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With the growing demand of personalized medicine for children, it is especially important to develop medicines for children. In this study, using metoprolol tartrate as model drug, we developed 3D printed chewable tablets suitable for children with automated dosage distribution using semi-solid extruded (SSE) 3D printing technology. Based on the quality by design concept, this study prepared a semi-solid material with good printability using gelatin as the substrate, constructed 3D models and printed tablets with the aid of computer-aided design. The printing parameters were optimized and determined as follows: print temperature of 35-37 ℃, print speed of 25 mm·s-1, fill rate of 15%, and number of outer profile layers of 2. Subsequently, the printing process and the quality uniformity of the tablets were verified, and a linear relationship between the dose and the number of model layers was obtained. Finally, 3D printed chewable tablets were superior in terms of appearance, dose accuracy and compliance compared with traditional split-dose commercially available tablets. In this study, 3D printed metoprolol tartrate chewable tablets with good performance were successfully prepared to address the personalized medication needs of pediatric patients.
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Abstract Quality is paramount and needs to be maintained throughout the shelf life of pharmaceuticals. The current study aimed to evaluate the quality, potency, and drug-drug interaction in an in vivo animal model by using two drugs, namely, metoprolol and glimepiride. Tablets were selected for their physical characteristics, such as shape, size, and color. Quality control tests, such as weight variation, hardness, friability, and disintegration tests, and invitro drug release studies were performed as per USP. Drug-drug interaction and in vivo studies were carried out according to the standard protocol of the animal ethics committee. Quality control tests of both the tablets were within the specified range. The cumulative release percentages of the drugs were 81.12% and 85.36% for Metoprolol Tartrate and Glimepiride, respectively, in a physiological buffer solution within 1 h. The combination of metoprolol and Glimepiride also significantly decreased the blood glucose level in diabetic animals. However, the blood glucose level increased in the group receiving metoprolol only, but the difference was not significant. The result suggested that the formulations are safe. However, the chronic use of this combination requires frequent monitoring of blood glucose level to improve its efficacy and for the patient's safety.
Subject(s)
Animals , Male , Female , Mice , Quality Control , Tablets/classification , Drug Interactions , Metoprolol/analysis , In Vitro Techniques/methods , Pharmaceutical Preparations/analysis , Total Quality Management/statistics & numerical dataABSTRACT
Background The time rhythm of human body is associated with the occurrence and development of manydiseases, and it also affects the efficacy and pharmacokinetic characteristics of the corresponding therapeuticdrugs. Therefore, the chronopharmacological drug delivery system has potential applications. Aim In this work, it is proposed to develop a kind of pulsatile release tablet of simple structure and preparingprocess, thus to provide an alternative drug delivery system for therapeutic agents used in treatment of diseasesof typical onset biorhythm at period inconvenient to take drug.Methods Metoprolol tartrate (MT), a drug widely used clinically to treat cardiovascular diseases was selected asa model drug for developing pulsatile tablets of time-controlled explosive system (TES). The MT pulsatile tabletswere ethyl cellulose (EC) coating tablets produced by pan coating process, and the core tablets were preparedby direct compression. The formulation and process was optimized by single factor test and orthogonal design.Also, the pulsatile release mechanism of the tablets was discussed through investigating the water absorptionand swelling capacity of tablets as well as the mechanical properties of EC free film.Results A kind of pulsatile tablets of MT were developed with a drug release lag time around 7 h and a fastrelease of drug after lag time. When the swelling force of core tablet caused by water uptake was high enoughover the tensile strength of EC coating film, the MT pulsatile tablets demonstrated a shell-type exploding rupturedue to the great rigidity and weak flexibility of EC film, and then a fast pulsatile release of drug was observed.Both the swelling capacity of core tablet and the thickness of coating film together controlled the lag time of drugrelease. The lag time showed a good linear relationship with the thickness of coating film (r = 0.9984, P < 0.01).The sort and amount of fillers and disintegrants dominated the release behaviour after lag time.Conclusion The developed MT pulsatile tablets can exert a timely release of drug before peak onset period ofhypertension and angina pectoris early in the morning after drug taking around 22:00 P.M the night before. Thegood linear relationship between lag time and coating thickness enabled the pulsatile tablets to be used fordelivery of other therapeutic agents of similar chronotherapy demand by adjusting the coating thickness toachieve the appropriate lag time of drug release to match the different high attack rhythm of the exact diseases.
