Clopidogrel Tablets Research Articles

Apixaban and clopidogrel in a fixed-dose combination: Formulation and in vitro evaluation

Fixed-dose combination (FDC) products represent a novel, safe, and cost-effective formulation. Combined use of anticoagulant and antiplatelet medications is common among comorbid cardiovascular patients. This study aimed to formulate FDC tablets for Apixaban and Clopidogrel, as prophylaxis and treatment of thrombo-embolic events. FDC tablets were developed by combining small tablets of Immediate-Release Clopidogrel 75 mg and Extend-Release Apixaban 5 mg through direct compression and wet granulation. Particularly, Apixaban tablets were developed using design expert software, and various types and concentrations of polymers were entered. For Clopidogrel tablets, various diluents were used to develop the formulation. Then, the dissolution profile for each formula was studied. Finally, the optimized formulations were encapsulated within hard gelatin capsules. Apixaban formulation followed zero-order with super case Ⅱ transport mechanism as the dominant mechanism of drug release. The Apixaban drug release rate was affected by the type and concentration of the polymers in the formulation (P < 0.05). As the HPMC concentration was increased, Apixaban release was retarded. For, Clopidogrel, the formulated tablets with spray-dried lactose filler and sodium stearyl fumarate lubricant were found to be stable with good properties. In conclusion, the optimum formulation yielded Clopidogrel and extended-release Apixaban for 24 h with the desired in vitro drug dissolution.

The Effect of Formulation Variables on the Manufacturability of Clopidogrel Tablets via Fluidized Hot-Melt Granulation-From the Lab Scale to the Pilot Scale.

Solid pharmaceutical formulations with class II active pharmaceutical ingredients (APIs) face dissolution challenges due to limited solubility, affecting in vivo behavior. Robust computational tools, via data mining, offer valuable insights into product performance, complementing traditional methods and aiding in scale-up decisions. This study utilizes the design of experiments (DoE) to understand fluidized hot-melt granulation manufacturing technology. Exploratory data analysis (MVDA) highlights similarities and differences in tablet manufacturability and dissolution profiles at both the lab and pilot scales. The study sought to gain insights into the application of multivariate data analysis by identifying variations among batches produced at different manufacturing scales for this technology. DoE and MVDA findings show that the granulation temperature, time, and Macrogol type significantly impact product performance. These factors, by influencing particle size distribution, become key predictors of product quality attributes such as resistance to crushing, disintegration time, and early-stage API dissolution in the profile. Software-aided data mining, with its multivariate and versatile nature, complements the empirical approach, which is reliant on trial and error during product scale-up.

Thromboelastographic and Gene Polymorphism Bimodality Detection for Dual Antiplatelet Aggregation Therapy in Individuals with Clopidogrel-resistant Symptomatic Intracranial Artery Stenosis.

Recent research indicates that clopidogrel resistance is connected with a patient's future ischemia risk, hence increasing the likelihood of recurrent ischemic cerebrovascular disease. Thromboelastographic and clopidogrel gene polymorphism testing can be used to see how a person responds to antiplatelet therapy and change the treatment plan accordingly. This may be a good way to make antiplatelet aggregation therapy more effective and safer. The objective of this study was to investigate the efficacy of dual antiplatelet aggregation therapy in patients with symptomatic intracranial large artery stenosis being resistant to clopidogrel tablets. The thromboelastographic and gene polymorphism bimodality detection techniques were used to analyze the clopidogrel resistance influencing factors. 89 patients with symptomatic intracranial large arterial stenosis who were admitted to our hospital from February 2021 to February 2022 were selected, classified as large artery atherosclerotic type by TOAST, and confirmed as having severe intracranial large arterial stenosis (70 % to 99 %) by magnetic resonance angiography (MRA), computed tomographic angiography (CTA), and digital subtraction angiography (DSA). All patients were treated with dual antiplatelet therapy with aspirin and clopidogrel, and thromboelastography and clopidogrel gene polymorphism were monitored 1 week later. 44 of 89 patients were clopidogrel-resistant. Among 44 patients, 20 were ticagrelorresistant and 24 were cilostazol-resistant. Clopidogrel had a resistance rate of 49.4%. The recurrence of ischemic cerebrovascular disease in the three groups was statistically significant (P<0.05) after 3 months of follow-up treatment, but bleeding (intracranial, gastrointestinal, respiratory, urinary, and mucocutaneous) and dyspnea were not. The clopidogrel-resistant group had a higher number of females, as well as higher levels of hypertension, diabetes, and platelet count than the sensitive group (P<0.05), but there was no significant difference in age, smoking, alcohol consumption, previous stroke, glycosylated haemoglobin, creatinine, or low-density cholesterol. Using thromboelastographic and gene polymorphism bimodality detection, we found switching to ticagrelor antiplatelet aggregation therapy as better than switching to cilostazol in patients with symptomatic intracranial large artery stenosis being resistant to clopidogrel tablets. The results may be biased due to the study being a single-centre study and having a limited sample size.

