Acetylsalicylic Acid Formulations Research Articles

DETERMINATION OF SALICYLIC ACID RESIDUE IN ACETYLSALICYLIC ACID TABLETS

The pharmacological indications for acetyl salicylic acid have been on the increase over the years. It was initially indicated for the management of inflammation but its use as a cardioprotective agent is now more prominent. However, one of the major drawbacks of this drug is gastric irritation and bleeding which could lead to ulcer, anemia and several medical complications. These drawbacks are attributable to salicylic acid residue in acetyl salicylic acid. The determination of salicylic acid residue in acetylsalicylic acid (ASA) tablets was carried out using a spectrophotometric method.
 Twenty one formulations of acetylsalicylic acid (ASA) tablets were assayed. From the results, 71.43% of the formulations failed to meet up the British pharmacopoeia standard of 0.75% limit of free salicylic acid in acetylsalicylic acid tablets. This work highlights the need for regulatory agencies to routinely determine the level of free salicylic acid in acetylsalicylic acid formulations to ensure that they conform to pharmacopoeia standard

Bioavailability study of two 81-mg coated tablet formulations of acetylsalicylic acid in fed healthy subjects

To perform a comparative bioavailability study between a test (re-formulation) and a reference acetylsalicylic acid formulation (Ecasil-81, 81mg coated tablet) in healthy subjects under fed condition. Healthy subjects (n=48) were included in this monocentric, open-label, randomized, two-way crossover pharmacokinetic study. They received a single 81-mg oral dose of a test or a reference formulation of acetylsalicylic acid under fed condition, with a 7-day washout period between the treatments. Blood samples were collected over a period of 36 hours. The salicylic acid plasma concentration was measured by liquid chromatography coupled to tandem mass spectrometry (LC-MS/MS). Pharmacokinetic analysis was performed using WinNonlin software. The geometric mean and 90% confidence interval of test/reference formulation ratios were 109.32% (102.54-116.54%) and 106.94% (102.97-111.07%) for salicylic acid Cmax and AUC0-last, respectively. Food decreased the AUC and Cmax (p<0.001) and delayed the tmax (p=0.0077). The investigated women presented higher AUC0-∞ and Cmax values (p<0.001) than men. The clinical and laboratory exams did not show significant alterations. The re-formulation is bioequivalent to the reference formulation regarding the absorption extent and rate in fed healthy subjects. The administration of acetylsalicylic acid with food decreased its bioavailability. Moreover, differences in salicylic acid disposition related to sex were observed. The treatments were well tolerated by the investigated subjects.

QUANTITATIVE ANALYSIS OF ASPIRIN IN TABLETS USING ATTENUATED TOTAL REFLECTANCE FTIR WITH FULL SPECTRUM PLS ALGORITHM

Acetyl salicylic acid (ASA) is widely used globally to treat pain, rheumatic fever and inflammation since more than a century. It is also a prototypical molecule categorized as a platelet aggregation inhibitor, that could be widely used to reduce the risk of arterial and venous thrombosis in long term therapy. Various ASA formulations are available in the market and estimation of their quantity and efficacy is of utmost importance since it is largely being produced by many pharmaceutical companies all over the world. Literature is supported with many analytical methods using UV-visible spectrophotometer, liquid chromatography, liquid chromatography integrated with mass spectrometer (LC-MS), UHPLCMS/MS, Gas chromatography, electrochemical and titrimetric methods. In this study, an Attenuated total Reflectance Fourier transform Infrared Spectroscopy (ATR-FTIR) method was developed for the estimation of ASA in tablets and validated as per ICH guidelines. The calibration curve was constructed on peak height location at a specific wavenumber of 1750 cm-1 (Strong c=O stretching vibration of ASA) in the concentration range from 1-100 (%w/w) with a correlation coefficient of 1.000. the limit of detection (LOD) and limit of quantification (LOQ) were 0.94 (%w/w) and 0.31 (%w/w), respectively. the method was found to be precise over a range of 10- 100%, with intra-day and inter-day precision values were estimated as 0.94 and 8.26 respectively. The percentage of mean recovery was estimated at 103.04 ±2.58 with margin of error (± 2.50%) at 95% confidence interval. This new method was used for the quantification of ASA in tablets and percentage of labeled amount was found within the range of 103.04 ±2.58. No significant interference was observed by excipients in the tablet formulation during the spectral analysis.

