{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T01:12:12Z","timestamp":1760145132867,"version":"build-2065373602"},"reference-count":47,"publisher":"MDPI AG","issue":"13","license":[{"start":{"date-parts":[[2024,6,27]],"date-time":"2024-06-27T00:00:00Z","timestamp":1719446400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"National Key R&amp;D Program of China","award":["2022YFD1802100"],"award-info":[{"award-number":["2022YFD1802100"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>The phenylpyrazole derivative 5-amino-3-[1-cyano-2-(3-phenyl-1H-pyrazol-4-yl) vinyl]-1-phenyl-1H-pyrazole-4-carbonitrile (LN002), which was screened out through high-throughput molecular docking for the AOX target, exhibits promising efficacy against Cryptosporidium. However, its poor water solubility limits its oral bioavailability and therapeutic utility. In this study, solid dispersion agents were prepared by using HP-\u03b2-CD and Soluplus\u00ae and characterized through differential scanning calorimetry, Fourier transform infrared, powder X-ray diffraction, and scanning electron microscopy. Physical and chemical characterization showed that the crystal morphology of LN002 transformed into an amorphous state, thus forming a solid dispersion of LN002. The solid dispersion prepared with an LN002\/HP-\u03b2-CD\/Soluplus\u00ae mass ratio of 1:3:9 (w\/w\/w) exhibited significantly increased solubility and cumulative dissolution. Meanwhile, LN002 SDs showed good preservation stability under accelerated conditions of 25 \u00b0C and 75% relative humidity. The complexation of LN002 with HP-\u03b2-CD and Soluplus\u00ae significantly improved water solubility, pharmacological properties, absorption, and bioavailability.<\/jats:p>","DOI":"10.3390\/ijms25137025","type":"journal-article","created":{"date-parts":[[2024,6,27]],"date-time":"2024-06-27T05:11:39Z","timestamp":1719465099000},"page":"7025","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Preparation, Characterization, and Oral Bioavailability of Solid Dispersions of Cryptosporidium parvum Alternative Oxidase Inhibitors"],"prefix":"10.3390","volume":"25","author":[{"given":"Yongxiang","family":"Zhang","sequence":"first","affiliation":[{"name":"Guangdong Provincial Key Laboratory of Veterinary Pharmaceutics Development and Safety Evaluation, College of Veterinary Medicine, South China Agricultural University, Guangzhou 510642, China"},{"name":"National Risk Assessment Laboratory for Antimicrobial Resistance of Animal Original Bacteria, Guangzhou 510642, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Minglang","family":"Ma","sequence":"additional","affiliation":[{"name":"Guangdong Provincial Key Laboratory of Veterinary Pharmaceutics Development and Safety Evaluation, College of Veterinary Medicine, South China Agricultural University, Guangzhou 510642, China"},{"name":"National Risk Assessment Laboratory for Antimicrobial Resistance of Animal Original Bacteria, Guangzhou 510642, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jinyu","family":"Yang","sequence":"additional","affiliation":[{"name":"Guangdong Provincial Key Laboratory of Veterinary Pharmaceutics Development and Safety Evaluation, College of Veterinary Medicine, South China Agricultural University, Guangzhou 510642, China"},{"name":"National Risk Assessment Laboratory for Antimicrobial Resistance of Animal Original Bacteria, Guangzhou 510642, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Xiaotong","family":"Qiu","sequence":"additional","affiliation":[{"name":"Guangdong Provincial Key Laboratory of Veterinary Pharmaceutics Development and Safety Evaluation, College of Veterinary Medicine, South China Agricultural University, Guangzhou 510642, China"},{"name":"National Risk Assessment Laboratory for Antimicrobial Resistance of Animal Original Bacteria, Guangzhou 510642, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Lin","family":"Xin","sequence":"additional","affiliation":[{"name":"Guangdong Provincial Key Laboratory of Veterinary Pharmaceutics Development and Safety Evaluation, College of Veterinary Medicine, South China Agricultural University, Guangzhou 510642, China"},{"name":"National Risk Assessment Laboratory for Antimicrobial Resistance of Animal Original