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APAP-induced liver injury (AILI) is a common cause of acute liver failure (ALF). Nobiletin (NOB) is a potential hepatoprotective agent for the treatment of APAP-induced liver injury. However, the poor solubility and low bioavailability of NOB hinders its application. In this study, a novel self-assembly nano-drug delivery system of nobiletin (solid dispersion of NOB, termed as NOB/SD) was developed based on solid dispersion technology to improve the bioavailability and hepatoprotective ability of NOB for APAP-induced liver injury therapy.PurposeAPAP-induced liver injury (AILI) is a common cause of acute liver failure (ALF). Nobiletin (NOB) is a potential hepatoprotective agent for the treatment of APAP-induced liver injury. However, the poor solubility and low bioavailability of NOB hinders its application. In this study, a novel self-assembly nano-drug delivery system of nobiletin (solid dispersion of NOB, termed as NOB/SD) was developed based on solid dispersion technology to improve the bioavailability and hepatoprotective ability of NOB for APAP-induced liver injury therapy.The optimized NOB/SD system was constructed using the amphiphilic copolymers of Soluplus and PVP/VA 64 via hot melt extrusion technology (HME). NOB/SD was characterized by solubility, physical interaction, drug release behavior, and stability. The bioavailability and hepatoprotective effects of NOB/SD were evaluated in vitro and in vivo.MethodsThe optimized NOB/SD system was constructed using the amphiphilic copolymers of Soluplus and PVP/VA 64 via hot melt extrusion technology (HME). NOB/SD was characterized by solubility, physical interaction, drug release behavior, and stability. The bioavailability and hepatoprotective effects of NOB/SD were evaluated in vitro and in vivo.NOB/SD maintained NOB in matrix carriers in a stable amorphous state, and self-assembled NOB-loaded nanomicelles in water. Nanostructures based on solid dispersion technology exhibited enhanced solubility, improved release behavior, and promoted cellular uptake and anti-apoptosis in vitro. NOB/SD displayed significantly improved bioavailability in healthy Sprague Dawley (SD) rats in vivo. Furthermore, NOB/SD alleviated the APAP-induced liver injury by improving anti-oxidative stress with reactive oxygen species (ROS) scavenging and nuclear factor erythroid 2-related factor 2 (Nrf2) activation.ResultsNOB/SD maintained NOB in matrix carriers in a stable amorphous state, and self-assembled NOB-loaded nanomicelles in water. Nanostructures based on solid dispersion technology exhibited enhanced solubility, improved release behavior, and promoted cellular uptake and anti-apoptosis in vitro. NOB/SD displayed significantly improved bioavailability in healthy Sprague Dawley (SD) rats in vivo. Furthermore, NOB/SD alleviated the APAP-induced liver injury by improving anti-oxidative stress with reactive oxygen species (ROS) scavenging and nuclear factor erythroid 2-related factor 2 (Nrf2) activation.These results suggested that NOB/SD could be considered as a promising hepatoprotective nano-drug delivery system for attenuating APAP-induced acute liver injury with superior bioavailability and efficient hepatoprotection, which might provide an effective strategy for APAP-induced acute liver injury prevention and treatment.ConclusionThese results suggested that NOB/SD could be considered as a promising hepatoprotective nano-drug delivery system for attenuating APAP-induced acute liver injury with superior bioavailability and efficient hepatoprotection, which might provide an effective strategy for APAP-induced acute liver injury prevention and treatment.

