{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,1,10]],"date-time":"2026-01-10T03:47:30Z","timestamp":1768016850589,"version":"3.49.0"},"reference-count":56,"publisher":"MDPI AG","issue":"3","license":[{"start":{"date-parts":[[2022,3,15]],"date-time":"2022-03-15T00:00:00Z","timestamp":1647302400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"John and Mary Kibble Trust","award":["2017002693"],"award-info":[{"award-number":["2017002693"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Pharmaceutics"],"abstract":"<jats:p>Dogs undergo various surgical procedures such as castration, ovariohysterectomy, and other orthopedic procedures, which are known to cause inflammation and pain. Non-steroidal anti-inflammatory drugs (NSAIDs) are very effective analgesics for alleviating postoperative pain in veterinary medicine. Ketoprofen is currently approved in Australia and the United States for treating different painful conditions in dogs. This study evaluated the pharmacokinetic parameters of ketoprofen after intravenous (IV) and transdermal (TD) administration in healthy dogs. A novel transdermal ketoprofen (TDK) formulation containing 20% ketoprofen, dissolved in a combination of 45:45% isopropanol and Transcutol, along with 10% eucalyptus oil, was developed and evaluated for in vitro dermal permeation using Franz diffusion cells. A crossover study was then conducted to determine the pharmacokinetic parameters of the formulation in six dogs following IV ketoprofen (1 mg\/kg) and TDK (10 mg\/kg) administration. A liquid chromatography\u2013mass spectrometry (LC-M\/MS) method was used to measure plasma concentrations of ketoprofen over time, and a non-compartmental analysis determined the pharmacokinetic parameters. The mean terminal elimination half-life (T\u00bd h), AUC0-t (\u00b5g\u00b7h\/mL), and mean residence time (MRT, h) between IV and TDK groups were 4.69 \u00b1 1.33 and 25.77 \u00b1 22.15 h, 15.75 \u00b1 7.72 and 8.13 \u00b1 4.28 \u00b5g\u00b7h\/mL, and 4.86 \u00b1 1.81 and 41.63 \u00b1 32.33 h, respectively. The calculated bioavailability (F%) was ~7%, with a lag time of 30 min to achieve effective plasma concentrations after the application of TDK.<\/jats:p>","DOI":"10.3390\/pharmaceutics14030646","type":"journal-article","created":{"date-parts":[[2022,3,16]],"date-time":"2022-03-16T03:36:23Z","timestamp":1647401783000},"page":"646","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":12,"title":["Pharmacokinetic Evaluation of a Novel Transdermal Ketoprofen Formulation in Healthy Dogs"],"prefix":"10.3390","volume":"14","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-1539-4167","authenticated-orcid":false,"given":"Halley Gora","family":"Ravuri","sequence":"first","affiliation":[{"name":"School of Veterinary Science, The University of Queensland, Gatton, QLD 4343, Australia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Nana","family":"Satake","sequence":"additional","affiliation":[{"name":"School of Veterinary Science, The University of Queensland, Gatton, QLD 4343, Australia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Alexandra","family":"Balmanno","sequence":"additional","affiliation":[{"name":"School of Veterinary Science, The University of Queensland, Gatton, QLD 4343, Australia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0270-0740","authenticated-orcid":false,"given":"Jazmine","family":"Skinner","sequence":"additional","affiliation":[{"name":"School of Agriculture and Environment, University of Southern Queensland, Toowoomba, QLD 4350, Australia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Samantha","family":"Kempster","sequence":"additional","affiliation":[{"name":"School of Veterinary Science, The University of Queensland, Gatton, QLD 4343, Australia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Paul C.","family":"Mills","sequence":"additional","affiliation":[{"name":"School of Veterinary Science, The University of Queensland, Gatton, QLD 4343, Australia"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2022,3,15]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1204","DOI":"10.1002\/jor.20864","article-title":"Expression and Activity of COX-1 and 2 and 5-LOX in Joint Tissues from Dogs with Naturally Occurring Coxofemoral Joint Osteoarthritis","volume":"27","author":"Lascelles","year":"2009","journal-title":"J. Orthop. Res."