Novel rhein-phospholipid complex targeting skin diseases: development, in vitro, ex vivo, and in vivo studies.

Rhein (RH), an anthraquinone derivative, has proven to be a promising molecule for treating several skin disorders thanks to its pleiotropic pharmacological activities like antimicrobial, antifungal, antioxidant, and anticancer. However, RH's low water and oil solubility and poor skin permeability halted its topical delivery. This is the first work to investigate the expediency of tailoring a rhein-phospholipid complex (RH-PLC) to improve RH challenging physicochemical and skin permeability properties. The phospholipid complex was prepared by employing different methods and different RH/PL molar ratios. RH-PLC was successfully developed at a stoichiometric ratio of 1:1 using a novel pH-dependent method where at a certain pH, it exhibits the highest complexation efficiency (95%). RH-PLC formation was confirmed using FTIR, DSC, and XRPD analysis. RH-PLC showed a significant increase in water and n-octanol solubility. RH-PLC was self-assembled upon dispersion into water forming nano-sized particles (196.6 ± 1.6 nm) with high negatively charged surface (- 29.7 ± 2.45 mV). RH-PLC exhibited a significant 3.3- and 2.46-fold increase in ex vivo and in vivo skin permeability when compared with RH suspension, respectively. Confocal microscopy study confirmed the ability of RH-PLC to penetrate deeply into rat skin. Besides, skin irritation test on healthy rats indicated compatibility and safety of RH-PLC. Conclusively, phospholipid complex might be a suitable approach to improve permeability of RH and other promising abandoned poor-permeable drugs. The proposed RH-PLC is expected to be a major progressive step toward the development of a topical RH formulation. Graphical abstract.

Novel skin penetrating berberine oleate complex capitalizing on hydrophobic ion pairing approach.

Berberine hydrochloride (Brb) is a well-known herbal drug that holds a great promise in the recent years thanks to its various pharmacological actions. Currently, Brb is extensively researched as a natural surrogate with evidenced potentiality against numerous types of skin diseases including skin cancer. However, Brb's high aqueous solubility and limited permeability hinder its clinical topical application. In the current work, to enhance Brb's dermal availability, hydrophobic ion pairing approach was implemented combining the privileges of altering the solubility characteristics of Brb and the nanometric size that is usually gained during the ion pairing precipitation process. Sodium oleate (SO) was selected as the complexing agent due to its low toxicity and skin penetrating characteristics. Ion paired berberine oleate complex (Brb-OL) was prepared by simple precipitation technique. Brb-OL complex formation was confirmed by differential scanning calorimetry (DSC), infrared spectroscopy (IR), X-ray powder diffraction (XRD) and saturation solubility studies. It was found that Brb-OL complex formed at stoichiometric binding between oleate and Brb had an average particle size of 195.9 nm and zeta potential of -53.6 mV. The proposed Brb-OL showed 251-fold increase in saturation solubility in n-octanol which confirmed the augmented lipid solubility of the complex compared with free drug. Comparative in-vitro release study showed that Brb-OL complex had much slow and sustained release profile compared to that of free Brb. Furthermore, ex-vivo permeation study using rat skin revealed the enhanced skin permeation of ion-paired Brb-OL complex compared with free Brb. In-vivo study on healthy rats confirmed that topical application of hydrogels enriched with Brb-OL had superior skin penetration and deposition than free Brb as revealed by confocal microscope. Conclusively, ion pair formation between Brb and oleate lead to the formation of more lipophilic Brb-OL complex with nanometric particle size which is expected to be a major progressive step towards the development of a topical berberine formulation.

A new approach for treatment of precancerous lesions with curcumin solid-lipid nanoparticle-loaded gels: in vitro and clinical evaluation.

OBJECTIVE: Preparation and characterization of curcumin solid-lipid nanoparticle (CurSLN)-loaded mucoadhesive gel for local treatment of oral precancerous lesions with low dose. METHODOLOGY: The formulated CurSLNs were dispersed in a mucoadhesive gel matrix to be applied to the buccal mucosa. Conventional mucoadhesive gel using binary system was adopted. The prepared gels were evaluated for in vitro drug dialysis, ex vivo mucoadhesion test and ex vivo permeation study using chicken buccal mucosa. Short-term clinical evaluation was carried out on 10 patients suffering oral erythroplakia in terms of pain index and lesion size measurement. (1) RESULTS: The results showed that the loaded gel with CurSLN showed good mucoadhesion property and 25 min in vivo residence time. In addition to stability enhancement for the Cur powder. All formulae did not show any drug permeated, however, significant amount of Cur was retained within the chicken buccal mucosal tissue confirmed by histological examination. Significant reduction in pain, and complete healing was observed after 6 weeks of treatment. CONCLUSION: The local use of Cur in low dose is a promising option for treatment of precancerous lesions. The lack of local anti-inflammatory compounds with reduced side effects intensifies the importance of studying natural products for this purpose.