Phenytoin-loaded bioactive nanoparticles for the treatment of diabetic pressure ulcers: formulation and in vitro/in vivo evaluation.

Drug repurposing offers the chance to explore the full potential of existing drugs while reducing drug development time and costs. For instance, the anticonvulsant drug phenytoin (PHT) has been investigated for its wound healing properties. However, its poor solubility and variability of doses used topically limit its use. Hence, the aim of this study was to improve the properties and wound healing efficacy of PHT for the treatment of diabetic bedsores. PHT was encapsulated, using a modified ionic gelation method, in either positively or negatively charged chitosan-alginate nanoparticles (NPs), which possess previously demonstrated wound healing potential. These NPs were characterized by transmission electron microscopy, differential scanning calorimetry, and Fourier-transform infrared spectroscopy. PHT-loaded NPs were evaluated in vivo for their pressure ulcers' healing potential using diabetic rats. The prepared NPs, especially the positively charged particles, exhibited superior wound healing efficacy compared to PHT suspension, with respect to healing rates, granulation tissue formation, tissue maturation, and collagen content. The positively charged NPs resulted in a 56.54% wound closure at day 7, compared to 37% for PHT suspension. Moreover, skin treated with these NPs showed a mature dermis structure with skin appendages, which were absent in all other groups, in addition to the highest collagen content of 63.65%. In conclusion, the use of a bioactive carrier enhanced the healing properties of PHT and allowed the use of relatively low doses of the drug. Our findings suggest that the prepared NPs offer an effective antibiotic-free delivery system for diabetic wound healing applications.

Chondroitin sulfate-functionalized lipid nanoreservoirs: a novel cartilage-targeting approach for intra-articular delivery of cassic acid for osteoarthritis treatment.

Novel intra-articular nanoreservoirs were implemented employing different cartilage targeting approaches to improve cartilage bioavailability of a chondroprotective drug, cassic acid (CA), for effective amelioration of cartilage deterioration off-targeting CA gastrointestinal disorders. Herein, we compared active cartilage-targeting approach via chondroitin sulfate (CHS) functionalization versus passive targeting using positively charged nanoparticles to target negatively charged cartilage matrix. Firstly, CA integrated nanoreservoirs (CA-NRs) were fabricated based on ionic conjugation between CA and cationic hydrophobic surface modifier octadecylamine (ODA) and were further functionalized with CHS to develop CHS-CA-NRs. Confocal laser microscope was used to visualize the accumulation of nanoparticles into the cartilage tissue. Both targeting approaches promoted CA local cartilage availability and prolonged its residence time. Compared to passive targeted CA-NRs, active targeted CHS-CA-NRs showed higher fluorescence signals in proximity to and inside chondrocytes which lasted for up to 21 days. In MIA-osteoarthritic rats, CHS-CA-NRs showed superior antiosteoarthritic activity, exhibiting highest cartilage repair compared to CA-NRs. Additionally, CHS-CA-NRs significantly inhibited OA inflammatory cytokine, degradation enzyme and oxidative stress and improved cartilage matrix biosynthesis. Conclusively, CHS-CA-NRs improved OA repair showing a superior efficacy for articular cartilage targeting with CHS which could be a potential advance for OA therapy.

Chitosan alginate nanoparticles as a platform for the treatment of diabetic and non-diabetic pressure ulcers: Formulation and in vitro/in vivo evaluation.

Chitosan and alginate are natural bioactive polymers with wound healing properties, in addition to chitosan's anti-bacterial properties. In this study, these two polymers were combined in a drug-free nanosystem with positive or negative surface charges, for the treatment of non-diabetic and diabetic pressure ulcers. Chitosan alginate nanoparticles (CA NPs) were prepared by a modified ionic gelation method. Interaction between the polymers and formation of the NPs were confirmed by Fourier-Transform infrared spectroscopy, differential scanning calorimetry and transmission electron microscopy. For in vivo study, selected CA NPs with optimum particle size, polydispersity index, positive and negative zeta potential, were evaluated for their pressure ulcers-healing effect using non-diabetic and diabetic rats. Rate of wound closure, histological examination and histomorphometric assessment were used to evaluate the CA NPs' wound healing potential. Positively and negatively charged CA NPs significantly enhanced wound closure rates, compared to control untreated group. Histological and histomorphometric analysis revealed higher quality and maturation of the formed granulation tissue, less inflammation and higher collagen content with positively charged CA NPs containing higher amount of chitosan. These results suggest that chitosan alginate nanoparticles offer a promising platform for diabetic and non-diabetic wound healing applications.