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"399","DOI":"10.2478\/jvetres-2019-0051","article-title":"Effect of Selected Nonsteroidal Anti-Inflammatory Drugs on the Viability of Canine Osteosarcoma Cells of the D-17 Line: In Vitro Studies","volume":"63","author":"Poradowski","year":"2019","journal-title":"J. Vet. Res."},{"key":"ref_3","first-page":"203","article-title":"Bioavailability File: Ketoprofen","volume":"34","author":"Karavana","year":"2009","journal-title":"FABAD J. Pharm. Sci."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"410","DOI":"10.1111\/jvp.12186","article-title":"Enantioselective Pharmacokinetics of Ketoprofen in Calves after Intramuscular Administration of a Racemic Mixture","volume":"38","author":"Plessers","year":"2015","journal-title":"J. Vet. Pharmacol. Ther."},{"key":"ref_5","first-page":"8","article-title":"A Review of Nonsteroidal Anti-Inflammatory Drugs","volume":"82","author":"Schellack","year":"2015","journal-title":"SA Pharm. J."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"847","DOI":"10.1292\/jvms.67.847","article-title":"Effects of Long-Term Oral Administration of Ketoprofen in Clinically Healthy Beagle Dogs","volume":"67","author":"Narita","year":"2005","journal-title":"J. Vet. Med. Sci."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/0304-3959(89)90065-1","article-title":"Central Analgesic Effect of Ketoprofen in Humans: Electrophysiological Evidence for a Supraspinal Mechanism in a Double-Blind and Cross-over Study","volume":"438","author":"Willer","year":"1989","journal-title":"Pain"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"201","DOI":"10.1016\/0006-8993(90)90026-8","article-title":"Anatomical Mapping of Brain Sites Involved in the Antinociceptive Effects of Ketoprofen","volume":"536","author":"Suaudeau","year":"1990","journal-title":"Brain Res."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"241","DOI":"10.1016\/j.ejphar.2003.10.036","article-title":"Evidence for a Central Mechanism of Action of S-(+)-Ketoprofen","volume":"483","year":"2004","journal-title":"Eur. J. Pharmacol."},{"key":"ref_10","doi-asserted-by":"crossref","unstructured":"Monteiro, B.P., Lambert, C., Bianchi, E., Genevois, J.P., Soldani, G., and Troncy, E. (2019). Safety and Efficacy of Reduced Dosage Ketoprofen with or without Tramadol for Long-Term Treatment of Osteoarthritis in Dogs: A Randomized Clinical Trial. BMC Vet. Res., 15.","DOI":"10.1186\/s12917-019-1960-3"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"164","DOI":"10.3923\/ajas.2012.164.173","article-title":"Comparison of the Analgesic Effects of Meloxicam with Those of Ketoprofen in Male Stray Dogs Undergoing Pinhole Castration","volume":"6","author":"Baba","year":"2012","journal-title":"Asian J. Anim. Sci."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"11","DOI":"10.1136\/vr.152.1.11","article-title":"Reduced Dosage of Ketoprofen for the Short-Term and Long-Term Treatment of Joint Pain in Dogs","volume":"152","author":"Hazewinkel","year":"2003","journal-title":"Vet. Rec."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"650","DOI":"10.1111\/j.1532-950X.2004.04088.x","article-title":"Analgesic Comparison of Meloxicam or Ketoprofen for Orthopedic Surgery in Dogs","volume":"33","author":"Deneuche","year":"2004","journal-title":"Vet. Surg."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"1019","DOI":"10.2460\/ajvr.71.9.1019","article-title":"Maxillectomy or Mandibulectomy","volume":"71","author":"Martins","year":"2010","journal-title":"Am. J. Vet. Res."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"258","DOI":"10.2460\/ajvr.68.3.258","article-title":"Evaluation of Adverse Effects of Long-Term Oral Administration of Carprofen, Etodolac, Flunixin Meglumine, Ketoprofen, and Meloxicam in Dogs","volume":"68","author":"Luna","year":"2007","journal-title":"Am. J. Vet. Res."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"421","DOI":"10.1111\/j.1748-5827.1998.tb03748.x","article-title":"Endoscopy of the Gastroduodenal Mucosa after Carprofen, Meloxicam and Ketoprofen Administration in Dogs","volume":"39","author":"Forsyth","year":"1998","journal-title":"J. Small Anim. Pract."