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Journal of Medicinal Chemistry Sep 2023The oxetane ring is an emergent, underexplored motif in drug discovery that shows attractive properties such as low molecular weight, high polarity, and marked... (Review)
Review
The oxetane ring is an emergent, underexplored motif in drug discovery that shows attractive properties such as low molecular weight, high polarity, and marked three-dimensionality. Oxetanes have garnered further interest as isosteres of carbonyl groups and as molecular tools to fine-tune physicochemical properties of drug compounds such as p, LogD, aqueous solubility, and metabolic clearance. This perspective highlights recent applications of oxetane motifs in drug discovery campaigns (2017-2022), with emphasis on the effect of the oxetane on medicinally relevant properties and on the building blocks used to incorporate the oxetane ring. Based on this analysis, we provide an overview of the potential benefits of appending an oxetane to a drug compound, as well as potential pitfalls, challenges, and future directions.
Topics: Drug Discovery; Ethers, Cyclic; Kinetics; Solubility
PubMed: 37676858
DOI: 10.1021/acs.jmedchem.3c01101 -
Drug Discovery Today Feb 2024Poor solubility of drugs and therapeutic candidates poses a significant challenge in drug research and development. Biopharmaceutical class II drugs exhibit limited... (Review)
Review
Poor solubility of drugs and therapeutic candidates poses a significant challenge in drug research and development. Biopharmaceutical class II drugs exhibit limited absorption because of their weak solubility and high permeability. Co-amorphous systems (CAMs) have been studied widely as a way to improve the solubility of drugs. This review summarizes recent advancements in dual-drug CAMs, including improvements in formulation, manufacturing, and solid-state characterization, and highlights the importance of enhancing solubility and stability. It emphasizes the potential synergistic effects of two drugs in CAMs and explores formulation strategies and challenges related to maintaining the amorphous state. Case studies demonstrate the successful application of CAMs in combination therapies that offer improved therapeutic efficacy.
Topics: Polymers; Solubility; Drug Stability
PubMed: 38141778
DOI: 10.1016/j.drudis.2023.103863 -
Nature Reviews. Chemistry Jan 2024Molecular chameleons possess a flexibility that allows them to dynamically shield or expose polar functionalities in response to the properties of the environment.... (Review)
Review
Molecular chameleons possess a flexibility that allows them to dynamically shield or expose polar functionalities in response to the properties of the environment. Although the concept of molecular chameleons was introduced already in 1970, interest in them has grown considerably since the 2010s, when drug discovery has focused to an increased extent on new chemical modalities. Such modalities include cyclic peptides, macrocycles and proteolysis-targeting chimeras, all of which reside in a chemical space far from that of traditional small-molecule drugs. Both cell permeability and aqueous solubility are required for the oral absorption of drugs. Engineering these properties, and potent target binding, into the larger new modalities is a more daunting task than for traditional small-molecule drugs. The ability of chameleons to adapt to different environments may be essential for success. In this Review, we provide both general and theoretical insights into the realm of molecular chameleons. We discuss why chameleons have come into fashion and provide a do-it-yourself toolbox for their design; we then provide a glimpse of how advanced in silico methods can support molecular chameleon design.
Topics: Drug Discovery; Peptides, Cyclic; Permeability; Solubility; Water
PubMed: 38123688
DOI: 10.1038/s41570-023-00563-1 -
Journal of Microencapsulation Dec 2023Propolis has beneficial health properties attributed to of phenolic compounds. However, its application is limited. Thus, encapsulation protects the bioactive compounds... (Review)
Review
Propolis has beneficial health properties attributed to of phenolic compounds. However, its application is limited. Thus, encapsulation protects the bioactive compounds of propolis from degradation, allowing their release under controlled and specific conditions and increasing their solubility. In addition to protecting flavonoids, encapsulation also minimises the undesirable characteristics of propolis, such as strong odour. We brought attention to the high antioxidant and antimicrobial activities of encapsulated propolis, and its maintained biological activity enables more uses in different areas. Encapsulated propolis can be applied in food products as an ingredient. This review describes recent advances in improving the bioactivity of propolis extracts by using encapsulation techniques, and biopolymer research strategies, focusing on applications in food products. Encapsulated propolis has a promising market perspective due to the industrial and scientific-technological advancement, the increase in the amount of research, the improvement of propolis extraction techniques, and the need of consumers for innovative products.
