Bioavailability Of Furosemide Research Articles

Effects of Functional Biomaterials on the Attributes of Orally Disintegrating Tablets Loaded with Furosemide Nanoparticles: In Vitro and In Vivo Evaluations.

Furosemide (FUR) is a diuretic used to relieve edema, congestive heart failure, cirrhosis, end-stage renal disease, and hypertension. FUR is a class IV according to the Biopharmaceutics Classification System. It is practically insoluble in water. This study aimed to optimize and formulate porous orally disintegrating tablets (ODTs) prepared by sublimation and loaded with FUR nanoparticles prepared by using a planetary ball mill. Different functional biomaterials called stabilizers were used to stabilize the nanoparticle formula. Pluronic F-127 was the optimum stabilizer in terms of particle size (354.07 ± 6.44), zeta potential (-25.3 ± 5.65), and dissolution efficiency (56.34%). The impact of the stabilizer concentration was studied as well, and a concentration of 3% showed the smallest particle size (354.07 ± 6.44), best zeta potential value (-25.3 ± 5.65), and percentage of dissolution rate (56.34%). A FUR-loaded nanoparticle formula was successfully prepared. The nanoparticle formula was stabilized by using 3% pluronic F-127, and 3% was chosen for further study of the incorporation into oral disintegration tablets prepared by the sublimation technique. The impact of the matrix sublimating agent and superdisintegrant on the ODTs' attributes (in vitro disintegration, wetting time, and in vitro dissolution efficiency) was studied using 32 full factorial designs. In vivo, the diuretic activity was tested for the optimized FUR ODTs by calculating the Lipschitz value using rats as an animal model. The stability of the ODTs loaded with FUR nanoparticles was assessed under accelerated conditions for 6 months. Finally, the ODT formula loaded with FUR NPs showed a rapid onset of action that was significantly faster than untreated drugs. Nanonization and ODT formulation enhances the dissolution rate and bioavailability of FUR. Many factors can be controlled to achieve optimization results, including the formulation and process parameters.

FORMULATION AND OPTIMIZATION OF FUROSEMIDE SNEDDS: A COMPREHENSIVE STUDY

This research explores the development and optimization of Self-Nanoemulsifying Drug Delivery Systems (SNEDDS) for enhancing the oral bioavailability of Furosemide, a widely used diuretic with poor aqueous solubility. The study focuses on the systematic formulation of Furosemide-loaded SNEDDS to overcome the challenges associated with its limited solubility, thereby improving its therapeutic efficacy. the SNEDDS formulations were meticulously designed using various excipients, including oils, surfactants, and co-surfactants, with the goal of achieving a stable and efficient nano emulsion. The selection of these components was based on their compatibility, emulsification capability, and ability to enhance drug solubility. The prepared formulations underwent a comprehensive optimization process employing experimental design methodologies to determine the optimal concentration of each component, ensuring the attainment of a balanced and stable SNEDDS. Physicochemical characterization of the optimized Furosemide SNEDDS was conducted to evaluate its particle size, zeta potential, polydispersity index, and drug-loading capacity. Additionally, the in vitro release profiles were assessed to understand the release kinetics of Furosemide from the SNEDDS. The optimized formulation exhibited favourable characteristics, including a small particle size, high drug-loading efficiency, and sustained drug release, suggesting its potential for improved oral bioavailability. Furthermore, the pharmacokinetic performance of the optimized Furosemide SNEDDS was investigated through in vivo studies, comparing it with conventional Furosemide formulations. The results demonstrated a significant enhancement in the bioavailability of Furosemide when delivered through the SNEDDS, attributed to the increased solubility and improved absorption of the drug. the formulated and optimized Furosemide SNEDDS presents a promising approach to address the solubility challenges associated with Furosemide, offering a potential solution to enhance its oral bioavailability. The study contributes valuable insights into the formulation design and optimization of SNEDDS for poorly water-soluble drugs, paving the way for improved therapeutic outcomes in the pharmaceutical field.

