Name: Desarrollo, caracterización y evaluación de sistemas de líquidos iónicos basados en CAGE para administración transdérmica (Video) | JoVE Journal
Uploaded: 2025-09-26T13:20:00.000+00:00
Duration: 9 min 44 s
Description: Aprende a preparar líquidos iónicos basados en CAGE con métodos estandarizados para garantizar reproducibilidad entre laboratorios. Este protocolo optimiza flujos de trabajo en ciencia de materiales y bioquímica.

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This work was supported by the LEO Foundation grant no. LF15007 and LF-FE-23-700013.

All experimental procedures were carried out in compliance with the European Union Directive 2010/63 and were approved by the Danish Veterinary and Food Administration (License No. DK-13-oth-931833).
1. CAGE preparation by salt metathesis reaction
<ol>
	<li>Recrystallization of geranic acid (85% purity, mol wt 168.23 g/mol)
	<ol>
		<li>Take a 500 mL round-bottom flask and measure its weight.</li>
		<li>Weigh 40.0 g geranic acid in the flask. This corresponds to 0.2&#160;mol of geranic acid.</li>
		<li>Recrystallize geranic acid in a 70:30% (w/w) geranic acid:acetone: Add (40 g*0.85*0.30)/(0.70*0.784 g/mL) = 18.42 mL of acetone to the round bottom flask.</li>
		<li>Take a 5 L beaker and prepare approximately 0.5 L&#160;of dry ice and ethanol.</li>
		<li>Place the round-bottom flask in the dry ice-ethanol cold mix without swirling to allow external cooling. Decant acetone and impurities from the solid/recrystallized geranic acid when crystallization has reached equilibrium (corresponding to approximately the volume of the added acetone, typically within 0.5-2 hours). Repeat this step 5&#8211;6 times to ensure sufficient purity.</li>
		<li>Remove the remaining acetone by rotatory evaporation under vacuum at 40 rpm for at least 20 min or until the round-bottom flask no longer feels cold when touching it (acetone has a vapor pressure of 240 mbar at 20 &#176;C).</li>
		<li>Weigh and note the mass of the flask and recrystallized geranic acid. Calculate the yield based on the initial empty flask weight. The expected yield range is 60-80%.</li>
	</ol>
	</li>
	<li>Salt metathesis reaction
	<ol>
		<li>For a 2:1 molar ratio of geranic acid:choline calculate the number of moles of choline, taking into account the yield of the geranic acid recrystallization. For example, with a yield of 70% 0.07 mol of choline should be added (0.2*70/100=0.14, 0.14/2 = 0.07).</li>
		<li>Choline bicarbonate has 80% purity and a molecular weight of 165.19 g/mol. Accordingly, add 14.45&#160;g (0.07*165.19 = 11.56 g; 100/80*11.56 g = 14.45&#160;g) of choline bicarbonate dropwise to prevent spillover.</li>
		<li>Stir the sample overnight at a speed of 300 rpm (or appropriate) at&#160;room temperature (18 &#177; 3 h) or until CO2 evaporation ceases.</li>
		<li>Dry the sample by rotatory evaporation at 60 &#176;C, 30 mbar for 40 min.&#160;First, increase the temperature, then slowly reduce the pressure to avoid foaming.</li>
		<li>Aliquot CAGE into glass vials in volumes appropriate for the intended application (e.g., 2 mL of CAGE in 4 mL glass vials).</li>
		<li>Dry the vials under vacuum at 60 &#176;C for 48 h.</li>
	</ol>
	</li>
</ol>
2. Characterization of CAGE
<ol>
	<li>Nuclear magnetic resonance (NMR) spectroscopy
	<ol>
		<li>Dissolve CAGE to a concentration of 25 mg/mL in deuterated dimethyl sulfoxide (d-DMSO), ensuring a final volume of at least 500 &#181;L. 
		NOTE: Deuterated solvents are essential in NMR to avoid interference from hydrogen atoms in the solvent.</li>
		<li>Transfer 500 &#181;L of the prepared solution into a clean, dry NMR tube (typically 5 mm diameter, depending on the instrument). Seal the tube with a cap to prevent evaporation and contamination. 
		NOTE: Avoid introducing air bubbles, as they can affect magnetic field homogeneity.</li>
		<li>Use an NMR spectrometer (e.g. 400 MHz) with the following parameters: 
		-Number of scans: 8-16 for 1H NMR; 1,000-5,000 for 13C NMR (depending on concentration and desired signal-to-noise (S/N) ratio. 
		&#8203;-Relaxation delay (D1): 1-2 s for 1H and 13C NMR.</li>
		<li>Process data using appropriate software.
		<ol>
			<li>Adjust for optimal peak shapes via phase and baseline correction. 
			NOTE: This is typically performed in the NMR software within the Processing or Correction tab (depending on the software used), where automatic tools for phase adjustment and baseline correction are available.</li>