Repurposing ibuprofen-loaded microemulsion for the management of Alzheimer's disease: evidence of potential intranasal brain targeting.

Studies have shown the use of non-steroidal anti-inflammatory drugs, such as ibuprofen could reduce the risk of Alzheimer's disease. The drug-repurposing strategy offers a bright opportunity for these patients. Intranasal administration through the olfactory pathway provides noninvasive and direct drug delivery to the target brain. A novel ibuprofen microemulsion was prepared, characterized and assessed the brain uptake in rats. The solubility of ibuprofen in various oils, surfactants, co-surfactants, and different ratios of surfactant/co-surfactant mixtures was screened and the phase diagrams were constructed. The colloidal particle size was 166.3 ± 2.55 nm and the zeta potential was -22.7 mV. Conductivity and dilution test identified an O/W type microemulsion with pH 4.09 ± 0.08. The rheological study showed a Newtonian flow behavior with cP 10.633 ± 0.603 (mPa⋅s). A steady drug release and linear permeation profiles were observed and showed a 90% permeation rate from the released drug. Ibuprofen microemulsion showed excellent stability in 3-months accelerated storage conditions, heating-cooling and freeze-thaw cycles, accelerated centrifugation, and 6- and 12-months long-term storage conditions. In vivo studies in rats further demonstrated a 4-fold higher brain uptake of ibuprofen from the microemulsion compared to the reference solution and nearly 4-fold and 10-fold higher compared to the intravenous and oral administrations. This study provides an exciting repurposing strategy and new administration route for the treatment of Alzheimer's disease.

Novel rhein integrate transphytosomes as non-invasive local therapy for osteoarthritis to ameliorate cartilage deterioration in MIA-arthritic rats.

Rhein (RH), a natural chondroprotective agent, suffers from poor systemic availability (20-25%) after oral administration concomitant to side effects on the gastrointestinal tract and liver. We present a new approach for non-invasive local targeted delivery of rhein to ameliorate cartilage deterioration employing cartilage-homing phospholipids nanocarriers. This is the first work to elaborate RH loaded transphytosome (RH-T-PHY) as novel nanovesicular systems for transdermal drug delivery based on an advantageous hybrid between phytosomes and transfersomes or bilosomes. Here, we developed transphytosomes through incorporating various edge activators (EAs) such as Tween 80, Span 80 and sodium deoxycholate into the lipid bilayer of RH phytosomes to affix the flexibility. RH-T-PHY with high flexibility and entrapment efficacy showed the highest significant skin permeation compared to conventional phytosomes. Additionally, RH-T-PHY have a magnificent potential in maintaining high chondroprotective activity as demonstrated by enhanced repair, regeneration of chondrocytes and GAG formation in MIA-induced osteoarthritis (OA) rat model. Besides, histological examination of vital organs revealed the formulation safety. Confocal laser microscopy images revealed the highest drug availability in the articular cartilage of RH-T-PHY treated group. Conclusively, novel RH-T-PHY can serve as a promising alternative means for delivery of chondroprotective drugs for effective non-invasive local therapy of OA.

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.

Mesoporous silica nanoparticles, a safe option for silymarin delivery: preparation, characterization, and in vivo evaluation.

The present work aimed to prepare silymarin-loaded mesoporous silica nanoparticles (MSNs) and to assess the system's dissolution enhancement ability on the pharmacodynamic performance of silymarin as a hepatoprotective agent. For this purpose, a soft-templating technique was used to prepare silymarin-loaded MSNs. The loaded MSNs were further characterized for their particle size, zeta potential, surface properties, and in vitro drug dissolution testing. In addition, differential scanning calorimetry (DSC) and Fourier transform infrared spectroscopy (FTIR) were also carried out. DSC and specific surface area data confirmed deposition of silymarin in an amorphous state in MSNs' pores. In vitro drug dissolution testing displayed enhanced dissolution rate of silymarin upon loading on MSNs compared with the free drug. Paracetamol-induced rat model of liver injury was used for the in vivo study. Plasma aspartate aminotransferase (AST), alanine aminotransferase (ALT), total proteins, liver homogenate content of thiobarbituric acid reactive species (TBARS), or lactate dehydrogenase (LDH) were assessed for all animal groups, treated and control ones. Based on parameters indicative of liver function, our results showed that the oral use of silymarin loaded onto MSNs at a dose of 250 mg/kg is significantly superior to free silymarin. Moreover, prolonged administration of the formulation had no evident toxicity on rats.

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.

Formulation, in-vitro characterization and clinical evaluation of curcumin in-situ gel for treatment of periodontitis.

