Drug Delivery and Translational Research最新文献

Resveratrol is a polyphenolic compound showing anti-inflammatory activity by inhibition of high mobility group box 1 cytokine responsible for the activation of nuclear factor-κB pathway in atopic dermatitis. To evaluate the efficacy of resveratrol through topical route we have developed resveratrol-loaded nanoemulgel for the effective management of atopic dermatitis in mice model. The resveratrol-loaded nanoemulsion (0.5%, 0.75% and 1% w/w) was optimized by spontaneous nano-emulsification. The optimized resveratrol-loaded nanoemulsions showed average globule size in the 180-230 nm range and found to be monodispersed. The resveratrol nanoemulgel was prepared with a SEPINEO™ P 600 gel base and propylene glycol. Ex vivo permeation and retention study resulted in significantly higher skin retention of resveratrol from resveratrol-loaded nanoemulgel than free resveratrol-loaded gel. Preclinical efficacy of resveratrol nanoemulgel displayed promising therapeutic outcomes where, western blotting of skin tissues disclosed a significant reduction in the relative expression of high mobility group box 1, the receptor for advanced glycation end products, toll-like receptor-4 and phosphorylated nuclear factor-κB. Further, real-time polymerase chain reaction also disclosed a significant reduction in pro-inflammatory cytokines such as thymic stromal lymphopoietin, interleukin-4, interleukin-13, interleukin-31, tumor necrosis factor-α and interleukin-6. The histopathological examination of skin sections showed improvement in the skin condition. Collectively, the findings from our study showcased the significant improvement in the atopic dermatitis skin condition in mice model after topical application of resveratrol loaded nanoemulgel.

In this technical note we show with two simple experiments how Perfluorodecalin (PFD), an injectable perfluorocarbon, can be used as an agent for resuspending microparticulate suspensions in primary packaging containers for injection. Furthermore, we explain how this can be a substantial improvement regarding patient compliance in comparison to the commonly used gas headspace for resuspension. Our experiments are conducted with poly(lactic-co-glycolic acid) particles (often used in extended-release pharmaceutical formulations for injection) and in primary packaging that is commonly used in injection devices (glass cartridges). The results show that our method is feasible for resuspension and moreover even sediment solidification/caking is reduced. The differences between the two datasets collected are statistically significant with p < 0.01 in both cases.

Nanostructured lipid carriers (NLCs) hold significant promise as drug delivery systems (DDS) owing to their small size and efficient drug-loading capabilities. Surface functionalization of NLCs can facilitate interaction with specific cell receptors, enabling targeted cell delivery. Mannosylation has emerged as a valuable tool for increasing the ability of nanoparticles to be recognized and internalized by macrophages. Nevertheless, the design and development of functionalized NLC is a complex task that entails the optimization of numerous variables and steps, making the process challenging and time-consuming. Moreover, no previous studies have been focused on evaluating the functionalization efficiency. In this work, hybrid Artificial Intelligence technologies are used to help in the design of mannosylated drug loaded NLCs. Artificial neural networks combined with fuzzy logic or genetic algorithms were employed to understand the particle formation processes and optimize the combinations of variables for the different steps in the functionalization process. Mannose was chemically modified to allow, for the first time, functionalization efficiency quantification and optimization. The proposed sequential methodology has enabled the design of a robust procedure for obtaining stable mannosylated NLCs with a uniform particle size distribution, small particle size (< 100 nm), and a substantial positive zeta potential (> 20mV). The incorporation of mannose on the surfaces of these DDS following the established protocols achieved > 85% of functionalization efficiency. This high effectiveness should enhance NLC recognition and internalization by macrophages, thereby facilitating the treatment of chronic inflammatory diseases.