FORMULATION AND OPTIMIZATION OF FUROSEMIDE SNEDDS: A COMPREHENSIVE STUDY

This research explores the development and optimization of Self-Nanoemulsifying Drug Delivery Systems (SNEDDS) for enhancing the oral bioavailability of Furosemide, a widely used diuretic with poor aqueous solubility. The study focuses on the systematic formulation of Furosemide-loaded SNEDDS to overcome the challenges associated with its limited solubility, thereby improving its therapeutic efficacy. the SNEDDS formulations were meticulously designed using various excipients, including oils, surfactants, and co-surfactants, with the goal of achieving a stable and efficient nanoemulsion. The selection of these components was based on their compatibility, emulsification capability, and ability to enhance drug solubility. The prepared formulations underwent a comprehensive optimization process employing experimental design methodologies to determine the optimal concentration of each component, ensuring the attainment of a balanced and stable SNEDDS. Physicochemical characterization of the optimized Furosemide SNEDDS was conducted to evaluate its particle size, zeta potential, polydispersity index, and drug-loading capacity. Additionally, the in vitro release profiles were assessed to understand the release kinetics of Furosemide from the SNEDDS. The optimized formulation exhibited favorable characteristics, including a small particle size, high drug-loading efficiency, and sustained drug release, suggesting its potential for improved oral bioavailability. Furthermore, the pharmacokinetic performance of the optimized Furosemide SNEDDS was investigated through in vivo studies, comparing it with conventional Furosemide formulations. The results demonstrated a significant enhancement in the bioavailability of Furosemide when delivered through the SNEDDS, attributed to the increased solubility and improved absorption of the drug. the formulated and optimized Furosemide SNEDDS presents a promising approach to address the solubility challenges associated with Furosemide, offering a potential solution to enhance its oral bioavailability. The study contributes valuable insights into the formulation design and optimization of SNEDDS for poorly water-soluble drugs, paving the way for improved therapeutic outcomes in the pharmaceutical field.Keywords: Furosemide, SNEDDS, nanoemulsion, formulation, optimization, solubility, bioavailability.

Interplay of Breast Cancer Resistance Protein (Bcrp/Abcg2), Sex, and Fed State in Oral Pharmacokinetic Variability of Furosemide in Rats

Poor and variable oral bioavailability of furosemide (FUR) presents critical challenges in pharmacotherapy. We investigated the interplay of breast cancer resistance protein (Bcrp)-mediated transport, sex, and fed state on FUR pharmacokinetics (PK) in rats. A crossover PK study of FUR (5 mg/kg, oral) was performed in Sprague-Dawley rats (3 males and 3 females), alone or with a Bcrp inhibitor, novobiocin (NOV) (20 mg/kg, oral), in both fed and fasted states. Co-administration of NOV significantly increased FUR extent (AUC) and rate (Cmax) of exposure by more than two-fold, which indicates efficient Bcrp inhibition in the intestine. The female rats showed two-fold higher AUC and Cmax, and two-fold lower renal clearance of FUR compared to the male rats. The latter was correlated with higher renal abundance of Bcrp and organic anion transporters (Oats) in the male rats compared to age-matched female rats. These findings suggest that the PK of Bcrp and/or Oat substrates could be sex-dependent in rats. Moreover, allometric scaling of rat PK and toxicological data of Bcrp substrates should consider species and sex differences in Bcrp and Oat abundance in the kidney. Considering that Bcrp is abundant in the intestine of rats and humans, a prospective clinical study is warranted to evaluate the effect of Bcrp inhibition on FUR PK. The potential confounding effect of the Bcrp transporter should be considered when FUR is used as a clinical probe of renal organic anion transporter-mediated drug-drug interactions. Unlike human data, no food-effect was observed on FUR PK in rats.

Preparation and Characterization of Furosemide Solid Dispersion with Enhanced Solubility and Bioavailability.

