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Molecules (Basel, Switzerland) Sep 2021The amorphous form of carvedilol phosphate (CVD) was obtained as a result of grinding. The identity of the obtained amorphous form was confirmed by powder X-ray...
The amorphous form of carvedilol phosphate (CVD) was obtained as a result of grinding. The identity of the obtained amorphous form was confirmed by powder X-ray diffraction (PXRD), different scanning calorimetry (DSC), and FT-IR spectroscopy. The process was optimized in order to obtain the appropriate efficiency and time. The crystalline form of CVD was used as the reference standard. Solid dispersions of crystalline and amorphous CVD forms with hydrophilic polymers (hydroxypropyl-β-cyclodextrin, Pluronic F-127, and Soluplus) were obtained. Their solubility at pH 1.2 and 6.8 was carried out, as well as their permeation through a model system of biological membranes suitable for the gastrointestinal tract (PAMPA-GIT) was established. The influence of selected polymers on CVD properties was defined for the amorphous form regarding the crystalline form of CVD. As a result of grinding (four milling cycles lasting 15 min with 5 min breaks), amorphous CVD was obtained. Its presence was confirmed by the "halo effect" on the diffraction patterns, the disappearance of the peak at 160.5 °C in the thermograms, and the changes in position/disappearance of many characteristic bands on the FT-IR spectra. As a result of changes in the CVD structure, its lower solubility at pH 1.2 and pH 6.8 was noted. While the amorphous dispersions of CVD, especially with Pluronic F-127, achieved better solubility than combinations of crystalline forms with excipients. Using the PAMPA-GIT model, amorphous CVD was assessed as high permeable ( > 1 × 10 cm/s), similarly with its amorphous dispersions with excipients (hydroxypropyl-β-cyclodextrin, Pluronic F-127, and Soluplus), although in their cases, the values of apparent constants permeability were decreased.
PubMed: 34500748
DOI: 10.3390/molecules26175318 -
Journal of Pharmacy & Bioallied Sciences 2017Carvedilol phosphate (CDP) is a nonselective beta-blocker used for the treatment of heart failures and hypertension. In this work, moisture sorption-desorption...
AIMS
Carvedilol phosphate (CDP) is a nonselective beta-blocker used for the treatment of heart failures and hypertension. In this work, moisture sorption-desorption characteristics and thermodynamic properties of CDP have been investigated.
MATERIALS AND METHODS
The isotherms were determined using dynamic vapor sorption analyzer at different humidity conditions (0%-90% relative humidity) and three pharmaceutically relevant temperatures (20°C, 30°C, and 40°C). The experimental sorption data determined were fitted to various models, namely, Brunauer-Emmett-Teller; Guggenheim-Anderson-De Boer (GAB); Peleg; and modified GAB. Isosteric heats of sorption were evaluated through the direct use of sorption isotherms by means of the Clausius-Clapeyron equation.
STATISTICAL ANALYSIS USED
The sorption model parameters were determined from the experimental sorption data using nonlinear regression analysis, and mean relative percentage deviation (P), correlation (Correl), root mean square error, and model efficiency were considered as the criteria to select the best fit model.
RESULTS
The sorption-desorption isotherms have sigmoidal shape - confirming to Type II isotherms. Based on the statistical data analysis, modified GAB model was found to be more adequate to explain sorption characteristics of CDP. It is noted that the rate of adsorption and desorption is specific to the temperature at which it was being studied. It is observed that isosteric heat of sorption decreased with increasing equilibrium moisture content.
CONCLUSIONS
The calculation of the thermodynamic properties was further used to draw an understanding of the properties of water and energy requirements associated with the sorption behavior. The sorption-desorption data and the set of equations are useful in the simulation of processing, handling, and storage of CDP and further behavior during manufacture and storage of CDP formulations.
PubMed: 28584488
DOI: 10.4103/0975-7406.206216 -
Scientific Reports Feb 2017Glass is an ultraviscous liquid that ceases to flow on a laboratory timescale but continues to relax on a geological timescale. Quintessentially, it has become hopeless...
Glass is an ultraviscous liquid that ceases to flow on a laboratory timescale but continues to relax on a geological timescale. Quintessentially, it has become hopeless for humans to explore the equilibrium behavior of glass, although the technology of glass making witness a remarkable advance. In this work, we propose a novel thermodynamic path to prepare a high density amorphous state of matter (carvedilol dihydrogen phosphate) using high pressure. In addition, we provide the impeccable experimental evidence of heterogeneous nature of secondary β-relaxation and probe its properties to understand the various aspects of pressure densified glass, such as dynamics, packing and disorder. These features are expected to provide new horizons to glass preparation and functional response to pharmaceutical applications.