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Background The time rhythm of human body is associated with the occurrence and development of manydiseases. Kinds of diseases of particular onset biorhythm provided the room for the development ofchronopharmacological drug delivery systems.Aim In this work, the drug release and pharmacokinetics behavior of metoprolol tartrate (MT) pulsatile tabletdeveloped in our lab was investigated to figure out its feasibility of convenient drug taking to exert effectivechronotherapy for cardiovascular diseases like hypertension and angina pectoris.Methods The in vitro release behavior of MT pulsatile tablets was investigated by using basket method. Theappearance and morphology of MT pulsatile tablets during drug release was observed by naked eye and scanning electronic microscope, respectively. In vivo pharmacokinetics performance was studied in NewZealand rabbits.Results The lag time of MT pulsatile tablets was approximately 7 h in vitro, and a fast release was observedthereafter, with more than 90% releasing within 10 min. The pharmacokinetics study in rabbits demonstrateda perfect consistence in the absorption lag time of 7.04 ± 0.29 h in vivo. Compared with the marketedconventional tablet, the MT pulsatile tablet showed a bioequivalence in absorption extent with a relativebioavailability of 110.04%, but not in absorption rate.Conclusion The designed lag time of 7 hours enabled the MT pulsatile tablets to achieve effectivechronotherapy for cardiovascular diseases like hypertension and angina pectoris with a high attack rhythmaround 4:00-6:00 A.M by giving medicine conveniently around 22:00 P.M. the night before.
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Aryloxypropanolamine is an essential structural scaffold for a variety of β-adrenergic receptor antago-nists such as metoprolol. Molecules with such a structural motif tend to degrade into α, β-hydroxypropanolamine impurities via a radical-initiated oxidation pathway. These impurities are typically polar and nonchromophoric, and are thus often overlooked using traditional reversed phase chromatography and UV detection. In this work, stress testing of metoprolol confirmed the generation of 3-isopropylamino-1,2-propanediol as a degradation product, which is a specified impurity of metoprolol in the European Pharmacopoeia (impurity N). To ensure the safety and quality of metoprolol drug products, hydrophilic interaction chromatography (HILIC) methods using Halo Penta HILIC column (150 mm×4.6 mm, 5 μm) coupled with charged aerosol detection (CAD) were developed and optimized for the separation and quantitation of metoprolol impurity N in metoprolol drug products including metoprolol tartrate injection, metoprolol tartrate tablets, and metoprolol succinate extended-release tablets. These HILIC-CAD methods were validated per USP validation guidelines with respect to speci-ficity, linearity, accuracy, and precision, and have been successfully applied to determine impurity N in metoprolol drug products.
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The current United States Pharmacopeia–National Formulary (USP–NF) includes more than 250 mono-graphs of fixed dose combinations (FDCs), and some of them need to be updated due to incompleteness of impurity profiles and obsolescence of analytical methodologies. A case study of metoprolol tartrate and hydrochlorothiazide tablets is presented to summarize challenges encountered during the USP monograph modernization initiative of FDCs and to highlight an "adoption and adaptation" approach employed for method development. To this end, a single stability-indicating HPLC method was devel-oped to separate the two drug substances and eight related compounds with resolution 2.0 or higher between all critical pairs. Chromatographic separations were achieved on a Symmetry column (C18, 100 mm × 4.6 mm, 3.5 μm) using sodium phosphate buffer (pH 3.0; 34 mM) and acetonitrile as mobile phase in a gradient elution mode. The stability-indicating capability of this method has been demon-strated by analyzing stressed samples of the two drug substances. The developed HPLC method was validated for simultaneous determination of metoprolol tartrate and hydrochlorothiazide and relevant impurities in the tablets. Moreover, the developed method was successfully applied to the analysis of commercial tablet dosage forms and proved to be suitable for routine quality control use. The case study could be used to streamline USP's monograph modernization process of FDCs and strengthen compendial procedures.
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OBJECTIVE:To establish the method for dissolution determination of Metoprolol tartrate tablets,and to evaluate the similarity of dissolution curves of generics and original drugs. METHODS:The paddle method was adopted with rotational the speed of 50 r/min,using pH 1.2 hydrochloric acid solution,pH 4.5 acetate buffer solution and pH 6.8 phosphate buffer solution as dissolution media. Fiber-optical drug dissolution real-time measurement instrument was used to determine the dissolution curves of generic and original Metoprolol tartrate tablets with optical distance of 10 mm. Similarity factor (f2) method was used to evaluate its similarity. RESULTS:In 3 dissolution mediums,the f2 of generic and original Metoprolon tartrate tablets were 80.5,66.8, 69.4,respectively,which indicated that the dissolution curves showed similarity. CONCLUSIONS:Established real-time dissolution process analysis method is suitabe for the dissolution determination of Metoprolol tartrate tablets. Generic and eriginal show the sim-ilarity in dissolation behavier,so they have good consistency in quality.