Furosemide (FMD), as a potent circulating diuretic, is commonly used for the treatment of hypertension and edema arising from cardiac, renal, and hepatic failure. However, the low solubility of furosemide restricts its dissolution and bioavailability. In this study, Polyvinylpyrrolidone K30 (PVP-K30), mesoporous (Syloid 244FP, Syloid XDP 3050), and non-mesoporous (Aeroperl 300, Aerosil 200) silica were chosen as combined carrier to develop novel amorphous solid dispersions of furosemide, and then its dissolution and bioavailability were evaluated. Characterization study included XRD, DSC, TGA, SEM, FT-IR, and molecular docking. We found that FMD:PVP-K30:244FP achieved its best performance in terms of dissolution at the ratio of 1:1:1 when PVP-K30 and mesoporous silica Syloid 244FP (244FP) were chosen as combined carrier. SEM, DSC, and XRD studies indicated that furosemide existed in an amorphous form in the solid dispersion. FT-IR and molecular docking analysis showed that there might be an intermolecular interaction between FMD and the carrier. Moreover, the in vivo pharmacokinetics study revealed that the bioavailability of solid dispersion in rats had significant improvement. In particular, Cmax and AUClast were greatly increased by 2.69- and 2.08-fold in the solid dispersion (FMD-PVP-K30-244FP) group, respectively, and the relative bioavailability was 208.00%. In conclusion, the solid dispersion (FMD-PVP-K30-244FP) can significantly improve the solubility and oral bioavailability of furosemide. Mesoporous silica can be used as an excellent carrier material for furosemide, which can provide new ideas and methods for improving the stability of solid dispersion and further improving the dissolution of insoluble drugs. Graphical Abstract.

NOVEL FLOATING AGENT SACCHAROMYCES BOULARDII FORMULATION BASED FLOATING DRUG DELIVERY SYSTEM

Objective: The objective is to design and optimize a floating tablet of furosemide using a novel floating agent Saccharomyces boulardii. Methods: In this study floating tablet based on principle of combination of floating and swelling prepared by direct compression technique. Saccharomyces boulardii probiotics preparation is used as a floating agent due to its bloating property i.e. production of CO2 gas and hydrophilic polymer HPMC E LV 15 used as swellable polymer. Furosemide is a BCS class IV drug selected as model drug which shows pH dependent solubility and permeability and it is better absorbed from the gastric region, hence to improve dissolution and residence at absorption site of such drug, floating drug delivery system is needed. Calcium hydroxide used as pH modifier which increase rate of dissolution of furosemide and also maintain integrity of tablet matrix. Formulation designed and developed using central composite design response surface methodology technique, so as to explore the effect of formulation variables such as amount of Saccharomyces boulardii preparation and calcium hydroxide on floating lag time and % drug release after 12h. Results: The numerical and graphical optimization technique were used to choose the optimal formulation. Floating lag time was found to be 12.6 min and 88.18% drug release for the optimized formulation. In vivo buoyancy studies depicted that formulation stay more then 6h in stomach. Conclusion: Study indicate that Saccharomyces boulardii is a promising floating agent, and the formulation containing this novel floating agent is suitable for gastro retention and it increases bioavailability of furosemide.

Pharmacokinetics of furosemide in goats following intravenous, intramuscular, and subcutaneous administrations.

Furosemide, a loop diuretic drug, is recommended for use in cases of edema, ascites, congestive heart failure, toxicosis, and acute renal failure in goats. However, its pharmacokinetics and bioavailability have not been reported yet in this species. The aim of this study was to determine the pharmacokinetics and bioavailability of furosemide in goats following intravenous (IV), intramuscular (IM), and subcutaneous (SC) administrations at a dose of 2.5mg/kg. Six clinically healthy goats received furosemide by each route in a three-way crossover pharmacokinetic design with a 15-day washout period between administrations. The plasma concentrations of furosemide were determined using the high-performance liquid chromatography-UV method and analyzed by non-compartmental analysis. The elimination half-life following IV, IM, and SC administration was 0.71 (0.67-0.76)h, 0.69 (0.61-0.74)h, and 0.70 (0.67-0.79)h, respectively. The volume of distribution at steady state and total clearance for the IV route were 0.17 (0.16-0.19)L/kg and 0.30 (0.27-0.33)L/h/kg, respectively. The peak plasma concentrations of furosemide following IM and SC administrations were 11.19 (10.33-11.95) and 6.49 (5.92-7.00)μg/ml at 0.23 (0.16-0.25) and 0.39 (0.33-0.42)h, respectively. The bioavailability was 109.84 (104.92-116.99)% and 70.80 (55.77-86.67)% for the IM and SC routes, respectively. The pharmacokinetics of furosemide following the IV, IM, and SC administrations in goats demonstrated significant differences, which may have clinical and toxicological implications requiring further investigations.