Bacteria, Guangzhou 510642, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yixing","family":"Lu","sequence":"additional","affiliation":[{"name":"Guangdong Provincial Key Laboratory of Veterinary Pharmaceutics Development and Safety Evaluation, College of Veterinary Medicine, South China Agricultural University, Guangzhou 510642, China"},{"name":"National Risk Assessment Laboratory for Antimicrobial Resistance of Animal Original Bacteria, Guangzhou 510642, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Huiguo","family":"Huang","sequence":"additional","affiliation":[{"name":"Guangdong Provincial Key Laboratory of Veterinary Pharmaceutics Development and Safety Evaluation, College of Veterinary Medicine, South China Agricultural University, Guangzhou 510642, China"},{"name":"National Risk Assessment Laboratory for Antimicrobial Resistance of Animal Original Bacteria, Guangzhou 510642, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Zhenling","family":"Zeng","sequence":"additional","affiliation":[{"name":"Guangdong Provincial Key Laboratory of Veterinary Pharmaceutics Development and Safety Evaluation, College of Veterinary Medicine, South China Agricultural University, Guangzhou 510642, China"},{"name":"National Risk Assessment Laboratory for Antimicrobial Resistance of Animal Original Bacteria, Guangzhou 510642, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2006-5755","authenticated-orcid":false,"given":"Dongping","family":"Zeng","sequence":"additional","affiliation":[{"name":"Guangdong Provincial Key Laboratory of Veterinary Pharmaceutics Development and Safety Evaluation, College of Veterinary Medicine, South China Agricultural University, Guangzhou 510642, China"},{"name":"National Risk Assessment Laboratory for Antimicrobial Resistance of Animal Original Bacteria, Guangzhou 510642, China"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2024,6,27]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"115","DOI":"10.1128\/CMR.00076-12","article-title":"Cryptosporidium pathogenicity and virulence","volume":"26","author":"Bouzid","year":"2013","journal-title":"Clin. Microbiol. Rev."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"S57","DOI":"10.1093\/clinids\/21.Supplement_1.S57","article-title":"Cryptosporidiosis: Sources of infection and guidelines for prevention","volume":"21","author":"Juranek","year":"1995","journal-title":"Clin. Infect. Dis."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"118","DOI":"10.1093\/oxfordjournals.epirev.a017920","article-title":"Epidemiologic aspects of human cryptosporidiosis and the role of waterborne transmission","volume":"18","author":"Meinhardt","year":"1996","journal-title":"Epidemiol. Rev."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"325","DOI":"10.1128\/CMR.4.3.325","article-title":"Cryptosporidiosis","volume":"4","author":"Current","year":"1991","journal-title":"Clin. Microbiol. Rev."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"470","DOI":"10.1186\/s13071-022-05606-y","article-title":"Cryptosporidium parvum regulates HCT-8 cell autophagy to facilitate survival via inhibiting miR-26a and promoting miR-30a expression","volume":"15","author":"Jiang","year":"2022","journal-title":"Parasites Vectors"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"201","DOI":"10.2174\/1570163814666170727130003","article-title":"Update on Nitazoxanide: A Multifunctional Chemotherapeutic Agent","volume":"15","author":"Shakya","year":"2018","journal-title":"Curr. Drug Discov. Technol."},{"key":"ref_7","doi-asserted-by":"crossref","unstructured":"Hennessey, K.M., Rogiers, I.C., Shih, H.W., Hulverson, M.A., Choi, R., McCloskey, M.C., Whitman, G.R., Barrett, L.K., Merritt, E.A., and Paredez, A.R. (2018). Screening of the Pathogen Box for inhibitors with dual efficacy against Giardia lamblia and Cryptosporidium parvum. PLoS Neglect. Trop. Dis., 12.","DOI":"10.1371\/journal.pntd.0006673"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"1375","DOI":"10.1016\/S0140-6736(02)11401-2","article-title":"Effect of nitazoxanide on morbidity and mortality in Zambian children with cryptosporidiosis: A randomised controlled trial","volume":"360","author":"Amadi","year":"2002","journal-title":"Lancet"},{"key":"ref_9","doi-asserted-by":"crossref","unstructured":"Yu, L., Liu, Q., Luo, W., Zhao, J., Alzan, H.F., and