Topics: Propolis; Antioxidants; Phenols; Solubility; Flavonoids
PubMed: 37867427
DOI: 10.1080/02652048.2023.2274059 -
Food Chemistry Oct 2023Nanotechnology is an advanced field that has remarkable nutraceutical and food applications. Phyto-bioactive compounds (PBCs) play critical roles in promoting health and... (Review)
Review
Nanotechnology is an advanced field that has remarkable nutraceutical and food applications. Phyto-bioactive compounds (PBCs) play critical roles in promoting health and disease treatment. However, PBCs generally encounter several limitations that delay their widespread application. For example, most PBCs have low aqueous solubility, poor biostability, poor bioavailability, and a lack of target specificity. Moreover, the high concentrations of effective PBC doses also limit their application. As a result, encapsulating PBCs into an appropriate nanocarrier may increase their solubility and biostability and protect them from premature degradation. Moreover, nanoencapsulation could improve absorption and prolong circulation with a high opportunity for targeted delivery that may decrease unwanted toxicity. This review addresses the main parameters, variables, and barriers that control and affect oral PBC delivery. Moreover, this review discusses the potential role of biocompatible and biodegradable nanocarriers in improving the water solubility, chemical stability, bioavailability, and specificity/selectivity of PBCs.
Topics: Nanotechnology; Dietary Supplements; Solubility; Biological Availability; Nanoparticles; Drug Delivery Systems
PubMed: 37244187
DOI: 10.1016/j.foodchem.2023.136438 -
International Journal of Pharmaceutics Nov 2023Thiabendazole is an anthelmintic drug used to treat strongyloidiasis (threadworm), cutaneous and visceral larva migrans, trichinosis, and other parasites. The active...
Thiabendazole is an anthelmintic drug used to treat strongyloidiasis (threadworm), cutaneous and visceral larva migrans, trichinosis, and other parasites. The active pharmaceutical ingredient is typically administered orally as tablets that should be chewed before swallowing. Current formulations combine the active ingredient with excipients, including sodium saccharinate as a sweetener. Thiabendazole's low aqueous solubility hinders fast dissolution and absorption through the mucous membranes. We sought to reformulate this medicine to improve both solubility and palatability. We utilized the possibility of protonation of the azole nitrogen atom and selected four different hydrogen donors: saccharin, fumaric, maleic, and oxalic acids. Solvothermal synthesis resulted in salts with each co-former, whereas neat and liquid-assisted grinding enabled the synthesis of additional formulations. Product formation was observed by powder X-ray diffraction. To better understand the structural basis of the proton transfer, we solved the crystal structures of the salts with saccharin, maleic acid, and oxalic acid using single-crystal X-ray diffraction. The structure of the salt with fumaric acid was solved by powder X-ray diffraction. We further characterized the salts with vibrational spectroscopic and thermoanalytical methods. We report a broad tunability of the aqueous solubility of thiabendazole by salt formation. Reformulation with maleic acid provided a 60-fold increase in solubility, while saccharin and oxalic acid gave a modest improvement. Fumaric acid resulted in a solid with only slightly higher solubility. Furthermore, saccharin is a sweetener, while the acids taste sour. Therefore, the salts formed also result in an intrinsic improvement of palatability. These results can inform new strategies for oral and chewable tablet formulations for treating helminthic infections.
Topics: Salts; Saccharin; Powders; Thiabendazole; X-Ray Diffraction; Solubility; Anti-Infective Agents; Sweetening Agents; Tablets; Anthelmintics; Oxalic Acid
PubMed: 37863447
DOI: 10.1016/j.ijpharm.2023.123516 -
Journal of Pharmaceutical Sciences Mar 2024Targeted Protein degraders (TPDs) show promise in harnessing cellular machinery to eliminate disease-causing proteins, even those previously considered undruggable.... (Review)
Review
Targeted Protein degraders (TPDs) show promise in harnessing cellular machinery to eliminate disease-causing proteins, even those previously considered undruggable. Especially if protein turnover is low, targeted protein removal bestows lasting therapeutic effect over typical inhibition. The demonstrated safety and efficacy profile of clinical candidates has fueled the surge in the number of potential candidates across different therapeutic areas. As TPDs often do not comply with Lipinski's rule of five, developing novel TPDs and unlocking their full potential requires overcoming solubility, permeability and oral bioavailability challenges. Tailored in-vitro assays are key to precise profiling and optimization, propelling breakthroughs in targeted protein degradation.
Topics: Proteins; Proteolysis; Permeability; Solubility; Biological Availability
PubMed: 37926234
DOI: 10.1016/j.xphs.2023.10.023 -
Drug Development and Industrial Pharmacy Jun 2024In this research paper, an investigation has been made to assess the simultaneous effect of a solubility enhancement approach, i.e., hydrotropy on the solubility and...