This study aimed to develop syringeable in-situ curcumin (cur) gel for the treatment of periodontal pockets as well as to evaluate the clinical efficacy of Cur in-situ gel formulation. Different in-situ gel formulations of Cur were prepared using 30% of pluronic F127, and 1% of carbopol P934. The formulations were evaluated regarding gelation temperature, pH, viscosity, syringeability study, in-vitro release and chemical stability of cur. The effect of aging of gel formulations for 3months in refrigerator was investigated. The selected formulation was clinically evaluated through the determination of probing depth, plaque index, and bleeding index at baseline and 1 month after application. The formulations showed accepted gelation temperature ranging from 28 to 34 °C and all had pH value of 4. The viscosity of the formulations at 4 °C ranged from 19 000 to 37 000 cP. All formulations were easily syringeable through 21 gauge needle at cold temperature. Curcumin stability during the release study was maintained. Aging showed no significant effect on release profile, drug content, or the pH after 3 months, while it showed a slight increase in viscosity with concomitant decrease in gelation temperature. Selected formulations delivered into periodontal pocket evaluated clinically showed to be effective. The treated group revealed that the adjunctive use of intracrevicular 2% curcumin in-situ gel adjunct to mechanical treatment in patients with adult periodontitis could aid in significant clinical reduction of probing depth, bleeding index, and to less extent of plaque. This indicates that curcumin in this novel drug delivery system is an excellent candidate for periodontal disease treatment.

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.

Gelucire-Based Nanoparticles for Curcumin Targeting to Oral Mucosa: Preparation, Characterization, and Antimicrobial Activity Assessment.

The purpose of the study was to prepare and characterize curcumin (Cur) solid lipid nanoparticles (CurSLN) with a high-loading capacity and chemical stability for the treatment of oral mucosal infection. CurSLN were formulated using different lipids, namely, Gelucire 39/01, Gelucire 50/13, Precirol, Compritol, and poloxamer 407 as a surfactant. Formulae were evaluated for their entrapment efficiency, particle size, and ex vivo mucoadhesion test. Microbiological evaluation was carried out on six microorganisms, five of which are the most commonly affecting oral cavity in terms of determination of minimum inhibitory concentration (MIC), and minimum bactericidal concentration. Transmission electron microscopy was conducted for ultrathin section for Candida albicans-treated with formulated Cur. The results showed high entrapment efficiency and stability enhancement for Cur powder. Significant amount of Cur was retained onto the mucosal tissue indicating preferential mucosal uptake. CurSLN showed higher antimicrobial activity as compared with Cur raw material and chemically stabilized Cur where it showed MIC (0.185, 0.09375, 0.75, 3, 1.5, and 0.1875 mg/mL) against Staphylococcus aureus, Streptococcus mutans, Viridansstrept, Escherichia coli, Lactobacillus acidophilus, and Candida albicans, respectively. The prepared lipid nanoparticles maintained Cur chemical stability and microbiological activity. The lack of local antimicrobial therapeutics with minimum side effects augments the importance of studying natural products for this purpose.

Lyophilized sponges loaded with curcumin solid lipid nanoparticles for buccal delivery: Development and characterization.

This study aimed to prepare and evaluate mucoadhesive sponges as dosage forms for delivering solid lipid nanoparticles. For this purpose curcumin (Cur) was formulated as solid nanoparticles (SLN) using Gelucire 50/13, and polaxomer 407. The prepared CurSLN dispersion was thickened with different mucoadhesive polymers. Different concentrations of glycerol, and mannitol of range (0.25-20%), and (0-1%), respectively were also examined. The formed gel was poured into oblong molds and freeze dried to form mucoadhesive sponge to be applied to the buccal mucosa. The prepared sponges were evaluated for their, in-vivo residence time, in-vitro and in-vivo drug release, and hydration capacity. Surface morphology for the different sponges were examined using SEM. TEM was also carried out for sponge fragments previously dispersed into water. Infrared spectroscopy was conducted to investigate interaction between used ingredients. The results showed that the CurSLN loaded HPMC, and Polycarbophil sponges showed 4, and 15 h in-vivo residence time, respectively, providing a considerable amount of curcumin into saliva. The incorporation of glycerol and mannitol at concentration of 1% provided elegant and flexible sponges. The SEM showed that the deposition of CurSLN differed according to the type of polymer used. TEM confirmed the integrity of liberated CurSLN from sponges. IR spectra showed an interaction between HPMC and poloxamer 407, which affected its behavior as a gelling agent. The obtained results provide an efficient approach for delivering solid lipid nanoparticles in a solid dosage form keeping the nanoparticle characters and integrity.