Delayed-release Tablets Research Articles

Comparative Bioavailability of Tizanidine in Three Dosage Forms (6-MG Delayed-Release Tablets, Sirdalud Preparation, and 2-MG Tablets)

Valenta Pharm Co. compared the pharmacokinetic parameters in healthy volunteers of three prototype tizanidine dosage forms (delayed-release 6-mg tablets) and the reference drug sirdalud (2-mg tablets for a total dose of 6 mg, three tablets). This allowed the relative bioavailability of the three prototype tizanidine forms relative to sirdalud to be assessed. All three prototypes showed signs of delay based on MRT parameters of (2.217 ± 0.441) h for the sirdalud instant-release form and (6.529 ± 1.990), (5.951 ± 1.295), and (6.384 ± 2.339) h for prototypes T1, T2, and T3, respectively. High relative exposure levels of prototypes T1, T2, and T3 [AUC 103.80% (73.69 – 146.20), 124.14% (88.14 – 174.86), and 131.93% (93.66 – 185.82), respectively] with a significant decrease of C max (to 35.83, 38.78, and 40.79%, respectively) were demonstrated by analyzing the comparative bioavailability. A model pharmacokinetic study of the forms produced secondary modeling parameters that were similar to those obtained by an off-model method (89.19 – 122.71%). This confirmed that the developed model was acceptable for planning future clinical tests of these drugs.

Esomeprazole immediate release tablets: Gastric mucosa ex vivo permeation, absorption and antisecretory activity in conscious rats

The aim of this work was to study the esomeprazole activity on the control of gastric secretion after administration of a novel immediate release tablet. The ex vivo permeation of esomeprazole across porcine gastric mucosa from immediate release tablets, containing sodium carbonate or magnesium oxide as alkalinizing agents, was firstly assessed. Pharmacokinetics and pharmacodynamics studies in conscious rats following the administration of immediate release tablets with sodium carbonate, in comparison with delayed-release tablets having the same formula, were also conducted. The results showed an important effect of sodium carbonate and magnesium oxide on the drug release, on the ex vivo trans-mucosal transport and the stability in acid environment. In particular, the presence of sodium carbonate in esomeprazole tablet formulation provided the maximum increase of the drug in vitro transport across the mucosa. Then, the absorption and the antisecretory activity of this proton pump inhibitor orally administered in rats as immediate release tablets containing Na2CO3, was superior but not significantly different compared to delayed-release tablets having the same formula. In the adopted animal model, an activity of esomeprazole from immediate release alkaline formulation was seen also in presence of partial gastric absorption allowing inhibition of proton pumps reached via systemic circulation. This esomeprazole immediate release formulation could be used for the on-demand treatment of acid-related disorders such as gastro-esophageal reflux disease.

Salvage Treatment of Mucormycosis Post-Liver Transplant With Posaconazole During Sirolimus Maintenance Immunosuppression

We describe the first successful case of posaconazole salvage therapy for mucormycosis with concomitant sirolimus (SRL) maintenance immunosuppression following liver transplantation, despite black box drug interaction following intolerance to first-line tacrolimus and amphotericin due to nephrotoxicity and neurotoxicity. This case describes a 55-year-old female who developed rhinocerebral mucormycosis 108 days after liver transplantation. After 3 months of posaconazole therapy, the patient remains free of disease at 3 years posttransplant. This case report illustrates successful resolution of mucormycosis without SRL toxicity to resolve nephrotoxicity of long-term amphotericin on top of already nephrotoxic immunosuppression. With higher bioavailability of recently FDA-approved posaconazole delayed release tablets, this azole may be a therapeutic option for transplant patients who need to remain on CYP3A4-metabolized immunosuppressive agents.