Tingjie Yin,* Lihui Dong,* Bei Cui, Lei Wang, Lifang Yin, Jianping Zhou, Meirong Huo State Key Laboratory of Natural Medicines, Department of Pharmaceutics, China Pharmaceutical University, Nanjing, People's Republic of China *These authors contributed equally tothis work Abstract: Clinically, paclitaxel (PTX) is one of most commonly prescribed therapies against a wide range of solid neoplasms. Despite its success, the clinical applicability of PTX (Taxol®) is severely hampered by systemic toxicities induced by Cremophor EL. While attempts to bypass the need for Cremophor EL have been developed through platforms such as Abraxane™, nab™ relies heavily on the use of organic solvents, namely, chloroform. The toxicity introduced by residual chloroform poses a potential risk to patient health. To mitigate the toxicities of toxic organic solvent-based manufacture methods, we have designed a method for the formulation of PTX nanosuspensions (PTX-PEG [polyethylene glycol]-HSA [human serum albumin]) that eliminates the dependence on toxic organic solvents. Coined the solid-dispersion technology, this technique permits the dispersion of PTX into PEG skeleton without the use of organic solvents or Cremophor EL as a solubilizer. Once the PTX-PEG dispersion is complete, the dispersion can be formulated with HSA into nanosuspensions suitable for intravenous administration. Additionally, the incorporation of PEG permits the prolonged circulation through the steric stabilization effect. Finally, HSA-mediated targeting permits active receptor-mediated endocytosis for enhanced tumor uptake and reduced side effects. By eliminating the need for both Cremophor EL and organic solvents while simultaneously increasing antitumor efficacy, this method provides a superior alternative to currently accepted methods for PTX delivery. Keywords: human serum albumin, nanosuspension, paclitaxel, polyethylene glycol, solid-dispersion technology

Oleanolic acid (OA) is an active ingredient of the traditional Chinese medicine (TCM) Fructus ligustri lucidi (FLL). Its clinical use is restricted because it is water-insoluble and has limited dosage forms of administration at present. Hence, the FFL dropping pills were prepared by the hot-melt method of solid dispersion technology. A 23 factorial design was used to examine the effects of the materials used to prepare the dropping pills (e.g., different ratios of PEG4000 and PEG6000, FLL extract loading, and percentage of Tween 80) on parameters such as dropping pill roundness, weight variation, and disintegration time. Moreover, 23 full factorial design was utilized to search for the optimal formulation for dissolution experiments. The results showed that the percentage of Tween 80 demonstrated significant effects on dropping pill roundness, weight variation, and disintegration time; FLL extract loading affected roundness and weight variation; and different ratios of PEG4000 and PEG6000 only affected disintegration time. The optimal formulation of the dropping pills released 70% of the drug after 30 min of dissolution release, which was faster than commercially available FLL Chinese medicines. Furthermore, the amount released was higher than that of commercially available formulations. In this study, a solid dispersion technique was used to successfully produce FLL dropping pills. In addition to improving the water insolubility of FLL and increasing the dissolution release percentage of the drug, we increased the application value of FLL and reduced the issues of traditional administration dosage forms.

Clinically, paclitaxel (PTX) is one of most commonly prescribed therapies against a wide range of solid neoplasms. Despite its success, the clinical applicability of PTX (Taxol) is severely hampered by systemic toxicities induced by Cremophor EL. While attempts to bypass the need for Cremophor EL have been developed through platforms such as Abraxane, nab relies heavily on the use of organic solvents, namely, chloroform. The toxicity introduced by residual chloroform poses a potential risk to patient health. To mitigate the toxicities of toxic organic solvent-based manufacture methods, we have designed a method for the formulation of PTX nanosuspensions (PTX-PEG [polyethylene glycol]-HSA [human serum albumin]) that eliminates the dependence on toxic organic solvents. Coined the solid-dispersion technology, this technique permits the dispersion of PTX into PEG skeleton without the use of organic solvents or Cremophor EL as a solubilizer. Once the PTX-PEG dispersion is complete, the dispersion can be formulated with HSA into nanosuspensions suitable for intravenous administration. Additionally, the incorporation of PEG permits the prolonged circulation through the steric stabilization effect. Finally, HSA-mediated targeting permits active receptor-mediated endocytosis for enhanced tumor uptake and reduced side effects. By eliminating the need for both Cremophor EL and organic solvents while simultaneously increasing antitumor efficacy, this method provides a superior alternative to currently accepted methods for PTX delivery.