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"547","DOI":"10.1111\/j.1748-5827.2000.tb03151.x","article-title":"Effect of NSAID Administration on Creatinine Clearance in Healthy Dogs Undergoing Anaesthesia and Surgery","volume":"41","author":"Forsyth","year":"2000","journal-title":"J. Small Anim. Pract."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"2017","DOI":"10.1001\/archinte.164.18.2017","article-title":"Efficacy and Safety of a Topical Diclofenac Solution (Pennsaid) in the Treatment of Primary Osteoarthritis of the Knee: A Randomized, Double-Blind, Vehicle-Controlled Clinical Trial","volume":"164","author":"Roth","year":"2004","journal-title":"Arch. Intern. Med."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"200","DOI":"10.1097\/00042752-200307000-00002","article-title":"Efficacy of Transdermal Ketoprofen for Delayed Onset Muscle Soreness","volume":"13","author":"Cannavino","year":"2003","journal-title":"Clin. J. Sport Med."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"488","DOI":"10.1007\/s12663-017-1048-1","article-title":"Pre-Emptive Diclofenac Versus Ketoprofen as a Transdermal Drug Delivery System: How They Face","volume":"17","author":"Jadhav","year":"2018","journal-title":"J. Maxillofac. Oral Surg."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"974","DOI":"10.1002\/jps.2600791106","article-title":"Anti-inflammatory Activity of Ketoprofen Gel on Carrageenan-induced Paw Edema in Rats","volume":"79","author":"Chi","year":"1990","journal-title":"J. Pharmac. Sci."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"2783","DOI":"10.1208\/s12249-017-0749-6","article-title":"Ketoprofen Microemulsion for Improved Skin Delivery and In Vivo Anti-Inflammatory Effect","volume":"18","author":"Aliberti","year":"2017","journal-title":"AAPS PharmSciTech"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"217","DOI":"10.1007\/s40744-020-00196-6","article-title":"Topical Diclofenac, an Efficacious Treatment for Osteoarthritis: A Narrative Review","volume":"7","author":"Fayet","year":"2020","journal-title":"Rheumatol. Ther."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"36","DOI":"10.1186\/s40798-017-0103-2","article-title":"Topical Administration of Ibuprofen for Injured Athletes: Considerations, Formulations, and Comparison to Oral Delivery","volume":"3","author":"Manoukian","year":"2017","journal-title":"Sport. Med. Open"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"34","DOI":"10.1016\/j.clinthera.2010.01.016","article-title":"Efficacy and Safety Profile of a Topical Methyl Salicylate and Menthol Patch in Adult Patients with Mild to Moderate Muscle Strain: A Randomized, Double-Blind, Parallel-Group, Placebo-Controlled, Multicenter Study","volume":"32","author":"Higashi","year":"2010","journal-title":"Clin. Ther."},{"key":"ref_26","doi-asserted-by":"crossref","unstructured":"Mills, P.C., Ghodasara, P., Satake, N., Alawneh, J., Fraser, B., Kopp, S., and McGowan, M. (2020). A Novel Transdermal Ketoprofen Formulation Provides Effective Analgesia to Calves Undergoing Amputation Dehorning. Animals, 10.","DOI":"10.3390\/ani10122442"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"415","DOI":"10.1016\/j.ejpb.2011.03.005","article-title":"Microdialysis Assessment of Percutaneous Penetration of Ketoprofen after Transdermal Administration to Hairless Rats and Domestic Pigs","volume":"78","author":"Shinkai","year":"2011","journal-title":"Eur. J. Pharm. Biopharm."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"745","DOI":"10.1111\/jvp.12993","article-title":"Pharmacokinetics of Transdermal Flunixin Meglumine and Effects on Biomarkers of Inflammation in Horses","volume":"44","author":"Knych","year":"2021","journal-title":"J. Vet. Pharmacol. Ther."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"309","DOI":"10.1111\/jvp.12756","article-title":"Pharmacokinetics and Pharmacodynamics of Intravenous and Transdermal Flunixin Meglumine in Meat Goats","volume":"42","author":"Reppert","year":"2019","journal-title":"J. Vet. Pharmacol. Ther."