			<li>Use the residual solvent peak (d-DMSO) as a reference: ~ approximately 2.50 ppm for 1H, ~ approximately 39.52 ppm for 13C NMR. See Fulmer et al.15for impurity references.</li>
		</ol>
		</li>
		<li>Integrate peaks and assign them to protons in the structure (see Figure 1).</li>
	</ol>
	</li>
	<li>Water content as determined by Karl Fischer titration
	<ol>
		<li>Dissolve 300 mg of CAGE in 300 &#181;L of methanol. Load into a 1 mL syringe and weigh before and after injection.</li>
		<li>Determine water content using a coulometric Karl Fischer titrator as per the manufacturer&#39;s instructions.
		<ol>
			<li>Inject the sample into the titration cell through the septum using a syringe, input the empty syringe weight, and press Enter. The result will appear as % w/w.</li>
			<li>Adjust for the water content of methanol to obtain the actual water content in CAGE (typically 1&#8211;2% w/w). (Wsample = Wsample+diluent*(msample+mdiluent) - (Wdiluent*mdiluent)/msample).</li>
		</ol>
		</li>
	</ol>
	</li>
	<li>Thermal stability of CAGE by Differential Scanning Calorimetry (DSC)
	<ol>
		<li>Place 3-5 mg of each sample in aluminium Tzero pans and seal with a hermetic lid.</li>
		<li>Analyze the samples using a DSC in the temperature range from 80 &#176;C to - 80 &#176;C with a 10 min isothermal period before cooling to - 80&#176;C.</li>
		<li>Use a constant heating/cooling rate of 5 &#176;C/min and a nitrogen purge of 50 mL/min.</li>
		<li>Process the data using appropriate software.</li>
	</ol>
	</li>
</ol>
3. Ex vivo assessment of skin barrier interaction
<ol>
	<li>Dermatome-processing of porcine skin
	<ol>
		<li>Cut expanded polystyrene (EPS) to fit the dermatome blade and wrap it with grafting tape. Utilize the skin collected from the loin region of pigs using a scalpel. Here, skin was obtained from 3.5-month-old female Danish Landrace or Yorkshire pigs (30-40 kg).</li>
		<li>Remove the muscle and fat tissue.&#160;To ease the dermatoming of the tissue it is important to ensure a flat and even basolateral side.</li>
		<li>Remove as much hair as possible from the skin using a hair trimmer.</li>
		<li>Rinse the skin with phosphate-buffered saline (PBS, pH 7.4) to remove blood and loose hair.</li>
		<li>Cut the skin into smaller pieces (5 cm x 15 cm) using a knife to fit the EPS blocks.</li>
		<li>Attach the skin to the EPS block with needles.</li>
		<li>Set the dermatome to 0.5 mm thickness and section the skin.</li>
		<li>Store the dermatomed skin between two layers of grafting tape and store at -70 &#176;C.</li>
	</ol>
	</li>
	<li>Trans-epidermal water loss (TEWL)
	<ol>
		<li>Prepare PBS (pH 7.4) by dissolving 1 tablet in 200 mL of ultrapure water. Degas for 20 min in an ultrasonic bath.</li>
		<li>Turn on the water bath connected to the Franz diffusion cells. Add approximately 12 mL of degassed PBS and a magnetic bead to each cell. Turn on the magnetic stirring (e.g. at 600 RPM) ensuring a uniform distribution in the receptor medium without creating turbulence. Note that not all Franz cell setups allow for precise control of stirring speed. Adjust the heating source to reach a temperature of 37 &#176;C in the receptor medium.</li>
		<li>Cut the dermatomed skin into pieces with a diameter of approximately 3 cm (or appropriate size) using a scalpel and carefully mount the dermatomed skin onto Franz diffusion cells using clamps and sealing rings, with the stratum corneum facing up.</li>
		<li>Next, fill the receptor chambers completely with PBS using a glass Pasteur pipette, making sure they are filled up to the mark that indicates the known volume of receptor medium. Remove air bubbles by carefully inverting the cells. Hydrate for 30 min.</li>
		<li>Turn on the TEWL device and equilibrate for 20 min until stable according to the manufacturer&#8217;s guidelines.</li>
		<li>Place the TEWL probe on each Franz cell and press Start in the software. Hold it until a reading is displayed.</li>
		<li>Add 300 &#181;L of sample on top of the skin (in triplicates, n=3) and occlude by placing grafting tape on top of the Franz cell. Incubate for 24 h at 37 &#176;C (receptor medium temperature).</li>
		<li>Remove the sample by wiping the tissue with lint-free wipes. Leave for 30 min.</li>
		<li>Measure TEWL for each cell to examine the effect of the samples on the skin barrier. Calculate TEWL values relative to pre-exposure values and adjust relative to PBS control (Relative TEWL = (TEWLpost-TEWL-pre/TEWLpre)/(TEWL(PBS)post-TEWL(PBS)pre/TEWL(PBS)pre))*100.</li>
	</ol>
	</li>
</ol>

