Transdermal Delivery Of Hydrophilic Drugs Research Articles

Multifunctional Ionic Hydrogel-Based Transdermal Delivery of 5-Fluorouracil for the Breast Cancer Treatment.

Transdermal drug delivery systems (TDDS) are a promising and innovative approach for breast cancer treatment, offering advantages such as noninvasiveness, potential for localized and prolonged drug delivery while minimizing systemic side effects through avoiding first-pass metabolism. Utilizing the distinctive characteristics of hydrogels, such as their biocompatibility, versatility, and higher drug loading capabilities, in the present work, we prepared ionic hydrogels through synergistic interaction between ionic liquids (ILs), choline alanine ([Cho][Ala]), and choline proline ([Cho][Pro]) with oleic acid (OA). ILs used in the study are biocompatible and enhance the solubility of 5-fluorouracil (5-FU), whereas OA is a known chemical penetration enhancer. The concentration-dependent (OA) change in morphological aggregates, that is, from cylindrical micelles to worm-like micelles to hydrogels was formed with both ILs and was characterized by SANS measurement, whereas the interactions involved were confirmed by FTIR spectroscopy. The hydrogels have excellent mechanical properties, which studied by rheology and their morphology through FE-SEM analysis. The in vitro skin permeation study revealed that both hydrogels penetrated 255 times ([Cho][Ala]) and 250 times ([Cho][Pro]) more as compared to PBS after 48 h. Those ionic hydrogels exhibited the capability to change the lipid and keratin arrangements within the skin layer, thereby enhancing the transdermal permeation of the 5-FU. Both ionic hydrogels exhibit excellent biocompatibility with normal cell lines (L-132 cells) as well as cancerous cell lines (MCF-7 cells), demonstrating over 92% cell viability after 48 h in both cell lines. In vitro, the cytotoxicity of the 5-FU-loaded hydrogels was evaluated on MCF-7 and HeLa cell lines. These results indicate that the investigated biocompatible and nontoxic ionic hydrogels enable the transdermal delivery of hydrophilic drugs, making them a viable option for effectively treating breast cancer.

Terpene-augmented novasomal gels for the sustainment of rasagiline mesylate delivery; A new approach for treating Parkinson's disease induced by rotenone in rats

Rasagiline mesylate (RSM) is a potent anti-Parkinson's Disease (PD) drug; nevertheless, it has limited oral bioavailability due to hepatic first pass metabolism. RSM is a highly hydrophilic drug hurdled by several barriers to reach the central nervous system (CNS). This study aimed to prepare RSM-loaded novasomal gels for the transdermal delivery of the drug to CNS. Novasomes were prepared by ethanol injection method using terpenes as penetration enhancers. Design Expert® software was applied to select the optimum formulation by varying the type of terpene, amount of cholesterol, besides surface active agents (SAA): free fatty acid (FFA) ratio. The desirability calculations revealed that the optimum formulation composed of cholesterol (60 mg), SAA:FFA ratio (1:1) in the presence of eugenol. Particle size, zeta potential and entrapment efficiency of the optimum formulation were 265.90 ± 2.40 nm, −33.45 ± 0.49 mV and 83.09 ± 0.42%, respectively. TEM showed spherical well-defined nanovesicles. The optimum novasomal formulation was incorporated into gel system composed of 2% HPMC and 2% CMC. In vivo study revealed the feasibility of reversing PD symptoms regarding the behavioral, biochemical and histopathological analyses in rotenone-induced Parkinsons' rat model. A marked elevation in the number of crossovers, grooming score, frequency of rearing, gripe strength, and dopamine level besides a reduction in interleukin-17 and NLRP-3 inflammasome level when compared to positive control group were detected. No histopathological alterations were detected in examined brain sections of treated rats. In conclusion, the obtained results suggest that RSM-loaded novasomal gel formulations are promising carriers for the transdermal delivery of hydrophilic drugs like RSM.

An Ultraswelling Microneedle Device for Facile and Efficient Drug Loading and Transdermal Delivery.