P1935Pharmacokinetic and pharmacodynamic assessment of a lipid-based aspirin formulation: results of a prospective, randomised, crossover study

Abstract Objectives Aspirin, or acetylsalicylic acid (ASA), can lead to gastrointestinal mucosal injury through disruption of its protective phospholipid bilayer, underscoring the need for ASA formulations with a more favorable safety profile while maintaining an effective pharmacologic profile. A liquid formulation using a novel pharmaceutical lipid aspirin complex (PL-ASA) has been designed to prevent the disruption of the protective mucosal bilayer. We sought to determine the pharmacokinetic (PK)/pharmacodynamic (PD) characteristics of PL-ASA compared with traditional, immediate release aspirin (IR-ASA). Methods In this active-control crossover study, 16 healthy volunteers were randomized to receive a single dose of either IR-ASA 325 mg or PL-ASA 325 mg in a sequential fashion with a 2-week washout period between treatment assignments. The primary objectives of the study were to assess PK (i.e., plasma salicylic acid levels) and PD (i.e., serum thromboxane B2 levels) bioequivalence over a 24–hour period after drug administration, of PL-ASA and IR-ASA using established criteria. Results The PK parameter values were similar for PL-ASA and IR-ASA, with median AUC 0-t and Cmax values nominally higher for PL-ASA. Log-transformed PK parameters meeting FDA-criteria for bioequivalence (80% to 125%) are provided in the Table. Serum thromboxane B2 levels were similar for PL-ASA and IR-ASA, with Cmin values below 3.1 ng/mL (cut-off associated with decreased cardiovascular events) for both drugs. Both drugs also showed &gt;99% inhibition of serum thromboxane B2 levels (≥95% inhibition represents the cut-off to define aspirin responders). Several secondary PK/PD parameters showed similarities between the two drugs (data not shown). Overall, these findings support functional and clinical equivalence between PL-ASA and IR-ASA. PK Results Parameter Ratio (PL-ASA/IR-ASA) 90% Confidence Interval AUC0-t 96.51 89.24, 104.37 Cmax 103.73 92.06, 116.89 Conclusions PL-ASA's novel liquid formulation has similar PK and PD performance compared with IR-ASA. The improved endoscopic safety profile of PL-ASA coupled with its pharmacologic efficacy equivalent to IR-ASA may result in an improved benefit-risk performance, warranting evaluation in future trials. Acknowledgement/Funding PLx Pharma, Inc.

Acetylsalicylic acid in critically ill patients: a cross-sectional and a randomized trial.

BackgroundDespite decades of clinical use, the pharmacokinetics and the effects of acetylsalicylic acid (ASA) in critically ill patients remain ill‐defined. We aimed to investigate the pharmacokinetics and the effects of different ASA formulations during critical illness.DesignA cross‐sectional study and a randomized, parallel‐group trial were performed. Critically ill patients under chronic oral ASA treatment (100 mg enteric‐coated) were screened for high ‘on‐treatment’ platelet reactivity (HTPR) according to arachidonic acid‐induced whole‐blood aggregometry. Thirty patients with HTPR were randomized to receive 100 mg ASA intravenously, 100 mg enteric‐coated ASA bid (bis in die) or 81 mg chewable ASA (n = 10 per group). Serum thromboxane B2 (TXB2) levels, ASA and salicylic acid levels were quantified.ResultsOf 66 patients, 85% (95% confidence intervals 74–93%) had HTPR. Compared to baseline infusion of 100 mg, ASA significantly reduced platelet aggregation after 24 h to median 80% (Quartiles: 66–84%). Intake of 81 mg chewable ASA significantly reduced platelet aggregation to 75% (54–86%) after four hours, but increased it to 117% after 24 h (81–163%). Treatment with 100 mg enteric‐coated ASA bid decreased platelet aggregation after 24 h to median 56% (52–113%). Baseline TXB2 levels were median 0·35 ng/mL (0·07–0·94). Infusion of ASA or intake of 100 mg ASA bid reduced TXB2 levels to 0·07–0·18 ng/mL after 24 h, respectively. Chewable ASA reduced TXB2 levels only transiently. Pharmacokinetic analysis revealed highly variable absorption patterns of oral ASA formulations.ConclusionThere is a very high prevalence of HTPR in critically ill patients on peroral ASA therapy, caused by an incomplete suppression of TXB2 and/or by impaired absorption of ASA.