<ol><li>Dąbrowska, A. K., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/pubmed?term=((The+relationship+between+skin+function%2C+barrier+properties%2C+and+body-dependent+factors%5BTitle%5D)+AND+%22Skin+Res+Technol%22%5BJournal%5D)">The relationship between skin function, barrier properties, and body-dependent factors.</a> Skin Res Technol. 24 (2), 165-174 (2018).</li>
<li>Date, A. A., Naik, B., Nagarsenker, M. S. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/pubmed?term=((Novel+drug+delivery+systems%3A+Potential+in+improving+topical+delivery+of+antiacne+agents%5BTitle%5D)+AND+%22Skin+Pharmacol+Physiol%22%5BJournal%5D)">Novel drug delivery systems: Potential in improving topical delivery of antiacne agents.</a> Skin Pharmacol Physiol. 19 (1), 2-16 (2005).</li>
<li>Phatale, V., Vaiphei, K. K., Jha, S., Patil, D., Agrawal, M., Alexander, A. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/pubmed?term=((Overcoming+skin+barriers+through+advanced+transdermal+drug+delivery+approaches%5BTitle%5D)+AND+%22J+Control+Release%22%5BJournal%5D)">Overcoming skin barriers through advanced transdermal drug delivery approaches.</a> J Control Release. 351, 361-380 (2022).</li>
<li>Kasting, G. B., Smith, R. L., Cooper, E. R. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/pubmed?term=((Effect+of+lipid+solubility+and+molecular+size+on+percutaneous+absorption%5BTitle%5D)+AND+%22Skin+Pharmacokinet%22%5BJournal%5D)">Effect of lipid solubility and molecular size on percutaneous absorption.</a> Skin Pharmacokinet. 1, 138-153 (1987).</li>
<li>Wickett, R. R., Visscher, M. O. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/pubmed?term=((Structure+and+function+of+the+epidermal+barrier%5BTitle%5D)+AND+%22Am+J+Infect+Control%22%5BJournal%5D)">Structure and function of the epidermal barrier.</a> Am J Infect Control. 34 (10), S98-S110 (2006).</li>
<li>Elias, P. M. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/pubmed?term=((Epidermal+barrier+function%3A+intercellular+lamellar+lipid+structures%2C+origin%2C+composition+and+metabolism%5BTitle%5D)+AND+%22J+Control+Release%22%5BJournal%5D)">Epidermal barrier function: intercellular lamellar lipid structures, origin, composition and metabolism.</a> J Control Release. 15 (3), 199-208 (1991).</li>
<li>Moser, K., Kriwet, K., Naik, A., Kalia, Y. N., Guy, R. H. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/pubmed?term=((Passive+skin+penetration+enhancement+and+its+quantification+in+vitro%5BTitle%5D)+AND+%22Eur+J+Pharm+Biopharm%22%5BJournal%5D)">Passive skin penetration enhancement and its quantification in vitro.</a> Eur J Pharm Biopharm. 52 (2), 103-112 (2001).</li>
<li>Lu, Y., Qi, J., Wu, W. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/pubmed?term=((Ionic+liquids-based+drug+delivery%3A+A+perspective%5BTitle%5D)+AND+%22Pharm+Res%22%5BJournal%5D)">Ionic liquids-based drug delivery: A perspective.</a> Pharm Res. 39 (10), 2329-2334 (2022).</li>
<li>Welton, T. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/pubmed?term=((Room-temperature+ionic+liquids.+Solvents+for+synthesis+and+catalysis%5BTitle%5D)+AND+%22Chem+Rev%22%5BJournal%5D)">Room-temperature ionic liquids. Solvents for synthesis and catalysis.</a> Chem Rev. 99 (8), 2071-2084 (1999).</li>