The advancement and extensive demand for transdermal therapies can benefit from a safe, and efficient and user-friendly transdermal technology with broad applicability in delivering various hydrophilic drugs. Here the design and proof of concept applications of an ultraswelling microneedle device that enables the facile and efficient loading and transdermal delivery of hydrophilic drugs with different molecular weights is reported. The device consists of a super-hydrophilic hydrogel microneedle array and a resin base substrate. Using a special micromolding technique that involves hydrated crosslinking and cryogenic-demolding, the microneedle part displays a rapid swelling ratio of ≈3800%, enabling the loading of drugs up to 500kDa in molecular weight. The drug loading process using the device just involves incubating the microneedle part in a drug solution for 1min, followed by 15min of drying. The microneedles can easily penetrate the skin under press and detach from the base substrate under shear, thereby releasing the payload. Administration of desired therapeutic agents using the device outperformed conventional administration methods in mitigating psoriasis and eliciting immunity. This biocompatible device, capable of withstanding ethylene oxide sterilization, can enhance the efficacy and accessibility of transdermal therapies in research institutes, hospitals, and even home settings.

Transformation of Hydrophilic Drug into Oil-Miscible Ionic Liquids for Transdermal Drug Delivery.

The transdermal delivery of hydrophilic drugs remains challenging owing to their poor ability to permeate the skin; formulation with oil media is difficult without adding chemical permeation enhancers or co-solvents. Herein, we synthesized 12 oil-miscible ionic liquid (IL) drugs comprising lidocaine-, imipramine-, and levamisole (Lev)-hydrochloride with fatty acid permeation enhancers, i.e., laurate, oleate, linoleate, and stearate as counterions. A set of in vitro and in vivo studies was performed to investigate the potency and deliverability of the transdermal drug formulations. All of the synthesized compounds were freely miscible with pharmaceutically acceptable solvents/agents (i.e., ethanol, N-methyl pyrrolidone, Tween 20, and isopropyl myristate (IPM)). In vitro permeation studies revealed that the oleate-based Lev formulation had 2.6-fold higher skin permeation capability than the Lev salts and also superior ability compared with the laurate-, linoleate-, and stearate-containing samples. Upon in vivo transdermal administration to mice, the peak plasma concentration, elimination half-life, and area under the plasma concentration curve values of Lev-IL were 4.6-, 2.9-, and 5.4-fold higher, respectively, than those of the Lev salt. Furthermore, in vitro skin irritation and in vivo histological studies have demonstrated that Lev-IL has excellent biocompatibility compared with a conventional ionic liquid-based carrier. The results indicate that oil-miscible IL-based drugs provide a simple and scalable strategy for the design of effective transdermal drug delivery systems.

Laser facilitates week-long sustained transdermal drug delivery at high doses

Traditional patches are most successful in transdermal delivery of low-dose hydrophobic drugs. Week-long transdermal delivery of high-dose hydrophilic drugs remains a big challenge. This study explored ablative fractional laser (AFL) to assist 3-day to week-long sustained transdermal delivery of powder hydrophilic drugs in murine models. Bulk drug powder was coated into reservoir patches followed by topical application onto AFL-treated skin. Water evaporated from AFL-generated skin microchannels (MCs) gradually dissolve topical drug powder to elicit multi-day sustained drug delivery. Using sulforhodamine b, zidovudine, and bovine serum albumin as model hydrophilic drugs, we found tapped coating could coat 10–20 mg drug per 0.5 cm2 reservoir patch to elicit 3-day sustained delivery, while compression coating could coat ~35–70 mg drug per 0.5 cm2 reservoir patch to elicit week-long sustained delivery. Besides sustained drug delivery, AFL-assisted powder reservoir patch delivery showed a good safety. AFL-generated skin MCs resealed in 1–2 days and completely recovered in 3 days after the week-long sustained delivery. AFL-assisted powder reservoir patch delivery involves no complex powder formulation and only requires incorporation of highly water-soluble mannitol or a similar excipient to elicit the high-efficient delivery. Enlarging reservoir patch size to 10 cm2 can conveniently expand the delivery capacity to gram scale. To our knowledge, this is the first time that high-dose week-long sustained transdermal delivery of hydrophilic drugs was achieved via a simple laser-based powder delivery platform.

