Comparative Study on Cannabidiol-Loaded Solubilizing Systems for Improvement of Oral Bioavailability: Liposome and Cyclodextrin-Based Formulations.

Food Effect on Oral Bioavailability: Old and New Questions.

Professor William I. Higuchi: Teacher and Scientist

Liposomal Avicequinone-B formulations: Aqueous solubility, physicochemical properties and apoptotic effects on cutaneous squamous cell carcinoma cells

Food, gastrointestinal pH, and models of oral drug absorption

Stealth Amphotericin B nanoparticles for oral drug delivery: In vitro optimization

Phytochemicals have gained significant recognition for their potential therapeutic uses against a variety of human diseases. However, the poor water solubility, limited intestinal absorption and low water stability of phytochemicals generally prevent from achieving a high oral bioavailability and even detectable plasma levels of the parent compound. Dose escalation is not always a solution to address limited oral bioavailability, and may increase the risk of adverse events, most frequently in the gastrointestinal system [1]. Low water solubility is a common reason for the limited bioavailability of drug candidates because passing through the unstirred aqueous layer on the surface of the intestinal epithelium is a pre-requisite for the intestinal absorption of compounds. It has been estimated that over 40 % of the drugs being identified through combinatorial screening programs are poorly soluble in water [2]. Therefore, formulation improvement into highly stable, water-soluble and orally bioavailable forms is regarded as a prerequisite for the clinical application of phytochemicals. Nanotechnology has emerged as an efficient tool to address the problems regarding solubility, stability and oral bioavailability of phytochemicals [3]. Several nano-sized delivery systems have been utilized to enhance the physicochemical properties of phytochemicals. Characteristics of the most common biocompatible and biodegradable nanoparticulate systems used for the delivery of natural products are summarized in Table 1. Nanoparticulate delivery systems confer a number of advantages, including facilitated transport of incorporated phytochemicals across the biological barriers, enhanced bioavailability of poorly water-soluble phytochemicals, targeted delivery of phytochemicals, protection of sensitive compounds from biological and environmental degradation, and controlled release [4]. Some famous examples of nanoformulated phytochemicals are shown in Table 2 [5-7]. Furthermore, many nanomaterials are being studied in clinical trials or have been approved by the Food and Drug Administration to be used in humans. Liposomal daunorubicin (Daunoxome®; described in patents EP0004467 and US20070286897) and albumin-bound paclitaxel (Abraxane®, described in patents WO2014105644 and WO2008057562) are two breakthrough examples of successful formulation of natural products using nanotechnology-based approaches. Table 2 summarizes some pharmacologically important phytochemicals with optimized nanoformulations [8, 9]. Curcumin is another important anti-cancer and cardioprotective phytopharmaceutical [10-12] for which various nanoformulations have been developed [12], as described in patents WO2013108270 and EP2349237. While nanotechnology offers promising solutions for the formulation of phytochemicals, some challenges still remain to be overcome before developing any nanoparticulate system to be used in clinical practice. These considerations include potential long-term toxicity of nanoparticles, non-specific uptake into cells, off-target biodistribution and tissue accumulation, and costly and complicated manufacturing process of some nanocomposites particularly in the targeted forms [8]. In spite of these challenges, biocompatible and biodegradable nanocarriers are increasingly finding applications in pharmaceutical and nutraceutical industries. Future investigations should address long-term safety issues of nanomaterials particularly when used repeatedly for chronic diseases.

Although resveratrol (RES) possesses potentially attractive activities, it has poor oral bioavailability due to its poor solubility. Solid dispersion (SD) is an efficient strategy to address the restricted dissolution rate and poor bioavailability of compounds that have poor water solubility. In this study, resveratrol solid dispersion (RES-SD) was prepared with mixture carriers through the melt method and optimized by an orthogonal array experimental design. The physicochemical properties and oral absorption of RES-SD formulations in vivo were measured. Analyses indicated that RES was dispersed in the optimal RES-SD formulation in the form of amorphous molecularly dispersed particles; as a result, the optimal SD exhibited a more than 80-fold increase in solubility and the dissolution rate was significantly improved relative to RES. Furthermore, pharmacokinetic studies in mice indicated that the optimal RES-SD formulation exhibited significantly improved RES oral bioavailability. Based on these findings, RES–SD developed through melt method was suitable for industrial production and avoid solvent remained. Moreover, the RES-SD with PEG6000 and F68 appears to be a promising approach to enhance the dissolution, bioavailability of RES.

