Current NanomedicineCurrent NanomedicineCurrent Nanomedicine2468-18732468-1881Bentham Science67584610.2174/0124681873262019231105201433PharmacologyResearch ArticleDesign Formulation of Nanospanlastic Novel Carriers as a Promising Approach to Enhanced Bioavailability in Intranasal Drug Delivery for Sinusitis: Statistical Optimization and In vitro and In vivo CharacterizationChettupalliAnandainfo@benthamscience.netAjmeraSrivaniinfo@benthamscience.netKuchukuntlaMounikainfo@benthamscience.netPalanivelVenkatesaninfo@benthamscience.netKattaSunandinfo@benthamscience.netDepartment of Pharmaceutical Science, School of Pharmacy, Anurag UniversityDepartment of Pharmacy, Annamalai University0103202414326628828022025Copyright ©; 2024, Bentham Science Publishers2024Bentham Science Publishershttps://journals.eco-vector.com/2468-1873/article/view/675846

Background:Most new biologically active chemicals require better water solubility and slower dissolution rates. Cefdinir (CFD) has a very low bioavailability in its crystalline form and is poorly soluble in water.

Objective:By preparing cefdinir's spanlastic nanovesicles (SNVs) using the ethanol injection method, the current study has attempted to enhance the drug's solubility and bioavailability using a statistical design approach.

Methods:Independent variables, including the nonionic surfactant concentration, edge activator (EA), sonication time, SNVs entrapment efficiency, particle size, zeta potential, PDI, and in vitro release, have been evaluated. The best CFD-SNVs were positioned within in situ gel with muco-adhesive properties made of hydroxypropyl methylcellulose and deacetylated gellan gum. By contrasting intranasal injection of the produced gel with an IV solution, animal models have been used to investigate CFD's systemic and cerebral dynamics.

Results:Statistical analysis has suggested an ideal SNVs formulation with nonionic surfactant (65 mg), EA (15 mg), and sonication (3 min). The sol-gel temperature for forming the mucoad-hesive in situ gel containing SNVs has been found to be 34.03°C, and 18.36 minutes has been the extended mucociliary transit time. Following intranasal injection, compared to SNV dispersion, the gelling system has exhibited higher brain bioavailability (2251.9 ± 75 vs. 5281.6 ± 51%, re-spectively). The gel has also demonstrated effective drug targeting of the brain with higher direct transport percentage indices.

Conclusion:Mucoadhesive in situ gel with CFD-loaded SNVs can be administered via the in-tranasal route. To enhance bioavailability in the brain and drug targeting from the nose to the brain, nasal in situ gel loaded with CFD-SNVs could be a new carrier to be employed in sinusitis.

Cefdinirintranasalspanlastic nanovesiclesnonionic surfactantmucoadhesive gelbrain targeting.Guay DRP. Pharmacodynamics and pharmacokinetics of cefdinir, an oral extended spectrum cephalosporin. Pediatr Infect Dis J 2000; 19(12): S141-6. doi: 10.1097/00006454-200012001-00002 PMID: 11144395Lu Q, Zhang H, Che DT, Li WH. In vitro antibacterial activity of cefdinir against isolates of respiratory tract pathogens in children. Zhonghua Er Ke Za Zhi 2004; 42(9): 697-700. PMID: 15482675Guay DRP. Cefdinir: An advanced-generation, broad-spectrum oral cephalosporin. Clin Ther 2002; 24(4): 473-89. doi: 10.1016/S0149-2918(02)85125-6 PMID: 12017394Stuchlík M, Žák S. Lipid-based vehicle for oral drug delivery. Biomed Pap Med Fac Univ Palacky Olomouc Czech Repub 2001; 145(2): 17-26. doi: 10.5507/bp.2001.008 PMID: 12426768Schreier H, Bouwstra J. Liposomes and niosomes as topical drug carriers: Dermal and transdermal drug delivery. J Control Release 1994; 30(1): 1-15. doi: 