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OBJECTIVE@#To study the plasma concentration and pharmacokinetics of 3, 29-Dibenzoyl Karounitriol (3, 29-DK) from sustained- release pellets and extracts of Trichosanthes at different time points in rats using high-performance liquid chromatography- tandem mass spectrometry (LC-MS/MS).@*METHODS@#Healthy male SD rats were given a single gavage of Trichosanthes sustained-release pellets or Trichosanthes extract, and orbital blood samples were taken at different time points within 48 h after drug administration in the pellet group and within 5 h in Trichosanthes extract group for determination of the plasma concentrations of 3, 29-DK using LC-MS/MS. The standard curve of 3, 29-DK content was established, and the specificity, minimum detection limit, precision and accuracy, extraction recovery, stability and matrix effect of LC-MS/MS analysis were assessed. The mean plasms levels of 3, 29-DK at different time points after the drug administration were determined and its pharmacokinetic parameters were calculated using Das 2.0 software.@*RESULTS@#LC-MS/MS analysis showed a good linearity of 3, 29-DK concentration within the range of 0.5-32 ng/mL, and the results of methodological validation confirmed the validity of this method for biological sample determination. Trichosanthes sustained-release pellets and Trichosanthes extract showed significant differences in their AUC, AUC, MRT, MRT, t and T of 3, 29-DK after administration in rats ( < 0.05).@*CONCLUSIONS@#Trichosanthes sustained-release pellets are capable of sustained-release of 3, 29-DK in rats, and thus provides a basis for the study of new dosage forms of Trichosanthes.
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Animals , Male , Rats , Chromatography, High Pressure Liquid , Delayed-Action Preparations , Rats, Sprague-Dawley , Reproducibility of Results , Tandem Mass Spectrometry , TrichosanthesABSTRACT
Objective: To prepare Trichosanthes sustained-release pellets and investigate its in vitro release. Methods: Trichosanthes sustained-release pellets were prepared by fluid-bed coating technique.The preparation process of its drug loading layer was optimized by orthogonal experiment with binder, solvent, drug loading and creeping speed of peristaltic pump as the factors of investigation and the yield as the investigation index. The optimum prescription and preparation of the pellets were optimized by single factor test with the content of coating material EC, the amount of poreforming agent PEG4000, the amount of talc powder, the coating weight and the curing time as the factors of investigation and the in vitro release as the investigation index. The in vitro release of the pellets was investigated by high performance liquid chromatography with 3, 29-Diphenyl of Trichosanthes Kirilowii Triol(3, 29-DK)as the detection index. Results: The optimum preparation technology of the drug loading layer was 5% binder, 60% ethanol, 35% drug loading and 0.3 r/min peristaltic velocity of fluid-bed peristaltic pump. The optimum preparation technology of sustained-release layer was 5% EC, 1.5% PEG 4000, 1.25% talc powder, 10% weight gain of coating and 6 h curing. Conclusion: The Tricho- santhes sustained-release pellets prepared in this study were released smoothly. Its production method was simple and easy for operation.
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OBJECTIVE： To establish a method for the concentration determination of levofloxacin in rat plasma and compare the pharmacokinetic difference between Levofloxacin tablets and gastric floating sustained-release pellets in rats. METHODS： SD rats were randomly divided into Levofloxacin tablets group and Levofloxacin gastric floating sustained-release pellets group， with 6 rats in each group. They were given relevant medicine intragastrically 40 mg/kg （taking normal saline as solvent）， and the blood samples 0.3 mL were collected before medication and 0.25， 0.5， 1， 2， 4， 8， 12， 24 h after medication. The plasma concentration of levofloxacin in rats was determined by UPLC. The determination was performed on Waters Acquity UPLC BEH C18 column with mobile phase consisted of 0.1％ formic acid-acetonitrile （78 ∶ 22，V/V） at the flow rate of 0.3 mL/min. The detection wavelength was set at 294 nm， and column temperature was 40 ℃. The sample size was 2 μL. The pharmacokinetic parameters of rats were calculated by using DAS 3.0 software， and the difference between them were detected by F-test. RESULTS： The linear range of levofloxacin was 0.20-20.12 μg/mL， and limit of quantitation was 0.20 μg/mL. The limit of detection was 0.04 μg/mL. The intra-day and inter-day RSDs were less than 10％. The recoveries were all in line with the related requirements of quantitation analysis of the biological samples stated in 2015 edition of Chinese Pharmacopeia. Average drug concentration-time curves of single dose of Levofloxacin tablets group and Levofloxacin gastric floating sustained-release pellets group were all in line with two-compartment model after intragastric administration. The pharmacokinetic parameters cmax were （12.13±1.67） and （8.76±1.13） μg/mL； tmax were（0.86±0.15） and （2.48±0.45）h； t1/2β were（4.67±0.95） and （6.67±1.01）h； AUC0-t were （42.95±4.21） and （126.48±9.44） μg·h/mL； AUC0-∞ were （50.66±6.72） and （132.61±10.63） μg·h/mL， respectively. Compared with Levofloxacin tablets， cmax of Levofloxacin gastric floating sustained-release pellets were decreased significantly， and tmax， t1/2β， AUC and mean retention time were prolonged or increased significantly （P＜0.05）， and relative bioavailability was 294％. CONCLUSIONS： Established UPLC method is simple， specific， sensitive and precise， and can be used for the determination of levofloxacin concentration in rat plasma and its pharmacokinetic study. After levofloxacin is made into gastric floating sustained-release pellets， pharmacokinetic parameters are changed significantly， retention time is prolonged significantly and bioavailability is improved significantly.
