{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,11]],"date-time":"2026-04-11T09:44:03Z","timestamp":1775900643067,"version":"3.50.1"},"reference-count":63,"publisher":"MDPI AG","issue":"10","license":[{"start":{"date-parts":[[2022,10,18]],"date-time":"2022-10-18T00:00:00Z","timestamp":1666051200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Pharmaceutics"],"abstract":"<jats:p>Bacterial conjunctivitis significantly impacts public health, including more than one-third of eye diseases reported worldwide. It is an infection caused by various aerobic and anaerobic bacteria and is highly contagious. Therefore, it has a high incidence of bacterial resistance to the antibiotics commonly used for treatment. Among the most recent antibiotics, besifloxacin is a fourth-generation fluoroquinolone antibiotic indicated exclusively for topical ophthalmic use. Due to its importance in treating bacterial conjunctivitis and its low solubility in water, limiting its efficacy, a nanotechnology-based drug delivery preparation was developed to overcome this hurdle. Besifloxacin nanocrystals were prepared by small-scale wet milling and response surface methodology, using Povacoat\u00ae as a stabilizer. The particle\u2019s average hydrodynamic diameter (Z-ave) was approximately 550 nm (17 times smaller than raw material), with a polydispersity index (PdI) of less than 0.2. The saturation solubility increased about two times compared to the raw material, making it possible to increase the dissolution rate of this drug substance, potentially improving its bioavailability and safety. The optimized preparation was stable under an accelerated stability study (90 days). The Z-ave, PZ, PdI, and content did not alter significantly during this period. Furthermore, the 0.6% m\/m besifloxacin nanocrystals at the maximum dose and the Povacoat\u00ae stabilizer did not show toxicity in Galleria mellonella larvae. The innovative ophthalmic preparation minimum inhibitory concentration (MIC) was 0.0960 \u00b5g\/mL and 1.60 \u00b5g\/mL against Staphylococcus aureus and Pseudomonas aeruginosa, respectively, confirming in vitro efficacy. Therefore, besifloxacin nanocrystals revealed the potential for reduced dosing of the drug substance, with a minor occurrence of adverse effects and greater patient adherence to treatment.<\/jats:p>","DOI":"10.3390\/pharmaceutics14102221","type":"journal-article","created":{"date-parts":[[2022,10,19]],"date-time":"2022-10-19T00:58:51Z","timestamp":1666141131000},"page":"2221","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":9,"title":["Besifloxacin Nanocrystal: Towards an Innovative Ophthalmic Preparation"],"prefix":"10.3390","volume":"14","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-5043-8436","authenticated-orcid":false,"given":"Jos\u00e9 Izo Santana da Silva de","family":"Jesus","sequence":"first","affiliation":[{"name":"Department of Pharmacy, Faculty of Pharmaceutical Sciences, University of S\u00e3o Paulo, Professor Lineu Prestes Av 580, Cidade Universit\u00e1ria, S\u00e3o Paulo 05508-000, Brazil"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2630-151X","authenticated-orcid":false,"given":"Felipe Rebello","family":"Louren\u00e7o","sequence":"additional","affiliation":[{"name":"Department of Pharmacy, Faculty of Pharmaceutical Sciences, University of S\u00e3o Paulo, Professor Lineu Prestes Av 580, Cidade Universit\u00e1ria, S\u00e3o Paulo 05508-000, Brazil"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4602-0926","authenticated-orcid":false,"given":"Kelly","family":"Ishida","sequence":"additional","affiliation":[{"name":"Department of Microbiology, Institute of Biomedical Sciences, University of S\u00e3o Paulo, Professor Lineu Prestes Av 2415, Cidade Universit\u00e1ria, S\u00e3o Paulo 05508-000, Brazil"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Thayn\u00e1 