10.1016/0168-3659(94)90039-6Montone KT. Pathology of fungal rhinosinusitis: A review. Head Neck Pathol 2016; 10(1): 40-6. doi: 10.1007/s12105-016-0690-0 PMID: 26830404Chakrabarti A, Das A, Panda NK. Controversies surrounding the categorization of fungal sinusitis. Med Mycol 2009; 47(s1): S299-308. doi: 10.1080/13693780802213357 PMID: 18663658Kammoun AK, Khedr A, Hegazy MA, et al. Formulation, optimization, and nephrotoxicity evaluation of an antifungal in situ nasal gel loaded with voriconazole-clove oil transferosomal nanoparticles. Drug Deliv 2021; 28(1): 2229-40. doi: 10.1080/10717544.2021.1992040 PMID: 34668818Misra A, Jogani V, Jinturkar K, Vyas T. Recent patents review on intranasal administration for CNS drug delivery. Recent Pat Drug Deliv Formul 2008; 2(1): 25-40. doi: 10.2174/187221108783331429 PMID: 19075895Laverdiere M, Bow EJ, Rotstein C, et al. Therapeutic drug monitoring for triazoles: A needs assessment review and recommendations from a Canadian perspective. Can J Infect Dis Med Microbiol 2014; 25(6): 327-43. doi: 10.1155/2014/340586 PMID: 25587296Bellmann R, Smuszkiewicz P. Pharmacokinetics of antifungal drugs: Practical implications for optimized treatment of patients. Infection 2017; 45(6): 737-79. doi: 10.1007/s15010-017-1042-z PMID: 28702763Patra JK, Das G, Fraceto LF, et al. Nano based drug delivery systems: Recent developments and future prospects. J Nanobiotechnology 2018; 16(1): 71. doi: 10.1186/s12951-018-0392-8 PMID: 30231877Abou-Taleb HA, Khallaf RA, Abdel-Aleem JA. Intranasal niosomes of nefopam with improved bioavailability: Preparation, optimization, and in-vivo evaluation. Drug Des Devel Ther 2018; 12: 3501-16. doi: 10.2147/DDDT.S177746 PMID: 30410310Sharma A, Pahwa S, Bhati S, Kudeshia P. Spanlastics: A modern approach for nanovesicular drug delivery system. Int J Pharm Sci Res 2020; 11: 1057-65.Shah HS, Usman F, Ashfaq-Khan M, et al. Preparation and characterization of anticancer niosomal withaferin-A formulation for improved delivery to cancer cells: in vitro, in vivo, and in silico evaluation. J Drug Deliv Sci Technol 2020; 59: 101863. doi: 10.1016/j.jddst.2020.101863Parthasarathi G, Udupa N, Umadevi P, Pillai G. Niosome encapsulated of vincristine sulfate: Improved anticancer activity with reduced toxicity in mice. J Drug Target 1994; 2(2): 173-82. doi: 10.3109/10611869409015907 PMID: 8069596Zaki RM, Ibrahim MA, Alshora DH, El Ela AESA. Formulation and evaluation of transdermal gel containing tacrolimus-loaded spanlastics: In vitro, ex vivo and in vivo studies. Polymers 2022; 14(8): 1528. doi: 10.3390/polym14081528 PMID: 35458277Elhabak M, Ibrahim S, Abouelatta SM. Topical delivery of l -ascorbic acid spanlastics for stability enhancement and treatment of UVB induced damaged skin. Drug Deliv 2021; 28(1): 445-53. doi: 10.1080/10717544.2021.1886377 PMID: 33620008Hosny KM, Alhakamy NA, Sindi AM, Khallaf RA. Coconut oil nanoemulsion loaded with a statin hypolipidemic drug for management of burns: Ormulation and in vivo evaluation. Pharmaceutics 2020; 12(11): 1061. doi: 10.3390/pharmaceutics12111061 PMID: 33171816Ahmed OAA, Kurakula M, Banjar ZM, Afouna MI, Zidan AS. Quality by design coupled with near infrared in formulation of transdermal glimepiride liposomal films. J Pharm Sci 2015; 104(6): 2062-75. doi: 10.1002/jps.24448 PMID: 25873019Zhu L, Ao J, Li P. A novel in situ gel base of deacetylase gellan gum for sustained ophthalmic drug delivery of ketotifen: In vitro and in vivo evaluation. Drug Des Devel Ther 2015; 9: 3943-9. PMID: 26251573Singh NK, Lee DS. In situ gelling pH- and temperature-sensitive biodegradable block copolymer hydrogels for drug delivery. J Control Release 2014; 193: 