<li>Lei, Z., Chen, B., Koo, Y. M., MacFarlane, D. R. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/pubmed?term=((Introduction%3A+Ionic+liquids%5BTitle%5D)+AND+%22Chem+Rev%22%5BJournal%5D)">Introduction: Ionic liquids.</a> Chem Rev. 117 (10), 6633-6635 (2017).</li>
<li>Huang, W., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/pubmed?term=((Ionic+liquids%3A+Green+and+tailor-made+solvents+in+drug+delivery%5BTitle%5D)+AND+%22Drug+Discov+Today%22%5BJournal%5D)">Ionic liquids: Green and tailor-made solvents in drug delivery.</a> Drug Discov Today. 25 (5), 901-908 (2020).</li>
<li>Mitragotri, S. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/pubmed?term=((Choline+geranate+%28CAGE%29%3A+A+multifaceted+ionic+liquid+for+drug+delivery%5BTitle%5D)+AND+%22J.+Control.+Release%22%5BJournal%5D)">Choline geranate (CAGE): A multifaceted ionic liquid for drug delivery.</a> J. Control. Release. 376, 593-600 (2024).</li>
<li>Banerjee, A., Ibsen, K., Iwao, Y., Zakrewsky, M., Mitragotri, S. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/pubmed?term=((Transdermal+protein+delivery+using+choline+and+geranate+%28CAGE%29+deep+eutectic+solvent%5BTitle%5D)+AND+%22Adv+Healthc+Mater%22%5BJournal%5D)">Transdermal protein delivery using choline and geranate (CAGE) deep eutectic solvent.</a> Adv Healthc Mater. 6 (15), 1601411(2017).</li>
<li>Edwardson, T. G., Mori, T., Hilvert, D. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/pubmed?term=((Rational+engineering+of+a+designed+protein+cage+for+siRNA+delivery%5BTitle%5D)+AND+%22J+Am+Chem+Soc%22%5BJournal%5D)">Rational engineering of a designed protein cage for siRNA delivery.</a> J Am Chem Soc. 140 (33), 10439-10442 (2018).</li>
<li>Fulmer, G. R., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/pubmed?term=((NMR+chemical+shifts+of+trace+impurities%3A+common+laboratory+solvents%2C+organics%2C+and+gases+in+deuterated+solvents+relevant+to+the+organometallic+chemist%5BTitle%5D)+AND+%22Organometallics%22%5BJournal%5D)">NMR chemical shifts of trace impurities: common laboratory solvents, organics, and gases in deuterated solvents relevant to the organometallic chemist.</a> Organometallics. 29 (9), 2176-2179 (2010).</li>
<li>Zakrewsky, M., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/pubmed?term=((Ionic+liquids+as+a+class+of+materials+for+transdermal+delivery+and+pathogen+neutralization%5BTitle%5D)+AND+%22Proc+Natl+Acad+Sci.+U.S.A%22%5BJournal%5D)">Ionic liquids as a class of materials for transdermal delivery and pathogen neutralization.</a> Proc Natl Acad Sci. U.S.A. 111 (37), 13313-13318 (2014).</li>
<li>Torres, A. M., Price, W. S. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/pubmed?term=((Common+problems+and+artifacts+encountered+in+solution-state+NMR+experiments%5BTitle%5D)+AND+%22Concepts+Magn+Reson.+A%22%5BJournal%5D)">Common problems and artifacts encountered in solution-state NMR experiments.</a> Concepts Magn Reson. A. 45 (2), e21387(2016).</li>
<li>Takeda, J., Iwao, Y., Karashima, M., Yamamoto, K., Ikeda, Y. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/pubmed?term=((Structural+evaluation+of+the+choline+and+geranic+acid%2Fwater+complex+by+SAXS+and+NMR+analyses%5BTitle%5D)+AND+%22ACS+Biomater+Sci+Eng%22%5BJournal%5D)">Structural evaluation of the choline and geranic acid/water complex by SAXS and NMR analyses.</a> ACS Biomater Sci Eng. 7 (2), 595-604 (2021).</li>
</ol>