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Objective:To prepare febuxostat nanosuspension and prepare sustained-release pellets,and investigate the in vitro dis-solution.Methods: Febuxostat nanosuspension was prepared by a high pressure homogenization method. Febuxostat nanosuspension pellets were prepared by fluidized bed coating technique. Eudragit RL30D and Eudragit RS30D were used to prepare the sustained-re-lease pellets. The dissolution mechanism of febuxostat nanosuspension sustained-release pellets was evaluated. Results: The average particle size of the prepared febuxostat nanosuspension was (212.5 ± 36.3) nm, PdI was (0.193 ± 0.018), zeta potential was ( -12.4 ± 0.3) mV,and the scanning electron microscopy showed that the particle size distribution of febuxostat nanosuspension was narrow. The in vitro dissolution of febuxostat nanosuspension sustained-release pellets was more stable and conformed to the first-order release model. Conclusion: The in vitro dissolution of febuxostat nanosuspension sustained-release pellets is more stable, and the preparation provides a new choice for febuxostat clinical application.
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@#To conduct the characterization of its pharmacokinetics in rats of nifedipine sustained-release pellets and to study the relationship between the pellets and CYP3A4 activity. A gradient HPLC method was developed to simultaneously determine 6β-hydroxycortisol and hydrocortisone. CYP3A4 activity of rats was quantified by urinary ratio of 6β-hydroxycortisol/hydrocortisone after intravenous injection of hydrocortisone as a biomarker. HPLC method was also developed to quantify the drug concentration in plasma of rats, and the studies of pharmacokinetics were performed after oral administration of single dose of two formulations: Nifedipine matrix sustained-release pellets and nifedipine tablet(using as control). The results showed that the ratio of ten rats was 0. 271±0. 129. cmax of nifedipine sustained-release pellets decreases by nearly 70%, tmax significantly increased by 400% and t1/2 and MRT significantly increased by 230% compared to control. Nifedipine sustained-release pellets had a significant sustained-release property compared to the control and CYP3A4 activity affected its pharmacokinetics behavior.
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Objective The relationship between the in vivo absorption kinetics and the in vitro release kinetics of various components (including flavonoids and terpenoids) contained in Ginkgo biloba extract (GBE) sustained-release pellets were evaluated using multi-component integration kinetics which could provide a reference for more accurate assessment of in vitro and in vivo correlation. Methods The release rates in vitro of main ingredients (quercetin, isorhamnetin, bilobalide, ginkgolide A, ginkgolide B and ginkgolide C) were detected by HPLC-MS/MS. The integrated drug concentration was calculated, and the release rates in vitro of integrated components were then depicted according to the results. Plasma was collected at different time points after oral administration of GBE sustained-release pellets, multiple components contained in GBE sustained-release pellets were then determined. A novel approach of self-defined weighting coefficient (Wj) based on the area under the curve from zero to infinity AUC0—∞ had been created to obtain the holistic pharmacokinetic profiles of GBE sustained-release pellets. To evaluation the in vitro-in vivo correlation of GBE sustained-release pellets, the percent of integrated in vivo absorption calculated by the Wagner-Nelson methodwas plotted versus the percent of integrated in vitro drug release at the same time. Results The components contained in sustained- release pellets had a good release, the Wj of each component in GBE sustained-release pellets were as follows: quercetin, 0.248 1; isorhamnetin, 0.009 2; bilobalide, 0.228 2; ginkgolide A, 0.296 4; ginkgolide B, 0.132 4; ginkgolide C, 0.090 3. The in vivo-in vitro correlation equation was Y = 0.930 8 X + 12.84, r = 0.962 9, indicated that the correlation between in vivo absorption kinetics and in vitro release kinetics is good. Conclusion The efficacy of the herbal medicines depends on a variety of components combined effect, using the integrated pharmacokinetic to analyze IVIVC could take the characteristic of each component into account, which is helpful for the study of the correlation between in vivo absorption kinetics and in vitro release kinetics.