Lopes","family":"Barreto","sequence":"additional","affiliation":[{"name":"Department of Microbiology, Institute of Biomedical Sciences, University of S\u00e3o Paulo, Professor Lineu Prestes Av 2415, Cidade Universit\u00e1ria, S\u00e3o Paulo 05508-000, Brazil"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7821-0356","authenticated-orcid":false,"given":"Valdir Carlos","family":"Avino","sequence":"additional","affiliation":[{"name":"Department of Research and Development, Pearson Sa\u00fade Animal S.A., Rua Arizona 491, Edif\u00edcio Itaporanga, 18\u00b0 Andar, Conjunto 182, Cidade Mon\u00e7\u00f5es, S\u00e3o Paulo 04567-001, Brazil"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Edson dos Santos","family":"Neto","sequence":"additional","affiliation":[{"name":"Ophthalmology Division, Clinical Hospital of the Faculty of Medicine, University of S\u00e3o Paulo, Avenida Dr. Eneas de Carvalho Aguiar, 255, Cerqueira C\u00e9sar, S\u00e3o Paulo 05403-000, Brazil"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"N\u00e1dia Araci","family":"Bou-Chacra","sequence":"additional","affiliation":[{"name":"Department of Pharmacy, Faculty of Pharmaceutical Sciences, University of S\u00e3o Paulo, Professor Lineu Prestes Av 580, Cidade Universit\u00e1ria, S\u00e3o Paulo 05508-000, Brazil"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2022,10,18]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1721","DOI":"10.1001\/jama.2013.280318","article-title":"Conjunctivitis: A Systematic Review of Diagnosis and Treatment","volume":"310","author":"Azari","year":"2013","journal-title":"JAMA"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"7","DOI":"10.4137\/OED.S4102","article-title":"Besifloxacin Ophthalmic Suspension: Emerging Evidence of Its Therapeutic Value in Bacterial Conjunctivitis","volume":"3","author":"Khimdas","year":"2011","journal-title":"Ophthalmol. Eye Dis."},{"key":"ref_3","doi-asserted-by":"crossref","unstructured":"Mejia-Lopez, H., Alberto, C., Climent-Flores, A., and Bautista-de Lucio, V.M. (2011). Epidemiological Aspects of Infectious Conjunctivitis. Conjunctivitis\u2014A Complex and Multifaceted Disorder, Intech Open.","DOI":"10.5772\/27755"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"22","DOI":"10.1016\/j.jddst.2015.11.004","article-title":"Levofloxacin Hemihydrate Ocular Semi-Sponges for Topical Treatment of Bacterial Conjunctivitis: Formulation and in-Vitro\/in-Vivo Characterization","volume":"31","author":"Saher","year":"2016","journal-title":"J. Drug Deliv. Sci. Technol."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"132","DOI":"10.1080\/10408347.2018.1429885","article-title":"Besifloxacin: A Critical Review of Its Characteristics, Properties, and Analytical Methods","volume":"48","author":"Salgado","year":"2018","journal-title":"Crit. Rev. Anal. Chem."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"325","DOI":"10.1016\/j.pop.2015.05.001","article-title":"Conjunctivitis","volume":"42","author":"Alfonso","year":"2015","journal-title":"Prim. Care Clin. Off. Pract."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"1445","DOI":"10.1001\/jamaophthalmol.2015.3888","article-title":"Antibiotic Resistance among Ocular Pathogens in the United States Five-Year Results from the Antibiotic Resistance Monitoring in Ocular Microorganisms (ARMOR) Surveillance Study","volume":"133","author":"Asbell","year":"2015","journal-title":"JAMA Ophthalmol."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"215","DOI":"10.2147\/OPTH.S9604","article-title":"Besifloxacin: A Novel Anti-Infective for the Treatment of Bacterial Conjunctivitis","volume":"4","author":"Comstock","year":"2010","journal-title":"Clin. Ophthalmol."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"4126","DOI":"10.1038\/s41598-018-22416-4","article-title":"Genomics-Based Identification of Microorganisms in Human Ocular Body Fluid","volume":"8","author":"Kirstahler","year":"2018","journal-title":"Sci. Rep."