Hot-melt pressure-sensitive adhesives based on SIS-g-PB copolymer for transdermal delivery of hydrophilic drugs

SIS-g-PB copolymers were successfully synthesized by grafting living polybutadiene (PB) lithium macroanions onto epoxidized SIS copolymers. Their molecular structures and thermal properties were characterized by TGA, 1H-NMR and DSC, respectively. SIS, epoxidized SIS (ESIS) and SIS-g-PB copolymers were melt-blended with tackifiers to develop hot-melt pressure-sensitive adhesives (HMPSAs), respectively (named of H-SIS, H-ESIS and H-SIS-g-PB). Their adhesive performances were measured in terms of 180° peel strength and holding power. A modified Franz type horizontal diffusion cell was used to carry out In vitro drug release experiments, in which geniposides were chosen as hydrophilic model drugs. The results showed that H-SIS-g-PB has two times as high a 180° peel strength as H-SIS. Meanwhile H-SIS-g-PB has a slightly lower drug cumulative release rate than H-ESIS. It is indicated that the PB branches not only could impart good adhesive performance to H-SIS-g-PB via improving the compatibility between the epoxidized main chains and tackifier resins but also provide release channels to hydrophilic drugs by retaining most of the epoxide groups in the SIS-g-PB copolymers.

Microemulsions as Platforms for Transdermal Delivery of Hydrophilic Drugs - A Review

Background: Delivery rates in cutaneous applications are limited by the skin barrier and also by the physical-chemical properties of the drug in the formulation. A lipophilic drug has more affinity, and can permeate the epidermis more easily than a hydrophilic drug. The potential use of nano-sized dispersions as distribution systems for hydrophilic drugs is being investigated. Objective: To analyze the literature with regard to the development of microemulsions (ME) for transdermal delivery of hydrophilic drugs, with a view to identifying strategies to increase the permeation of these drugs. Results: One hundred and eleven articles were potentially relevant to the combination of search criteria. After excluding duplicated articles, the abstracts of 83 articles were read. Of these, 73 did not meet the inclusion criteria. To complete the review process, the whole text of 10 articles was evaluated. Conclusion: The main factors that positively influenced the permeation of hydrophilic drugs were low hydrophilic-lipophilic balance (HLB) values of the surfactant; concentrations of about 40% of surfactants and 30% of aqueous phase for the water-in-oil (W/O) systems; the addition of permeation promoters to the systems; and the association of physical methods during the application of the ME. The results offered support for the development of new topical microemulsions for hydrophilic drug delivery.

Sustained epidermal powder drug delivery via skin microchannels

Transdermal delivery of hydrophilic drugs is challenging. This study presents a novel sustained epidermal powder delivery technology (sEPD) for safe, efficient, and sustained delivery of hydrophilic drugs across the skin. sEPD is based on coating powder drugs into high-aspect-ratio, micro-coating channels (MCCs) followed by topical application of powder drug-coated array patches onto ablative fractional laser-generated skin MCs to deliver drugs into the skin. We found sEPD could efficiently deliver chemical drugs without excipients and biologics drugs in the presence of sugar excipients into the skin with a duration of ~12h. Interestingly the sEPD significantly improved zidovudine bioavailability by ~100% as compared to oral gavage delivery. sEPD of insulin was found to maintain blood glucose levels in normal range for at least 6h in chemical-induced diabetes mice, while subcutaneous injection failed to maintain blood glucose levels in normal range. sEPD of anti-programmed death-1 antibody showed more potent anti-tumor efficacy than intraperitoneal injection in B16F10 melanoma models. Tiny skin MCs and ‘bulk’ drug powder inside relatively deep MCCs are crucial to induce the sustained drug release. The improved bioavailability and functionality warrants further development of the novel sEPD for clinical use.

