Cross-Linked Alginate Dialdehyde/Chitosan Hydrogel Encompassing Curcumin-Loaded Bilosomes for Enhanced Wound Healing Activity.

The current study aimed to fabricate curcumin-loaded bilosomal hydrogel for topical wound healing purposes, hence alleviating the poor aqueous solubility and low oral bioavailability of curcumin. Bilosomes were fabricated via the thin film hydration technique using cholesterol, Span® 60, and two different types of bile salts (sodium deoxycholate or sodium cholate). Bilosomes were verified for their particle size (PS), polydispersity index (PDI), zeta potential (ZP), entrapment efficiency (EE%), and in vitro drug release besides their morphological features. The optimum formulation was composed of cholesterol/Span® 60 (molar ratio 1:10 w/w) and 5 mg of sodium deoxycholate. This optimum formulation was composed of a PS of 246.25 ± 11.85 nm, PDI of 0.339 ± 0.030, ZP of -36.75 ± 0.14 mv, EE% of 93.32% ± 0.40, and the highest percent of drug released over three days (96.23% ± 0.02). The optimum bilosomal formulation was loaded into alginate dialdehyde/chitosan hydrogel cross-linked with calcium chloride. The loaded hydrogel was tested for its water uptake capacity, in vitro drug release, and in vivo studies on male Albino rats. The results showed that the loaded hydrogel possessed a high-water uptake percent at the four-week time point (729.50% ± 43.13) before it started to disintegrate gradually; in addition, it showed sustained drug release for five days (≈100%). In vivo animal testing and histopathological studies supported the superiority of the curcumin-loaded bilosomal hydrogel in wound healing compared to the curcumin dispersion and plain hydrogel, where there was a complete wound closure attained after the three-week period with a proper healing mechanism. Finally, it was concluded that curcumin-loaded bilosomal hydrogel offered a robust, efficient, and user-friendly dosage form for wound healing.

Investigating the bone regeneration activity of PVA nanofibers scaffolds loaded with simvastatin/chitosan nanoparticles in an induced bone defect rabbit model.

This study aims at preparing electrospun PVA NFs incorporating simvastatin/chitosan nanoparticles (SIM CS NPs) as a controlled drug eluting scaffold for bone regeneration. Optimization was performed by Design Expert® software through establishing two factor, three level factorial design, where the independent variables were the applied voltage, flow rate and PVA solution/SIM CS NPs ratio. Formulation variables values for the optimized formula were 18KV, 0.5 mL/h, and 3:1 respectively. NFs diameter and mesh pore size were chosen as the dependent variables. The optimized NFs were evaluated morphologically, chemically, and physically. Additionally, in-vitro SIM release from the scaffolds was investigated along 24 days. Optimum NFs possessed 136 nm diameter size and 6.5 nm porosity. Also, they showed sustained SIM release for 24 days to achieve the desired goal in bone regeneration. The optimized NFs were implanted within induced bone defects in rabbits. In-vivo assessments were performed through cone beam computed tomography 3D images, bone density measurements, histological analysis and bone morphogenetic protein 2 (BMP 2) level. The obtained results proved the high potential of the optimized NFs in promoting bone regeneration compared to untreated group, non-medicated NFs group, free SIM group and NFs loaded with SIM group after 6 weeks of implantation.

Different Curcumin-Loaded Delivery Systems for Wound Healing Applications: A Comprehensive Review.

Curcumin or turmeric is the active constituent of Curcuma longa L. It has marvelous medicinal applications in many diseases. When the skin integrity is compromised due to either acute or chronic wounds, the body initiates several steps leading to tissue healing and skin barrier function restoration. Curcumin has very strong antibacterial and antifungal activities with powerful wound healing ability owing to its antioxidant activity. Nevertheless, its poor oral bioavailability, low water solubility and rapid metabolism limit its medical use. Tailoring suitable drug delivery systems for carrying curcumin improves its pharmaceutical and pharmacological effects. This review summarizes the most recent reported curcumin-loaded delivery systems for wound healing purposes, chiefly hydrogels, films, wafers, and sponges. In addition, curcumin nanoformulations such as nanohydrogels, nanoparticles and nanofibers are also presented, which offer better solubility, bioavailability, and sustained release to augment curcumin wound healing effects through stimulating the different healing phases by the aid of the small carrier.

In Situ-Forming Microparticles for Controlled Release of Rivastigmine: In Vitro Optimization and In Vivo Evaluation.