Cannabidiol (CBD) is a natural product isolated from the Cannabis sativa plant that was approved by the United States Food and Drug Administration (US FDA) for the treatment of resistant epilepsy. Despite its therapeutic potential, CBD's clinical application is limited by its poor aqueous solubility and low oral bioavailability. The primary aim of this research was to enhance the aqueous solubility and oral bioavailability of CBD by developing nanostructured lipid carriers (NLCs) using conventional hot homogenization method (CHH). In the current study, nine CBD NLC formulations were developed through CHH, of which, NLC5 emerged as the most promising formulation, exhibiting high CBD entrapment efficiency (99.23%), particle size of 207 nm, a polydispersity index of 0.19, and a zeta potential of -26 mV. Additionally, drug release testing for NLC5 showed a high CBD release rate of more than 90% within 15 min, indicating an enhancement of CBD dissolving rate compared to pure CBD. The in vivo pharmacokinetic study of NLC5 formulation showed 27% CBD oral bioavailability. Furthermore, Stability studies conducted at 4 °C and 25 °C on this formulation over three months, revealed consistent parameters, underscoring the robustness of the formulation. In conclusion, the successful formulation of CBD-loaded NLCs resulted in improved CBD release rate, enhanced oral bioavailability of CBD, and maintained stability, making it a promising approach for the effective delivery of CBD.

Ablative fractional laser-assisted drug delivery has gained attention as a promising method for enhancing dermal drug absorption and improving therapeutic outcomes in dermatological conditions, particularly for hypertrophic and keloid scars. However, despite the growing number of clinical trials and case reports supporting its efficacy, there remains a scarcity of robust evidence on the topical bioavailability and dermato-pharmacokinetics of drugs in human subjects. This study aimed to examine the enhancement of triamcinolone acetonide (TAC) bioavailability following treatment with a fractional Erbium-Doped Yttrium Aluminum Garnet (Er: YAG) laser. Stratum corneum (SC) uptake and transport of TAC from 0.1% TAC cream and 10 mg/mL TAC solution/suspension with and without the laser pre-treatment were determined through tape stripping method for SC collection. TAC therein was quantified by an ultra-performance liquid chromatography coupled with photodiode array (UPLC-PDA) detection. TAC from both formulations without laser assistance was percutaneously absorbed within 6 h and TAC was delivered out from the solution to the SC remarkably higher. When the skin was pre-treated with the laser, permeability of TAC from the solution was escalated by 5 folds. TAC distribution profiles in the SC also confirmed this increased drug uptake, mainly the outer skin layers. On the other hand, amounts of absorbed TAC and their distribution patterns from the cream remained unchanged and low. No adverse events and unbearable pain were observed throughout the experiments. The fractional Er: YAG laser enhanced the dermal absorption of TAC, but this effect was confined to the solution formulation, with no significant improvement seen in the cream. This finding highlights the critical role that drug formulation plays in laser-assisted drug delivery. Moreover, factors such as drug selection, laser type, and optimal laser settings may also impact the efficacy of this approach and require further exploration.

Poly(glycerol sebacate) (PGS) is a biodegradable, elastomeric polymer that has been explored for applications including tissue engineering, drug delivery, and wound repair. Despite its promise, its biomedical utility is limited by its rapid, and largely fixed, degradation rate. Additionally, its preparation requires prolonged curing at high temperatures, rendering it incompatible with heat-sensitive molecules, complex device geometries, and high-throughput production. In this study, we synthesized methacrylated PGS (PGS-M), imparting the ability to rapidly photocross-link the polymer. Increasing the degree of methacrylation was found to slow PGS-M degradation; PGS-M (5.5 kDa) disks with 21% methacrylation lost 40.1 ± 11.8% of their mass over 11 weeks in vivo whereas 47% methacrylated disks lost just 14.3 ± 1.4% of their mass over the period. Daunorubicin release from PGS-M occurred in a linear fashion without a substantial initial burst. Further, increasing the degree of methacrylation extended the release of encapsulated drug. After 60 days, 21%, 27%, and 47% methacrylated disks with the same drug loading (w/w) released 56.8 ± 5.4%, 15.1 ± 0.4%, and 15.4 ± 0.3% of encapsulated drug, respectively. Importantly, the 27% and 47% methacrylated disks consistently released ~ 0.25% (w/w) of encapsulated drug per day with no burst release. Histological evaluation also suggested that PGS-M is biocompatible, eliciting limited inflammation and fibrous encapsulation when implanted subcutaneously. This report presents the first long-term in vitro studies and first in vivo studies using PGS-M and demonstrates the ability to tune PGS-M degradation rate, use PGS-M to encapsulate drug, and obtain sustained drug release over months.