Enhanced diuretic action of furosemide by complexation with β-cyclodextrin in the presence of sodium lauryl sulfate

AbstractPreparation of inclusion complex using cyclodextrins is a well-known formulation strategy to elevate the solubility of drugs. However, often cyclodextrins alone may not bring a considerable improvement in the solubility of low solubility drugs. In this study, the inclusion complexation of furosemide (FSM) was tried with β-cyclodextrin (β-CD) either with the use or without the use of sodium lauryl sulfate (SLS), which is a surfactant. By using the kneading method, the binary complex of FSM/β-CD in the equal molar ratio was used. FSM and β-CD were kneaded continuously until a thick past was achieved, which was evaporated for a period of about 24 h. The solid complexed product was then crushed and stored in airtight container until use. Phase solubility studies confirmed a stoichiometric ratio of 1:1 (FSM/β-CD and FSM/β-CD with SLS). The apparent stability constant and complexation efficiencies of significantly enhanced in the presence of SLS. The prepared complexes were evaluated for DSC, PXRD, 1H NMR, and in vitro release studies. The results exhibited a significant enhancement in diuresis in rats. It is evident that the addition of SLS with β-CD significantly enhances the solubilizing efficiencies and hence bioavailability of FSM.

Pharmacokinetics and bioavailability of furosemide in sheep.

The pharmacokinetics and bioavailability of furosemide were determined following intravenous (IV), intramuscular (IM), and subcutaneous (SC) administrations at 2.5mg/kg dose in sheep. The study was conducted on six healthy sheep in a three-way, three-period, crossover pharmacokinetic design with a 15-day washout period. In first period, furosemide was randomly administered via IV to 2 sheep, IM to 2 sheep and SC to 2 sheep. In second and third periods, each sheep received furosemide via different routes of administration with the 15-day washout period. Plasma concentrations were determined using a high-performance liquid chromatography assay and analyzed by noncompartmental method. The mean total clearance and volume of distribution at steady state following IV administration were 0.24 Lh-1 kg-1 and 0.17 L/kg, respectively. The elimination half-life was similar for all administration routes. The mean peak plasma concentrations of IM and SC administration were 10.33 and 3.18μg/ml at 0.33 and 0.42hr, respectively. The mean bioavailability of IM and SC administration was 97.91% and 37.98%, respectively. The IM injection of furosemide may be the alternative routes in addition to IV. However, further research is required to determine the effect of dose and route of administration on the clinical efficacy of furosemide in sheep.

P.482 Comparative effectiveness of antipsychotics for risk of attempted or completed suicide among persons with schizophrenia

Novel ternary systems with β-cyclodextrin or maltodextrin and triethanolamine as the third component were developed with the aim of improving the oral bioavailability of furosemide. These new solids were characterized by solid-state nuclear magnetic resonance, Fourier transform infrared and Raman spectroscopy, X-ray powder diffractometry, scanning electron microscopy, thermogravimetric analysis, and differential scanning calorimetry. The solubility, dissolution and stability (chemical and physical) were studied. Among the most important results, it was observed that both ternary systems showed an important enhancement in the solubility of the drug. In particular, the system obtained by combination of β-cyclodextrin and TEA exhibited improvement in the dissolution profiles and photo-stability of furosemide compared with the binary system previously reported. Moreover, this system constitutes an interesting therapeutic alternative as it did not produce cellular toxicity compared with free furosemide. In conclusion, the results obtained revealed that this ternary system establishes a promising approach for oral delivery of the drug.

P.130 Bumetanide versus placebo for core symptoms of autism spectrum disorder at 91 days (BAMBI): a single-centre, double-blinded, patient-randomized, placebo-controlled, phase-2-trial

Novel ternary systems with β-cyclodextrin or maltodextrin and triethanolamine as the third component were developed with the aim of improving the oral bioavailability of furosemide. These new solids were characterized by solid-state nuclear magnetic resonance, Fourier transform infrared and Raman spectroscopy, X-ray powder diffractometry, scanning electron microscopy, thermogravimetric analysis, and differential scanning calorimetry. The solubility, dissolution and stability (chemical and physical) were studied. Among the most important results, it was observed that both ternary systems showed an important enhancement in the solubility of the drug. In particular, the system obtained by combination of β-cyclodextrin and TEA exhibited improvement in the dissolution profiles and photo-stability of furosemide compared with the binary system previously reported. Moreover, this system constitutes an interesting therapeutic alternative as it did not produce cellular toxicity compared with free furosemide. In conclusion, the results obtained revealed that this ternary system establishes a promising approach for oral delivery of the drug.