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Objective To explore the influence of intravenous injection combined with oral of metoprolol tartrate on left ventricular function and adverse cardiovascular events of patients with acute anterior myocardial infarction.Methods84 cases of Patients with acute anterior myocardial infarction treated in the First Hospital of Hebei Medical University were selected as the study objects, and were divided into vein group and combination group according to drugs-taking modes, 42 cases in each groups.The vein group were treated with intravenous injection of metoprolol tartrate, and the combination group were treated with intravenous injection combined with oral of metoprolol tartrate.Clinical effect, left ventricular function, BP and HR levels, and incidence of adverse cardiovascular events were observed in the two groups.ResultsThe total effective rate of the combination group was 95.24% significantly higher than that of 80.95% in the vein group(P0.05).ConclusionIntravenous injection combined with oral of metoprolol tartrate can effectively improve left ventricular function of patients with acute anterior myocardial infarction, and reduce incidence of adverse cardiovascular events.
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Objective To investigate the therapeutic effect of Danhong injection combined with metoprolol tartrate tablets on cardiac arrhythmia in climacteric women.Methods Retrospective a total of 115 patients with arrhythmia in The First People’s Hospital of Guiyang from May 2014 to May 2016 were divided into the western medicine treatment group and the traditional Chinese and western medicine treatment group.Western medicine treatment group were treated by metoprolol tartrate tablets, the traditional Chinese and western medicine treatment group were treated by Danhong injection combined with metoprolol tartrate tablets.The effect of two groups of patients after two months of treatment were observed,the heart rate variability,heart function index,sleep quality and the incidence of adverse reaction rate were compared between two groups of patients before and after treatment .Results After treatment,the effective rate of the traditional Chinese and western medicine treatment group was 98.33%, higher than the western medicine treatment group (P<0.05);the levels of SDNN,SDANN,RMSSD and PNN50 (%) were significantly higher in the the traditional Chinese and western medicine treatment group than those in the western medicine group (P<0.05);the levels of SV,LVPS and LVEF in the traditional Chinese and western medicine treatment group were higher than that in the western medicine treatment group ( P <0.05 );the sleep quality of the traditional Chinese and western medicine treatment group was significantly improved compared with the western medicine treatment group(P<0.05);the abdominal distension, nausea and vomiting,fatigue and cough incidence were no difference between the two groups.Conclusion Danhong injection combined with metoprolol tartrate tablets arrhythmia in menopausal women has a better therapeutic effect ,can obviously improve the patients with heart rate variability and cardiac function and adverse reactions occurred rate is low.
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OBJECTIVE: To establish an HPLC method for determining the contents and related substances of felodipine and metoprolol tartrate in compound felodipine sustained-release tablets. METHODS: The analysis of felodipine was performed on an Agilent Eclipse XDB-C18 column (4.6 mm × 150 mm, 5 μm), using a mobile phase of methanol-acetonitrile-water (50:20:30) at the flow rate of 1.0 mL · min-1. The column temperature was maintained at 25℃. The detection wavelength was set at 238 nin and injection volume was 20 μL. The analysis of metoprolol tartrate was performed on an Agela Venusil MP C18 column (4.6 mm × 150 mm, 5 μm), using a mobile phase of 0.48% ammonium acetate (pH adjusted to 7.5 with triethylamine and glacial acetic: acid)-acetonitrile-methanol (65:20:15) at the flow rate of 1.0 mL · min-1. The column temperature was maintained at 30℃. The detection wavelength was set al 275 nm and injection volume was 20 μL. RESULTS The linear ranges of felodipine and metoprolol tartrate were 0.005-0.06 mg · mL-1 and 0.05-0.60 mg · mL-1, respectively. The average recoveries of felodipine and metoprolol tartrate were 100.70% and 99.62%, respectively. The RSDs of this method were all less than 2% (n=9). CONCLUSION: The method is applicable for the contents and related substances control of compound felodipine sustained-release tablets.
