Preparation And In Vitro/in Vivo Evaluation Of Oral Bupropion Sustained-release/Dextromethorphan Regular-release Compound Suspension

Axsome Therapeutics launched Auvelity^TM（Dextromethorphan hydrobromide and Bupropion hydrochloride extended-release tablets）in August 2022,which was the first oral N-Methyl-D-Aspartate（NMDA）receptor antagonist for the treatment of adult major depression.As the first generation of compound solid preparation,Auvelity^TM had some deficiencies such as patient swallowing difficulties,poor compliance,and drug burst release.The development of its liquid compound preparation was helpful to solve the above problems.Therefore,in this thesis,cation exchange resin（Amberlite^?IRP69）was used as drug carrier of bupropion hydrochloride（BH）and dextromethorphan hydrobromide（DMH）to prepare the oral BH sustained-release/DMH regular-release compound suspension with clinical advantage,and systematic in vitro and in vivo studies were conducted on it.The specific contents were as follows:1.Preparation of BH resin complex and DMH resin complexThe optimum preparation process of BH Drug Resin Complex（BH-DRC）by bath method was as follows:Amberlite^?IRP69 was added to 100 m L of 7 mg·m L^-1 BH drug solution（drug:resin=1:1）,and stirred at 45±0.5°C for 3 h.The drug loading（Q_∞）was 0.86mg·mg^-1（0.86 mg BH was loaded in 1 mg resin）,and the drug utilization rate（E）was86.90%.The optimum preparation process of DMH Drug Resin Complex（DMH-DRC）by bath method was as follows:Amberlite^?IRP69 was added to 100 m L of 30 mg·m L^-1 DMH drug solution（drug:resin=1:1）,stirred at 45±0.5°C for 2 h.The drug loading（Q_∞）was 0.96mg·mg^-1（0.96 mg DMH was loaded in 1 mg resin）,and the drug utilization rate（E）was95.45%.2.Characterization and in vitro release of BH-DRC and DMH-DRCBH,DMH,blank Amberlite^?IRP69,physical mixture of drugs and resins,BH-DRC,and DMH-DRC were characterized and analyzed using SEM,XRD,and FTIR.The results showed that BH and DMH were combined with blank Amberlite^?IRP69 to form BH-DRC and DMH-DRC not by simple physical adsorption,but by ionic bonds.The principle was that the free active groups between the drug and Amberlite^?IRP69 were combined into the drug-resin complex by ion exchange.The effects of in vitro release conditions on the release of BH-DRC and DMH-DRC were investigated.The final in vitro released conditions was as follows:paddle method,dissolution medium was 900 m L 0.15 mol·L^-1 Na Cl,rotation speed was 50 r/min,the temperature was 37.0±0.5°C.In this thesis,DMH-DRC was the regular-release,and BH-DRC needed to achieve a sustained-release effect of about 12 h.However,BH in BH-DRC was completely released within 2 h.Therefore,it needed to be further prepared into BH sustained-release microcap-sules with good sustained release effect.3.Preparation of BH sustained-release microcapsulesThe acrylic resin was used as coating material,and the impregnating BH-DRC（the impregnating agent was PEG 4000）was coated by surface coating method.The relevant factors in the coating process（type and concentration of coating material,volume of reaction medium,reaction temperature,etc.）were optimized.the optimal prescription process was as follows:the blocking material was Eudragit^?RS100:Eudragit^?RL 100 1:1,the concentration was 2.2%,the volume ratio of the reaction medium was（blocking material:reaction medium volume）1:10,and the temperature was 45°C,reaction time was 4h.The morphology,density,particle size,drug content,and in vitro release of BH-coated microcapsule（BH-CM）were investigated.The results indicated that BH-CM had sustained-release effect of about 12 h and good reproducibility.The release curve of BH-CM fitted well with the first-order kinetic equation（R²=0.999）.It was showed that the release mechanism of BH-CM was membrane-controlled release and the release was Fick diffusion.4.Preparation of BH sustained-release/DMH regular-release compound suspensionThe related properties（particle size,density,wettability,etc.）of DMH-DRC and BH-CM were investigated,and the results indicated that they were suitable for preparing suspensions with excellent properties.The amount of the suspending agent and wetting agent in the basic prescription was optimized using redispersibility,sedimentation ratio,the presence of hanging wall,and particle aggregation as evaluation indexes to prepare oral sustained-release BH/regular-release DMH compound suspension with good stability.The results of affecting factor testing and accelerated testing showed that the indexes（content,drug release behavior,drug leakage,sedimentation ratio,redispersibility and suspension properties）of self-made oral BH sustained-release/DMH regular-release compound suspension met the requirements of pharmacopoeia and the properties were stable.5.Pharmacokinetic study of oral BH sustained-release/DMH regular-release compou-nd suspensionThe HPLC analysis method for BH and DMH in vivo of SD rats was established.The results showed that the specificity,precision,recovery,stability met the requirements of the pharmacopeia for in vivo analysis.The in vivo pharmacokinetics of oral BH sustained-release/DMH regular-release compound suspension was studied.As in vivo parameters results showed,the T_max and t_1/2 of BH in self-made suspension were 4 h and 3.52 h,respectively.And the T_max and t_1/2 of BH in BH ordinary tablets were 2 h and 3.34 h,respectively.The C_max of the suspension(353.59 ng·L^-1)was lower than BH ordinary tablets(491.83 ng·L^-1).The above results signified that the BH in the self-made suspension had an obvious sustained-release effect.The T_max of DMH in both self-made suspension and ordinary tablets was 2 h.The t_1/2 and C_max of DMH in self-made suspension were 88.6 h and4.95 ng·L^-1,respectively,and the t_1/2 and C_max of the DMH ordinary tablets were 4.22 h and2.17 ng·L^-1,respectively.The C_max results for both formulations indicated that the plasma concentration of DMH was enhanced in the self-made suspension,while the t_1/2 results indicated that the plasma concentration was continuously increased for a long time,the reason was that BH was an inhibitor of cytochrome P450 2D6（CYP2D6）,which inhibited CYP2D6 from metabolizing DMH,thereby increasing the plasma concentration of DMH in the body.The relative bioavailability of BH in self-made suspension was 116.53%.The relative bioavailability of DMH in self-made suspension was 252.25%.