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Objective: To optimize the formula of memantine hydrochloride sustained release pellets and investigate the drug release in vitro.Methods: Memantine hydrochloride sustained release pellets were prepared by a fluidized bed.The factors such as inlet air temperature, spray pressure and feeding rate were optimized by orthogonal tests.The Box-Behnken response surface methodology was used to screen the major influencing factors (ethyl cellulose aqueous dispersion, PEG 6000 and the coating weight) in the release of memantine hydrochloride.The coating formula and coating weight were optimized with the cumulative release rate of memantine hydrochloride in 2, 6,and 12 h as the response values.The drug release in vitro was also studied.Results: The optimum preparation parameters of the pellets were as follows: the inlet air temperature of 45℃, the spray pressure of 1.0 bar, and the feeding rate of 1.5 r·min-1.The best sustained release coating formula was as follows: the content of ethyl cellulose aqueous dispersion of 8.4%, the content of PEG 6000 of 2.3%, and the weight gain of sustained release layer of 16.7%.The memantine hydrochloride sustained release pellets had notable sustained release effect.Conclusion: Orthogonal tests and Box-Behnken response surface method can be used for the formula optimization of memantine hydrochloride sustained-release pellets.The established fitting model is simple with good predictability.
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OBJECTIVE: To study the preparation technology of tamsulosion hydrochloride sustained-release capsules and investigate the release degree in vitro. METHODS: The pellets containing tamsulosin hydrochloride were prepeared in the fluid-bed using bottom gush medicine. Then, it was coated with ethylcellulose aqueous dispersion (surelease), and in the following procedures, water-based acrylic resin enteric system (Acryl-EZE®) was used as coating material, hydroxypropylmethylcellulose E6 (HPMCE6) was considered as porous agent by fluid-bed. Based on the release degree in vitro, prescription influence factors were evaluated, as well as drug releases curve was compared, according to the single factor experiment. RESULTS: The preparation technology referred in our research was available to make tamsulosin hydrochloride sustained-release capsules, and drug release curve of self-made sustained-release capsules was similar to the commercial one. Additionally, the products reproducibility of intra-batch and inter-batch was excellent. CONCLUSION: The tamsulosin hydrochloride sustained-release capsules prepared in this study exhibited ideal sustained-release characteristics in vitro. The formulation is reasonable and feasible. It is suitable for industrial production.
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OBJECTIVE:To prepare dexibuprofen sustained-release pellets,and to analyze the drug release behavior in vitro. METHODS:Centrifugal granulation powder layering-eudragit dispersion coating method was used to prepare dexibuprofen sus-tained-release pellets using 3%HPMC as adhesive agent. The formula of the pellets was optimized by orthogonal test with weight ra-tio of sucrose to dexibuprofen,weight ratio of HPMC to Eudragit NE30D and coating weight as factors,using 1,4 and 10 h accu-mulated release rate (Q) as index. The release of the drug from the pellets was analyzed. RESULTS:The optimized formulation was that the proportion of sucrose to drug was 1:10,the weight ratio of HPMC to Eudragit NE30D was 1.5:1,the increased weight of coating material was 8%. Q1 h,Q4 h and Q10 h of prepared pellets were 21%,57% and 89%,respectively(n=3). The co-rrelation coefficient of zero-order,one-order and Higuchi equation release model were 0.956 6,0.989 9,0.996 5. CONCLUSIONS:Prepared pellets show good sustained-release effect in vitro. Drug release of pellets is more in accordance with Higuchi equation.