Nanodispersion of lutein with use of metastable polymorph for improved dissolution and oral absorption

R-α-lipoic acid (RLA) and dihydrolipoic acid (DHLA), a reduced form of RLA, are potent endogenous antioxidants that can reduce oxidative damage. Despite their numerous nutraceutical potentials, clinical applications of RLA are still limited due to its poor solubility and stability problems. This study aimed to develop an RLA-loaded liposome (LIP/RLA) for the improvement of nutraceutical properties. LIP/RLA was developed by a typical solvent injection method. Uniform liposomes of LIP/RLA were observed by transmission electron microscopy, and the mean particle size was calculated to be ∼150 nm from the data of dynamic light scattering. LIP/RLA could prevent the degradation of RLA even under acidic conditions (pH 1.2) possibly due to the encapsulation of RLA into the liposomal structure. In the release test under pH6.8 with lipase, LIP/RLA showed relatively rapid release of RLA, possibly due to the lipolysis of phospholipids by lipase. After the oral administration of LIP/RLA (10 mg-RLA/kg, p.o.) in rats, the systemic exposures of RLA and DHLA increased by 2.8- and 5.8-fold, respectively. In a rat model of acute hepatic injury induced by carbon tetrachloride (CCl4) (0.7 mL-CCl4/kg, p.o.), orally dosed LIP/RLA (3 mg-RLA/kg, p.o.) resulted in 78.7% and 86.4% reductions of plasma alanine aminotransferase, and aspartate aminotransferase, respectively; however, RLA was found to be less effective possibly due to the poor oral absorption. The RLA-loaded liposomal system might be a promising carrier for poorly water-soluble materials with poor stability under acidic conditions, as well as RLA, to improve their oral absorption and nutraceutical properties.

To explore the effects of particle size distribution on its physicochemical, functional, and structural properties, alfalfa leaf powders with mean particle sizes (D50) of 506.1, 246.3, 209.8, 92.01, and 20.68 μm were prepared by sieving. The physicochemical, functional, and structural properties of alfalfa were compared, and correlation and principal component analyses were conducted. As the D50 of alfalfa leaf decreased, the bulk density, tap density, and the swelling capacity increased first and then decreased, but the compressibility, transition temperature, and melting temperature exhibited an opposite trend. The solubility, lightness, and inhibition of angiotensin-converting enzymes and tyrosinase were enhanced. Specifically, the alfalfa leaf with a D50 of 209.8 μm exhibited a higher bulk density and swelling capacity and a lower compressibility, transition temperature, and melting temperature. The alfalfa leaf with a D50 of 20.68 μm presented better solubility, lightness, and inhibition of angiotensin-converting enzymes and tyrosinase. Additionally, the surface roughness and the number of surface hydroxyls improved and the crystallinity index decreased, but the type of surface functional groups was unchanged. These changes in microstructure can provide an explanation for the trend of the physicochemical and functional properties. Moreover, based on the results of the correlation analysis and principal component analysis, it can be concluded that there are strong correlations among the particle size, physicochemical properties, and functional properties of alfalfa leaf. Overall, this conclusion can help determine the appropriate grinding particle size range for alfalfa leaf in different functional food products.

In this study, RESS process was applied for recrystallization and micronization of three model drugs including antipyrine, benzocaine and 4-dimethylaminoantipyrine. After RESS treatment, the physicochemical properties of the precipitated particles were evaluated by SEM, DSC, FTIR, and XRD analysis. In addition, the dissolution rate studies were conducted to investigate the influence of particle size reduction on the bioavailability of drug. For antipyrine, the particle size was significantly reduced from 35.12 μm to 2.28 μm using RESS method. The processed samples showed narrow size distribution. The variation of some process parameters including extraction temperature, pre-expansion temperature and post-expansion temperature had slight effect on the mean particle size. It was discovered that micronized antipyrine did not revealed noticeable enhancement on the dissolution profile. After RESS process, benzocaine particles were successfully micronized from original size of 153.33 μm to around 3 μm with much narrower size distribution. The effect of pre-expansion temperature, post-expansion temperature and nozzle diameter on the mean particle size and size distribution was studied; and slight influence was noticeable. Dissolution studies showed that dissolution rate of processed particles was enhanced by 2.44 times with new dissolution profile. The untreated 4-dimethylaminoantipyrine was large in size with very wide size distribution ranging from 22 μm to 2468 μm. With RESS treatment, the mean particle size of the drugs was drastically reduced to submicron size, in the range of 1.92 to 7.64 μm. Furthermore, very uniform and narrow size distribution was obtained after RESS micronization. Several operating parameters including pre-expansion temperature, post-expansion temperature and nozzle diameter were investigated. It was proved that pre-expansion temperature and post-expansion temperature have significant effect on the mean particle size, size distribution and morphology. In addition, DSC and XRD results showed that there was polymorphic transformation during RESS process. From dissolution rate study, the results demonstrated that higher dissolution efficiency (enhance degree = 4.37) was obtained as a consequence of significant particle size reduction.