214-27. doi: 10.1016/j.jconrel.2014.04.056 PMID: 24815421Hamed SF, Sadek Z, Edris A. Antioxidant and antimicrobial activities of clove bud essential oil and eugenol nanoparticles in alcohol-free microemulsion. J Oleo Sci 2012; 61(11): 641-8. doi: 10.5650/jos.61.641 PMID: 23138253Darvishi E, Omidi M, Bushehri AAS, Golshani A, Smith ML. The antifungal eugenol perturbs dual aromatic and branched-chain amino acid permeases in the cytoplasmic membrane of yeast. PLoS One 2013; 8(10): e76028. doi: 10.1371/journal.pone.0076028 PMID: 24204588Lee SJ, Han JI, Lee GS, et al. Antifungal effect of eugenol and nerolidol against Microsporum gypseum in a guinea pig model. Biol Pharm Bull 2007; 30(1): 184-8. doi: 10.1248/bpb.30.184 PMID: 17202684Galgatte UC, Kumbhar AB, Chaudhari PD. Development of in situ gel for nasal delivery: Design, optimization, in vitro and in vivo evaluation. Drug Deliv 2014; 21(1): 62-73. doi: 10.3109/10717544.2013.849778 PMID: 24191774Database of select committee on GRAS substances (SCOGS) Reviews. Silver Spring, MD, USA: US Food and Drug Administration 2006.US Food and Drug Administration. Inactive ingredient search for approved drug products. FDA Database 2017.Salim M, Minamikawa H, Sugimura A, Hashim R. Amphiphilic designer nano-carriers for controlled release: From drug delivery to diagnostics. MedChemComm 2014; 5(11): 1602-18. doi: 10.1039/C4MD00085DAbdelbary GA, Amin MM, Zakaria MY. Ocular ketoconazole-loaded proniosomal gels: Formulation, ex vivo corneal permeation and in vivo studies. Drug Deliv 2017; 24(1): 309-19. doi: 10.1080/10717544.2016.1247928 PMID: 28165809Fahmy AM, El-Setouhy DA, Ibrahim AB, Habib BA, Tayel SA, Bayoumi NA. Penetration enhancer-containing spanlastics (PECSs) for transdermal delivery of haloperidol: In vitro characterization, ex vivo permeation and in vivo biodistribution studies. Drug Deliv 2018; 25(1): 12-22. doi: 10.1080/10717544.2017.1410262 PMID: 29219628Jaafar-Maalej C, Diab R, Andrieu V, Elaissari A, Fessi H. Ethanol injection method for hydrophilic and lipophilic drug-loaded liposome preparation. J Liposome Res 2010; 20(3): 228-43. doi: 10.3109/08982100903347923 PMID: 19899957Farghaly DA, Aboelwafa AA, Hamza MY, Mohamed MI. Topical delivery of fenoprofen calcium via elastic nano-vesicular spanlastics: Optimization using experimental design and in vivo evaluation. AAPS PharmSciTech 2017; 18(8): 2898-909. doi: 10.1208/s12249-017-0771-8 PMID: 28429293El Gamal SS, Naggar VF, Allam AN. Optimization of acyclovir oral tablets based on gastroretention technology: Factorial design analysis and physicochemical characterization studies. Drug Dev Ind Pharm 2011; 37(7): 855-67. doi: 10.3109/03639045.2010.546404 PMID: 21401342New RR. Liposomes: A practical approach. In: Preparation of liposomes. IRL Press 1990.Amarachinta PR, Sharma G, Samed N, Chettupalli AK, Alle M, Kim JC. Central composite design for the development of carvedilol-loaded transdermal ethosomal hydrogel for extended and enhanced anti-hypertensive effect. J Nanobiotechnology 2021; 19: 1-15.Beg S, Al Robaian M, Rahman M, Imam SS, Alruwaili N, Panda SK. Pharmaceutical drug product development and process optimization: Effective use of quality by design. CRC Press 2020. doi: 10.1201/9780367821678Jahangir MA, Anand C, Muheem A, et al. Nano phytomedicine based delivery system for CNS disease. Curr Drug Metab 2020; 21(9): 661-73. doi: 10.2174/1389200221666200523161003 PMID: 32445453Shntaif AH, Khan S, Tapadiya G, et al. Rational drug design, synthesis, and biological evaluation of novel N-(2-arylaminophenyl)-2,3-diphenylquinoxaline-6-sulfonamides as potential antimalarial, antifungal, and antibacterial agents. Digital Chinese