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"537","DOI":"10.1111\/ceo.13419","article-title":"Intracameral Antibiotics for Prophylaxis of Postoperative Endophthalmitis in Australia: A Review","volume":"47","author":"Lipsky","year":"2019","journal-title":"Clin. Exp. Ophthalmol."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"338","DOI":"10.1038\/nature17967","article-title":"A Platform for the Discovery of New Macrolide Antibiotics","volume":"533","author":"Seiple","year":"2016","journal-title":"Nature"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"367","DOI":"10.1016\/j.talanta.2013.10.051","article-title":"Quantitative Evaluation of Besifloxacin Ophthalmic Suspension by HPLC, Application to Bioassay Method and Cytotoxicity Studies","volume":"119","author":"Costa","year":"2014","journal-title":"Talanta"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"89","DOI":"10.1038\/nrd3101","article-title":"2009 FDA Drug Approvals","volume":"9","author":"Hughes","year":"2010","journal-title":"Nat. Rev. Drug Discov."},{"key":"ref_14","unstructured":"(2022, September 06). Bausch & Lomb Incorporated BesivanceTM Material Safety Data Sheet. Available online: \/\/s3-us-west-2.amazonaws.com\/drugbank\/msds\/DB06771.pdf?1365982762."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"1599","DOI":"10.3109\/03639045.2012.736515","article-title":"Recent Advances in Ocular Drug Delivery","volume":"39","author":"Achouri","year":"2013","journal-title":"Drug Dev. Ind. Pharm."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"418","DOI":"10.1016\/j.jconrel.2012.03.013","article-title":"Drug Nanocrystals: In Vivo Performances","volume":"160","author":"Gao","year":"2012","journal-title":"J. Control. Release"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"19285","DOI":"10.1038\/s41598-020-76381-y","article-title":"Besifloxacin Liposomes with Positively Charged Additives for an Improved Topical Ocular Delivery","volume":"10","author":"Dalmolin","year":"2020","journal-title":"Sci. Rep."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"229","DOI":"10.1007\/s13346-021-00902-z","article-title":"Besifloxacin-Loaded Ocular Nanoemulsions: Design, Formulation and Efficacy Evaluation","volume":"12","author":"Kassaee","year":"2022","journal-title":"Drug Deliv. Transl. Res."},{"key":"ref_19","first-page":"412","article-title":"Design of Besifloxacin HCl-Loaded Nanostructured Lipid Carriers: In Vitro and Ex Vivo Evaluation","volume":"38","author":"Polat","year":"2022","journal-title":"J. Ocul. Pharmacol. Ther."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"119552","DOI":"10.1016\/j.ijpharm.2020.119552","article-title":"Development of Besifloxacin HCl Loaded Nanofibrous Ocular Inserts for the Treatment of Bacterial Keratitis: In Vitro, Ex Vivo and in Vivo Evaluation","volume":"585","author":"Polat","year":"2020","journal-title":"Int. J. Pharm."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"812","DOI":"10.3109\/10837450.2015.1063650","article-title":"Physical\u2013Chemical Properties of Furosemide Nanocrystals Developed Using Rotation Revolution Mixer","volume":"21","author":"Barbosa","year":"2016","journal-title":"Pharm. Dev. Technol."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"642","DOI":"10.1208\/s12248-017-0064-x","article-title":"Development Considerations for Nanocrystal Drug Products","volume":"19","author":"Chen","year":"2017","journal-title":"AAPS J."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"6712","DOI":"10.1038\/s41598-018-29393-8","article-title":"Topical Curcumin Nanocarriers Are Neuroprotective in Eye Disease","volume":"8","author":"Davis","year":"2018","journal-title":"Sci. Rep."