In this work, sucrose acetate isobutyrate (SAIB) and polylactic co-glycolic acid (PLGA) were used alone or in combination as a matrix-former (MF) to prepare long-acting injectable rivastigmine (RV) in situ-forming microparticles (ISM). RV-ISM were prepared by the emulsification of an internal phase, containing the drug and the matrix former(s), into an external oily phase containing a stabilizer. The statistical design, Central Composite Design (CCD), was adopted as a quality by design (QbD) approach to optimize the formulation of RV-ISM systems. The fabricated RV-ISM systems was designed to minimize the initial burst drug release and maximize the sustainment of RV release from the ISM and ease of injection. The influence of critical formulation variables such as the matrix-former to drug (MF/D) ratio and SAIB to PLGA (S/P) ratio in the internal phase with respect to critical quality attributes (CQAs), such as the percentage drug release within the first day (Q1), the time required for 50% drug release (T50%) and the rate of injection, were studied using the CCD. The optimal RV-ISM system with the highest desirability value (0.74) was predicted to have an MF/D ratio of 11.7:1 (w/w) and an S/P ratio of 1.64:1 (w/w). The optimal RV-ISM system was assessed for its release profile, injectability, rheological properties, morphology, effect on cell viability, tolerance to γ-sterilization and in vivo performance in male albino rabbits. In vitro release studies revealed that the optimal RV-ISM system released 100% of its drug content throughout a release period of 30 days with only 15.5% drug release within the first day (Q1) and T50% of 13.09 days. Moreover, the optimal system showed a high injection rate of 1.012 mL/min, pseudoplastic flow, uniform spherical globules with homogenous particle size, minimal cytotoxicity and high tolerability to γ-sterilization. In vivo pharmacokinetic (PK) studies revealed that the rate of absorption of RV from the optimal RV-ISM system was controlled compared to a drug solution following either intramuscular (IM) or subcutaneous (SC) injection. Furthermore, the optimal RV-ISM was found to follow flip-flop PK with poor correlation between in vitro release and in vivo findings. These findings suggest that the optimal RV-ISM is a promising tool to achieve a sustained release therapy for RV; however, further investigation is still required to optimize the in vivo performance of RV-ISM.

Formulation of simvastatin chitosan nanoparticles for controlled delivery in bone regeneration: Optimization using Box-Behnken design, stability and in vivo study.

This study aims to formulate and optimize simvastatin loaded chitosan-tripolyphosphate nanoparticles (SIM CS-TPP NPs) using ionic gelation method to provide a local delivery system that controls and sustains the release of simvastatin in the desired dose to promote bone regeneration. Box-Behnken design was adopted for optimization of the formulation variables of the prepared nanoparticles namely, CS percentage, TPP percentage and homogenization time. The optimized formula was selected and characterized by transmission electronic microscopy, in-vitro release, swelling index and storage stability. The ability of the optimum formula to stimulate bone regeneration upon implantation in bone defect generated in rabbits was also evaluated. The optimum SIM CS-TPP NPs had particle size of 106 nm, zeta potential of 43.3 mv, polydispersity index of 0.295 and entrapment efficiency of 98.78% and also showed good storage stability over the first month in addition to controlled and steady release over 2 weeks that effectively delivered simvastatin in a therapeutic dose needed for bone regeneration. Cone beam computed tomography 3D images, bone density measurements and histopathological analysis confirmed the high potential of SIM CS-TPP NPs in promoting bone regeneration in the generated defects compared to both the non-medicated formula and untreated groups after 6 weeks of implantation.

Enhanced Permeation of Methotrexate via Loading into Ultra-permeable Niosomal Vesicles: Fabrication, Statistical Optimization, Ex Vivo Studies, and In Vivo Skin Deposition and Tolerability.

The aim of this study was to incorporate methotrexate (MTX) into ultra-permeable niosomal vesicles, containing cremophor RH40 as an edge activator (EA) and polyvinyl alcohol (PVA) as a stabilizer to enhance the drug permeation. Formulae were prepared by ethanol injection method following a Box-Behnken design in order to optimize the formulation variables (EA%, stabilizer %, and sonication time). To investigate the role of both cremophor RH40 and PVA, conventional MTX niosomes and MTX niosomes containing PVA only were fabricated. Drug entrapment efficiency percent (EE%), particle size (PS) analysis, zeta potential (ZP) measurements, and transmission electron microscopy (TEM) were conducted to characterize the vesicles. Cell viability studies and ex vivo permeation experiments of the optimized formula were conducted. Lastly, in vivo skin deposition of MTX from both the optimized formula and MTX solution was performed in rats. Besides, histopathological changes in rat skin were assessed. The optimized MTX ultra-permeable niosomal formula demonstrated spherical morphology, with an EE% of 65.16% and a PS of 453.6 nm. The optimized formula showed better physical stability in comparison with that of the same composition but lacking PVA. The cell viability studies verified the superior cytotoxicity of the optimized formula, and the ex vivo permeation studies revealed its ability to improve the drug permeation. The optimized formula demonstrated a significant deposition of MTX in rat dorsal skin, and histopathological evaluation confirmed the tolerability of the optimized formula in rats upon topical application. Accordingly, ultra-permeable noisomes, as a stable nanosystem, could be promising for effective delivery of MTX.

Enhancement of dissolution and oral bioavailability of lacidipine via pluronic P123/F127 mixed polymeric micelles: formulation, optimization using central composite design and in vivo bioavailability study.