The prevalence of active pharmaceutical ingredients (APIs) with low water solubility has experienced a significant increase in recent years. These APIs present challenges in formulation, particularly for oral dosage forms, despite their considerable therapeutic potential. Therefore, the improvement of solubility has become a major concern for pharmaceutical enterprises to increase the bioavailability of APIs. A promising formulation approach that can effectively improve the dissolution profile and the bioavailability of poorly water-soluble drugs is the utilization of amorphous systems. Numerous formulation methods have been developed to enhance poorly water-soluble drugs through amorphization systems, including co-amorphous formulations, amorphous solid dispersions (ASDs), and the use of mesoporous silica as a carrier. Furthermore, the successful enhancement of certain drugs with poor aqueous solubility through amorphization has led to their incorporation into various commercially available preparations, such as ASDs, where the crystalline structure of APIs is transformed into an amorphous state within a hydrophilic matrix. A novel approach, known as ternary solid dispersions (TSDs), has emerged to address the solubility and bioavailability challenges associated with amorphous drugs. Meanwhile, the introduction of a third component in the ASD and co-amorphous systems has demonstrated the potential to improve performance in terms of solubility, physical stability, and processability. This comprehensive review discusses the preparation and characterization of poorly water-soluble drugs in ternary solid dispersions and their mechanisms of drug release and physical stability.

Amorphous solid dispersions (ASDs) can increase the oral bioavailability of poorly soluble drugs. However, their use in drug development is comparably rare due to a lack of basic understanding of mechanisms governing drug liberation and absorption in vivo. Furthermore, the lack of a unified nomenclature hampers the interpretation and classification of research data. In this review, we therefore summarize and conceptualize mechanisms covering the dissolution of ASDs, formation of supersaturated ASD solutions, factors responsible for solution stabilization, drug uptake from ASD solutions, and drug distribution within these complex systems as well as effects of excipients. Furthermore, we discuss the importance of these findings on the development of ASDs. This improved overall understanding of these mechanisms will facilitate a rational ASD formulation development and will serve as a basis for further mechanistic research on drug delivery by ASDs.

The low water solubility of pharmacoactive molecules limits their pharmacological potential, but the solubility parameter cannot compromise, and so different approaches are employed to enhance their bioavailability. Pharmaceutically active molecules with low solubility convey a higher risk of failure for drug innovation and development. Pharmacokinetics, pharmacodynamics, and several other parameters, such as drug distribution, protein binding and absorption, are majorly affected by their solubility. Among all pharmaceutical dosage forms, oral dosage forms cover more than 50%, and the drug molecule should be water-soluble. For good therapeutic activity by the drug molecule on the target site, solubility and bioavailability are crucial factors. The pharmaceutical industry’s screening programs identified that around 40% of new chemical entities (NCEs) face various difficulties at the formulation and development stages. These pharmaceuticals demonstrate less solubility and bioavailability. Enhancement of the bioavailability and solubility of drugs is a significant challenge in the area of pharmaceutical formulations. According to the Classification of Biopharmaceutics, Class II and IV drugs (APIs) exhibit poor solubility, lower bioavailability, and less dissolution. Various technologies are discussed in this article to improve the solubility of poorly water-soluble drugs, for example, the complexation of active molecules, the utilization of emulsion formation, micelles, microemulsions, cosolvents, polymeric micelle preparation, particle size reduction technologies, pharmaceutical salts, prodrugs, the solid-state alternation technique, soft gel technology, drug nanocrystals, solid dispersion methods, crystal engineering techniques and nanomorph technology. This review mainly describes several other advanced methodologies for solubility and bioavailability enhancement, such as crystal engineering, micronization, solid dispersions, nano sizing, the use of cyclodextrins, solid lipid nanoparticles, colloidal drug delivery systems and drug conjugates, referring to a number of appropriate research reports.