SISO-based hot-melt pressure-sensitive adhesives for transdermal delivery of hydrophilic drugs

A monomer-activated anionic polymerization approach was utilized to synthesize poly(styrene-b-isoprene-b-styrene-b-ethylene oxide) tetrablock terpolymers (SISO), which were melt-mixed with tackifiers and plasticizer to develop polar SISO-based hot-melt pressure-sensitive adhesives (HMPSAs) for transdermal delivery of hydrophilic drugs. Their hydrophilic performance was characterized using contact angle analysis. Their adhesive performances were measured in terms of 180° peel strength and holding power. In vitro drug release experiments were carried out using a modified Franz type horizontal diffusion cell, in which geniposide was chosen as a hydrophilic model drug. The results show that poly(ethylene oxide) (PEG) blocks exhibit substantial effects on adhesive performance and the release behavior of the model drug. The shorter PEG molecular chains enhance adhesive performance and the cumulative release rate of the model drug in the SISO-based HMPSAs. The longer PEG molecular chains tend to crystallize. Their crystallization structures have negative effects on adhesive performance and limit the dissolution and diffusion of drugs in the SISO-based HMPSAs. Therefore, appropriate PEG molecular chains are required to fabricate SISO-based HMPSAs with excellent adhesive performance for transdermal delivery of hydrophilic drugs.

Optimization of SIS-based hot-melt pressure-sensitive adhesives for transdermal delivery of hydrophilic drugs

To optimize hot-melt pressure-sensitive adhesives (HMPSAs) for transdermal delivery of hydrophilic drugs, styrene–isoprene–styrene copolymer (SIS), epoxidized SIS (ESIS), tackifiers, and plasticizer were melt-mixed with polyethylene glycol 2000 (PEG2000) or poly (ethyl acrylate-co-methyl methacrylate-co-trimethylammonioethyl methacrylate chloride) (RLPO). Their compatibility was studied with DSC and FT-IR. Their 180° peel strength and holding power was measured for their adhesive performances. In vitro drug release experiments were carried out using a modified Franz type horizontal diffusion cell, in which geniposide was chosen as a hydrophilic model drug. Although PEG2000 can greatly enhance the accumulative release rate of geniposide in a manner of burst release, its poor compatibility with the components of SIS/ESIS-based HMPSAs makes the adhesive performance hardly meet the practical requirement of transdermal drug delivery. RLPO not only provides sustained release behavior to geniposide through its low content of quaternary ammonium groups but also preserves excellent adhesive performance due to its partial compatibility with the components of SIS/ESIS-based HMPSAs. Therefore, RLPO is preferred to develop ideal SIS/ESIS-based HMPSAs for transdermal delivery of hydrophilic drugs.

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.

Microneedle-Based Drug Delivery Systems for Transdermal Route

Transdermal delivery offers an attractive, noninvasive administration route but it is limited by the skin's barrier to penetration. Minimally invasive techniques, such as the use of microneedles (MNs), bypass the stratum corneum (SC) barrier to permit the drug's direct access to the viable epidermis. These novel micro devices have been developed to puncture the skin for the transdermal delivery of hydrophilic drugs and macromolecules, including peptides, DNA and other molecules, that would otherwise have difficulty passing the outermost layer of the skin, the SC. Using the tools of the microelectronics industry, MNs have been fabricated with a range of sizes, shapes and materials. MNs have been shown to be robust enough to penetrate the skin and dramatically increase the skin permeability of several drugs. Moreover, MNs have reduced needle insertion pain and tissue trauma and provided controlled delivery across the skin. This review focuses on the current state of the art in the transdermal delivery of drugs using various types of MNs and developments in the field of microscale devices, as well as examples of their uses and clinical safety.

Synthesis of SIS-based hot-melt pressure sensitive adhesives for transdermal delivery of hydrophilic drugs

A series of epoxidized styrene–isoprene–styrene (SIS) copolymer was obtained with in situ epoxidation. Their epoxidation degrees were analyzed by 1H nuclear magnetic resonance spectroscopy and Fourier transform infrared spectroscopy. SIS, Epoxidized SIS (ESIS), C5 resin, mineral oil and antioxidants were melt-blended to prepare SIS/ESIS-based hot-melt pressure sensitive adhesives (HMPSAs). Their compatibility was studied with differential scanning calorimetry (DSC). The adhesive performances of the HMPSAs were measured, including holding power and 180° peel strength. Geniposide was chosen as a representative hydrophilic drug and it’s in vitro release behavior in the HMPSAs was investigated using a modified Franz type horizontal diffusion cells. It was shown that SIS was successfully epoxidized without side reactions. Although the epoxidation impaired the compatibility between ESIS and other additives, the 180° peel strength increased with the epoxidation degrees of ESIS. Furthermore, the in vitro release behavior of hydrophilic drugs was obviously enhanced with the increment of epoxidation degrees.