Med 2021; 4(4): 290-304. doi: 10.1016/j.dcmed.2021.12.004Jahangir MA, Imam SS, Muheem A, et al. Nanocrystals: Characterization overview, applications in drug delivery, and their toxicity concerns. J Pharm Innov 2020; 1-12.Chettupalli AK, Ananthula M, Amarachinta PR, Bakshi V, Yata VK. Design, formulation, in-vitro and ex-vivo evaluation of atazanavir loaded cubosomal gel. Biointerface Res Appl Chem 2021; 11(4): 12037-54.Chettupalli AK, Rao PA, Kuchukuntla M, Bakshi V. Development and optimization of aripiprazole ODT by using box-behnken design. Res J Pharma Technol 2020; 13(12): 6195-201. doi: 10.5958/0974-360X.2020.01080.XDandamudi SP, Chettupalli AK, Dargakrishna SP, Nerella M, Amara RR, Yata VK. Response Surface Method for the Simultaneous Estimation of Atorvastatin and Olmesartan. Trends Sci 2022; 19(18): 5799-9. doi: 10.48048/tis.2022.5799Jahangir MA, Muheem A, Anand C, Imam SS. Traditional and modern applications of honey: An insight. In: Therapeutic Applications of Honey and its Phytochemicals. Singapore: Springer 2020; 1: pp. 151-69.Bakshi V, Amarachinta PR, Chettupalli AK. Design, development and optimization of solid lipid nanoparticles of rizatriptan for intranasal delivery: in vitro & in vivo assessment. Mater Today Proc 2022; 66: 2342-57. doi: 10.1016/j.matpr.2022.06.329Chettupalli AK, Amara RR, Amarachinta PR, Manda RM, Garige BSR, Yata VK. Formulation and evaluation of poly herbal liqui-solid compact for its anti-inflammatory effect. Biointerface Res Appl Chem 2022; 12: 3883-9.Al-mahallawi AM, Khowessah OM, Shoukri RA. Nano-transfersomal ciprofloxacin loaded vesicles for non-invasive trans-tympanic ototopical delivery: in-vitro optimization, ex-vivo permeation studies, and in-vivo assessment. Int J Pharm 2014; 472(1-2): 304-14. doi: 10.1016/j.ijpharm.2014.06.041 PMID: 24971692Mali N, Darandale S, Vavia P. Niosomes as a vesicular carrier for topical administration of minoxidil: Formulation and in vitro assessment. Drug Deliv Transl Res 2013; 3(6): 587-92. doi: 10.1007/s13346-012-0083-1 PMID: 25786376Bhatia M, Ahuja M. Psyllium arabinoxylan: Carboxymethylation, characterization and evaluation for nanoparticulate drug delivery. Int J Biol Macromol 2015; 72: 495-501. doi: 10.1016/j.ijbiomac.2014.08.051 PMID: 25199870Kurakula M, Ahmed TAT. Co-delivery of atorvastatin nanocrystals in PLGA based in situ gel for anti-hyperlipidemic efficacy. Curr Drug Deliv 2016; 13(2): 211-20. doi: 10.2174/1567201813666151109102718 PMID: 26549039Hosny KM, Rizg WY, Khallaf RA. Preparation and optimization of in situ gel loaded with rosuvastatin-ellagic acid nanotransfersomes to enhance the anti-proliferative activity. Pharmaceutics 2020; 12(3): 263. doi: 10.3390/pharmaceutics12030263 PMID: 32183144Chang JY, Oh YK, Choi H, Kim YB, Kim CK. Rheological evaluation of thermosensitive and mucoadhesive vaginal gels in physiological conditions. Int J Pharm 2002; 241(1): 155-63. doi: 10.1016/S0378-5173(02)00232-6 PMID: 12086731Kim CK, Lee SW, Choi HG, et al. Trials of in situ-gelling and mucoadhesive acetaminophen liquid suppository in human subjects. Int J Pharm 1998; 174(1-2): 201-7. doi: 10.1016/S0378-5173(98)00258-0Bansal K, Rawat MK, Jain A, Rajput A, Chaturvedi TP, Singh S. Development of satranidazole mucoadhesive gel for the treatment of periodontitis. AAPS PharmSciTech 2009; 10(3): 716-23. doi: 10.1208/s12249-009-9260-z PMID: 19479385Pathan IB, Mene H, Bairagi S. Quality by design (QbD) approach to formulate in situ gelling system for nose to brain delivery of Fluoxetine hydrochloride: Ex-vivo and In-vivo study. Ars Pharmaceut 2017; 58(3): 107-14. doi: 10.30827/ars.v58i3.6528Buss N, Snell P, Bock J, Hsu A, Jorga K. Saquinavir