Human cells, such as fibroblasts and particularly human mesenchymal stem cells (hMSCs), represent a promising and effective therapeutic tool for a range of cell-based therapies used to treat various diseases. The effective delivery of therapeutic cells remains a challenge due to limitations in targeting, invasiveness, and cell viability. To address these challenges, we developed a microneedle (MN) system for minimally invasive cell delivery with high cellular stability. The MN system comprises a core of gelatin methacryloyl (GelMA) hydrogel embedded with fibroblasts, encased in a polylactic-co-glycolic acid (PLGA) shell that enhances structural integrity for efficient skin penetration. The fabrication process involves UV-crosslinking of the GelMA hydrogel with cells, optimizing both cell encapsulation and structural strength. This MN system achieves over 80% cell viability after seven days in vitro, with the conventional GelMA formulation providing superior stability and cellular outcomes. This platform's ability to ensure sustained cell viability presents promising implications for future applications in regenerative medicine, wound healing, and localized treatments for skin conditions. This MN system opens new avenues for cell-based therapies, offering a versatile and scalable solution for therapeutic cell delivery.

The aim of this study was to develop an alternative strategy to sufficiently increase the lipophilicity of anionic model macromolecules (MM) without the use of cationic counterions. Enoxaparin (ENO), insulin (INS) and poly-L-glutamic acid (PLG) were ion paired with anionic surfactants (sodium decanoate (DEC), sodium dodecyl sulfate (SDS), sodium stearate (SS) and sodium octadecyl sulfate (SOS)), mediated by divalent cations such as magnesium, calcium and zinc. Complexes were evaluated regarding their precipitation efficiency and logD_{n-butanol/water}. SEDDS were developed, loaded with the complexes and characterized for their size and stability. Finally, payloads and logD_{SEDDS/release medium} were determined. Divalent cation mediated ENO, INS and PLG complexes were successfully formed as underlined by high precipitation efficiencies above 90% in case of Zn²⁺-mediated complexes. Most pronounced increase in logD_{n-butanol/water} was achieved for ENO-Zn²⁺-SOS (1.85), INS-Zn²⁺-SOS (0.80) and PLG-Zn²⁺-SS (0.48) providing suitable solubilities in commonly used SEDDS components. Developed SEDDS displayed droplet sizes below 200 nm without major changes after loading with MM complexes. Payloads up to 18.72 mg/ml could be achieved in developed SEDDS for ENO-Zn²⁺-SOS, and 2.44 mg/ml and 6.93 mg/ml for INS-Zn²⁺-SOS and PLG-Zn²⁺-SS, respectively. In general, highest lipophilicity enhancement and thus solubility in SEDDS was obtained with Zn²⁺-mediated complexes among the investigated cations and particularly with the highly negatively charged polysaccharide ENO. The formation of complexes between anionic MM and anionic surfactants mediated by divalent cations, substituting normally used cationic counterions exhibiting higher toxicity, offers a promising alternative to enhance their lipophilicity for oral drug delivery.

Ocular diseases have a major impact on patient's vision and quality of life, with approximately 2.2 billion people have visual impairment worldwide according to the findings from the World Health Organization (WHO). The eye is a complex organ with unique morphology and physiology consisting of numerous ocular barriers which hinders the entry of exogenous substances and impedes drug absorption. This in turn has a substantial impact on effective drug delivery to treat ocular diseases, especially intraocular disorders which has consistently presented a challenge to eye care professionals. The most common method of delivering medications to the eye is topical instillation of eye drops. Although this approach is a viable option for treating many ocular diseases remains a major challenge for the effective treatment of posterior ocular conditions. Up till now, incessant efforts have been committed to design innovative drug delivery systems with the hopes of potential clinical application. Modern developments in nanocarrier's technology present a potential chance to overcome these obstacles by enabling targeted delivery of the loaded medication to the eyes with improved solubility, delayed release, higher penetration and increased retention. This review covers the anatomy of eye with associated ocular barriers, ocular diseases and administration routes. In addition it primarily focuses on the latest progress and contemporary applications of ophthalmic formulations providing specific insight on nanostructured drug delivery carriers reported over the past 5 years highlighting their values in achieving efficient ocular drug delivery to both anterior and posterior segments. Most importantly, we outlined in this review the macro and nanotechnology based ophthalmic drug formulations that are being patented or marketed so far for treating ocular diseases. Finally, based on current trends and therapeutic concepts, we highlighted the challenges faced by novel ocular drug delivery systems and provided prospective future developments for further research in these directions. We hope that this review will serve as a source of motivation and ideas for formulation scientists in improving the design of innovative ophthalmic formulations.