Pathophysiology of Diuretic Resistance and Its Implications for the Management of Chronic Heart Failure.

Diuretic resistance implies a failure to increase fluid and sodium (Na+) output sufficiently to relieve volume overload, edema, or congestion, despite escalating doses of a loop diuretic to a ceiling level (80 mg of furosemide once or twice daily or greater in those with reduced glomerular filtration rate or heart failure). It is a major cause of recurrent hospitalizations in patients with chronic heart failure and predicts death but is difficult to diagnose unequivocally. Pharmacokinetic mechanisms include the low and variable bioavailability of furosemide and the short duration of all loop diuretics that provides time for the kidneys to restore diuretic-induced Na+ losses between doses. Pathophysiological mechanisms of diuretic resistance include an inappropriately high daily salt intake that exceeds the acute diuretic-induced salt loss, hyponatremia or hypokalemic, hypochloremic metabolic alkalosis, and reflex activation of the renal nerves. Nephron mechanisms include tubular tolerance that can develop even during the time that the renal tubules are exposed to a single dose of diuretic, or enhanced reabsorption in the proximal tubule that limits delivery to the loop, or an adaptive increase in reabsorption in the downstream distal tubule and collecting ducts that offsets ongoing blockade of Na+ reabsorption in the loop of Henle. These provide rationales for novel strategies including the concurrent use of diuretics that block these nephron segments and even sequential nephron blockade with multiple diuretics and aquaretics combined in severely diuretic-resistant patients with heart failure.

Development and Evaluation of Floating and Expanding Gastroretentive Film of Furosemide

Objectives: Furosemide is BCS class IV drug which shows pH dependent solubility and permeability. It is very poorly soluble in stomach medium (0.006 mg/mL) and having high permeability through stomach, but its solubility increases with pH but it is impermeable through intestine due to its permeation limitation. The objective of this study is to develop integrated floating film of Furosemide to enhance its solubility by increasing gastric residence, by changing pH so that insoluble furosemide get dissolved, convert from crystalline form to amorphous form so ultimately enhance its bioavailability. Methods: Drug loaded polymeric film prepared by solvent casting method using different polymers such as gelatin and carboxy methyl cellulose sodium (sodium CMC), sodium alginate and glycerin as plasticizer, sodium hydroxide as solubility enhancer. The prepared floating films were evaluated for physicochemical parameters such as thickness, weight variation, floating properties, drug content, stability study and in vitro drug release. The drug- polymer interaction was studied by Differential Scanning Calorimetry (DSC) and Fourier transform Infrared (FT-IR). Results: The result of in vitro drug buoyancy and drug release study showed that the floating films were found to be floated up to maximum period of 18.58 ± 2 hr and maximum 86.78±0.86 % drug release up to 12 hr. Conclusion: Floating Film enhance the bioavailability of Furosemide by prolonging its duration in the stomach via the floating dosage forms and also enhance its solubility by using hydrophilic polymers and sodium hydroxide as solubility enhancer.

Evaluating ternary systems with oligosaccharides as a strategy to improve the biopharmaceutical properties of furosemide.

Novel ternary systems with β-cyclodextrin or maltodextrin and triethanolamine as the third component were developed with the aim of improving the oral bioavailability of furosemide. These new solids were characterized by solid-state nuclear magnetic resonance, Fourier transform infrared and Raman spectroscopy, X-ray powder diffractometry, scanning electron microscopy, thermogravimetric analysis, and differential scanning calorimetry. The solubility, dissolution and stability (chemical and physical) were studied. Among the most important results, it was observed that both ternary systems showed an important enhancement in the solubility of the drug. In particular, the system obtained by combination of β-cyclodextrin and TEA exhibited improvement in the dissolution profiles and photo-stability of furosemide compared with the binary system previously reported. Moreover, this system constitutes an interesting therapeutic alternative as it did not produce cellular toxicity compared with free furosemide. In conclusion, the results obtained revealed that this ternary system establishes a promising approach for oral delivery of the drug.

