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Dextromethorphan hydrobromide (DM) sustained release matrix pellets containing 10% w/w drug were prepared by an extrusion/spheronization technique. The effect of mixing different concentrations of ethyl cellulose (EC), hydroxypropyl methylcellulpse (HPMC K10), and Carbopol 934 with Avicel PH101 on the rheological properties of pellet wet mass was evaluated using mixer torque rheometry (MTR). The prepared pellets were characterized for size, drug content, and in-vitro DM release rate. The results showed that increasing the concentration of the hydrophobic polymer (EC) with Avicel PH101 decreased wet mass consistency, represented by mass mean line torque. Lower binder ratio was required for optimum wet massing, while mixing with swellable polymers (HPMC and Carbopol) caused a noticeable increase in both mean line torque and binder ratio. Combinations of HPMC and Carbopol at higher concentrations resulted in controlled in vitro release of DM from the prepared pellets. Furthermore, mathematical treatment of the in vitro release data of DM from the prepared pellets showed that all formulations except those containing 5% Carbopol plus 5% HPMC (F10) follow first order release. n values of these formulation were in the range of 0.09-0.40, which support an anomalous non-Fickian release.
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Dextromethorphan/analysis , Drug Implants/pharmacology , In Vitro Techniques , Dosage FormsABSTRACT
Objective To study the dose-time-toxicity relationship of hepatotoxicity in mice with multiple administration of Paracetamol Tablets (PT),Compound Paracetamol and Amantadine Hydrochloride Tablets (CPAH),Compound Dextromethorphan Hydrobromide Tablets (CDH),and Chaiqin Qingning capsules (CQC).Methods Mice were randomly divided into control,PT,CPAH,CDH,and CQC high,medium,and low dose groups.The acetaminophen contents of high,medium,and low doses were 266.24,425.98,and 681.57 mg/kg in PT,CPAH,and CDH groups,and the doses of CQC group were 1437.70,2300.31,and 3 680.50 mg/kg,ig administration,once daily for 5 d.General state and toxicity of mice were observed.The changes of ALT,AST,AKP,TBIL,and ALB levels in serum and organ indexes of liver,spleen,thymus,and kidney were tested on day 1,3,7,11,and 14 after multiple administration.Results CQC with the dosage range of 1 437.70-3 680.50 mg/kg to mice within 14 d,has not yet induced the increase of AST,ALT,AKP,TBIL,and ALB levels and changes of organ indexes of liver,thymus spleen,and kidney compared with normal control (P ＞ 0.05).PT,CPAH,and CDH with repeated dose of 425.98-681.57 mg/kg could induce significant increase of the levels ofALT,AST,AKP,and TBIL which reached the peak on day 1 (P ＜ 0.05),and then gradually decreased on day 3-14.The level of ALB significant decreased on day 1-11 (P ＜ 0.05),and then gradually recovered on day 11-14.The liver index significant increased on day 1-3 (P ＜ 0.05),and recovered on day 7-14.Conclusion Multiple administration of CQC could not induce liver injury in mice within 14 d,while multiple administration ofPT,CPAH,and CDH could induce hepatotocixity in mice with a certain dose,and show an obvious dose-time-toxicity relationship.
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Objective To study the time-toxicity and dose-toxicity relationship of hepatotoxicity induced by Paracetamol Tablets (PT),Compound Paracetamol and Amantadine Hydrochloride Tablets (CPAH),Compound Dextromethorphan Hydrobromide Tablets (CDH),and Chaiqin Qingning Capsules (CQC) with single dose in mice.Methods In the Time-Toxicity relationship study,Kunming mice were randomly divided into control,PT,CPAH,CDH,and CQC group,and mice of.each drug administration group were randomly divided into nine subgroups according to the time (1,2,4,8,12,24,48,72 and 96 h after administration) of blood collection.The acetaminophen contents in PT,CPAH,and CDH groups were 425.98 mg/kg,and the dose of CQC group was 3 680.50 mg/kg.In the Dosage-Time relationship study,mice were randomly divided into control,PT,CPAH,CDH,and CQC high,medium and low dose group.The acetaminophen contents of high,medium,and low dose were 266.24,425.98,and 681.57 mg/kg in PT,CPAH,and CDH group,and the dose of CQC group was 1437.70,2300.31,and 3680.50 mg/kg,10 mice in each group,sex in half.Blood was collected 12 h after administration.Animal behavior was observed every day,blood and organs were collected at the corresponding time points,serum alanine aminotransferase (ALT),aspartate aminotransferase (AST),and alkaline phosphatase (ALP) level were detected,and the organs index of spleen and thymus,liver were calculated.Results There were no significant changes of ALT,AST,ALP,and organs index after once ig administration of CQC at dosage of 1437.70 mg/kg to 3680.50 mg/kg in mice.The study on time-toxicity relationship indicated that,after once administration of PT,CPAH,and CDH at 425.98 mg/kg,mice showed toxic symptom such as hypokinesia,dry hair and so on,12 h was the most obvious,24 ～ 72 h disappeared.The level of ALT,AST,and ALP in serum increased and reached to the peak at 12 h and then restored near normality after 72,24,and 24 h in PT,CPAH,and CDH group.Their organ index of liver,spleen and thymus all had no significant changes.The study on the dosage-toxicity relationship indicated that,there were no significant changes of animal behavior,ALT,AST,ALP,and organs index after once ig administration of PT,CPAH,and CDH at 266.24 mg/kg.Obvious liver injury can be induced by the three drugs with dosage of 425.98 to 681.57 mg/kg and the level of ALT,AST,and ALP increased significantly with the increase of dosage.Their liver index increased significantly with dosage of 681.57 mg/kg,but the organs index of spleen,thymus had no significant changes.Conclusion There was no hepatotoxicity after once ig administration of CQC with dosage of 3680.50 mg/kg in mice.Mice were once ig administration ofPT,CPAH,and CDH with a large dose,may induce acute liver injury and show obvious time-toxicity and dose-toxicity relationships.