and ritonavir pharmacokinetics following combined ritonavir and saquinavir (soft gelatin capsules) administration. Br J Clin Pharmacol 2001; 52(3): 255-64. doi: 10.1046/j.0306-5251.2001.01452.x PMID: 11560557El-Nabarawy NA, Teaima MH, Helal DA. Assessment of spanlastic vesicles of zolmitriptan for treating migraine in rats. Drug Des Devel Ther 2019; 13: 3929-37. doi: 10.2147/DDDT.S220473 PMID: 31819367Dalpiaz A, Marchetti N, Cavazzini A, et al. Quantitative determination of zolmitriptan in rat blood and cerebrospinal fluid by reversed phase HPLC-ESI-MS/MS analysis: Application to in vivo preclinical pharmacokinetic study. J Chromatogr B Analyt Technol Biomed Life Sci 2012; 901: 72-8. doi: 10.1016/j.jchromb.2012.06.001 PMID: 22743338Chen X, Liu D, Luan Y, Jin F, Zhong D. Determination of zolmitriptan in human plasma by liquid chromatography-tandem mass spectrometry method: Application to a pharmacokinetic study. J Chromatogr B Analyt Technol Biomed Life Sci 2006; 832(1): 30-5. doi: 10.1016/j.jchromb.2005.12.008 PMID: 16413836Vyas TK, Babbar AK, Sharma RK, Misra A. Intranasal mucoadhesive microemulsions of zolmitriptan: Preliminary studies on brain-targeting. J Drug Target 2005; 13(5): 317-24. doi: 10.1080/10611860500246217 PMID: 16199375Jacob S, Nair AB, Al-Dhubiab BE. Preparation and evaluation of niosome gel containing acyclovir for enhanced dermal deposition. J Liposome Res 2017; 27(4): 283-92. doi: 10.1080/08982104.2016.1224897 PMID: 27558522Guideline IHT. Stability testing of new drug substances and products.Q1A (R2). 2003. Available from: https://www.fda.gov/regulatory-information/search-fda-guidance-documents/q1ar2-stability-testing-new-drug-substances-and-productsJacob S, Nair AB, Shah J. Emerging role of nanosuspensions in drug delivery systems. Biomater Res 2020; 24(1): 3. doi: 10.1186/s40824-020-0184-8 PMID: 31969986Agrawal A, Maheshwari RK. Formulation development and evaluation of in situ nasal gel of poorly water soluble drug using mixed solvency concept. Asian J Pharm 2011; 5(3): 131. doi: 10.4103/0973-8398.91988Abdelbary G, El-gendy N. Niosome-encapsulated gentamicin for ophthalmic controlled delivery. AAPS PharmSciTech 2008; 9(3): 740-7. doi: 10.1208/s12249-008-9105-1 PMID: 18563578Patel J, Patel D, Raval J. Formulation and evaluation of propranolol hydrochloride-loaded carbopol-934p/ethyl cellulose mucoadhesive microspheres. Iran J Pharm Res 2010; 9(3): 221-32. PMID: 24363731Araújo J, Gonzalez-Mira E, Egea MA, Garcia ML, Souto EB. Optimization and physicochemical characterization of a triamcinolone acetonide-loaded NLC for ocular antiangiogenic applications. Int J Pharm 2010; 393(1-2): 168-76. doi: 10.1016/j.ijpharm.2010.03.034 PMID: 20362042Turk CTS, Oz UC, Serim TM, Hascicek C. Formulation and optimization of nonionic surfactants emulsified nimesulide-loaded PLGA-based nanoparticles by design of experiments. AAPS PharmSciTech 2014; 15(1): 161-76. doi: 10.1208/s12249-013-0048-9 PMID: 24222270Al-mahallawi AM, Khowessah OM, Shoukri RA. Enhanced non invasive trans -tympanic delivery of ciprofloxacin through encapsulation into nano-spanlastic vesicles: Fabrication, in-vitro characterization, and comparative ex-vivo permeation studies. Int J Pharm 2017; 522(1-2): 157-64. doi: 10.1016/j.ijpharm.2017.03.005 PMID: 28279741Kao LS, Green CE. Analysis of variance: Is there a difference in means and what does it mean? J Surg Res 2008; 144(1): 158-70. doi: 10.1016/j.jss.2007.02.053 PMID: 17936790Petchsomrit A, Sermkaew N, Wiwattanapatapee R. Effect of alginate and surfactant on physical properties of oil entrapped alginate bead formulation of curcumin. Int J Pharm Pharm Sci 2013; 7(12): 864-8.Danaei M, Dehghankhold