Nose to Brain Delivery of Ziprasidone Microemulsion: Desigen and Characterization

Abstract

Nasal administration offers an interesting promising alternative technique to the parenteral route for achieving systemic drug effects. Now a day many drugs have better systemic bioavailability through nasal route as compared to oral administration. Microemulsion is dispersed, macroscopically homogenous thermodynamically stable, optically transparent, single phase system, formed by spontaneous solubilisation of two immiscible liquid, in the presence of surfactants. Microemulsion offers number of advantages than drug formulation for nasal drug delivery. Ziprasidone is lipophilic, benz-isothiazoyl-piperazine derivative, used in the treatment of schizophrenia, mania and mixed states associated with bipolar disorder. The microemulsion was prepared by precipitation method. The characterization of microemulsion formulation includes determination of viscosity, pH, drug content, refractive, conductivity measurement, zeta potential analysis and particle size analysis. In-vitro drug permeation studies were done by using Keshary Diffusion cell. All ME formulations were shown fast drug permeation 99.50 % for ME 2 within 1 h and 99.40 % for ME 6 within 100 minutes since the ME 2 which is optimized on the basis of in-vitro study. Nasal mucoadhesive drug delivery system is designed with an aim to target the drug and to maintain the dosage form at its absorption site for a rapid onset of time. This will result in the enhancement of the absorption of the drug, which will in turn reduce the presystemic metabolism; increase the bioavailability of the drug, initiate rapid onset of action and thus will decrease the dosing frequency and dose related side effects of the drug. For this purpose in microemulsion system is preferred over conventional solution system

Synthesis and antitumor evaluation of some new derivatives and fused heterocyclic compounds derived from thieno[2,3‐b]pyridine: Part 2

“…Formation of S-methylation was achieved by treating a stirred solution of pyrimidine-2,4-dithione derivative 15 in an aqueous sodium hydroxide with methyl iodide at room temperature [36] to yield the target 2,4-bis(methylthio)pyrimidine analogue 18. However, the reaction of 2,4-di(methylthio)pyrimidine derivative 18 with different nucleophiles, namely, thiosemicarbazide and benzohydrazide (20), [37] in a basic medium [36] resulted in the ring closure to the corresponding 3substituted [1,2,4]triazole analogues 19 and 21, respectively. Both compounds 19 and 21 were established by spectral data and elemental analyses.…”

“…Ethoxymethyleneamino derivative [19] 23 was stirred with benzohydrazide (20) [37] in the presence of absolute ethanol at room temperature and left overnight to afford the target compound 24, which was heated under reflux in N,N-dimethylformamide [39,40] for a short period to yield the corresponding fused (pyrimidine-3-4H-yl) benzamide derivative 25 as outlined in Scheme 4. The 1 H NMR spectrum of compound 24 showed two deuterium oxide exchangeable singlet signals at δ 8.08 and δ 9.77 ppm attributed to ═ CH-NH and NH-C═O protons, respectively, while the appearance of a singlet at δ 8.39 ppm attributed to the pyrimidine-C 2 proton as well as two deuterium oxide exchangeable singlet signals at δ 7.31 and 12.93 ppm corresponding to imino and amide protons, respectively, in the 1 H NMR spectrum of compound 25 confirmed the formation of the pyrimidine ring.…”

“…Compound (1) was synthesized according to the published procedure, [11] while compounds (8), (10), (23), (26), and (37) were prepared according to our previously published procedures. [19] However, reagents (16a), [29] (16b), [30] and (20) [37] were prepared according to the reported methods. All other chemicals in this study were purchased.…”

“…Yield: 0.50 g (66%); mp: >300°C. 1 A mixture of compound 18 (0.74 g, 2 mmol) and an equimolar amount of benzohydrazide (20) [37] (0.27 g, 2 mmol) was heated under reflux in pyridine (10 mL) for 24 hours. The reaction mixture was left to cool at room temperature, and the separated solid was filtered off, washed with methanol, and dried.…”

“…Yield: 0.62 g (60%); mp: >300°C. 1 C 6 H 4 -C 3,5 ); 114.22 (C 4 -4-OCH 3 -C 6 H 4 -C 3,5 ); 118.00 (C 8 ); 120.99 (C 2 -4-OCH 3 -C 6 H 4 -C 2,6 ); 121.28 (C 4 -4-OCH 3 -C 6 H 4 -C 2,6 ); 127.46 (C 6 H 5 -C 2,4,6 ); 128.00 (C 9a ); 129.00 (C 6 H 5 -C 3,5 ); 132.00 (C 2 -4-OCH 3 -C 6 H 4 -C 1 ); 133.16 (C 4 -4-OCH 3 -C 6 H 4 -C 1 ); 140.03 (C 6 H 5 -C 1 ); 146.98 (C 9 ); 153.36 (4-OCH 3 -C 6 H 5 -C 4 ); 154.00 (C 5a ); 155.45 (C 7 ); 162.40 (C 9b ); 168.19 (C 2 ); 170.89 (C 4 (24) To a solution of compound 23 [19] (1.61 g, 5 mmol) in absolute ethanol (20 mL), a solution of benzohydrazide 20 [37] (0.68 g, 5 mmol) in absolute ethanol (10 mL) was added and stirred at room temperature for 3 hours. A gray solid was precipitated after leaving the mixture to stand overnight, filtered off, washed with water and then methanol, dried, and crystallized from ethanol to form gray crystals.…”