The authors declare no competing financial interest.

The preparation method of CAGE described in this work was adopted from the literature15. However, it is important to acknowledge that the synthesis process is sensitive to various external factors, which can influence the properties of the final product. Therefore, once prepared, the CAGE system should be characterized using techniques such as NMR spectroscopy to confirm the formation of CAGE.
As shown in Figure 1, the proton spectra of CAG...

The skin is the body's largest and most vital organ, serving as a protective barrier against harmful substances while also preventing water loss1. At the same time, applying drugs to and through the skin offers a wide range of advantages. Compared to injectables and oral delivery, cutaneous administration increases patient compliance and avoids first-pass metabolism in the liver2. Especially for skin conditions, cutaneously administered formulations excel in providing a localized effect, diminishing the systemic exposure3. However, the almost impermeable nature of the skin significantly challenges successful cutaneous delivery4. The human skin consists of three different layers: the epidermis, dermis, and hypodermis4. The epidermis is the outer layer of skin and can be further divided into different sublayers, with the stratum corneum being the outermost layer, comprised primarily of keratinocytes. The stratum corneum acts as a prominent permeation barrier for most of the molecules, inhibiting their transport into deeper layers of the skin5. This barrier function arises from the presence of corneocytes embedded in a tightly packed lipid arrangement, comprising mainly phospholipids, sterols, and ceramides, often referred to as the brick-and-mortar structure6. To overcome this skin barrier, chemical permeation enhancers (CPEs) have been deployed to deliver macromolecules, as they disrupt the structure of the stratum corneum by interacting with the lipids and proteins present in it7.
Ionic liquids (ILs) have emerged as the next-generation CPEs8. These consist of bulky organic cations and anions, arranged in an asymmetric manner and coordinated by weak, non-directional ionic interactions9. Due to these weak intermolecular forces, ILs exist as liquids below 100 &#176;C, and are unable to pack into a well-defined crystal structure10. ILs are highly tunable, as their efficacy is highly dependent on the choice of cations or anions and the stoichiometric ratio between these ions. Hence, they have high solubilizing and stabilizing capacity for drugs with varied hydrophobicities11. ILs serve the unique properties of both lipids and polymers by providing sustained release and encapsulation of macromolecules, respectively12.
Biocompatible ILs based on choline and geranic acid (CAGE), present in a stoichiometric molar ratio of 1:2, have significant applications in transdermal delivery of both hydrophilic and hydrophobic compounds. CAGE has been reported to significantly enhance the transdermal delivery of proteins (insulin13) and nucleic acids (siRNA14). CAGE is prepared by salt metathesis reaction between choline bicarbonate and geranic acid, with CO2 as a by-product15. Salt metathesis reaction offers the formation of new compounds via ion exchange under mild conditions in a direct, rapid, and highly selective manner. In general, there is a lack of easy-to-follow workflows for CAGE IL development and evaluation. Thus, here we provide one such workflow, detailing each stage of CAGE preparation to enable researchers across different backgrounds to enter this research space.