He, L. (2021). The Structural Basis of Babesia orientalis Lactate Dehydrogenase. Front. Cell. Infect. Microbiol., 11.","DOI":"10.3389\/fcimb.2021.790101"},{"key":"ref_10","doi-asserted-by":"crossref","unstructured":"Mendoza, H., Culver, C.D., Lamb, E.A., Schroeder, L.A., Khanal, S., Muller, C., Schirawski, J., and Perlin, M.H. (2022). Identification and Functional Characterization of a Putative Alternative Oxidas (Aox) in Sporisorium reilianum f. sp. zeae. J. Fungi, 8.","DOI":"10.3390\/jof8020148"},{"key":"ref_11","doi-asserted-by":"crossref","unstructured":"Zhang, H., Guo, F., and Zhu, G. (2015). Cryptosporidium Lactate Dehydrogenase Is Associated with the Parasitophorous Vacuole Membrane and Is a Potential Target for Developing Therapeutics. PLoS Pathog., 11.","DOI":"10.1371\/journal.ppat.1005250"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"1553","DOI":"10.1002\/med.21560","article-title":"Alternative oxidase inhibitors: Mitochondrion-targeting as a strategy for new drugs against pathogenic parasites and fungi","volume":"39","author":"Ebiloma","year":"2019","journal-title":"Med. Res. Rev."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"5312","DOI":"10.3390\/cimb44110361","article-title":"In Silico Identification of Promising New Pyrazole Derivative-Based Small Molecules for Modulating CRMP2, C-RAF, CYP17, VEGFR, C-KIT, and HDAC-Application towards Cancer Therapeutics","volume":"44","author":"Bennani","year":"2022","journal-title":"Curr. Issues Mol. Biol."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"6660","DOI":"10.1038\/s41598-020-63377-x","article-title":"Design and efficient synthesis of pyrazoline and isoxazole bridged indole C-glycoside hybrids as potential anticancer agents","volume":"10","author":"Kumari","year":"2020","journal-title":"Sci. Rep."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"256","DOI":"10.1021\/jm00380a020","article-title":"3,4-Diphenyl-1H-pyrazole-1-propanamine antidepressants","volume":"28","author":"Bailey","year":"1985","journal-title":"J. Med. Chem."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"1396","DOI":"10.1021\/jm00377a003","article-title":"(1,3-Dialkyl-5-amino-1H-pyrazol-4-yl)arylmethanones. A series of novel central nervous system depressants","volume":"27","author":"Butler","year":"1984","journal-title":"J. Med. Chem."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"2278","DOI":"10.1016\/j.bmcl.2006.01.026","article-title":"Stereoselective synthesis and fungicidal activities of (E)-alpha-(methoxyimino)-benzeneacetate derivatives containing 1,3,4-oxadiazole ring","volume":"16","author":"Li","year":"2006","journal-title":"Bioorg. Med. Chem. Lett."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"4427","DOI":"10.1021\/jm401427c","article-title":"Targeting Receptor Tyrosine Kinase MET in Cancer: Small Molecule Inhibitors and Clinical Progress","volume":"57","author":"Cui","year":"2014","journal-title":"J. Med. Chem."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"145","DOI":"10.1002\/arch.10112","article-title":"Chloride channels as tools for developing selective insecticides","volume":"54","author":"Bloomquist","year":"2003","journal-title":"Arch. Insect. Biochem. Physiol."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"1209","DOI":"10.1080\/03639040802005024","article-title":"Production and in vitro characterization of solid dosage form incorporating drug nanoparticles","volume":"34","author":"Basa","year":"2008","journal-title":"Drug Dev. Ind. Pharm."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"3","DOI":"10.1016\/S0169-409X(00)00118-6","article-title":"Nanosuspensions as particulate drug formulations in therapy. Rationale for development and what we can expect for the future","volume":"47","author":"Muller","year":"2001","journal-title":"Adv. Drug Deliv. Rev."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"3640","DOI":"10.1021\/mp400127r","article-title":"Formation and physicochemical properties of crystalline and amorphous salts with different stoichiometries formed between ciprofloxacin and succinic acid","volume":"10","author":"Paluch","year":"2013","journal-title":"Mol. Pharm."