Gastrointestinal and Systemic Monitoring of Posaconazole in Humans After Fasted and Fed State Administration of a Solid Dispersion

The purpose of this study was to explore the intraluminal behavior and systemic exposure of posaconazole in humans after oral intake of a novel delayed-release tablet (Noxafil®), containing posaconazole dispersed in a matrix of hydroxypropyl methylcellulose acetate succinate. Five healthy volunteers were asked to ingest the tablet in the fasted and fed state condition, after positioning one aspiration catheter in the stomach and one in the jejunum. Subsequently, gastric and jejunal fluids were aspirated and analyzed for posaconazole. In parallel, blood samples were collected. In gastric aspirates, dissolved concentrations were negligible regardless of the test condition, confirming the delayed-release properties of the tablet. In fasted state jejunal aspirates, sustained supersaturation was observed during an average period of time of 93 ± 78.2 min, with a mean maximum degree of supersaturation of 7.28 ± 8.81. In the fed state condition, supersaturation was negligible in the jejunum with a pronounced presence of solid posaconazole, suggesting the importance of more distal intestinal regions for posaconazole absorption.

Therapeutic Drug Monitoring of Posaconazole: an Update.

Posaconazole is a second-generation triazole agent with a potent and broad antifungal activity. In addition to the oral suspension, a delayed-release tablet and intravenous formulation with improved pharmacokinetic properties have been introduced recently. Due to the large interindividual and intraindividual variation in bioavailability and drug-drug interactions, therapeutic drug monitoring (TDM) is advised to ensure adequate exposure and improve clinical response for posaconazole. Here, we highlight and discuss the most recent findings on pharmacokinetics and pharmacodynamics of posaconazole in the setting of prophylaxis and treatment of fungal infections and refer to the challenges associated with TDM of posaconazole.

Comparison of efficacy and safety of choline fenofibrate (fenofibric acid) to micronized fenofibrate in patients of mixed dyslipidemia: A randomized, open-label, multicenter clinical trial in Indian population.

Introduction:Choline fenofibrate is a newly developed choline salt of fenofibric acid, which is more hydrophilic than fenofibrate. This study was initiated to evaluate the safety and efficacy of choline fenofibrate in comparison to micronized fenofibrate among Indian patients of mixed dyslipidemia.Methods:A multicenter, open-label, randomized, active controlled, comparative, parallel group study was conducted at around 10 centers spread all across the country. Mixed dyslipidemia patients (serum triglycerides [TG] levels between 150 and 500 mg/dl), aged 18–70 years and taking stable statin dose for 8 weeks were randomized to choline fenofibrate 135 mg delayed release tablets and micronized fenofibrate 160 mg tablets once daily for 12 weeks. The primary endpoint of the study was percentage change in serum TG level at the end of 12 weeks.Results:A total of 226 patients were enrolled in this study, of which 116 patients were administered choline fenofibrate and 110 patients were administered micronized fenofibrate. At the end of 12 weeks, there was a significant reduction in TG level (34.24% in choline fenofibrate group and 38.13% reduction in micronized fenofibrate group). However, the difference between group was not statistically different (P = 0.471). Similarly, there was a significant increase in high-density lipoprotein cholesterol at the end of 12 weeks (10% increase in choline fenofibrate group and 9% increase in micronized fenofibrate group); but the difference between the group was not statistically significant (P = 0.598). Both the treatment was safe and well tolerated.Conclusion:Choline fenofibrate delayed release 135 mg is as safe and effective as 160 mg of micronized fenofibrate in Indian patients with mixed dyslipidemia.

Comparison of Serum Concentrations Between Posaconazole Delayed-Release Tablet and Oral Suspension at a Large Academic Medical Center

Study goal Evaluate differences between PCZ serum concentrations in patients receiving the DRT versus the OS and in patients receiving higher doses than 300 mg/day of the DRT Study design • Retrospective cohort study Inclusion criteria • Adult patients at Cleveland Clinic Health System • In-patient administration of posaconazole from July 1, 2014 through December 31, 2014 Patient groups • Divided and analyzed based on dosage form and dose of PCZ Contact information: Sarah Welch, Pharm.D. 9500 Euclid Ave. HB-65 Cleveland, OH, 44195 Email: welchs@ccf.org

Pharmacokinetics and safety of posaconazole delayed-release tablets for invasive fungal infections