In vitro dissolution and bioavailability study of furosemide nanosuspension prepared using design of experiment (DoE)

BackgroundNanotechnology can offer the advantages of increasing solubility and bioavailability of delivering drugs like Furosemide. The aim of the current study is to investigate the in vitro and in vivo performance of furosemide nanosuspensions. MethodsFurosemide nanosuspensions were prepared by antisolvent precipitation method using full factorial experimental design. Four factors were employed namely; Stirring time, Injection rate, antisolvent: solvent ratio & stabilizer: drug ratio (at two levels = high & low). The in vitro dissolution experiments were conducted to compare the representative formulation with raw drug powder. The bioavailability of nanosuspension was, also, evaluated in mice as an animal model. ResultsSolid state characterization (PXRD, DSC and FESEM) did show physical changes during preparation and optimization of the furosemide nanosuspensions. Individual material attributes showed more significant impact on the average particle size of the nanocrystals compared to process parameters. Two-way interactions between material attributes and process parameters significantly affected nanosuspension particle size distribution. Dissolution rate of furosemide nanosuspemsion was significantly higher than that observed for raw furosemide powder. The in vivo pharmacokinetics parameters of nanosuspension in comparison to pure drug showed significant increase in Cmax and AUC(0-t), about 233% and 266%, respectively. The oral bioavailability of furosemide from nanosuspension was about 2.3 fold higher as compared with the bioavailability from pure drug. ConclusionsFurosemide nanosuspensions prepared using antisolvent precipitation method enhanced the dissolution rate and oral bioavailability compared to raw furosemide powder.

Mucopenetrating nanoparticles for enhancement of oral bioavailability of furosemide: In vitro and in vivo evaluation/sub-acute toxicity study

The aim of this study was to formulate and evaluate chitosan (CS)/alginate (ALG) nanoparticles (NPs) loaded with furosemide (FSM) in an attempt to enhance its release, permeability and bioavailability. Non-everted gut sac method was used to evaluate the ex vivo permeation of FSM from its suspension and the selected CS/ALG NPs formulation. The pharmacokinetic parameters of FSM subsequent to oral administration of the selected formulation were assessed in rats. In vivo subacute toxicity study of the prepared blank and FSM loaded formulations was evaluated in rats.The selected optimized formulation (F3) showed optimum particle size (PS), polydispersity index (PDI), zeta potential (ZP) and acceptable percentage entrapment efficiency (%EE) of 253.8nm±4.6, 0.25±0.03, −35mV±1 and 96%±1, respectively. The release profile of FSM from the selected formulation was characterized by initial burst effect in 0.1N HCl. Scanning electron microscope (SEM) demonstrated a smooth surface and spherical shape for the lyophilized optimized NPs.Selected CS/ALG NPs (F3) presented a significant enhancement (p≤0.01) in permeation parameters of FSM as well as in Tmax, Cmax, AUC0-24 and AUC0-∞. Subacute toxicity study results revealed that the selected formulation was safe and nontoxic. The histopathological inspection of the stomach and small intestine tissues of the loaded NPs (F3) and blank groups reflected no obvious signs of cellular toxicity or inflammatory reaction.CS/ALG NPs loaded with FSM enhanced both drug release and mucus-penetrating ability leading to an overall increase in FSM bioavailability. In addition, the in vivo subacute toxicity study results indicated the safety of the prepared NPs for oral drug delivery.

Comparative evaluation of coprecipitation, solvent evaporation, and kneading as techniques to improve solubility and dissolution profiles of a BCS class IV drug

Purpose Furosemide bioavailability is limited by poor solubility and permeability. This study aimed to compare coprecipitation, kneading, and solvent evaporation as solubility and dissolution improvement techniques. Materials and methods Products were prepared with furosemide : polyvinylpyrrolidone : lactose at 1 : 1 : 2, 1 : 2 : 3, 1 : 3 : 4, 1 : 1 : 4, 1 : 2 : 6, 1 : 3 : 8 by coprecipitation, kneading, solvent evaporation or physical blending. They were characterized for physicochemical properties and interaction. Solubilities of furosemide from products were evaluated in water and n-octanol. Dissolution studies on the products were conducted in 0.1 N HCl using USP apparatus II. Results Solubility of pure furosemide was lowest in n-octanol (11.86 μg/ml) and highest in PBS (28.68 μg/ml). Infrared spectra revealed that characteristic peaks in pure furosemide were retained in its formulations, indicating chemical compatibility of furosemide and the excipients. Differential scanning calorimetry thermogram of furosemide showed a melting point at 220°C, which disappeared in its formulations − attributable to amorphization of the drug or overshadow by excipients. Furosemide significantly partitioned more (P kneading>physical mixtures>coprecipitation. Cumulative amount of furosemide dissolved from pure sample was 8%, whereas amounts from formulations were significantly higher (P Conclusion All the methods improved the solubilities and dissolution profiles of furosemide to various degrees; however, solvent evaporation method was the best.