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Objective:To prepare loxoprofen sodium sustained release pellets, and investigate the in vitro drug release behavior. Methods:Loxoprofen sodium loaded pellets were prepared by extrusion-spheronization technology, and the sustained release pellets were prepared with Eudragit RL 30D and Eudragit RS 30D as the sustained release coating film materials. The drug release behavior of loxoprofen sodium sustained release pellets in vitro was studied. Results:Eudragit RL 30D and Eudragit RS 30D with the ratio of 20 ∶80 was used as the sustained release coating film materials, the coating weight was 20%, the plasticizer content was 10%, and the content of talc was 45%. The in vitro release of loxoprofen sodium from the sustained release pellets was steady and entire in 12 h. Conclusion:The release behavior of loxoprofen sodium sustained release pellets is quite satisfactory. And the preparation technology may be used in the industrial production.
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Objective: To find a new method to evaluate the in vitro release of Ginkgo biloba extract (GBE) sustained-release pellets, f2 fit factor method was used to study the correlation of in vitro release between total flavonoids and different ingredients (including flavonoids and terpenoids). Methods: The release rates in vitro of total flavonoids and different ingredients (quercitrin, isorhamnetin, lutin, quercetin, ginkgolide A, ginkgolide B, ginkgolide C, and bilobalide) were detected by UV and HPLC-MS respectively, and then f2 fit factor was calculated between total flavonoids and different ingredients. Also the micro-structures of pellets before and after drug release were detected by scanning electron microscopy (SEM), which could explain the drug release mechanism combined with the fitted equation. Results: All f2 values were greater than 50 between the total flavonoids and different ingredients of the in vitro release from GBE pellets of optimized preparation, which indicated that there might be a good correlation between them. The drug release mechanism further verified the reliability of the results. Conclusion: The f2 fit factor method could be applied in the evaluation of in vitro release for multi-component sustained-release preparations of Chinese materica medicine.
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Objective:To prepare sustained-release pellets of memantine hydrochloride and investigate the in vitro drug release be-havior. Methods:The drug-loaded pellets were prepared by a fluid bed coating technology, the sustained-release pellets were prepared with Eudragit RL 30D and Eudragit RS 30D as the coating materials, and in vitro drug release behavior of the sustained-release pellets was studied. Results:The in vitro drug release was steady and complete in 24h, which fit a zero-order kinetics model. Conclusion:The memantine hydrochloride sustained-release pellets has the sustained-release property.
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Objective To establish an HPLC method for determination of related substances of dexmethylphenidate hydrochloride and their content .Methods The HPLC method was used on an Agilent ZORBAX SB-C18 column with a mo-bile phase of methanol-0.2%triethyl citrate in 25 mmol/L potassium dihydrogen phosphate ( pH was adjusted to 3.5 with phosphoric acid) (35∶65) at a flow rate of 1.0 ml/min.The detection wavelength was 209 nm and column temperature was 40℃.Results Under the selected chromatographic condition , dexmethylphenidate hydrochloride was completely separated from impurity.The limit of detection was 81.12 ng/ml.The calibration curve was linear in the range of 2-30 μg/ml ( r=0.9995).The average recovery of the method was 100.83%, and the stability of the working solution was acceptable in 12 h(RSD=0.10%).Conclusion This method is simple,specific,accurate and suitable for analyzing the related substances and their content in dexmethylphenidate hydrochloride .
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Diclofenac potassium delayed-sustained release pellets were prepared by double-layer coating method with ethylcellulose aqueous dispersion.The effects of release condition and pellet compositions on the in vitro drug release were evaluated.The formulation was optimized by the central composite design-response surface methodology.It was shown that the pH of the media greatly affected the in vitro drug release of the pellets while the viscosity of the media had little influence.Drug release from the pellets was related to the proportion of the inner coat to the outer coat and the amount of pore forming agent in the outer coat.The optimization of the formulation could be achieved by the central composite design-response surface methodology.
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The aim of the study was to optimize the coating formulation of sustained release pellets of loxoprofen sodium by the central composite design-response surface methodology(RSM plus CCD).In the formulation design using RSM plus CCD,independent variables were the ratio of HPMC to EC(X_1) in the sustained coating formulation and polymer load(weight gain,X_2) were selected as in dependent variables,and in vitro accumulated releases from the pellets at 1,4,and 8 h were dependent variables.Multilinear,two and three order quadratic models were used to estimate the relationship between the dependent and the independent variables,and to delineate RSM and overlay contour plots in order to select the optimal formulations in compliance to the hypothesized in vitro releases (%) at 1,4,and 8 h.The results showed that the relationship between dependent and independent variables was best fitted to three-order quadratic equation.The regression equation generated for the hypothesized in vitro cumulative releases(%) at 1,4,and 8 h were Q_(1h) =227.699 2-30.785 9X_1-43.395 4X_2 + 0.917 4X_1~2 +1.820 3X_2~2 +6.803 9X_1X_2-0.131 5X_1~2X_2-0.268 2X_1X_2~2,Q_(4h) =408.254 0-47.427 8X_1-75.229 2X_2 +3.304 0X_2~2 +12.357 3X_1X_2-0.111 8X_1~2X_2-0.5425X_1X_2~2,Q_(8h) =303.539 0-30.417 6X_1-45.114 0X_2 +2.064 4X_2~2 +6.865 0X_1X_2-0.3341X_1X_2~2,respectively.In the optimized coating formulation,the ratio of HPMC to EC was 4.0% and the polymer load 9.0%.Bias between observed and predicted values in vitro accumulated releases were negligible,indicating the high predictability of the selected models.Therefore,RSM plus CCD is applicable in the optimization of the coating formulation of loxoprofen sodium sustained-release pellets.