Posaconazole is a broad-spectrum triazole antifungal agent with potent activity against various pathogenic fungi, including yeast and moulds. Clinical studies have demonstrated that this agent is efficacious as prophylaxis against invasive fungal infections in patients at high risk, and may also be useful as salvage therapy against invasive aspergillosis and mucormycosis. However, the bioavailability of posaconazole following administration by oral suspension, which was the only formulation clinically available for many years, is highly variable and negatively influenced by several factors. Because of this, many patients had subtherapeutic or undetectable posaconazole levels when the oral suspension was used. To overcome this limitation, a delayed-release tablet was developed and is now available for clinical use. Hot-melt extrusion technology is used to combine a pH-sensitive polymer with posaconazole to produce a formulation that releases the drug in the elevated pH of the intestine where absorption occurs rather than in the low-pH environment of the stomach. This results in enhanced bioavailability and increased posaconazole exposure. Studies in healthy volunteers have demonstrated significantly higher and more consistent exposures with the tablet formulation compared to the oral suspension. In addition, pharmacokinetic parameters following administration of the tablets were not significantly affected by medications that raise gastric pH or increase gastric motility, and the tablets could also be administered without regard to food. Similar results have also been found in patients at high risk for invasive fungal infections who have received posaconazole tablets. The tablet formulation also appears to be well tolerated to date, although data regarding clinical efficacy are needed.

Posaconazole: An Update of Its Clinical Use.

Posaconazole (PCZ) is a relatively new addition to the azole antifungals. It has fungicidal activities against Aspergillus fumigatus, Blastomyces dermatitidis, selected Candida species, Crytopcoccus neoformans, and Trichosporon. PCZ also has fungistatic activities against Candida, Coccidioides, selected Fusarium spp., Histoplasma, Scedosporium and Zygomycetes. In addition, combining the drug with caspofungin or amphotericin B results in a synergistic interaction against A. fumigatus, C. glabrata and C. neoformans. The absorption of PCZ suspension is enhanced when given with food, nutritional supplements, and carbonated beverages. Oral administration of PCZ in divided doses also increases its bioavailability. PCZ has a large volume of distribution and is highly protein bound (>95%). The main elimination route of PCZ is fecal. PCZ is an inhibitor of the CYP3A4 enzyme; therefore, monitoring for drug-drug interactions is warranted with other CYP3A4 substrates/inhibitors/inducers. The most common adverse effects include headache, fatigue, nausea, vomiting and elevated hepatic enzymes. PCZ, with its unique antifungal activities, expands the azole class of antifungal agents. Because of its limit in formulation, PCZ oral suspension is recommended in immunocompromised patients with functional gastrointestinaltracts who fail conventional antifungal therapies or who are suspected to have a breakthrough fungal infection. However, a delayed-release tablet formulation and intravenous (IV) injection became available in 2014, expanding the use of PCZ in other patient populations, including individuals who are unable to take oral formulations.

Role of New Antifungal Agents in the Treatment of Invasive Fungal Infections in Transplant Recipients: Isavuconazole and New Posaconazole Formulations.

Invasive fungal infections are a major cause of morbidity and mortality among solid organ transplant (SOT) and hematopoietic stem cell transplant (HSCT) recipients. Transplant patients are at risk for such invasive fungal infections. The most common invasive fungal infections are invasive candidiasis in the SOT and invasive aspergillosis in the HSCT. In this article, we will discuss the epidemiology of invasive fungal infections in the transplant recipients and susceptibility patterns of the fungi associated with these infections. Additionally, the pharmacology and clinical efficacy of the new antifungal, isavuconazole, and the new posaconazole formulations will be reviewed. Isavuconazole is a new extended-spectrum triazole that was recently approved for the treatment of invasive aspergillosis and mucormycosis. Advantages of this triazole include the availability of a water-soluble intravenous formulation, excellent bioavailability of the oral formulation, and predictable pharmacokinetics in adults. Posaconazole, a broad-spectrum triazole antifungal agent, is approved for the prevention of invasive aspergillosis and candidiasis in addition to the treatment of oropharyngeal candidiasis. Posaconazole oral suspension solution has shown some limitations in the setting of fasting state absorption, elevated gastrointestinal pH, and increased motility. The newly approved delayed-release oral tablet and intravenous solution formulations provide additional treatment options by reducing interpatient variability and providing flexibility in these set of critically ill patients. This review will detail these most recent studies.

Prevention of invasive fungal infections in immunocompromised patients: the role of delayed-release posaconazole.