HPLC Method Development and Validation for the Determination of Apixaban and Clopidogrel in Novel Fixed-Dose Combination Tablets

A simple, fast, and accurate high-performance liquid chromatographic (HPLC) method is developed, optimized, and validated for a fixed-dose combination of apixaban (APX) and clopidogrel (CLOP) tablets according to ICH guidelines. Chromatographic separation of the drugs was performed on a BDS Hypersil C18 (4.6 ∗ 150 mm, 5 μm), with acetonitrile (ACN) and trifluoroacetic acid (TFA) in the ratio 48 : 52 (v/v) as a mobile phase, at a flow rate of 0.9 ml/min., injection volume of 5 μL, and column temperature 45°C. The proposed method was linear over the level 25–200% for a concentration of APX 5 μg/ml and CLOP 75 μg/ml (R2 &gt; 0.999). The detection limit for APX and CLOP was found to be 0.3465 and 3.8496 μg/ml, whereas the quantification limit was 1.0499 and 11.6656 μg/ml, respectively. The recovery was more than 99% using the standard addition method. The developed method was found to be specific, accurate, precise, and robust against changes in column temperature (±5°C) and mobile phase composition (±5% ACN); hence, it can be used for the determination of APX and CLOP in the fixed-dose combination tablets.

A Case of Recurrent Oral Ulcer Caused by Oral Clopidogrel Tablets Treated With Traditional Chinese Medicine

A Case of Recurrent Oral Ulcer Caused by Oral Clopidogrel Tablets Treated With Traditional Chinese Medicine

Analysis of the Effect of Aspirin and Clopidogrel Tablets on Acute Cerebral Infarction and NIHSS Score

Analysis of the Effect of Aspirin and Clopidogrel Tablets on Acute Cerebral Infarction and NIHSS Score

A Quality Control Study of Different Brands of Clopidogrel Tablets

A Quality Control Study of Different Brands of Clopidogrel Tablets

Abstract TP261: Oenanthe Javanica , A Potential Therapeutic Agent For Dual Antiplatelet Therapy To Overcome Clopidogrel Resistance

Background: Dual antiplatelet therapy with clopidogrel and aspirin prescription is standard for various clinical settings such as Acute Coronary Syndrome. However, the therapy is less effective on a large portion of the Asian population due to clopidogrel resistance. Oenanthe javanica (O. J.) has been used in traditional Chinese medicine for a range of ailments. In this study, we aimed to evaluate Oenanthe javanica extract’s antithrombotic effects and its potential to be used in Dual Antiplatelet Therapy (DAPT) to overcome clopidogrel resistance. Method: Prothrombin time (PT), activated partial thromboplastin time (aPTT), ADP and ASPI were measured using blood samples collected from 2 healthy volunteers. One volunteer took 2 75mg clopidogrel (CPG) tablets 2 hours before the experiment. The blood samples were incubated with O. J. extract for 30min before the measurement. For in vivo experiments, FeCl 3 thrombosis were induced to right common carotid arteries of Sprague Dawley rats (270-300g). The rats were divided into 5 groups (N=5-6): Control group, O. J. group, CPG group, CPG+O. J. group, and CPG+ASA group. O. J. extract was orally administered 200mg/kg per day for 3 days. CPG and ASA were orally administered 10mg/kg 2 hours before the experiment. Thrombosis was induced using filter paper doused with 10μL of 20% FeCl 3 solution. After the induction, blood flow was measured for 55min and thrombus weight was measured. Results: O. J. extract did not have any effect on PT, aPTT, and ASPI. However, O. J. extract did have an effect on ADP value, even though the volunteer had clopidogrel resistance. In FeCl 3 thrombosis model, O. J., CPG, CPG+ASA, and CPG+O. J. group all significantly increased the time-to-occlusion (TTO) compared to the Control group. This was true for thrombus weight as well. Conclusion: Our results indicate that O. J. extracts is a potential antiplatelet agent for dual antiplatelet therapy for patients with clopidogrel resistance.