Introduction: Oral drug delivery is the most favored route of drug administration. However, poor oral bioavailability is one of the leading reasons for insufficient clinical efficacy. Improving oral absorption of drugs with low water solubility and/or low intestinal membrane permeability is an active field of research. Cocrystallization of drugs with appropriate coformers is a promising approach for enhancing oral bioavailability. Methods: In the present review, we have focused on recent advances that have been made in improving oral absorption through cocrystallization. The covered areas include supersaturation and its importance on oral absorption of cocrystals, permeability of cocrystals through membranes, drug-coformer pharmacokinetic (PK) interactions, conducting in vivo-in vitro correlations for cocrystals. Additionally, a discussion has been made on the integration of nanocrystal technology with supramolecular design. Marketed cocrystal products and PK studies in human subjects are also reported. Results: Considering supersaturation and consequent precipitation properties is necessary when evaluating dissolution and bioavailability of cocrystals. Appropriate excipients should be included to control precipitation kinetics and to capture solubility advantage of cocrystals. Beside to solubility, cocrystals may modify membrane permeability of drugs. Therefore, cocrystals can find applications in improving oral bioavailability of poorly permeable drugs. It has been shown that cocrystals may interrupt cellular integrity of cellular monolayers which can raise toxicity concerns. Some of coformers may interact with intestinal absorption of drugs through changing intestinal blood flow, metabolism and inhibiting efflux pumps. Therefore, caution should be taken into account when conducting bioavailability studies. Nanosized cocrystals have shown a high potential towards improving absorption of poorly soluble drugs. Conclusions: Cocrystals have found their way from the proof-of-principle stage to the clinic. Up to now, at least two cocrystal products have gained approval from regulatory bodies. However, there are remaining challenges on safety, predicting in vivo behavior and revealing real potential of cocrystals in the human.

Novel formulation strategies for enhancing oral delivery of methoxyflavones in Kaempferia parviflora by SMEDDS or complexation with 2-hydroxypropyl-β-cyclodextrin

Introduction: Poor solubility is a common challenge in pharmaceuticals, hindering oral bioavailability. High throughput screening has led to an increase in poorly soluble drug candidates. Enhancing solubility and dissolution rates is crucial for drug development. Various methods, including solid dispersion, aim to improve solubility. A solid dispersion formulation process involves dispersing one or more active chemicals in a solid state within an inert carrier or matrix. It can be made using solvent, melting, or melting-solvent procedures, among other techniques. By increasing the surface area and dispersibility of poorly soluble pharmaceuticals, this method improves their solubility and rate of dissolution, ultimately leading to an improvement in bioavailability. Background: Nifedipine solid dispersion emerged in the late 1970s to address its poor solubility and erratic bioavailability for cardiovascular treatment. Researchers explored methods like fusion, solvent evaporation, and melt extrusion to enhance its solubility and dissolution rate. Over the years, these efforts resulted in commercial products, highlighting the importance of solid dispersion in improving drug delivery and patient outcomes for nifedipine therapy. Aim: The aim of this work is to use the surface solid dispersion approach to increase the solubility of nifedipine. Objective: The objective of the study is to develop surface solid dispersion formulations of nifedipine, evaluate their physicochemical properties, assess solubility enhancement, analyze dissolution behavior and stability, and determine the potential of this technique to enhance the pharmaceutical performance of nifedipine. Materials and Methods: Nifedipine was dissolved in the solvent-ethanol, and a carrier was then added at various drug-to-carrier ratios. The mixture was allowed to sit for an hour before the solvent was evaporated on a water bath at 40-42ºC with occasional stirring. The resulting dried mass was pulverized, sieved, and then dried further at 40ºC for 3 hours. For further study the powder was stored in desiccators. Results: Formulation S3 shows better increase in the solubility by solid dispersion technique, increases solubility from 0.002576 ± 0.00013 to 0.04379 ± 0.00013. Dissolution profile data found to be improved from 98.45 ± 0.41 to 99.57 ± 0.088%. Conclusion: This study explores the challenge of poor solubility in pharmaceutical formulation, focusing on Nifedipine. Surface solid dispersions (SSDs) are investigated as a solution, with various polymers showing promise in enhancing solubility. SSDs, particularly with sodium starch glycolate (SSG) as a carrier, significantly improve solubility, as confirmed by saturation solubility studies. Evaluation indicates SSD efficacy, with S3 emerging as a promising formulation. This study underscores the potential of SSD technology in addressing solubility challenges and improving drug bioavailability.