A drug’s aqueous solubility is defined as the ability to dissolve in a particular solvent, and it is currently a major hurdle in bringing new drug molecules to the market. According to some estimates, up to 40% of commercialized products and 70–90% of drug candidates in the development stage are poorly soluble, which results in low bioavailability, diminished therapeutic effects, and dosage escalation. Because of this, solubility must be taken into consideration when developing and fabricating pharmaceutical products. To date, a number of approaches have been investigated to address the problem of poor solubility. This review article attempts to summarize several conventional methods utilized to increase the solubility of poorly soluble drugs. These methods include the principles of physical and chemical approaches such as particle size reduction, solid dispersion, supercritical fluid technology, cryogenic technology, inclusion complex formation techniques, and floating granules. It includes structural modification (i.e., prodrug, salt formation, co-crystallization, use of co-solvents, hydrotrophy, polymorphs, amorphous solid dispersions, and pH variation). Various nanotechnological approaches such as liposomes, nanoparticles, dendrimers, micelles, metal organic frameworks, nanogels, nanoemulsions, nanosuspension, carbon nanotubes, and so forth have also been widely investigated for solubility enhancement. All these approaches have brought forward the enhancement of the bioavailability of orally administered drugs by improving the solubility of poorly water-soluble drugs. However, the solubility issues have not been completely resolved, owing to several challenges associated with current approaches, such as reproducibility in large scale production. Considering that there is no universal approach for solving solubility issues, more research is needed to simplify the existing technologies, which could increase the number of commercially available products employing these techniques.

Co-amorphous drug delivery systems (CAMS) are characterized by the combination of two or more (initially crystalline) low molecular weight components that form a homogeneous single-phase amorphous system. Over the past decades, CAMS have been widely investigated as a promising approach to address the challenge of low water solubility of many active pharmaceutical ingredients. Most of the studies on CAMS were performed on a case-by-case basis, and only a few systematic studies are available. A quantitative analysis of the literature on CAMS under certain aspects highlights not only which aspects have been of great interest, but also which future developments are necessary to expand this research field. This review provides a comprehensive updated overview on the current published work on CAMS using a quantitative approach, focusing on three critical quality attributes of CAMS, i.e., co-formability, physical stability, and dissolution performance. Specifically, co-formability, molar ratio of drug and co-former, preparation methods, physical stability, and in vitro and in vivo performance were covered. For each aspect, a quantitative assessment on the current status was performed, allowing both recent advances and remaining research gaps to be identified. Furthermore, novel research aspects such as the design of ternary CAMS are discussed.

Approximately 40% of new chemical entities (NCEs), including anticancer drugs, have been reported as poorly water-soluble compounds. Anticancer drugs are classified into biologic drugs (monoclonal antibodies) and small molecule drugs (nonbiologic anticancer drugs) based on effectiveness and safety profile. Biologic drugs are administered by intravenous (IV) injection due to their large molecular weight, while small molecule drugs are preferentially administered by gastrointestinal route. Even though IV injection is the fastest route of administration and ensures complete bioavailability, this route of administration causes patient inconvenience to visit a hospital for anticancer treatments. In addition, IV administration can cause several side effects such as severe hypersensitivity, myelosuppression, neutropenia, and neurotoxicity. Oral administration is the preferred route for drug delivery due to several advantages such as low cost, pain avoidance, and safety. The main problem of NCEs is a limited aqueous solubility, resulting in poor absorption and low bioavailability. Therefore, improving oral bioavailability of poorly water-soluble drugs is a great challenge in the development of pharmaceutical dosage forms. Several methods such as solid dispersion, complexation, lipid-based systems, micronization, nanonization, and co-crystals were developed to improve the solubility of hydrophobic drugs. Recently, solid dispersion is one of the most widely used and successful techniques in formulation development. This review mainly discusses classification, methods for preparation of solid dispersions, and use of solid dispersion for improving solubility of poorly soluble anticancer drugs.