Pharmaceutical Research

Lu, Yi; Qi, Jianping; Wu, Wei

doi: 10.1007/s11095-022-03362-3pmid: 35974125

Abstract Ionic liquids (ILs) recently draw attention for addressing unmet needs in biomedicines. By converting solids into liquids, ILs are emerging as novel platforms to overcome some critical drawbacks associated with the application of solid or crystalline active pharmaceutical ingredients (APIs). ILs have shown promise in liquidizing or solubilizing APIs, or as green solvents, novel permeation enhancers or active ingredients, alone or synergistically with APIs. Meanwhile, challenges turn up in company with the deepening understanding of ILs as drug delivery carrier systems. This perspective aims to provide a sketchy overview on the status quo with specific attention paid to new problems arising from the utilization of ILs-based technologies in drug delivery.

Ali, Md. Korban; Moshikur, Rahman Md; Goto, Masahiro; Moniruzzaman, Muhammad

doi: 10.1007/s11095-022-03322-xpmid: 35773446

Ionic liquids (ILs) have attracted growing interest as designer solvents/materials for exploring unrealized functions in many areas of research including drug formulations and delivery owing to their inherent tunable physicochemical and biological properties. The use of ILs in the pharmaceutical industry can address challenges related to the use of conventional organic solvent-based chemical permeation enhancers. Their tunability in forming ion pairs with a diverse range of ions enables the task-specific optimization of ILs at the molecular level. In particular, ILs comprising second- and third-generation cations and anions have been extensively used to design biocompatible drug delivery systems to address the challenges related to conventional topical and transdermal drug delivery, including limited permeability, high cytotoxicity, and skin irritation. This review highlights the progress in IL-related research with particular emphasis on the very recent conceptual developments in transdermal drug delivery. Technological advancement and approaches for the formation of IL-based topical and transdermal delivery systems, as well as their promising application in drug delivery, are also discussed.

Jiang, Linxia; Sun, Yi; Lu, An; Wang, Xiangyu; Shi, Yujie

doi: 10.1007/s11095-022-03260-8pmid: 35449344

Oral administration is the most preferred route for drug administration in clinic. However, due to unsatisfactory physicochemical properties of drugs and various physiological barriers, the oral bioavailability of most poorly water-soluble and macromolecules drugs is low and the therapeutic effect is unsatisfactory. Ionic liquids (ILs), molten salts with unique properties, show amazing potential for oral delivery. In addition to being able to form active pharmaceutical ingredients based ILs (API-ILs) to overcome drug solubility and polymorphism issues, ILs have also been used to enhance the solubility of poorly soluble drugs, enhance drug stability in the gastrointestinal environment, improve drug permeability in intestinal mucus, and facilitate drug penetration across the intestinal epithelial barrier. Furthermore, ILs were attempted as formulation components to develop novel oral drug delivery systems. This review focus on the application progress of ILs in oral drug delivery and the mechanisms. The challenges and perspectives of the development of ILs-based oral delivery systems are also discussed.Graphical AbstractThis article reviews the latest advances of ionic liquids for oral drug delivery, focusing on the application and related mechanisms of ionic liquids in improving the drug physicochemical properties and enhancing drug delivery across physiological barriers.[graphic not available: see fulltext]

Qader, Idrees B.; Prasad, Kamalesh

doi: 10.1007/s11095-022-03315-wpmid: 35739370

The field of Ionic liquids (ILs) and deep eutectic solvents (DESs) is continuously expanding due to their exceptional unique properties and highly tunable nature, which finds applications in broad areas of modern science. Considering numerous possible IL and DES combinations prepared with active pharmaceutical ingredients (APIs), they find applications in pharmaceutical sciences. They can also serve as potential components of drug formulations and hence they have drawn the attention of formulation scientists. Herein, the concept of pharmaceutical ILs and DESs are discussed briefly. The possible applications of these solvent systems for slow drug delivery including nanoscale drug delivery are discussed citing various examples from the published literature. Although the ILs and DESs are found to be suitable for various drug delivery applications but still none of the slow drug delivery vehicles based on these solvents is in practical use. The data relating to long-term toxicity upon administration in the human body followed by various safety evaluations, clinical trials, etc. are pending for such new drug delivery systems. However, proof of concept studies done on the retention of biological activities in the ionic form is quite encouraging and such studies indicate the possibility of application of such new systems in the development of biomedical research and related industries in near future.