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"1369","DOI":"10.2147\/IJN.S124276","article-title":"The functional curcumin liposomes induce apoptosis in C6 glioblastoma cells and C6 glioblastoma stem cells in vitro and in animals","volume":"12","author":"Wang","year":"2017","journal-title":"Int. J. Nanomed."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"2415","DOI":"10.1080\/10717544.2021.1998248","article-title":"Enhanced oral bioavailability of koumine by complexation with hydroxypropyl-beta-cyclodextrin: Preparation, optimization, ex vivo and in vivo characterization","volume":"28","author":"Hu","year":"2021","journal-title":"Drug Deliv."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"47","DOI":"10.1016\/j.powtec.2010.10.009","article-title":"Improvement of dissolution rate of aceclofenac by solid dispersion technique","volume":"207","author":"Maulvi","year":"2011","journal-title":"Powder Technol."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"69","DOI":"10.1016\/j.ijpharm.2011.04.066","article-title":"Development of a liposomal formulation of the natural flavonoid fisetin","volume":"423","author":"Mignet","year":"2012","journal-title":"Int. J. Pharm."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"3763","DOI":"10.2147\/IJN.S164228","article-title":"Novel nanocrystal-based solid dispersion with high drug loading, enhanced dissolution, and bioavailability of andrographolide","volume":"13","author":"Ma","year":"2018","journal-title":"Int. J. Nanomed."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"761","DOI":"10.1093\/jpp\/rgab179","article-title":"Effect of carrier material on the thermodynamic properties and recrystallization kinetics of andrographolide-solid dispersion","volume":"74","author":"Zhao","year":"2022","journal-title":"J. Pharm. Pharmacol."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"91","DOI":"10.1016\/j.jconrel.2018.08.016","article-title":"Electrospun amorphous solid dispersions of poorly water-soluble drugs: A review","volume":"292","author":"Yu","year":"2018","journal-title":"J. Control. Release"},{"key":"ref_30","doi-asserted-by":"crossref","unstructured":"Lee, J.H., Jeong, H.S., Jeong, J.W., Koo, T.S., Kim, D.K., Cho, Y.H., and Lee, G.W. (2021). The Development and Optimization of Hot-Melt Extruded Amorphous Solid Dispersions Containing Rivaroxaban in Combination with Polymers. Pharmaceutics, 13.","DOI":"10.3390\/pharmaceutics13030344"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"322","DOI":"10.1021\/acs.jcim.5b00574","article-title":"Hydrogen-Bond Accepting Properties of New Heteroaromatic Ring Chemical Motifs: A Theoretical Study","volume":"56","author":"Graton","year":"2016","journal-title":"J. Chem. Inf. Model."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"4849","DOI":"10.2147\/IJN.S132114","article-title":"Inhibitory effect of a new orally active cedrol-loaded nanostructured lipid carrier on compound 48\/80-induced mast cell degranulation and anaphylactic shock in mice","volume":"12","author":"Chakraborty","year":"2017","journal-title":"Int. J. Nanomed."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"2824","DOI":"10.1080\/10717544.2022.2118400","article-title":"Enhancement of the oral bioavailability of isopropoxy benzene guanidine though complexation with hydroxypropyl-beta-cyclodextrin","volume":"29","author":"Lu","year":"2022","journal-title":"Drug Deliv."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"240","DOI":"10.1016\/j.ejps.2017.04.007","article-title":"Effect of micro-environment modification and polymer type on the in-vitro dissolution behavior and in-vivo performance of amorphous solid dispersions","volume":"104","author":"Sun","year":"2017","journal-title":"Eur. J. Pharm. Sci."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"14791","DOI":"10.1021\/acsami.2c01087","article-title":"Self-Assembly of Soluplus in Aqueous Solutions: Characterization and Prospectives on Perfume Encapsulation. ACS Appl","volume":"14","author":"Sofroniou","year":"2022","journal-title":"Mater. Interfaces"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"102877","DOI":"10.1016\/j.jddst.2021.102877","article-title":"Novel ezetimibe-loaded fibrous microparticles for enhanced solubility and oral bioavailability by electrospray technique","volume":"66","author":"Kim","year":"2021","journal-title":"J. Drug Deliv. Sci. Technol."