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Objective To study the antipyretic effect of Paracetamol Tablets,Compound Paracetamol and Amantadine Hydrochloride Tablets,Compound Dextromethorphan Hydrobromide Tablets,and Chaiqin Qingning Capsules on the fever model induced by LPS and dry yeast in rats.Methods Fever was induced by ip injecting LPS (100 μg/kg) or sc injecting dry yeast (20％) in rats.We observed the changes of temperature of the rats after administration of Paracetamol Tablets,Compound Paracetamol and Amantadine Hydrochloride Tablets,Compound Dextromethorphan Hydrobromide Tablets (the acetaminophen contents were 205.67,102.83,and 51.42 mg/kg)and Chaiqin Qingning Capsules (1110.60,555.30,and 277.65 mg/kg).Maximum temperature rise height (△T) and temperature response index (TRI) were calculated,and the curve of average rise in temperature was drawn.Results Each dose group of Paracetamol Tablets,Compound Paracetamol and Amantadine Hydrochloride Tablets,Compound Dextromethorphan Hydrobromide Tablets,and Chaiqin Qingning Capsules had obvious antipyretic effect on the fever model induced by LPS and dry yeast in rats,and there was a certain dose-effect relationship.Conclusion Paracetamol Tablets,Compound Paracetamol and Amantadine Hydrochloride Tablets,Compound Dextromethorphan Hydrobromide Tablets,and Chaiqin Qingning Capsules has certain antipyretic effect on LPS and dry yeast fever model in rats,and on the whole,the Western medicine acts rapid but continue for a short time,while the traditional Chinese medicine acts slow but continues for a long time.
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Objective:To establish an HPLC method for the determination of two components and the preservative in compound dextromethorphan hydrobromide syrups. Methods:An Agilent Zobax SB-C18 column(250 mm × 4. 6 mm,5 μm) was used with meth-anesulfonic acid solution (adding 4. 8g methanesulfonic acid and 10ml triethylamine into 750ml water,and adjusting the pH value to 3. 5 by phosphoric acid)-acetonitrile (75∶25) as the mobile phase at the flow rate of 1. 0 ml·min-1 and 280nm as the detection wave-length. Results:The calibration curve was linear within the range of 102-1 025μg·ml-1 for guaifenesin,15-619μg ·ml-1 for dextro-methorphan hydrobromide and 10-407μg·ml-1 for benzoic acid. The average recovery of guaifenesin, dextromethorphan hydrobromide and benzoic acid was 100. 0% (RSD=0. 35%), 100. 1%(RSD=0. 77%)and 100. 8%(RSD=0. 49%), respectively. Conclusion:The method is simple,rapid and accurate,and suitable for the quality assessment of compound dextromethorphan hydrobromide syrups.
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OBJECTIVE:To optimize the formulation of dextromethorphan hydrobromide sustained-release tablets. METHODS: The dextromethorphan hydrobromide sustained-release tablets were prepared with HPMC as sustained release matrix. Orthogonal test was performed to optimize the formulation with in vitro accumulative drug release rate as index and the amount of HPMC and lactose as well as ethylcellulose (EC) concentration as factors. Then verification test on the in vitro drug release characteristics of the optimized tablets were performed and the influencing factors (high temperature,high light,and high moisture) were investigated as well. RESULTS: The optimized formulation of dextromethorphan hydrobromide sustained-release tablets was as follows: 30 mg HPMC,50 mg lactose,and 8% EC. The accumulative drug release rate at 8 h was above 70%. In the influencing factor test,the tablets were stable under all conditions except at high moisture condition. CONCLUSION: The optimized formulation of dextromethorphan hydrobromide sustained-release tablets is feasible.
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OBJECTIVE:To establish a HPLC method for determination of concentration of dextromethorphan hydrobro?mide in human serum.METHODS:The assay was conducted on HiQsil C 18 column(4.6mm?150mm,5?m)with acetonitrile-water-acetic acid(35∶63∶2,V/V/V)as mobile phase.The fluorescence detector measured with the excitation wavelength of280nm and the emission wavelength of320nm,and carvedilol was taken as internal standard.RESULTS:The linear range of calibration curve of dextromethorphan hydrobromide was0.27～21.90ng/ml with a regressive equation of Y=0.1197X+0.0086,r=0.9986.The recovery was high.CONCLUSION:This method is accurate,rapid and simple,and can be used for de?termining the concentration of dextromethorphan hydrobromide in human serum.
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OBJECTIVE:To establish an HPLC method for the content determination of pseudoephedrine hydrochloride and dextromethorphan hydrobromide in pediatric pseudoephedrine dextromethorphan drops. METHODS:The separation was performed nomn .A Tghilee nftl oCw18 rcaotelu wmans wseitth a tm 0o.b6i lme Lp?hmasien -o1f amnedt hthaen oiln-j ewcatitoern- vtroieluthmynla mwainse 1(05 ?60L .∶ 4R3E0S ∶ U10L,TSp:H=Th3e. 0l)ineaat rd reatnegctei own ewrea v7e.3le4n～gt7h3 o.4f ?2g0?9 mL-1 for pseudoephedrine hydrochloride(r=0.999 9,n=5)with an average recovery of 99.1%(RSD=0.76%,n=9)and 2.55～25.5 ?g?mL-1 for dextromethorphan hydrobromide(r=0.999 9,n=5)with an average recovery of 98.0%(RSD=0.87%,n=9). CONCLUSION:The method is accurate and reproducible for quality control of pediatric pseudoephedrine dextrometharphan drops.