Moisture transport across porcine skin: experiments and implementation of diffusion-based models

In this paper, the mechanism of moisture transport across porcine skin has been investigated. Such work has implications on transdermal delivery of hydrophilic drugs. Past studies conducted in this area mostly relied on studying the process of moisture absorption. Mathematical models proposed for this transport process have been very basic. In this study, desorption as opposed to absorption has been used as the experimental approach for studying moisture transport. Low temperature convective drying experiments of the skin samples were conducted. Prior to the drying experiments, the skin samples were pre-treated by soaking in water at different temperatures for one hour. It was observed that the pre-treatment method had an effect on the drying rate. The mathematical models implemented were similar to the Fickian diffusion equation. The study yielded useful findings, which would interest researchers working in the area of drug delivery, toxicology and thermal burn analysis as well as those involved in the area of passive moisture transport through porous materials notably encountered in process engineering applications such as leather drying.

Laser treatments on skin enhancing and controlling transdermal delivery of 5‐fluorouracil

Laser ablation of stratum corneum (SC) enhances transdermal delivery of hydrophilic drugs. The influence of the infrared (IR) (lambda = 1,064 nm), visible (lambda = 532 nm), and ultraviolet (UV) (lambda = 355 nm) radiations of a Nd:YAG laser on transdermal delivery of 5-Fluorouracil (5-Fu) across skin was studied in vitro. Pinna skin of the inner side of rabbit ear, was used for the skin permeation. The light source for laser treatment was a Q-switched Nd:YAG laser (Lotis TII SL-2132). Ablation thresholds were estimated by using a photoacoustic technique. In addition, permeation study, and morphological and structural skin examination by histology and differential scanning calorimetry (DSC) were carried out. A significant increase in the permeation of 5-Fu across skin pre-treatment with the three different wavelengths studied was obtained. Since irradiation at 1,064 nm allows deep penetration of the radiation, collagen fibers were affected [7.7 J/cm(2) (15 Hz)]. Visible radiation of Nd:YAG laser showed the wider range of fluences (3-8.4 J/cm(2) at 15 Hz) to enhance skin delivery of 5-Fu, without risk of skin lesion. UV radiation required minor energy contribution to produce the same effects within a narrower range of fluences [0.3 J/cm(2) (5 Hz)-1.5 J/cm(2) (15 Hz)] so the process is less controlled and this radiation shows greater impact on the lipidic structure than visible and IR radiations. Use of the visible radiation of a Nd:YAG laser is a good method for improving the efficacy of topical chemotherapy of 5-Fu.

Radiofrequency-driven skin microchanneling as a new way for electrically assisted transdermal delivery of hydrophilic drugs

The aim of this study was to increase the skin penetration of two drugs, granisetron hydrochloride and diclofenac sodium, using a microelectronic device based on an ablation of outer layers of skin using radiofrequency high-voltage currents. These radiofrequency currents created an array of microchannels across the stratum corneum deep into the epidermis. The percutaneous penetration studies were first performed in vitro using excised full thickness porcine ear skin. An array of 100 microelectrodes/cm 2 was used in these studies. The skin permeability of both molecules was significantly enhanced after pretreatment with the radiofrequency microelectrodes, as compared to the delivery through the untreated control skin. Steady state fluxes of 41.6 μg/cm 2/h ( r=0.997) and 23.0 μg/cm 2/h ( r=0.989) were obtained for granisetron and diclofenac, respectively. The enhanced transdermal delivery was also demonstrated in vivo in rats. It was shown that diclofenac plasma levels in the pretreated rats reached plateau levels of 1.22±0.32 μg/ml after 3 h to 1.47±0.33 μg/ml after 6 h, as compared to 0.16±0.04 μg/ml levels obtained after 6 h in untreated rats. Similarly, application of granisetron patches (3% in crosslinked hydrogel) onto rats’ abdominal skin pretreated with radiofrequency electrodes resulted in an averaged peak plasma level of 239.3±43.7 ng/ml after 12 h, which was about 30 times higher than the plasma levels obtained by 24-h passive diffusion of the applied drug. The results emphasize, therefore, that the new transdermal technology is suitable for therapeutic delivery of poorly penetrating molecules.