},{"key":"ref_37","doi-asserted-by":"crossref","unstructured":"Choi, M.J., Woo, M.R., Choi, H.G., and Jin, S.G. (2022). Effects of Polymers on the Drug Solubility and Dissolution Enhancement of Poorly Water-Soluble Rivaroxaban. Int. J. Mol. Sci., 23.","DOI":"10.3390\/ijms23169491"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"12","DOI":"10.1208\/s12249-018-1266-y","article-title":"The Influence of Cellulosic Polymer\u2019s Variables on Dissolution\/Solubility of Amorphous Felodipine and Crystallization Inhibition from a Supersaturated State","volume":"20","author":"Shi","year":"2018","journal-title":"AAPS Pharm. Sci. Tech."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"1031","DOI":"10.2147\/IJN.S395266","article-title":"Solubilisation and Enhanced Oral Absorption of Curcumin Using a Natural Non-Nutritive Sweetener Mogroside V","volume":"18","author":"Zhang","year":"2023","journal-title":"Int. J. Nanomed."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"79","DOI":"10.1016\/j.ejps.2019.03.012","article-title":"Combining amorphous solid dispersions for improved kinetic solubility of posaconazole simultaneously released from soluble PVP\/VA64 and an insoluble ammonio methacrylate copolymer","volume":"133","author":"Melo","year":"2019","journal-title":"Eur. J. Pharm. Sci."},{"key":"ref_41","doi-asserted-by":"crossref","unstructured":"Lorenzo-Veiga, B., Sigurdsson, H.H., Loftsson, T., and Alvarez-Lorenzo, C. (2019). Cyclodextrin(-)Amphiphilic Copolymer Supramolecular Assemblies for the Ocular Delivery of Natamycin. Nanomaterials, 9.","DOI":"10.3390\/nano9050745"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"886","DOI":"10.1007\/s11095-007-9469-z","article-title":"Appearance of double peaks in plasma concentration-time profile after oral administration depends on gastric emptying profile and weight function","volume":"25","author":"Metsugi","year":"2008","journal-title":"Pharm. Res."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"720","DOI":"10.1080\/10717544.2017.1311968","article-title":"A novel matrix dispersion based on phospholipid complex for improving oral bioavailability of baicalein: Preparation, in vitro and in vivo evaluations","volume":"24","author":"Zhou","year":"2017","journal-title":"Drug Deliv."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"2189630","DOI":"10.1080\/10717544.2023.2189630","article-title":"Merging konjac glucomannan with other copolymeric hydrogels as a cutting-edge liquid raft system for dual delivery of etoricoxib and famotidine","volume":"30","author":"Shoman","year":"2023","journal-title":"Drug Deliv."},{"key":"ref_45","doi-asserted-by":"crossref","unstructured":"Zafar, A., Alruwaili, N.K., Imam, S.S., Yasir, M., Alsaidan, O.A., Alquraini, A., Rawaf, A., Alsuwayt, B., Anwer, M.K., and Alshehri, S. (2022). Development and Optimization of Nanolipid-Based Formulation of Diclofenac Sodium: In Vitro Characterization and Preclinical Evaluation. Pharmaceutics, 14.","DOI":"10.3390\/pharmaceutics14030507"},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"25","DOI":"10.1081\/DDC-43947","article-title":"Development and evaluation of fast-dissolving film of salbutamol sulphate","volume":"31","author":"Mashru","year":"2005","journal-title":"Drug Dev. Ind. Pharm."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"447","DOI":"10.1016\/j.ajps.2022.04.004","article-title":"Salvianolic acid B dry powder inhaler for the treatment of idiopathic pulmonary fibrosis","volume":"17","author":"Lu","year":"2022","journal-title":"Asian J. Pharm. Sci."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/25\/13\/7025\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T15:06:00Z","timestamp":1760108760000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/25\/13\/7025"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,6,27]]},"references-count":47,"journal-issue":{"issue":"13","published-online":{"date-parts":[[2024,7]]}},"alternative-id":["ijms25137025"],"URL":"https:\/\/doi.org\/10.3390\/ijms25137025","relation":{},"ISSN":["1422-0067"],"issn-type":[{"type":"electronic","value":"1422-0067"}],"subject":[],"published":{"date-parts":[[2024,6,27]]}}}