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"586","DOI":"10.3389\/fvets.2020.00586","article-title":"Pharmacokinetics of Intravenous, Intramuscular, Oral, and Transdermal Administration of Flunixin Meglumine in Pre-Wean Piglets","volume":"7","author":"Kittrell","year":"2020","journal-title":"Front. Vet. Sci."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"623","DOI":"10.1002\/(SICI)1099-081X(199710)18:7<623::AID-BDD46>3.0.CO;2-V","article-title":"Pharmacokinetic and Local Tissue Disposition Studies of Naproxen Following Topical and Systemic Administration in Dogs and Rats","volume":"18","author":"Suh","year":"1997","journal-title":"Biopharm. Drug Dispos."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"1128","DOI":"10.2460\/ajvr.2005.66.1128","article-title":"Penetration of a Topically Applied Nonsteroidal Anti-Inflammatory Drug into Local Tissues and Synovial Fluid of Dogs","volume":"66","author":"Mills","year":"2005","journal-title":"Am. J. Vet. Res."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"1060","DOI":"10.1038\/aps.2009.73","article-title":"Pharmacokinetic Studies of Meloxicam Following Oral and Transdermal Administration in Beagle Dogs","volume":"30","author":"Yuan","year":"2009","journal-title":"Acta Pharmacol. Sin."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"2809","DOI":"10.2147\/JPR.S177967","article-title":"Penetration and Efficacy of Transdermal NSAIDs in a Model of Acute Joint Inflammation","volume":"11","author":"Baranowski","year":"2018","journal-title":"J. Pain Res."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"3","DOI":"10.1111\/j.1365-2885.2012.01416.x","article-title":"The History and Pharmacology of Fentanyl: Relevance to a Novel, Long-Acting Transdermal Fentanyl Solution Newly Approved for Use in Dogs","volume":"35","author":"Kukanich","year":"2012","journal-title":"J. Vet. Pharmacol. Ther."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"335","DOI":"10.1016\/j.tvjl.2010.01.013","article-title":"Antinociceptive Efficacy and Plasma Concentrations of Transdermal Buprenorphine in Dogs","volume":"187","author":"Pieper","year":"2011","journal-title":"Vet. J."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"1975","DOI":"10.1200\/JCO.2004.10.524","article-title":"Nonsteroidal Anti-Inflammatory Drugs, Alone or Combined with Opioids, for Cancer Pain: A Systematic Review","volume":"22","author":"McNicol","year":"2004","journal-title":"J. Clin. Oncol."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"583","DOI":"10.1016\/j.eururo.2017.11.001","article-title":"A Systematic Review and Meta-Analysis Comparing the Efficacy of Nonsteroidal Anti-Inflammatory Drugs, Opioids, and Paracetamol in the Treatment of Acute Renal Colic [Figure Presented]","volume":"73","author":"Pathan","year":"2018","journal-title":"Eur. Urol."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"121","DOI":"10.1016\/j.ejps.2017.09.034","article-title":"Evaluation of Critical Parameters for in Vitro Skin Permeation and Penetration Studies Using Animal Skin Models","volume":"111","author":"Medina","year":"2018","journal-title":"Eur. J. Pharm. Sci."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"456","DOI":"10.1111\/j.1365-2885.2007.00879.x","article-title":"The Effects of Freezing Skin on Transdermal Drug Penetration Kinetics","volume":"30","author":"Ahlstrom","year":"2007","journal-title":"J. Vet. Pharmacol. Ther."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"218","DOI":"10.1016\/j.tvjl.2005.09.006","article-title":"Transdermal drug delivery: Basic principles for the veterinarian","volume":"172","author":"Mills","year":"2006","journal-title":"Vet. J."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"1184","DOI":"10.4236\/ajac.2014.517126","article-title":"Doping Control Analysis of 16 Non-Steroidal Anti-Inflammatory Drugs in Equine Plasma Using Liquid Chromatography-Tandem Mass Spectrometry","volume":"5","author":"You","year":"2014","journal-title":"Am. J. Anal. Chem."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"306","DOI":"10.1016\/j.cmpb.2010.01.007","article-title":"PKSolver: An Add-in Program for Pharmacokinetic and Pharmacodynamic Data Analysis in Microsoft Excel","volume":"99","author":"Zhang","year":"2010","journal-title":"Comput. Methods Programs Biomed."