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Aim: To establish a linear additive model for the predication of in vitro sinomenine hydrochloride release from the combination of immediate release, enteric-coated and sustained-release pellets based on the release profiles of each pellet type. Methods: Immediate release pellets were manufactured by extrusion/spher-onization technology. The operation of bottom-spraying in the fluid-bed equipment was conducted to enteric-coating using Eudragit~(R) L-30D-55 and sustained-release coating using Surelease~(R) . In vitro sinomenine hydrochloride release profiles of both uncoated and coated pellets were fitted to the chosen mathematical equations offered by the curve fitting toolbox of Matlab~(R) before a linear additive model was created based upon the best-to-fitting equations. The proportion of each pellet type in the combined format to generate the desired 24 h sinomenine hydrochloride release profile was solved by Matlab~(R). The predicted and assayed sinomenine hydrochloride release from the polled pellets was compared. Results: It was shown that the actual sinomenine hydrochloride release profiles of each pellet type were approximate to those of predicted ones. A linear additive model of the appropriate mathematical equations of each pellet was proven to be capable of controlling in vitro release of sinomenine hydrochloride multiple-unit pellets. Conclusion: A multiple-unit combined system of the selected pellets, as a novel sustained-release system, was successfully prepared. In vitro release performance of the calculated combination of each pellet type could be guaranteed by this approach in designing sustained-release drug delivery system.
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OBJECTIVE: To optimize the formulation of metformin hydrochloride sustained-release pellets prepared using film coating technology. METHODS: Taking release rate in vitro as index, the formulation of the film-coat was prelimilarily selected using one facotr sreening method and optimzed using orthogonal test. The release rate of the prepared metformin hydrochloride sustained-release pellets was determined and compared with that metformin hydrochloride pellets. RESULTS: The optimized formulation was as follows: the film material of Eudragit NE 30D and Eudragit L 30D55 at a ratio of 10∶1 were added with 40% talcum powder and 0.25% sodium dodecyl sulfate. The release rate of the metformin hydrochloride sustained-release pellets was higher than that of metformin hydrochloride pellets. CONCLUSION: The metformin hydrochloride sustained-release pellets were up to the requirements of sustained release and characterized by 24h continuous drug release.
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Objective To prepare totel glucosides in paeony(TGP) pellets by extrusion-spheronization and to optimize the formulation of TGP sustained-release pellets coated with Eudragit RS 100.Methods The TGP sustained-release pellets were prepared by mini Glatt fluidized bed coating method.The factors to influence the drug release behaviors and their properties were evaluated.Results The optimal TGP sustained-release pellet was shown significant sustained-releasing at the loading weight of copolymers of 6% and the plasticizer concentration of 10%.And the curves of cumulative drug release were fit for Peppas and Higuchi equation.Conclusion The pellets showed an obviously sustained-release effect.
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AIM: To prepare the sodium ferulate sustained-release pellets and evaluate its release characteristics and release mechanism in vitro. METHODS: Sugar core beads and drug-containing pellets were prepared by centrifugal granulation,and then coated by Surelease using the fluid-bed.The release characteristics and release mechanism of the pellets were studied by the dissolution method. RESULTS: The surface of the coated pellets was smooth and glossy and round.The release rate of sodium ferulate met lot-to-lot uniformity.The release rate of the pellet consisted of two kinds of pellets decreased with the increasing of the film thickness.The finishing time was 24 h.The dissolution profiles of sodium ferulate from the pellets showed a good fit of the Higuchi equation.(CONCLUSION): The pellets exhibit more ideal sustained-release characteristics in vitro.