Comparative Bioavailability Study of Two 81 mg Coated Tablet Formulations of Acetylsalicylic Acid in Fasting Healthy Volunteers

Introduction: Low-dose acetylsalicylic acid is used as antithrombotic agent and the enteric-coated formulations are widely used to minimize the gastrointestinal side effects. Aim: To compare the bioavailability of two acetylsalicylic acid formulations (Ecasil-81®, 81 mg coated tablet) in fasting healthy volunteers. Methods: Healthy volunteers (n=16) were recruited to a monocentric, open label, randomized, two-way crossover pharmacokinetic study, with seven days washout period between the treatments. They received a single 81 mg oral dose of a test (new formulation) or a standard reference formulation of acetylsalicylic acid (Ecasil-81®) after about 8 h fasting. Blood samples were collected over a period of 36 h. The salicylic acid plasma concentration was evaluated by high-performance liquid chromatography coupled to tandem mass spectrometry (HPLC-MS/MS). Noncompartmental pharmacokinetic analysis was performed using the WinNonlin program. Results: The maximum plasma concentration (Cmax) of salicylic acid was 5433 and 5719 ng/mL reached in 3.66 and 4.02 h (tmax) for the test and the reference formulation, respectively. The 90% confidence interval of the ratios of geometric means of Cmax and area under curve of plasma concentration until the last concentration observed (AUC0- last) were within the interval 80-125%. Conclusion: The new acetylsalicylic acid formulation has a bioavailability equivalent to the reference formulation for the rate and the extent of absorption.

Эффективность и безопасность разных лекарственных форм ацетилсалициловой кислоты

Эффективность и безопасность разных лекарственных форм ацетилсалициловой кислоты

Impurity profile analysis of drug products containing acetylsalicylic acid: a chemometric approach

Abstract In this work attention is focused on impurity profile analysis in combination with infrared spectroscopy and chemometric methods. This approach is considered as an alternative to generally complex and time-consuming classic analytical techniques such as liquid chromatography. Various strategies for constructing descriptive models able to identify relations among drug impurity profiles hidden in multivariate chromatographic data sets are also presented and discussed. The hierarchical (cluster analysis) and non-hierarchical segmentation algorithms (k-means method) and principal component analysis are applied to gain an overview of the similarities and dissimilarities among impurity profiles of acetylsalicylic acid formulations. A tree regression algorithm based on infrared spectra is used to predict the relative content of impurities in the drug products investigated. Satisfactory predictive abilities of the models derived indicate the possibility of implementing them in the quality control of drug products.

ACETYLSALICYLIC ACID IN THE PREVENTION OF ATHEROTHROMBOTIC EVENTS

The results of large-scale clinical trials have convincingly demonstrated the effectiveness of acetylsalicylic acid (ASA) in primary and secondary prevention of atherothrombotic events. Studies on the safety of different ASA formulations have been continuing. Magnesium hydroxide included in combined medicine, Сardiomagnil, prevents ASA adverse effects on the gastric mucosa and reduces in severity of dyspeptic symptoms.

