Sustained-release compositions comprising a therapeutic agent for treating depression or anxiety and uses thereof
A technology of composition and therapeutic agent, applied in the field of sustained-release liposome composition, which can solve the problems of high dose-dependent adverse side effects, regular visits to the doctor, equipment and personnel costs, restrictions on scopolamine infusion, etc.
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example 1
[0051] Example 1, the preparation of ketamine liposome formulation
[0052] Empty liposomes were prepared by the lipid film hydration-extrusion method. HSPC, cholesterol and DSPE-PEG2000 (59.5 / 39.6 / 0.9 mole percent) were dissolved in chloroform, and the organic solvent was removed under vacuum by a rotary evaporator to form a thin lipid film. The dried lipid film was hydrated with 75 mM triethylammonium sucrose octasulfate (pH 6.0) at 60° C. for 30 minutes to form liposomes with aqueous core entrapped with triethylammonium sucrose octasulfate. After six freeze-thaw cycles between liquid nitrogen and 60°C water, the liposomes were then squeezed 10 times through a polycarbonate filter with a pore size of 0.2 μm. Unentrapped triethylammonium sucrose octasulfate was removed by dialysis against a 9.4% sucrose solution.
[0053] A reaction mixture containing 3.75 mg / mL ketamine hydrochloride (Tocris Bioscience), empty liposomes of 25 mM lipid, and 10 mM histidine buffer (pH 6.5) w...
example 2
[0056] Example 2, the impact of different capture agents on the loading of ketamine
[0057] Liposome formulations were prepared according to Example 1 with the following capture agents: (1) 75 mM sucrose octasulfate triethylammonium, (2) 250 mM ammonium sulfate, and (3) 300 mM ammonium sulfate. Particle size distribution was measured by a dynamic light scattering instrument (ZetasizerNano-ZS90, Malvern). Table 1 shows the effect of different capture agents on ketamine loading.
[0058] Table 1. Ketamine loading curves of different capture agents
[0059]
[0060] n.d. not detected
example 3
[0061] The pharmacokinetic (PK) study of example 3, ketamine liposome formulation
[0062] In vivo PK assessment of ketamine liposomal formulations was performed using 7-8 week old female Sprague-Dawley rats. Rats were housed in a holding room with a 12-hour light / 12-hour dark cycle operation and no restriction on water and food intake.
[0063] The rats were divided into two groups (n=3 in each group), and one group received subcutaneous injection of 5 mg / kg free ketamine hydrochloride dissolved in 9.4% sucrose solution as ketamine salt salt to a final concentration of 1.0 mg / mL. Another group received a subcutaneous injection of 25 mg / kg liposomal ketamine formulation prepared according to Example 1. Blood samples were collected 15 minutes, 0.5 hours, 1 hour, 2 hours, 4 hours, 6 hours, 8 hours, 24 hours and 48 hours after injection. Plasma samples were obtained by centrifugation, kept frozen at -80°C and analyzed using the noncompartmental analysis model in PKSolver (Comp...
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