PubMed: 28225060
DOI: 10.1038/srep43091 -
Biological & Pharmaceutical Bulletin 2010It was reported that coadministration of amiodarone with carvedilol increased the serum concentration to dose (C/D) ratio of S-carvedilol in patients with heart failure,...
It was reported that coadministration of amiodarone with carvedilol increased the serum concentration to dose (C/D) ratio of S-carvedilol in patients with heart failure, but not of R-carvedilol. The aim of the present study was to investigate the effect of amiodarone and its metabolite on the metabolism of R- and S-carvedilol in human liver microsomes (HLM). Oxidation of carvedilol in HLM was evaluated in the presence of reduced nicotinamide adenine dinucleotide phosphate (NADPH), whereas glucuronidation was evaluated in the presence of uridine 5'-diphosphate (UDP)-glucuronic acid. The oxidation and glucuronidation activities of HLM for S-carvedilol were approximately 2- and 4-fold greater, respectively, than those for R-carvedilol. In the presence of amiodarone (50 microM) and/or desethylamiodarone (25 microM), the oxidation activity for R- and S-carvedilol decreased significantly. In contrast, the glucuronidation activity for R-carvedilol was increased 1.6- and 1.4-fold by amiodarone and desethylamiodarone, respectively, whereas the glucuronidation of S-carvedilol was only slightly changed by amiodarone and desethylamiodarone. These results suggested that inhibition of S-carvedilol oxidation by amiodarone and/or desethylamiodarone is implicated in the increased C/D ratio of S-carvedilol associated with coadministration of amiodarone. On the other hand, the stimulative effect of amiodarone and/or desethylamiodarone on the glucuronidation of R-carvedilol may compensate for the inhibitory effect of those on R-carvedilol oxidation.
Topics: Amiodarone; Carbazoles; Carvedilol; Drug Interactions; Humans; Isomerism; Metabolic Detoxication, Phase II; Microsomes, Liver; NADP; Oxidation-Reduction; Propanolamines; Uridine Diphosphate Glucuronic Acid
PubMed: 20410613
DOI: 10.1248/bpb.33.717 -
The Journal of Clinical Investigation Feb 2013CLINICAL VIGNETTE: A 48-year-old man with chronic kidney disease stage five due to type II diabetes mellitus and hypertension was referred for hemodialysis initiation.... (Review)
Review
CLINICAL VIGNETTE: A 48-year-old man with chronic kidney disease stage five due to type II diabetes mellitus and hypertension was referred for hemodialysis initiation. His physical exam showed a blood pressure of 150/80, normal fundi, a positive fourth heart sound (S4), and trace pedal edema. Moderate aortic calcification was present on prior chest X-ray. The ECG showed left ventricle hypertrophy by voltage and slight prolongation of the QT interval. Medications included chlorthalidone, amlodipine, carvedilol, cholecalciferol, erythropoietin, and a phosphate binder. What additional therapy should be initiated to reduce vascular calcifications and cardiovascular mortality?
Topics: Cardiovascular Diseases; Fibroblast Growth Factor-23; Fibroblast Growth Factors; Humans; Hypertrophy, Left Ventricular; Male; Middle Aged; Renal Insufficiency, Chronic; Renin-Angiotensin System; Translational Research, Biomedical
PubMed: 23298840
DOI: 10.1172/JCI67203 -
Acta Pharmaceutica (Zagreb, Croatia) Dec 2014The objective of the study was to enhance the solubility of carvedilol phosphate and to formulate it into non-effervescent floating tablets using swellable polymers....
The objective of the study was to enhance the solubility of carvedilol phosphate and to formulate it into non-effervescent floating tablets using swellable polymers. Solid dispersions (SD) of carvedilol were prepared with hydrophilic carriers such as polyvinylpyrrolidone and poloxamer to enhance solubility. Non-effervescent floating tablets were prepared with a combination of optimized solid dispersions and release retarding polymers/swellable polymers such as xanthan gum and polyethylene oxide. Tablets were evaluated for physicochemical properties such as hardness, thickness and buoyancy. SD prepared with the drug to poloxamer ratio of 1:4 by melt granulation showed a higher dissolution rate than all other dispersions. Formulations containing 40 mg of polyethylene oxide (C-P40) and 50 mg xanthan gum (C-X50) were found to be best, with the drug retardation up to 12 hours. Optimized formulations were characterized using FTIR and DSC and no drug and excipient interactions were detected.