Posaconazole is a triazole antifungal agent that has broad-spectrum activity against many yeasts and filamentous fungi, including Candida species, Cryptococcus neoformans, Aspergillus species, and Zygomycetes. This drug has been approved for the prevention of invasive fungal infections in patients with neutropenia and for the treatment of invasive fungal infections in hematopoietic stem cell transplant recipients with graft-versus-host disease. Studies on the clinical efficacy, safety, tolerability, and cost-effectiveness of posaconazole therapy were performed using the oral suspension form of the drug. Pharmacokinetic studies have found that the oral suspension form of posaconazole has problemeatic bioavailability: its absorption is affected by concomitant medication and food. This article discusses the pharmacokinetic properties of the newly developed posaconazole delayed-release tablet formulation and reviews the efficacy, safety, and cost-effectiveness of both the oral suspension and the new tablet formulation. In conclusion, the posaconazole tablet formulation has better systemic bioavailability, thereby enabling once-daily administration and better absorption in the presence of concomitant medication and food. However, well-designed clinical studies are needed to evaluate the use of the tablet formulation in real-life settings.

Treatment Options for Mucormycosis

Mucormycosis, which occurs primarily in immunosuppressed patients and patients with diabetes mellitus, remains one of the most difficult fungal infections to treat. In part, this is due to the poor immune response of those patients who have hematological malignancies or have received a hematopoietic cell or solid organ transplant, but also very important is the paucity of available non-toxic effective antifungal agents. Correction of underlying risk factors is helpful, but this is possible mostly in those with diabetes. Surgical debridement of all necrotic tissue is crucially important in decreasing mortality. Lipid formulations of amphotericin B are the treatment of choice. Posaconazole oral suspension has been used successfully in salvage trials and allows long-term therapy that was not possible previously. The new delayed-release tablet achieves higher serum concentrations and should prove to be more efficacious than the suspension in step-down therapy after initial amphotericin B treatment. Isavuconazole is a newly approved azole that appears to be efficacious against mucormycosis in salvage studies. Similar to posaconazole, the oral capsule is available to use as step-down therapy after initial amphotericin B treatment. Both of these azoles are now available as intravenous formulations that perhaps may prove effective as primary therapy for mucormycosis, but until clinical trials have shown that indeed, they are efficacious, these agents should not be considered appropriate for primary therapy of mucormycosis.

Serum posaconazole levels among haematological cancer patients taking extended release tablets is affected by body weight and diarrhoea: single centre retrospective analysis.

The posaconazole extended release tablet formulation was developed to improve bioavailability relative to the oral suspension. Therapeutic drug monitoring has been used to optimise posaconazole dosing to achieve a target trough level ≥0.7 μg ml(-1). We retrospectively evaluated 28 patients with haematological malignancies who received posaconazole tablets for antifungal prophylaxis. Posaconazole serum trough levels were obtained 5 days after initiation of therapy. Mean trough level was 1.19 ± 0.63 μg ml(-1), and 71% achieved a trough level ≥0.7 μg ml(-1). Diarrhoea was associated with lower mean trough levels (0.65 ± 0.08 μg ml(-1) vs. 1.31 ± 0.13 μg ml(-1)), P = 0.002. Mean trough levels were lower in patients ≥90 kg (0.74 ± 0.09 μg ml(-1)) vs. <90 kg (1.32 ± 0.14 μg ml(-1)), P = 0.002 and in patients with body mass index (BMI) ≥30 (0.89 ± 0.13 μg ml(-1)) vs. BMI <30 (1.29 ± 0.14 μg ml(-1)), P = 0.05. Posaconazole delayed release tablets attain appropriate trough levels in most patients, but patients with a higher weight and those experiencing diarrhoea are more likely to have lower levels.

Superior Serum Concentrations with Posaconazole Delayed-Release Tablets Compared to Suspension Formulation in Hematological Malignancies.