Comparative Quality Evaluation of Different Brands of Clopidogrel Tablet Available in Bangladesh

This study aims to assess the quality parameters of Clopidogrel tablets from different manufacturers available in the Bangladeshi market. Clopidogrel is a potent antiplatelet and antithrombotic drug. Clopidogrel has been approved and marketed globally with the primary indication being to reduce atherosclerotic events in patients with several comorbid conditions due to stroke, myocardial infarction and cardiovascular disease. The aim and the objective of our present study are to evaluate the quality parameters of some marketed Clopidogrel tablet and to compare the parameters among them. To assess the quality, three different marketed Clopidogrel 75 mg tablet are selected and invitro dissolution test, potency, disintegration time are carried out. Other general quality parameters of these tablets like weight variation, hardness, friability are also determined according to established protocols. All the brands comply the requirements of United State Pharmacopoeia as they show acceptable weight variation range. Friability of all brands is less than 1%. No significant differences are found in disintegration time as they disintegrate within 15 minutes. In case of dissolution profile all brands show better dissolution time as they release more than 75% of drug in 45 minutes. The hardness of one brand is within the range 40-60N. The limitation of the potency must be within 95- 105%. All three brands meet this specification. This study suggests that most commercially available Clopidogrel tablets in Bangladesh maintain the quality and comply with the USP specifications which are essential for better therapeutic activity of this antiplatelet drug.

Analysis of the Effect of Aspirin Tablets Combined with Clopidogrel Tablets on the Progression of Acute Cerebral Infarction

Analysis of the Effect of Aspirin Tablets Combined with Clopidogrel Tablets on the Progression of Acute Cerebral Infarction

Quantitative analysis, cost comparison, physician, and patient perceptions on generic versus branded clopidogrel bisulfate tablets marketed in Kerala, India

Background: Clopidogrel bisulfate is sold in more than 60 advertised brand names (trade names) in the Indian market. Government health sector in India emphasizes on prescribing clopidogrel in its generic form, which refers to the chemical makeup of the drug, rather than to the advertised brand name, to reduce the economic burden. Preference for branded drugs and cost difference with generics are already well established, however physicians are apprehensive regarding the quality of generic drugs and have concerns about their reliability. Objective: We studied perspective of physicians and patients regarding generic versus branded medicines among hospitals in our locality. Cost difference incurred while prescribing various brands and generic clopidogrel tablets were calculated. Percentage purity of generic and branded clopidogrel tablets were analyzed to find if any difference really exists between them. Methodology: Perspective of 150 physicians and patients were studied using questionnaire method. Using ultraviolet spectrophotometer, generic and most commonly prescribed brands of clopidogrel were analyzed for percentage purity. Once analyzed, their costs were compared. Results: Eighty- six percent (n = 129) of physicians and 81% (n = 122) of patients surveyed, preferred branded medicines over generic ones. Among 10 branded clopidogrel tablets, only three complied with the Indian Pharmacopoeia standards of drug percentage purity. Pricing pattern of various brands of clopidogrel ranged from $1.4 to $3.13 per month. Generic clopidogrel tablets are available free of cost for patients from government-run hospitals but did not meet recommended percentage purity standards. Conclusion: Both branded and generic versions of clopidogrel have their merits and demerits. The general notion and doubt regarding difference in quality of generic versus branded version of medicines as evidenced by our perspective evaluation of physician and patients is appropriate in the present scenario. More large scale studies of different cardiovascular drugs are required to ensure their quality. Improved quality of generic medicines has to be ensured prior to marketing in India.

Comparative Evaluation of Some Commercial Clopidogrel Tablets Available in Yemen

Clopidogrel is a medication to reduce the risk of heart disease and taken orally. Quality of drug characterizes the production process and every phamaceutical company strives for it but often it is very difficult to achieve. This study was to investigate quality control parameters of some marketed Clopidogrel tablets. To assess the quality, eight different marketed brands of Clopidogrel 75 mg tablets available in Yemeni market collected from different pharmacies in Hodeida city. Different quality parameters like weight variation, hardness, thickness and friability were determined according to established protocols. Then the in-vitro dissolution test, potency, disintegration time were also carried out. UV-spectrophotometer was used to determine the percentage released and assay at 218 nm. All the brands comply the requirements of Pharmacopoeia as they showed acceptable weight variation range. Friability of all brands was less than 1% and no significant differences in disintegration times as they disintegrated within 15 minutes. In case of dissolution profile, all brands except C6 showed acceptable dissolution time as they released more than 60% of drug in 45 minute. The hardness of only two brands was within the range. All brands also meet the potency specifications. This study suggested that most commercially Clopidogrel tablets in Yemen maintain the quality and comply with the pharmacopeia specifications.