PREVENTION OF THROMBOSES IN ANTIPHOSPHOLIPID SYNDROME

Warfarin and acetylsalicylic acid (ASA) are most frequently used to prevent thromboses of different localizations in general medical practice and in patients with antiphospholipid syndrome (APS). The mechanism of action of warfarin is associated with the ceased synthesis of blood coagulation factors VII, X, IX, and II. ASA inhibits platelet aggregation due to irreversible inactivation of СОХ 1. Patients with antiphospholipid (aPL) antibodies and venous thromboses need long-term moderate-intensity warfarin therapy. Patients with ischemic strokes without other indications for the use of anticoagulants may be given either warfarin or ASA. In the latter case, there is no need for laboratory control or an individual dose adjustment. The primary prevention of thromboses in the presence of aPL is also performed with ASA. When pregnancy occurs, women with obstetric manifestations of APS may be given small-dose ASA in combination with heparins. To reduce the risk of hemorrhages, warfarin dosage adjustment is initiated with the minimum doses (<5 mg/day). Novel ASA formulations, such as ASA with the unabsorbed antacid magnesium hydroxide, have been developed to prevent gastrointestinal tract complications.

A clinical trial of a slow-release formulation of acetylsalicylic acid in patients at risk for preeclampsia.

The formation of thromboxane A2 (TXA2) in maternal and foetal cord serum was measured at birth in eight control patients and in 13 patients taking 100 mg of a slow-release formulation of acetylsalicylic acid. The serum concentrations of TXB2 (a stable end product of TXA2 hydrolysis) in both maternal and cord serum from patients who ingested the acetylsalicylic acid formulation were significantly lower (P < 0.01) than those in control subjects. Acetylsalicylic acid was not detected (< 30 ng ml-1) in maternal plasma from six mothers and in cord plasma from seven foetuses in the acetylsalicylic acid-treated group. The mean cord to maternal plasma concentration ratios for detectable acetylsalicylic acid and salicylate were 0.62 +/- 0.19 (s.d.) (n = 6) and 0.84 +/- 0.16 (n = 13), respectively. We conclude that low doses of acetylsalicylic acid given in a slow-release form to mothers during pregnancy cause depression of TXA2 formation in the foetal blood.

Comparative Assessment of Oral Mucosal Response to Buffered and Unbuffered Acetylsalicylic Acid Formulations and Citric Acid

A randomised parallel group comparison was conducted in 36 healthy subjects to investigate changes in the buccal mucosa after contact with buffered chewable acetylsalicylic acid (ASA) tablets compared with unbuffered chewable ASA tablets and compressed tablets of citric acid. Each of the 3 agents was tested in 12 subjects. Following a 6-day run-in period without medication, the buccal mucosa was exposed to the respective agent twice daily for 6 days, the agents being applied to the right buccal mucosa for 30 seconds and to the left for 120 seconds. During the run-in and the exposure phases cytological smears were taken and the keratinisation index determined.

Acetylsalicylic acid metabolites in blood and urine after plain and enteric-coated tablets.

Acetylsalicylic acid (ASA) was administered orally as a single dose to 7 healthy male volunteers as plain or enteric-coated (Entrophen) tablets using a crossover design. Blood and urine samples were collected and analysed for ASA metabolites by high performance liquid chromatography. Labile and stable glucuronide conjugates of salicylic acid (SA) were measured in urine after differential hydrolysis with glucuronidase. Plasma kinetic parameters for the ASA metabolites SA and salicyluric acid were not different for the 2 formulations, apart from the delayed appearance after the enteric-coated tablets. Total urinary recovery, and recovery of salicyluric acid and the two SA glucuronides were not different, thus confirming the equivalent bioavailability and metabolite profile of the 2 ASA formulations.

Inhibition of platelet function by a controlled release acetylsalicylic acid formulation — Single and chronic dosing studies

The extent to which a controlled release acetylsalicylic acid (ASA) formulation inhibited platelet function has been evaluated in single and chronic dosing studies. In the single dose study, the platelet inhibitory effect of the controlled release formulation was compared with that of an equivalent dose of soluble ASA and an equimolar dose of sodium salicylate (SA). In the chronic dosing study, ASA dose-response curves for platelet function, including cyclooxygenase activity, were determined for various doses (20-1300 mg) of the controlled release (enteric coated pellets) ASA formulation taken by volunteers daily for one week. Platelet function was assessed by the degree of inhibition of aggregation for several aggregating agents, and the degree of inhibition of activity of platelet cyclooxygenase quantified by the estimation of malondialdehyde (MDA) production. Plasma ASA and SA concentrations were also determined in each study. The controlled release product inhibited platelet function to the same extent as an equimolar dose of soluble ASA, but did so with much lower and sometimes undetectable peak systemic plasma ASA concentrations. SA, the direct metabolite of aspirin, did not have any effect on platelet function. The ASA dose-platelet function response curves obtained from chronic dosing with the controlled release formulation appeared to be similar to those reported previously for the soluble product. The inhibition of platelet function appeared to be unrelated to plasma ASA concentrations.