Lipid-based formulations encompass a wide variety of delivery modes and technologies, ranging from immediate release to sustained release formulations, from liquids to semi-solids, from crystalline suspensions to lipid solutions, from systems containing small-molecule active pharmaceutical ingredients (APIs) to those containing more complex peptide-based molecules, and finally from those intended for oral administrations through to topicals and parenterals. The flexibility of lipid formulation technologies provides the potential to modify pharmaceutical properties such as stability and ease of manufacture, and pharmacokinetic properties such as enhanced absorption and bioavailability, sustained exposure and targeted delivery. With the exception of liposomal technologies (that represent a class of delivery system in their own right and have not been considered here), much of the interest in lipid-based formulations has focused on their use to enhance the oral bioavailability of poorly water-soluble drugs. Drugs with low water solubility continue to present a formidable challenge to effective drug development (1) and commonly show poor, variable, and fooddependent absorption and bioavailability after oral administration. Whilst great strides have been made in lead optimization strategies to design-out the physicochemical properties that lead to low water solubility, in many cases, structural changes that increase solubility also result in unacceptable reductions in potency. Indeed, the majority of reports describing changes in the patterns of physicochemical properties for new drug discovery candidates suggest that trends towards low water solubility are increasing rather than decreasing (2,3). Formulation strategies that facilitate the ‘rescue’ of compounds with intrinsically low water solubility, and that provide for robust and reproducible exposure after oral administration, therefore remain an important weapon in the drug development armory. Several strategies that enable effective delivery of poorly water-soluble compounds are apparent (1) and, in general, may be stratified as technologies that modify solute–solute interactions in the solid state, that enhance solute–solvent interactions in solution, that promote dissolution via changes in surface area, or combinations of the three approaches. Formulation technologies to enhance solubility and dissolution rate include salt formulation,modification of crystal form (amorphous, cocrystals, polymorphs), particle size reduction/nanomilling, alteration of solution/solubilisation conditions (cosolvents, surfactants, cyclodextrins etc.), and approaches such as solid dispersions and lipidbased formulations that may, in practice, achieve a number of these goals. For example, many solid dispersion and lipid-based formulations contain drug in a non-crystalline (amorphous/molecularly dispersed) form, circumventing the challenge to solubility provided by the crystal lattice, and also provide for ongoing solubilisation or stabilization of supersaturation via the inclusion of surfactants, lipids and/or polymers. The current theme issue focuses on the potential utility of lipid-based formulations as a means of enhancing the oral bioavailability of poorly water-soluble drugs. In addition, several manuscripts provide insight into the broader application of lipid-based drug delivery technologies, for example, to facilitate parenteral or site-specific delivery of lipophilic compounds. This is not to suggest any inherent superiority of lipid-based formulation technologies over others, and the appropriate choice of an enabling technology is clearly drug specific. However, for poorly water-soluble lipophilic drugs, lipid-based formulations provide a tried and tested delivery solution to overcome poor and variable oral bioavailability and are increasingly being utilized as a vehicle to achieve modulated or targeted delivery. Nonetheless, whilst lipid-based formulations have been used to good effect in a range of oral and parenteral drug products (4), several challenges to their broader utility remain. These C. J. H. Porter (*) :H. D. Williams :N. L. Trevaskis Drug Delivery Disposition and Dynamics Monash Institute of Pharmaceutical Sciences Monash University (Parkville campus) Melbourne, Victoria, Australia e-mail: chris.porter@monash.edu