<table><tbody><tr><td>5 mm NMR tubes</td><td>Sigma Aldrich</td><td>41121705</td><td></td></tr><tr><td>Acetone</td><td>VWR</td><td>23L064039</td><td></td></tr><tr><td>Aluminium Tzero Pans</td><td>TA Instruments</td><td>90,16,83,901</td><td></td></tr><tr><td>Aqua Flux Device</td><td>Biox Systems</td><td></td><td></td></tr><tr><td>Bruker Avance III NMR</td><td>Bruker</td><td></td><td>Instrument for NMR spectroscopy</td></tr><tr><td>Choline Bicarbonate</td><td>Sigma Aldrich</td><td>C7519</td><td></td></tr><tr><td>Dermatome</td><td>Zimmer Biomet</td><td></td><td></td></tr><tr><td>Differential Scanning Calorimeter</td><td>TA Instruments</td><td></td><td></td></tr><tr><td>Ethanol</td><td>VWR</td><td>23J314009</td><td></td></tr><tr><td>Expanded Polystyrene</td><td>Styrofoam</td><td></td><td></td></tr><tr><td>Franz Diffusion Cells</td><td>PermeGear</td><td></td><td></td></tr><tr><td>Geranic Acid</td><td>Sigma Aldrich</td><td>427764</td><td></td></tr><tr><td>Grafting Tape</td><td>Parafilm</td><td></td><td></td></tr><tr><td>Karl Fischer Titrator</td><td>Mettler Toledo</td><td>30252662</td><td></td></tr><tr><td>Methanol</td><td>VWR</td><td>85681.32</td><td></td></tr><tr><td>PBS</td><td>Fischer Scientific</td><td>10388739</td><td></td></tr><tr><td>TA universal analysis 2000 software</td><td>TA Instruments</td><td></td><td>Software for DSC data analysis</td></tr><tr><td>TopSpin Software</td><td>Bruker</td><td></td><td>Software for NMR data analysis</td></tr></tbody></table>

development, characterization, and evaluation of cage-based ionic liquid systems for transdermal delivery

Development, Characterization, and Evaluation of CAGE-based Ionic Liquid Systems for Transdermal Delivery

Ionic liquids have recently gained remarkable recognition for their applications within drug delivery, in particular their potential to enable cutaneous drug penetration and enhance drug permeation. In addition to enhancing barrier permeability, ionic liquids have excellent solvation properties, addressing the challenge of dissolving poorly soluble drugs. Due to the large asymmetry between the organic cations and anions, these functional salts remain liquid at room temperature. From an application perspective, ionic liquids provide a promising and highly tunable approach to serve multiple therapeutic areas. A biocompatible ionic liquid composed of choline and geranic acid (CAGE), in a stoichiometric ion ratio of 1:2, holds immense potential for transdermal delivery of a wide range of active pharmaceutical ingredients, including small molecules, peptides, proteins, and nucleic acids. This has a minimal impact on skin barrier function. Herein, we share our methods for the preparation, characterization, and evaluation of CAGE. Representative results are shown for CAGE characterization using NMR spectroscopy, differential scanning calorimetry, Karl-Fischer titration for water content analysis, and ex vivo barrier interaction studies on porcine skin.

NMR-spectra 
The goal of this technique is to confirm the successful formation of CAGE by analyzing the chemical environments of hydrogen and carbon atoms using 1H and 13C NMR spectroscopy. The resulting spectra provide characteristic chemical shifts, splitting patterns, and integration values that reflect the molecular structure and composition of the synthesized IL. The proton NMR spectrum in Figure 1 confirms the 2:1 molar ratio of geranic acid to...

This protocol discusses standardization for the preparation of CAGE-based ionic liquid systems to ensure reproducibility and streamline the overall workflow across different scientific labs.

Ionic liquids have recently gained remarkable recognition for their applications within drug delivery, in particular their potential to enable cutaneous ...

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