6 - Gastroduodenal Damage due to Drugs, Alcohol and Smoking

In man, convincing data have been obtained in short-term observations that some drugs can cause acute gastroduodenal damage including gastritis and erosions. Useful clinical and epidemiological studies on the relationship between these acute lesions and peptic ulceration, and between the chronic ingestion of these drugs and peptic ulceration or massive upper gastrointestinal haemorrhage are, however, rare. Even for the most widely used and studied greatest offender--acetylsalicylic acid (ASA)--an association with major bleeding or gastric ulceration could only be established for frequent and heavy ASA intake. The percentage of those ASA users who will experience such a serious event each year is about 0.01 to 0.05 per cent. By the use of special (e.g. enteric-coated) ASA formulations and other precautions, this low rate may be further reduced. Although for most of the other non-steroidal anti-inflammatory drugs (NSAIDs), anecdotal reports on putative drug-related major gastric bleeding or peptic ulceration exist, the ulcerogenicity of these drugs has not yet been conclusively proven in controlled studies. Some of the newer NSAIDs seem at normal dosage to be far less damaging than traditional ASA or indomethacin. Glucocorticoids might enhance ulcer risk to a minor extent when administered at high dosage for prolonged periods to susceptible individuals. Chronic moderate alcohol consumption by itself does not seem to increase the liability to peptic ulceration. With highly concentrated alcoholic beverages, gastric bleeding from acute lesions may, however, be occasionally precipitated under certain circumstances, such as when unbuffered ASA is taken concomitantly. Smoking of cigarettes is associated, and perhaps causally related, with an increased incidence of gastric and duodenal ulcerations, impaired ulcer healing, and more frequent ulcer recurrences. Duodenal ulcer patients in particular should be advised to stop smoking.

The effect of acetylsalicylic acid in 3 different formulations on in vitro and in vivo platelet function tests: An experimental study on healthy male volunteers

The template bleeding time (TBT), ADP-induced platelet aggregation, and serum production of TXB2 were measured in healthy young male subjects immediately before, and on days 1, 4 and 6 after the ingestion of 1 single dose of 500 mg acetylsalicylic acid (ASA) in 3 different formulations: Aspirin (Bayer), and the 2 enteric-coated formulations Reumyl (Hässle) and Premaspin (Lääke). The ingestion of Aspirin resulted in a significant prolongation of the TBT over a period of 6 d. However, after the ingestion of the same amount of ASA in the 2 enteric coated formulations, the TBT as measured on day 6 had become normalized. After the ingestion of Aspirin, there was no reappearance of the second wave of ADP-induced platelet aggregation during the study period; however, after the ingestion of the 2 enteric-coated formulations, secondary platelet aggregation occasionally returned on day 6. In response to the intake of each of the 3 ASA formulations, the serum TXB2 production as measured 24 h later was almost completely inhibited. In each of the 3 study groups, the TXB2 formation as measured on day 6 was still significantly impaired.

Inhibition of platelet function by a controlled release acetylsalicylic acid formulation ? Single and chronic dosing studies

Inhibition of platelet function by a controlled release acetylsalicylic acid formulation ? Single and chronic dosing studies

Pharmacokinetics and in vivo scintigraphic monitoring of a sustained release acetylsalicylic acid formulation

The in vivo dissolution and pharmacokinetics of a sustained release aspirin formulation labelled with ( 99mTc]diethylenetriaminepentaacetic acid has been monitored in 5 subjects by the use of gamma scintigraphy and drug analysis undertaken of blood and urine samples. The data obtained enabled the position of the tablet in vivo to be related to the plasma and urinary salicylate levels. The study confirms the sustained release properties of the cellulose acetate phthalate formulation.