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"1071","DOI":"10.1208\/s12248-017-0084-6","article-title":"How Has CDER Prepared for the Nano Revolution? A Review of Risk Assessment, Regulatory Research, and Guidance Activities","volume":"19","author":"Tyner","year":"2017","journal-title":"AAPS J."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"315","DOI":"10.1124\/pr.112.005660","article-title":"Strategies to Address Low Drug Solubility in Discovery and Development","volume":"65","author":"Williams","year":"2013","journal-title":"Pharmacol. Rev."},{"key":"ref_26","unstructured":"Markets, R. (2020). Nanotechnology\u2014Global Market Trajectory & Analytics, Global Industry Analysts, Inc."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"100396","DOI":"10.1016\/j.mtchem.2020.100396","article-title":"The Glucocorticoid Derivative with the Phthalimide Group Cationic Nanocrystal for Ophthalmic Application: A Design Space Development Approach","volume":"19","author":"Peters","year":"2021","journal-title":"Mater. Today Chem."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"101486","DOI":"10.1016\/j.jddst.2019.101486","article-title":"Design Space Approach in the Development of Esculetin Nanocrystals by a Small-Scale Wet-Bead Milling Process","volume":"55","author":"Zuo","year":"2020","journal-title":"J. Drug Deliv. Sci. Technol."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"1441","DOI":"10.1093\/jac\/dkq127","article-title":"Bactericidal Activity of Besifloxacin against Staphylococci, Streptococcus Pneumoniae and Haemophilus Influenzae","volume":"65","author":"Haas","year":"2010","journal-title":"J. Antimicrob. Chemother."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"215","DOI":"10.1016\/j.ejpb.2016.07.005","article-title":"Development of Cationic Nanocrystals for Ocular Delivery","volume":"107","author":"Romero","year":"2016","journal-title":"Eur. J. Pharm. Biopharm."},{"key":"ref_31","unstructured":"(2022, August 10). MALVERN Zetasizer Nano Series\u2014Performance, Simplicity, Versatility. Malvern Instruments Ltd. Available online: https:\/\/www.malvernpanalytical.com\/en\/assets\/MRK1839_tcm50-17228.pdf."},{"key":"ref_32","unstructured":"(2022, September 06). VICH ICH Topic Q2 (R1) Validation of Analytical Procedures: Text and Methodology. Available online: https:\/\/www.ema.europa.eu\/en\/documents\/scientific-guideline\/ich-q-2-r1-validation-analytical-procedures-text-methodology-step-5_en.pdf."},{"key":"ref_33","unstructured":"United States Pharmacopeia (2021). \u23291225\u232a Validation of Compendial Procedures, Pharmacopeial. USP 43-NF 38."},{"key":"ref_34","unstructured":"Brazilian Health Surveillance Agency (ANVISA) (2022, September 06). Resolu\u00e7\u00e3o da Diretoria Colegiada RDC No 166, de 24 de Julho de 2017. Disp\u00f5e sobre a valida\u00e7\u00e3o de m\u00e9todos anal\u00edticos e d\u00e1 outras provid\u00eancias, Available online: https:\/\/www.in.gov.br\/materia\/-\/asset_publisher\/Kujrw0TZC2Mb\/content\/id\/19194581\/do1-2017-07-25-resolucao-rdc-n-166-de-24-de-julho-de-2017-19194412."},{"key":"ref_35","unstructured":"Brazilian Health Surveillance Agency (ANVISA) (2022, September 06). Resolu\u00e7\u00e3o da Diretoria Colegiada RDC No 37, de 03 de Agosto de 2011. Disp\u00f5e Sobre o Guia Para Isen\u00e7\u00e3o e Substitui\u00e7\u00e3o de Estudos de Biodisponibilidade Relativa\/Bioequival\u00eancia e D\u00e1 Outras Provid\u00eancias, Available online: https:\/\/bvsms.saude.gov.br\/bvs\/saudelegis\/anvisa\/2011\/res0037_03_08_2011.html."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"5187","DOI":"10.2147\/IJN.S205350","article-title":"Alginate Nanoparticles as Non-Toxic Delivery System for Miltefosine in the Treatment of Candidiasis and Cryptococcosis","volume":"14","author":"Lopes","year":"2019","journal-title":"Int. J. Nanomed."