Dib, Nahir; Silber, Juana J.; Correa, N. Mariano; Falcone, R. Dario

doi: 10.1007/s11095-022-03342-7pmid: 35854078

The present review describes the state of the art in the conversion of pharmaceutically active ingredients (API) in amphiphilic Ionic Liquids (ILs) as alternative drug delivery systems. In particular, we focus our attention on the compounds generated by ionic exchange and without original counterions which generate different systems in comparison with the simple mixtures. In water, these new amphiphiles show similar or even better properties as surfactants in comparison with their precursors. Cations such as 1-alkyl-3-methyl-imidazolium and anions such as dioctyl sulfosuccinate or sodium dodecyl sulfate appear as the amphiphilic components most studied. In conclusion, this work shows interesting information on several promissory compounds and they appear as an interesting challenge to extend the application of ILs in the medical field.

Fang, Zhezheng; Zheng, Xianzi; Li, Lu; Qi, Jianping; Wu, Wei; Lu, Yi

doi: 10.1007/s11095-022-03336-5pmid: 35879499

Antimicrobial resistance has become a serious threat to global health. New antimicrobials are thus urgently needed. Ionic liquids (ILs), salts consisting of organic cations and anions with melting points less than 100°C, have been recently found to be promising in antimicrobial field as they may disrupt the bacterial wall and membrane and consequently lead to cell leakage and death. Different types of antimicrobial ILs are introduced in the review, including cationic, polymeric, and anionic ILs. Being the main type of the antimicrobial ILs, the review focuses on the structure and the antimicrobial mechanisms of cationic ILs. The quantitative structure-activity relationship (QSAR) models of the cationic ILs are also included. Increase in alkyl chain length and lipophilicity is beneficial to increase the antimicrobial effects of cationic ILs. Polymeric ILs are homopolymers of monomer ILs or copolymers of ILs and other monomers. They have great potential in the field of antibiotics as they provide stronger antimicrobial effects than the sum of the monomer ILs. Anionic ILs are composed of existing anionic antibiotics and organic cations, being capable to enhance the solubility and bioavailability of the original form. Nonetheless, the medical application of antimicrobial ILs is limited by the toxicity. The structural optimization aided by QSAR model and combination with existing antibiotics may provide a solution to this problem and expand the application range of ILs in antimicrobial field.Graphical Abstract[graphic not available: see fulltext]

Lai, Anthony; Leong, Nathania; Zheng, Dan; Ford, Leigh; Nguyen, Tri-Hung; Williams, Hywel D.; Benameur, Hassan; Scammells, Peter J.; Porter, Christopher J. H.

doi: 10.1007/s11095-022-03305-ypmid: 35661084

PurposeThe use of ionic liquids (ILs) in drug delivery has focused attention on non-toxic IL counterions. Cationic lipids can be used to form ILs with weakly acidic drugs to enhance drug loading in lipid-based formulations (LBFs). However, cationic lipids are typically toxic. Here we explore the use of lipoaminoacids (LAAs) as cationic IL counterions that degrade or digest in vivo to non-toxic components.MethodsLAAs were synthesised via esterification of amino acids with fatty alcohols to produce potentially digestible cationic LAAs. The LAAs were employed to form ILs with tolfenamic acid (Tol) and the Tol ILs loaded into LBF and examined in vitro and in vivo.ResultsCationic LAAs complexed with Tol to generate lipophilic Tol ILs with high drug loading in LBFs. Assessment of the LAA under simulated digestion conditions revealed that they were susceptible to enzymatic degradation under intestinal conditions, forming biocompatible FAs and amino acids. In vitro dispersion and digestion studies of Tol ILs revealed that formulations containing digestible Tol ILs were able to maintain drug dispersion and solubilisation whilst the LAA were breaking down under digesting conditions. Finally, in vivo oral bioavailability studies demonstrated that oral delivery of a LBF containing a Tol IL comprising a digestible cationic lipid counterion was able to successfully support effective oral delivery of Tol.ConclusionsDigestible LAA cationic lipids are potential IL counterions for weakly acidic drug molecules and digest in situ to form non-toxic breakdown products.