Comparative In Vitro Quality Evaluation of Some Clopidogrel Tablets, Commercially Available in Bangladesh Drug Market

Comparative In Vitro Quality Evaluation of Some Clopidogrel Tablets, Commercially Available in Bangladesh Drug Market

Formulation and evaluation of orally disintegrating clopidogrel tablets

ABSTRACT Recent advances in drug delivery systems have aimed to achieve better patient compliance. One of these advances is the formulation of orally disintegrating tablets (ODTs) that dissolve instantaneously, releasing drugs within a few seconds without the need of water. The main objective of this paper was to prepare and develop ODTs of clopidogrel. The ODTs were prepared by direct compression. The effect of three superdisintegrants, namely crospovidone, croscarmellose sodium, and sodium starch glycolate, using three different disintegration times on the dissolution rate was investigated. The prepared tablets were evaluated for hardness, friability, disintegration time and in vitro drug release. Furthermore, the interaction of clopidogrel with the formulation excipients was studied using differential scanning calorimetry (DSC). DSC studies revealed that there were no interactions between the drug and the excipients used. All tablets had hardness values in the range 4.0-5.2 kp and friability lower than 1%. The weight and drug content uniformity of all formulations was within official limits according to BP. In vitro drug release studies of the ODTs showed that more than 90% of the drug was released within ten minutes. A palatability test in human volunteers showed acceptable taste and mouth feel. Thus, the obtained results conclusively demonstrated successful rapid disintegration of the formulated tablets and acceptable palatability.

Development and validation of an HPLC–MS/MS method to determine clopidogrel in human plasma

A quantitative method for clopidogrel using online-SPE tandem LC–MS/MS was developed and fully validated according to the well-established FDA guidelines. The method achieves adequate sensitivity for pharmacokinetic studies, with lower limit of quantifications (LLOQs) as low as 10pg/mL. Chromatographic separations were performed on reversed phase columns Kromasil Eternity-2.5-C18-UHPLC for both methods. Positive electrospray ionization in multiple reaction monitoring (MRM) mode was employed for signal detection and a deuterated analogue (clopidogrel-d4) was used as internal standard (IS). Adjustments in sample preparation, including introduction of an online-SPE system proved to be the most effective method to solve the analyte back-conversion in clinical samples. Pooled clinical samples (two levels) were prepared and successfully used as real-sample quality control (QC) in the validation of back-conversion testing under different conditions. The result showed that the real samples were stable in room temperature for 24h. Linearity, precision, extraction recovery, matrix effect on spiked QC samples and stability tests on both spiked QCs and real sample QCs stored in different conditions met the acceptance criteria. This online-SPE method was successfully applied to a bioequivalence study of 75mg single dose clopidogrel tablets in 48 healthy male subjects.

Development of an LC−MS/MS method for determination of 2-oxo-clopidogrel in human plasma

A sensitive and selective liquid chromatography–tandem mass spectrometric (LC−MS/MS) method was established to determine 2-oxo-clopidogrel, a crucial intermediate metabolite in human plasma. A chromatographic separation was performed on a Sapphire C18 column following a liquid–liquid extraction sample preparation with methyl t-butyl ether. Detection was carried out on a triple quadrupole mass spectrometer operated in multiple reaction monitoring (MRM) with an electrospray ionization (ESI) mode. The method was validated in terms of specificity, accuracy, precision and limit of quantification. The calibration curves ranged from 0.50 to 50.0ng/mL with good linearity. The stability was fully validated with addition of 1,4-dithio-DL-threitol (DTT) into the plasma sample prior to and in the preparation procedure. The validated method was proved to be suitable for use in pharmacokinetic study after single oral administration of 75mg clopidogrel tablets in human subjects, which could make contribution to intensive study of the clinical drug–drug interactions of clopidogrel and individual treatment.

HPLC in determination of effective contents and related substances in clopidogrel hydrogen sulfate produced by 3 manufacturers

Objective To establish a high performance liquid chromatography( HPLC) method for quantitative determination of S-clopidogrel and its related substance R-clopidogrel in clopidogrel tablets,and to compare their contents between clopidogrel tablets produced by three different manufacturers. Methods An ULTRON ES-OVM column( 4. 6 mm × 150 mm,5μm) was used in this study. The mobile phase consisted of a mixture of acetonitrile and 0. 01 mol/L potassium dihydrogen phosphate solution( 20∶ 80). The flow-rate was 1 mL /min,with the column temperature being 17℃ and the UV detection wave lenth being 220 nm. Results S-clopidogrel and its related substance R-clopidogrel were in good linear relationship within 50-117 mg /L and 1. 52-30.04 mg /L,respectively( both r = 0. 999 8). The precision of our method was satisfactory and the average recoveries were 99. 7% and98. 8%,respectively. The test solution remained stable for 12 h. S-clopidogrel and R-clopidogrel in clopidogrel tablets produced by three manufacturers were in line with the quality requirements of pharmacopoeia. Conclusion Our method is accurate and has good specificity. It can be used for the quality control of clopidogrel tablets.

