title: Nasal delivery of analgesic ketorolac tromethamine thermo- and ion-sensitive in situ hydrogels.
abstract: Ketorolac tromethamine (KT) was potent to treat moderate to moderately severe pains. However, KT solutions for nasal delivery lost quickly from the nasal route. Thermo- and ion-sensitive in-situ hydrogels (ISGs) are appropriate for nasal drug delivery because the intranasal temperature maintains ∼37 °C and nasal fluids consist of plentiful cations. In this study, a novel nasal thermo- and ion-sensitive ISG of KT was prepared with thermo-sensitive poloxamer 407 (P407) and ion-sensitive deacetylated gellan gum (DGG). The optimal formulation of the KT ISG consisted of 3% (w/v) DGG and 18% (w/v) P407 and its viscosity was up to 7.63 Pas at 37 °C. Furthermore, penetration enhancers and bacterial inhibitors were added and their fractions in the ISG were optimized based on transmucosal efficiencies and toxicity on toad pili. Sulfobutyl ether-β-cyclodextrin of 2.5% (w/v) and chlorobutanol of 0.5% (w/v) were chosen as the penetration enhancer and the bacterial inhibitor, respectively. The Fick's diffusion and dissolution of KT could drive it continuous release from the dually sensitive ISG according to the in vitro investigation. Two methods, writhing frequencies induced by acetic acid and latency time of tails retracting from hot water, were used to evaluate the pharmacodynamics of the KT ISG on the mouse models. The writhing frequencies significantly decreased and the latency time of tail retracting was obviously prolonged (p<0.05) for the KT ISG compared to the control. The thermo- and ion-sensitive KT ISG had appropriate gelation temperature, sustained drug release, improved intranasal absorption, obvious pharmacodynamic effect, and negligible nasal ciliotoxicity. It is a promising intranasal analgesic formulation.
authors.affiliation: Chinese PLA General Hospital, Beijing 100853, China.
authors.forename: Xin
authors.initials: X
authors.lastname: Li
authors.affiliation: Department of Pharmaceutical Sciences, Beijing Institute of Radiation Medicine, Beijing 100850, China.
authors.forename: Lina
authors.initials: L
authors.lastname: Du
authors.affiliation: Chinese PLA General Hospital, Beijing 100853, China; Department of Pharmaceutical Sciences, Beijing Institute of Radiation Medicine, Beijing 100850, China.
authors.forename: Xu
authors.initials: X
authors.lastname: Chen
authors.affiliation: Institute of Pharmacy, Pharmaceutical College of Henan University, Kaifeng 475004, China.
authors.forename: Pingju
authors.initials: P
authors.lastname: Ge
authors.affiliation: Department of Pharmaceutical Sciences, Beijing Institute of Radiation Medicine, Beijing 100850, China.
authors.forename: Yu
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Chinese PLA General Hospital, Beijing 100853, China.
authors.forename: Yangmu
authors.initials: Y
authors.lastname: Fu
authors.affiliation: Affiliated Hospital of Academy of Military Medical Sciences, Beijing 100071, China.
authors.forename: Haiyan
authors.initials: H
authors.lastname: Sun
authors.affiliation: Beijing Institute of Tianheng Drug Development, Beijing 100141, China. Electronic address: qingwei_j@126.com.
authors.forename: Qingwei
authors.initials: Q
authors.lastname: Jiang
authors.affiliation: Department of Pharmaceutical Sciences, Beijing Institute of Radiation Medicine, Beijing 100850, China. Electronic address: jinyg@bmi.ac.cn.
authors.forename: Yiguang
authors.initials: Y
authors.lastname: Jin
mesh_terms: D000281:Administration, Intranasal; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000008:administration & dosage* / Q000737:chemistry; D001001:Anura; D001381:Azepines / Q000737:chemistry; D002232:Carbocyanines / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology; D002724:Chlorobutanol / Q000737:chemistry; D003692:Delayed-Action Preparations / Q000008:administration & dosage / Q000737:chemistry; D005260:Female; D020100:Hydrogels / Q000008:administration & dosage* / Q000737:chemistry; D020911:Ketorolac Tromethamine / Q000008:administration & dosage* / Q000737:chemistry; D008297:Male; D008807:Mice, Inbred BALB C; D009297:Nasal Mucosa / Q000187:drug effects; D020442:Poloxamer / Q000737:chemistry; D011135:Polysaccharides, Bacterial / Q000737:chemistry; D012756:Sheep; D014783:Viscosity; D047392:beta-Cyclodextrins / Q000737:chemistry
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D001381:Azepines; D002232:Carbocyanines; D003692:Delayed-Action Preparations; D020100:Hydrogels; D011135:Polysaccharides, Bacterial; D047392:beta-Cyclodextrins; C501744:indotricarbocyanine; D020442:Poloxamer; C035229:laurocapram; C093196:SBE4-beta-cyclodextrin; D020911:Ketorolac Tromethamine; C048288:gellan gum; D002724:Chlorobutanol
keywords: In situ hydrogels; Ion-sensitive; Ketorolac tromethamine (PubChem CID: 84003); Nasal delivery; Penetration enhancers; Thermo-sensitive