M, Ataei S, et al. Impact of particle size and polydispersity index on the clinical applications of lipidic nanocarrier systems. Pharmaceutics 2018; 10(2): 57. doi: 10.3390/pharmaceutics10020057 PMID: 29783687Elsherif NI, Shamma RN, Abdelbary G. Terbinafine hydrochloride trans-ungual delivery via nanovesicular systems: in vitro characterization and ex vivo evaluation. AAPS PharmSciTech 2017; 18(2): 551-62. doi: 10.1208/s12249-016-0528-9 PMID: 27138036Abdelrahman FE, Elsayed I, Gad MK, Elshafeey AH, Mohamed MI. Response surface optimization, Ex vivo and in vivo investigation of nasal spanlastics for bioavailability enhancement and brain targeting of risperidone. Int J Pharm 2017; 530(1-2): 1-11. doi: 10.1016/j.ijpharm.2017.07.050 PMID: 28733244Ghaderi S, Ghanbarzadeh S, Mohammadhassani Z, Hamishehkar H. Formulation of gammaoryzanol-loaded nanoparticles for potential application in fortifying food products. Adv Pharm Bull 2014; 4 (Suppl. 2): 549-54. PMID: 25671188Lasoń E, Sikora E, Ogonowski J. Influence of process parameters on properties of Nanostructured Lipid Carriers (NLC) formulation. Acta Biochim Pol 2013; 60(4): 773-7. PMID: 24432330Fahmy UA, Ahmed OAA, Badr-Eldin SM, et al. Optimized nanostructured lipid carriers integrated into in situ nasal gel for enhancing brain delivery of flibanserin. Int J Nanomedicine 2020; 15: 5253-64. doi: 10.2147/IJN.S258791 PMID: 32801690El-Helw AR, Fahmy U. Improvement of fluvastatin bioavailability by loading on nanostructured lipid carriers. Int J Nanomedicine 2015; 10: 5797-804. doi: 10.2147/IJN.S91556 PMID: 26396513Wang N, Hsu C, Zhu L, Tseng S, Hsu JP. Influence of metal oxide nanoparticles concentration on their zeta potential. J Colloid Interface Sci 2013; 407: 22-8. doi: 10.1016/j.jcis.2013.05.058 PMID: 23838331Basha M, Abd El-Alim SH, Shamma RN, Awad GEA. Design and optimization of surfactant-based nanovesicles for ocular delivery of Clotrimazole. J Liposome Res 2013; 23(3): 203-10. doi: 10.3109/08982104.2013.788025 PMID: 23607316Uchechi O, Ogbonna JD, Attama AA. Nanoparticles for dermal and transdermal drug delivery.In: Application of nanotechnology in drug delivery InTech. 2014; 4: pp. 193-227. doi: 10.5772/58672Mazyed EA, Zakaria S. Enhancement of dissolution characteristics of clopidogrel bisulphate by proniosomes. Int J Appl Pharmaceut 2019; pp. 77-85. doi: 10.22159/ijap.2019v11i2.30575Das MK, Palei NN. Sorbitan ester niosomes for topical delivery of rofecoxib. Indian J Exp Biol 2011; 49(6): 438-5.Garg V, Singh H, Bhatia A, et al. Systematic development of transethosomal gel system of piroxicam: Formulation optimization, in vitro evaluation, and ex vivo assessment. AAPS PharmSciTech 2017; 18(1): 58-71. doi: 10.1208/s12249-016-0489-z PMID: 26868380Hosny KM, Hassan AH. Intranasal in situ gel loaded with saquinavir mesylate nanosized microemulsion: Preparation, characterization, and in vivo evaluation. Int J Pharm 2014; 475(1-2): 191-7. doi: 10.1016/j.ijpharm.2014.08.064 PMID: 25178831Baboota S, Shakeel F, Ahuja A, Ali J, Shafiq S. Design, development and evaluation of novel nanoemulsion formulations for transdermal potential of celecoxib. Acta Pharm 2007; 57(3): 315-32. doi: 10.2478/v10007-007-0025-5 PMID: 17878111Abd-Elal RMA, Shamma RN, Rashed HM, Bendas ER. Trans-nasal zolmitriptan novasomes: in-vitro preparation, optimization and in-vivo evaluation of brain targeting efficiency. Drug Deliv 2016; 23(9): 3374-86. doi: 10.1080/10717544.2016.1183721 PMID: 27128792Shang Y, Inthavong K, Qiu D, Singh N, He F, Tu J. Prediction of nasal spray drug absorption influenced by mucociliary clearance. PLoS One 2021; 16(1): e0246007. doi: 10.1371/journal.pone.0246007 PMID: 33507973