Topics: Adrenergic beta-Antagonists; Calorimetry, Differential Scanning; Carbazoles; Carvedilol; Chemistry, Pharmaceutical; Drug Carriers; Drug Compounding; Drug Delivery Systems; Excipients; Poloxamer; Polyethylene Glycols; Polysaccharides, Bacterial; Povidone; Propanolamines; Solubility; Spectroscopy, Fourier Transform Infrared; Tablets
PubMed: 25531788
DOI: 10.2478/acph-2014-0038 -
AAPS PharmSciTech Mar 2012The exudates from the incised trunk of Terminalia randii has been evaluated as controlled release excipient in comparison with xanthan gum and... (Comparative Study)
Comparative Study
The exudates from the incised trunk of Terminalia randii has been evaluated as controlled release excipient in comparison with xanthan gum and hydroxypropylmethylcellulose (HPMC) using carvedilol (water insoluble) and theophylline (water soluble) as model drugs. Matrix tablets were prepared by direct compression and the effects of polymer concentration and excipients-spray dried lactose, microcrystalline cellulose and dicalcium phosphate dihydrate on the mechanical (crushing strength (CS) friability (F) and crushing strength-friability ratio (CSFR)) and drug release properties of the matrix tablets were evaluated. The drug release data were fitted into different release kinetics equations to determine the drug release mechanism(s) from the matrix tablets. The results showed that the CS and CSFR increased with increase in polymer concentration while F decreased. The ranking of CS and CSFR was HPMC > terminalia > xanthan while the ranking was reverse for F. The ranking for t(25) (i.e. time for 25% drug release) at a polymer concentration of 60% was xanthan > terminalia = HPMC. The dissolution time, t(25), of theophylline matrices was significantly lower (p < 0.001) than those of carvedilol matrix tablets. Drug release from the matrices was by swelling, diffusion and erosion. The mechanical and drug release properties of the tablets were significantly (p < 0.05) dependent on the type and concentration of polymer and excipients used with the release mechanisms varying from Fickian to anomalous. Terminalia gum compared favourably with standard polymers when used in controlled release matrices and could serve as a suitable alternative to the standard polymers in drug delivery.
Topics: Carbazoles; Carvedilol; Compressive Strength; Drug Delivery Systems; Excipients; Plant Gums; Propanolamines; Tablets; Terminalia
PubMed: 22068290
DOI: 10.1208/s12249-011-9712-0 -
European Journal of Pharmaceutics and... May 2020It is widely recognised that drug solubility within the gastrointestinal tract (GIT) differs from values determined in a simple aqueous buffer and to circumvent this...
It is widely recognised that drug solubility within the gastrointestinal tract (GIT) differs from values determined in a simple aqueous buffer and to circumvent this problem measurement in biorelevant fluids is determined. Biorelevant fluids are complex mixtures of components (sodium taurocholate, lecithin, sodium phosphate, sodium chloride, pancreatin and sodium oleate) at various concentrations and pH levels to provide systems simulating fasted (FaSSIF) or fed (FeSSIF) intestinal media. Design of Experiment (DoE) studies have been applied to investigate FaSSIF and FeSSIF and indicate that a drug's equilibrium solubility varies over orders of magnitude, is influenced by the drug type and individual or combinations of media components, with some of these interactions being drug specific. Although providing great detail on the drug media interactions these studies are resource intensive requiring up to ninety individual experiments for FeSSIF. In this paper a low sample number or reduced DoE system has been investigated by restricting components with minimal solubility impact to a single value and only investigating variations in the concentrations of sodium taurocholate, lecithin, sodium oleate, pH and additionally in the case of fed media, monoglyceride. This reduces the experiments required to ten (FaSSIF) and nine (FeSSIF). Twelve poorly soluble drugs (Ibuprofen, Valsartan, Zafirlukast, Indomethacin, Fenofibrate, Felodipine, Probucol, Tadalafil, Carvedilol, Aprepitant, Bromocriptine and Itraconazole) were investigated and the results compared to published DoE studies and literature solubility values in human intestinal fluid (HIF), FaSSIF or FeSSIF. The solubility range determined by the reduced DoE is statistically equivalent to the larger scale published DoE results in over eighty five percent of the cases. The reduced DoE range also covers HIF, FaSSIF or FeSSIF literature solubility values. In addition the reduced DoE provides lowest measured solubility values that agree with the published DoE values in ninety percent of the cases. However, the reduced DoE only identified single and in some cases none of the major components influencing solubility in contrast to the larger published DoE studies which identified multiple individual components and component interactions. The identification of significant components within the reduced DoE was also dependent upon the drug and system under investigation. The study demonstrates that the lower experimental number reduces statistical power of the DoE to resolve the impact of media components on solubility. However, in a situation where only the solubility range is required the reduced DoE can provide the desired information, which will be of benefit during in vitro development studies. Further refinements are possible to extend the reduced DoE protocol to improve biorelevance and application into areas such as PBPK modelling.
Topics: Administration, Oral; Animals; Fasting; Humans; Hydrogen-Ion Concentration; Intestinal Secretions; Models, Chemical; Pharmaceutical Preparations; Postprandial Period; Solubility
PubMed: 32035969
DOI: 10.1016/j.ejpb.2020.01.016 -
The American Journal of Managed Care Mar 2012To compare adherence between once-daily (QD) and twice-daily (BID) dosing with chronic-use prescription medications used by patients with cardiovascular disease.