This study aims at preparing and optimizing lacidipine (LCDP) polymeric micelles using thin film hydration technique in order to overcome LCDP solubility-limited oral bioavailability. A two-factor three-level central composite face-centered design (CCFD) was employed to optimize the formulation variables to obtain LCDP polymeric micelles of high entrapment efficiency and small and uniform particle size (PS). Formulation variables were: Pluronic to drug ratio (A) and Pluronic P123 percentage (B). LCDP polymeric micelles were assessed for entrapment efficiency (EE%), PS and polydispersity index (PDI). The formula with the highest desirability (0.959) was chosen as the optimized formula. The values of the formulation variables (A and B) in the optimized polymeric micelles formula were 45% and 80%, respectively. Optimum LCDP polymeric micelles had entrapment efficiency of 99.23%, PS of 21.08 nm and PDI of 0.11. Optimum LCDP polymeric micelles formula was physically characterized using transmission electron microscopy. LCDP polymeric micelles showed saturation solubility approximately 450 times that of raw LCDP in addition to significantly enhanced dissolution rate. Bioavailability study of optimum LCDP polymeric micelles formula in rabbits revealed a 6.85-fold increase in LCDP bioavailability compared to LCDP oral suspension.

Enhanced Solubility and Dissolution Rate of Lacidipine Nanosuspension: Formulation Via Antisolvent Sonoprecipitation Technique and Optimization Using Box-Behnken Design.

Lacidipine (LCDP) is a highly lipophilic calcium channel blocker of poor aqueous solubility leading to poor oral absorption. This study aims to prepare and optimize LCDP nanosuspensions using antisolvent sonoprecipitation technique to enhance the solubility and dissolution of LCDP. A three-factor, three-level Box-Behnken design was employed to optimize the formulation variables to obtain LCDP nanosuspension of small and uniform particle size. Formulation variables were as follows: stabilizer to drug ratio (A), sodium deoxycholate percentage (B), and sonication time (C). LCDP nanosuspensions were assessed for particle size, zeta potential, and polydispersity index. The formula with the highest desirability (0.969) was chosen as the optimized formula. The values of the formulation variables (A, B, and C) in the optimized nanosuspension were 1.5, 100%, and 8 min, respectively. Optimal LCDP nanosuspension had particle size (PS) of 273.21 nm, zeta potential (ZP) of -32.68 mV and polydispersity index (PDI) of 0.098. LCDP nanosuspension was characterized using x-ray powder diffraction, differential scanning calorimetry, and transmission electron microscopy. LCDP nanosuspension showed saturation solubility 70 times that of raw LCDP in addition to significantly enhanced dissolution rate due to particle size reduction and decreased crystallinity. These results suggest that the optimized LCDP nanosuspension could be promising to improve oral absorption of LCDP.

Lyophilized sustained release mucoadhesive chitosan sponges for buccal buspirone hydrochloride delivery: formulation and in vitro evaluation.

This work aims to prepare sustained release buccal mucoadhesive lyophilized chitosan sponges of buspirone hydrochloride (BH) to improve its systemic bioavailability. Chitosan sponges were prepared using simple casting/freeze-drying technique according to 3(2) factorial design where chitosan grade was set at three levels (low, medium, and high molecular weight), and concentration of chitosan solution at three levels (0.5, 1, and 2%). Mucoadhesion force, ex vivo mucoadhesion time, percent BH released after 8 h (Q8h), and time for release of 50% BH (T50%) were chosen as dependent variables. Additional BH cup and core buccal chitosan sponge were prepared to achieve uni-directional BH release toward the buccal mucosa. Sponges were evaluated in terms of drug content, surface pH, scanning electron microscopy, swelling index, mucoadhesion strength, ex vivo mucoadhesion time, and in vitro drug release. Cup and core sponge (HCH 0.5E) were able to adhere to the buccal mucosa for 8 h. It showed Q8h of 68.89% and exhibited a uni-directional drug release profile following Higuchi diffusion model.

Enhanced bioavailability of buspirone hydrochloride via cup and core buccal tablets: formulation and in vitro/in vivo evaluation.

This work aims to prepare sustained release buccal mucoadhesive tablets of buspirone hydrochloride (BH) to improve its systemic bioavailability. The tablets were prepared according to 5×3 factorial design where polymer type was set at five levels (carbopol, hydroxypropyl methylcellulose, sodium alginate, sodium carboxymethyl cellulose and guar gum), and polymer to drug ratio at three levels (1:1, 2:1 and 3:1). Mucoadhesion force, ex vivo mucoadhesion time, percent BH released after 8 h (Q8h) and time for release of 50% BH (T(50%)) were chosen as dependent variables. Additional BH cup and core buccal tablets were prepared to optimize BH release profile and make it uni-directional along with the tablets mucoadhesion. Tablets were evaluated in terms of content uniformity, weight variation, thickness, diameter, hardness, friability, swelling index, surface pH, mucoadhesion strength and time and in vitro release. Cup and core formula (CA10) was able to adhere to the buccal mucosa for 8h, showed the highest Q8h (97.91%) and exhibited a zero order drug release profile. Pharmacokinetic study of formula CA10 in human volunteers revealed a 5.6 fold increase in BH bioavailability compared to the oral commercial Buspar® tablets. Conducting level A in vitro/in vivo correlation showed good correlation (r²=0.9805) between fractions dissolved in vitro and fractions absorbed in vivo.