},{"key":"ref_37","unstructured":"(2022, September 06). ICH Q1\u2014Evaluation of Stability Data. Guideline 2003. Available online: https:\/\/www.ema.europa.eu\/en\/documents\/scientific-guideline\/ich-q-1-r2-stability-testing-new-drug-substances-products-step-5_en.pdf."},{"key":"ref_38","unstructured":"Brazilian Health Surveillance Agency (ANVISA) (2022, August 26). Resolu\u00e7\u00e3o da Diretoria Colegiada RDC N\u00b0 318, de 6 de Novembro de 2019. Estabelece os crit\u00e9rios para a realiza\u00e7\u00e3o de Estudos de Estabilidade de insumos farmac\u00eauticos ativos e medicamentos, exceto biol\u00f3gicos, e d\u00e1 outras provid\u00eancias, Available online: https:\/\/www.in.gov.br\/web\/dou\/-\/resolucao-rdc-n-318-de-6-de-novembro-de-2019-226513805."},{"key":"ref_39","first-page":"1987","article-title":"Besifloxacin Ophthalmic Suspension 0.6% in the Treatment of Bacterial Conjunctivitis Patients with Pseudomonas Aeruginosa Infections","volume":"6","author":"Silverstein","year":"2012","journal-title":"Clin. Ophthalmol."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"1848","DOI":"10.1016\/j.xphs.2018.12.015","article-title":"Highly Water-Soluble Orotic Acid Nanocrystals Produced by High-Energy Milling","volume":"108","author":"Takatsuka","year":"2019","journal-title":"J. Pharm. Sci."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"376","DOI":"10.1016\/j.ajps.2015.09.005","article-title":"Povacoat Affecting Solid-State Polymorphic Changes of Indomethacin after Co-Evaporation from Different Types of Solvents via Conventional and Microwave Drying Techniques","volume":"11","author":"Lin","year":"2016","journal-title":"Asian J. Pharm. Sci."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"110895","DOI":"10.1016\/j.msec.2020.110895","article-title":"Rifampicin Nanocrystals: Towards an Innovative Approach to Treat Tuberculosis","volume":"112","author":"Melo","year":"2020","journal-title":"Mater. Sci. Eng. C"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"151","DOI":"10.1016\/j.ijpharm.2014.08.022","article-title":"Development of Nanocrystal Formulation of Meloxicam with Improved Dissolution and Pharmacokinetic Behaviors","volume":"474","author":"Ochi","year":"2014","journal-title":"Int. J. Pharm."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"2829","DOI":"10.1002\/jps.24023","article-title":"Anti-Plasticizing Effect of Amorphous Indomethacin Induced by Specific Intermolecular Interactions with PVA Copolymer","volume":"103","author":"Ueda","year":"2014","journal-title":"J. Pharm. Sci."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"3772","DOI":"10.1002\/jps.24147","article-title":"Preparation and Evaluation of High Dispersion Stable Nanocrystal Formulation of Poorly Water-Soluble Compounds by Using Povacoat","volume":"103","author":"Yuminoki","year":"2014","journal-title":"J. Pharm. Sci."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"48","DOI":"10.1016\/j.ajps.2015.10.037","article-title":"Application of Povacoat as Dispersion Stabilizer of Nanocrystal Formulation","volume":"11","author":"Yuminoki","year":"2016","journal-title":"Asian J. Pharm. Sci."},{"key":"ref_47","unstructured":"(2022, September 06). ICH Q8(R2). Pharmaceutical Development. Guideline. Available online: https:\/\/www.ema.europa.eu\/en\/ich-q8-r2-pharmaceutical-development."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"259","DOI":"10.1080\/1061186X.2019.1663858","article-title":"Advances in Ophthalmic Preparation: The Role of Drug Nanocrystals and Lipid-Based Nanosystems","volume":"28","author":"Peters","year":"2020","journal-title":"J. Drug Target."