Duration of dual antiplatelet treatment with clopidogrel and aspirin in patients with acute coronary syndrome

Dual antiplatelet treatment (DAPT) is a cornerstone in the treatment of acute coronary syndrome (ACS) but the optimal treatment duration is unclear. We aimed to evaluate the effect of DAPT duration with clopidogrel and aspirin on the recurrence of ischaemic events and bleeding in a large, unselected ACS population. We performed a prospective, observational cohort study of patients in Sweden (n = 56 440) admitted for ACS, with prescribed DAPT and hospitalized between January 2006 and July 2010. Patients were obtained from the SWEDEHEART register and data were merged with registers from the National Board of Health and Welfare. Depending on dispensed clopidogrel tablets, patients were divided into groups based on DAPT duration with clopidogrel and aspirin (3 months: 84-100 clopidogrel tablets (t); >3 months: >100 t; 6 months: 168-200 t; >6 months: >200 t). For the combined primary endpoint, defined as all-cause death, stroke, or re-infarction, only patients with an uneventful first 3-month period (no death, stroke, re-infarction, bleeding, stent thrombosis, or revascularization) were included. The incidence of the primary endpoint was 45 events per 1000 person-years in the >3 months DAPT group compared with 65 events per 1000 person-years in the 3 months DAPT group [adjusted HR 0.84, 95% CI (0.75; 0.95)]. Bleeding was more common in the >3 months treatment group (adjusted HR 1.56, 95% CI (1.18; 2.07), but the number of events was small. For >6 vs. 6 months DAPT, the adjusted HR for the combined endpoint was 0.75 with 95% CI (0.59; 0.95). In this contemporary, large real-life ACS population, DAPT for more than 3 months compared with a shorter duration was associated with a lower risk of death, stroke, or re-infarction. Clinicaltrials.gov (NCT01623700).

Beneficial effects of clopidogrel on glycemic indices and oxidative stress in patients with type 2 diabetes

Objective of present study is to evaluate the possible role of clopidogrel in improving glycemic indices and oxidative stress in patients with type 2 diabetes. This study was performed on 42 uncontrolled type 2 diabetic patients at the specialized center for Endocrinology and Diabetes, Al-Rasafa Directorate of Health, Baghdad. All of the patients were treated with (glibenclamide 5 mg at morning) and randomized into two groups: the first group includes 22 patients treated with clopidogrel tablets (75 mg/day) for 2 months; the second group includes 20 patients treated with a placebo formula (sodium bicarbonate 200 mg/day) for the same period. Treatment with clopidogrel produced significant improvement ( P < 0.05) in fasting serum glucose (FSG), fasting serum insulin level, quantitative insulin sensitivity check index (QUICKI); and oxidative stress markers: serum malondialdehyde (MDA) and serum reduced glutathione (GSH) compared to their baseline levels. There was significant elevation ( P < 0.05) in both FSG and fasting serum insulin and the MDA level with significant reduction ( P < 0.05) in QUICKI of placebo group compared to their baseline levels. However, clopidogrel produced significant elevation ( P < 0.05) in AST and ALT levels but placebo formula caused no significant alteration ( P > 0.05) in the serum levels of these two enzymes. In conclusion the treatment with clopidogrel improved glycemic indices and reduced oxidative stress in patients with type 2 diabetes.

Development of sustained release formulation of an antithrombotic drug and application of fuzzy logic

Clopidogrel bisulphate has quite low bioavailability (40–50%). It was aimed to increase its bioavailability by designing a controlled release dosage form of clopidogrel, which is different from available current dosage forms in the market. There are also some attempts to overcome patent protection of clopidogrel by combination of active substances or preparation of controlled release tablets. Therefore, it was also aimed to determine in vitro and in vivo properties of controlled release clopidogrel tablets. The amounts of releases from formulations were subjected computer program and effects of components in the formulation on release were investigated (INFORM v.3.7 and FORMRULES, Intelligensys Ltd). Two sustained release formulations and innovator product were selected and their effectiveness was compared by in vivo tests in rabbits. In conclusion, proposed controlled release formulations were found to be an alternative and to be more effective for longer periods than the commercial one.