Posaconazole (PCZ), approved for prophylaxis against invasive fungal disease in high-risk patients, is commercially available orally as a suspension formulation (PCZ-susp) and as a delayed-release tablet (PCZ-tab). We evaluated the serum steady-state concentrations (Css) of PCZ stratified by the administered formulation for antifungal prophylaxis in patients with myeloid malignancies (n = 150). The primary outcome was the attainment rate of the target Css of ≥700 ng/ml. Secondary outcomes included toxicity assessment (hepatotoxicity and corrected QT [QTc] interval prolongation) and breakthrough fungal infections. Patients who received the PCZ-susp (n = 118) or PCZ-tab (n = 32) and had PCZ Css assessment after at least 7 days of therapy were eligible. The median Css in the PCZ-susp group was 390 ng/ml (range, 51 to 1,870 ng/ml; mean, 436 ng/ml) compared to 1,740 ng/ml (range, 662 to 3,350 ng/ml; mean, 1,781 ng/ml) in the PCZ-tab group (P < 0.0001). The percentages of patients achieving the target goal of ≥700 ng/ml were 17% versus 97%, respectively (P < 0.0001). Hepatotoxicity (grade 2 or higher) occurred in 1 patient in each group. QTc interval measurements were available for 32 patients in the PCZ-susp group and for 12 patients in the PCZ-tab group, and prolonged intervals of grade 2 or higher were noted in 9% (n = 3) and 17% (n = 2), respectively (P = 0.6). Breakthrough fungal infections in the PCZ-susp and PCZ-tab groups were 7% (n = 8) and 3% (n = 1), respectively (P = 0.68). We conclude that the use of PCZ-tab was associated with higher Css and with the probability of achieving therapeutic goals without worsening of adverse effects.

Posaconazole pharmacokinetics after administration of an intravenous solution, oral suspension, and delayed-release tablet to dogs.

To determine pharmacokinetics of posaconazole in dogs given an IV solution, oral suspension, and delayed-release tablet. 6 healthy dogs. Posaconazole was administered IV (3 mg/kg) and as an oral suspension (6 mg/kg) to dogs in a randomized crossover study. Blood samples were collected before (time 0) and for 48 hours after each dose. In an additional experiment, 5 of the dogs received posaconazole delayed-release tablets (mean dose, 6.9 mg/kg); blood samples were collected for 96 hours. Plasma concentrations were analyzed with high-performance liquid chromatography. IV solution terminal half-life (t1/2) was 29 hours (coefficient of variation [CV], 23%). Clearance and volume of distribution were 78 mL/h/kg (CV, 59%) and 3.3 L/kg (CV, 38%), respectively. Oral suspension t1/2 was 24 hours (CV, 42%). Maximum plasma concentration (Cmax) of 0.42 μg/mL (CV, 56%) was obtained at 7.7 hours (CV, 92%). Mean bioavailability was 26% (range, 7.8% to 160%). Delayed-release tablet t1/2 was 42 hours (CV, 25%), with a Cmax of 1.8 μg/mL (CV, 44%) at 9.5 hours (CV, 85%). Mean bioavailability of tablets was 159% (range, 85% to 500%). Bioavailability of delayed-release tablets was 497% (range, 140% to 1,800%) relative to that of the oral suspension. Absorption of posaconazole oral suspension in dogs was variable. Absorption of the delayed-release tablets was greater than absorption of the oral suspension, with a longer t1/2 that may favor its clinical use in dogs. Administration of delayed-release tablets at a dosage of 5 mg/kg every other day can be considered for future studies.

(651) - Posaconazole Delayed Release Tablets for Antifungal Prophylaxis in Lung Transplant Patients

In November 2013, a delayed release (DR) tablet formulation of posaconazole was approved with improved absorption compared to suspension. There have not been studies demonstrating the appropriate dose for antifungal prophylaxis in lung transplant recipients (LTR). The current labeled dose for prophylaxis is 300mg daily. Our goal is to determine the most appropriate dose of posaconazole for prophylaxis in LTR and correlate serum concentrations with different dosing regimens.

Effect of a high-fat meal on the pharmacokinetics of 300-milligram posaconazole in a solid oral tablet formulation.