OBJECTIVES
In this research paper, an investigation has been made to assess the simultaneous effect of a solubility enhancement approach, i.e., hydrotropy on the solubility and apparent permeability of piroxicam. The solubility of piroxicam (PRX) a BCS (biopharmaceutics classification system) class II drug has been increased using a mixed hydrotropy approach. This study is based on identifying the pattern of solubility-permeability interplay and confirming whether every solubility gain results in a concomitant decrease in permeability or permeability remains unaffected.
METHOD
Solid dispersions of PRX were formulated using two hydrotropes, viz., sodium benzoate (SB) and piperazine (PP) by solvent evaporation method. A comprehensive 3factorial design was employed to study the effect of hydrotropes on the solubility and permeability of PRX. Subsequently, PRX tablets containing these solid dispersions were formulated and evaluated.
KEY FINDINGS
SB and PP displayed a significant increase in the solubility of PRX ranging from 0.99 to 2.21 mg/mL for F1-F9 batches attributed to the synergistic effect of hydrotropes. However, there is a reduction in PRX permeability with increasing hydrotrope levels. The decline in permeability was notably less pronounced compared to the simultaneous rise in aqueous solubility of PRX.
CONCLUSION
An evident tradeoff between permeability and solubility emerged through the mixed hydrotropic solubilization for PRX. As PRX has generally higher intrinsic permeability, it has been assumed that this permeability loss will not affect the overall absorption of PRX. However, it may affect the absorption of drugs with limited permeability. Therefore, solubility permeability interplay should be investigated during solubility enhancement.
Topics: Piroxicam; Solubility; Permeability; Chemistry, Pharmaceutical; Tablets; Excipients; Solvents
PubMed: 38717346
DOI: 10.1080/03639045.2024.2349576 -
Chemical Record (New York, N.Y.) Aug 2023Ionic liquids (ILs) have been extensively used in drug formulation and delivery as designer solvents and other components because of their inherent tunability and useful... (Review)
Review
Ionic liquids (ILs) have been extensively used in drug formulation and delivery as designer solvents and other components because of their inherent tunability and useful physicochemical and biopharmaceutical properties. ILs can be used to manage some of the operational and functional challenges of drug delivery, including drug solubility, permeability, formulation instability, and in vivo systemic toxicity, that are associated with conventional organic solvents/agents. Furthermore, ILs have been recognized as potential solvents to address the polymorphism, limited solubility, poor permeability, instability, and low bioavailability of crystalline drugs. In this account, we discuss the technological progress and strategies toward designing biocompatible ILs and explore potential biomedical applications, namely the solubilization of small and macromolecular drugs, the creation of active pharmaceutical ingredients, and the delivery of pharmaceuticals.
Topics: Pharmaceutical Preparations; Ionic Liquids; Solvents; Solubility; Drug Delivery Systems
PubMed: 37042429
DOI: 10.1002/tcr.202300026 -
International Journal of Nanomedicine 2024Nanosuspensions have garnered recent attention as a promising strategy for mitigating the bioavailability challenges of hydrophobic drugs, particularly those... (Review)
Review
Nanosuspensions have garnered recent attention as a promising strategy for mitigating the bioavailability challenges of hydrophobic drugs, particularly those characterized by poor solubility in both aqueous and organic environments. Addressing solubility issues associated with poorly water-soluble drugs has largely resolved the need to enhance drug absorption and bioavailability. As mucosal formulations and topical administration progress in the future, nanosuspension drug delivery, straightforward formulation techniques, and versatile applications will continue to be subjects of interest. Nanosuspensions have undergone extensive scrutiny in preparation for topical applications, encompassing ocular, pulmonary, and dermal usage. Among the numerous methods aimed at improving cutaneous application, nanocrystals represent a relatively recent yet profoundly intriguing approach. Despite the increasing availability of various nanosuspension products, primarily designed for oral administration, only a limited number of studies have explored skin permeability and drug accumulation in the context of nanosuspensions. Nevertheless, the scant published research unequivocally underscores the potential of this approach for enhancing cutaneous bioavailability, particularly for active ingredients with low to medium solubility. Nanocrystals exhibit increased skin adhesiveness in addition to heightened saturation solubility and dissolution rate, thereby augmenting cutaneous distribution. The article provides a comprehensive overview of nanosuspensions for topical application. The methodology employed is robust, with a well-defined experimental design; however, the limited sample size raises concerns about the generalizability of the findings. While the results demonstrate promising outcomes in terms of enhanced drug delivery, the discussion falls short of addressing certain limitations. Additionally, the references largely focus on recent studies, but a more diverse inclusion of historical perspectives could offer a more holistic view of the subject.
Topics: Humans; Suspensions; Drug Delivery Systems; Biological Availability; Nanoparticles; Administration, Oral; Solubility; Particle Size
PubMed: 38293608
DOI: 10.2147/IJN.S447429