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"427","DOI":"10.1111\/j.1365-2885.2004.00600.x","article-title":"Plasma Terminal Half-Life","volume":"27","author":"Toutain","year":"2004","journal-title":"J. Vet. Pharmacol. Ther."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"166","DOI":"10.1016\/j.ijpharm.2007.08.005","article-title":"Possibility of Enterohepatic Recycling of Ketoprofen in Dogs","volume":"349","author":"Granero","year":"2008","journal-title":"Int. J. Pharm."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"523","DOI":"10.1016\/j.rvsc.2014.03.021","article-title":"Pharmacokinetics of the Individual Enantiomer S-(+)-Ketoprofen after Intravenous and Oral Administration in Dogs at Two Dose Levels","volume":"96","author":"Serrano","year":"2014","journal-title":"Res. Vet. Sci."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"415","DOI":"10.1016\/j.rvsc.2010.08.017","article-title":"Species Comparison of Enantioselective Oral Bioavailability and Pharmacokinetics of Ketoprofen","volume":"91","author":"Neirinckx","year":"2011","journal-title":"Res. Vet. Sci."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"418","DOI":"10.1111\/j.1365-2885.2010.01180.x","article-title":"Current Challenges Facing the Determination of Product Bioequivalence in Veterinary Medicine","volume":"33","author":"Martinez","year":"2010","journal-title":"J. Vet. Pharmacol. Ther."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"517","DOI":"10.2174\/1389200043335360","article-title":"Chiral Inversion of Drugs: Coincidence or Principle?","volume":"5","author":"Wsol","year":"2004","journal-title":"Curr. Drug Metab."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"197","DOI":"10.2165\/00003088-199019030-00004","article-title":"Clinical Pharmacokinetics of Ketoprofen and Its Enantiomers","volume":"19","author":"Jamali","year":"1990","journal-title":"Clin. Pharmacokinet."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"503","DOI":"10.1111\/j.1365-2885.2009.01058.x","article-title":"Plasma Buprenorphine Concentrations after the Application of a 70 \u039cg\/h Transdermal Patch in Dogs. Preliminary Report","volume":"32","author":"Andaluz","year":"2009","journal-title":"J. Vet. Pharmacol. Ther."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"168","DOI":"10.1023\/A:1016014308638","article-title":"Percutaneous Absorption of Ketoprofen from Different Anatomical Sites","volume":"13","author":"Shah","year":"1996","journal-title":"Pharm. Res."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"2541","DOI":"10.1093\/ajhp\/61.23.2541","article-title":"Relative Bioavailability of Ketoprofen 20% in a Poloxamer-Lecithin Organogel","volume":"61","author":"Dowling","year":"2004","journal-title":"Am. J. Health Pharm."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"415","DOI":"10.1023\/B:VERC.0000034995.81994.49","article-title":"A Pharmacokinetic Comparison of Meloxicam and Ketoprofen Following Oral Administration to Healthy Dogs","volume":"28","author":"Montoya","year":"2004","journal-title":"Vet. Res. Commun."},{"key":"ref_55","first-page":"539","article-title":"Non-Steroidal Anti-Inflammatory Analgesics for Acute Pain Management in Dogs and Cats","volume":"37","author":"Mathews","year":"1996","journal-title":"Can. Vet. J."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"555","DOI":"10.2165\/00003495-200060030-00004","article-title":"Oral versus Topical NSAIDs in Rheumatic Diseases: A Comparison","volume":"60","author":"Heyneman","year":"2000","journal-title":"Drugs"}],"container-title":["Pharmaceutics"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1999-4923\/14\/3\/646\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T22:37:03Z","timestamp":1760135823000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1999-4923\/14\/3\/646"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,3,15]]},"references-count":56,"journal-issue":{"issue":"3","published-online":{"date-parts":[[2022,3]]}},"alternative-id":["pharmaceutics14030646"],"URL":"https:\/\/doi.org\/10.3390\/pharmaceutics14030646","relation":{},"ISSN":["1999-4923"],"issn-type":[{"value":"1999-4923","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,3,15]]}}}