OBJECTIVES
To compare adherence between once-daily (QD) and twice-daily (BID) dosing with chronic-use prescription medications used by patients with cardiovascular disease.
STUDY DESIGN
Retrospective cohort database analysis.
METHODS
Analysis consisted of 1,077,474 patients aged >18 years with a prescription index date from January 1 to December 31, 2007, for an antidiabetic, antihyperlipidemic, antiplatelet, or cardiac agent with QD or BID dosing. Adherence (medication possession ratio [MPR]) was the number of days of medication supplied between the first prescription fill date and the subsequent 365 days divided by 365 days. Overall mean MPR and comparisons between dosing frequency groups were assessed with a generalized estimating equation. Covariates included age at index date, gender, Charlson comorbidity index, therapeutic class, dosing frequency, and the interaction between therapeutic class and dosing frequency group.
RESULTS
Overall, the adjusted mean MPR ± standard error (SE) value for QD agents was 13.6% greater than BID agents (0.66 ± 0.0006 vs 0.57 ± 0.0016; P <.01). The adjusted mean MPR value for QD agents was 2.9%, 17.5%, and 29.4% greater than BID agents in the antidiabetic, antihyperlipidemic, and antiplatelet therapeutic classes, respectively. For cardiac agents, the adjusted mean MPR value was similar between QD and BID agents. Carvedilol represented approximately 80% of the cardiac agents in the BID group. The adjusted mean MPR ± SE for carvedilol phosphate QD was 0.73 ± 0.0024 and 0.65 ± 0.0027 for carvedilol BID (11% difference; P <.01).
CONCLUSIONS
In this large analysis, the QD dosing regimen was related to greater adherence versus a BID regimen.
Topics: Age Factors; Anti-Arrhythmia Agents; Anticholesteremic Agents; Antihypertensive Agents; Cardiovascular Diseases; Chronic Disease; Female; Health Status Indicators; Humans; Hypoglycemic Agents; Insurance Claim Review; Male; Medication Adherence; Retrospective Studies; Sex Factors; Time Factors; United States
PubMed: 22435907
DOI: No ID Found -
International Journal of Nanomedicine 2015Carvedilol (CRV) is an antihypertensive drug with both alpha and beta receptor blocking activity used to preclude angina and cardiac arrhythmias. To overcome the low,...
Carvedilol (CRV) is an antihypertensive drug with both alpha and beta receptor blocking activity used to preclude angina and cardiac arrhythmias. To overcome the low, variable oral bioavailability of CRV, niosomal formulations were prepared and characterized: plain niosomes (without bile salts), bile salt-enriched niosomes (bilosomes containing various percentages of sodium cholate or sodium taurocholate), and charged niosomes (negative, containing dicetyl phosphate and positive, containing hexadecyl trimethyl ammonium bromide). All formulations were characterized in terms of encapsulation efficiency, size, zeta potential, release profile, stability, and morphology. Various formulations were administered orally to ten groups of Wistar rats (n=6 per group). The plasma levels of CRV were measured by a validated high-performance liquid chromatography (HPLC) method and pharmacokinetic properties of different formulations were characterized. Contribution of lymphatic transport to the oral bioavailability of niosomes was also investigated using a chylomicron flow-blocking approach. Of the bile salt-enriched vesicles examined, bilosomes containing 20% sodium cholate (F2) and 30% sodium taurocholate (F5) appeared to give the greatest enhancement of intestinal absorption. The relative bioavailability of F2 and F5 formulations to the suspension was estimated to be 1.84 and 1.64, respectively. With regard to charged niosomes, the peak plasma concentrations (Cmax) of CRV for positively (F7) and negatively charged formulations (F10) were approximately 2.3- and 1.7-fold higher than after a suspension. Bioavailability studies also revealed a significant increase in extent of drug absorption from charged vesicles. Tissue histology revealed no signs of inflammation or damage. The study proved that the type and concentration of bile salts as well as carrier surface charge had great influences on oral bioavailability of niosomes. Blocking the lymphatic absorption pathway significantly reduced oral bioavailability of CRV niosomes. Overall twofold enhancement in bioavailability in comparison with drug suspension confers the potential of niosomes as suitable carriers for improved oral delivery of CRV.
Topics: Administration, Oral; Animals; Bile Acids and Salts; Biological Availability; Carbazoles; Carvedilol; Hydrophobic and Hydrophilic Interactions; Liposomes; Nanomedicine; Propanolamines; Rats; Rats, Wistar
PubMed: 26251598
DOI: 10.2147/IJN.S84703