Physical–chemical properties of furosemide nanocrystals developed using rotation revolution mixer

Recently, several approaches have been reported to improve the dissolution rate and bioavailability of furosemide, a class IV drug. However, to the best of our knowledge, none of them proposed nanocrystals. In the last decade, nanocrystals successfully addressed solubility issues by increasing surface area and saturation solubility, both leading to an increase in the dissolution rate of poor water soluble drugs. The preparation of furosemide nanocrystals was by a rotation revolution mixer method. Size distribution and morphology were performed using laser diffraction and scanning electron microscopy, respectively. In addition, differential scanning calorimetry, thermogravimetry, X-ray powder diffraction (XRD) and low frequency shift-Raman spectroscopy allowed investigating the thermal properties and crystalline state. Solubility saturation and intrinsic dissolution rate (IDR) studies were conducted. The thermal analysis revealed lower melting range for the nanocrystals comparing to furosemide. Moreover, a slight crystalline structure change to the amorphous state was observed by XRD and confirmed by low frequency shift Raman. The particle size was reduced to 231 nm with a polydispersity index of 0.232, a 30-fold reduction from the original powder. Finally, the saturation solubility and IDR showed a significant increase. Furosemide nanocrystals showed potential for development of innovative formulations as an alternative to the commercial products.

Loop Diuretics in Clinical Practice.

Diuretics are commonly used to control edema across various clinical fields. Diuretics inhibit sodium reabsorption in specific renal tubules, resulting in increased urinary sodium and water excretion. Loop diuretics are the most potent diuretics. In this article, we review five important aspects of loop diuretics, in particular furosemide, which must be considered when prescribing this medicine: (1) oral versus intravenous treatment, (2) dosage, (3) continuous versus bolus infusion, (4) application in chronic kidney disease patients, and (5) side effects. The bioavailability of furosemide differs between oral and intravenous therapy. Additionally, the threshold and ceiling doses of furosemide differ according to the particular clinical condition of the patient, for example in patients with severe edema or chronic kidney disease. To maximize the efficiency of furosemide, a clear understanding of how the mode of delivery will impact bioavailability and the required dosage is necessary.

Formulation, optimization, and in vitro/in vivo evaluation of furosemide nanosuspension for enhancement of its oral bioavailability

Furosemide is a poorly soluble diuretic used for treatment of hypertension and edema. It has very poor or variable oral bioavailability due to its reduced solubility in gastric fluid and reduced permeability in intestinal fluid. The aim of this study was to prepare nanosuspension of furosemide to enhance its oral bioavailability by increasing its dissolution in stomach where it has better permeability. Full factorial design was used for a systematic approach of formulation and optimization. The nanosuspensions were prepared by precipitation with ultrasonication method. Polyvinyl acetate was used for sterically stabilizing the nanosuspensions. The diffusing drug concentration and stabilizer were used as the factors and the particle size, polydispersity index, and drug release were selected as dependent variables and characterized. The effect of nanoprecipitation on enhancement of oral bioavailability of furosemide nanosuspension was studied by in vitro dissolution and in vivo absorption studies in rats and compared to pure drug. Quality by design using full factorial design provided a systematic approach in optimizing nanosuspensions to produce products with desired quality. Stable nanosuspension were obtained with average size range of the precipitated nanoparticles between 150 and 300 nm and were found to be homogenous showing a narrow polydispersity index of 0.3 ± 0.1. The in vivo studies on rats revealed a significant increase in the oral absorbtion of furosemide in the nanosuspension compared to pure drug. The AUC0→24 and C max values of nanosuspension were approximately 1.38- and 1.68-fold greater than that of pure drug, respectively. Furosemide nanosuspension showed 20.06 ± 0.02 % decrease in systolic blood pressure compared to 13.37 + 0.02 % in plain furosemide suspension, respectively. The improved oral bioavailability and pharmacodynamic effect of furosemide may be due to the improved dissolution of furosemide in simulated gastric fluid which results in enhanced oral systemic absorption of furosemide from stomach region where it has better permeability.