Hypericin emulsomes combined with hollow microneedles as a non-invasive photodynamic platform for rheumatoid arthritis treatment.

Rheumatoid arthritis (RA) is a joint-destructive autoimmune disease that severely affects joint function. Despite the variability of treatment protocols, all of them are associated with severe side effects that compromise patient compliance. The main aim of the current study is to prepare localized effective RA treatment with reduced side effects by combining nanoencapsulation, photodynamic therapy (PDT) and hollow microneedles (Ho-MNs) to maximize the pharmacological effects of hypericin (HYP). To attain this, HYP-loaded emulsomes (EMLs) were prepared, characterized and administered through intradermal injection using AdminPen™ Ho-MNs combined with PDT in rats with an adjuvant-induced RA model. The prepared EMLs had a spherical shape and particle size was about 93.46 nm with an absolute entrapment efficiency. Moreover, confocal imaging indicated the interesting capability of Ho-MNs to deposit the HYP EMLs to a depth reaching 1560 µm into the subcutaneous tissue. In vivo, study results demonstrated that the group treated with HYP EMLs through Ho-MNs combined with PDT had no significant differences in joint diameter, TNF-α, IL1, HO-1, NRF2 and SD levels compared with the negative control group. Similarly, rats treated with the combination of HYP EMLs, Ho-MNs and PDT showed superior joint healing efficacy compared with the groups treated with HYP EMLs in dark, HYP ointment or HYP in microneedles in histopathological examination. These findings highlight the promising potential of photoactivated HYP EMLs when combined with Ho-MNs technology for RA management. The presented therapeutic EMLs-MNs platform could serve as a powerful game-changer in the development of future localized RA treatments.

Non-invasive management of rheumatoid arthritis using hollow microneedles as a tool for transdermal delivery of teriflunomide loaded solid lipid nanoparticles.

Conventional RA treatments required prolonged therapy courses that have been accompanied with numerous side effects impairing the patient's quality of life. Therefore, microneedles combined with nanotechnology emerged as a promising alternative non-invasive, effective and self-administrating treatment option. Hence, the main aim of this study is to reduce the side effects associated with systemic teriflunomide administration through its encapsulation in solid lipid nanoparticles (TER-SLNs) and their administration through transdermal route using AdminPen™ hollow microneedles array in the affected joint area directly. In vitro characterization studies were conducted including particle size, zeta potential, encapsulation efficiency and in vitro drug release. Also, ex vivo insertion properties of AdminPen™ hollow microneedles array was carried out. Besides, in vivo evaluation in rats with antigen induced arthritis model were also conducted by assessment of joint diameter, histopathological examination of the dissected joints and testing the levels of TNF-α, IL1B, IL7, MDA, MMP 3, and NRF2 at the end of the experiment. The selected TER-SLNs formulation was about 155.3 nm with negative surface charge and 96.45 % entrapment efficiency. TER-SLNs had a spherical shape and provided sustained release for nearly 96 h. In vivo results demonstrated that nanoencapsulation along with the use of hollow microneedles had a significant influence in improving TER anti-arthritic effects compared with TER suspension with no significant difference from the negative control group.

Hollow microneedle assisted intradermal delivery of hypericin lipid nanocapsules with light enabled photodynamic therapy against skin cancer.

Photodynamic therapy (PDT) to manage non-melanoma skin cancers has garnered great attention over the past few years. Hypericin (Hy) is a potent lipid-soluble photosensitiser with promising anticancer therapeutic activities. Nevertheless, its poor water-solubility, aggregation in biological systems and insufficient skin penetration restricted its effective exploitation. Herein, we report for the first-time encapsulation of Hy into lipid nanocapsules (Hy-LNCs), and then application of an AdminPen™ hollow microneedles (Ho-MNs) array and an in-house fabricated Ho-MN to enable efficient intradermal delivery. The physicochemical properties, photoactivity, ex vivo drug distribution and cellular uptake were evaluated. Results showed that Hy-LNCs were successfully formed with a particle size of 47.76 ± 0.49 nm, PDI of 0.12 ± 0.02, high encapsulation efficiency (99.67% ± 0.35), 396 fold higher photoactivity, 7 fold higher skin drug deposition, significantly greater cellular uptake and higher photocytotoxicity compared to free Hy. The therapeutic effect of Hy-LNCs was finally assessed in vivo using a nude mouse model with transplanted tumours. Interestingly, Hy-LNCs delivered by Ho-MN exhibited remarkable anti-tumour destruction (85.84%) after irradiation with 595 nm. This study showed that Ho-MNs-driven delivery of Hy-LNCs followed by irradiation could form a promising minimally invasive, effective and site-specific approach for managing non-melanoma skin cancers.

Entrapment efficiency of pyridoxine hydrochloride in unilamellar liposomes: experimental versus model-generated data.

The present study investigates the effect of the preparation method (four methods) and formulation additives (propylene glycol (PG) and cholesterol (CH)) on the entrapment efficiency (EE) of pyridoxine hydrochloride (vitamin B6 (VB6)), representing hydrophilic water-soluble low permeable vitamins, in unilamellar liposomes. The main aim is to compare determined EE with predicted values generated using a web-published, computational model. Results showed that among the different preparation methods, modified film hydration showed significantly higher EE (p < 0.05). With regard to formulation additives, PG (5% w/v) produced smaller vesicles size with narrow size distribution. Agreement between determined and model-generated EE values was more evident in formulae with narrow size distribution (polydispersity index (PdI) below 0.23). Formulae containing PG showed slightly higher determined than predicted EE values indicating vitamin-phospholipid bilayer interaction. Meanwhile, agreement between determined and predicted EE was limited to VB6-to-phospholipid ratio below (1.2:2). The comparison provided further insight into the usefulness of the prediction model factors affecting agreement between determined and predicted EE data.

Liposomal buccal mucoadhesive film for improved delivery and permeation of water-soluble vitamins.

This study aims at improving the buccal delivery of vitamin B6 (VB6) as a model highly water-soluble, low permeable vitamin. Two main strategies were combined; first VB6 was entrapped in liposomes, which were then formulated as mucoadhesive film. Both plain and VB6-loaded liposomes (LPs) containing Lipoid S100 and propylene glycol (∼ 200 nm) were then incorporated into mucoadhesive film composed of SCMC and HPMC. Results showed prolonged release of VB6 (72.65%, T50% diss 105 min) after 6h from LP-film compared to control film containing free VB6 (96.37%, T50% diss 30 min). Mucoadhesion was assessed both ex vivo on chicken pouch and in vivo in human. Mucoadhesive force of 0.2N and residence time of 4.4h were recorded. Ex vivo permeation of VB6, across chicken pouch mucosa indicated increased permeation from LP-systems compared to corresponding controls. Interestingly, incorporation of the vesicles in mucoadhesive film reduced the flux by 36.89% relative to LP-dispersion. Meanwhile, both films provided faster initial permeation than the liquid forms. Correlating the cumulative percent permeated ex vivo with the cumulative percent released in vitro indicated that LPs retarded VB6 release but improved permeation. These promising results represent a step forward in the field of buccal delivery of water-soluble vitamins.