteinised natural rubber used as a controlling layer membrane in reservoir-type nicotine transdermal patches

Reservoir-type nicotine transdermal patches (NTPs), composed of a concentrated nicotine solution embedded between a backing layer and a controlling layer membrane, were constructed by a heat-sealing technique. The aim of this research was the preparation of a novel controlling layer membrane from deproteinised natural rubber latex (DNRL). The ultimate tensile strength and percentage of elongation at breakage of the DNRL membrane were 0.23 ± 0.04 MPa and 604.46 ± 95.38%, respectively. The DNRL membrane existed as an amorphous phase and was poorly hygroscopic and dense. FT-IR and DSC analysis demonstrated that the membrane consisted almost entirely of isoprene functional groups with a T_g of −64.79 °C. The effects of the DNRL membrane thickness (100–300 μm) and different nicotine concentrations in the reservoir (1.75–4.25 mg/cm²) on the nicotine release rate and nicotine permeation through a pig skin membrane were studied in vitro. The in vitro nicotine release rate and skin permeation rate increased with decreasing membrane thickness and increasing nicotine content in the reservoir. The release and permeation profiles followed first- and zero-order kinetics, respectively. The release and permeation performance was similar to a commercially available Nicotinell TTS-20 patch. The newly developed NTPs were stable under storage in a tightly sealed container at 4 °C or at ambient temperature for up to 3 months. Thus, DNRL is suitable for use as a controlling layer membrane in NTPs in transdermal drug delivery systems.     

Enhanced transdermal deposition and characterization of quercetin-loaded ethosomes

We sought to evaluate the transdermal permeation potential of quercetin-loaded ethosomes. Quercetinloaded ethosomes were prepared and characterized with regard to particle size, loading efficiency, stability, and in vitro skin permeation. The optimized formulation of ethosomes was confirmed using 2% egg phosphatidylcholine and hydrated 20% ethanol. After quercetin was applied using this formulation, the stability of the ethosomes was determined when loaded with up to 0.04% quercetin. We observed that loading efficiency was improved with increasing concentrations of quercetin. Ethosomes loaded with 0.04% quercetin showed both the greatest loading efficiency (63.9%±6.0%) and an optimal size range (132±32 nm). Ethosomes loaded with quercetin were superior in skin permeation ability (29.5±7.0 μg/cm²) compared to either ethanolic solution or liposomes. Therefore, we concluded that quercetin-loaded ethosomes increased the skin delivery of quercetin. Our results suggest that quercetin-loaded ethosomes may enhance the effect of cosmetic materials.     

The Emerging Role of Ionic Liquid-Based Approaches for Enhanced Skin Permeation of Bioactive Molecules: A Snapshot of the Past Couple of Years

Topical and transdermal delivery systems are of undeniable significance and ubiquity in healthcare, to facilitate the delivery of active pharmaceutical ingredients, respectively, onto or across the skin to enter systemic circulation. From ancient ointments and potions to modern micro/nanotechnological devices, a variety of approaches has been explored over the ages to improve the skin permeation of diverse medicines and cosmetics. Amongst the latest investigational dermal permeation enhancers, ionic liquids have been gaining momentum, and recent years have been prolific in this regard. As such, this review offers an outline of current methods for enhancing percutaneous permeation, highlighting selected reports where ionic liquid-based approaches have been investigated for this purpose. Future perspectives on use of ionic liquids for topical delivery of bioactive peptides are also presented.     

Methoxy poly(ethylene glycol)‐block‐poly(D,L‐lactic acid) copolymer nanoparticles as carriers for transdermal drug delivery

This work evaluates the transdermal drug delivery properties of amphiphilic copolymer self‐assembled nanoparticles by skin penetration experiments in vitro. Paclitaxel‐loaded methoxy poly(ethylene glycol)‐block‐poly(D ,L ‐lactic acid) diblock copolymer nanoparticles (PNPs) were prepared by a solid dispersion technique and were applied to the surface of excised full‐thickness rat skin in Franz diffusion cells. HPLC, transmission electron microscopy, Fourier transform infrared spectroscopy and ¹H NMR were used to assay the receptor fluid. The results show that the amphiphilic copolymer nanoparticles with the entrapped paclitaxel are able to penetrate rat skin. Ethanol can improve the delivery of PNPs and increase the cumulative amount of paclitaxel in the receptor fluid by 3 times. Fluorescence microscopy measurements indicate that the PNPs can penetrate the skin not only via appendage routes including sweat ducts and hair follicles but also via epidermal routes. Copyright © 2007 Society of Chemical Industry     