Posaconazole in oral suspension must be taken multiple times a day with food (preferably a high-fat meal) to ensure adequate exposure among patients. We evaluated the effect of food on the bioavailability of a new delayed-release tablet formulation of posaconazole at the proposed clinical dose of 300 mg once daily in a randomized, open-label, single-dose, two-period crossover study with 18 healthy volunteers. When a single 300-mg dose of posaconazole in tablet form (3 tablets × 100 mg) was administered with a high-fat meal, the posaconazole area under the concentration-time curve from 0 to 72 h (AUC0-72) and maximum concentration in plasma (Cmax) increased 51% and 16%, respectively, compared to those after administration in the fasted state. The median time to Cmax (Tmax) shifted from 5 h in the fasted state to 6 h under fed conditions. No serious adverse events were reported, and no subject discontinued the study due to an adverse event. Six of the 18 subjects reported at least one clinical adverse event; all of these events were mild and short lasting. The results of this study demonstrate that a high-fat meal only modestly increases the mean posaconazole exposure (AUC), ∼1.5-fold, after administration of posaconazole tablets, in contrast to the 4-fold increase in AUC observed previously for a posaconazole oral suspension given with a high-fat meal.

Evaluation of Luffa aegyptica mill Powder: A Novel Superdisintegrant in Delayed Release Tablets

2full factorial design was employed for the optimization of developed formulation. The developed formulations showed uniform appearance, average weight, drug content and adequate hardness. The increase in lag time was observed with an increase in HPMC concentration and decreased concentration of a superdisintegrant. Further comparison of Luffa aegyptica mill powder in the concentration suggested in the optimized formulation with pharmaceutically acceptable superdisintegrant in same concentration showed equivalent drug release behavior. It can be concluded from the outcome of the present research that Luffa aegyptica mill powder, a natural superdisintegrant, can prove to be best alternative to the existing superdisintegrants.

A Review of Kinetics of Nanoparticulated Delayed Release Formulations

The history and development of chemical kinetics gives a fascinating insight into the way in which theory and experiment can become mutually interdependent. Kinetics plays a key role in the study of what the body dose to a drug so these areas of study move towards pharmacokinetics. In the last decade or so there has been a vast upsurge of interest in the physical mechanism of reaction. The United States Pharmacopeia (USP) defines delayed-release tablets as enteric-coated to delay release of the medication until the tablet has passed through the stomach. To prevent the drug from being destroy or inactivate by gastric juices or where it may irritate the gastric mucosa. The suitability of several equations which have been reported in the literature to define drug release mechanism was tested with respect to the release data. To analyze the mechanism of drug release from the matrix tablet data obtained from the drug release studies were analyzed according to zero order model, Higuchi model, and Korsmeyer - Peppas model respectively

Comparative pharmacodynamics of posaconazole in neutropenic murine models of invasive pulmonary aspergillosis and mucormycosis.

We used two established neutropenic murine models of pulmonary aspergillosis and mucormycosis to explore the association between the posaconazole area under the concentration-time curve (AUC)-to-MIC ratio (AUC/MIC) and treatment outcome. Posaconazole serum pharmacokinetics were verified in infected mice to ensure that the studied doses reflected human exposures with the oral suspension, delayed-release tablet, and intravenous formulations of posaconazole. Sinopulmonary infections were then induced in groups of neutropenic mice with Aspergillus fumigatus strain 293 (posaconazole MIC, 0.5 mg/liter) or Rhizopus oryzae strain 969 (posaconazole MIC, 2 mg/liter) and treated with escalating daily dosages of oral posaconazole, which was designed to achieve AUCs ranging from 1.10 to 392 mg · h/liter. After 5 days of treatment, lung fungal burden was analyzed by quantitative real-time PCR. The relationships of the total drug AUC/MIC and the treatment response were similar in both models, with 90% effective concentrations (EC90s) corresponding to an AUC/MIC threshold of 76 (95% confidence interval [CI], 46 to 102) for strain 293 versus 87 (95% CI, 66 to 101) for strain 969. Using a provisional AUC/MIC target of >100, these exposures correlated with minimum serum posaconazole concentrations (Cmins) of 1.25 mg/liter for strain 293 and 4.0 mg/liter for strain 969. The addition of deferasirox, but not liposomal amphotericin or caspofungin, improved the activity of a suboptimal posaconazole regimen (AUC/MIC, 33) in animals with pulmonary mucormycosis. However, no combination was as effective as the high-dose posaconazole monotherapy regimen (AUC/MIC, 184). Our analysis suggests that posaconazole pharmacodynamics are similar for A. fumigatus and R. oryzae when indexed to pathogen MICs.