},{"key":"ref_49","doi-asserted-by":"crossref","unstructured":"(2014). U.S. Food and Drug Administration Food and Drug Administration\u2014Guidance for Industry Considering Whether an FDA-Regulated Product Involves the Application of Nanotechnology. Biotechnol. Law Rep., 30, 613\u2013616.","DOI":"10.1089\/blr.2011.9814"},{"key":"ref_50","doi-asserted-by":"crossref","unstructured":"Kornecki, M., and Strube, J. (2018). Process Analytical Technology for Advanced Process Control in Biologics Manufacturing with the Aid of Macroscopic Kinetic Modeling. Bioengineering, 5.","DOI":"10.3390\/bioengineering5010025"},{"key":"ref_51","unstructured":"(2022, August 02). HORIBA A Guidebook to Particle Size Analysis. Available online: https:\/\/static.horiba.com\/fileadmin\/Horiba\/Products\/Scientific\/Particle_Characterization\/Particle_Guidebook_06-2021.pdf."},{"key":"ref_52","unstructured":"(2022, August 02). Australian Government Department of Health and Ageing AusPAR: Besifloxacin Hydrochloride, Available online: https:\/\/www.tga.gov.au\/resources\/auspar\/auspar-besifloxacin-hydrochloride."},{"key":"ref_53","unstructured":"Pharmacopeia, U.S. (2021). \u2329771\u232a Ophthalmic Products\u2014Quality Tests, Pharmacopeial. USP 43-NF 38."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"301","DOI":"10.1001\/archopht.1981.03930010303017","article-title":"Normal Human Tear Ph by Direct Measurement","volume":"99","author":"Abelson","year":"1981","journal-title":"Arch. Ophthalmol."},{"key":"ref_55","first-page":"1","article-title":"Ophthalmic Preparations","volume":"39","author":"Aldrich","year":"2013","journal-title":"Pharmacop. Forum"},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"34","DOI":"10.1208\/s12249-018-1257-z","article-title":"On the Stability of Nano-Formulations Prepared by Direct Synthesis: Simulated Ostwald Ripening of a Typical Nanocrystal Distribution Post-Nucleation","volume":"20","author":"Skrdla","year":"2019","journal-title":"AAPS PharmSciTech"},{"key":"ref_57","unstructured":"United States Pharmacopeia (2021). \u2329785\u232a Osmolality and Osmolarity, Pharmacopeial. USP 43-NF 38."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"124755","DOI":"10.1016\/j.colsurfa.2020.124755","article-title":"Cationic Rifampicin Nanoemulsion for the Treatment of Ocular Tuberculosis","volume":"597","year":"2020","journal-title":"Colloids Surf. A: Physicochem. Eng. Asp."},{"key":"ref_59","unstructured":"(2022, August 02). Food and Drug Administration 2018 NEW DRUG THERAPY APPROVALS, Available online: https:\/\/www.fda.gov\/files\/drugs\/published\/New-Drug-Therapy-Approvals-2018_3.pdf."},{"key":"ref_60","unstructured":"Harry, M., and King, J. (2013). Fluoroquinolone Carboxylic Acid Molecular Crystals. (No. 8,481,526), U.S. Patent."},{"key":"ref_61","doi-asserted-by":"crossref","unstructured":"Piatek, M., Sheehan, G., and Kavanagh, K. (2021). Galleria Mellonella: The Versatile Host for Drug Discovery, in Vivo Toxicity Testing and Characterising Host-Pathogen Interactions. Antibiotics, 10.","DOI":"10.3390\/antibiotics10121545"},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"129235","DOI":"10.1016\/j.chemosphere.2020.129235","article-title":"Utility of Galleria Mellonella Larvae for Evaluating Nanoparticle Toxicology","volume":"266","author":"Vukomanovic","year":"2021","journal-title":"Chemosphere"},{"key":"ref_63","first-page":"57","article-title":"Galleria Mellonella L. as Model Organism Used in Biomedical and Other Studies","volume":"72","author":"Mikulak","year":"2018","journal-title":"Prz. Epidemiol."}],"container-title":["Pharmaceutics"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1999-4923\/14\/10\/2221\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T00:56:42Z","timestamp":1760144202000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1999-4923\/14\/10\/2221"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,10,18]]},"references-count":63,"journal-issue":{"issue":"10","published-online":{"date-parts":[[2022,10]]}},"alternative-id":["pharmaceutics14102221"],"URL":"https:\/\/doi.org\/10.3390\/pharmaceutics14102221","relation":{},"ISSN":["1999-4923"],"issn-type":[{"value":"1999-4923","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,10,18]]}}}