明胶作为左旋肉碱贴膏剂载体的体外经皮渗透性评价

探讨左旋肉碱贴膏剂与微针经皮给药系统联合使用后对其经皮渗透性的影响。以卡波姆及明胶作为贴膏剂的主要基质,选择改良的Franze扩散池,采用针高150μm的实心硅微针作用于猪耳朵皮肤进行体外经皮渗透性评价,以体外经皮渗透性及制剂外观作为评价指标,优化贴膏剂处方,并与市售的左旋肉碱外用制剂进行渗透性比较。结果表明:贴膏剂基质处方中明胶-PVP K30-卡波姆-甘油-尼泊金甲酯以4:3:0.5:3:0.1的比例为最佳用量配比。该贴膏剂经微针作用后皮肤的累积透过量高于市售制剂及卡波姆水凝胶制剂。因此,以明胶为主要基质的贴膏剂可显著提高左旋肉碱的微针经皮渗透性且具有给药准确便捷的特点。     

Elastic and Ultradeformable Liposomes for Transdermal Delivery of Active Pharmaceutical Ingredients (APIs)

Administration of active pharmaceutical ingredients (APIs) through the skin, by means of topical drug delivery systems, is an advanced therapeutic approach. As the skin is the largest organ of the human body, primarily acting as a natural protective barrier against permeation of xenobiotics, specific strategies to overcome this barrier are needed. Liposomes are nanometric-sized delivery systems composed of phospholipids, which are key components of cell membranes, making liposomes well tolerated and devoid of toxicity. As their lipid compositions are similar to those of the skin, liposomes are used as topical, dermal, and transdermal delivery systems. However, permeation of the first generation of liposomes through the skin posed some limitations; thus, a second generation of liposomes has emerged, overcoming permeability problems. Various mechanisms of permeation/penetration of elastic/ultra-deformable liposomes into the skin have been proposed; however, debate continues on their extent/mechanisms of permeation/penetration. In vivo bioavailability of an API administered in the form of ultra-deformable liposomes is similar to the bioavailability achieved when the same API is administered in the form of a solution by subcutaneous or epi-cutaneous injection, which demonstrates their applicability in transdermal drug delivery.     

Influence of a pore-forming agent on swelling,network parameters,and permeability of poly(ethylene glycol)-crosslinked poly(methyl vinyl ether-co-maleic acid) hydrogels: Application in transdermal delivery systems

We characterized hydrogels, prepared from aqueous blends of poly(methyl vinyl ether-co-maleic acid) (PMVE/MA) and poly(ethylene glycol) (PEG 10,000 Daltons) containing a pore-forming agent (sodium bicarbonate, NaHCO₃). Increase in NaHCO₃ content increased the equilibrium water content (EWC) and average molecular weight between crosslinks (M_c) of hydrogels. For example, the %EWC was 731, 860, 1109, and 7536% and the M_c was 8.26, 31.64, 30.04, and 3010.00 × 10⁵ g/mol for hydrogels prepared from aqueous blends containing 0, 1, 2, and 5% w/w of NaHCO₃, respectively. Increase in NaHCO₃ content also resulted in increased permeation of insulin. After 24 h, percentage permeation was 0.94, 3.68, and 25.71% across hydrogel membranes prepared from aqueous blends containing 0, 2, and 5% w/w of NaHCO₃, respectively. Hydrogels containing the pore-forming agent were fabricated into microneedles (MNs) for transdermal drug delivery applications by integrating the MNs with insulin-loaded patches. It was observed that the mean amount of insulin permeating across neonatal porcine skin in vitro was 20.62% and 52.48% from hydrogel MNs prepared from aqueous blends containing 0 and 5% w/w of NaHCO₃. We believe that these pore-forming hydrogels are likely to prove extremely useful for applications in transdermal drug delivery of biomolecules. © 2012 Wiley Periodicals, Inc. J Appl Polym Sci, 2012