Wu, Xiying; Xuan, Jingjing; Yu, Qin; Wu, Wei; Lu, Yi; Zhu, Quangang; Chen, Zhongjian; Qi, Jianping

doi: 10.1007/s11095-022-03238-6pmid: 35352282

PurposeThe aim of this study is to convert tretinoin (Tr), an active pharmaceutical ingredient (API), into ionic liquid for improving aqueous solubility and permeability of Tr in transdermal drug delivery applications.MethodsThree ionic liquids of Tr (TrILs) were synthesized through neutralization reactions, which were characterized to confirm the compositions and ionic interactions. The in vitro drug release studies and skin penetration tests were carried out to assess the performance of formulations containing TrILs.ResultsThe TrIL formed by choline and Tr at the molar ratio of 2:1 (2[Ch][Tr]), was found to have prominent solubility, stability as well as permeability. In contrast with the insoluble Tr, 2[Ch][Tr] presented as clear and transparent aqueous solution even after diluted to 14%. The aqueous solution of 2[Ch][Tr] demonstrated better permeation effect, of which the solution with 20% of 2[Ch][Tr] showed the optimal delivery efficiency in both epidermis (2.09 ± 0.18‰) and dermis (3.31 ± 0.48‰), realizing the improvement on the permeability of API. Meanwhile, TrILs can be easily fabricated as o/w emulsions as transdermal formulation. The emulsions are also able to improve the skin permeability of Tr, though the enhanced effect is inferior to TrILs solutions.ConclusionsIonic liquid technology can be used to improve solubility and permeability of Tr, providing a high potential strategy for the development of topical formulations and the desired transdermal application of drugs.

Xiao, Suyun; Wang, Liyun; Han, Wei; Gu, Liyun; Cui, Xiuming; Wang, Chengxiao

doi: 10.1007/s11095-022-03239-5pmid: 35359240

In this study, a novel hydrogel system incorporating an amino acid–based deep eutectic solvent (DES) was prepared, and the skin-permeation enhancement of traditional Chinese herb medicine was evaluated using “sanwujiaowan” extract as the model formula. Briefly, a DES–extract complex was constructed by co-heating the herb formula extracts with the amino acid as the hydrogen receptor and citric acid as the hydrogen donor. The DES–extract complex demonstrated excellent dissolution and skin permeability of the complicated ingredients in the extracts. Consequently, the DES–extract complex was introduced to a hydrogel system, which showed better mechanical properties and viscoelasticity performance. Using a collagen-induced arthritis rat model, the DES–hydrogels exerted an enhanced therapeutic effect that significantly reduced the inflammatory response with systemic toxicity of the extracts. Therefore, our work suggests a novel strategy for synergistic transdermal delivery of Chinese herb medicine and local treatments for rheumatoid arthritis.

Hitaishi, Prashant; Seth, Ajit; Mitra, Saheli; Ghosh, Sajal K.

doi: 10.1007/s11095-022-03348-1pmid: 35902532

This article presents the effects of an imidazolium-based ionic liquid (IL) on the thermodynamics and in-plane viscoelastic properties of model membranes of anionic phospholipids. The negative Zeta potential of multilamellar vesicles of 14 carbon lipid 1,2-dimyristoyl-sn-glycero-3-phospho-(1'-rac-glycerol) (DMPG) is observed to reduce due to the presence of few mole % of an IL 1-butyl-3-methylimidazolium tetrafluoroborate ([BMIM][BF4]). The effect was found to be stronger on enhancing the chain length of the lipid. The surface pressure–area isotherms of lipid monolayer formed at air–water interface are modified by the IL reducing the effective area per molecule. Further, the equilibrium elasticity of the film is altered depending upon the thermodynamic phase of the lipids. While the presence of the IL in the DMPG lipid makes it ordered in the gel phase by reducing the entropy, the effect is opposite in the fluid phase. The in-plane viscoelastic parameters of the lipid film is quantified by dilation rheology using the oscillatory barriers of a Langmuir trough. Even though the low chain lipid DMPG does not show any effect of IL on its storage and loss moduli, the longer chain lipids exhibit a prominent effect in the liquid extended (LE) phase. Further, the dynamic response of the lipid film is found to be distinctly different in the liquid condensed (LC) phase from that of the LE phase.