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Objective To investigate the clinical effect of losartan combined with metoprolol tartrate in treat -ment of elderly patients with coronary heart failure and its effect on heart function ,plasma brain natriuretic peptide and hemorheology.Methods 88 elderly patients with coronary heart failure were randomly divided into two groups ,and 44 cases were in each group .All of the patients were given conventional treatment , and the control group was given losartan while the observation group was received metoprolol tartrate on the basis of the control group ,the clinical effi-cacy and effect on cardiac function ,plasma brain natriuretic peptide ,hemorheology indexes were compared between the two groups.Results The total effective rate of the observation group was 95.45% significantly higher than 77.27%of the control group (χ2 =7.728,P<0.05);cardiac function and plasma BNP were significant improvement compared with the control group(t=6.55,6.02,7.41 and 13.24,all P<0.05);after the treatment,except the plate-let adhesion rate ,the hemorheology of the observation group were significant improvement compared with the control group(t=7.84,7.32,6.55,7.02,5.89 and 5.70,all P<0.05).Conclusion Losartan combined with metoprolol tartrate in treatment of coronary heart failure is significant effect ,and it can effectively improve the patient′s cardiac function,plasma brain natriuretic peptide levels and blood rheology ,and it is worth to be applied in clinical .
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OBJECTIVE: To establish an HPLC method to determine the dissolutions of felodipine and metoprolol tartrate in compound felodipine controlled release tablets. METHODS: An HPLC method was established with Agilent Eclipse C18 column (4.6 mm×250 mm, 5 μm).A mixture of 0.3% SDS (pH adjusted to 2.5 with phosphoric acid)-acetonitrile-methanol V:V:V(40:50:10) was used as the mobile phase. The column temperature was 25°C. The flow rate was 1 mL·min-1 and the detection wavelength was set at 233 nm. RESULTS: The relative retention time of felodipine and metoprolol tartrate was 6.20 and 8.45 min respectively. The linear ranges of these two drugs were 1-24 μg·mL-1 (r=0.9999) and 10-240 μg·mL-1 (r=0.9999). The average recoveries of felodipine and metoprolol tartrate were 99.99% and 99.91% respectively. The RSDs of this method were all less than 2%. CONCLUSION: The established method is sensitive, accurate and reliable for determination of the dissolutions of felodipine and metoprolol tartrate in compound felodipine controlled release tablets.
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OBJECTIVE: To prepare metoprolol tartrate sustained-release pellets and investigate the relative bioavailability in Beagle dogs. METHODS: Taking aspect ratio(AR), circularity, yield, friability, fluidity as key indexes, orthogonal design was atopted to optimize the formulation, and sustained-release pellets were prepared with Surelease. RESULTS: The optimal formulation was as follows: drug loading rate 90%, adhesive 40 mL·100 g-1, spheronization rate 30 Hz, coating weight gain 12%, and aging at 60°C for 2 h. CONCLUSION: The prepared metoprolol tartrate sustained-release pellets are bioequivalent with Betaloc in Beagle dogs.
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The demand for fast dissolving tablets has been growing during the last decade, especially for elderly and children who have swallowing difficulties. In the present work, fast dissolving tablets of metoprolol tartrate, were prepared using sodium starch glycolate, sodium croscarmellose and crospovidone as superdisintegrants, by the direct compression method. The tablets prepared were evaluated for various parameters including weight variation, hardness, friability, in vitro dispersion time, drug-polymer interaction, drug content water absorption ratio, wetting time, in vitro drug release, FTIR and DSC studies. The tablets prepared by the direct compression method had a weight variation in the range of 145 mg to 152 mg, which is below ± 7.5%, a hardness of 3.6 kg/cm² to 4.5 kg/cm², percentage friability of 0.46% to 0.73%, in vitro dispersion time of 18 s to 125 s, drug content uniformity of between 98.12% and 100.03%, a water absorption ratio of 67% to 87%, wetting time of 32 sec. to 64 sec., and an in vitro drug release of 53.92% - 98.82% within 15 min. The IR spectral analysis and DSC study showed no drug interaction with formulation additives of the tablet, and the formulations indicated no significant changes in hardness, friability, drug content or in vitro drug release. Fast dissolving tablets of metoprolol tartrate have enhanced dissolution and will lead to improved bioavailability and more effective therapy.
A exigência por comprimidos de dissolução rápida aumentou durante a última década, especialmente para idosos e crianças, com dificuldades de deglutição . No presente trabalho prepararam-se, pelo método de compressão direta, comprimidos de tartarato de metoprolol de rápida dissolução, utilizando glicolato sódico de amido, croscarmellose sódica e crospovidona como superdisintegrantes. Os comprimidos preparados foram avaliados em relação a diferentes parâmetros, como variação de peso, dureza, friabilidade, tempo de dispersão in vitro, interação fármaco-polímero, taxa de absorção de água pelo fármaco, tempo de umedecimento, liberação do fármaco in vitro,, FTIR e estudos de DSC. Os comprimidos preparados por compressão direta apresentaram variação de peso de 145 mg a 152 mg, abaixo de ±7,5%, dureza de 3,6 kg/cm² a 4,5 kg/cm² , porcentagem de friabilidade de 0,46% a 0,73%, tempo de dispersão in vitro de 18 s a 125 s, uniformidade de conteúdo de fármaco entre 98,12% e 100,03%, taxa de absorção de água de 67% a 87%, tempo de umidificaçãode 32 s a 64 s liberação do fármaco in vitro entre 53,92% e 98,82%, em 15 min. A análise no IV e de DSC mostrou que não houve interação de fármacos com os aditivos de formulação do comprimido e as formulações indicaram que não houve mudança significativa na dureza, friabilidade, s uniformidade de conteúdo de fármaco e na liberação do fármaco in vitro. Os comprimidos de liberação rápida apresentaram aumento na dissolução de tartarato metoprolol e conduzem à melhoria dabiodisponibilidade e à terapia eficaz.
