Resveratrol (3,4’,5-trihydroxy-trans-stilbene, RES) is a non-flavonoid polyphenolic phytoalexin and belongs to the group of stilbenes found in grapes, peanuts, berries, and many natural foods . The chemical structure of RES is responsible for biological activity, which enables the interaction between cellular receptors and enzymes. RES has a potent antioxidant activity by targeting extracellular radical oxygen species when administered orally . RES has many pharmacological activities, including antioxidant, anti-inflammatory, anti-cancer, anti-microbial, anti-hypertensive, cardioprotective, and anti-diabetic, and formulations are being developed by pharmaceutical companies or academic research [3, 4]. RES is practically insoluble in water (0.03–0.05 mg/mL); however, it exhibits high membrane permeability (log P: 3.1) and belongs to the Biopharmaceutical Classification System (BCS) Class II drugs . Due to the very low bioavailability (< 5% of the oral dose is detected in plasma) and fast metabolism, the biological effectiveness of RES has been restricted to use in cosmetics, foods, and drugs [6, 7]. RES has two geometric isomers, cis- and trans-, trans isomer is the primary, biologically more active, and more stable natural form. However, RES is very sensitive to sunlight or artificial, and natural UV, heat, enzymes, and cis-isomerization can occur after light exposure [8, 9].
Nanocrystals, also known as nanosuspensions, are a feasible approach to increase water solubility, drug stability and overcome the limitations of BCS Class II drugs such as trans-RES by diminishing the particle size typically between 200–600 nm [10–12]. The primary advantages of nanocrystals are high-drug loading capacity, applicability to various administration routes, ease of scale-up, relatively low-cost formulation, and production processes . Several commercially available products (Rapamune, Emend, Avinza, Ritalin LA, Tricor) were released regarding formulation development and scale-up success of the system .
There are two main approaches to prepare nanocrystal formulations, top-down and bottom-up. In the top-down method, micrometre range drug crystals break up into nanoscale by high-pressure homogenization or wet ball grinding techniques . The bottom-up approaches are solvent evaporation, supercritical fluid, chemical, and anti-solvent precipitation . Among them, with the simplicity and cost-effectiveness benefits, the antisolvent precipitation method is the most common and effective technique to produce nanocrystals . In this method, the drug is dissolved in the organic solvent and added to the antisolvent phase immediately. Thus, the drug particles precipitate under the super-saturated conditions achieved by the solution transfer . Although top-down methods do not require organic solvents and are more beneficial for the industry, they usually need more prolonged formulation and production time. In addition, they consume higher energy resulting in heat and deformation of crystals, making it difficult to process the thermolabile compounds . On the contrary, the bottom-up method has some advantages, such as simple instruments, fewer validation parameters, and lower energy demand .
Because of the tendency to reduce the excessive surface energy, nanocrystals in suspension can agglomerate, or Ostwald ripening phenomenon can arise. Surfactants, polymers, or lipids can stabilize the nanocrystal system by generating steric and ionic stabilization . Nanocrystal dispersion can be solidified by lyophilization, spray drying, or fluid bed granulation to improve physical stability and develop solid dosage forms or transformed to semi-solid dosage forms, such as gels or films [16, 20].
Solid dosage forms, especially tablets, have always been the first choice for drug development and administration. However, geriatric and paediatric patients, and those who suffer from swallowing difficulty or vomiting, have the most compliance issues about the proper dosage forms for their needs . Orodispersible films (ODFs) can be advantageous for these patients with rapid disintegration in the mouth, no need for water intake, chew or swallow, and no risk of choking . According to European Pharmacopeia, the definition of ODFs are single or multilayered sheets of suitable materials to be placed in the mouth where they disperse rapidly . ODFs are prepared using methods of solvent casting, hot-melt extrusion, electrospinning, or printing (inkjet, flexographic, and 3D printing) . The solvent casting method is most common to produce ODFs. In this technique, the drug compound is dissolved or dispersed in a polymer solution. If necessary, plasticizers, taste-masking agents, and fillers can be added. After that, the polymer solution is cast with the desired thickness on a flat surface, dried, and films are collected . Nanocrystal-loaded ODFs can be an innovative drug delivery system for individual patient needs with enhanced solubility and stability properties of BCS Class II drugs.
The objective of the present study was to develop RES nanocrystals-loaded ODFs. Nanocrystals were prepared by the anti-solvent precipitation method. After obtaining nanoscale range particle size, RES nanocrystals were loaded into ODFs to develop easy-to-use patches and hence improve patient compliance. The characterization, disintegration, and in vitro release studies were conducted to evaluate the nanocrystal-loaded film formulations.