Subject(s)
Tablets/analysis , Tartrates/pharmacokinetics , In Vitro Techniques/classification , Dissolution/classification , Deglutition , GlycolatesABSTRACT
Objective To investigate the clinical effects of Metoprolol Tartrate Tablets and Sodium Fructose Diphosphate(FDP) :injection in the early treatment of 48 cases of acute myocardial infarction(AMI) patients with thrombolytic therapy.Methods 84 cases of acute myocardial infarction who were in accordance with the indications for thrombolytic therapy in patients were randomly divided into a treatment group(group A,48 cases,treated with Metoprolol Tartrate Tablets and Sodium Fructose Diphosphate Injection) and a control group(group B,36 cases,treated with the conventional therapy).The occurrence of reperfusion arrhythmias,early sighs and symptms,and retoration of myocardial injury were observed in patients after thrombolytic therapy in order to understand clinical effect on the patients with that treatment.Results In treatment group there were decreased incidence of heart symptoms (chest pain,cardiopalmus) and RA(group A,36.1%;group B,71.4%),improved recovery of cardiac muscde enzymogram as compared to control,which was significantly different with control and between treatment groups (P
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OBJECTIVE: To optimize the formulation of metoprolol tartrate sustained-release tablets in compound hydrochlorothiazide double layer tablet.METHODS: The formulation of metoprolol tartrate sustained-release tablets was optimized using orthogonal experiment with release rate in vitro as index,total amount of HPMC and carbomer (A) and its ratio (B),amount of MCC (C) and the concentration of PVP ethanol solution (D) as factors.RESULTS: The optimal formulation was as follows: A=30%,B=1 ∶ 2,C=20% and D=5%.Accumulative release rate of 3 batches of metoprolol tartrate sustained-release tablet prepared by optimized formulation were 25%～45% within 1 h,40%～75% within 4 h,more than 75% within 8 h and more than 90% within 24 h.CONCLUSION: Optimized formulation of metoprolol tartrate sustained-release tablets is reasonable and simple.
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OBJECTIVE:To establish the Second-order Derivative UV-spectrophotometry for the determination of transdermal osmolality of metoprolol tartrate (MP)in vitro.METHODS:The quantitation of the vibration amplitude (?A)between the characteristic valley and the characteristic peak of MP appeared at 224nm and 234nm in UV-scanning.RESULTS:The linear concentration range of metoprolol tartrate was 5～60?g/ml,the average recovery was 98.89%with average RSD at 2.05%.CONCLUSION:This method can accurately determine the transdermal osmolality of MP in vitro yet without the interference of skin exudates,its operation is simple and fast and the results are accurate and reliable.
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AIM: To study the bioequivalence of domestic and imported Metoprolol Tartrate Tablets in Chinese healthy volunteers.METHODS: According to the rule published by SFDA,the serum concentration of 20 selected volunteers among 18 to 40 years old was determined by HPLC-fluorescence detection after giving domestic and imported Metoprolol Tartrate Tablets 0.1g,and the pharmacokinetic parameters were calculated by DAS software.RESULTS: The method of HPLC-fluorescence detection to study the pharmakokinetics of Metoprolol Tartrate was sensitive,reliable,accurate and reasonable.The main pharmakokinetics parameters of domestic and imported Metoprolol Tartrate Tablets were T_(max):(1.11)?(0.36 h) and(1.39)?(0.65 h) respectively;C_(max):(269.20)?(87.15)(?g?L~(-1)) and(262.03)?(75.52)(?g?L~(-1)) respectively;AUC_(0-12h):(1088.91)?(510.52)(?g?L~(-1)?h) and(1098.29)?5(55.14)(?g?L~(-1)?h) respectively.The relative bioavailability of domestic Metoprolol Tartrate Tablets was(100.09)%.CONCLUSION: The domestic and imported Metoprolol Tartrate Tablets was bioequivalents.